PMID: 28705709 (Patient)   Terms:
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0		A novel sclerosing atypical lipomatous tumor/well-differentiated liposarcoma in a 7-year-old girl : Report of a case with molecular confirmation .
1		LONGTOKEN is a common type of liposarcoma in late adulthood .
2		However , pediatric ALT/WDL/DDL is extremely rare , and only 3 cases have been described in children younger than 10years of age .
3	Μ	Notably , none of these cases harbored MDM2 gene amplification .
4		Here , we reported a sclerosing ALT/WDL in a 7-year-old Chinese girl .
5		Histologically , in most areas , the neoplastic cells were embedded within the collagenous background and typical lipogenic areas were inconspicuous throughout the sclerotic areas .
6		Additionally , scattered small foci of atypical osseous/chondrous elements were identified .
7		Notably , a small typical lipoma-like ALT/WDL area was detected in the periphery of the mass .
8		Immunohistochemically , all the neoplastic components demonstrated positivity for MDM2 , CDK4 , and p16 .
9	Μ	Fluorescence in situ hybridization revealed MDM2 gene amplification in all the tumor components .
10		To the best of our knowledge , this is the first example of MDM2-amplified ALT/WDL in this age group .

PMID: 28670134 (Cell)   Terms:
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0		Identification of key genes and molecular mechanisms associated with dedifferentiated liposarcoma based on bioinformatic methods .
1		BACKGROUND :
2		Dedifferentiated liposarcoma ( DDLPS ) is one of the most deadly types of soft tissue sarcoma .
3		To date , there have been few studies dedicated to elucidating the molecular mechanisms behind the disease ; therefore , the molecular mechanisms behind this malignancy remain largely unknown .
4		MATERIALS AND METHODS :
5		Microarray profiles of 46 DDLPS samples and nine normal fat controls were extracted from Gene Expression Omnibus ( GEO ) .
6		Quality control for these microarray profiles was performed before analysis .
7		Hierarchical clustering and principal component analysis were used to distinguish the general differences in gene expression between DDLPS samples and the normal fat controls .
8		Differentially expressed genes ( DEGs ) were identified using the Limma package in R .
9		Next , the enriched Gene Ontology ( GO ) terms and Kyoto Encyclopedia of Genes and Genomes ( KEGG ) pathways were obtained using the online tool DAVID ( http : //davidabccncifcrfgov/ ) .
10		A protein -protein interaction ( PPI ) network was constructed using the STRING database and Cytoscape software .
11		Furthermore , the hub genes within the PPI network were identified .
12		RESULTS :
13		All 55 microarray profiles were confirmed to be of high quality .
14		The gene expression pattern of DDLPS samples was significantly different from that of normal fat controls .
15		In total , 700 DEGs were identified , and 83 enriched GO terms and three KEGG pathways were obtained .
16		Specifically , within the DEGs of DDLPS samples , several pathways were identified as being significantly enriched , including the PPAR signaling pathway , cell cycle pathway , and pyruvate metabolism pathway .
17		Furthermore , the dysregulated PPI network of DDLPS was constructed , and 14 hub genes were identified .
18	Μ	Characteristic of DDLPS , the genes CDK4 and MDM2 were universally found to be up-regulated and amplified in gene copy number .
19		CONCLUSION :
20		This study used bioinformatics to comprehensively mine DDLPS microarray data in order to obtain a deeper understanding of the molecular mechanism of DDLPS .

PMID: 28652867 (None)   Terms:
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0		Scattered genomic amplification in dedifferentiated liposarcoma .
1		BACKGROUND :
2		Atypical lipomatous tumor ( ALT ) , well differentiated liposarcoma ( WDLS ) and dedifferentiated liposarcoma ( DDLS ) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes , although DDLS tend to have somewhat more complex rearrangements .
3		In contrast , pleomorphic liposarcomas ( PLS ) have highly aberrant and heterogeneous karyotypes .
4		The ring and giant marker chromosomes contain discontinuous amplicons , in particular including multiple copies of the target genes CDK4 , HMGA2 and MDM2 from 12q , but often also sequences from other chromosomes .
5		RESULTS :
6		The present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes .
7	Μ	SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes , in particular CDK4 .
8		In addition , amplicons from 1q , 3q , 7p , 9p , 11q and 20q , covering from 2 to 14 Mb , were present .
9		FISH analyses showed that sequences from 5p and 12q were scattered , separately or together , over more than 10 chromosomes of varying size .
10		At RNA sequencing , significantly elevated expression , compared to myxoid liposarcomas , was seen for TRIO and AMACR in 5p and of CDK4 , HMGA2 and MDM2 in 12q .
11		CONCLUSIONS :
12	Μ	The observed pattern of scattered amplification does not show the characteristics of chromothripsis , but is novel and differs from the well known cytogenetic manifestations of amplification , i.e. , double minutes , homogeneously staining regions and ring chromosomes .
13		Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis .

PMID: 28629371 (None)   Terms: Xenograft, in vivo, xenograft, clinical trial, mouse models, mouse
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0		Combined targeting of MDM2 and CDK4 is synergistic in dedifferentiated liposarcomas .
1		PURPOSE :
2	Μ	MDM2 and CDK4 are frequently co-amplified in well-differentiated/dedifferentiated liposarcoma ( WDLPS/DDLPS ) .
3		We aimed to determine whether combined MDM2/CDK4 targeting is associated with higher antitumour activity than a single agent in preclinical models of DDLPS .
4		EXPERIMENTAL DESIGN :
5		DDLPS cells were exposed to RG7388 (MDM2 antagonist) and palbociclib ( CDK4 inhibitor ) , and apoptosis and signalling/survival pathway perturbations were monitored by flow cytometry and Western blotting .
6		Xenograft mouse models were used to assess tumour growth and survival .
7		Treatment efficacy was assessed by Western blotting , histopathology and tumour volume .
8		RESULTS :
9		RG7388 and palbociclib together exerted a greater antitumour effect than either drug alone , with significant differences in cell viability after a 72-h treatment with RG7388 and/or palbociclib .
10		The combination treatment significantly increased apoptosis compared to the single agents .
11		We then analysed the in vivo antitumour activity of RG7388 and palbociclib in a xenograft model of DDLPS .
12		The combination regimen reduced the tumour growth rate compared with a single agent alone and significantly increased the median progression-free survival .
13		CONCLUSIONS :
14		Our results provide a strong rationale for evaluating the therapeutic potential of CDK4 inhibitors as potentiators of MDM2 antagonists in DDLPS and justify clinical trials in this setting .

PMID: 28546131 (Patient)   Terms:
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0		Lipoblasts in Spindle Cell and Pleomorphic Lipomas : a Close Scrutiny .
1		The presence and frequency of lipoblasts ( LPB ) in spindle cell lipomas ( SCL ) and pleomorphic lipomas ( PL ) has never been studied in detail on histologically , immunohistochemically and molecular genetically validated set of tumors .
2		The authors investigated this feature by reviewing 91 cases of SCL and 38 PL .
3	Μ	When more than three unequivocal LPB were found , the case was regarded as positive for the presence of LPB .
4		All positive cases were then stained with CD34 and Retinoblastoma ( Rb ) protein antibodies and tested by FISH for MDM2 and CDK4 amplifications and the FUS gene rearrangements .
5		The patients with SCL and PL containing LPB were 14 women and 47 men , the rest was of unknown gender .
6		The cases usually presented as superficial , well-circumscribed soft tissue masses and most commonly occurred in the upper back and neck .
7		CD34 was expressed in all cases , while Rb protein was consistently absent in all .
8		Molecular genetic results , when available , were in concordance with the morphological diagnosis of SCL/PL .
9		LPB were found in 37 ( 41% ) cases of SCL and 25 cases of PL ( 66% ) .
10		While in many cases they are inconspicuous , in some others they constitute a very prominent component of the tumor .
11		It is important to be aware of this fact in order to avoid misinterpretation as liposarcoma .

PMID: 28477272 (Patient)   Terms:
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0		HIF-1alpha , MDM2 , CDK4 , and p16 expression in ischemic fasciitis , focusing on its ischemic condition .
1		Ischemic fasciitis is a benign myofibroblastic lesion , occurring in the sacral region or proximal thigh of elderly or bedridden individuals .
2		The pathogenesis of ischemic fasciitis is thought to be based on ischemic condition ; however , it has never been demonstrated .
3		In this study , we examined the expression of ischemia-associated proteins in ischemic fasciitis by immunohistochemical and genetic methods .
4	Μ	Specifically , this study aimed to reveal the expression of HIF-1alpha , MDM2 , CDK4 , p16 , and gene amplification of MDM2 gene .
5		Seven cases of ischemic fasciitis from among the soft - tissue tumors registered at our institution were retrieved .
6		Histopathological findings were as follows : poorly demarcated nodular masses , a proliferation of spindle-shaped fibroblastic or myofibroblastic cells with oval nuclei and eosinophilic or pale cytoplasm , zonal fibrinous deposition , pseudocystic degeneration , granulation-like proliferation of capillary vessels , ganglion-like cells , myxoid or hyalinized stroma , and chronic inflammatory infiltration .
7		Immunohistochemically , the spindle cells were positive for HIF-1alpha ( 7/7 cases ) , MDM2 ( 4/7 cases ) , CDK4 ( 4/7 cases ) , p16 ( 7/7 cases ) , p53 ( 2/7 case ) , cyclin D1 ( 7/7 cases ) , and alpha-smooth muscle actin ( 6/7 cases ) .
8	Μ	Neither MDM2 gene amplification nor USP6 gene split signal was detected in any case .
9		Overexpression of the above proteins may be associated with the pathogenic mechanism of ischemic fasciitis .
10		It is noted that the immunohistochemical positivity of MDM2 , CDK4 , and p16 do not necessarily indicate malignant neoplasm such as dedifferentiated liposarcoma .

PMID: 28447036 (None)   Terms: This review
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0		Recent translational research into targeted therapy for liposarcoma .
1		Liposarcomas ( LPS ) are among the most common soft tissue sarcomas , originating from adipocytes .
2		Treatment for LPS typically involves surgical resection and radiation therapy , while the use of conventional cytotoxic chemotherapy for unresectable or metastatic LPS remains controversial .
3		This review summarizes the results of recent translational research and trials of novel therapies targeting various genetic and molecular aberrations in different subtypes of LPS .
4		Genetic aberrations such as the 12q13-15 amplicon , genetic amplification of MDM2 , CDK4 , TOP2A , PTK7 , and CHEK1 , point mutations in CTNNB1 , CDH1 , FBXW7 , and EPHA1 , as the fusion of FUS-DDIT3/EWSR1-DDIT3 are involved in the pathogenesis LPS and represent potential therapeutic candidates .
5		Tyrosine kinase inhibitors targeting MET , AXL , IGF1R , EGFR , VEGFR2 , PDGFR-beta and Aurora kinase are effective in certain types of LPS .
6		Abnormalities in the PI3K/Akt signaling pathway deregulation of C/EBP-alpha and its partner PPAR-gamma , and the interaction between calreticulin ( CRT ) and CD47 are also promising therapeutic targets .
7		These promising new approaches may help to supplement existing treatments for LPS .

PMID: 28424409 (Patient)   Terms: clinical trial
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0		Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas .
1		BACKGROUND :
2		There are currently no United States Food and Drug Administration approved molecularly matched therapies for sarcomas except gastrointestinal stromal tumors .
3		Complicating this is the extreme diversity , heterogeneity , and rarity of these neoplasms .
4		Few therapeutic options exist for relapsed and refractory sarcomas .
5		In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy .
6		However , a systematic analysis of actionable mutations has yet to be completed .
7		We analyzed genomic profiling results in patients referred to MD Anderson Cancer Center with advanced sarcomas to elucidate the frequency of potentially actionable genomic alterations in this population .
8		METHODS :
9		We reviewed charts of patients with advanced sarcoma who were referred to investigational cancer therapeutics department and had CLIA certified comprehensive genomic profiling ( CGP ) of 236 or 315 cancer genes in atleast 50ng of DNA .
10		Actionable alterations were defined as those identifying anti-cancer drugs on the market , in registered clinical trials , or in the Drug - Gene Interaction Database .
11		RESULTS :
12		Among the 102 patients analyzed median age was 45.5 years ( range 8-76 ) , M : F ratio 48 : 54 .
13		The most common subtypes seen in our study were leiomyosarcoma ( 186% ) , dedifferentiated liposarcoma ( 11% ) , osteosarcoma ( 11% ) , well-differentiated liposarcoma ( 7% ) , carcinosarcoma ( 6% ) , and rhabdomyosarcoma ( 6% ) .
14	Μ	Ninety-five out of 102 patients ( 93% ) had atleast one genomic alteration identified with a mean of six mutations per patient .
15	Μ	Of the 95 biopsy samples with identifiable genomic alterations , the most commonly affected genes were TP53 ( 314% ) , CDK4 ( 235% ) , MDM2 ( 216% ) , RB1 ( 186% ) , and CDKN2A/B ( 137% ) .
16	Μ	Notable co-segregating amplifications included MDM2-CDK4 and FRS2-FGF .
17		Sixteen percent of patients received targeted therapy based on CGP of which 50% had atleast stable disease .
18		CONCLUSIONS :
19		Incorporating CGP into sarcoma management may allow for more precise diagnosis and sub-classification of this diverse and rare disease , as well as personalized matching of patients to targeted therapies such as those available in basket clinical trials .

PMID: 28404975 (None)   Terms: Xenograft, in vivo, xenograft, mouse models, mouse
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0		MDM2 antagonists synergize with PI3K/mTOR inhibition in well-differentiated/dedifferentiated liposarcomas .
1		BACKGROUND :
2		Well-differentiated/dedifferentiated liposarcoma ( WDLPS/DDLPS ) are characterized by a consistent amplification of the MDM2 gene .
3		The PI3K/AKT/mTOR pathway has been suggested to play also an important role in their tumorigenesis .
4		Our goal was to determine whether combined MDM2 and PI3K/AKT/mTOR targeting is associated with higher anti-tumor activity than single agent alone in preclinical models of WDLPS/DDLPS .
5		METHODS :
6		WDLPS/DDLPS cells were exposed to RG7388 (MDM2 antagonist) and BEZ235 ( PI3K/mTOR dual inhibitor ) after which apoptosis and signaling/survival pathway perturbations were monitored by flow cytometry and Western blot analysis .
7		Xenograft mouse models were used to assess tumor growth and animal survival .
8		Western blotting , histopathology , and tumor volume evolution were used for the assessment of treatment efficacy .
9		RESULTS :
10		The PI3K/AKT/mTOR was upregulated in up to 81% of the human WDLPS/DDLPS samples analysed .
11		Treatment with RG7388 and BEZ235 resulted in a greater tumor activity than either drug alone with a significant difference in terms of cell viability after 72h of treatment with RG-73888 alone , BEZ235 alone and a combination of both agents .
12		Consistent with these observations , we found a significant increase in apoptosis with the combination versus the single agent treatment alone .
13		We then analysed the in vivo antitumor activity of RG7388 and BEZ235 in a xenograft model of DDLPS .
14		The combination regimen significantly reduced tumor growth rate in comparison with single agent alone .
15		CONCLUSIONS :
16		Our results represent the first in vivo evidence of synergy between MDM2 and PI3K/AKT/mTOR antagonists and represent a strong rationale to evaluate the therapeutic potential of such a combination in WDLPS/DDLPS .

PMID: 28377828 (Patient)   Terms:
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0		Paravertebral Well-Differentiated Liposarcoma with Low-Grade Osteosarcomatous Component : Case Report with 11-Year Follow-Up , Radiological , Pathological , and Genetic Data , and Literature Review .
1		Despite being one of the most frequent soft - tissue sarcomas , well-differentiated liposarcoma has never been reported near the spine .
2		The authors present the case of a 67-year-old man with progressive history of back pain .
3		Physical examination revealed a mass located within the right paravertebral muscles .
4		MR and CT imaging showed a heavily ossified central mass surrounded by a peripheral fatty component .
5		No connection with the underlying bone was detected on imagery and during surgery .
6	Μ	After surgical resection , histopathological examination revealed a tumor harboring combined features of well-differentiated liposarcoma and low-grade osteosarcoma .
7	Μ	Tumor cells displayed overexpression of MDM2 , CDK4 , and P16 by immunohistochemistry and CGH revealed amplification of 12q13-15 as the only genetic imbalance .
8		MDM2 FISH analysis was performed but was inconclusive .
9		The pathological , immunohistochemical , and genetic features , the differential diagnoses , and the therapeutic management of this unusual tumor are discussed .
10		No complementary treatment was performed initially .
11		Following first treatment , two recurrences occurred 6 and 9 years later , both displaying histological features similar to the first occurrence .
12		Radiotherapy was started after the second recurrence .
13		Follow-up shows no evidence of disease 11 years after initial diagnosis .
14		This case was unusual due to the paravertebral location of the tumor and its divergent differentiation .

PMID: 28337832 (Patient)   Terms:
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0		Retroperitoneal dedifferentiated liposarcoma with huge cystic degeneration : A case report .
1		Prominent cyst formation is an unusual feature of liposarcoma .
2		We report here a case of dedifferentiated liposarcoma with huge cystic change without preoperative chemo - or radiation therapy .
3		The lesion arose in the retroperitoneum juxtaposed to the right kidney of a 67-year-old woman .
4		She underwent a surgical removal of the retroperitoneal cyst .
5	Μ	The cystic tumor contained 1600 mL of old bloody fluid , and its wall was composed of edematous , inflamed or sclerosing fibrous tissue with fatty tissue containing abundant atypical stromal cells , which were immunohistochemically positive for MDM2 and CDK4 , and demonstrated MDM2 gene amplification by fluorescence in situ hybridization .
6		The wall was contiguous to an atypical lipomatous nodule located in the mesentery .
7		The following surgical specimens of the right hemicolectomy and right nephrectomy revealed atypical cells infiltrating into the subserosa of the colon and the perirenal fat tissue or that in the renal sinus .
8		This case indicates that well differentiated or dedifferentiated liposarcoma should be also considered as a differential diagnosis of perirenal cystic mass .

PMID: 28135854 (None)   Terms: This review, clinical trial
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0		Pharmacological therapies for Liposarcoma .
1		INTRODUCTION :
2		Liposarcoma ( LS ) is one of the most common adult soft tissue sarcomas ( STS ) .
3		For metastatic disease , systemic treatment options were historically represented by standard cytotoxic chemotherapy .
4		More recently , innovative therapies have been introduced and they are currently part of the therapeutic armamentarium , positively impacting disease control and patients' quality of life .
5		Moreover , in the last decade , a better understanding of the molecular characteristics of each STS subtype allowed to detect new potential targets and develop novel , biology-driven compounds at different stages of testing .
6		Areas covered : This review is focused on LS , retracing their pharmacological management , starting with a summary of results achieved with standard chemotherapy , then moving to a deeper analysis on data obtained with new , approved therapies and finally reporting an update on ongoing clinical trials , thus providing an overview on the current scenario and outlining how it might evolve in the coming years .
7		Expert commentary : Important strides have been made in the knowledge and treatment of LS .
8		Peculiar molecular features and fundamental signalling pathways represent nowadays druggable targets for novel therapies .
9		However , predictive biomarkers still need to be identified in order to better select the target population , to possibly test combinations of drugs , with the ultimate goal of improving outcomes .

PMID: 28099935 (Patient)   Terms:
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0		Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma .
1		LONGTOKEN are closely related tumors commonly characterized by MDM2/CDK4 gene amplification , and lack clinically effective treatment options when inoperable .
2		To identify novel therapeutic targets , we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancer-related genes ( NCC oncopanel v3 ) developed specifically for genomic testing to select suitable molecular targeted therapies .
3		The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes .
4	Μ	Potential driver mutations were found in only six ( 11% ) samples ; however , gene amplification events ( other than MDM2 and CDK4 amplification ) were identified in 30 ( 54% ) samples .
5		Receptor tyrosine kinase ( RTK ) genes in particular were amplified in 18 ( 32% ) samples .
6		In addition , growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R , using palbociclib and NVP-AEW541 , respectively .
7		Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification .

PMID: 27909788 (Patient)   Terms:
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0		Dedifferentiated liposarcoma of the lower extremity with low-grade dedifferentiation and low-grade osteosarcomatous component .
1		Dedifferentiated liposarcoma can arise de novo or as a complication of a preexisting well-differentiated liposarcoma .
2		We describe the radiologic and pathologic features of a long-standing liposarcoma with multiple recurrences in a 59-year-old male .
3		Imaging demonstrated a heterogeneous fat-containing mass in the anterior thigh .
4		The adjacent proximal femur showed irregular cortical new bone , eventually followed by intramedullary osteoblastic involvement and pathologic fracture .
5	Μ	Histologic assessment at resection revealed dedifferentiated liposarcoma with low-grade osteosarcomatous component .
6		The patient subsequently developed metastatic lesions in the lungs containing osteoid and osteoblastic bone metastases .
7		We discuss the radiologic and pathologic features of this rare entity that , to our knowledge , has previously been reported to directly involve osseous structures in only one other case and discuss the potential pitfalls in diagnosis .

PMID: 27879515 (Patient)   Terms:
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0		Atypical Spindle Cell Lipomatous Tumor : Clinicopathologic Characterization of 232 Cases Demonstrating a Morphologic Spectrum .
1		The classification of atypical adipocytic neoplasms with spindle cell features remains challenging .
2		To better define this category of low-grade lipomatous neoplasms , we present herein the clinical , histologic , and immunohistochemical characteristics of a large series of 232 atypical spindle cell lipomatous tumors .
3		The lesions affected 140 males and 92 females , at an average age of 54 years ( range , 6 to 87 y ) , clinically presenting as a persistent or enlarging mass with a median size of 5 cm .
4		The anatomic distribution of the tumors was wide , predominating in the limbs and limb girdles ( 147 cases , 63% ) , mainly in the hands and feet ( 17% and 11% , respectively ) , with equal distribution between subcutaneous and deeper locations .
5		Microscopic examination revealed a spectrum of histologic appearances .
6	Μ	All cases consisted of a poorly marginated proliferation of mildly atypical spindle cells set in a fibrous or myxoid stroma , with a variably prominent admixed adipocytic component showing variation in adipocyte size and scattered nuclear atypia , frequently with univacuolated or multivacuolated lipoblasts .
7		Tumor cellularity and the relative proportion of the different components were very variable .
8		Tumor margins were often ill defined with invasion into surrounding tissues .
9		Two tumors showed morphologic features reminiscent of dedifferentiation .
10		By immunohistochemistry , the neoplastic spindle cells expressed CD34 ( 64% ) , S100 protein ( 40% ) and , less frequently , desmin ( 23% ) .
11		Expression of Rb was lost in 57% of cases examined .
12		MDM2 and CDK4 were never coexpressed and FISH for MDM2 amplification was consistently negative , highlighting critical biological differences from atypical lipomatous tumor/dedifferentiated liposarcoma .
13		The morphologic differential diagnosis of atypical spindle cell lipomatous tumor is broad , and includes spindle cell lipoma , diffuse neurofibroma , mammary-type myofibroblastoma , dermatofibrosarcoma protuberans , fat-forming solitary fibrous tumor , and morphologically low-grade malignant peripheral nerve sheath tumor .
14		Most patients underwent surgical excision of the primary mass .
15		With a median follow-up of 4 years ( range , 1 mo to 20 y ) , 87% of patients ( 63/72 ) were alive with no evidence of recurrence or metastatic disease .
16		Local recurrence of the tumor was observed in 12% of patients ( 9 out of 72 , multiple in 3 of them ) at intervals between 6 months and 17 years after resection of the primary tumor .
17		None of the patients developed tumor metastasis or died of disease .
18		Identification of the neoplastic adipocytic component admixed with spindle cells , and recognition of the range of histologic appearances are key for the diagnosis of atypical spindle cell lipomatous tumor .
19		Whereas the risk of metastatic dissemination is minimal , there is a non-negligible risk for local recurrence ( 13% ) which warrants surgical resection with clear margins whenever feasible .

PMID: 27778364 (Patient)   Terms:
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0		Primary dermal pleomorphic liposarcoma : utility of adipophilin and MDM2/CDK4 immunostainings .
1		Liposarcoma , usually arises in deep soft tissues and pleomorphic liposarcoma ( PL ) , is the rarest histopathologic variant .
2		However , 15 cases of entirely dermal PL have been reported .
3		We describe a case of a 79-year-old man who developed a rapidly growing nodule on his thorax .
4		Excisional biopsy was performed and immunohistochemical studies were carried .
5		The lesion was a well-circumscribed dermal nodule composed of multivacuolated pleomorphic lipoblasts and atypical mitotic figures .
6	Μ	Neoplastic cells expressed CD10 and resulted negative S100 protein , Melan-A , MITF-1 , AE1/AE3 , CD4 , CD68 (PGM1) , retinoblastoma gene family protein , pericentrine and lysozyme .
7		Adipophilin stain showed the lipid contents in the cytoplasm of the neoplastic cells .
8		MDM2 and CDK4 resulted both negative .
9		A diagnosis of primary dermal PL was made .
10		This case shows the utility of adipophilin immunostaining to prove the lipid contents in neoplastic cells , which has the advantage of using formalin-fixed paraffin-embedded tissue and making needless frozen sections and ultrastructural studies to show these findings .
11		Negative MDM2/CDK4 staining in our case argues against the possibility of dedifferentiated liposarcoma and further supports the diagnosis of true PL .

PMID: 27597521 (None)   Terms:
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0		Differential diagnosis of atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma : utility of p16 in combination with MDM2 and CDK4 immunohistochemistry .
1		The differential diagnosis between LONGTOKEN from their morphologic counterparts is challenging .
2		Currently , the diagnosis is guided by MDM2 and CDK4 immunohistochemistry ( IHC ) and is confirmed by the amplification of the corresponding genes .
3		Recently , p16 IHC has been proposed as a useful diagnostic biomarker .
4		The objective was to assess the utility of p16 IHC in the differential diagnosis of ALT/WDLPS and DDLPS .
5		Our series included 101 tumors that were previously analyzed using fluorescence in situ hybridization for MDM2 and CDK4 amplification .
6		We compared sensitivity and specificity of p16 IHC to MDM2 and CDK4 IHC in the differential diagnosis of ALT-WDLPS ( n = 19 ) versus benign adipocytic tumors ( n = 44 ) and DDLPS ( n = 18 ) versus mimicking sarcomas ( n = 20 ) .
7		In the differential diagnosis of ALT-WDLPS , p16 had a sensitivity of 89.5% but a specificity of 68.2% , which was impaired by false-positive lipomas with secondary changes , especially in biopsies .
8		Likewise , in the differential diagnosis of DDLPS , p16 had a sensitivity of 94.4% and a specificity of 70% , which hampered its use as a single marker .
9		However , adding p16 to MDM2 and/or CDK4 increased diagnostic specificity .
10		Indeed , MDM2+/p16+ tumors were all ALT-WDLPS , and MDM2-/p16 - tumors were all benign adipocytic tumors .
11		Moreover , all MDM2+/CDK4+/p16+ tumors were DDLPS , and the MDM2-/CDK4-/p16 - tumor was an undifferentiated sarcoma .
12		Although the use of p16 as a single immunohistochemical marker is limited by its specificity , its combination with MDM2 and CDK4 IHC may help discriminate ALT-WDLPS/DDLPS .

PMID: 27591497 (None)   Terms:
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0		Liposarcoma : Multimodality Management and Future Targeted Therapies .
1		There are 3 biologic groups of liposarcoma : well-differentiated and dedifferentiated liposarcoma , myxoid/round cell liposarcoma , and pleomorphic liposarcoma .
2		In all 3 groups , complete surgical resection is central in treatment aimed at cure and is based on grade .
3		Radiation can reduce risk of local recurrence in high-grade lesions or minimize surgical morbidity in the myxoid/round cell liposarcoma group .
4		The groups differ in chemosensitivity , so adjuvant chemotherapy is selectively used in histologies with metastatic potential but not in the resistant subtype dedifferentiated liposarcoma .
5		Improved understanding of the genetic aberrations that lead to liposarcoma initiation is allowing for the rapid development of targeted therapies for liposarcoma .

PMID: 27508976 (None)   Terms:
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0		MDM2 and CDK4 Immunohistochemistry : Should It Be Used in Problematic Differentiated Lipomatous Tumors? : A New Perspective .
1		Although most cases of atypical lipomatous tumor/well-differentiated liposarcoma ( ALT/WDL ) can be diagnosed solely on the basis of histologic features , those lacking diagnostic histologic features require ancillary studies for accurate classification .
2		Fluorescent in situ hybridization ( FISH ) for amplification of MDM2 has been considered the gold standard for diagnosis in these situations .
3		Immunostaining for MDM2 and/or CDK4 has been adopted as a surrogate method because of its high concordance rate with FISH and lower cost .
4		However , studies examining the concordance of the 2 methods have been based preferentially on cases in which the diagnosis could be established histologically .
5		No study has explored the concordance between the 2 methods in histologically ambiguous cases or in cases in which the diagnosis of ALT/WDL is not apparent after a review of all slides .
6		To address this , we performed immunostaining for MDM2 and CDK4 on 183 well-differentiated lipomatous tumors that could not be diagnosed on purely histologic grounds and that were , therefore , subjected to FISH analysis .
7		These included ALT/WDLs ( n = 56 ) , lipomas ( n = 96 ) , and lipoma variants ( n = 31 ) .
8		Staining for MDM2 and CDK4 was noted in 25/56 and 23/56 ALT/WDL , respectively , giving a sensitivity of 45% and 41% and a specificity of 98% and 92% .
9		Staining was noted exclusively in the nuclei of atypical cells and not in the nuclei of adipocytes .
10		Staining for MDM2 and CDK4 occurred in 2/125 and 10/117 benign lipomatous lesions , respectively .
11		False-positive staining was equivalent in intensity to ALT/WDL .
12		We conclude that MDM2 and CDK4 staining is a relatively insensitive method for diagnosing ALT/WDL in cases that are histologically ambiguous , as staining is restricted to neoplastic cells with atypia that are underrepresented in these cases .
13		Therefore , in cases like ours that closely simulate clinical practice , FISH is the more reliable and cost-effective option .

PMID: 27409346 (Patient)   Terms: in vitro
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0		Preclinical evaluation of potential therapeutic targets in dedifferentiated liposarcoma .
1		Sarcomas are rare cancers with limited treatment options .
2		Patients are generally treated by chemotherapy and/or radiotherapy in combination with surgery , and would benefit from new personalized approaches .
3	Μ	In this study we demonstrate the potential of combining personal genomic characterization of patient tumors to identify targetable mutations with in vitro testing of specific drugs in patient-derived cell lines .
4		We have analyzed three metastases from a patient with high-grade metastatic dedifferentiated liposarcoma ( DDLPS ) by exome and transcriptome sequencing as well as DNA copy number analysis .
5		Genomic aberrations of several potentially targetable genes , including amplification of KITLG and FRS2 , in addition to amplification of CDK4 and MDM2 , characteristic of this disease , were identified .
6		We evaluated the efficacy of drugs targeting these aberrations or the corresponding signaling pathways in a cell line derived from the patient .
7		Interestingly , the pan-FGFR inhibitor NVP-BGJ398 , which targets FGFR upstream of FRS2 , strongly inhibited cell proliferation in vitro and induced an accumulation of cells into the G0 phase of the cell cycle .
8		This study indicates that FGFR inhibitors have therapeutic potential in the treatment of DDLPS with amplified FRS2 .

PMID: 27402219 (Patient)   Terms:
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0		Follicular dendritic cell sarcoma : clinicopathologic study of 15 cases with emphasis on novel expression of MDM2 , somatostatin receptor 2A , and PD-L1 .
1		Follicular dendritic cell sarcoma ( FDCS ) is a rare low-grade neoplasm with the phenotype of FDC cells .
2		This rare sarcoma has been well known for being mistaken for a variety of neoplasms ( mainly meningioma ) , particularly at extranodal sites .
3		Diagnosis of FDCS mainly relies on characteristic histologic appearance supplemented by immunohistochemistry and electron microscopy .
4		In this study , we reviewed 15 FDCSs retrieved from our consultation files and stained them for newly reported or novel markers ( PD-L1 , Rb1 , MDM2 , and somatostatin receptor 2A [SSTR2A] ) in addition to conventional FDC markers .
5		Patients were 7 men and 7 women ( 1 unspecified ) with a mean age of 47 years ( 20-75 years ) .
6		The tumor site was lymph nodes (6) or spleen (2) , both (1) and extranodal sites of head and neck (4) or abdominal cavity (2) .
7		Treatment was variable combinations of surgery and aggressive chemotherapy/radiotherapy .
8		Four of 8 patients with follow-up died of disease within 1 to 10 years .
9	Μ	All tumors expressed atleast 1 FDC marker : CD21 ( 8/13 ) , CD23 ( 2/13 ) , CD35 ( 8/12 ) , CNA.42 ( 13/14 ) , Clusterin ( 8/13 ) , Fascin ( 15/15 ) and D2-40/podoplanin ( 7/14 ) .
10		Epstein-Barr virus ( EBER-1/2 in situ hybridization ) was performed successfully in 10 conventional variants ; all were negative .
11		Five of 14 cases ( 36% ) stained strongly for SSTR2A with a distinctive membranous pattern .
12		Residual lymphoid follicles surrounding some of the tumors stained similarly for SSTR2A .
13		Seven ( 54% ) of 13 assessable cases showed moderate to strong membranous staining for PD-L1 in greater than 5% of the neoplastic cells .
14		The Rb1 antigen was lost in 4 ( 28% ) of 14 cases .
15	Μ	MDM2 stained less than 5% to 20% of the tumor cells in 5 ( 36% ) of 14 cases ; 2 of them showed amplification by fluorescence in situ hybridization ( FISH ) .
16		CDK4 was negative except for weak staining in 1 of 14 cases .
17		This study adds to the existing few clinicopathologic series on FDCS and represents the first study to show MDM2 amplification in this entity .
18		Our results regarding frequent SSTR2A expression in FDCS are novel and might be of potential diagnostic and therapeutic relevance .
19		SSTR2A expression in FDCS represents a further confusing factor when thinking of meningioma which uniformly expresses this receptor .
20		FDCS occurring within the retroperitoneum and/or the abdominal cavity may closely mimic dedifferentiated liposarcoma , particularly if MDM2 positive and/or amplified and should thus be carefully assessed for expression of FDC markers .

PMID: 27272683 (Patient)   Terms:
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0		Well-Differentiated Liposarcoma With Hibernoma-Like Morphology .
1		Well-differentiated liposarcoma ( WDL ) can show a morphologic spectrum , including lipoma-like , sclerosing and inflammatory subtypes .
2		It does not metastasize but can dedifferentiate , acquiring metastatic potential .
3		Hibernomas are benign neoplasms that show variable differentiation toward brown fat , and can sometimes occur in the abdomen or retroperitoneum .
4		We illustrate a case of retroperitoneal WDL that showed extensive hibernoma-like morphology , with sheets of multivacuolated adipocytes of varying sizes , with abundant cytoplasm and numerous lipid vacuoles or granular eosinophilic cytoplasm .
5		However , very focally there were fibrous septa containing spindle cells with enlarged , hyperchromatic , mildly pleomorphic nuclei .
6		Further sampling showed areas of typical WDL , with lobules of mature fat intersected by fibrous septa containing atypical , enlarged spindle cells , as well as small foci of dedifferentiation .
7	Μ	Immunohistochemistry for CDK4 and p16 showed strong and diffuse nuclear expression in the hibernoma-like areas , and fluorescence in situ hybridization showed MDM2 gene amplification , all in keeping with WDL .
8		We highlight hibernoma-like morphology as part of the histologic spectrum of WDL , and recognition of this variant is important for correct treatment and prognostication .

PMID: 27255162 (Patient)   Terms:
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0		Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity .
1		Malignant phyllodes tumors of the breast are poorly understood rare neoplasms with potential for aggressive behavior .
2		Few efficacious treatment options exist for progressed or metastatic disease .
3		The molecular features of malignant phyllodes tumors are poorly defined , and a deeper understanding of the genetics of these tumors may shed light on pathogenesis and progression and potentially identify novel treatment approaches .
4		We sequenced 510 cancer-related genes in 10 malignant phyllodes tumors , including 5 tumors with liposarcomatous differentiation and 1 with myxoid chondrosarcoma-like differentiation .
5		Intratumoral heterogeneity was assessed by sequencing two separate areas in 7 tumors , including non-heterologous and heterologous components of tumors with heterologous differentiation .
6	Μ	Activating hotspot mutations in FGFR1 were identified in 2 tumors .
7		Additional recurrently mutated genes included TERT promoter ( 6/10 ) , TP53 ( 4/10 ) , PIK3CA ( 3/10 ) , MED12 ( 3/10 ) , SETD2 ( 2/10 ) and KMT2D ( 2/10 ) .
8		Together , genomic aberrations in FGFR/EGFR PI-3 kinase and RAS pathways were identified in 8 ( 80% ) tumors and included mutually exclusive and potentially actionable activating FGFR1 , PIK3CA and BRAF V600E mutations , inactivating TSC2 mutation , EGFR amplification and PTEN loss .
9	Μ	Seven ( 70% ) malignant phyllodes tumors harbored TERT aberrations ( six promoter mutations , one amplification ) .
10	Μ	For comparison , TERT promoter mutations were identified by Sanger sequencing in 33% borderline ( n = 12 ) and no ( 0% , n = 8 ) benign phyllodes tumors ( P = 0391 and P = 0013 versus malignant tumors , respectively ) .
11	Μ	Genetic features specific to liposarcoma , including CDK4/MDM2 amplification , were not identified .
12		Copy number analysis revealed intratumoral heterogeneity and evidence for divergent tumor evolution in malignant phyllodes tumors with and without heterologous differentiation .
13		Tumors with liposarcomatous differentiation revealed more chromosomal aberrations in non-heterologous components compared with liposarcomatous components .
14		EGFR amplification was heterogeneous and present only in the non-heterologous component of one tumor with liposarcomatous differentiation .
15		The results identify novel pathways involved in the pathogenesis of malignant phyllodes tumors , which significantly increase our understanding of tumor biology and have potential clinical impact .

PMID: 27124835 (Patient)   Terms: Clinical Trial, clinical trial, NCT01209598
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0		Progression-Free Survival Among Patients With Well-Differentiated or Dedifferentiated Liposarcoma Treated With CDK4 Inhibitor Palbociclib : A Phase 2 Clinical Trial .
1		IMPORTANCE :
2		More than 90% of well-differentiated or dedifferentiated liposarcomas ( WD/DDLS ) have CDK4 amplification .
3		The selective CDK4 and CDK6 inhibitor palbociclib inhibits growth and induces senescence in liposarcoma cell lines and xenografts .
4		Our prior phase 2 study demonstrated that treatment with palbociclib ( 200 mg daily for 14 days every 21 days ) resulted in clinical benefit in WD/DDLS but moderate hematologic toxic effects .
5		It is important to understand whether palbociclib at a new dose and schedule-125 mg daily for 21 days every 28 days-results in clinical benefit and manageable toxic effects .
6		OBJECTIVE :
7		To determine the progression-free survival ( PFS ) at 12 weeks of patients with WD/DDLS treated with palbociclib ( PD0332991 ) .
8		DESIGN , SETTING , AND PARTICIPANTS :
9		In this phase 2 , nonrandomized , open-label clinical trial conducted at the Memorial Sloan Kettering Cancer Center , 60 patients 18 years and older with advanced WD/DDLS and measurable disease by RECIST 1.1 were enrolled from December 2011 to January 2014 and followed to March 2015 .
10		Patients received oral palbociclib at 125 mg daily for 21 days in 28-day cycles .
11		MAIN OUTCOMES AND MEASURES :
12		Primary end point was PFS .
13		Secondary end points included response rate and toxic effects .
14		RESULTS :
15		Overall , 30 patients were enrolled in the initial cohort and 30 more in an expansion cohort .
16		Median ( range ) age was 61.5 ( 35-87 ) years ; 31 patients ( 52% ) were male ; median ( range ) Eastern Cooperative Oncology Group score was 0 ( 0-1 ) .
17		Progression-free survival at 12 weeks was 57.2% ( 2-sided 95% CI , 424%-688% ) , and the median PFS was 17.9 weeks ( 2-sided 95% CI , 119-240 weeks ) .
18		There was 1 complete response .
19		Toxic effects were primarily hematologic and included neutropenia ( grade 3 , n = 20 [33%] ; grade 4 , n = 2 [3%] ) but no neutropenic fever .
20		CONCLUSIONS AND RELEVANCE :
21		In patients with advanced WD/DDLS , treatment with palbociclib was associated with a favorable PFS and occasional tumor response .
22		This dose and schedule appears active and may have less toxic effects than 200 mg for 14 days .
23		TRIAL REGISTRATION :
24		clinicaltrials .
25		gov Identifier : NCT01209598 .

PMID: 27102568 (Patient)   Terms:
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0		Critical reappraisal of primary osseous composite sarcoma ( malignant mesenchymoma ) - analysis of four cases and literature review .
1		In accordance with recent terminology , it is proposed that malignant mesenchymoma should be renamed 'composite sarcoma' and defined as 'a sarcoma composed of two or more cellular types each of which is sufficiently differentiated to permit clear recognition of its histogenetic type microscopically , immunohistochemically or ultrastructurally ; excluding fibrosarcomatous and high-grade pleomorphic undifferentiated sarcomatous component , dedifferentiated sarcoma and the combination of osteosarcoma and chondrosarcoma which is regarded as a single histogenetic type' .
2		Four cases of primary osseous composite sarcoma ( POCS ) were identified among 928 primary bone sarcomas .
3		Their age ranged from 10 to 87 years , peak incidence in the second decade with equal sex distribution .
4		Most presented with pain , commonest in the knee , affecting the metaphysis , appearing radiologically as expansile infiltrative osteolytic lesions with cortical erosion , periosteal reaction , variable extent of osteoblastic areas and soft tissue extension .
5		All contained variable amounts of conventional high-grade osteosarcoma with or without chondrosarcoma component ; the other constituents were liposarcoma , rhabdomyosarcoma and leiomyosarcoma .
6		In all cases , Ki67 proliferative index was over 35% , there was no CDK4 and MDM2 amplification .
7		The absence of low-grade component supported the de novo origin of POCS rather than derivation from divergent dedifferentiation .
8		The two older patients with hitherto undescribed osteoleiomyosarcoma died 2 and 10 months after operation , whereas the two younger with osteorhabdomyosarcoma and osteoliposarcoma enjoyed disease-free survival at 16 and 6 years after chemotherapy despite the latter showing lung metastasis at presentation .
9		Identification of the different lines of differentiation together with their approximate amounts and histological grades is therefore mandatory for POCS as multi-agent chemotherapy catered for each sarcoma component might offer hope for long-term disease-free survival .

PMID: 27020493 (Patient)   Terms:
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0		MDM2/CDK4 gene amplification in large/deep-seated 'lipomas' : incidence , predictors and clinical significance .
1		This study of 140 cases assessed the incidence of MDM2/CDK4 gene amplification in lipomatous neoplasms with histological features of a lipoma but which were of clinical concern due to large size ( >/ = 50 mm ) and/or deep-seated ( subfascial ) location .
2	Μ	Univariate and multivariate statistical analyses were used to identify clinical , radiological and pathological predictors of gene amplification .
3		Differences in local recurrence rates between amplified and non-amplified cases were assessed using survival analysis .
4		The findings indicate that the incidence of MDM2/CDK4 amplification in this setting is low at 5% ( 95%CI 14-86% ) .
5		Variables associated with amplification on univariate analysis were tumour site ( thigh , p = 0004 ) , size ( >100 mm , p = 0033 ) and presence of equivocal atypia ( p = 0001 ) .
6		Independent predictors on multivariate analysis were size ( OR 39 , 95%CI 14-113 , p = 0012 ) and presence of equivocal atypia ( OR 125 , 95%CI 19-803 , p = 0008 ) .
7		There was no significant difference in local recurrence rates between amplified and non-amplified cases ( p = 0461 ) based on a median follow-up time of 31 months .
8		Assessment for MDM2/CDK4 amplification , therefore , should be considered in 'lipomas' which are >100 mm in size , show equivocal atypia and arise in the thigh .
9		However , the clinical significance of gene amplification in this setting is unclear and requires confirmation in larger studies .

PMID: 26993784 (Patient)   Terms: retrospective
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0		Histological Classification and Immunohistochemical Evaluation of MDM2 and CDK4 Expression in Canine Liposarcoma .
1		Canine liposarcoma is an uncommon soft tissue sarcoma usually arising in the subcutis .
2		While liposarcoma classification in dogs is based solely on histology , in humans it depends on the detection of genetic abnormalities that can lead to specific protein overexpression .
3		This study is an immunohistochemical evaluation of MDM2 and CDK4 expression in canine liposarcoma designed to assess the correlation of these proteins with histologic type , grade , mitotic index and Ki67 labeling index and evaluate their utility in improving tumor classification .
4	Μ	Fifty-three liposarcomas were retrospectively collected : 24 were well differentiated liposarcomas ( WDL ) , 16 of which expressed MDM2 and 21 CDK4 ; 7 were myxoid liposarcomas ( ML ) , 1 of which expressed MDM2 and 5 expressed CDK4 ; 18 were pleomorphic liposarcomas ( PL ) , all were MDM2 negative and 12 expressed CDK4 .
5		Four tumors were morphologically consistent with dedifferentiated liposarcoma ( DDL ) a subtype described only in humans : 3 expressed MDM2 and 4 expressed CDK4 .
6	Μ	MDM2 expression correlated with histotype ( highly expressed in WDL and DDL ) and grade ( highly expressed in grade 1 tumors ) .
7		Histotype correlated with the Ki67 labeling index ( lowest in WDL and highest in DDL ) .
8		A revised classification , considering MDM2 expression , allowed 8 WDL to be reclassified as PL and correlated significantly with mitotic and Ki67 labeling index ( both significantly lower in WDL and progressively higher in ML and DDL ) .
9	✓	These results partially parallel data reported for human liposarcomas , suggesting that WDL and DDL are distinct neoplastic entities characterized by MDM2 expression , which may represent a useful diagnostic and potentially prognostic marker for canine liposarcoma .	GE-MRK-DS

PMID: 26962163 (None)   Terms: clinical trial
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0		Managing Liposarcomas : Cutting Through the Fat .
1		Liposarcomas are one of the most common of more than 50 histologic subtypes of soft tissue sarcomas that , themselves , are heterogeneous .
2		Liposarcomas fall into four distinct histologic subtypes : atypical lipomatous tumor/well-differentiated liposarcoma , dedifferentiated liposarcoma , myxoid ( round cell ) liposarcoma , and pleomorphic liposarcoma .
3		Definitive treatment remains surgical resection with negative margins for resectable disease .
4		However , well-differentiated liposarcomas that are large or difficult to operate upon should be followed with close surveillance as long as there is no radiologic concern for a dedifferentiated component .
5		In contrast , first - line chemotherapy with anthracycline with or without ifosfamide , or gemcitabine and docetaxel should be used for inoperable myxoid ( round cell ) or pleomorphic liposarcomas , which are relatively responsive to chemotherapy .
6		In the second - and third - line setting , myxoid liposarcomas , in particular , seem to be sensitive to trabectedin , which was recently approved by the US Food and Drug Administration ( FDA ) .
7		Eribulin offered a survival benefit when compared with dacarbazine in the third - line setting in liposarcomas ( other than the well-differentiated subtype ) and is now FDA approved .
8		Recent studies have identified distinct genetic aberrations that not only aid in the diagnosis of liposarcoma subtypes but represent actionable targets .
9		Cyclin -dependent kinase 4 and murine double minute 2 are overexpressed in well-differentiated and dedifferentiated liposarcomas and offer opportunities that are being pursued in clinical trials .
10		It is critical that liposarcomas are not approached by oncologists as one disease entity but rather subclassified into distinct subtypes using histologic and molecular tools before formalizing a treatment plan .

PMID: 26918731 (Cell)   Terms: in vivo, in vitro, xenograft, clinical trial, tumor xenograft
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0		Preclinical activity of selinexor , an inhibitor of XPO1 , in sarcoma .
1		Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers .
2		In this study , we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes .
3		The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor ( GIST ) , liposarcoma ( LPS ) , leiomyosarcoma , rhabdomyosarcoma , undifferentiated sarcomas , and alveolar soft part sarcoma ( ASPS ) .
4		Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM ( median : 66.1 nM ) .
5		Selinexor suppressed sarcoma tumor xenograft growth , including models of ASPS that were resistant in vitro .
6		In GIST cells with KIT mutations , selinexor induced G1 - arrest without attenuation of phosphorylation of KIT , AKT , or MAPK , in contrast to imatinib .
7		In LPS cell lines with MDM2 and CDK4 amplification , selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression .
8		Selinexor increased p53 and p21 expression at the protein but not RNA level , indicating a post-transcriptional effect .
9		These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS .
10		These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes .

PMID: 26887042 (None)   Terms: xenograft
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0		MLN-8237 : A dual inhibitor of aurora A and B in soft tissue sarcomas .
1		Aurora kinases have become an attractive target in cancer therapy due to their deregulated expression in human tumors .
2		Liposarcoma , a type of soft tissue sarcoma in adults , account for approximately 20% of all adult soft tissue sarcomas .
3		There are no effective chemotherapies for majority of these tumors .
4		Efforts made to define the molecular basis of liposarcomas lead to the finding that besides the amplifications of CDK4 and MDM2 , Aurora Kinase A , also was shown to be overexpressed .
5		Based on these as well as mathematic modeling , we have carried out a successful preclinical study using CDK4 and IGF1R inhibitors in liposarcoma .
6		MLN8237 has been shown to be a potent and selective inhibitor of Aurora A .
7		MLN-8237 , as per our results , induces a differential inhibition of Aurora A and B in a dose dependent manner .
8		At a low nanomolar dose , cellular effects such as induction of phospho-Histone H3 (Ser10) mimicked as that of the inhibition of Aurora kinase A followed by apoptosis .
9		However , micromolar dose of MLN-8237 induced polyploidy , a hallmark effect of Aurora B inhibition .
10		The dose dependent selectivity of inhibition was further confirmed by using siRNA specific inhibition of Aurora A and B .
11		This was further tested by time lapse microscopy of GFP-H2B labelled cells treated with MLN-8237 .
12		LS141 xenograft model at a dose of 30 mg/kg also showed efficient growth suppression by selective inhibition of Aurora Kinase A .
13		Based on our data , a dose that can target only Aurora A will be more beneficial in tumor suppression .

PMID: 26843318 (Patient)   Terms:
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0		Heterologous Liposarcomatous Differentiation in Malignant Phyllodes Tumor is Histologically Similar but Immunohistochemically and Molecularly Distinct from Well-differentiated Liposarcoma of Soft Tissue .
1		Malignant phyllodes tumor ( PT ) infrequently displays heterologous differentiation , and when present is most often liposarcomatous .
2		We identified five cases of malignant PT with regions identical to well-differentiated liposarcoma ( WDLS ) of soft tissue and evaluated them for MDM2 and CDK4 gene expression and amplification using immunohistochemistry ( IHC ) and fluorescence in situ hybridization ( FISH ) , respectively .
3		Despite indistinguishable morphology all cases of malignant PT with WDLS-like liposarcomatous differentiation were negative for MDM2 and CDK4 IHC and FISH , supporting different underlying pathogenesis .

PMID: 26645460 (None)   Terms: clinical trial
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0		Dedifferentiated Liposarcoma : Updates on Morphology , Genetics , and Therapeutic Strategies .
1		LONGTOKEN form the largest subgroup of liposarcomas , and represent a morphologic and behavioral spectrum of 1 disease entity , which arises typically in middle to late adult life , most frequently within the retroperitoneum or extremities .
2		DDL is defined as nonlipogenic sarcoma that is juxtaposed to WDL , occurs as a recurrence of WDL or which can arise de novo , and typically has the appearance of undifferentiated pleomorphic or spindle cell sarcoma .
3		DDL have a propensity for local recurrence , whereas distant metastasis is rarer , and behavior is related to anatomic site , with retroperitoneal neoplasms showing a significantly worse prognosis .
4		Surgical resection remains the mainstay of treatment , and medical options for patients with aggressive recurrent or metastatic disease are limited .
5		DDL share similar genetic abnormalities to WDL , with high-level amplifications of chromosome 12q14-15 , including the MDM2 and CDK4 cell cycle oncogenes , and DDL harbor additional genetic changes , particularly coamplifications of 6q23 and 1p32 .
6		Novel therapies targeted at the gene products of chromosome 12 are being tested in clinical trials .
7		We review the pathology and genetics of DDL , discussing morphologic patterns , immunohistochemical and genetic findings , the differential diagnosis , and future therapeutic strategies .

PMID: 26643872 (None)   Terms: in vivo, in vitro
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0		Genomic landscape of liposarcoma .
1		Liposarcoma ( LPS ) is the most common type of soft tissue sarcoma accounting for 20% of all adult sarcomas .
2		Due to absence of clinically effective treatment options in inoperable situations and resistance to chemotherapeutics , a critical need exists to identify novel therapeutic targets .
3	Μ	We analyzed LPS genomic landscape using SNP arrays , whole exome sequencing and targeted exome sequencing to uncover the genomic information for development of specific anti-cancer targets .
4	Μ	SNP array analysis indicated known amplified genes ( MDM2 , CDK4 , HMGA2 ) and important novel genes ( UAP1 , MIR557 , LAMA4 , CPM , IGF2 , ERBB3 , IGF1R ) .
5		Carboxypeptidase M ( CPM ) , recurrently amplified gene in well-differentiated/de-differentiated LPS was noted as a putative oncogene involved in the EGFR pathway .
6	Μ	Notable deletions were found at chromosome 1p ( RUNX3 , ARID1A ) , chromosome 11q ( ATM , CHEK1 ) and chromosome 13q14.2 ( MIR15A , MIR16-1 ) .
7		Significantly and recurrently mutated genes ( false discovery rate <005 ) included PLEC ( 27% ) , MXRA5 ( 21% ) , FAT3 ( 24% ) , NF1 ( 20% ) , MDC1 ( 10% ) , TP53 ( 7% ) and CHEK2 ( 6% ) .
8		Further , in vitro and in vivo functional studies provided evidence for the tumor suppressor role for Neurofibromin 1 ( NF1 ) gene in different subtypes of LPS .
9	Μ	Pathway analysis of recurrent mutations demonstrated signaling through MAPK , JAK-STAT , Wnt , ErbB , axon guidance , apoptosis , DNA damage repair and cell cycle pathways were involved in liposarcomagenesis .
10		Interestingly , we also found mutational and copy number heterogeneity within a primary LPS tumor signifying the importance of multi - region sequencing for cancer - genome guided therapy .
11		In summary , these findings provide insight into the genomic complexity of LPS and highlight potential druggable pathways for targeted therapeutic approach .

PMID: 26642065 (None)   Terms: clinical trial
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0		Cyclin -dependent kinase pathways as targets for women's cancer treatment .
1		PURPOSE OF REVIEW :
2		In this article , we not only review the preclinical and clinical studies of cyclin-dependent kinase ( CDK ) 4/6 inhibitors in breast cancer , liposarcoma , mantel cell lymphoma , melanoma and germ cell tumors , but also examine promising preclinical data in glioblastoma , renal and ovarian cancer models that may provide directions for future development .
3		RECENT FINDINGS :
4		Targeting CDKs has been the focus of considerable basic science and clinical research .
5		The CDK 4/6 inhibitors are a novel class of therapeutics that target the CDK 4/6 kinases that promote transition through the cell cycle .
6		Currently , palbociclib ( PD0332991 , Pfizer ) , abemaciclib ( LY2835219 , Lilly ) and ribociclib ( LEE011 , Novartis ) are being investigated in clinical trials .
7		These oral agents offer the hope of clinical efficacy in many tumor types , and have been associated with minimal toxicity .
8		Amplification/overexpression of cyclin D , loss of CDKN2A ( p16 ) and amplification/overexpression of CDK4 are proposed biomarkers of improved response to CDK4/6 inhibition .
9		SUMMARY :
10		Palbociclib , abemaciclib and ribociclib have demonstrated very promising clinical activity in breast cancer , liposarcoma , mantel cell lymphoma and melanoma .
11		Moreover , CDK4/6 inhibitors have shown promising preclinical activity in glioblastoma , renal and ovarian cancer models that may provide directions for their future clinical development .
12		Further preclinical and clinical research is needed to better understand mechanisms of resistance and develop rational combination therapies with other targeted agents .

PMID: 26633733 (None)   Terms: clinical trial
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0		Palbociclib ( PD0332991 ) -a Selective and Potent Cyclin -Dependent Kinase Inhibitor : A Review of Pharmacodynamics and Clinical Development .
1		IMPORTANCE :
2		Palbociclib ( PD0332991 ) is a newly developed drug that received breakthrough designation and recent US Food and Drug Administration approval in combination with endocrine therapy in the treatment of hormone receptor positive , ERBB2-negative ( formerly HER2 or HER2/neu ) breast cancer in the first - line metastatic setting .
3		OBJECTIVE :
4		Herein we describe the preclinical and translational data and early - and late-phase clinical trials in which palbociclib has been investigated in a broad array of tumor types .
5		We discuss the pharmacodynamics , pharmacokinetics , toxic effects , and clinical response rates .
6		EVIDENCE REVIEW :
7		On March 1 , 2015 , we conducted a review of the literature describing the development of palbociclib .
8		We used the PubMed search terms "PD0332991 , " "palbociclib , " and "CDK4/6 inhibitor" to find all published articles of interest , without limitation as to publication date .
9		FINDINGS :
10		Palbociclib is a potent and specific oral cyclin-dependent kinase ( CDK ) 4/6 inhibitor that has strong preclinical data to support its activity in retinoblastoma protein -expressing tumors .
11		Phase 1 trials have demonstrated safety , and phase 2 trials have shown single-agent activity in mantle - cell lymphoma , breast cancer , liposarcoma , and teratoma with reversible neutropenia as the main toxic effect .
12		Addition of palbociclib to endocrine therapy improves progression-free survival in endocrine therapy-naive and endocrine therapy-resistant metastatic settings .
13		CONCLUSIONS AND RELEVANCE :
14		Palbociclib is well tolerated and has therapeutic potential for multiple cancers , including breast cancer , where its efficacy has been demonstrated alone and in combination with endocrine therapy .
15		Additional combinations of palbociclib with endocrine therapy , chemotherapy , and targeted therapy have potential in various tumors , and phase 3 trials are under way .

PMID: 26542423 (Patient)   Terms:
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0		Liposarcomatous differentiation in malignant phyllodes tumours is unassociated with MDM2 or CDK4 amplification .
1		AIMS :
2		Breast sarcomas are rare , usually occurring in the setting of malignant phyllodes tumour ( MPT ) .
3		Heterologous differentiation commonly resembles well-differentiated or pleomorphic liposarcoma .
4		In extramammary sites , these subtypes have different biological behaviours and distinct genetic alterations : MDM2 and CDK4 amplification in well-differentiated liposarcoma , and polyploidy with complex structural rearrangements in pleomorphic liposarcoma .
5		The aim of this study was to investigate foci resembling well-differentiated liposarcoma in MPT for MDM2 and CDK4 amplification .
6		METHODS AND RESULTS :
7		We evaluated the clinicopathological characteristics of MPTs received by the Vanderbilt Breast Consultation Service containing components resembling well-differentiated or pleomorphic liposarcoma .
8		Cases with available tissue blocks were subjected to fluorescence in-situ hybridization with MDM2 and CDK4 probes .
9		Thirty-eight MPTs with liposarcomatous components were available for review .
10		The mean patient age was 49.8 years ( range 26-84 years ) .
11		In addition to well-differentiated liposarcoma , the following components were also present : high-grade undifferentiated sarcoma ( n = 9 ; 237% ) , pleomorphic liposarcoma ( n = 4 ; 105% ) , non-high-grade sarcoma not otherwise specified ( n = 22 ; 579% ) , and malignant peripheral nerve sheath tumour-like ( n = 2 ; 52% ) .
12	Μ	Among 10 cases tested , none showed amplification of MDM2 or CDK4 .
13		CONCLUSIONS :
14		This study examined molecular changes in the well-differentiated liposarcomatous components of MPT .
15		Despite histological similarity to well-differentiated liposarcoma of soft tissues , liposarcomatous differentiation in MPT lacks the molecular phenotype characteristic of extramammary well-differentiated liposarcoma .

PMID: 26514741 (Patient)   Terms:
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0		Immunohistochemical expression of p16 in lipoblastomas .
1		Lipoblastoma ( LB ) is a rare benign adipocytic tumor of childhood occasionally showing histological similarities to myxoid liposarcoma ( ML ) or well-differentiated liposarcoma ( WDL ) .
2		p16 immunohistochemistry has proved to be useful in distinguishing various types of liposarcomas , in particular WDL from lipoma , with higher sensitivity and specificity than MDM2 and CDK4 immunohistochemistry .
3		In this study , we reported the histologic features of a series of 30 LB with emphasis on the potential diagnostic pitfalls and investigated the immunohistochemical expression of p16 .
4		Moreover , p16 immunostaining was performed in 16 liposarcomas ( 11 WDL and 5 ML ) , 16 lipomas , and 16 cases of liponecrosis in order to evaluate its usefulness in the differential diagnosis of challenging lesions occurring in older children .
5		Overall , p16 immunostaining was positive in 3 LBs and in 12 out of 16 liposarcomas ( 10 WDL and 2 ML ) , with a sensitivity of 75% , a specificity of 90% , a positive predictive value of 80% , and a negative predictive value of 87% .
6		All lipomas were p16 negative , whereas 5 liponecroses were positive .
7	Μ	Accounting altogether the benign lesions versus liposarcomas , p16 showed a sensitivity of 75% , a specificity of 87% , a positive predictive value of 60% , and a negative predictive value of 93% .
8		Our data suggest that a negative p16 immunostaining may be helpful in excluding a liposarcoma when occurring in unusual clinical contexts , such as in adolescence or late recurrence .
9		However , such finding should be interpreted with caution since also some liposarcomas lack p16 and occasional LBs are positive .

PMID: 26509911 (Patient)   Terms:
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0		p16 Immunohistochemistry is Less Useful Than MDM2 and CDK4 to Distinguish Dedifferentiated Liposarcomas From Other Retroperitoneal Mimics .
1		Dedifferentiated liposarcoma ( DDL ) frequently involves the retroperitoneum .
2		In the absence of a lipogenic component histologically , the differential diagnosis of a retroperitoneal DDL includes other sarcomas and , if the tumor has visceral involvement , sarcomatoid carcinoma .
3		DDL demonstrates amplification of chromosome subregion 12q13-q15 .
4		Detection of the amplification itself , or the resulting overexpression of the MDM2 and CDK4 genes by genetic and immunohistochemical methods , is a useful ancillary test in the diagnosis of DDL .
5		More recently , immunohistochemistry for p16 , the product of the CDKN2A gene , was shown to be a useful adjunct in differentiating well-differentiated liposarcoma from benign adipocytic tumors .
6		In the present study , we examined the utility of p16 immunohistochemistry to distinguish DDL ( n = 44 ) from other high-grade and low-grade retroperitoneal mimics ( n = 73 ) .
7		p16 positivity was observed in 43/44 ( 98% ) DDLs , with the majority of these showing strong , diffuse , staining .
8		The rate of p16 positivity in other retroperitoneal tumors was lower ( 37/73 , 51% ) and staining was not as consistently diffuse or intense .
9		Furthermore , p16 positivity varied between the control sarcomas based on tumor type as follows : 11/11 leiomyosarcomas , 8/11 pleomorphic undifferentiated sarcomas , 9/39 sarcomatoid carcinomas , 7/7 desmoid tumors , 1/3 endometrial stromal sarcomas , and 1/2 malignant gastrointestinal stromal tumors .
10		On the basis of these findings , we conclude that p16 is highly sensitive for retroperitoneal DDL .
11		However , the lack of specificity limits the diagnostic utility compared with the more established markers MDM2 and CDK4 .

PMID: 26464734 (None)   Terms:
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0		Primary cardiac dedifferentiated liposarcoma with homologous and heterologous differentiation : a case report .
1		Liposarcoma originating in the heart is extraordinarily rare .
2		Herein , we report a dedifferentiated liposarcoma arising from the left atrium in a 59-year-old Chinese man .
3		Histologically , the neoplasm predominantly consisted of undifferentiated pleomorphic sarcoma .
4		In addition , the neoplasm exhibited lipoblastic differentiation and osteo-/chondrosarcomatous components .
5		Immunohistochemically , the neoplastic cells were strongly positive for p16 , MDM2 , and CDK4 .
6	Μ	Fluorescence in situ hybridization showed MDM2 gene amplification in all of the tumor components .
7		To the best of our knowledge , this is the first published example of cardiac dedifferentiated liposarcoma exhibiting homologous and heterologous differentiation without a well-differentiated liposarcoma component .

PMID: 26418953 (Patient)   Terms:
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0		Molecular inimitability amongst tumors : implications for precision cancer medicine in the age of personalized oncology .
1		Tumor sequencing has revolutionized oncology , allowing for detailed interrogation of the molecular underpinnings of cancer at an individual level .
2		With this additional insight , it is increasingly apparent that not only do tumors vary within a sample ( tumor heterogeneity ) , but also that each patient's individual tumor is a constellation of unique molecular aberrations that will require an equally unique personalized therapeutic regimen .
3		We report here the results of 439 patients who underwent Clinical Laboratory Improvement Amendment ( CLIA )- certified next generation sequencing ( NGS ) across histologies .
4		Among these patients , 98.4% had a unique molecular profile , and aside from three primary brain tumor patients with a single genetic lesion ( IDH1 R132H ) , no two patients within a given histology were molecularly identical .
5		Additionally , two sets of patients had identical profiles consisting of two mutations in common and no other anomalies .
6		However , these profiles did not segregate by histology ( lung adenocarcinoma-appendiceal cancer ( KRAS G12D and GNAS R201C ) , and lung adenocarcinoma-liposarcoma ( CDK4 and MDM2 amplification pairs ) ) .
7		These findings suggest that most advanced tumors are molecular singletons within and between histologies , and that tumors that differ in histology may still nonetheless exhibit identical molecular portraits , albeit rarely .

PMID: 26336885 (None)   Terms:
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0		Prognostic value of HMGA2 , CDK4 , and JUN amplification in well-differentiated and dedifferentiated liposarcomas .
1		HMGA2 , CDK4 , and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor , well-differentiated liposarcoma , and dedifferentiated liposarcoma .
2		We studied the frequency of amplification of these genes in a series of 48 dedifferentiated liposarcomas and 68 atypical lipomatous tumors/well-differentiated liposarcomas .
3		We correlated their amplification status with clinicopathological features and outcomes .
4	✓	Histologically , both CDK4 ( P = 0007 ) and JUN ( P = 0005 ) amplifications were associated with dedifferentiated liposarcoma , whereas amplification of the proximal parts of HMGA2 ( 5'-untranslated region ( UTR ) and exons 1-3 ) was associated with atypical lipomatous tumor/well-differentiated liposarcoma ( P = 001 ) .	GM-ASS-DS
5		CDK4 amplification was associated with axial tumors .
6		Amplification of 5'-UTR and exons 1-3 of HMGA2 was associated with primary status and grade 1 .
7		Shorter overall survival was correlated with : age >64 years ( P = 003 ) , chemotherapy used in first intent ( P<0001 ) , no surgery ( P = 0003 ) , grade 3 ( P<0001 ) , distant metastasis ( P<0001 ) , node involvement ( P = 0006 ) , and CDK4 amplification ( P = 007 ) .
8		In multivariate analysis , distant metastasis ( HR = 88 ) and grade 3 ( HR = 182 ) were associated with shorter overall survival .
9		A shorter recurrence-free survival was associated with dedifferentiated liposarcoma ( P<0001 ) , grade 3 ( P<0001 ) , node involvement ( P<0001 ) , distant metastasis ( P = 002 ) , recurrent status ( P = 0009 ) , axial location ( P = 0001 ) , and with molecular features such as CDK4 ( P = 005 ) and JUN amplification ( P = 007 ) .
10	✓	Amplification of 5'-UTR and exons 1-3 ( P = 008 ) and 3'-UTR ( P = 001 ) of HMGA2 were associated with longer recurrence-free survival .	GM-ASS-RO
11		Distant metastasis was associated with shorter recurrence-free survival ( HR = 58 ) in multivariate analysis .
12		Dedifferentiated liposarcoma type was associated with axial location , grade 3 and recurrent status .
13	✓ Μ	In conclusion , we showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis , whereas CDK4 and JUN amplifications were associated with dedifferentiated liposarcoma histology and a bad prognosis .	GE-ASS-RO
14		In addition , we also provided the first description of the molecular evolution of a well-differentiated liposarcoma into four successive dedifferentiated liposarcoma relapses , which was consistent with our general observations .

PMID: 26173427 (Patient)   Terms:
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0		p16 Expression in Fat Necrosis : A Potential Diagnostic Pitfall in the Evaluation of Differentiated Adipocytic Neoplasms .
1		Distinguishing well-differentiated liposarcoma ( WDL ) from lipoma is of clinical and prognostic importance , but can be difficult on imaging and histology alone .
2		WDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes and overexpress the cell cycle regulator p16 .
3		Fluorescence in situ hybridization ( FISH ) to assess for MDM2 and CDK4 gene amplification is the diagnostic gold standard , and immunohistochemistry for the overexpressed MDM2 and CDK4 proteins is also useful but may not be routinely offered by pathology laboratories .
4		p16 immunohistochemistry is a sensitive marker for WDL and is in the repertoire of most laboratories , and it has been suggested as a useful method of distinguishing WDL from lipomas when other ancillary modalities are not readily available .
5		We describe a case of a large retroperitoneal adipocytic mass occurring in a 27-year-old male , which was clinically and radiologically in keeping with WDL .
6		Histologically this was a differentiated adipocytic neoplasm with prominent fibrous septa and fat necrosis , more suggestive of retroperitoneal lipoma .
7	Μ	Immunohistochemistry showed diffuse , strong nuclear expression of p16 in the areas of fat necrosis .
8		However , CDK4 was negative and the lesion lacked evidence of MDM2 amplification with FISH .
9		Diffuse expression of p16 in areas of fat necrosis in large or deep lipomas highlights the potential for diagnostic misinterpretation as well differentiated liposarcoma , and we therefore emphasize that p16 immunohistochemistry should always be interpreted as part of a panel with CDK4 +/- MDM2 in the differential diagnosis of WDL and lipoma .

PMID: 25993159 (None)   Terms: retrospective studies, clinical trial
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0		Application of molecular biology to individualize therapy for patients with liposarcoma .
1		Liposarcomas are one the most common of over 50 histologic subtypes of soft tissue sarcomas that are mostly resistant to chemotherapy .
2		Histologically , liposarcomas themselves are heterogeneous and fall into four distinct subtypes : well-differentiated/atypical lipomatous tumor , dedifferentiated liposarcoma , myxoid ( round cell ) liposarcoma , and pleomorphic liposarcoma .
3		Surgical resection with negative margins remains the mainstay for definitive treatment for operable disease .
4		For unresectable disease , retrospective studies have identified myxoid ( round cell ) and pleomorphic sarcomas to be relatively responsive to chemotherapy .
5		Recent studies have identified distinct genetic aberrations that not only aid in the diagnosis of particular liposarcoma subtypes , but represent actionable targets as they are considered central to disease pathogenesis .
6		Cyclin-dependent kinase 4 ( CDK4 ) and murine double minute 2 ( MDM2 ) are overexpressed in well-differentiated and dedifferentiated liposarcomas and offer tantalizing opportunities that are being pursued in clinical trials .
7		Myxoid ( round cell ) liposarcomas appear to be sensitive to trabectedin , which is currently under U .
8		S .
9		Food and Drug Administration ( FDA ) review .
10		Liposarcomas do not represent a uniform disease and understanding the underlying molecular mechanism will help not only in accurate diagnosis but in selecting the appropriate treatment .

PMID: 25986682 (Patient)   Terms:
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0		Paratesticular dedifferentiated liposarcoma with prominent myxoid stroma : report of a case and review of the literature .
1		Paratesticular sarcoma is rare , but liposarcoma is its most common type .
2		Paratesticular liposarcoma sometimes presents as dedifferentiated liposarcoma .
3		Both high-grade and low-grade dedifferentiation have been reported .
4		Herein , we presented a unique case of a 64-year-old man with low-grade dedifferentiated liposarcoma with prominent myxoid stroma .
5		Well-differentiated liposarcoma components extended along the spermatic cord .
6		The constituent cells of the dedifferentiated component were peculiar in that , they were relatively uniform cells with atypia and did not have pleomorphism to such an extent that it mimicked myxofibrosarcoma .
7		This myxoid component was confidently differentiated from myxoid liposarcoma with the help of immunohistochemical analysis using CDK4 and MDM2 .
8		These two markers were also expressed in the well-differentiated component .
9		It could therefore be confirmed that this sarcoma is dedifferentiated liposarcoma but is not mixed-type liposarcoma comprising well-differentiated liposarcoma and myxoid liposarcoma .

PMID: 25941111 (None)   Terms:
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0		Molecular Pathways : Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment .
1		Cancer cells bypass normal controls over mitotic cell -cycle progression to achieve a deregulated state of proliferation .
2		The retinoblastoma tumor suppressor protein ( pRb ) governs a key cell -cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals .
3		Cancer cells frequently overcome pRb -dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase ( CDK ) 4 or CDK6 partnered with D-type cyclins .
4		Three selective CDK4/6 inhibitors , palbociclib ( Ibrance ; Pfizer ) , ribociclib ( Novartis ) , and abemaciclib ( Lilly ) , are in various stages of development in a variety of pRb-positive tumor types , including breast cancer , melanoma , liposarcoma , and non-small cell lung cancer .
5		The emerging , positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy .

PMID: 25888633 (Patient)   Terms:
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0		HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN , irrespective of p53 mutational status .
1		The MDM2-p53 pathway plays a prominent role in well-differentiated liposarcoma ( LPS ) pathogenesis .
2		Here , we explore the importance of MDM2 amplification and p53 mutation in LPS independently , to determine whether HDACi are therapeutically useful in LPS .
3		We demonstrated that simultaneous knockdown of MDM2 and p53 in p53-mutant LPS lines resulted in increased apoptosis , anti-proliferative effects , and cell cycle arrest , as compared to either intervention alone .
4		HDACi treatment resulted in the dephosphorylation and depletion of MDM2 and p53 without affecting CDK4 and JUN expression , irrespective of p53 mutational status in MDM2-amplified LPS .
5		In control mesothelioma cell lines , HDACi treatment resulted in down-regulation of p53 in the p53 mutant cell line JMN1B , but resulted in no changes of MDM2 and p53 in two mesothelioma lines with normal MDM2 and wild-type p53 .
6		HDACi treatment substantially decreased LPS and mesothelioma proliferation and survival , and was associated with upregulation of PTEN and p21 , and inactivation of AKT .
7		Our findings indicate that wild-type p53 depletion by HDACi is MDM2 amplification -dependent .
8		These findings underscore the importance of targeting both MDM2 and p53 in LPS and other cancers harboring p53 mutations .
9		Moreover , the pro-apoptotic and anti-proliferative effect of HDACi warrants further evaluation as a therapeutic strategy in MDM2-amplified LPS .

PMID: 25862836 (Patient)   Terms:
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0		Characterization of the 12q amplicons in lipomatous soft tissue tumors by multiplex ligation -dependent probe amplification-based copy number analysis .
1		BACKGROUND/AIM :
2		Well-differentiated liposarcoma ( WDLPS ) and de-differentiated liposarcoma ( DDLPS ) are characterized by amplified sequences derived from the long arm of chromosome 12 .
3		The goal of the present study was to identify , besides the well-known candidate genes , novel relevant genes in these large , complex 12q amplicons .
4		MATERIALS AND METHODS :
5		Using multiplex ligation -dependent probe amplification , genetic alterations in 19 different genes of 12q12-24 were evaluated in 77 lipomatous soft tissue tumors ( including lipomas , WDLPS , DDLPS and pleomorphic liposarcomas ) .
6		RESULTS :
7		We recorded several amplified genes of 12q13-15 , including miR-26a-2 , a gene not well studied in liposarcoma , and the well-known and previously described genes murine double minute 2 ( MDM2 ) , YEATS domain-containing protein 4 ( YEATS4 ) , high-mobility AT-hook 2 ( HMGA2 ) , cyclin-dependent kinase 4 ( CDK4 ) and tetraspanin 31 ( TSPAN31 ) .
8	Μ	Interestingly , the amplification profiles of these six genes were found to be significantly different between WDLPS and DDLPS , more frequently having a high-level status in DDLPS than in WDLPS .
9	Μ	In addition , DDLPS were found to have significantly higher mean amplification ratios compared to WDLPS .
10	Μ	Moreover , we identified additional genes exclusively amplified in DDLPS in 12q13 , 12q21 and 12q24 , including glioma-associated oncogene homolog 1 ( GLI1 ) , mitogen activated protein kinase kinase kinase 12 ( MAP3K12 ) , cyclin-dependent kinase 2 ( CDK2 ) , ALX homeobox 1 ( ALX1 ) and T-box 5 ( TBX5 ) .
11		CONCLUSION :
12		Differences in amplification profiles among WDLPS and DDLPS may be related to progression/de-differentiation in liposarcomas and show how in the future amplification profiles could provide an adjunctive tool in characterizing progression to DDLPS .
13	Μ	In addition , we identified additional genes exclusively amplified in DDLPS , which may play a role in liposarcomagenesis , particularly in the de-differentiation process .

PMID: 25822339 (None)   Terms: , mouse model, mouse
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0		Involvement of tumor suppressors PTEN and p53 in the formation of multiple subtypes of liposarcoma .
1		Liposarcoma ( LPS ) is a type of soft tissue sarcoma that mostly occurs in adults , and in humans is characterized by amplifications of MDM2 and CDK4 .
2		The molecular pathogenesis of this malignancy is still poorly understood and , therefore , we developed a mouse model with conditional inactivation of PTEN and p53 to investigate these pathways in the progression of the disease .
3		We show that deletion of these two tumor suppressors cooperate in the formation of multiple subtypes of LPS ( from well-differentiated LPS to pleomorphic LPS ) .
4		In addition , progression of the tumors is further characterized by the expression of D cyclins and CDK4/6 , which allow for continued cell division .
5		Microarray analysis also revealed novel genes that are differentially expressed between different subtypes of LPS , which could aid in understanding the disease and to unravel potential new therapeutic targets .

PMID: 25810375 (Cell)   Terms: xenograft
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0		CDK4 Amplification Reduces Sensitivity to CDK4/6 Inhibition in Fusion-Positive Rhabdomyosarcoma .
1		PURPOSE :
2		Rhabdomyosarcoma ( RMS ) is the most common pediatric soft tissue sarcoma and includes a PAX3 - or PAX7-FOXO1 fusion-positive subtype .
3	Μ	Amplification of chromosomal region 12q13-q14 , which contains the CDK4 proto-oncogene , was identified in an aggressive subset of fusion-positive RMS .
4		CDK4/6 inhibitors have antiproliferative activity in CDK4-amplified liposarcoma and neuroblastoma , suggesting CDK4/6 inhibition as a potential therapeutic strategy in fusion-positive RMS .
5		EXPERIMENTAL DESIGN :
6		We examined the biologic consequences of CDK4 knockdown , CDK4 overexpression , and pharmacologic CDK4/6 inhibition by LEE011 in fusion-positive RMS cell lines and xenografts .
7		RESULTS :
8		Knockdown of CDK4 abrogated proliferation and transformation of 12q13-14-amplified and nonamplified fusion-positive RMS cells via G1-phase cell -cycle arrest .
9		This arrest was mediated by reduced RB phosphorylation and E2F-responsive gene expression .
10	Μ	Significant differences in E2F target expression , cell -cycle distribution , proliferation , or transformation were not observed in RMS cells overexpressing CDK4 .
11		Treatment with LEE011 phenocopied CDK4 knockdown , decreasing viability , RB phosphorylation , and E2F-responsive gene expression and inducing G1-phase cell -cycle arrest .
12	✓ Μ	Although all fusion-positive cell lines showed sensitivity to CDK4/6 inhibition , there was diminished sensitivity associated with CDK4 amplification and overexpression .
13		This variable responsiveness to LEE011 was recapitulated in xenograft models of CDK4-amplified and nonamplified fusion-positive RMS .
14		CONCLUSIONS :
15		Our data demonstrate that CDK4 is necessary but overexpression is not sufficient for RB-E2F -mediated G1-phase cell -cycle progression , proliferation , and transformation in fusion-positive RMS .
16		Our studies indicate that LEE011 is active in the setting of fusion-positive RMS and suggest that low CDK4-expressing fusion-positive tumors may be particularly susceptible to CDK4/6 inhibition .

PMID: 25803170 (Cell)   Terms:
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0		MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition .
1		CDK4 inhibitors ( CDK4i ) earned Breakthrough Therapy Designation from the FDA last year and are entering phase III clinical trials in several cancers .
2		However , not all tumors respond favorably to these drugs .
3		CDK4 activity is critical for progression through G1 phase and into the mitotic cell cycle .
4		Inhibiting this kinase induces Rb-positive cells to exit the cell cycle into either a quiescent or senescent state .
5		In this report , using well-differentiated and dedifferentiated liposarcoma ( WD/DDLS ) cell lines , we show that the proteolytic turnover of MDM2 is required for CDK4i -induced senescence .
6		Failure to reduce MDM2 does not prevent CDK4i -induced withdrawal from the cell cycle but the cells remain in a reversible quiescent state .
7		Reducing MDM2 in these cells drives them into the more stable senescent state .
8		CDK4i -induced senescence associated with loss of MDM2 is also observed in some breast cancer , lung cancer and glioma cell lines indicating that this is not limited to WD/DDLS cells in which MDM2 is overexpressed or in cells that contain wild type p53 .
9		MDM2 turnover depends on its E3 ligase activity and expression of ATRX .
10	✓	Interestingly , in seven patients the changes in MDM2 expression were correlated with outcome .	GE-ASS-RO
11		These insights identify MDM2 and ATRX as new regulators controlling geroconversion , the process by which quiescent cells become senescent , and this insight may be exploited to improve the activity of CDK4i in cancer therapy .

PMID: 25765001 (Patient)   Terms: retrospective, case, control
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0	✓	Association of FPGS genetic polymorphisms with primary retroperitoneal liposarcoma .	GM-ASS-DS
1		Primary retroperitoneal liposarcoma is generally regarded as a genetic disorder .
2		We have retrospectively genotyped 8 single nucleotide polymorphisms ( SNPs ) in 6 candidate genes ( MDM2 , CDK4 , CDC27 , FPGS , IGFN1 , and PRAMEF13 ) in 138 patients and 131 healthy control subjects to evaluate the effects of genetic factors on individual susceptibility to primary retroperitoneal liposarcoma in Chinese population .
3	Μ	Three SNPs ( rs2870820 , rs1695147 , rs3730536 ) of MDM2 showed significant differences in single - loci genotypes and allele frequencies between case and control groups ( p <005 ) .
4		The minor allele G of SNP rs10760502 in FPGS ( folylpolyglutamate synthase ) gene was significantly associated with increased risk for primary retroperitoneal liposarcoma , compared with major allele A .
5		Our data suggest that FPGS variant in Chinese population may affect individual susceptibility to primary retroperitoneal liposarcoma .

PMID: 25690861 (Patient)   Terms:
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0		Dedifferentiated Liposarcoma of the Gastroesophageal Junction .
1		Liposarcoma is one of the most common sarcomas in adults , but very rarely presents as a primary in the upper gastrointestinal system .
2		Herein , we present a 71-year-old male patient who underwent wedge excision biopsy twice and then fine needle aspiration and total gastrectomy for a recurrent gastroeosophageal junction mass .
3		In microscopic sections , both well-differentiated and dedifferentiated components were seen .
4		Tumor cells were positive for MDM2 , CDK4 and negative for CD117 , DOG1 , CD34 , SMA , Desmin , S-100 , HMB45 , SOX10 , AE1/AE3 , CAM5.2 , CK18 .
5	Μ	Fluorescence in situ hybridization ( FISH ) was performed and MDM2 gene ( 12q15 ) amplification was detected .
6		According to these findings , a diagnosis of dedifferentiated liposarcoma was supported .
7		We believe this is the first reported case of dedifferentiated liposarcoma of the gastroesophageal junction .

PMID: 25679065 (Patient)   Terms:
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0		Detection of MDM2/CDK4 amplification in lipomatous soft tissue tumors from formalin-fixed , paraffin-embedded tissue : comparison of multiplex ligation-dependent probe amplification ( MLPA ) and fluorescence in situ hybridization ( FISH ) .
1		In this study , the detection of MDM2 and CDK4 amplification was evaluated in lipomatous soft tissue tumors using multiplex ligation-dependent probe amplification ( MLPA ) , a PCR-based technique , in comparison with fluorescence in situ hybridization ( FISH ) .
2		These 2 techniques were evaluated in a series of 77 formalin-fixed , paraffin-embedded lipomatous tumors ( 27 benign adipose tumors , 28 atypical lipomatous tumors/well-differentiated liposarcomas , 18 dedifferentiated liposarcomas , and 4 pleomorphic liposarcomas ) .
3	Μ	Using MLPA , with a cut-off ratio of >2 , 36/71 samples ( 22 atypical lipomatous tumors/well-differentiated liposarcomas , and 14 dedifferentiated liposarcomas ) showed MDM2 and CDK4 amplification .
4		Using FISH as gold standard , MLPA showed a sensitivity of 90% ( 36/40 ) and a specificity of 100% ( 31/31 ) in detecting amplification of MDM2 and CDK4 in lipomatous soft tissue tumors .
5		In case of high-level amplification ( MDM2-CDK4/CEP12 ratio >5 ) , concordance was 100% .
6	Μ	Four cases of atypical lipomatous tumor/well-differentiated liposarcoma ( 4/26 , 15% ) with a low MDM2 and CDK4 amplification level ( MDM2-CDK4/CEP12 ratio ranging between 2 and 25 ) detected by FISH showed no amplification by MLPA , although gain of MDM2 and CDK4 ( ratios ranging between 16 and 19 ) was seen with MLPA .
7	Μ	No amplification was detected in benign lipomatous tumors and pleomorphic liposarcomas .
8		Furthermore , there was a very high concordance between the ratios obtained by FISH and MLPA .
9		In conclusion , MLPA proves to be an appropriate and straightforward technique for screening MDM2/CDK4 amplification in lipomatous tumors , especially when a correct cut-off value and reference samples are chosen , and could be considered a good alternative to FISH to determine MDM2 and CDK4 amplification in liposarcomas .
10		Moreover , because MLPA , as a multiplex technique , allows simultaneous detection of multiple chromosomal changes of interest , it could be in the future a very reliable and fast molecular analysis on paraffin-embedded material to test for other diagnostically , prognostically , or therapeutically relevant genomic mutations in lipomatous tumors .

PMID: 25650275 (None)   Terms:
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0		Extensive lipoma-like changes of myxoid liposarcoma : morphologic , immunohistochemical , and molecular cytogenetic analyses .
1		Myxoid liposarcomas ( MLSs ) with extensive lipoma-like changes ( MLSLC ) are rare , and it is often difficult to distinguish them from well-differentiated liposarcoma ( LS ) /dedifferentiated LS (WDLS/DDLS) with myxoid changes .
2		For the characterization of these neoplasms , we studied 8 MLSLCs , 11 ordinary MLSs , 4 WDLSs , and 6 DDLSs .
3		Cytogenetically , MLSLC and ordinary MLS were characterized by t ( 12 ; 16 ) ( q13 ; p11 ) and FUS-DDIT3 fusion gene , whereas WDLS/DDLS lacked the fusion gene but possessed giant marker/ring chromosomes .
4		Both lipoma-like and myxoid components of the same MLSLC exhibited the identical FUS-DDIT3 , as confirmed by fluorescence in situ hybridization ( FISH ) and reverse transcription polymerase chain reaction ( RT-PCR ) .
5		Immunohistochemically , MDM2 and CDK4 were positive in WDLS/DDLS but negative in MLSLC and ordinary MLS .
6		PPARgamma , C/EBPalpha , adipophilin , and perilipin were found in each type of LS .
7	Μ	Adipophilin was expressed chiefly in tiny fat droplets of immature lipoblasts , whereas perilipin showed a strong positive staining in large fat vacuoles of signet ring and multivacuolated lipoblasts .
8		The Ki-67 labeling index was lower in the lipoma-like component of MLSLC when compared with the myxoid component of the same tumors as well as ordinary MLS ( p <0001 ) .
9		When compared with ordinary MLS , MLSLC may be less aggressive in clinical behavior ( rare recurrences or metastases ) after a wide surgical excision .
10		In conclusion , the distinction between MLSLC and WDLS/DDLS is important , because of the differences of molecular cytogenetic features as well as clinical behaviors between these distinct sarcomas presenting similar morphologic features .
11		In addition , the combined immunohistochemical detection of adipophilin and perilipin may provide a useful ancillary tool for identification of lipoblastic cells in soft tissue sarcomas .

PMID: 25594652 (Patient)   Terms:
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0		Dedifferentiated liposarcoma involving the spleen and splenic hilum : a report of a case with a rare growth pattern .
1		We present a rare case of dedifferentiated liposarcoma confined to the spleen and splenic hilum .
2		An 81-year-old man was referred to our hospital with a large asymptomatic splenic tumor .
3		The patient underwent splenectomy , and the adipose tissue surrounding the splenic hilum was also resected .
4		Microscopically , the tumor mainly consisted of high-grade spindle cells similar to those seen in undifferentiated pleomorphic liposarcoma .
5		In the splenic hilum , scattered atypical cells were detected in the sclerosing component and adipose tissue .
6		Immunohistochemically , both the spindle cells in the spleen and the atypical cells in the splenic hilum were positive for MDM2 and CDK4 .
7		The histopathologic diagnosis was dedifferentiated liposarcoma derived from an atypical lipomatous tumor/well-differentiated liposarcoma of the adipose tissue in the splenic hilum with extension into the spleen .
8		Dedifferentiated liposarcoma in the spleen and splenic hilum should be considered as a differential diagnosis of splenic tumors .

PMID: 25554652 (Patient)   Terms:
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0		Malignant solitary fibrous tumor with high-grade nuclear atypia : an alternate entity for the undetermined tumor group .
1		Recently , a novel fusion transcript , NAB2-STAT6 , and its variants have also been reported to be specific diagnostic markers for solitary fibrous tumors ( SFTs ) .
2		In this study , we validated the existence of the NAB2-STAT6 fusion gene in SFTs and examined its relation with the pathological features .
3		Frozen samples from 9 tumors were assessed for fusion gene .
4	Μ	The detected fusion genes exhibited large intron sequences and the insertion of unknown and previously unreported sequences .
5	Μ	The fusion genes were not detected in the 2 malignant cases with high-grade nuclear atypia , nuclear pleomorphism and necrosis , that was confirmed by multiplex PCR method .
6	Μ	In addition , 1 of the 2 NAB2-STAT6 fusion gene -negative tumors showed amplification of the MDM2 and CDK4 genes .
7		It was suggested that a certain proportion of tumors previously diagnosed as malignant SFTs with high-grade nuclear atypia lacking NAB2-STAT6 should be categorized into a special subtype of SFT , which is genetically different from conventional SFTs , and which cannot be apparently distinguished from dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma .

PMID: 25550570 (Patient)   Terms:
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0		Immunohistochemical , cytogenetic , and molecular cytogenetic characterization of both components of a dedifferentiated liposarcoma : implications for histogenesis .
1		Dedifferentiated liposarcoma ( DDLS ) is a malignant adipocytic tumor showing transition from an atypical lipomatous tumor ( ALT ) /well-differentiated liposarcoma ( WDLS ) to a non-lipogenic sarcoma of variable histological grades .
2		We present the immunohistochemical , cytogenetic , and molecular cytogenetic findings of DDLS arising in the right chest wall of a 76-year-old man .
3		Magnetic resonance imaging exhibited a large mass composed of two components with heterogeneous signal intensities , suggesting the coexistence of a fatty area and another soft tissue component .
4		The grossly heterogeneous mass was histologically composed of an ALT/WDLS component transitioning abruptly into a dedifferentiated component .
5		Immunohistochemistry was positive for murine double-minute 2 ( MDM2 ) , cyclin-dependent kinase 4 ( CDK4 ) , and p16 in both components , although a more strong and diffuse staining was found in the dedifferentiated area .
6		The MIB-1 labeling index was extremely higher in the dedifferentiated area compared to the ALT/WDLS area .
7		Cytogenetic analysis of the ALT/WDLS component revealed the following karyotype : 46 , X , -Y , +r .
8		Notably , cytogenetic analysis of the dedifferentiated component revealed a similar but more complex karyotype .
9		Spectral karyotyping demonstrated that the ring chromosome was entirely composed of material from chromosome 12 .
10	Μ	Interphase fluorescence in situ hybridization analysis revealed amplification of MDM2 and CDK4 in both components .
11		These findings suggest that multiple abnormal clones derived from a single precursor cell would be present in DDLS , with one or more containing supernumerary rings or giant marker chromosomes .

PMID: 25126005 (Patient)   Terms:
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0		Challenging dedifferentiated liposarcoma identified by MDM2-amplification , a report of two cases .
1		BACKGROUND :
2		Liposarcoma is the most frequent soft tissue sarcoma .
3		Well differentiated liposarcoma may progress into dedifferentiated liposarcoma with pleomorphic histology .
4		A minority additionally features myogenic , osteo - or chondrosarcomatous heterologous differentiation .
5		Genomic amplification of the Mouse double minute 2 homolog ( MDM2 ) locus is characteristic for well differentiated and dedifferentiated liposarcomas .
6		Detection of MDM2 amplification may supplement histopathology and aid to distinguish liposarcoma from other soft tissue neoplasia .
7		CASE PRESENTATION :
8		Here we present two cases of dedifferentiated liposarcoma with challenging presentation .
9		Case 1 features a myogenic component .
10	Μ	As the tumour infiltrated the abdominal muscles and showed immunohistochemical expression of myogenic proteins , rhabdomyosarcoma had to be ruled out .
11		Case 2 has an osteosarcomatous component resembling extraosseous osteosarcoma .
12		The MDM2 status was determined in both cases and helped making the correct diagnosis .
13		Overexpression of MDM2 and co-overexpression of Cyclin -dependent kinase 4 is demonstrated by immunohistochemistry .
14		The underlying MDM2 amplification is shown by fluorescence in situ hybridisation .
15		Since low grade osteosarcoma may also harbour MDM2 amplification it is emphasised that the amplification has to be present in the lipomatous parts of the tumour to distinguish liposarcoma from extraosseous osteosarcoma .
16		CONCLUSIONS :
17		The two cases exemplify challenges in the diagnoses of dedifferentiated liposarcoma .
18		Liposarcoma often has pleomorphic histology and additionally may feature heterologous components that mimic other soft tissue neoplasms .
19		Amplification of MDM2 is characteristic for well differentiated and dedifferentiated liposarcomas .
20		Determination of the MDM2 status by in situ hybridisation may assist histopathology and help to rule out differential diagnoses .

PMID: 25121597 (None)   Terms:
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0		CDK4 amplification predicts recurrence of well-differentiated liposarcoma of the abdomen .
1		BACKGROUND :
2		The absence of CDK4 amplification in liposarcomas is associated with favorable prognosis .
3		We aimed to identify the factors associated with tumor recurrence in patients with well-differentiated ( WD ) and dedifferentiated ( DD ) liposarcomas .
4		METHODS :
5		From 2000 to 2010 , surgical resections for 101 WD and DD liposarcomas were performed .
6		Cases in which complete surgical resections with curative intent were carried out were selected .
7		MDM2 and CDK4 gene amplification were analyzed by quantitative real-time polymerase chain reaction ( Q-PCR ) .
8		RESULTS :
9		There were 31 WD and 17 DD liposarcomas .
10		Locoregional recurrence was observed in 11 WD and 3 DD liposarcomas .
11		WD liposarcomas showed better patient survival compared to DD liposarcomas ( P<005 ) .
12	Μ	Q-PCR analysis of the liposarcomas revealed the presence of CDK4 amplification in 44 cases ( 917% ) and MDM2 amplification in 46 cases ( 958% ) .
13	✓	WD liposarcomas with recurrence after surgical resection had significantly higher levels of CDK4 amplification compared to those without recurrence ( P = 0041 ) .	GM-ASS-DS
14	✓	High level of CDK4 amplification ( cases with CDK4 amplification higher than the median 754 ) was associated with poor recurrence-free survival compared to low CDK4 amplification in both univariate ( P = 0012 ) and multivariate analyses ( P = 0020 ) .	GM-ASS-RO
15		CONCLUSIONS :
16		Level of CDK4 amplification determined by Q-PCR was associated with the recurrence of WD liposarcomas after surgical resection .

PMID: 25059573 (Patient)   Terms:
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0		Prognostic relevance of Federation Nationale des Centres de Lutte Contre le Cancer grade and MDM2 amplification levels in dedifferentiated liposarcoma : a study of 50 cases .
1		Dedifferentiated liposarcoma represents a form of liposarcoma composed of a non-lipogenic sarcoma associated with well-differentiated liposarcoma .
2		The prognostic significance of histological grading of the dedifferentiated component remains to be elucidated due to vague grading criteria employed in previous studies .
3		Molecular markers of tumor behavior , including amplification levels of murine double minute-2 ( MDM2 ) and cyclin-dependent kinase -4 ( CDK4 ) genes , have been explored in a limited number of cases .
4		Here we investigate whether 'Federation Nationale des Centres de Lutte Contre le Cancer' ( FNCLCC ) grade and MDM2 gene amplification levels have prognostic value in dedifferentiated liposarcoma in terms of local recurrence and disease-specific survival .
5		Fifty cases were retrieved , reviewed and FNCLCC grade was scored for the dedifferentiated component .
6		Testing for MDM2 gene amplification was performed by fluorescence in situ hybridization .
7		Amplification was categorized as high level ( >/ = 20 copies ) and as low level ( <20 copies ) .
8		Follow-up data was obtained through chart review .
9		Log-rank test and Cox proportional hazard models were used to determine the effect of grade and level of MDM2 amplification on outcomes .
10		Our series includes 50 patients ( male n = 28 , female n = 22 ) with an average age of 63 years ( range , 28-88 ) and a median follow-up of 28 months ( range , 2-120 ) .
11		Tumors were graded as grade 1 ( 6% ) , grade 2 ( 58% ) , and grade 3 ( 36% ) .
12		When adjusted for age , sex , site , tumor size , and margin status , grade 3 patients had a higher recurrence rate than grades 1 and 2 ( HR = 2.07 , 95% CI : 1.24 , 7.62 ; P = 0.015 ) .
13		Patients with high-level MDM2 amplification had higher recurrence rate on univariate analysis ( P = 0028 ) , but not on multivariate analysis ( HR = 1.69 , 95% CI : 0.73 , 3.94 ; P = 0.221 ) .
14		FNCLCC grade 3 dedifferentiation confers a worse prognosis in dedifferentiated liposarcoma in terms of local recurrence .
15		MDM2 amplification level remains a useful diagnostic tool in dedifferentiated liposarcoma , but has no prognostic value in terms of local recurrence .

PMID: 25028469 (Cell)   Terms: in vivo, in vitro, xenograft, tumor xenografts, mice bearing human liposarcoma xenografts, mice, mouse
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0		Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo .
1		Well-differentiated/dedifferentiated liposarcomas ( WD/DDLPS ) are among the most common subtypes of soft tissue sarcomas .
2		Conventional systemic chemotherapy has limited efficacy and novel therapeutic strategies are needed to achieve better outcomes for patients .
3		The cyclin-dependent kinase 4 ( CDK4 ) gene is highly amplified in more than 95% of WD/DDLPS .
4		In this study , we explored the role of CDK4 and the effects of NVP-LEE011 ( LEE011 ) , a novel selective inhibitor of CDK4/CDK6 , on a panel of human liposarcoma cell lines and primary tumor xenografts .
5		We found that both CDK4 knockdown by siRNA and inhibition by LEE011 diminished retinoblastoma ( RB ) phosphorylation and dramatically decreased liposarcoma cell growth .
6		Cell -cycle analysis demonstrated arrest at G0-G1 .
7		siRNA -mediated knockdown of RB rescued the inhibitory effects of LEE011 , demonstrating that LEE011 decreased proliferation through RB .
8		Oral administration of LEE011 to mice bearing human liposarcoma xenografts resulted in approximately 50% reduction in tumor ( 18 ) F-fluorodeoxyglucose uptake with decreased tumor biomarkers , including RB phosphorylation and bromodeoxyuridine incorporation in vivo .
9		Continued treatment inhibited tumor growth or induced regression without detrimental effects on mouse weight .
10		After prolonged continuous dosing , reestablishment of RB phosphorylation and cell -cycle progression was noted .
11		These findings validate the critical role of CDK4 in maintaining liposarcoma proliferation through its ability to inactivate RB function , and suggest its potential function in the regulation of survival and metabolism of liposarcoma , supporting the rationale for clinical development of LEE011 for the treatment of WD/DDLPS .

PMID: 24965044 (None)   Terms:
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0		Real-time polymerase chain reaction analysis of MDM2 and CDK4 expression using total RNA from core-needle biopsies is useful for diagnosing adipocytic tumors .
1		BACKGROUND :
2		Diagnosing adipocytic tumors can be challenging because it is often difficult to morphologically distinguish between benign , intermediate and malignant adipocytic tumors , and other sarcomas that are histologically similar .
3	Μ	Recently , a number of tumor-specific chromosome translocations and associated fusion genes have been identified in adipocytic tumors and atypical lipomatous tumors/well-differentiated liposarcomas ( ALT/WDL ) , which have a supernumerary ring and/or giant chromosome marker with amplified sequences of the MDM2 and CDK4 genes .
4		The purpose of this study was to investigate whether quantitative real-time polymerase chain reaction ( PCR ) could be used to amplify MDM2 and CDK4 from total RNA samples obtained from core-needle biopsy sections for the diagnosis of ALT/WDL .
5		METHODS :
6	Μ	A series of lipoma ( n = 124 ) and ALT/WDL ( n = 44 ) cases were analyzed for cytogenetic analysis and lipoma fusion genes , as well as for MDM2 and CDK4 expression by real-time PCR .
7		Moreover , the expression of MDM2 and CDK4 in whole tissue sections was compared with that in core-needle biopsy sections of the same tumor in order to determine whether real-time PCR could be used to distinguish ALT/WDL from lipoma at the preoperative stage .
8		RESULTS :
9		In whole tissue sections , the medians for MDM2 and CDK4 expression in ALT/WDL were higher than those in the lipomas ( P <005 ) .
10		Moreover , karyotype subdivisions with rings and/or giant chromosomes had higher MDM2 and CDK4 expression levels compared to karyotypes with 12q13-15 rearrangements , other abnormal karyotypes , and normal karyotypes ( P <005 ) .
11		On the other hand , MDM2 and CDK4 expression levels in core-needle biopsy sections were similar to those in whole - tissue sections ( MDM2 : P = 0.6 , CDK4 : P = 0.8 , Wilcoxon signed-rank test ) .
12		CONCLUSION :
13		Quantitative real-time PCR of total RNA can be used to evaluate the MDM2 and CDK4 expression levels in core-needle biopsies and may be useful for distinguishing ALT/WDL from adipocytic tumors .
14		Thus , total RNA from core-needle biopsy sections may have potential as a routine diagnostic tool for other tumors where gene overexpression is a feature of the tumor .

PMID: 24922675 (None)   Terms:
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0		Atypical lipomatous tumor with structural rearrangements involving chromosomes 3 and 8 .
1		Atypical lipomatous tumor ( ALT ) is an intermediate ( locally aggressive ) mesenchymal neoplasm with the potential to dedifferentiate to higher grades over time .
2		It is cytogenetically characterized by the presence of one or more supernumerary ring and giant marker chromosomes .
3		These abnormal chromosomes invariably contain amplified sequences derived from the 12q14-15 region .
4		We describe a unique cytogenetic finding of ALT arising in the right lower back of a 42-year-old man .
5		Magnetic resonance imaging demonstrated a predominantly fatty mass with irregularly thickened , linear , swirled , and nodular septa .
6		Contrast-enhanced fat-suppressed T1-weighted images showed significant enhancement of the non-adipose areas .
7		A sub-extensive resection was performed .
8		Histologically , the tumor consisted predominantly of mature fat cells with atypical stromal cells and multivacuolated lipoblasts .
9		Immunohistochemically , the tumor cells were positive for p16 ( diffuse and strong signal ) and cyclin -dependent kinase -4 ( focal and weak signal ) but negative for murine double-minute 2 .
10		Cytogenetic analysis displayed a t ( 3 ; 8 ) ( q28 ; q13 ) translocation as the sole anomaly or concomitant with a few other numerical and structural alterations .
11		There has been no evidence of local recurrence two months after surgery .
12		To the best of our knowledge , this is the first case of ALT with structural aberrations involving chromosomes 3 and 8 , associated with an absence of 12q rearrangements .

PMID: 24788530 (Patient)   Terms:
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0		Immunohistochemical analysis of expressions of RB1 , CDK4 , HSP90 , cPLA2G4A , and CHMP2B is helpful in distinction between myxofibrosarcoma and myxoid liposarcoma .
1		The role and diagnostic efficacy of gene and protein products RB1 , CDK4 , CHMP2B , HSP90 , and cPLA2G4A , all previously shown to be involved in tumor genesis and cell proliferation , were examined by immunohistochemical techniques in 32 cases of myxofibrosarcomas and 29 myxoid liposarcomas ( all diagnosis had been confirmed by fluorescence in situ hybridization ) .
2		HSP90 demonstrated strong nuclear and cytoplasmic positivity in all myxoid liposarcoma cases , while only 4 myxofibrosarcomas showed scattered HSP90 positivity .
3		All but 4 cases of myxofibrosarcoma displayed strong positivity for cPLA2G4A , while only 2 myxoid liposarcoma cases were cPLA2G4A positive and both were CHMP2B negative .
4		Overexpression of both cPLA2G4A and CHMP2B also suggested higher tumor grade .
5		In conclusion , HSP90 and cPLA2G4A immunohistochemical stains are useful markers to distinguish myxofibrosarcoma from myxoid liposarcoma .

PMID: 24659226 (None)   Terms:
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0		Atypical spindle cell lipoma : a clinicopathologic , immunohistochemical , and molecular study emphasizing its relationship to classical spindle cell lipoma .
1	Μ	We studied a series of spindle cell lipomas arising in atypical sites and showing unusual morphologic features ( which we called atypical spindle cell lipoma ) to assess if these lesions have the same chromosomal alterations as classical spindle cell lipoma but different from those found in atypical lipomatous tumor/well-differentiated liposarcoma .
2		We investigated alterations of different genes in the 13q14 region and the amplification status of the MDM2 and CDK4 genes at 12q14-15 by multiplex ligation-dependent probe amplification ( MLPA ) and fluorescence in situ hybridization ( FISH ) analysis .
3	Μ	In the atypical spindle cell lipomas , MLPA revealed deletions in the two nearest flanking genes of RB1 ( ITM2B and RCBTB2 ) and in multiple important exons of RB1 .
4	Μ	In contrast , in classical spindle cell lipomas , a less complex loss of RB1 exons was found but no deletion of ITM2B and RCBTB2 .
5	Μ	Moreover , MLPA identified a deletion of the DLEU1 gene , a finding which has not been reported earlier .
6		We propose an immunohistochemical panel for lipomatous tumors which comprises of MDM2 , CDK4 , p16 , Rb , which we have found useful in discriminating between atypical or classical spindle cell lipomas and other adipocytic neoplasms , especially atypical lipomatous tumor/well-differentiated liposarcoma .
7		Our findings strengthen the link between atypical spindle cell lipoma and classical spindle cell lipoma , and differentiate them from atypical lipomatous tumor/well-differentiated liposarcoma .

PMID: 24588545 (Patient)   Terms:
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0		Absence of chromosomal abnormalities in herniated orbital fat .
1		AIMS :
2		Lipomatous tumours of the orbit are rare , and can sometimes be difficult to characterize .
3		Herniated orbital fat is thought to be a reactive process , but its presentation can mimic a lipomatous tumour such as an atypical lipomatous tumour or spindle cell/pleomorphic lipoma .
4		Genetic studies to determine if it is indeed a reactive process rather than an adipocytic neoplasm have not been performed .
5		METHODS AND RESULTS :
6		Four samples of herniated orbital fat were reviewed clinically , histopathologically and immunohistochemically .
7		Array comparative genomic hybridization ( aCGH ) was used to search for genome -wide copy number alterations within the tumours .
8		Histological evaluation revealed that all four tumours contained collections of adipocytes surrounded by fibrous septae .
9		Lochkern cells and floret-like multinucleated giant cells were present , consistent with herniated orbital fat .
10		CD34 was positive in all tumours .
11		Staining for MDM2 and CDK4 was negative .
12	Μ	ACGH analysis demonstrated no copy number alterations .
13		CONCLUSIONS :
14		Herniated orbital fat may share some histopathological features with lipoma and atypical lipomatous tumour , but the absence of copy number gains or losses is consistent with the impression that herniated orbital fat is a reactive process .
15		Genetic analysis may be another method to help differentiate herniated orbital fat from a lipomatous orbital tumour when the diagnosis is in question .

PMID: 24558126 (Patient)   Terms:
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0		Retroperitoneal liposarcoma with colonic involvement : a case report .
1		A 72-year-old male visited a local hospital on presentation of melena .
2		Colonoscopy revealed a protruded lesion in the ascending colon , and computed tomography revealed a 20 cm retroperitoneal tumor .
3		Biopsy failed to provide a definitive diagnosis of the colonic lesion .
4		He was diagnosed as having a retroperitoneal liposarcoma and an ascending colon tumor using computed tomography , and referred to our hospital .
5		Biopsy of the ascending colon lesion showed spindle cells with fibrosis .
6		On immunohistochemical staining , tumor cells were positive for cyclin -dependent kinase 4 and murine double minute 2 , and the lesion was diagnosed as a well-differentiated or dedifferentiated liposarcoma .
7		The retroperitoneal liposarcoma , which had infiltrated the ascending colon , was resected along with the right colon and the right kidney .
8		Macroscopically , the tumor had infiltrated the ascending colon , forming a multinodular solid mass in the lumen and the right kidney .
9		Microscopic finding of the main tumor revealed a well-differentiated liposarcoma , and that of the colonic lesion revealed a dedifferentiated liposarcoma with nuclei of different sizes and shapes and increased spindle cell morphology .
10		The right kidney and ureter were surrounded by tumor cells but were not infiltrated , and there was no lymph node involvement .
11		The diagnosis of retroperitoneal liposarcoma is often difficult because symptoms appear only after the tumor becomes very large .
12		Some retroperitoneal liposarcomas are found on computed tomography by chance .
13		The clinical course of this case was very rare because of the presentation of melena as the first symptom and the detection of an invasive mass in the ascending colon using colonoscopy .

PMID: 24487315 (Patient)   Terms:
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0		Detection of MDM2/CDK4 Amplification in Lipomatous Soft Tissue Tumors From Formalin-fixed , Paraffin-embedded Tissue : Comparison of Multiplex Ligation-dependent Probe Amplification ( MLPA ) and Fluorescence In Situ Hybridization ( FISH ) .
1		In this study , the detection of MDM2 and CDK4 amplification was evaluated in lipomatous soft tissue tumors using multiplex ligation-dependent probe amplification ( MLPA ) , a PCR-based technique , in comparison with fluorescence in situ hybridization ( FISH ) .
2		These 2 techniques were evaluated in a series of 77 formalin-fixed , paraffin-embedded lipomatous tumors ( 27 benign adipose tumors , 28 atypical lipomatous tumors/well-differentiated liposarcomas , 18 dedifferentiated liposarcomas , and 4 pleomorphic liposarcomas ) .
3	Μ	Using MLPA , with a cut-off ratio of >2 , 36/71 samples ( 22 atypical lipomatous tumors/well-differentiated liposarcomas , and 14 dedifferentiated liposarcomas ) showed MDM2 and CDK4 amplification .
4		Using FISH as gold standard , MLPA showed a sensitivity of 90% ( 36/40 ) and a specificity of 100% ( 31/31 ) in detecting amplification of MDM2 and CDK4 in lipomatous soft tissue tumors .
5		In case of high-level amplification ( MDM2-CDK4/CEP12 ratio >5 ) , concordance was 100% .
6	Μ	Four cases of atypical lipomatous tumor/well-differentiated liposarcoma ( 4/26 , 15% ) with a low MDM2 and CDK4 amplification level ( MDM2-CDK4/CEP12 ratio ranging between 2 and 25 ) detected by FISH showed no amplification by MLPA , although gain of MDM2 and CDK4 ( ratios ranging between 16 and 19 ) was seen with MLPA .
7	Μ	No amplification was detected in benign lipomatous tumors and pleomorphic liposarcomas .
8		Furthermore , there was a very high concordance between the ratios obtained by FISH and MLPA .
9		In conclusion , MLPA proves to be an appropriate and straightforward technique for screening MDM2/CDK4 amplification in lipomatous tumors , especially when a correct cut-off value and reference samples are chosen , and could be considered a good alternative to FISH to determine MDM2 and CDK4 amplification in liposarcomas .
10		Moreover , because MLPA , as a multiplex technique , allows simultaneous detection of multiple chromosomal changes of interest , it could be in the future a very reliable and fast molecular analysis on paraffin-embedded material to test for other diagnostically , prognostically , or therapeutically relevant genomic mutations in lipomatous tumors .

PMID: 24457460 (Patient)   Terms: case, control
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0		STAT6 is amplified in a subset of dedifferentiated liposarcoma .
1		A recurrent intrachromosomal rearrangement on chromosome 12q in solitary fibrous tumor leads to the formation of a NAB2-STAT6 fusion oncogene .
2	Μ	As a result , nuclear expression of the cytoplasmic transcription factor STAT6 is found in solitary fibrous tumor and serves as a useful diagnostic marker .
3		STAT6 is located in 12q13 , a region containing well-characterized oncogenes that are commonly amplified in dedifferentiated liposarcoma ; we have previously reported that STAT6 is expressed in a subset of dedifferentiated liposarcoma .
4		The aim of this study was to determine the frequency of STAT6 expression in dedifferentiated liposarcoma and the underlying genetic mechanism .
5		STAT6 protein expression was analyzed by immunohistochemistry in a well-characterized series of 35 previously unpublished cases of dedifferentiated liposarcoma , all with nuclear MDM2 and/or CDK4 expression by immunohistochemistry and/or cytogenetic features of dedifferentiated liposarcoma .
6		FISH for STAT6 was performed in all cases with STAT6 expression , and a subset of control cases without STAT6 expression .
7	Μ	In total 4/35 cases ( 11% ) showed STAT6 expression ( three with multifocal staining of moderate to strong intensity and one with weak focal staining ) .
8	Μ	FISH demonstrated amplification of STAT6 in all cases positive for STAT6 by immunohistochemistry ; in contrast , FISH performed on four STAT6-negative dedifferentiated liposarcomas demonstrated no STAT6 amplification ( P = 00286 ) .
9		Of the four STAT6 amplified cases , three patients were male and one was female , ranging in age from 51 to 76 years .
10		Tumors were located in the mediastinum ( n = 2 ) , paratesticular soft tissue ( n = 1 ) , and perirenal soft tissue ( n = 1 ) .
11		Three patients received pre-operative chemotherapy +/- radiation therapy .
12		In conclusion , STAT6 is amplified in a subset of dedifferentiated liposarcoma , resulting in STAT6 protein expression that can be detected by immunohistochemistry and may be a potential pitfall in the differential diagnosis of dedifferentiated liposarcoma and solitary fibrous tumor .
13		These findings suggest a role for STAT6 -mediated transcriptional activity in some cases of dedifferentiated liposarcoma and highlight the genomic complexity and heterogeneity of dedifferentiated liposarcoma .

PMID: 24397249 (None)   Terms: this review, mouse
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0		Current management options for liposarcoma and challenges for the future .
1		Liposarcoma ( LS ) represents one of the most common soft tissue sarcomas .
2		There are three major subtypes , namely , well/dedifferentiated , myxoid/round cell and pleomorphic LS .
3		In general , LS is known to be a relatively chemo-resistant sarcoma subtype with the exception of the myxoid variant .
4		Conventional chemotherapy with doxorubicin and ifosfamide represents the mainstay of systemic treatment in the first line .
5		Other active cytotoxic agents include gemcitabine and docetaxel and the marine-derived compounds trabectedin .
6		Recent progress in molecular diagnostics of each single LS subtype has improved the knowledge of the molecular characteristics and has led to two recent treatment targets : the amplification of mouse double minute 2 homolog and cyclin -dependent kinase -4 in well - and dedifferentiated LS .
7		Thus far , only early-phase trials are reported and no new drugs have been introduced in daily clinical practice .
8		The focus of this review is on current systemic treatment options , including novel strategies .

PMID: 24227706 (None)   Terms: retrospective
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0		Dedifferentiated liposarcoma and pleomorphic liposarcoma : a comparative study of cytomorphology and MDM2/CDK4 expression on fine-needle aspiration .
1		BACKGROUND :
2		Dedifferentiated liposarcoma ( DDLPS ) and pleomorphic liposarcoma ( PLPS ) are distinct high-grade liposarcomas .
3		DDLPS is a nonlipogenic sarcoma characterized by amplification of MDM2 and CDK4 .
4		PLPS is a high-grade sarcoma containing lipoblasts , characterized by a complex karyotype and a more aggressive clinical course .
5		Rarely , DDLPS shows lipogenic differentiation , mimicking PLPS .
6		The cytomorphologic features of DDLPS and PLPS and the utility of ancillary studies have not been systemically analyzed .
7		METHODS :
8		Cytologic preparations of 25 DDLPS and 13 PLPS , all histologically confirmed , were retrospectively reviewed along with clinical and cytogenetic data .
9		Sample cellularity , vascular architecture , background material , predominant cell morphology , quality of the cytoplasm , and nuclear pleomorphism were compared for both tumor types .
10		Immunohistochemistry for MDM2 and CDK4 was performed on cell blocks and/or core needle biopsies .
11		RESULTS :
12		Fine-needle aspirate smears from both DDLPS and PLPS were variably cellular , composed of cellular clusters and noncohesive cells .
13		Abundant myxoid stroma was present in approximately 25% of DDLPS and PLPS cases , whereas branching curvilinear vessels were more common in DDLPS than in PLPS ( 7 of 25 versus 2 of 13 ) .
14		Tumors were composed of predominantly spindled ( 18 of 25 DDLPS versus 3 of 13 PLPS ) or epithelioid cells ( 7 of 25 DDLPS versus 6 of 13 PLPS ) .
15		Pleomorphic cells were predominant in 3 PLPS , and were frequent in both ( 13 of 25 DDLPS versus 10 of 13 PLPS ) .
16		The cytoplasm was mostly fibrillary and often vacuolated in both entities .
17		Other features included necrosis , mitoses , and a prominent inflammatory infiltrate .
18		The main cytologic differences were the presence of marked pleomorphism , abundant lipoblasts , and cells with microvacuolated cytoplasm in most PLPS .
19		A total of 24 ( 96% ) and 20 ( 80% ) cases of DDLPS expressed MDM2 and CDK4 , respectively , whereas none of the PLPS expressed both markers .
20	Μ	Six DDLPS tested showed ring or giant marker chromosomes and/or MDM2 amplification by fluorescence in situ hybridization ; 2 PLPS had complex karyotypes .
21		CONCLUSIONS :
22		DDLPS and PLPS exhibit variable and occasionally overlapping cytologic features .
23		The presence of lipoblasts , cells with microvacuolated cytoplasm , and marked pleomorphism are more suggestive of PLPS , but these characteristics can be present in DDLPS .
24		Coexpression of MDM2 and CDK4 distinguishes DDLPS from PLPS .

PMID: 24085196 (Cell)   Terms:
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0		Hyperexpression of HOXC13 , located in the 12q13 chromosomal region , in welldifferentiated and dedifferentiated human liposarcomas .
1		Liposarcoma ( LPS ) is the most common soft tissue neoplasm in adults and is characterized by neoplastic adipocyte proliferation .
2		Some subtypes of LPSs show aberrations involving the chromosome 12 .
3		The most frequent are t ( 12 ; 16 ) ( q13 ; p11 ) present in more than 90% of myxoid LPSs and 12q13-15 amplification in well-differentiated and dedifferentiated LPSs .
4		In this region , there are important oncogenes such as CHOP (DDIT3) , GLI , MDM2 , CDK4 , SAS , HMGA2 , but also the HOXC locus , involved in development and tumor progression .
5		In this study , we evaluated the expression of HOXC13 , included in this chromosomal region , in a series of adipocytic tumors .
6		We included 18 well-differentiated , 4 dedifferentiated , 11 myxoid and 6 pleomorphic LPSs as well as 13 lipomas in a tissue microarray .
7		We evaluated the HOXC13 protein and gene expression by immunohistochemistry and quantitative PCR .
8		Amplification/translocation of the 12q13-15 region was verified by FISH .
9	Μ	Immunohistochemical HOXC13 overexpression was observed in all well-differentiated and dedifferentiated LPSs , all characterized by the chromosome 12q13-15 amplification , and confirmed by quantitative PCR analysis .
10		In conclusion , our data show a deregulation of the HOXC13 marker in welldifferentiated and dedifferentiated LPSs , possibly related to 12q13-15 chromosomal amplification .

PMID: 24065374 (None)   Terms: this review
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0		The utility of immunohistochemistry for providing genetic information on tumors .
1		With advances in immunohistochemical technology and growing knowledge of the molecular genetics of tumors , immunohistochemistry is playing an increasingly important role in providing genetic information for tumors .
2		Specific chromosomal translocations can be demonstrated through detection of the protein product of one of the genes involved in gene fusion ( such as BCL2 , cyclin D , and ALK ) .
3	Μ	Some mutations can be detected by (1) aberrant localization of the protein product ( such as beta-catenin and nucleophosmin ) , (2) abnormal accumulation of the protein product as a result of stabilization of the protein ( such as p53 ) , and (3) mutation-specific antibodies directed against the mutant protein ( such as isocitrate dehydrogenase gene R132H mutation , epidermal growth factor receptor gene L858R and exon 19 deletion mutations , and BRAF gene V600E mutation ) .
4	Μ	Gene deletion or loss of function can be demonstrated by the loss of immunostaining for the protein product ( such as mismatch repair proteins in microsatellite-unstable tumors , E-cadherin in lobular carcinoma of the breast , and INI1 in rhabdoid tumors , atypical teratoid/rhabdoid tumors , and epithelioid sarcomas ) .
5	Μ	Gene amplification can be demonstrated by overexpression of the protein product ( such as HER2 in breast and gastric cancers , and MDM2 or CDK4 in well-differentiated/dedifferentiated liposarcomas ) .
6		Viruses associated with tumors can be demonstrated directly ( such as Epstein-Barr virus latent membrane protein -1 in Hodgkin lymphomas , human herpesvirus 8 in Kaposi sarcomas , and Merkel cell polyomavirus in Merkel cell carcinomas ) or by a surrogate marker ( such as p16 in human papillomavirus infection ) .
7		In this review , examples are given to illustrate the principles and pitfalls of these applications .

PMID: 24065146 (Patient)   Terms:
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0		Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets .
1		Dedifferentiated liposarcoma ( DDLS ) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies .
2		Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities .
3		To identify a possible multicomponent therapy , we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 ( CDK4 ) and insulin-like growth factor 1 receptor ( IGF1R ) as synergistic drug targets .
4		We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network .
5		These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway .
6		Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway .
7		Consistent with these findings , synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor ( EGFR ) , another receptor similar to IGF1R that activates AKT .
8		Thus , network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies .

PMID: 23971887 (Patient)   Terms:
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0		p53 mutations , ras mutations , and p53-heat shock 70 protein complexes in human lung carcinoma cell lines .
1		UNLABELLED :
2		Paratesticular liposarcoma is a rare neoplasm , described in single case studies or components of larger studies , as histologically well-differentiated liposarcoma ( WDL ) and dedifferentiated liposarcoma ( DL ) .
3		However , leiomyosarcomatous differentiation is an extremely rare occurrence in WDL and DL .
4		We report a case of leiomyosarcomatous differentiation in a 77-year-old man .
5		The patient presented with a painless right scrotal mass .
6		Magnetic resonance imaging showed a large mass along the right spermatic cord .
7		The resected mass , measuring 17.5 x 12 x 5 cm , was composed of a high-grade pleomorphic undifferentiated sarcomatous component with necrosis .
8		Atypical smooth muscle differentiation was also detected .
9		Additional tumor sampling revealed the presence of a WDL component .
10	Μ	Immunohistochemical analysis of the pleomorphic sarcomatous component showed positive staining for MDM2 and CDK4 , and negative staining for alpha smooth muscle actin ( alphaSMA ) and desmin .
11		The smooth muscle component was positive for alphaSMA and desmin , and negative for MDM2 and CDK4 .
12		Extension from primary retroperitoneal sarcoma was not proved .
13		We diagnosed of DL with leiomyosarcomatous differentiation .
14		VIRTUAL SLIDES :
15		The virtual slides for this article can be found here : http : //www .
16		diagnosticpathology .
17		diagnomx .
18		eu/vs/1484291498104021 .

PMID: 23910173 (None)   Terms:
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0		Dedifferentiated liposarcoma of the spermatic cord with a hemangioendothelioma-like component : a case report and review of the literature .
1		Atypical lipomatous tumor or well-differentiated liposarcoma/dedifferentiated liposarcoma ( DDLPS ) is the most frequent subtype of malignant adipocytic tumor .
2		This tumor typically presents in late adult life , most commonly in the retroperitoneum , extremities , or spermatic cord .
3		It has been reported that the dedifferentiated component consists mainly of high-grade sarcoma , including undifferentiated pleomorphic sarcoma , fibrosarcoma , and myxofibrosarcoma , and it has been recently reported that the dedifferentiated component can be also made up of a low-grade sarcomatous component .
4		Therefore , the dedifferentiated areas exhibit a wide morphological spectrum that commonly includes fibroblastic/myofibroblastic and fibrohistiocytic tumors but very rarely includes vascular tumors .
5		We present here the first reported case of DDLPS with a hemangioendothelioma-like component in the spermatic cord .

PMID: 23852861 (None)   Terms:
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0		High level of CDK4 amplification is a poor prognostic factor in well-differentiated and dedifferentiated liposarcoma .
1		CT and MRI findings in KIT-weak or KIT-negative atypical gastrointestinal stromal tumors .

PMID: 23832711 (None)   Terms:
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0		Survival after lobectomy versus segmentectomy for stage I non-small cell lung cancer : a population-based analysis .
1		Bone morphogenetic protein 7 protects prostate cancer cells from stress-induced apoptosis via both Smad and c-Jun NH2-terminal kinase pathways .

PMID: 23826426 (Patient)   Terms:
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0		Retroperitoneal dedifferentiated liposarcoma with osteosarcomatous components : a case report .
1		We report a rare case of recurrent retroperitoneal dedifferentiated liposarcoma with osteosarcomatous components .
2		An 82-year-old male diagnosed with recurrent retroperitoneal liposarcoma underwent a tumor resection .
3	Μ	Histologically , osseous matrix with osteoid and mature hyaline cartilaginous tissues with high cellularity were observed in a fibrous background through most of the tumor , and scattered MDM2 - and CDK4-positive atypical hyperchromatic stromal cells were detected surrounding the dedifferentiated areas .
4		Dedifferentiation occurs in up to 10% of well-differentiated liposarcomas , frequently resembling a malignant fibrous histiocytoma-like pleomorphic sarcoma .
5		In contrast , divergent differentiation with osteosarcomatous components is considered to be extremely rare .

PMID: 23661264 (None)   Terms: , tumor model
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0		Preclinical evaluation of nilotinib efficacy in an imatinib-resistant KIT-driven tumor model .
1		Loss of tumor suppressor in lung cancer-1 ( TSLC1 ) expression in meningioma correlates with increased malignancy grade and reduced patient survival .

PMID: 23569312 (None)   Terms: Phase II trial
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0		Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma .
1		A deficiency of gastric interstitial cells of Cajal accompanied by decreased expression of neuronal nitric oxide synthase and substance P in patients with type 2 diabetes mellitus .

PMID: 23529275 (None)   Terms:
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0		Can HMGI-C be used as an aid with MDM2 and CDK4 to differentiate liposarcoma subtypes from their mimics ?
1		PURPOSE :
2		Liposarcoma represents the most common soft tissue tumors in adults .
3		The tumors are characterized by a high morphological diversity and a great variation in biological behavior .
4		Atypical lipomatous tumors represent a distinctive subset of mesenchymal neoplasms featuring mature adipocytic differentiation .
5		Histologically , atypical lipomatous tumor might be easily confused with lipoma .
6		Conversely , dedifferentiated liposarcoma may be confused with other spindle cell/pleomorphic undifferentiated tumors .
7		METHODS :
8		A group of liposarcomas was analyzed by investigating the MDM2 , CDK4 , and HMGI-C proteins .
9		The study was extended to a group of lipomas and non-lipomatous sarcomas , to determine whether the immunohistochemical investigation of these proteins might play any diagnostic role .
10		RESULTS :
11		Our data suggest that ordinary lipomas may form a molecular genetic and morphological continuum with atypical lipomatous tumor .
12		At one end of the spectrum are lipomas characterized by HMGI-C activation and at the other end are atypical lipomatous tumors with overrepresentation of the HMGI-C , CDK4 , or MDM2 proteins .
13		These findings not only provide insights into the molecular pathogenesis of lipomatous tumors , but also indicate that the immunohistochemical analysis of HMGI-C , CDK4 , or MDM2 may help to increase diagnostic accuracy .
14		CONCLUSIONS :
15		HMGI-C is a useful adjunct in the diagnosis of atypical lipomatous tumor and dedifferentiated liposarcoma and differentiates them from their mimics .
16		Therefore , in our experience , HMGI-C expression alone is of rather limited value in the differential diagnosis of liposarcoma subtypes .

PMID: 23425231 (Patient)   Terms:
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0		Dedifferentiated liposarcoma with homologous lipoblastic differentiation : expanding the spectrum to include low-grade tumours .
1		AIMS :
2		Dedifferentiated liposarcoma ( DDLPS ) is traditionally defined as a non-lipogenic high-grade sarcoma arising from a well-differentiated liposarcoma that confers metastatic potential .
3		Recently , DDLPSs with lipoblastic differentiation , i.e.morphologically lipogenic DDLPSs , were reported .
4		Because of the lipoblastic differentiation , these tumours caused confusion , and were reported under different names .
5		However , cytogenetic and molecular studies have revealed their DDLPS nature .
6		So far , the cases reported have been high-grade pleomorphic liposarcoma-like tumours .
7		In this study we have collected another series that contains low-grade tumours , and expand the histological spectrum .
8		METHODS AND RESULTS :
9		Eighteen cases of DDLPS with lipoblastic differentiation from various anatomical locations were analysed by routine histology , immunohistochemistry , and MDM2 fluorescence in-situ hybridization .
10		Two main histological patterns were seen : one featured a spindle cell sarcoma containing lipoblasts with variable nuclear pleomorphism , and the other a pleomorphic liposarcoma-like tumour including the epithelioid variant .
11	Μ	Two cases showed low nuclear grade and lipogenic activity in the metastatic foci .
12		CDK4 , MDM2 and p16 ( INK ) ( 4a ) overexpression was seen in all except one case .
13	Μ	MDM2 amplification was found in all 16 cases tested .
14		CONCLUSIONS :
15		We have expanded the spectrum of this variant of DDLPS to include low-grade tumours , in which a careful search for increased mitotic activity is essential .
16		Like conventional DDLPS , these tumours are capable of metastasis .

PMID: 23393200 (Cell)   Terms:
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0		Amplification of FRS2 and activation of FGFR/FRS2 signaling pathway in high-grade liposarcoma .
1		Fibroblast growth factor ( FGF ) receptor ( FGFR ) substrate 2 ( FRS2 ) is an adaptor protein that plays a critical role in FGFR signaling .
2	Μ	FRS2 is located on chromosome 12q13-15 that is frequently amplified in liposarcomas .
3		The significance of FRS2 and FGFR signaling in high-grade liposarcomas is unknown .
4		Herein , we first comparatively examined the amplification and expression of FRS2 with CDK4 and MDM2 in dedifferentiated liposarcoma ( DDLS ) and undifferentiated high-grade pleomorphic sarcoma ( UHGPS ) .
5	Μ	Amplification and expression of the three genes were identified in 90% to 100% ( 9-11 of 11 ) of DDLS , whereas that of FRS2 , CDK4 , and MDM2 were observed in 55% ( 41 of 75 ) , 48% ( 36 of 75 ) , and 44% ( 33/75 ) of clinically diagnosed UHGPS , suggesting that these "UHGPS" may represent DDLS despite lacking histologic evidence of lipoblasts .
6		Immunohistochemical analysis of phosphorylated FRS2 protein indicated that the FGFR/FRS2 signaling axis was generally activated in about 75% of FRS2-positive high-grade liposarcomas .
7	Μ	Moreover , we found that FRS2 and FGFRs proteins are highly expressed and functional in three high-grade liposarcoma cell lines : FU-DDLS-1 , LiSa-2 , and SW872 .
8		Importantly , the FGFR selective inhibitor NVP-BGJ-398 significantly inhibited the growth of FU-DDLS-1 and LiSa-2 cells with a concomitant suppression of FGFR signal transduction .
9		Attenuation of FRS2 protein in FU-DDLS-1 and LiSa-2 cell lines decreased the phosphorylated extracellular signal-regulated kinase 1/2 and AKT and repressed cell proliferation .
10		These findings indicate that analysis of FRS2 in combination with CDK4 and MDM2 will more accurately characterize pathologic features of high-grade liposarcomas .
11		Activated FGFR/FRS2 signaling may play a functional role in the development of high-grade liposarcomas , therefore , serve as a potential therapeutic target .

PMID: 23308321 (None)   Terms:
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0		Giant gastric lipoma mimicking well-differentiated liposarcoma .
1		Authors report the case of a 51-year-old man , presenting with epigastralgia of recent onset .
2		Physical exam was unremarkable .
3		Endoscopy revealed a large , ulcerated , submucosal , antral tumor .
4		CT scan reveals an antral mass with fat attenuation .
5		The patient underwent a total gastrectomy .
6		Macroscopic examination identified in the antral wall a 9-cm , well-circumscribed , nodular lesion , with a yellow , greasy cut surface .
7		On histological examination , the tumor was composed of a mature adipocytes proliferation , showing significant variation in cell size , associated to some lipoblasts .
8		Nuclei were sometimes large , slightly irregular , but without hyperchromasia nor mitosis .
9	Μ	Diagnosis of a well-differentiated liposarcoma was suspected and molecular cytogenetic analyses showed no MDM2 nor CDK4 gene amplification on fluorescent in situ hybridization .
10		The diagnosis of lipoma was made .
11		Twelve months following surgery , the patient is doing well .

PMID: 23020289 (Patient)   Terms:
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0		Well-differentiated and dedifferentiated liposarcomas with prominent myxoid stroma : analysis of 56 cases .
1		AIMS :
2		Occasional cases of well-differentiated and dedifferentiated liposarcoma ( LPS ) contain myxoid stroma , leading to confusion with other sarcomas .
3		The aim of this study was to analyse the clinicopathological and genetic features of well-differentiated/dedifferentiated LPS with prominent myxoid stroma .
4		METHODS AND RESULTS :
5		Fifty-six cases of LPS ( 22 well-differentiated ; 34 dedifferentiated ) with prominent myxoid stroma were evaluated .
6		Most arose in the retroperitoneum , abdominal cavity , or spermatic cord .
7		The mean size was 170 mm .
8		Myxoid LPS-like plexiform vessels were conspicuous in 11 cases of well-differentiated LPS .
9		In 22 cases of dedifferentiated LPS , myxofibrosarcoma-like curvilinear vessels were prominent .
10		In other cases , the myxoid component had variably bland or pleomorphic morphology .
11		By immunohistochemistry , staining for MDM2 was positive in 95% of cases , and CDK4 in 78% .
12	Μ	Cytogenetics in 13 cases showed ring and giant marker chromosomes .
13	Μ	Fluorescence in-situ hybridization showed amplification of 12q13-15 in six cases evaluated .
14		Of 30 patients with follow-up , all but one had local recurrences ( up to four ) , but only one has so far had distant metastases .
15		CONCLUSIONS :
16		Well-differentiated/dedifferentiated LPS with prominent myxoid stroma can closely resemble other sarcoma types , especially myxoid LPS and myxofibrosarcoma .
17		The clinical presentation ( large retroperitoneal or abdominal tumour ) is a clue to the correct diagnosis ; the degree of nuclear atypia helps to exclude myxoid LPS .
18		Immunohistochemistry for MDM2 and CDK4 and genetic analysis can be useful to confirm the diagnosis .

PMID: 22790852 (Patient)   Terms: , mouse
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0		Loss of retinoblastoma protein expression in spindle cell/pleomorphic lipomas and cytogenetically related tumors : an immunohistochemical study with diagnostic implications .
1		Consistent rearrangements of chromosomes 13q and 16q have been identified in spindle cell and pleomorphic lipomas by cytogenetics .
2		Mammary-type myofibroblastoma and cellular angiofibroma show overlapping histologic features and similar chromosomal losses , suggesting a possible relationship among these tumor types .
3		The tumor suppressor gene RB1 , encoding the retinoblastoma ( Rb ) protein , is located at 13q14 , within a minimally deleted region in spindle cell lipoma .
4		The purpose of this study was to examine expression of Rb by immunohistochemistry in spindle cell lipoma , pleomorphic lipoma , mammary-type myofibroblastoma , and cellular angiofibroma , and in histologic mimics , to determine its potential diagnostic utility .
5		Whole - tissue sections of 194 tumors were evaluated : 18 spindle cell lipomas , 20 pleomorphic lipomas , 19 mammary-type myofibroblastomas , 16 cellular angiofibromas , 22 conventional lipomas ( 8 intramuscular ) , 18 atypical lipomatous tumors ( all positive for MDM2 and CDK4 ) , 19 solitary fibrous tumors , 19 myxoid liposarcomas , 14 hibernomas , 11 deep ( aggressive ) angiomyxomas , 9 angiomyofibroblastomas , and 9 vulval fibroepithelial stromal polyps .
6		Immunohistochemistry was performed after pressure cooker antigen retrieval using a mouse anti-Rb monoclonal antibody .
7		Nuclear staining for Rb was scored as "intact" or "deficient." Rb expression was deficient in all spindle cell lipomas , pleomorphic lipomas , and cellular angiofibromas and in 17 ( 89% ) mammary-type myofibroblastomas .
8		Rb staining was sometimes difficult to interpret in cellular angiofibromas with reactive stromal changes .
9		Rb was also deficient in 2 ( 9% ) conventional lipomas .
10		Rb expression was intact in all other tumor types evaluated .
11		In summary , of the soft tissue tumors associated with 13q deletions , all spindle cell lipomas , pleomorphic lipomas , and cellular angiofibromas and most mammary-type myofibroblastomas show loss of Rb expression .
12		Rb expression is intact in histologic mimics .
13		These findings reinforce the pathogenetic relationship among this group of tumors and demonstrate the potential diagnostic utility of immunohistochemistry for Rb .

PMID: 22699518 (Patient)   Terms:
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0		Sensitivity of MDM2 amplification and unexpected multiple faint alphoid 12 ( alpha 12 satellite sequences ) signals in atypical lipomatous tumor .
1		Cetuximab is an anti-epidermal growth factor receptor that helps effectively treat patients with advanced colorectal adenocarcinoma without KRAS activating mutations .
2		KRAS mutations are associated with 16% to 50% of isolated villous adenomas and approximately 30% of colorectal cancer .
3		Correlation between the gross and histological subset of colorectal adenocarcinoma with KRAS mutation is unknown .
4		Archived surgical resection specimens of colorectal adenocarcinoma ( n = 42 ) and villous adenoma ( n = 9 ) were collected .
5	Μ	The gross appearance and histopathological features of these lesions were thoroughly reviewed , including the presence of a pre-existing adenomatous polyp.DNA was extracted from formalin-fixed , paraffin-embedded tissue sections and then subjected to TaqMan real-time polymerase chain reaction to detect the seven most common KRAS mutations .
6	Μ	KRAS mutations were found in 13 of 42 cases ( 31% ) of colorectal adenocarcinoma and 7 of 9 cases ( 78% ) of villous adenoma .
7	Μ	All 13 cases of colorectal carcinoma with a KRAS mutation showed a gross polypoid configuration , compared to no KRAS mutation in the colorectal carcinomas with ulcerative configuration .
8		In addition , 13 of 17 of these cases ( 76% ) had histological features of adenocarcinoma with a persistent preexisting adenomatous polyp with villous architecture .
9		In summary , grossly polypoid colorectal adenocarcinomas with a persistent pre-existing adenomatous polyp with villous architecture are strongly associated with KRAS mutations .

PMID: 22678079 (Cell)   Terms:
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0		A newly characterized human well-differentiated liposarcoma cell line contains amplifications of the 12q12-21 and 10p11-14 regions .
1		While surgery is the usual treatment for localized well-differentiated and dedifferentiated liposarcomas ( WDLPS/DDLPS ) , the therapeutic options for patients with advanced disease are limited .
2		The classical antimitotic treatments are most often inefficient .
3		The establishment of genetically characterized cell lines is therefore crucial for providing in vitro models for novel targeted therapies .
4	Μ	We have used spectral karyotyping , fluorescence in situ hybridization with whole chromosome painting and locus -specific probes , and array-comparative genomic hybridization to identify the chromosomal and molecular alterations of a novel cell line established from a recurring sclerosing WDLPS .
5		The karyotype was hypertriploid and showed multiple structural anomalies .
6	Μ	All cells retained the presence of a giant marker chromosome that had been previously identified in the primary cell cultures .
7		This giant chromosome contained high-level amplification of chromosomal regions 12q13-21 and lacked the alpha-satellite centromeric sequences associated with WDLPS/DDLPS .
8		The 12q amplicon was large , containing 370 amplified genes .
9		The DNA copy number ranged from 3 to 57 .
10	Μ	The highest levels of amplification were observed at 12q14.3 for GNS , WIF1 , and HMGA2 .
11		We analyzed the mRNA expression status by real-time reverse transcription polymerase chain reaction for six genes from this amplicon : MDM2 , HMGA2 , CDK4 , TSPAN31 , WIF1 , and YEATS4 .
12		mRNA overexpression was correlated with genomic amplification .
13		A second amplicon originating from 10p11-14 was also present in the giant marker chromosome .
14		The 10p amplicon contained 62 genes , including oncogenes such as MLLT10 , previously described in chimeric fusion with MLL in leukemias , NEBL , and BMI1 .

PMID: 22675153 (Patient)   Terms: , mice
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0		Recurrent retroperitoneal liposarcoma in a patient with neurofibromatosis type I .
1		Germline mutations of the CDKN2A ( p16 ( INK4A ) ) tumor suppressor gene predispose patients to melanoma and pancreatic carcinoma .
2		In contrast , mutations of the murine CDKN2A gene predispose BALB/c mice to pristane-induced plasmacytoma .
3		We describe here a family in which a germline mutation of CDKN2A is present in 4 individuals who developed melanoma as well as in a fifth family member who is suffering from multiple myeloma .
4	Μ	To determine whether the CDKN2A mutation predisposed the myeloma patient to her disease , we carried out loss of heterozygosity studies on sorted bone marrow from this individual and observed loss of the wild type CDKN2A allele in the malignant plasma cells .

PMID: 22528826 (Patient)   Terms:
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0		Cervical dedifferentiated liposarcoma with meningothelial-like whorling .
1		Liposarcomas are the most common soft - tissue sarcoma of adults , but rare in the head and neck .
2		Recently , a subtype of dedifferentiated liposarcoma with meningiothelial-like whorls was reported and we present the first description of such a tumor in the head and neck .
3		A 65 year old male underwent a resection of a calcified retroesophageal mass that was in close relation to the left hemithyroid and recurrent laryngeal nerve .
4		It was resected en bloc with the left thyroid lobe .
5		Initial pathologic evaluation suggested the mass was a schwanomma of the recurrent laryngeal nerve , but positive staining for MDM2 and CDK4 indicated the tumor was a dedifferentiated liposarcoma .
6		Further evaluation elucidated the unique meningothelial-like whorls within the tumor .
7		This case demonstrates dedifferentiated liposarcomas do appear in the head and neck .
8		Furthermore , this is the first report in the head and neck of the mengiothelial-like whorling pattern type of dedifferentiated liposarcoma .

PMID: 22387046 (None)   Terms:
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0		Searching for molecular targets in sarcoma .
1		Sarcoma are about 1% of cancers .
2		Within that 1% are widely varied tumors now divided into types and subtypes .
3		Sarcoma occur in patients of all ages with frequency spread evenly over the human age range .
4		Although the specific cell of origin of many sarcoma remains unclear , sarcoma are all tumors of mesenchymal origin .
5		The mesenchymal stem cell , a pluripotent cell , which gives rise to varied differentiated cells including osteocytes , adipocytes , chondrocytes , muscle cells , fibroblasts , neural cells and stromal cells , is the most likely ultimate cell of origin for sarcoma .
6		When mesenchymal stem cell genetics go awry and malignant transformation occurs sarcoma including osteosarcoma , Ewing's sarcoma , chondrosarcoma , rhabdomyosarcoma , synovial sarcoma fibrosarcoma , liposarcoma and many others can initiate .
7		Our knowledge of sarcoma genetics is increasing rapidly .
8		Two general groups , sarcoma arising from chromosomal translocations and sarcoma with very complex genetics , can be identified .
9	Μ	Genes that are frequently mutated in sarcoma include TP53 , NF1 , PIK3CA , HDAC1 , IDH1 and 2 , KDR , KIT and MED12 .
10	Μ	Genes that are frequently amplified in sarcoma include CDK4 , YEATS4 , HMGA2 , MDM2 , JUN , DNM3 , FLT4 , MYCN , MAP3K5 , GLI1 and the microRNAs miR-214 and miR-199a2 .
11		Genes that are upregulated in sarcoma include MUC4 , CD24 , FOXL1 , ANGPTL2 , HIF1alpha , MDK , cMET , TIMP-2 , PRL , PCSK1 , IGFR-1 , TIE1 , KDR , TEK , FLT1 and several microRNAs .
12		While some alterations occur in specific subtypes of sarcoma , others cross several sarcoma types .
13		Discovering and developing new therapeutic approaches for these relentless diseases is critical .
14		The detailed knowledge of sarcoma genetics may allow development of sarcoma subtype-targeted therapeutics .

PMID: 22374332 (Patient)   Terms: phase I, clinical trial
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0		The cyclin -dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas : preclinical investigations and results of a phase I dose-escalation clinical trial .
1		AIMS/BACKGROUND :
2	Μ	The aim of this study was to identify p53 and K-ras gene mutations in carcinoma of the rectum among Finnish women .
3		Mutation patterns might give clues to aetiological factors when comparisons are made with other human tumours .
4		METHODS :
5		Of 134 women with carcinoma of the rectum , paraffin wax embedded specimens of the tumour tissue were obtained from 118 patients .
6	Μ	Genomic DNA was extracted , and exons 4-8 of the p53 gene and codons 12/13 and 61 of the K-ras gene were amplified , and analysed for mutations by single strand conformation polymorphism and direct sequencing .
7		The production of p53 and K-ras proteins was studied by immunohistochemistry .
8		RESULTS :
9		The overall crude frequency for mutations in the p53 gene was 35% but the true frequency appears to be higher ( up to 56% ) .
10		In the K-ras gene , the mutation frequency ( 15% ) was significantly lower than that reported for colon cancer .
11		In the p53 gene , the mutation frequency increased significantly with patient age .
12		In a high proportion of patients ( 14% ) the rectal tumours contained small subclones of tumour cells that displayed extremely rare mutations at codons 110 and 232 of the p53 gene .
13		Hot spot codon 175 mutations were significantly less common in rectal cancer than in cancer of the colon .
14		CONCLUSIONS :
15		Rectal cancer among Finnish women has characteristics in the mutations of the p53 and K-ras genes that are uncommon in other human tumours , including cancer of the colon .
16		A biological explanation of these findings is not clear at present , but might be associated with an unidentified genetic factor in Finland .

PMID: 22307930 (None)   Terms: in vivo, In vitro, in vitro, mice
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0		Microsatellite alterations and K-ras , TGFbetaRII , IGFRII and bax mutations in sporadic cancers of the gastrointestinal tract .
1		Mutations of proto-oncogene c-KIT in gastrointestinal stromal tumors ( GISTs ) are considered to cause a constitutive activation of KIT responsible for their oncogenesis .
2		Imatinib has therapeutic potential for GISTs because of its inhibitory effect on KIT kinase activity .
3	Μ	To investigate the effect of Imatinib on various c-KIT mutations found in GISTs , we examined kinase activity of KIT , cell proliferation and tumorigenicity of transfectants with various c-KIT mutations .
4		Murine lymphoid Ba/F3 cells transfected with one of the three types of mutants ( KIT ( del559-560 ) , KIT ( 642Glu ) , and KIT ( 820Tyr ) ) or wild-type KIT were used for the experiments .
5		Phosphorylation of KIT , mitogen -activated protein ( MAP ) and Akt was studied by immunoblotting with or without immunoprecipitation .
6		In vitro studies on cell proliferation using 3 - ( 4,5-dimethylthiazol-2-yl ) -2,5-diphenylcetrazolium bromide colorimetric assay and in vivo tumorigenicity assay using nude mice were also carried out .
7		Imatinib could inhibit the KIT , MAP and Akt phosphorylation of all the transfectants but had a weaker effect on KIT ( 820Tyr ) .
8		Imatinib potently inhibited the proliferation of cells transfected with KIT ( 820Tyr ) at the concentration of 10 microM whereas it inhibited the other 3 types at 1 microM .
9		Moreover , Imatinib could inhibit the tumor formation in nude mice transplanted with transfectants .
10		In various types of activating mutant KIT , Imatinib could inhibit the constitutive activation of KIT signal transduction and cell proliferation both in vitro and in vivo although the effect of Imatinib on KIT ( 820Tyr ) was weaker than that on KIT ( del559-560 ) or KIT ( 642Glu ) .

PMID: 22301498 (None)   Terms:
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0		Diagnostic utility of p16 , CDK4 , and MDM2 as an immunohistochemical panel in distinguishing well-differentiated and dedifferentiated liposarcomas from other adipocytic tumors .
1		Adipocytic tumors are the most common type of soft tissue neoplasms .
2		Distinguishing atypical lipomatous tumor-well-differentiated liposarcoma ( WDL ) from benign adipocytic neoplasms and dedifferentiated liposarcoma ( DDL ) from pleomorphic or myxoid liposarcoma ( LPS ) can be difficult .
3		WDL and DDL characteristically harbor amplifications of the MDM2 and CDK4 cell cycle oncogenes with protein overexpression and can also overexpress the cell cycle regulator p16 .
4		We assessed the utility of immunohistochemistry for CDK4 , MDM2 , and p16 in the routine histopathologic diagnosis of WDL/DDL from other adipocytic tumors .
5		Immunohistochemistry for the trio of markers was performed on 216 adipocytic neoplasms ( 31 WDLs , 57 DDLs , 11 myxoid LPS , 2 pleomorphic LPS , 91 lipomas ( including intramuscular , fibro , angio , and ossifying subtypes ) , 18 spindle/pleomorphic lipomas , and 6 hibernomas .
6		Sixty-eight percent of WDLs and 72% of DDLs expressed all 3 antigens , whereas 100% of WDLs and 93% of DDLs expressed atleast 2 antigens .
7		The sensitivity and specificity of the trio for detecting WDLs/DDLs were 71% and 98% , respectively .
8		The sensitivity and specificity of CDK4 for detecting WDLs/DDLs were 86% and 89% , those of MDM2 were 86% and 74% , and those of p16 were 93% and 92% , respectively .
9		The immunohistochemical trio of CDK4 , MDM2 , and p16 is a useful ancillary diagnostic tool that provides strong support in distinguishing WDLs and DDLs from other adipocytic neoplasms and is potentially more sensitive than previously assessed combinations of CDK4 and MDM2 .
10		p16 was the most sensitive and specific marker for detecting WDL/DDL , and the combination of CDK4 and p16 is of more discriminatory value than the combination of either with MDM2 , the least sensitive and specific of the 3 markers .

PMID: 24834200 (Patient)   Terms:
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0		Giant gastric lipoma mimicking well-differentiated liposarcoma .
1		Gastric lipoma is a rare tumor , accounting for only 5% of gastrointestinal tract lipomas and less than 1% of all gastric tumors .
2		Histological diagnosis is usually easy .
3		However , the tumor may sometimes undergo significant inflammatory changes leading to a difficult differential diagnosis with well-differentiated liposarcoma .
4		Authors report the case of a 51-year-old man , presenting with epigastralgia of recent onset .
5		Physical exam was unremarkable .
6		Endoscopy revealed a large , ulcerated , submucosal , and antral tumor .
7		CT scan showed an antral mass with fat attenuation .
8		The patient underwent a total gastrectomy .
9		Macroscopic examination identified in the antral wall a 9-cm , well-circumscribed , nodular lesion , with a greasy cut surface .
10		On histological examination , the tumor was composed of a mature adipocytes proliferation , showing significant variation in cell size , associated to some lipoblasts .
11		Nuclei were sometimes large , irregular , neither with hyperchromasia nor mitosis .
12	Μ	Diagnosis of a well-differentiated liposarcoma was suspected and molecular cytogenetic analyses showed neither MDM2 nor CDK4 gene amplification on fluorescent in situ hybridization .
13		The diagnosis of lipoma was made .
14		Twelve months after surgery , the patient is doing well .
15		In conclusion , Differentiating benign from malignant fatty tumors is sometimes difficult in morphologic features .
16		In these cases , cytogenetic procedures are the only means for an accurate diagnosis .

PMID: 22178310 (None)   Terms:
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0		Parosteal osteoliposarcoma : a new bone tumor ( from imaging to immunophenotype ) .
1		INTRODUCTION :
2		Cancer tissue is composed of various stromal cells forming cancer-specific microenvironments .
3		Peritumoral stroma is reportedly composed of activated fibroblasts that can influence the biological properties of tumor cells , mainly their local aggressiveness and their ability .
4		The aim of this study was to examine whether the histological properties of peritumoral stroma are correlated with squamous cell carcinoma ( SqCC ) aggressiveness and clinical outcome .
5		METHODS :
6		A series of 220 pathological stage I lung SqCC were categorized into two types according to the histological properties of the peritumoral stroma , "fibrous stroma type" ( n = 85 ) , and "thin stroma type" ( n = 135 ) , and compared the prognostic significance .
7		Furthermore , we compared the immunohistochemical properties of the SqCC cells surrounded by "fibrous stroma" with those of the SqCC cells surrounded by "thin stroma." RESULTS : The prognosis of the patients with fibrous stroma-type tumors was significantly poorer than that of the thin stroma type with regard to both recurrence-free survival ( p = 0005 ) and overall survival ( p = 0008 ) .
8		A multivariate analysis showed that the presence of a fibrous stroma was an independent prognostic factor ( p = 0030 ) .
9		Compared with the SqCC cells with a thin stroma , the SqCC cells with a fibrous stroma exhibited reduced expression of E-cadherin ( 559 versus 1260 , p <0001 ) and an increased expression of laminin-5gamma2 ( 946 versus 250 , p = 0001 ) , matrix metalloproteinase-7 ( 260 versus 350 , p = 0009 ) , and c-Met ( 640 versus 365 , p = 0033 ) .
10		CONCLUSION :
11		SqCC with a fibrous stroma displayed higher invasive phenotype and were associated with a significantly poor prognosis .
12		The current results suggest that the microenvironment created by both SqCC cells and the peritumoral fibroblasts may facilitate cancer aggressiveness .

PMID: 22160092 (None)   Terms:
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0		Cytogenetic and molecular cytogenetic findings in giant dedifferentiated liposarcoma of the thigh .
1		Non-retroperitoneal dedifferentiated liposarcoma ( DDLS ) is relatively uncommon and its characterization at the molecular genetic level has been limited .
2		We describe the cyto-genetic and molecular cytogenetic findings of giant DDLS arising in the right thigh of an 83-year-old woman .
3		Magnetic resonance imaging revealed a mass composed of two components with heterogeneous signal intensities , suggesting the coexistence of a fatty area and another soft tissue component .
4		A wide resection of the tumor was performed .
5		The resected , grossly heterogeneous mass , measuring 26x18x8 cm , was histopathologically composed of a well-differentiated liposarcomatous component transitioning abruptly into a dedifferentiated one .
6		Cytogenetic analysis exhibited a complex karyotype with several numerical and structural alterations , including ring and giant marker chromosomes .
7	Μ	Metaphase-based comparative genomic hybridization analysis showed high-level amplifications of 1q21-q25 and 12q13-q21 .
8	Μ	Interphase fluorescence in situ hybridization analysis revealed MDM2 and CDK4 gene amplification in both the well-differentiated and dedifferentiated components .
9		These findings indicate that DDLS of the extremity shares a similar genetic background to retroperitoneal DDLS .

PMID: 21910158 (None)   Terms:
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0		The CDKN2A/CDKN2B/CDK4/CCND1 pathway is pivotal in well-differentiated and dedifferentiated liposarcoma oncogenesis : an analysis of 104 tumors .
1		Simultaneous inactivation of Par-4 and PTEN in vivo leads to synergistic NF-kappaB activation and invasive prostate carcinoma .

PMID: 21793095 (Patient)   Terms:
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0		High-resolution genomic mapping reveals consistent amplification of the fibroblast growth factor receptor substrate 2 gene in well-differentiated and dedifferentiated liposarcoma .
1		Well-differentiated liposarcoma ( WDLS ) is one of the most common malignant mesenchymal tumors and dedifferentiated liposarcoma ( DDLS ) is a malignant tumor consisting of both WDLS and a transformed nonlipogenic sarcomatous component .
2		Cytogenetically , WDLS is characterized by the presence of ring or giant rod chromosomes containing several amplified genes , including MDM2 , TSPAN31 , CDK4 , and others mainly derived from chromosome bands 12q13-15 .
3		However , the 12q13-15 amplicon is large and discontinuous .
4	Μ	The focus of this study was to identify novel critical genes that are consistently amplified in primary ( nonrecurrent ) WDLS and with potential relevance for future targeted therapy .
5		Using a high-resolution ( 50 kb ) "single nucleotide polymorphism"/copy number variation microarray to screen the whole genome in a series of primary WDLS , two consistently amplified areas were found on chromosome 12 : one region containing the MDM2 and CPM genes , and another region containing the FRS2 gene .
6		Based on these findings , we further validated FRS2 amplification in both WDLS and DDLS .
7		Fluorescence in situ hybridization confirmed FRS2 amplification in all WDLS and DDLS tested ( n = 57 ) .
8		Real time PCR showed FRS2 mRNA transcriptional upregulation in WDLS ( n = 19 ) and DDLS ( n = 13 ) but not in lipoma ( n = 5 ) and normal fat ( n = 9 ) .
9	Μ	Immunoblotting revealed high expression levels of phospho-FRS2 at Y436 and slightly overexpression of total FRS2 protein in liposarcoma but not in normal fat or preadipocytes .
10		Considering the critical role of FRS2 in mediating fibroblast growth factor receptor signaling , our findings indicate that FRS2 signaling should be further investigated as a potential therapeutic target for liposarcoma .

PMID: 21790860 (Cell)   Terms: xenograft, mice
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0		Establishment and characterization of a novel dedifferentiated liposarcoma cell line , NDDLS-1 .
1		We established a dedifferentiated liposarcoma cell line (NDDLS-1) that produces interleukin-6 ( IL-6 ) and granulocyte-colony stimulating factor ( G-CSF ) .
2	Μ	The parental tumor showed high leukemoid reactions .
3		The NDDLS-1 cell line was established from a pleural effusion associated with a lung metastasis .
4		Pleomorphic tumor cells arranged in a haphazard growth pattern were seen in xenograft tumors .
5		Numerous inflammatory cells including neutrophils or eosinophils were present throughout the tumor cells .
6		This finding resembled the dedifferentiated area of the parental tumor .
7		The mice bearing NDDLS-1 showed marked leukocytosis .
8		In addition , the NDDLS-1 cells expressed IL-6 and G-CSF at both the mRNA and protein levels , while the NDDLS-1 cells produced near normal levels of tumor necrosis factor alpha ( TNF-alpha ) .
9	Μ	In the cytogenetic analysis , both the parental tumor and the NDDLS-1 cells showed a ring or giant marker chromosomes .
10	Μ	The NDDLS-1 cell line demonstrated the amplification and expression of both MDM2 and CDK4 by fluorescence in situ hybridization and immunohistochemical analysis .
11		The NDDLS-1 cell line is consistent with the parental dedifferentiated liposarcoma , and it should therefore be useful for further investigations of human dedifferentiated liposarcomas .

PMID: 21716088 (Patient)   Terms:
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0		Malignant fat-forming solitary fibrous tumor ( so-called "lipomatous hemangiopericytoma" ) : clinicopathologic analysis of 14 cases .
1		Fat-forming solitary fibrous tumor is a rare variant of solitary fibrous tumor ( SFT ) .
2		Generally regarded as benign , very few fat-forming SFTs with malignant histologic features have been reported .
3		Here , we report 14 histologically malignant fat-forming SFTs to better characterize this subset .
4		Seven patients were female and 7 were male , with ages ranging 20 to 93 years ( median , 57 y ) .
5		Five tumors were located in the lower limb , 3 in the trunk , 3 in abdominopelvic locations , 2 in the head and neck region , and 1 in the upper limb .
6		The tumor size ranged from 3.4 to 20 cm ( median , 86 cm ) .
7		Histologically , all exhibited atleast focal hypercellularity ; 12 tumors had mitoses >4/10 high-power fields ( range , 2 to 37 ; median , 8 ) , 12 showed atleast moderate atypia , and 8 showed necrosis .
8		It should be noted that 7 tumors contained only mature adipose tissue , whereas 5 contained multivacuolated lipoblasts and 2 had areas resembling atypical lipomatous tumor ( ALT ) .
9		Immunohistochemically , CD34 and CD99 were positive in most cases ( 11 of 14 and 8 of 10 , respectively ) ; MDM2 and CDK4 were both negative in all 4 cases tested ( including both tumors with ALT-like areas ) .
10		Follow-up data from 10 cases ( median duration , 475 mo ; range , 5 to 76 ) showed 2 patients with multiple metastases ( both to lung and bones , and 1 each to breast and to soft tissue ) , both of whom died of disease .
11		In conclusion , fat-forming SFTs exhibiting malignant histologic features have potential for aggressive behavior .
12		The presence of lipoblasts and/or ALT-like areas , although described in some "benign" examples of fat-forming SFT , seems much more common in the malignant subset and may prompt a careful search for morphologic evidence of malignancy in any case of fat-forming SFT .

PMID: 21552124 (Cell)   Terms: This review, clinical trial
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0		Clinical and molecular approaches to well differentiated and dedifferentiated liposarcoma .
1		PURPOSE OF REVIEW :
2		Liposarcoma , a rare disease , is classified into five histologic subtypes .
3		These include well differentiated liposarcoma ( WDLS ) and dedifferentiated liposarcoma ( DDLS ) , both characterized by chromosome 12q13-15 amplification .
4		This review will focus on the clinical management of WDLS and DDLS and examine recent molecular studies that have the potential to affect clinical management .
5		RECENT FINDINGS :
6		Outcome of patients with WDLS and DDLS depends on completeness of surgical resection as well as tumor location and histologic subtype .
7		Risk of recurrence is high for patients with dedifferentiated histology or retroperitoneal location .
8		We now understand that surgical outcomes are poor for patients with rapidly growing or incompletely resectable tumors , so these patients should be managed nonoperatively .
9		Radiation and chemotherapy have low response rates in WDLS and DDLS , but novel agents targeted at chromosome 12 gene products MDM2 and CDK4 have shown promise in preclinical studies and are being tested in clinical trials .
10		Cell line , tissue microarray , and genomic analyses have identified additional targets including ZIC1 , TOP2A , AURKA , and IGF-1R , which could form the basis of future therapies .
11		SUMMARY :
12		Although complete surgical resection is currently the most effective treatment for WDLS and DDLS , the majority of patients with retroperitoneal liposarcoma will eventually have recurrence and die of disease .
13		It is hoped that a multimodality approach , which incorporates targeted therapies and complete surgical resection , will significantly improve patient outcomes .

PMID: 21526137 (Patient)   Terms:
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0		Well-differentiated liposarcoma , an atypical lipomatous tumor , of the mesentery : a case report and review of the literature .
1		Mesenteric liposarcoma is a rare neoplasm .
2		Here , we report the case of a 73-year-old Japanese man with a well-differentiated ( WD ) liposarcoma of the mesentery .
3		Due to rapid growth of the abdominal mass and abdominal insufficiency , a tumorectomy was performed .
4		The excised tumor was 12.4 x 9.6 cm in size and weighed 548 g .
5		Cut sections showed a lobulated yellow and/or grayish-colored appearance .
6		The histological features were predominantly those of the sclerotic and lipoma-like variants of WD liposarcoma .
7		The cytoplasm of most spindle cells was diffusely immunoreactive for CD34 , while fat cells were positive for S-100 protein .
8		Some spindle cell nuclei were positive for CDK4 , and a few were positive for MDM2 .
9	Μ	The average Ki-67 proliferation index in tumor cells was 10% , and androgen receptor expression was detected in tumor cell nuclei .
10		The present case and 11 cases identified from a literature search were reviewed .
11		The WD mesenteric liposarcomas developed in patients in the fourth to seventh decades of life ( mean age 579 years ) .
12		The patients consisted of 7 men and 5 women .
13		All tumors were larger than 10 cm in diameter at the time of surgery .
14		Complete resection might be the only curative therapy for WD liposarcomas of the mesentery , but long-term follow-up is needed because of the possibility of a local recurrence of the tumor .

PMID: 21358383 (Patient)   Terms:
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0		Atypical lipomatous tumor/"well-differentiated liposarcoma" of the skin clinically presenting as a skin tag : clinicopathologic , immunohistochemical , and molecular analysis of 2 cases .
1		Liposarcomas are extremely rare in the skin .
2		When they involve the skin , it is usually by upward spread from a subcutaneous or deeper seated liposarcoma .
3		Very rarely , liposarcoma metastasize to the skin or arise as a primary dermal lesion .
4		We describe 2 cases of atypical lipomatous tumor "well-differentiated liposarcoma" located in dermis .
5		Both presented clinically as a skin tag .
6		The neoplasms arose in a 56-year-old female and a 69-year-old male patient .
7		Both lesions were treated by excision and reexcision .
8		In addition to classical morphology of atypical lipomatous tumor with evidence of lipoblasts and atypical adipocytes , immunohistochemistry with nuclear murine double-minute type 2 protein and cyclin -dependent kinase -4 expression as well as fluorescence in situ hybridization analysis showing an amplification of murine double-minute type 2 protein and cyclin -dependent kinase -4 were helpful to establish the diagnosis .
9		None of the cases recurred after surgical treatment .
10		These 2 cases show the importance of not to misdiagnose lesions which clinically may appear to be benign .

PMID: 21317707 (Patient)   Terms:
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0		Dedifferentiated liposarcoma with meningothelial-like whorls , metaplastic bone formation , and CDK4 , MDM2 , and p16 expression : a morphologic and immunohistochemical study .
1		We studied 5 cases of dedifferentiated liposarcoma with meningothelial-like whorls and metaplastic bone formation , assessing morphology and immunohistochemical expression of a panel of antigens ( CDK4 , MDM2 , and p16 proteins , desmin , smooth muscle actin , h-caldesmon , CD34 , AE1/AE3 , epithelial membrane antigen , claudin-1 , S100 protein , CD21 , CD35 , CD117 , beta-catenin , vimentin , and MIB1 ) .
2		The specimens were from the retroperitoneum (3) , pelvis (1) or paratesticular region (1) , and all 5 specimens comprised exclusively or predominantly dedifferentiated liposarcoma .
3		All 5 dedifferentiated liposarcomas showed prominent metaplastic bone , 3 produced cartilage , and 1 also had osteosarcomatous tissue .
4		The whorls comprised concentric distributions of spindle or epithelioid cells .
5		All cases expressed smooth muscle actin , 3 strongly , whereas 4 cases showed atleast focal claudin-1 positivity .
6		In all cases , the whorls expressed atleast 2 of CDK4 , MDM2 , and p16 .
7		The presence of 2 morphologic subsets and the immunohistochemical findings suggest that the whorls in these dedifferentiated liposarcomas exhibit divergent myofibroblastic and possibly perineurial differentiation .
8		The CDK4 , MDM2 , and p16 expression in the whorls suggests that they share a similar genetic background to well-differentiated and dedifferentiated liposarcoma , and that additional genetic events are causal to their distinct morphology .

PMID: 21274402 (None)   Terms:
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0		Contributions of cytogenetics and molecular cytogenetics to the diagnosis of adipocytic tumors .
1	Μ	Over the last 20 years , a number of tumor-specific chromosomal translocations and associated fusion genes have been identified for mesenchymal neoplasms including adipocytic tumors .
2		The addition of molecular cytogenetic techniques , especially fluorescence in situ hybridization ( FISH ) , has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal translocations and/or other rearrangements in adipocytic tumors .
3		Indeed , most resent molecular cytogenetic analysis has demonstrated a translocation t ( 11 ; 16 ) ( q13 ; p13 ) that produces a C11orf95-MKL2 fusion gene in chondroid lipoma .
4		Additionally , it is well recognized that supernumerary ring and/or giant rod chromosomes are characteristic for atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma , and amplification of 12q13-15 involving the MDM2 , CDK4 , and CPM genes is shown by FISH in these tumors .
5		Moreover , myxoid/round cell liposarcoma is characterized by a translocation t ( 12 ; 16 ) ( q13 ; p11 ) that fuses the DDIT3 and FUS genes .
6		This paper provides an overview of the role of conventional cytogenetics and molecular cytogenetics in the diagnosis of adipocytic tumors .

PMID: 21121069 (Patient)   Terms:
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0		Clinicopathological features of atypical lipomatous tumors of the laryngopharynx .
1		Atypical lipomatous tumor ( ALT ) of the laryngopharynx is rare .
2		Here we report five cases to demonstrate their clinicopathological features .
3		The patients were four males and one female , aged 41 to 69 years ( median 536 years ) .
4		All tumors ( two in the hypopharynx and three in the larynx ) presented as a slowly growing , painless mass .
5		Symptoms included dysphagia ( 2/5 ) , dysphonia ( 3/5 ) , and the feeling of a foreign body in the throat ( 5/5 ) .
6		Tumors were well circumscribed or focally infiltrative , ranging from 2.0 to 5.0 cm ( median , 34 cm ) in size , and microscopically showed the typical features of lipoma-like ALT .
7		Immunohistochemically , tumor cells were stained with S-100 , vimentin , murine double minute 2 ( MDM-2 ) , and cyclin-dependent kinase 4 ( CDK4 ) .
8		Two patients had local tumor recurrences at 6 and 14 months after initial surgery during follow-up.ALT of laryngopharynx is an indolent tumor .
9		Immunohistochemical staining for MDM-2 and CDK4 is helpful in pathological diagnosis .

PMID: 21117066 (None)   Terms:
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0		Evaluation of well-differentiated/de-differentiated liposarcomas by high-resolution oligonucleotide array-based comparative genomic hybridization .
1		Well-differentiated/de-differentiated liposarcomas ( WDLS/DDLS ) encompass an intriguing disease model in which a temporal intersection occurs between the malignant transformation of mesenchymal cells and the process of adipogenesis .
2		Deciphering the molecular events that trigger and are characteristic of the intersection of these oncogenic and normal processes is critical to affect the often morbid and lethal consequences of malignant tumors of fat .
3		High-resolution genome -wide oligonucleotide array-based comparative genomic hybridization ( aCGH ) with matched gene expression analyses was performed on seven lipomas , one hibernoma , and 38 WD and DDLS to define and compare the genomic events associated with these tumors .
4		WD and DDLS had complex karyotypes .
5		On average , WDLS had 11.1 and DDLS had 22.7 chromosomal copy number aberrations .
6		All of the liposarcomas had 12q13-q15 amplifications with varying peaks at CDK4 ( 12q141 ) , HMGA2 ( 12q143 ) , and MDM2 ( 12q15 ) ; 24% of the DDLS and no WDLS had 1p32.2 ( JUN ) amplifications ; 33% WDLS and 35% DDLS had 1q24.3 amplifications involving DNM3 and miR-214/miR-199a2 ; 24% of the liposarcomas had 6q23-q24 amplifications ( including MAP3K5 ) .
7		Amplifications in GLI1 ( 12q133 ) , JUN , and MAP3K5 ( 6q233 ) were mutually exclusive and occurred predominately in the DDLS. 6q amplifications occurred primarily in retroperitoneal tumors and females represented the majority of those patients who developed fatty tumors prior to the age of 50 years old .
8		This detailed genetic mapping provides insight into the heterogeneity of WD and DDLS and the chromosomal and genetic abnormalities that are present in and distinguish these mesenchymal malignancies .

PMID: 21084242 (None)   Terms:
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0		[ Molecular biology of soft - tissue sarcomas ] .
1		Sarcomas represent a heterogeneous group of tumors with a complex and poorly reproducible classification .
2		However , in the last ten years , several specific genetic alterations have been described allowing a molecular classification with : 1 ) sarcomas with a specific translocation which can be used as a diagnostic marker .
3		These translocations can be demonstrated by RT-PCR or by FISH with commercially available break apart probes ; 2 ) sarcomas with simple genomic profile showing amplification of a few genes .
4		Well differentiated liposarcomas , dedifferentiated liposarcomas and intimal sarcomas show a simple genomic profile characterised by MDM2 and CDK4 amplifications associated with amplification of other genes in dedifferentiated liposarcomas ; 3 ) sarcomas with activating mutations : about 90% of GIST show activating mutation of a receptor tyrosine kinase gene , either KIT or PDGFRA .
5		The most frequent mutation involves exon 11 of KIT followed by exon 9 of KIT and exon 18 of PDGFRA .
6	✓	Demonstration of these mutations is useful for the diagnosis of CD117 negative GIST , for predicting response to imatinib and to explain secondary resistance to imatinib ; 4 ) sarcomas with inactivating mutations : malignant rhabdoid tumors show biallelic inactivation of INI1 gene with a lost of INI1 expression which can be demonstrated by immunohistochemistry ; 5 ) other sarcomas usually show a complex genomic profile characterised by numerous gains and losses of genes with a frequent loss of RB1 and alterations of P53 .
7		Leiomyosarcomas , pleomorphic rhabdomyosarcomas , pleomorphic liposarcomas , myxofibrosarcomas , poorly differentiated sarcomas ( so-called MFH and fibrosarcomas ) belong to this category and show no specific molecular abnormality .

PMID: 21060307 (None)   Terms: in vivo, xenograft, mouse, mouse xenograft, mice
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0		Cellular and in vivo activity of JNJ-28871063 , a nonquinazoline pan-ErbB kinase inhibitor that crosses the blood-brain barrier and displays efficacy against intracranial tumors .
1		Therapeutic progress in well-differentiated/dedifferentiated liposarcoma ( WDLPS/DDLPS ) is hampered by lack of relevant experimental models , thereby limiting comprehensive molecularly based investigations .
2		Our goal is to bridge this experimental gap by establishing and characterizing an in vitro/in vivo model useful for examining WDLPS/DDLPS molecular pathogenesis and also therapeutic screening and testing .
3		WDLPS/DDLPS cells were isolated from freshly resected human surgical specimens and were phenotypically and molecularly characterized .
4		MDM2 amplification was determined via FISH analysis .
5		Adipogenic differentiation was evaluated using Oil Red O staining and western blotting ( WB ) .
6		Tyrosine kinase receptors' ( TKRs ) expression in pre-adipocytes , adipocytes , WDLPS , and DDLPS cells was determined via western blot analysis .
7		SCID mouse xenograft growth was assessed after subcutaneous and/or intraperitoneal tumor cell injection .
8		There was enhanced proliferation , migration , invasion , survival , and pro-angiogenic capacity in DDLPS cells versus WDLPS cells .
9		DDLPS cells formed tumors in SCID mice whereas WDLPS did not .
10		WDLPS/DDLPS cells , especially those that exhibited baseline PPARgamma expression , partially retained terminal adipogenic differentiation capacity .
11	Μ	MDM2 amplification was found in all WDLPS/DDLPS cell strains , CDK4 overexpression was observed in LPS cells as compared with normal adipocytes , and enhanced JUN expression and phosphorylation was seen in DDLPS cells as compared with WDLPS cells .
12		The TKRs : MET , AXL , KIT , and IGF-1R were overexpressed in LPS cells versus normal adipocytes and pre-adipocytes .
13		In conclusion , these newly established cellular and xenograft models can facilitate investigation of liposarcomagenesis , dedifferentiation , and tumor progression .
14		Further studies of the molecular deregulations so identified may lead to improved therapeutic strategies for patients afflicted by these unfavorable malignancies .

PMID: 21038090 (None)   Terms:
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0		Well-differentiated liposarcoma of the oesophagus : clinicopathological , immunohistochemical and array CGH analysis .
1		Liposarcoma develops extremely rarely in the oesophagus .
2		Microscopically , it exhibits subtle atypia of H& ; E-stained features .
3		Accordingly , immunohistochemical features and chromosomal alterations are used for its confirmatory diagnosis .
4		However , cytogenetic analysis has not been performed for oesophageal liposarcoma .
5		We studied chromosomal alterations using array comparative genomic hybridization ( CGH ) , as well as endoscopic , radiological , H& ; E-stained and immunohistochemical features in the oesophageal well-differentiated liposarcoma of a 67-year-old man .
6	Μ	Array CGH analysis revealed the presence of high-level amplifications at chromosomal locations 1p12-1q21.2 , 12q13.2-12q15 and 12q21.33-12q23.1 .
7		At least 29 genes were highly amplified ( log(2) ratio >2 ) , among which CDK4 and MDM2 were the most highly amplified ( log(2) ratio >4 ) and were accepted as major target genes .
8		Moreover , the amplification of AMDHD1 , HAL and LTA4H ( log(2) ratio = 3153 ) was a novel finding .
9		This case suggests the presence of a characteristic profile of gene amplification in well-differentiated liposarcoma of the oesophagus .
10		The amplified genes may be of pathogenic importance for primary oesophageal well-differentiated liposarcoma .

PMID: 20834238 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0	✓	p21WAF1 expression is associated with improved survival after adjuvant chemoradiation for pancreatic cancer .	GE-ASS-RO
1		AIMS :
2		To compare the molecular genetic changes in the Ki-ras and adenomatous polyposis coli ( APC ) genes between colorectal carcinomas and synchronous metastases , and then to compare and contrast those changes with previously reported changes in the two genes between these carcinomas and accompanying adenomas .
3		This expanded comparison would provide greater understanding of the progression of molecular changes in neoplastic tissue during the development of malignancy from a benign adenoma to carcinoma and then to metastatic spread of the malignancy .
4		METHODS :
5		DNA was extracted from paraffin wax embedded tissue .
6	Μ	This was followed by polymerase chain reaction and gel electrophoresis for mutations in the Ki-ras gene using single stranded conformational polymorphism analysis .
7		Amplification of a CA repeat marker was used to assess loss of heterozygosity ( LOH ) at the APC gene .
8		RESULTS :
9		The findings for the Ki-ras gene in 42 paired carcinomas and synchronous metastases were identical , regardless of whether or not the carcinoma and its companion adenoma had identical Ki-ras findings .
10		The results of APC LOH for 39 paired carcinomas and synchronous metastases were also identical , whether or not the carcinoma and its companion adenoma had identical APC LOH findings .
11		Results were uninformative for three pairs .
12		CONCLUSIONS :
13		With respect to these two genes , a carcinoma may be discordant from its companion adenoma , but the metastasis remains consistent with the colonic carcinoma .

PMID: 20697254 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Well-differentiated liposarcoma with low-grade osteosarcomatous component : an underrecognized variant .
1		Mature bone formation in well-differentiated liposarcoma and dedifferentiated liposarcoma has been described as a reactive or "metaplastic" change in most reports , and its neoplastic nature has not been widely appreciated .
2		We herein describe 9 cases of well-differentiated/dedifferentiated liposarcoma with distinct areas of fibroosseous tissue histologically indistinguishable from low-grade osteosarcomas , that is , parosteal osteosarcoma or low-grade central osteosarcoma .
3		The tumors affected middle-aged to elderly patients , and occurred in the retroperitoneum and deep soft tissue of the extremities without connection to the skeletal system .
4		Grossly , all the tumors showed biphasic appearance with lipogenic and osteogenic area , the latter representing 5% to 50% of the total tumor volume .
5		Histologically , the lipogenic component exhibited typical histology of well-differentiated liposarcoma , whereas the osteogenic area consisted of fibroosseous tissue with numerous mature neoplastic bone trabeculae largely lacking osteoblastic rimming , with intervening fascicles of spindle cell proliferation showing low nuclear grade .
6		All samples were positive for MDM2 and/or CDK4 on immunohistochemical analysis ; the antibodies stained many osteocytes , indicating that the bone is neoplastic rather than reactive .
7	Μ	Three cases showed high-grade osteosarcomatous transformation juxtaposed to the low-grade osteosarcomatous component , reminiscent of the "dedifferentiation" phenomenon of skeletal low-grade osteosarcoma .
8		Follow-up revealed local recurrence in 4 cases , but no distant metastases were documented .
9		Recognition of this earlier underappreciated subtype of well-differentiated/dedifferentiated liposarcoma is important , because the fibroosseous component may seem so bland that it may be confused with benign metaplasia such as myositis ossificans , or conversely , the lipomatous component may be inconspicuous that it may be dismissed as normal fat , and such misinterpretation may potentially result in suboptimal treatment .

PMID: 20606735 (Patient)   Terms:
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0		Chromophobe renal cell carcinoma with liposarcomatous dedifferentiation - report of a unique case .
1		Sarcomatous transformation of chromophobe renal cell carcinoma ( CRCC ) is a well recognized phenomenon .
2		Of the published cases with sarcomatous transformation of CRCC , none have shown liposarcomatous differentiation .
3		Out of a cohort of 250 cases of CRCC , 19 ( 76% ) showed sarcomatous differentiation .
4		In one case ( female , age 46 years ) , the sarcomatous component of the tumor displayed histological features of a pleomorphic liposar-coma .
5	Μ	Light microscopic examination revealed a biphasic pattern with a chromophobe renal cell carcinoma ( CRCC ) and a high-grade sarcomatous component containing large pleomorphic lipoblasts .
6		In several areas both components were intermingled .
7		The conventional CRCC component showed classic histological features with calcifications , medium-sized polygonal cells arranged in solid-alveolar structures with raisinoid nuclei , pale-eosinophilic flocculent cytoplasm with perinuclear haloes .
8		In addition , a microcystic-adenomatous component had luminal spaces filled with erythrocytes .
9		The CRCC was positive with Hale's colloidal iron-stain whereas the sarcomatous component was negative .
10		The CRCC component was diffusely positive for cytokeratin 7 , parvalbumin and racemase but negative for cy-tokeratin 20 , vimentin , CD10 , carboanhydrase IX and S100-protein .
11		The pleomorphic liposarcomatous component displayed immunereactivity for CD10 , vimentin , racemase and focally for carboanhydrase IX .
12		The proliferative activity ( Mib-1/Ki-67 ) was 5% in the CRCC and 30% in the pleomorphic liposarcomatous component .
13		No immunereactivity for MDM2 or CDK4 was detected .
14		This is the first reported case of a sarcomatoid CRCC where the sarcomatous component displayed features of a pleomorphic liposarcoma .
15		The patient died from widespread metastatic disease 12 months after nephrectomy .

PMID: 20601955 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Subtype-specific genomic alterations define new targets for soft - tissue sarcoma therapy .
1		Soft - tissue sarcomas , which result in approximately 10,700 diagnoses and 3,800 deaths per year in the United States , show remarkable histologic diversity , with more than 50 recognized subtypes .
2		However , knowledge of their genomic alterations is limited .
3		We describe an integrative analysis of DNA sequence , copy number and mRNA expression in 207 samples encompassing seven major subtypes .
4	Μ	Frequently mutated genes included TP53 ( 17% of pleomorphic liposarcomas ) , NF1 ( 105% of myxofibrosarcomas and 8% of pleomorphic liposarcomas ) and PIK3CA ( 18% of myxoid/round - cell liposarcomas , or MRCs ) .
5	✓	PIK3CA mutations in MRCs were associated with Akt activation and poor clinical outcomes .	GM-ASS-RO
6	Μ	In myxofibrosarcomas and pleomorphic liposarcomas , we found both point mutations and genomic deletions affecting the tumor suppressor NF1 .
7	Μ	Finally , we found that short hairpin RNA ( shRNA )- based knockdown of several genes amplified in dedifferentiated liposarcoma , including CDK4 and YEATS4 , decreased cell proliferation .
8		Our study yields a detailed map of molecular alterations across diverse sarcoma subtypes and suggests potential subtype-specific targets for therapy .

PMID: 20588177 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Gene expression profiling-based identification of molecular subtypes in stage IV melanomas with different clinical outcome .
1		Dedifferentiated liposarcoma ( LPS ) is a malignant adipocytic neoplasm defined as the transition from well-differentiated LPS to a nonlipogenic sarcoma .
2		Heterologous differentiation is seen in 5% to 10% of dedifferentiated LPS , usually with myogenic or osteo/chondrosarcomatous elements .
3		Adipocytic differentiation in the dedifferentiated component is incompatible with the current definition of dedifferentiated LPS .
4		Pleomorphic LPS is a high-grade sarcoma containing lipoblasts .
5		At least in areas , pleomorphic LPS can be indistinguishable from dedifferentiated LPS , except for the presence of lipoblasts in pleomorphic LPS and well-differentiated LPS areas in dedifferentiated LPS .
6		We evaluated 12 unusual liposarcomas : 11 cases with pleomorphic LPS-like morphology affecting patients with concomitant or previous well-differentiated/dedifferentiated LPS , and 1 case resembling inflammatory "MFH" with scattered lipoblasts .
7		Clinical and histologic features were reviewed .
8		Immunohistochemistry for MDM2 and CDK4 was carried out .
9		Amplification of 12q13 to q15 was studied by FISH analysis of the HMGA2 locus .
10		The tumors arose in the retroperitoneum (7) , proximal lower extremity (3) , chest wall (1) , and neck (1) of 9 males and 3 females ( median age 66 y ; range 49 to 76 ) .
11		Size ranged from 9 to 32 cm ( median 23 cm ) .
12		In 3 cases , there was an abrupt transition between well-differentiated LPS and sheets of pleomorphic lipoblasts , indistinguishable from pleomorphic LPS .
13		Four cases consisted of otherwise typical dedifferentiated LPS ( with adjacent well-differentiated LPS ) , except for the presence of lipoblasts in the high-grade component .
14		One case contained both nonlipogenic spindle cell areas and an inflammatory "MFH"-like component with numerous admixed lipoblasts .
15		Four cases were composed exclusively of pleomorphic LPS-like areas developing in 1 of the recurrences or metastases of a prior typical dedifferentiated LPS .
16		Two cases also showed heterologous smooth muscle differentiation .
17		MDM2 and CDK4 were positive in both the dedifferentiated LPS and pleomorphic LPS-like components in 12/12 and 11/12 cases , respectively .
18	Μ	FISH analysis showed high-level amplification of 12q14.3 in all 8 cases successfully tested .
19	Μ	Karyotypes were available for 3 cases and showed ring and giant marker chromosomes .
20		Follow-up , available for 11 patients , ranged from 19 to 196 months ( median 36 mo ) .
21		Seven patients developed local recurrences ( multiple in 3 ) , and 3 developed lung metastases .
22		Thus far , 5 patients have died of disease , 3 are alive with recurrent or metastatic disease , and 3 are alive with no evidence of disease .
23		We conclude that dedifferentiated LPS can show lipoblastic differentiation in the high-grade component , resulting in areas indistinguishable from pleomorphic LPS .
24		The available clinical and molecular data support the notion of "homologous" lipoblastic differentiation in dedifferentiated LPS , rather than mixed-type LPS .

PMID: 20508829 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0	✓	Impact of KIT and PDGFRA gene mutations on prognosis of patients with gastrointestinal stromal tumors after complete primary tumor resection .	GM-ASS-RO
1		Gastrointestinal stromal tumors ( GIST ) are the most common mesenchymal neoplasms of the digestive tract .
2		Inherent overexpression of receptor tyrosine kinase KIT (CD117) and mutations in c-Kit or PDGFRA genes are highly significant prognosticators .
3		A first Russian investigation of c-Kit and PDGFRA mutations in GIST was carried out in 60 patients .
4	Μ	c-Kit mutations were identified in 83.3% ( 50/60 ) , the most frequent being mutations in c-Kit exon 11 ( 734% , 44/60 ) .
5	Μ	Among them , different mutations were identified in the 5'-end of c-Kit exon 11 in 37 GISTs .
6		Duplications in the 3'-end of c-Kit exon 11 were reported in 7 tumors .
7	Μ	Mutations in c-Kit exon 9 ( 734% , 44/60 ) were found in 5 tumors ( 83 3% , 5/60 ) while mutations in c-Kit exon 13 ( 0% , 44/60 ) and 17 ( 17% , 1/60 ) were rare .
8	Μ	PDGFRA mutations in exon 18 were identified in ( 83 3% , 5/60 ) .
9	Μ	Substitution D842V occurred only in one gastric epithelioid - cell GIST .
10		The remaining PDGFRA mutations contained deletions with aminoacids 842-846 .
11		There were no c-Kit and PDGFRA mutations in five tumors .
12		Our findings point to a significant correlation between c-Kit and PDGFRA mutations , on the one hand , and tumor site and histological pattern , on the other .
13		Hence , c-Kit and PDGFRA mutation detection should be used as an additional prognosticator for efficacy of target therapy .

PMID: 20497911 (Patient)   Terms: phase I, clinical trial
Sent#	Symbols	Sentence	Mnemonics
0		[ Targeted treatment of rare connective tissue tumors and sarcomas ] .
1		The recent progress of the biology of the locally aggressive sarcomas of soft tissues and related connective tissue tumors enabled to reclassify molecular and histological entities of the disease .
2	Μ	Six subgroups of sarcomas are identified with specific molecular alterations , the targeted treatments of which are the object of this article : 1 ) sarcomas with specific translocations with fusion oncogenes ( DFSP , PVNS ) ; 2 ) sarcomas with tyrosine kinase mutations ( KIT in GIST ) ; 3 ) tumors with deletion of tumor suppressor genes ( TSC in the PEComes , NF1 involved in type 1 neurofibromatosis ; 4 ) sarcomas with MDM2/CDK4 amplification in the 12q13-15 amplicon , i.e. well differentiated or dedifferentiated liposarcomas ; 5 ) sarcomas with complex genetics present more unrefined genetic changes ( leiomyosarcomas , osteosarcomas ) .
3		On top these 5 groups , desmoids tumors characterized by alterations of the Wnt , beta catenin , APC , and giant cell tumors of the bone , in which RANK/RANKL operates a complex interaction between the cellular stroma and giant tumor cells .
4		The identification of these abnormal ways of road marking to licence the development of effective targeted therapeutic agents against certain rare histological connective subcategories of sarcomas and tumors with local aggressiveness , in particular DFSP , PVNS , GCST , PEComes , endometrial stromal sarcomas , Ewing sarcomas , etc .
5		Imatinib is used in the treatment of DFSP , characterized by a translocation of the gene PDGF , or in pigmented villonodular synovitis ( PVNS ) , a tumor of soft part also locally aggressive , caused by an abnormality of the gene coding for the M-CSF .
6	Μ	Several clinical trials of phase I and II trials demonstrated the antitumor activity of anti-IGF1R antibodies in Ewing , whose fusion gene downregulates IGFBP3 .
7		Inhibitors of MDM2 are in the course of clinical evaluation in liposarcomas .
8		Inhibitors of mTOR ( sirolimus , temsirolimus ) demonstrated an antitumoral activity in the PEComas .
9		The molecular characterization of sarcomas allowed to develop therapeutic targeted to correct the responsible abnormalities .
10		Translational research is and will be an essential tool for the development of new treatments and the identification of the mechanisms of answer and resistance set up by these tumors .

PMID: 20473880 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Oncogenesis and classification of mixed-type liposarcoma : a radiological , histopathological and molecular biological analysis .
1		PURPOSE :
2		The homeodomain transcription factor CDX2 is a relatively specific immunohistochemical marker for gastrointestinal carcinoma .
3		However , no study has comprehensively examined the relationship between CDX2 expression in colon cancer and clinical , pathologic , prognostic , and molecular features , including microsatellite instability and CpG island methylator phenotype ( CIMP ) .
4		EXPERIMENTAL DESIGN :
5		Utilizing 621 colorectal cancers with clinical outcome and molecular data , CDX2 loss was detected in 183 ( 29% ) tumors by immunohistochemistry .
6		RESULTS :
7		In multivariate logistic regression analysis , CDX2 loss was associated with female gender [odds ratio ( OR ) , 3.32 ; P <0.0001] , CIMP-high ( OR , 442 ; P = 00003 ) , high tumor grade ( OR , 269 ; P = 00085 ) , stage IV disease ( OR , 203 ; P = 0019 ) , and inversely with LINE-1 hypomethylation ( for a 30% decline ; OR , 033 ; P = 00031 ) , p53 expression ( OR , 055 ; P = 0011 ) , and beta-catenin activation ( OR , 060 ; P = 0037 ) , but not with body mass index , tumor location , microsatellite instability , BRAF , KRAS , PIK3CA , p21 , or cyclooxygenase-2 .
8		CDX2 loss was not independently associated with patient survival .
9		However , the prognostic effect of CDX2 loss seemed to differ according to family history of colorectal cancer ( P ( interaction ) = 0.0094 ) .
10		CDX2 loss was associated with high overall mortality ( multivariate hazard ratio , 240 ; 95% CI , 128-451 ) among patients with a family history of colorectal cancer ; no such association was present ( multivariate hazard ratio , 097 ; 95% CI , 066-141 ) among patients without a family history of colorectal cancer .
11		CONCLUSIONS :
12		CDX2 loss in colorectal cancer is independently associated with female gender , CIMP-high , high-level LINE-1 methylation , high tumor grade , and advanced stage .
13		CDX2 loss may be associated with poor prognosis among patients with a family history of colorectal cancer .

PMID: 20305534 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer .
1		Cellular angiofibroma is a mesenchymal neoplasm that is characterized by a bland spindle cell component , morphologically reminiscent of spindle cell lipoma , and thick-walled vessels .
2		The tumor occurs equally in men and women and usually arises in the inguino-scrotal or vulvovaginal regions .
3		An earlier study of 51 cases from our group showed that the tumor follows a benign course without any tendency for recurrence .
4		In 1 case , an intralesional microscopic nodule of pleomorphic liposarcoma was observed .
5		The biologic significance of atypia or sarcomatous transformation in cellular angiofibroma remains uncertain .
6		In this study , we characterized clinicopathologic features in 13 cases of cellular angiofibroma with morphologic atypia or sarcomatous transformation .
7		Thirteen cases with atypia or sarcomatous transformation among 154 usual cellular angiofibromas identified between 1993 and 2009 were retrieved from consultation files .
8		There were 12 females and 1 male ranging in age from 39 to 71 years ( median age , 46 y ) .
9		Tumor size ranged from 1.2 to 7.5 cm .
10		In 11 cases , the tumors occurred in the vulva .
11		One case each occurred in the paratesticular and hip regions .
12		Most tumors were located in subcutaneous tissue .
13		There were 4 cases of cellular angiofibroma with atypia .
14		Three showed severely atypical cells as scattered foci within the cellular angiofibroma .
15		One case showed a discrete nodule of atypical cells .
16		There were 9 cases of cellular angiofibroma with morphologic features of sarcomatous transformation .
17		In each case , abrupt transition to a discrete sarcomatous component was seen .
18		Of these 9 cases , the sarcomatous component in 2 cases showed features of pleomorphic liposarcoma with multivacuolated lipoblasts readily identified .
19		Three of these 9 cases showed discrete nodules closely resembling atypical lipomatous tumor within usual cellular angiofibroma .
20		In the remaining 4 cases , the sarcomatous component was composed of pleomorphic spindle cells arranged in various patterns .
21	Μ	By immunohistochemistry , atypical cells and sarcomatous areas showed either multifocal or more diffuse p16 expression compared with either scattered or negative expression in the conventional cellular angiofibroma .
22		The 3 cases with atypical lipomatous tumor-like areas were negative for MDM-2 and CDK4 .
23		Follow-up information was available for 7 patients ( range from 2 to 75 mo ; median : 14 mo ) .
24		Six patients did not develop recurrence or metastasis .
25		One patient died of metastatic carcinoma of unknown primary site 27 months after the diagnosis of cellular angiofibroma with sarcomatous transformation .
26		Cellular angiofibroma with atypia or morphologic sarcomatous transformation occurs predominantly in the subcutaneous tissue of the vulva and , as yet , shows no evident tendency to recur based on limited clinical follow-up available for 7 cases .
27		The sarcomatous component can show variable features including atypical lipomatous tumor , pleomorphic liposarcoma , and pleomorphic sarcoma NOS .
28		Overexpression of p16 in the atypical cells and sarcomatous component suggests a possible underlying molecular mechanism .

PMID: 20228779 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Well-differentiated spindle cell liposarcoma ( 'atypical spindle cell lipomatous tumor' ) does not belong to the spectrum of atypical lipomatous tumor but has a close relationship to spindle cell lipoma : clinicopathologic , immunohistochemical , and molecular analysis of six cases .
1		Well-differentiated spindle cell liposarcoma represents a rare atypical/low-grade malignant lipogenic neoplasm that has been regarded as a variant of atypical lipomatous tumor .
2		However , well-differentiated spindle cell liposarcoma tends to occur in subcutaneous tissue of the extremities , the trunk , and the head and neck region , contains slightly atypical spindled tumor cells often staining positively for CD34 , and lacks an amplification of MDM2 and/or CDK4 in most of the cases analyzed .
3		We studied a series of well-differentiated spindle cell liposarcomas arising in two female and four male patients ( age of the patients ranged from 59 to 85 years ) .
4		The neoplasms arose on the shoulder , the chest wall , the thigh , the lower leg , the back of the hand , and in paratesticular location .
5		The size of the neoplasms ranged from 1.5 to 10 cm ( mean : 6.0 cm ) .
6		All neoplasms were completely excised .
7		The neoplasms were confined to the subcutis in three cases , and in three cases , an infiltration of skeletal muscle was seen .
8		Histologically , the variably cellular neoplasms were composed of atypical lipogenic cells showing variations in size and shape , and spindled tumor cells with slightly enlarged , often hyperchromatic nuclei .
9		Multivacuolated lipoblasts were present in three neoplasms .
10		Focal myxoid stromal changes were seen in three cases .
11	Μ	Immunohistochemically , CD34 was atleast focally positive in all cases , whereas scattered tumor cells only showed a nuclear expression of MDM2 in two neoplasms .
12	Μ	FISH analysis revealed a deletion of the Rb-1 gene in all six cases , whereas no MDM2/CDK4 amplification was identified in all cases tested .
13		Follow-up information was available in four cases ( range from 4 to 24 months ) , and revealed a local recurrence in one case .
14		Although well-differentiated spindle cell liposarcoma and atypical lipomatous tumor behave clinically similar , it can be speculated on the basis of clinicopathologic and molecular findings that well-differentiated spindle cell liposarcoma may constitute an independent entity rather than a morphologic variant of atypical lipomatous tumor , and may represent the atypical/low-grade counterpart of spindle cell lipoma .

PMID: 20221763 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		[ Atypical lipomatous tumors of the stomach . Clinical , morphological and molecular findings ] .
1		AIM :
2		To clarify the significance of JC virus ( JCV ) T-antigen ( T-Ag ) expression in human gastric cancer .
3		METHODS :
4		We investigated the relationship between T-Ag detected by immunohistochemistry and Epstein-Barr virus ( EBV ) infection , microsatellite instability ( MSI ) , and genetic and epigenetic alterations in gastric cancers .
5	Μ	Mutations in the p53 , beta-catenin , KRAS , BRAF , PIK3CA genes were analyzed by polymerase chain reaction ( PCR )- single strand conformation polymorphism and DNA sequencing .
6		Allelic losses were determined by PCR at 7 microsatellite loci .
7		Aberrant DNA methylation was analyzed by MethyLight assay .
8		RESULTS :
9	Μ	JCV T-Ag protein expression was found in 49% of 90 gastric cancer tissues .
10		T-Ag positivity was not correlated with clinicopathological characteristics .
11	Μ	T-Ag expression was detected in a similar percentage of EBV positive cancers ( 4 of 9 , 44% ) and EBV negative cancers ( 35 of 73 , 48% ) .
12	Μ	T-Ag expression was detected in a significantly lower percentage of MSI-H cancers ( 14% ) than in non MSI-H cancers ( 55% , P = 0005 ) .
13	Μ	T-Ag expression was detected in a significantly higher percentage of cancers with nuclear/cytoplasmic localization of beta-catenin ( 15 of 21 , 71% ) than in cancers without ( 42% , P = 0018 ) .
14	Μ	p53 mutations were detected in a significantly lower percentage of T-Ag positive cancers ( 32% ) than in T-Ag negative cancers ( 57% , P = 0018 ) .
15		T-Ag positive gastric cancers showed a significant increase in the allelic losses and aberrant methylation compared with T-Ag negative gastric cancers ( P = 0008 and P = 0003 ) .
16		CONCLUSION :
17		The results suggest that JCV T-Ag is involved in gastric carcinogenesis through multiple mechanisms of genetic and epigenetic alterations .

PMID: 20063101 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		[ Lipoma and atypical lipomatous tumor within the same neoplasia : Evidence for a continuous transition ] .
1		Brain Tumors in Neurofibromatosis .

PMID: 19946100 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Can MDM2 and CDK4 make the diagnosis of well differentiated/dedifferentiated liposarcoma? An immunohistochemical study on 129 soft tissue tumours .
1		Similarity in genetic alterations between paired well-differentiated and dedifferentiated components of dedifferentiated liposarcoma .

PMID: 19823827 (Cell)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		[ Identification of genes over-expressed in myxoid/round cell liposarcoma . DNA microarray analysis and immunohistochemical correlation ] .
1		Myxoid/round cell liposarcoma are characterized by typical chromosomal translocations .
2		This genetic alteration might result in specific gene -expression profiles in this tumor entity .
3		To identify over-expressed genes in myxoid/round cell liposarcoma DNA microarray analysis was performed on four tumors and four samples of adult fat tissue .
4	Μ	Genes ret , cdk4 , cyclin D2 and c-myc showed over-expression by means of microarray analysis and Northern blotting .
5		Immunohistochemistry demonstrated cytoplasmic localization of associated proteins in 36 different tumors .
6		The localization of ret was seen in endothelial cells of plexiform vasculature in addition to its accumulation in tumor cells ( 25% of cases ) .
7		The results show an over-expression of cdk4 , cyclin D2 , c-myc and ret on both the transcriptional and protein level in myxoid/round cell liposarcoma .
8		For cyclin D2 and ret this finding has not been reported in this tumor type .
9		The increase of ret on transcriptional level might be explained by its expression in endothelium in intratumoral plexiform blood vessels .
10		For the molecular pathogenesis of myxoid/round cell liposarcoma our findings imply the involvement of these four genes in the deregulation of the cell cycle , especially as cdk4 and cyclin D2 are target genes of c-myc .

PMID: 19820690 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Carboxypeptidase M : a biomarker for the discrimination of well-differentiated liposarcoma from lipoma .
1		The discrimination between well-differentiated liposarcomas/atypical lipomatous tumors and lipomas can be diagnostically challenging at the histological level .
2		However , cytogenetic identification of ring and giant rod chromosomes supports the diagnosis of well-differentiated liposarcoma/atypical lipomatous tumor .
3		These abnormal chromosomes are mainly composed of amplified genomic sequences derived from chromosome 12q13-15 , and contain several genes , including MDM2 , CDK4 (SAS) , TSPAN31 , HMGA2 , and others .
4		MDM2 is consistently amplified in well-differentiated liposarcomas/atypical lipomatous tumors , and up to 25% in other sarcomas .
5	Μ	As part of a large genomic study of lipomatous neoplasms , we initially found CPM to be consistently amplified in well-differentiated liposarcomas/atypical lipomatous tumors .
6		To further explore this initial finding , we investigated the copy number status of MDM2 and CPM by fluorescent in situ hybridization ( FISH ) on a series of 138 tumors and 17 normal tissues , including 32 well-differentiated liposarcoma/atypical lipomatous tumors , 63 lipomas , 11 pleomorphic lipomas , 2 lipoblastomas , 30 other tumors and 17 normal fat samples .
7	Μ	All 32 well-differentiated liposarcoma/atypical lipomatous tumors showed amplification of MDM2 and CPM , usually >20 copies per cell .
8		The other tumors lacked MDM2 and/or CPM amplification .
9		Chromogenic in situ hybridization confirmed the above results on a subset of these tumors ( n = 27 ) .
10		These findings suggest that identification of CPM amplification could be used as an alternative diagnostic tool for the diagnosis of well-differentiated liposarcoma/atypical lipomatous tumors .

PMID: 19816710 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Atypical lipomatous tumors of the tongue : report of six cases .
1		The occurrence of liposarcoma in the tongue is rare with only 34 cases published so far .
2		We report six new cases of atypical lipomatous tumor ( ALT ) of the tongue , and detection of mdm-2 and CDK4 expression by immunohistochemistry and fluorescence in situ hybridization ( FISH ) , respectively , was performed .
3		The series comprised three males and three females , aged 11-78 years .
4		The tumors arose at the lateral side of the tongue , and in one case , multiple tumor nodules were noted .
5		Follow-up information in five cases ( range from 4 to 159 months ) revealed one local recurrence at 6 months .
6		Microscopically , four cases had features of lipoma-like ALT , whereas two cases displayed patterns of sclerosing ALT .
7	Μ	Immunohistochemically , tumor cells revealed expression of vimentin ( five of five ) , S100 ( five of five ) , mdm-2 ( three of five ) , and CDK4 ( four of five ) .
8	Μ	Two cases were also examined by FISH ; amplification of mdm-2 gene was found in both cases , whereas amplification of CDK4 gene was present in one case only .
9		To the best of our knowledge , this is the third largest series reporting occurrence of ALT in the tongue and the first one where analysis of mdm-2 and CDK4 proteins/genes expression/amplification was performed .
10		Both these markers may be of help in the differential diagnosis of ALT versus lipoma .
11		Although most ALTs of the tongue behave in the nonaggressive fashion , they may recur locally .
12		Based on current data , the term ALT is strongly recommended for tumors occurring in the tongue to prevent inadequate treatment .

PMID: 19737942 (None)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Clinical and biological significance of CDK4 amplification in well-differentiated and dedifferentiated liposarcomas .
1		PURPOSE :
2	Μ	The MDM2 and HMGA2 genes are consistently amplified in well-differentiated/dedifferentiated liposarcomas ( WDLPS/DDLPS ) whereas CDK4 is frequently but not always amplified in these tumors .
3		Our goal was to determine whether the absence of CDK4 amplification was (a) correlated to a specific clinico-histopathologic profile ; and (b) compensated by another genomic anomaly involving the CCND1/CDK4/P16INK4a/RB1/E2F pathway .
4		EXPERIMENTAL DESIGN :
5		We compared the clinical characteristics of a series of 143 WDLPS/DDLPS with amplification of both MDM2 and CDK4 ( MDM2+/CDK4+ ) to a series of 45 WDLPS/DDLPS with MDM2 amplification and no CDK4 amplification ( MDM2+/CDK4 - ) .
6		We used fluorescence in situ hybridization , real time quantitative reverse transcription PCR , and immunohistochemistry to explore the status of CCND1 , P16INK4a , P14ARF , and RB1 .
7		RESULTS :
8		We found that MDM2+/CDK4 - WDLPS/DDLPS represent a distinct clinical subgroup with favorable prognostic features , including low-grade lipoma-like histology , peripheral location , and lower rate of recurrence .
9		By using fluorescence in situ hybridization , we found that genomic aberrations expected to be alternative mechanisms for compensating the lack of CDK4 amplification , such as RB1 and CDKN2A deletions or CCND1 amplification , were very uncommon .
10	Μ	In contrast , by using real time quantitative reverse transcription PCR and immunohistochemistry , we observed that overexpression of P16INK4a ( and P14ARF ) and CCND1 and reduced expression of RB1 were very frequent , independently of the CDK4 status .
11		CONCLUSIONS :
12		Our results underscore the complex coordinated regulation of the RB and p53 growth-control pathways in WDLPS/DDLPS .
13		Because the absence of CDK4 amplification is not specifically counterbalanced by a genomic alteration of the CCND1/CDK4/P16INK4a/RB1/E2F pathway , CDK4 amplification may only represent a "MDM2-HMGA2-helper" in WDLPS/DDLPS tumorigenesis .

PMID: 19734852 (Patient)   Terms:
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0		Similarity in genetic alterations between paired well-differentiated and dedifferentiated components of dedifferentiated liposarcoma .
1		Liposarcoma represents a unique model insofar as some well-differentiated liposarcomas progress to non-lipogenic , so-called 'dedifferentiated , ' forms .
2		The well-differentiated and dedifferentiated family of liposarcomas demonstrates amplification of the chromosome subregion 12q13-q15 with resultant amplification of the MDM2 and CDK4 genes .
3		However , the specific genetic changes that distinguish between well-differentiated and dedifferentiated liposarcomas are less well understood .
4		To study the genetic changes in dedifferentiated liposarcomas , paired well-differentiated and dedifferentiated components of 29 tumors were analyzed separately by array-based comparative genomic hybridization .
5		A bacterial artificial chromosome array at approximately 1-Mb resolution was used .
6		The genetic changes were compared with clinical presentation , grade of the dedifferentiated component and overexpression of MDM2 and CDK4 .
7		Most tumors ( n = 21 , 72% ) were retroperitoneal , with both components present at initial diagnosis ( n = 25 , 86% ) .
8		Eight tumors ( 28% ) were classified as low-grade dedifferentiation .
9		In four cases ( 14% ) , a well-differentiated liposarcoma preceded the presentation of the dedifferentiated tumor by 1-5 years. 12q13-q15 was amplified in all tumors .
10		Using unsupervised hierarchical clustering of copy-number changes , all but two tumors showed close similarities between well-differentiated and dedifferentiated components , and segregated as pairs .
11		Dedifferentiated components had more total amplifications ( P = 0008 ) and a trend for gain at 19q13.2 , but no genetic changes were significant in distinguishing between the two components .
12		High-level amplifications of 1p21-32 ( n = 7 , 24% ) , 1q21-23 ( n = 9 , 31% ) , 6q23-24 ( n = 6 , 21% ) and 12q24 ( n = 3 , 10% ) were common , but none significantly correlated with differentiation .
13	Μ	Presentation and grade correlated with the frequency of changes at a number of genetic loci ( P<0001 ) , whereas CDK4 immunostaining showed negative correlation with 12q13.13 amplification .
14		The genotypic similarity , at the limit of the array's resolution , between components implies that most genetic changes precede phenotypic 'progression , ' early in tumorigenesis .
15		The relationship between genetic changes and presentation or grade may reflect differences in factors that control genomic instability or the background genotype of the tumor .

PMID: 19691106 (Patient)   Terms:
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0		Characterization of a hotspot region on chromosome 12 for amplification in ring chromosomes in atypical lipomatous tumors .
1		Ring chromosomes are cytogenetic hallmarks of genomic amplification in several bone and soft tissue tumors , in particular atypical lipomatous tumors ( ALT ) .
2		In ALT , the ring chromosomes invariably contain amplified material from the central part of the long arm of chromosome 12 , mainly 12q12-->15 , but often also segments from other chromosomes are involved .
3		Previous studies have shown that one of the recurrent amplicons in ALT , located in 12q13.3-14.1 and harboring the candidate target genes TSPAN31 and CDK4 , often has a sharp centromeric border .
4		To characterize this breakpoint region in more detail , 12 cases of ALT with ring chromosomes were analyzed by array comparative genomic hybridization and fluorescence in situ hybridization .
5		In the seven cases showing a sharply delineated amplicon in 12q13.3-14.1 , the breakpoint region was further investigated by real time quantitative polymerase chain reaction and Vectorette PCR .
6		The breakpoints clustered to a 146-kb region containing 11 genes .
7	Μ	Whereas there was no indication that the breakpoints gave rise to fusion genes , in silico analysis revealed that the breakpoint region was enriched for repeated elements that could be important for ring chromosome formation in ALT .

PMID: 19664496 (None)   Terms:
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0		Other targetable sarcomas .
1		Despite complex genetics , aneuploid tumors like dedifferentiated liposarcoma have specific and reproducible chromosomal changes such as amplification of HDM2 and CDK4 that represent potential targets for systemic therapy .
2		In addition , there are cancer cell survival pathways that may not be the target of chromosomal translocations or mutations that are still estimable targets for new systemic therapeutics , be it pathways involved in angiogenesis or apoptosis .
3		In this review , we examine target selection for specific sarcoma subtypes , and demonstrate with a few examples new techniques being used to delineate novel therapeutic inroads for patients with sarcoma .

PMID: 19654500 (None)   Terms:
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0		Retroperitoneal lipomatous tumors without cytologic atypia : are they lipomas? A clinicopathologic and molecular study of 19 cases .
1		Genetic alterations in the PI3K pathway in prostate cancer .

PMID: 19626636 (None)   Terms:
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0		Selective elimination of amplified CDK4 sequences correlates with spontaneous adipocytic differentiation in liposarcoma .
1		Well-differentiated and undifferentiated liposarcomas are characterized by high-level amplifications of chromosome 12 regions including the CDK4 and MDM2 genes .
2		These amplicons are either localized , in well-differentiated liposarcoma ( WDLPS ) , on extrachromosomal structures ( ring or rod chromosomes ) , or integrated into chromosome arms in undifferentiated tumors .
3		Our results reveal that extrachromosomal amplicons are unstable , and frequently lost by micronucleation .
4		This loss correlates with hypermethylation of eliminated sequences and changes of their replication time .
5		Treatment of cells with demethylating agents during early S-phase significantly decreases the rate of micronuclei positive for CDK4 .
6		We also demonstrate that , in our model , micronuclei are generated during anaphase as a consequence of anaphase abnormalities ( chromosome lagging and anaphase bridges ) .
7		Finally , a dramatic increase of adipocytic differentiation was noted in cells that have eliminated copies of CDK4 gene in micronuclei .
8		These findings provide evidence that , in WDLPS , adipocytic differentiation could be the consequence of CDK4 loss , an event occurring rarely in undifferentiated tumors in which the amplified sequences are integrated into chromosome arms .

PMID: 19574885 (Patient)   Terms:
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0		Sensitivity to gefitinib ( Iressa , ZD1839 ) in non-small cell lung cancer cell lines correlates with dependence on the epidermal growth factor ( EGF ) receptor/extracellular signal-regulated kinase 1/2 and EGF receptor/Akt pathway for proliferation .
1		Dedifferentiated liposarcoma ( DDL ) , occurring in up to 10% of well differentiated liposarcoma cases , has similar histologic features to that of undifferentiated high-grade pleomorphic sarcoma ( UHGPS ) ; the former develops in a background of atypical lipomatous tumors/well differentiated liposarcoma , whereas the latter shows no specific line of differentiation .
2		The retroperitoneum and thigh represent the most common anatomic locations for both the sarcomas .
3		Despite their morphologic similarity , the issue of whether these 2 sarcomas share overlapping immunohistochemical and molecular features has not been well studied .
4		We examined the expression of the lipogenic tumor-related markers peroxisome proliferator-activated receptor gamma ( PPAR-gamma ) , CDK4 , and MDM2 in 15 cases of DDL and 45 cases of retroperitoneal/thigh UHGPS .
5		Patients with DDL ranged from 31 to 82 years ( mean 63 y ) with a male : female ratio of 5 : 3 .
6		Patients with UHGPS ranged from 14 to 80 years ( mean 52 y ) with a male : female ratio of 3 : 2 .
7		All 15 DDLs expressed CDK4 and MDM2 ( 100% ) , and 8 of 15 cases expressed PPAR-gamma ( 53% ) .
8		Twenty-three of 45 ( 51% ) UHGPS expressed atleast 1 of these 3 markers .
9		We also studied MDM2 and CDK4 gene amplification by fluorescence in situ hybridization in 28 immunohistochemically positive cases , including 5 DDLs and 23 UHGPSs .
10	Μ	All 5 cases of DDL showed MDM2 and/or CDK4 amplification ( 100% ) , whereas 6 of 45 UHGPSs showed MDM2 and/or CDK4 amplification ( 13% ) .
11	Μ	Our results demonstrate that (1) the lipogenic tumor markers CDK4 and MDM2 can be used as surrogate immunohistochemical markers for the diagnosis of malignant lipomatous tumors with high sensitivity ; (2) approximately 26% of retroperitoneal/thigh UHGPS cases that were positive for PPAR-gamma , CDK4 , or MDM2 by immunohistochemistry showed characteristic CDK4 and MDM2 gene amplification , suggesting that a subset of UHGPS cases represent DDL despite lacking histologic evidence of lipoblasts .

PMID: 19454362 (Patient)   Terms:
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0		SNP genotyping of a sclerosing rhabdomyosarcoma : reveals highly aneuploid profile and a specific MDM2/HMGA2 amplification .
1		Since the first description of sclerosing rhabdomyosarcoma in 2000 , 19 pediatric cases have been reported in the literature .
2		However , it is debated whether sclerosing rhabdomyosarcoma represents a specific rhabdomyosarcoma entity or a variant of embryonal or alveolar rhabdomyosarcoma .
3		To date , 6 sclerosing rhabdomyosarcoma karyotypes and 1 sclerosing rhabdomyosarcoma comparative genomic hybridization profile have been reported .
4		We present the first whole - genome tumoral genotyping of a sclerosing rhabdomyosarcoma by high-density single nucleotide polymorphism array .
5	Μ	The single nucleotide polymorphism genotyping revealed a complex pattern including gains and losses of whole chromosomes and an amplification of the 12q13-15 region .
6		Amplification of the 12q13-q15 region containing SAS , GLI , CDK4 , and MDM2 has been observed in rhabdomyosarcoma .
7		In the present case , the 2 amplified target genes were MDM2 and HMGA2 , excluding CDK4 .
8		The identification of a specific MDM2-HGMA2 amplicon excluding CDK4 has only been described so far in well-differentiated and dedifferentiated liposarcoma .
9		Further studies are needed to assess if this anomaly is a specific marker of sclerosing rhabdomyosarcoma .

PMID: 19363435 (None)   Terms:
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0		Lipoleiomyosarcoma of the rectosigmoid colon : a unique site for a rare variant of liposarcoma .
1		OBJECTIVES :
2		Soft tissue tumors with dual adipocytic and smooth muscle differentiation are generally rare with most being benign .
3		Sarcomas with dual fatty and smooth muscle differentiation are even rarer .
4		The purpose of this paper is to discuss a rare presentation of a lipoleiomyosarcoma and review , the method of pathologic diagnosis and the literature .
5		METHODS :
6		Detailed clinical and histopathologic review of a clinical case and review of the literature using PUBMED for publications on lipoleiomyosarcoma .
7		RESULTS :
8		Based on the literature , lipoleiomyosarcomas favor body cavities and visceral sites although an occurrence in the intestine has been reported .
9		Pathologic diagnosis requires immunohistochemical staining with MDM2 and CDK4 .
10		CONCLUSIONS :
11		This is the first reported case of an intestinal lipoleiomyosarcoma .
12		Its diagnosis requires immunohistochemistry and awareness of its possible existence .

PMID: 18820664 (Patient)   Terms:
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0		Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease : an immunohistochemical and molecular biological analysis .
1		Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma .
2		Rarely , however , primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma , based on the presence of myxoid areas and vascular crow's feet pattern , which has resulted in a debate on the classification of liposarcoma in the retroperitoneum .
3		Genetically , myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases .
4		Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion , whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region , including MDM2 and CDK4 genes .
5		As myxoid/round cell liposarcoma is highly radio - and chemosensitive , differentiation between subtypes is important to optimize treatment .
6		We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma .
7		Primary retroperitoneal myxoid/round cell liposarcoma ( n = 16 ) were compared to primary extremity myxoid/round cell liposarcoma ( n = 20 ) .
8		Histopathological and immunohistochemical features were studied .
9		Amplification status of the 12q13-15 region was studied using a multiplex ligation -dependent probe amplification analysis , and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR .
10		In primary retroperitoneal myxoid/round cell liposarcoma , MDM2 and CDK4 staining was both positive in 12 of 15 cases .
11		In primary extremity myxoid/round cell liposarcoma , MDM2 was negative in 18/20 and CDK4 was negative in all cases .
12	Μ	Multiplex ligation -dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas .
13		Translocation was present in all ( 18/18 ) primary extremity myxoid/round cell liposarcomas , but absent in all primary retroperitoneal myxoid/round cell liposarcomas .
14		On the basis of immunohistochemical and molecular characteristics , apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma .
15		In these cases , treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma .
16		Moreover , finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum .

PMID: 18611926 (Patient)   Terms:
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0		Cowden syndrome-affected patients with PTEN promoter mutations demonstrate abnormal protein translation .
1		Massive localized lymphedema is a benign soft tissue lesion that usually presents as a large mass in morbidly obese adults .
2		The diagnosis may be challenging as it can mimic other lesions , including well-differentiated liposarcoma .
3		We report 2 cases of massive localized lymphedema with unusual presentation .
4		The first case is a recurrent massive localized lymphedema in the right thigh of a 40-year-old morbidly obese woman .
5		In addition to typical massive localized lymphedema features such as prominent edema and vascular proliferation in the adipose tissue , we observed prominent and abundant multinucleated stromal floret-like giant cells , arborizing network of capillaries , and areas of hyalinized collagen .
6		Our second case is in a rare location ( scrotum extending into penile soft tissue ) in an overweight 55-year-old male .
7		This lesion exhibits striking smooth muscle hyperplasia .
8		Lack of staining by antibodies against murine double minute 2 protein and cyclin dependent kinase 4 and absence of high mobility group AT - hook 2 transcription factor rearrangement by fluorescence in situ hybridization support our diagnosis of massive localized lymphedema in both cases .

PMID: 18551755 (Patient)   Terms:
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0		Primary retroperitoneal lipoma : a soft tissue pathology heresy? : report of a case with classic histologic , cytogenetics , and molecular genetic features .
1		Adipose tissue tumors of the retroperitoneum showing no identifiable cytologic atypia are usually classified as lipomalike well-differentiated liposarcoma .
2		Whether a subset of these tumors represents true examples of retroperitoneal lipoma remains a controversial subject , because the diagnostic liposarcoma cells may be of difficult identification , even after extensive sampling .
3		Herein , we describe a large retroperitoneal lipoma with classic histopathologic , cytogenetic , molecular cytogenetic , and molecular genetic features .
4		Extensive morphologic inspection showed no evidence of cytologic atypia .
5		Cytogenetic analysis performed on fresh tissue material revealed the classic lipoma chromosome t ( 3 ; 12 ) ( q27 ; q14-15 ) .
6		Fluorescence in situ hybridization on multiple sections excluded the presence of MDM2 and CDK4 amplification , but showed HMGA2 balanced rearrangement in most cells .
7	Μ	Reverse-transcriptase polymerase chain reaction followed by sequencing analysis confirmed the presence of the HMGA2-LPP fusion gene , a characteristic and the most common fusion product found in lipoma .
8		The patient has been followed for 2.5 years without evidence of recurrence or metastasis .
9		These results indicate that retroperitoneal lipomata do exist , but their diagnosis must rely on stringent histologic , cytogenetic , and molecular genetic analysis .

PMID: 18551309 (Patient)   Terms:
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0		Mixed-type liposarcoma : clinicopathological , immunohistochemical , and molecular analysis of a case arising in deep soft tissues of the lower extremity .
1		A rare case of mixed-type liposarcoma arising in deep soft tissue of the right thigh of a 45-year-old female patient is reported .
2		The neoplasm was completely excised and was composed of an irregular admixture of areas of atypical lipomatous tumor/well-differentiated liposarcoma of the lipoma-like subtype with areas of myxoid/round cell liposarcoma .
3		An amplification of the MDM2 and CDK4 genes respectively in the atypical lipomatous tumor/well-differentiated liposarcoma areas was detected by fluorescence in situ hybridization ( FISH ) analysis , and translocations of the CHOP and FUS genes were detected by FISH analysis in the myxoid/round cell liposarcoma areas .

PMID: 18517278 (None)   Terms:
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0		Translocations and amplifications of chromosome 12 in liposarcoma demonstrated by the LSI CHOP breakapart rearrangement probe .
1		CONTEXT :
2		Liposarcomas display a number of molecular abnormalities involving chromosome 12 .
3		Myxoid and round cell liposarcomas are characterized by t ( 12 ; 16 ) ( q13 ; p11 ) or t ( 12 ; 22 ) ( q13 ; q12 ) translocations .
4		Amplifications occur within the 12q13-15 region of atypical lipomatous tumors and well-differentiated liposarcomas but not lipomas .
5		OBJECTIVE :
6		To investigate the performance characteristics of the LSI CHOP Breakapart Rearrangement Probe for the diagnosis of myxoid/round cell liposarcomas and atypical lipomas/well-differentiated liposarcomas .
7		DESIGN :
8		We investigated a series of lipomatous neoplasms ( 5 lipomas , 5 well-differentiated liposarcomas , 22 myxoid/round cell liposarcomas , 2 liposarcomas not otherwise specified , and 2 dedifferentiated liposarcomas ) and normal myometrium for abnormalities in the q13-15 region of chromosome 12 .
9		Cases were studied for the presence or absence of t ( 12 ; 16 ) ( q13 ; p11 ) or t ( 12 ; 22 ) ( q13 ; q12 ) translocations by the LSI CHOP Breakapart Rearrangement Probe .
10		These probes contain a sequence encompassing the SAS and CDK4 genes .
11		Four or more copies of this sequence were considered to represent amplification of these genes .
12		RESULTS :
13		Rearrangement of the CHOP gene was seen in all evaluable myxoid liposarcomas .
14		Rearrangements were seen in 1 dedifferentiated liposarcoma but not in normal myometrium or lipomas .
15		Probe signal amplification was seen in all 5 well-differentiated liposarcomas and 1 myxoid liposarcoma .
16		No signal amplification was seen in lipomas or myometrium .
17		CONCLUSIONS :
18		Demonstration of translocations t ( 12 ; 16 ) ( q13 ; p11 ) and t ( 12 ; 22 ) ( q13 ; q12 ) by the LSI CHOP Breakapart Rearrangement Probe appears to correlate with round cell/myxoid liposarcoma .
19	Μ	The probe also demonstrated amplification of the 12q13-15 region in well-differentiated liposarcomas , making it useful for the diagnosis of these neoplasms .
20		In a significant percentage of cases , high background fluorescence or poor probe staining made interpretation difficult .

PMID: 18413802 (Cell)   Terms:
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0		Sorafenib inhibits growth and mitogen -activated protein kinase signaling in malignant peripheral nerve sheath cells .
1		Malignant peripheral nerve sheath tumors ( MPNST ) are soft - tissue tumors with a very poor prognosis and largely resistant to chemotherapy .
2		MPNSTs are characterized by activation of the Ras pathway by loss of tumor suppressor neurofibromatosis type 1 .
3		In view of this , MPNST may be susceptible to inhibition of the activated Ras/Raf/mitogen -activated protein kinase pathway by the B-Raf inhibitor sorafenib .
4		MPNST ( MPNST and ST8814 ) and dedifferentiated liposarcoma ( LS141 and DDLS ) human tumor cell lines were characterized for Ras activation and B-Raf expression .
5		Tumor cells were treated with sorafenib and examined for growth inhibition , inhibition of phospho-MEK , phospho-ERK , cell cycle arrest , and changes in cyclin D1 and pRb expression .
6		MPNSTs were sensitive to sorafenib at nanomolar concentrations .
7		This appeared to be due to inhibition of phospho-MEK , phospho-ERK , suppression of cyclin D1 , and hypophosphorylation of pRb at the CDK4-specific sites , resulting in a G(1) cell cycle arrest .
8		These effects were not seen in the liposarcoma cells , which either did not express B-Raf or showed decreased Ras activation .
9		Small interfering RNA -mediated depletion of B-Raf in MPNSTs also induced a G(1) cell cycle arrest in these cells , with a marked inhibition of cyclin D1 expression and Rb phosphorylation , whereas depletion of C-Raf did not affect either .
10		With growth inhibition at the low nanomolar range , sorafenib , by inhibiting the mitogen -activated protein kinase pathway , may prove to be a novel therapy for patients with MPNST .

PMID: 18269579 (Patient)   Terms:
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0		Lipoblastoma in adolescents and young adults : report of six cases with FISH analysis .
1		AIMS :
2		Lipoblastoma is a rare benign adipocytic neoplasm that occurs primarily in infancy and early childhood .
3		Histologically , there is some morphological overlap with atypical lipomatous tumour and myxoid liposarcoma and the age at presentation is often regarded as a major diagnostic criterion .
4		However , we recently encountered several cases of lipoblastoma occurring in adolescents and young adults .
5		The aim was to document the occurrence of lipoblastoma in older patients , with cytogenetic confirmation .
6		METHODS AND RESULTS :
7		Six cases of lipoblastoma in patients >12 years old were identified .
8		The tumours occurred in four male and two female patients ranging from 14 to 24 years old .
9		Our cases showed the classical histological features of lipoblastoma .
10		Three tumours were composed predominantly of mature adipocytes and the three other cases showed an immature appearance , with a prominent myxoid matrix .
11		Fluorescence in situ hybridization ( FISH ) demonstrated rearrangements of the PLAG1 region in two cases and polysomy for chromosome 8 in three other cases .
12		None of the tumours had amplification of MDM2 or CDK4 .
13		CONCLUSIONS :
14		Lipoblastoma occurs rarely in young adults and should enter into the differential diagnosis of 'atypical' fatty tumours in adults .
15		Our report underscores the diagnostic value of FISH analysis .

PMID: 18214854 (Patient)   Terms:
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0		HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon .
1		Data concerning the fine structure of the 12q13-15 amplicon which contains MDM2 and CDK4 in well-differentiated and dedifferentiated liposarcomas ( WDLPS/DDLPS ) are scarce .
2		We investigated a series of 38 WDLPS/DDLPS using fluorescence in situ hybridization analysis with 17 probes encompassing the 12q13-15 region .
3		In addition , using quantitative RT-PCR we studied the expression of MDM2 , CDK4 , DDIT3 (CHOP/GADD153) , DYRK2 , HMGA2 , TSPAN31 and YEATS4 (GAS41) in 11 cases .
4		We showed that CDK4 ( 12q141 ) belonged to a distinct amplicon than MDM2 ( 12q15 ) .
5		There was no continuity in the amplified sequences between MDM2 and CDK4 .
6		Moreover , while MDM2 was amplified and overexpressed in all cases , CDK4 was not amplified or overexpressed in 13% of cases .
7		The centromeric border of the CDK4 amplicon was located immediately downstream the 5' end of DDIT3 , a gene known for being involved in myxoid liposarcoma translocations .
8		DDIT3 was amplified in 3 cases and overexpressed in 9 cases .
9		The overexpression of DDIT3 was correlated to the CDK4 amplification and not to its own amplification status .
10		This suggested that the CDK4 amplicon , as well as the overexpression of DDIT3 , might be generated by the disruption of a fragile region in 5' DDIT3 .
11		HMGA2 was always amplified and rearranged indicating that it plays a central role in WDLPS/DDLPS .
12		HMGA2 rearrangement frequently resulted in a loss of the 3' end region that is a binding site for let-7 .
13	Μ	We also found a frequent amplification and overexpression of YEATS4 , an oncogene that inactivates P53 , suggesting that YEATS4 might play an important role together with MDM2 in WDLPS/DDLPS oncogenesis .

PMID: 18204431 (None)   Terms:
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0		Immunostaining for peroxisome proliferator gamma distinguishes dedifferentiated liposarcoma from other retroperitoneal sarcomas .
1		Dedifferentiated liposarcoma can be readily diagnosed by the juxtaposition of a well-differentiated liposarcoma to a nonlipogenic sarcoma .
2		However , if the lipogenic component is not abundant due to surgical sampling or small biopsy , dedifferentiated liposarcoma can be difficult to distinguish from other poorly different sarcomas .
3		Peroxisome proliferator-activated receptor gamma ( PPAR-gamma ) is a nuclear hormone receptor that plays a critical role in adipocyte differentiation .
4		Prior studies have not only demonstrated PPAR-gamma mRNA in various subtypes of liposarcoma but have also shown that adipocyte differentiation can be induced in some liposarcomas by a PPAR-gamma agonist .
5		In the present study , we investigated whether immunostaining for PPAR-gamma can be used to distinguish dedifferentiated liposarcoma from other retroperitoneal sarcomas .
6		We examined a series of 40 dedifferentiated liposarcoma and compared the staining for PPAR-gamma to a series of 24 retroperitoneal sarcomas that lacked lipogenic differentiation .
7		A monoclonal antibody against PPAR-gamma was used to stain formalin-fixed paraffin-embedded tissue .
8		Specific nuclear immunostaining was present in 37/40 ( 93% ) of the dedifferentiated liposarcoma and 6/24 ( 25% ) of the other sarcomas ( two leiomyosarcomas and four undifferentiated sarcomas ) .
9	Μ	Interestingly , immunostaining for CDK4 and/or MDM2 was identified in three of the four PPAR-gamma-positive undifferentiated sarcomas , raising the possibility that these may represent dedifferentiated liposarcoma .
10		This is the first study demonstrating the utility of PPAR-gamma immunohistochemistry in the diagnosis of dedifferentiated liposarcoma in tissue sections .
11		Although not completely specific , the presence of PPAR-gamma staining , in combination with histologic findings and other markers , can aid in the diagnosis of dedifferentiated liposarcoma , particularly on small biopsies that may not sample the well-differentiated component .

PMID: 18160213 (Cell)   Terms:
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0		Characterization of the 12q amplicons by high-resolution , oligonucleotide array CGH and expression analyses of a novel liposarcoma cell line .
1		The cytogenetic hallmark of well-differentiated liposarcoma ( WDLS ) is a giant marker chromosomes containing amplified genes from chromosome 12q13-q15 .
2		Here , we have employed SKY and high-resolution 244K oligonucleotide array CGH to characterize rearrangements and amplifications in a new WDLS cell line (GOT3) with a giant marker chromosome derived from chromosomes 12 , 1 , and X .
3	Μ	The most prominent amplifications included 144 genes in 12q11-q21.2 , 201 genes in 1q23.3-q44 , and six genes in 13q32.1-q32.2 .
4	Μ	In the 12q amplicons , MDM2 showed the highest level of amplification followed by LYZ , HMGA2 ( 5'-part ) , TSPAN8 , CNOT2 , YEATS4 , CDK4 , GNS , HELB , and TSFM .
5	Μ	Expression analysis of genes from the three major amplicons revealed that several highly amplified potential target genes , including HMGA2 , MDM2 , YEATS4 , CDK4 , PKP1 , IPO9 , and SOX21 , were strongly overexpressed .
6	Μ	Studies of cell cycle controlling proteins that interact with CDK4 and MDM2 revealed an abnormally strong expression of cyclins D1 and E .
7		The selective high-level amplification of the 5'-part of HMGA2 , including the DNA -binding domains , suggests that this gene is a major target of amplifications in WDLS .
8		Our results also identify several novel candidate genes of potential pathogenetic and therapeutic importance for WDLS .

PMID: 18036404 (None)   Terms:
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0		Dedifferentiated liposarcoma of the pleura mimicking a malignant solitary fibrous tumor and associated with dedifferentiated liposarcoma of the mediastinum : usefulness of cytogenetic and molecular genetic analyses .
1		Dedifferentiated liposarcoma of the pleura is an extremely rare malignancy mimicking a variety of tumors , such as other sarcomas , mesothelioma , and malignant solitary fibrous tumor of the pleura .
2		Liposarcoma of the pleura can be combined with mediastinal involvement , and in most cases it may be impossible to be certain where the primary tumor originated .
3		In this report , we describe a very rare occurence of a dedifferentiated liposarcoma of the pleura in a 76-year-old woman associated with a distinct second dedifferentiated liposarcoma of the mediastinum .
4		Histologically , the pleural tumor demonstrated spindle cells arranged in a fascicular pattern , whereas the mediastinal tumor was mostly adipocytic with small areas of spindle cells .
5		Vimentin and protein S100 were focally expressed by the tumor cells .
6		The differential diagnosis of the pleural mass included malignant solitary fibrous tumor .
7	Μ	Cytogenetic analysis showed supernumerary ring chromosomes in the pleural tumor , as well as strong amplification of MDM2 and CDK4 genes in both tumors .
8	Μ	Array comparative genomic hybridization showed amplifications of chromosome arms 6q , 12q , and 15q , shared by both tumors and strongly pointing to a common origin .

PMID: 17895758 (Patient)   Terms:
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0		Dedifferentiated liposarcomas with divergent myosarcomatous differentiation developed in the internal trunk : a study of 27 cases and comparison to conventional dedifferentiated liposarcomas and leiomyosarcomas .
1		Dedifferentiated liposarcoma ( DLPS ) is one of the most frequent sarcomas of the retroperitoneum and represents most undifferentiated sarcomas of the internal trunk .
2		In about 5% cases , the dedifferentiated component is an heterologous sarcoma such as leiomyosarcoma or rhabdomyosarcoma .
3		We reviewed a series of 65 sarcomas with a myogenic differentiation developed in the internal trunk for which initial diagnoses were leiomyosarcoma ( 37 ) , rhabdomyosarcoma (6) , malignant mesenchymoma (6) , and DLPS ( 16 ) .
4		Immunostainings for MDM2 , CDK4 , alpha smooth actin , desmin , caldesmon , myogenin , c-kit , and progesterone receptor were performed .
5		In 48 cases , the amplification status of MDM2 and CDK4 could be evaluated with quantitative polymerase chain reaction on paraffin-embedded tissues extracted DNAs .
6		After review of the cases , final diagnoses were leiomyosarcoma ( 35 ) , rhabdomyosarcomatous ( 20 ) or leiomyosarcomatous (7) DLPS , probable DLPS (2) , and malignant mesenchymoma (1) .
7		DLPS were bigger tumors ( median : 18.2 cm ) than leiomyosarcomas ( median : 12 cm ) .
8		They had a lower 5-year recurrence-free survival than leiomyosarcomas ( 45% vs. 71% ) but a higher 5-year metastasis-free survival ( 73% vs. 39% ) .
9		There was no significant difference in overall survival ( 57% vs. 34% ) .
10		Outcome of patients with a DLPS with a myosarcomatous component did not differ from conventional DLPS .
11		In conclusion , most sarcomas with a rhabdomyosarcomatous differentiation occurring in the internal trunk of adults are DLPS .
12		Moreover , DLPS with a myogenic component have a low metastatic potential , similar to conventional DLPS and significantly lower to the metastatic potential of leiomyosarcomas .

PMID: 17895748 (Patient)   Terms:
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0		Detection of MDM2-CDK4 amplification by fluorescence in situ hybridization in 200 paraffin-embedded tumor samples : utility in diagnosing adipocytic lesions and comparison with immunohistochemistry and real-time PCR .
1		Atypical lipomatous tumor/well-differentiated liposarcomas and dedifferentiated liposarcomas are characterized by the amplification of MDM2 and CDK4 genes .
2		To evaluate the accuracy of fluorescence in situ hybridization ( FISH ) analysis in the differential diagnosis of adipose tissue tumors , we investigated MDM2-CDK4 status by FISH , real-time polymerase chain reaction ( PCR ) [quantitative PCR ( Q-PCR )] and immunohistochemistry ( IHC ) in a series of 200 adipose tumors .
3		First , we evaluated MDM2-CDK4 amplification and expression in a series of 94 well-defined adipose tissue tumors .
4		Results showed that FISH was interpretable in 45 of 50 cases ( 90% ) , and was more specific and sensitive than Q-PCR and IHC .
5		We then used the same techniques as complementary diagnostic tools in a series of 106 adipose and soft tissue tumors of unclear diagnosis to distinguish between (i) lipomas and atypical lipomatous tumor/well-differentiated liposarcomas , ( ii ) malignant undifferentiated tumors and dedifferentiated liposarcomas , and ( iii ) a variety of benign tumors and liposarcomas .
6		Our results indicate that although helpful , IHC alone is often insufficient to solve diagnostic problems .
7		FISH and Q-PCR methods gave concordant results and were equally informative in most cases .
8		However , the proportion of noninterpretable cases was slightly higher with FISH than with Q-PCR .
9		When tumor cells represented a minor component of the tumor tissue , such as with inflammatory tumors , FISH was more powerful than Q-PCR by allowing visualization of individual cells .
10		In conclusion , we recommend that the evaluation of MDM2-CDK4 amplification using FISH or Q-PCR be used to supplement IHC analysis when diagnosis of adipose tissue tumors is not possible based on clinical and histologic information alone .

PMID: 17372913 (Patient)   Terms:
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0		Gains and complex rearrangements of the 12q13-15 chromosomal region in ordinary lipomas : the "missing link" between lipomas and liposarcomas ?
1		Well-differentiated liposarcomas ( WDLPS ) classically contain high-level amplification of 12q14-15 sequences , including the MDM2 and CDK4 genes , while lipomas are characterized by simple structural chromosome aberrations often involving HMGA2 at 12q15 .
2		Previous studies have shown that low-level gain of the 12q14-15 region , such as trisomy 12 and 12q15-24 duplication , might be sufficient for the development of minimal atypia and formation of WDLPS .
3		Moreover , because some features , such as overexpression of HMGA2 , are shared by both lipomas and WDLPS , it has been hypothesized that lipomas and WDLPS may form a genetic and morphological continuum .
4		We report here the results of molecular cytogenetic analysis of 8 lipomas that had unusual chromosomal features resulting in gains of 12q14-15 .
5		While 3 cases had simple numerical rearrangements ( trisomy 12 ) or structural rearrangements ( unbalanced translocations with 12q gains ) , 5 cases were particularly intriguing because of peculiar features such as giant chromosomes , supernumerary chromosomes or neocentromeres that usually are the hallmark of WDLPS .
6	Μ	Gain of 12q14-15 sequences including extra copies of MDM2 and CDK4 were detected by fluorescence in situ hybridization analysis in all analyzed cases but no expression of MDM2 and CDK4 was observed suggesting that these genomic imbalances had no functional consequence .
7		We observed rearrangements of HMGA2 in 5 out 8 cases .
8		Altogether , our results indicate that moderate gains of 12q are not always associated with a malignant phenotype , and that some intermediary forms exist between classical lipomas and classical WDLPS .
9		Some of these intermediary forms may correspond to a genomic premalignant condition while some may have no malignant potential .

PMID: 17214366 (None)   Terms:
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0		Chromosome-12 copy number alterations and MDM2 , CDK4 and TP53 expression in soft tissue liposarcoma .
1		BACKGROUND :
2		Liposarcoma is a heterogeneous group of soft tissue sarcomas in which definitive prognostic parameters need to be identified .
3		MATERIALS AND METHODS :
4		The series included 33 consecutive soft tissue ( well-differentiated , WDLPS , n = 19 ; and dedifferentiated , DDLPS , n = 14 ) liposarcoma .
5		Clinicopathological variables included age , gender , body location , degree of dedifferentiation and mitotic count .
6		The rrolecular analysis included MDM2 , CDK4 and TP53 expressions and chromosome -12 copy number alterations .
7		RESULTS :
8		Centrally located ( retroperitoneal , abdominal cavity or groin region ) WDLPS had more dedifferentiation ( p = 0001 ) .
9		Patients with DDLPS and a high mitotic rate died ( p = 0070 ) or experienced recurrencies ( p = 0029 ) more frequently .
10		Co-expression of MDM2/CDK4 ( p = 0001 ) and TP53 accumulation ( p = 0017 ) related to dedifferentiation but not to recurrence or death , both in WDLPS and DDLPS .
11	✓	DDLPS had higher centromeric chromosome -12 copy number than WDLPS ( p = 0013 ) , but this was unrelated to recurrence or death .	GM-ASS-DS
12		CONCLUSION :
13		Central location is a risk factor in WDLP .
14		Co-expression of MDM2/CDK4/TP53 and chromosome -12 alterations characterize DDLPS suggesting a link with dedifferentiation .

PMID: 21487465 (None)   Terms: ex vivo, Ex vivo, mice
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0		Rare cause of dysphagy : giant polypoid esophageal well-differentiated liposarcoma .
1		AIM :
2		To investigate whether bone marrow-derived denritic cells pulsed with tumor lysates induce immunity against gastric cancer ex vivo .
3		METHODS :
4		c-kit(+) hematopoietic progenitor cells were magnetically isolated with a MiniMACS separator from BALB/c mice bone marrow cells .
5		These cells were cultured with cytokines GM-CSF , IL-4 , and TNFalpha to induce their maturation .
6		They were analysed by morphological observation , phenotype analysis , and mixed lymphocyte reaction ( MLR ) .
7		Bone marrow-derived DCs ( BM-DCs ) were pulsed with tumor cell lysate obtained by rapid freezing and thawing at a 1 : 3 DC : tumor cell ratio .
8		Finally , cytotoxic T lymphocyte ( CTL ) activity and interferon gamma ( IFNgamma ) secretion was evaluated ex vivo .
9		RESULTS :
10		c-kit(+) hematopoietic progenitor cells from mice bone marrow cells cultured with cytokines for 8 d showed the character of typical mature DCs .
11		Morphologically , observed by light microscope , these cells were large with oval or irregularly shaped nuclei and with many small dendrites .
12	Μ	Phenotypically , FACS analysis showed that they expressed high levels of Ia , DEC-205 , CD11b , CD80 and CD86 antigen , moderate levels of CD40 , and negative for F4/80 .
13		Functionally , these cells gained the capacity to stimulate allogeneic T cells in MLR assay .
14		However , immature DCs cultured with cytokines for 5 d did not have typical DCs phenotypic markers and could not stimulate allogeneic T cells .
15		Ex vivo primed T cells with SGC-7901 tumor cell lysate-pulsed ( TP ) DCs were able to induce effective CTL activity against SGC-7901 tumor cells ( E : T = 100 : 1 , 6955% +/- 605% specific lysis ) , but not B16 tumor cells , and produced higher levels of IFNgamma when stimulated with SGC-7901 tumor cells but not when stimulated with B16 tumor cells ( 157531 +/- 6025 pg/mL in SGC-7901 group versus 16411 +/- 1852 pg/mL in B16 group , P <001 ) .
16		CONCLUSION :
17		BM-derived DCs pulsed with tumor lysates can induce anti-tumor immunity specific to gastric cancer ex vivo .

PMID: 16984623 (Patient)   Terms:
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0		Retroperitoneal lipomatous angiomyolipoma associated with amyloid deposition masquerading as well-differentiated liposarcoma .
1		Reported herein is a case of retroperitoneal angiomyolipoma associated with amyloid deposition , masquerading as well-differentiated liposarcoma .
2		A 16 x 13 cm lipomatous tumor was resected from the perirenal retroperitoneum of a 71-year-old woman .
3		Microscopically , the tumor was exclusively composed of mature adipose tissue and abnormal thick blood vessels , but bundles of smooth muscle were lacking .
4		In addition , amyloid was deposited between fat cells .
5		Initially , well-differentiated liposarcoma was highly suspected .
6		However , there were a few epithelioid cells with clear vacuolated cytoplasm within the vessel walls , which were immunoreactive for smooth muscle markers and HMB-45 .
7		Real-time polymerase chain reaction failed to demonstrate the amplification of the murine double-minute type 2 gene and cyclin -dependent kinase 4 gene in this tumor .
8		Therefore , the tumor was diagnosed as lipomatous angiomyolipoma .
9		After the diagnosis , it was found that the patient had multiple myeloma and cardiac amyloidosis , suggesting that the amyloid deposition within the tumor was a complication of the myeloma .
10		Lipomatous angiomyolipoma may be a diagnostic pitfall of retroperitoneal lipomatous tumors .

PMID: 16938516 (Patient)   Terms:
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0		The value of MDM2 and CDK4 amplification levels using real-time polymerase chain reaction for the differential diagnosis of liposarcomas and their histologic mimickers .
1		LONGTOKEN are reported to have murine double-minute type 2 ( MDM2 ) and cyclin-dependent kinase 4 ( CDK4 ) amplification as a characteristic genetic alteration .
2		To evaluate the diagnostic utility of this gene abnormality , we analyzed 19 liposarcomas , 21 malignant fibrous histiocytomas , 3 leiomyosarcomas , 5 malignant peripheral nerve sheath tumors , 23 lipomas , and 28 nonneoplastic fat tissues using real-time polymerase chain reaction ( PCR ) and fluorescence in situ hybridization ( FISH ) .
3		In real-time PCR , all ALT/WDLs and DDLs had both MDM2 and CDK4 amplifications .
4		The amplification levels in ALT/WDLs and DDLs were significantly higher than those in the other sarcomas , lipomas , and nonneoplastic fat tissues ( P <05 ) ; however , those in the other sarcomas and lipomas were not significantly higher than those in nonneoplastic tissues .
5		In FISH , all ALT/WDLs and DDLs had both MDM2 and CDK4 amplifications , and all of the myxoid/round cell liposarcomas , leiomyosarcomas , malignant peripheral nerve sheath tumors , and all but one of the malignant fibrous histiocytomas did not have the amplifications .
6		In this study , MDM2 and CDK4 amplifications were confirmed in ALT/WDLs and DDLs , and the amplification levels were significantly higher than those in the other tumors .
7		An analysis of MDM2 and CDK4 amplification using real-time PCR , as well as FISH , is useful for the differential diagnosis of liposarcomas and their histologic mimickers .

PMID: 16732325 (Cell)   Terms:
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0		Genomic profiling of bone and soft tissue tumors with supernumerary ring chromosomes using tiling resolution bacterial artificial chromosome microarrays .
1	Μ	Ring chromosomes and/or giant marker chromosomes have been observed in a variety of human tumor types , but they are particularly common in a subgroup of mesenchymal tumors of low-grade or borderline malignancy .
2		These rings and markers have been shown to contain amplified material predominantly from 12q13-15 , but also sequences from other chromosomes .
3		Such amplified sequences were mapped in detail by genome -wide array comparative genomic hybridization in ring-containing tumor samples from soft tissue ( n = 15 ) and bone ( n = 6 ) , using tiling resolution microarrays , encompassing 32 433 bacterial artificial chromosome clones .
4	Μ	The DNA copy number profiles revealed multiple amplification targets , in many cases highly discontinuous , leading to delineation of large numbers of very small amplicons .
5		A total number of 356 ( median size : 0.64 Mb ) amplicons were seen in the soft tissue tumors and 90 ( median size : 1.19 Mb ) in the bone tumors .
6		Notably , more than 40% of all amplicons in both soft tissue and bone tumors were mapped to chromosome 12 , and atleast one of the previously reported recurrent amplifications in 12q13.3-14.1 and 12q15.1 , including SAS and CDK4 , and MDM2 , respectively , were present in 85% of the soft tissue tumors and in all of the bone tumors .
7	Μ	Although chromosome 12 was the only chromosome displaying recurrent amplification in the bone tumors , the soft tissue tumors frequently showed recurrent amplicons mapping to other chromosomes , that is , 1p32 , 1q23-24 , 3p11-12 , 6q24-25 and 20q11-12 .
8	Μ	Of particular interest , amplicons containing genes involved in the c-jun NH2-terminal kinase/mitogen -activated protein kinase pathway , that is , JUN in 1p32 and MAP3K7IP2 ( TAB2 ) in 6q24-25 , were found to be independently amplified in eight of 11 cases with 12q amplification , providing strong support for the notion that aberrant expression of this pathway is an important step in the dedifferentiation of liposarcomas .

PMID: 16707369 (Cell)   Terms:
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0		Reproducibility of MDM2 and CDK4 staining in soft tissue tumors .
1		MDM2 and CDK4 immunostaining can be useful adjuncts in diagnosing liposarcoma among soft tissue neoplasms .
2		We examined the reproducibility of MDM2 and CDK4 staining between 2 laboratories and between tissue microarrays and whole tissue sections .
3		Sixty-two soft tissue tumors were immunostained at the Bergonie Institute , Bordeaux , France , and the Curie Institute , Paris , France .
4		We also examined 203 soft tissue neoplasms on standard tissue sections and tissue microarrays .
5		There was high concordance of results obtained from the 2 laboratories ( with 2 different pathologists ) for MDM2 ( kappa , 093 ) and CDK4 ( kappa , 08 ) staining .
6		There also was excellent concordance between results on tissue microarray and on whole tissue sections for MDM2 ( kappa , 080 ) and CDK4 ( kappa , 093 ) .
7		Immunostaining for MDM2 and CDK4 is a reproducible technique that may be exported to different laboratories for routine use .
8		Tissue microarray is indicated for studying large series .

PMID: 16489442 (Patient)   Terms:
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0		alpha-fetoprotein expression in a dedifferentiated liposarcoma .
1		Extremely rare cases of paraneoplastic syndromes or ectopic production of proteins associated with liposarcoma are reported in literature .
2		We describe a unique case of relapsing retroperitoneal dedifferentiated liposarcoma with biochemical , immunohistochemical , and molecular evidence of alpha-fetoprotein ( AFP ) ectopic production .
3		The lesion was associated to elevated AFP plasma levels that subsided after tumor removal .
4		Immunohistochemical studies showed AFP production by a minority of tumor cells and reverse transcriptase polymerase chain reaction confirmed AFP mRNA expression .
5		Finding of MDM2 and CDK4 iperexpression by immunohistochemistry confirmed the diagnosis of dedifferentiated liposarcoma .

PMID: 16442827 (None)   Terms:
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0		Phenotypic and molecular characteristics of hyperplastic polyposis .
1		Soft tissue sarcomas are rare and may be a source of problems for diagnosis and treatment .
2		Four types of genetic disorders can be distinguished : translocations , gene amplifications , mutations and complex genetic imbalances .
3		Detection of these disorders may help in diagnosis and in determining prognosis .
4		Detection of specific translocation is recommended in synovial sarcoma , alveolar rhabdomyosarcoma or PNET diagnosis because of therapeutic consequences ; in case of rarer histologic type ( low grade fibromyxoid sarcoma , clear cell sarcoma , infantile fibrosarcoma ) , it may confirm the diagnosis .
5		In some cases , some translocations have a prognostic value ( alveolar rhabdomyosarcoma ) whereas it is discussed in others ( synovial sarcoma ) .
6		The techniques used to detect these translocations are very sensitive so it may be used to detect microscopical metastasis ( bone marrow metastasis of alveolar rhabdomyosarcoma for example ) .
7		Detection of MDM2 and CDK4 genes amplifications ( FISH or quantitative PCR ) may be sometimes useful in well differentiated and dedifferentiated liposarcomas diagnosis .
8	✓	Mutation detection of KIT or PDGFRA may help in GIST diagnosis and type of mutation is predictive of response to treatment .	GM-MRK-RO
9		Study of complex genomic imbalances in sarcomas is not used in routine practice but remains useful in research .

PMID: 16419059 (None)   Terms:
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0		Amplification of CDK4 and MDM2 in malignant melanoma .
1		Amplification of the 12q13-15 region is a common event in several human tumors including liposarcomas , gliomas , and osteosarcomas .
2	Μ	We have demonstrated high-level amplification of 12q14 in a subset of uncultured malignant melanomas ( 3 of 53 ) .
3	Μ	High-resolution mapping of the amplicon using quantitative PCR revealed a bipartite amplicon consisting of a primary 50-kb amplicon centered on CDK4 and a secondary amplicon centered on MDM2 , without amplification of the intervening 11 Mb of genomic DNA .
4	Μ	Analysis of mRNA and protein levels in melanomas with 12q14 amplification demonstrated overexpression of target genes CDK4 and MDM2 without loss of CDKN2A-P16 ( P16INK4A ) or CDKN2A-P14ARF ( P14ARF ) expression , important regulators of the RB1 and TP53 pathways , which are commonly lost or mutated in melanoma .
5		These results suggest that coamplification of CDK4 and MDM2 may substitute for loss of P16INK4A and P14ARF function in a subset of melanomas .

PMID: 16160477 (Patient)   Terms:
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0		MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes : a comparative analysis of 559 soft tissue neoplasms with genetic data .
1		LONGTOKEN may be difficult to distinguish from benign adipose tumors and from poorly differentiated sarcomas , respectively .
2		Genetically , they are characterized by amplification of MDM2 and CDK4 genes on chromosome 12q13-15 .
3		We examined a series of 559 soft tissue tumors ( 44 ALT-WDLPS , 61 DDLPS , 49 benign adipose tumors , and 405 non-ALT-WDLPS/DDLPS sarcomas ) for MDM2 and CDK4 expression using immunohistochemistry .
4		MDM2 and CDK4 immunoexpressions were compared with gene amplification status ( as assessed by quantitative PCR and/or comparative genomic hybridization ) in 241 neoplasms .
5		Most ALT-WDLPS/DDLPS expressed MDM2 ( 97% ) and CDK4 ( 92% ) as opposed to few benign adipose tumors ( MDM2 , 5% ; CDK4 , 2% ) and a limited number of non-ALT-WDLSP/DDLPS sarcomas ( MDM2 , 19% ; CDK4 , 6% ) .
6		The sensitivity and specificity of MDM2 and CDK4 immunostainings in identifying ALT-WDLPS/DDLPS among other soft tissue tumors were 97% and 92% , and 83% and 95% , respectively .
7		MDM2 and CDK4 immunostainings were particularly useful to separate ALT-WDLPS from the large group of differentiated adipose tumors , and to distinguish DDLPS from poorly differentiated sarcomas .
8	Μ	A strong correlation was observed between MDM2 and CDK4 stainings and gene amplification status .
9		In conclusion , MDM2 and CDK4 immunostainings , which correlate with gene amplification , are helpful adjuncts to differentiate ALT-WDLPS from benign adipose tumors and to separate DDLPS from poorly differentiated sarcomas .

PMID: 16012847 (Patient)   Terms:
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0		Dedifferentiated liposarcoma with rhabdomyoblastic differentiation .
1		Dedifferentiated areas of dedifferentiated liposarcoma ( DDL ) usually show malignant fibrous histiocytoma ( MFH ) - or fibrosarcoma-like features and lack any histologic signs of specific differentiation .
2		However , some reports have demonstrated specific differentiation in these areas , with histologic features resembling those of rhabdomyosarcoma , leiomyosarcoma , and osteosarcoma .
3		We report here a pathologic and genetic analysis of three cases of DDLs with rhabdomyosarcomatous areas .
4		MFH - or fibrosarcoma-like areas of one primary DDL and two recurrent DDLs contained various amounts of rhabdomyoblasts , which were immunoreactive for desmin , myoglobin , muscle actin (HHF-35) , and myogenin .
5		An ultrastructural examination demonstrated rhabdomyoblasts with abundant cytoplasm containing thin and thick filaments and Z-bands .
6		By real-time PCR , amplification of mdm2 and cdk4 was confirmed in both well-differentiated and dedifferentiated areas with rhabdomyoblasts of all cases .
7		To our knowledge , only seven cases of DDLs with rhabdomyosarcomatous components have been reported , and furthermore , the genetic profiles of the rhabdomyosarcomatous components in DDLs have not been investigated .
8		This study demonstrates that DDLs with rhabdomyosarcomatous areas have genetic alterations that are common to well-differentiated/dedifferentiated liposarcomas .

PMID: 15991843 (Patient)   Terms:
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0		Dedifferentiated liposarcoma with extensive lymphoid component .
1		An unusual variant of dedifferentiated liposarcoma with extensive lymphocytic component is described .
2		A 71-year-old patient suffered from a relapse of an atypical LONGTOKEN dedifferentiation , which had been resected 4 years before .
3		The relapse revealed features of a dedifferentiated liposarcoma with spindle - cell , partly pleomorphic dedifferentiation and osseous metaplasia .
4		Clearly separated from the spindle - cell areas , an extensive homogeneously dense lymphoid ( lymphocytic ) tumor-component was evident , with relative abrupt transition to the well-differentiated liposarcoma component .
5		Using immunohistochemistry and PCR , the lymphoid ( "lymphoma-like" ) infiltrate proved to be a polyclonal lymphocytic proliferation .
6	Μ	Fluorescence in situ hybridization ( FISII ) analysis revealed no signs of MDM2 - and CDK4-gene amplification in the lymphoid areas , although within this mononuclear lymphoid population , large polymorphic nuclei displayed an amplified number of MDM2/CDK4 gene copies , indicating the presence of truly dedifferentiated tumor cells within the lymphoid component .
7		The results favor a reactive lymphocytic infiltration versus a neoplastic one , which might be caused for example by chemoattractive agents .
8		An extensive lymphoid "overgrowth" must be considered within the spectrum of unusual variants and in the differential diagnosis of dedifferentiated liposarcoma .

PMID: 15719245 (Patient)   Terms:
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0		Palmar atypical lipomatous tumour with spindle cell features ( well-differentiated spindle cell liposarcoma ) : a rare neoplasm arising in an unusual anatomical location .
1		Lipomatous tumours , both benign and malignant , arising on the hands are uncommon .
2		We present a rare atypical lipomatous tumour with spindle cell features ( synonym : well-differentiated spindle cell liposarcoma ) arising on the left palm of a 54-year-old male patient .
3		The neoplasm presented as a long-standing , exophytic neoplasm measuring 9 x 9 cm .
4		The well-circumscribed neoplasm was completely excised , and margins were tumour free .
5		Histologically , the neoplasm showed features closely resembling spindle cell lipoma , being composed of mature adipocytic cells associated with bland , neuroid spindle cells staining positively for CD34 .
6		However , focally , atypia of adipocytic and stromal cells as well as scattered lipoblasts were noted , and immunohistochemical stainings showed focal overexpression of MDM 2 and CDK4 .
7		Aypical lipomatous tumour with spindle cell features may arise very rarely in palmar location and has to be distinguished from a number of benign and malignant mesenchymal neoplasms .

PMID: 15492825 (Patient)   Terms: , transgenic mice, mice
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0		Abnormal expression of cell cycle regulators in FUS-CHOP carrying liposarcomas .
1		Myxoid/round cell liposarcomas ( MLS/RCLS ) are characterized by chromosome translocations that result in formation of FUS-CHOP or EWSR1-CHOP fusion oncogenes .
2		More than 95% of the tumors carry one of these fusion genes .
3		FUS-CHOP transforms 3T3 cells and causes MLS/RCLS-like tumors in transgenic mice .
4		The fusion oncoproteins act as abnormal transcription factors and are believed to induce abnormal expression of growth controlling genes as part of their transforming activities .
5		The aim of this study was to search for recurrent abnormal expression patterns of cell cycle regulating proteins and growth factor receptors .
6		A series of 14 MLS/RCLS , 2 MLS/RCLS derived cell lines and a FUS-CHOP transfected human sarcoma cell line were analyzed using immunohistochemistry , Western blotting , and cDNA microarray based screening .
7	Μ	The results revealed a highly abnormal expression pattern of several growth controlling proteins .
8		The G1 cyclins D1 and E and their associated kinases CDK4 and CDK2 were strongly overexpressed in all of the tumors .
9	Μ	High expression levels were also found for Cdk4/6 inhibitor P16 and CDK2 inhibitors P27 and P57 .
10		The growth factor tyrosine kinase receptors PDGFRB and EGFR were present in most cells of all investigated tumors .
11		We conclude that deregulation of G1 controlling proteins is common in MLS/RCLS and that aberrant expression of these proteins is of importance in the pathogenesis of this tumor type .

PMID: 15221942 (Patient)   Terms:
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0		Inflammatory malignant fibrous histiocytomas and dedifferentiated liposarcomas : histological review , genomic profile , and MDM2 and CDK4 status favour a single entity .
1		Inflammatory malignant fibrous histiocytoma ( inflammatory MFH ) is a very rare tumour that occurs most often in the retroperitoneum .
2		So far , it has been considered to be a special subtype of MFH .
3		As it is now widely accepted that most retroperitoneal pleomorphic MFHs are dedifferentiated liposarcomas , the present study compared histological features , genomic profile ( CGH analysis ) , and MDM2 and CDK4 status ( immunohistochemistry , FISH , and quantitative PCR ) in inflammatory MFHs from 12 patients and dedifferentiated liposarcomas that had an inflammatory MFH component from eight patients .
4		Metaphase cytogenetic and FISH analyses were also performed on one inflammatory MFH .
5		Histological review showed areas of well-differentiated liposarcoma in nine inflammatory MFHs .
6	Μ	CGH analysis showed 12q13-15 amplification or gain in six of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas .
7		Immunohistochemistry showed positivity of tumour cells for MDM2 in every tumour in both groups and for CDK4 in ten and seven inflammatory MFHs and dedifferentiated liposarcomas , respectively .
8	Μ	Metaphase cytogenetic and FISH analysis performed on one inflammatory MFH showed the presence of a supernumerary large marker chromosome and ring chromosome with high-level amplification of both MDM2 and CDK4 genes .
9	Μ	FISH analysis on paraffin wax-embedded sections showed amplifications of MDM2 and CDK4 in seven of seven inflammatory MFHs and in seven of seven dedifferentiated liposarcomas .
10	Μ	Quantitative PCR showed amplification of MDM2 in six and of CDK4 in seven of nine inflammatory MFHs .
11		In conclusion , this study strongly suggests that most so-called inflammatory MFHs are dedifferentiated liposarcomas .

PMID: 15187890 (None)   Terms:
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0		Atypical lipomatous tumor : molecular characterization .
1		PURPOSE OF REVIEW :
2		Atypical lipomatous tumors/well-differentiated liposarcomas ( ALT/WDLs ) are one of the more frequent mesenchymal neoplasms and are characterized by specific chromosome aberrations : supernumerary chromosome or giant marker chromosome or both .
3		Extra copies of known oncogenes such as MDM2 , CDK4 , SAS , HMGA2 and others are present in this abnormal genetic material .
4		RECENT FINDINGS :
5		In the past few years , several papers have further dissected the genetic alterations present in these tumors , allowing the identification of new potential oncogenes .
6		SUMMARY :
7		ALT/WDLs represent therefore an interesting model for assessing the potential role of these oncogenes , not only in the pathogenesis , but also as a therapeutic target .

PMID: 15154619 (Patient)   Terms:
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0		Well-differentiated liposarcoma associated with benign lipoma .
1		The objective of this study was to review the clinicopathological features of seven patients presenting with well-differentiated liposarcoma ( WDL ) , which was associated with subcutaneous lipoma .
2		From 1980 through 2002 , 34 individuals displaying WDL were treated in our institutions .
3		Lipoma was observed in seven of these 34 patients ( five men and two women , mean age of 667 years ) .
4		The rate of co-existence of lipoma in WDL [20.6% ( 7/34 )] cases was significantly higher than the corresponding rate in the other liposarcoma subtypes [2.5% ( 1/40 )] .
5		Immunohistochemically , cdk4 was positive in all WDLs ( 100% ) .
6		ki-67 was positive in 57.1% ( 4/7 ) and mdm2 and p53 were positive in 14.5% ( 1/7 ) of the WDL cases .
7		Weak cdk4 immunoreactivity was detected in two lipomas .
8		All lipomas were negative for mdm2 , p53 and ki-67 .
9		Comparison of the expression profile in these malignant and benign tumors , which had arisen in identical genetic backgrounds , confirmed the involvement of these proteins , especially cdk4 , in the tumorigenesis process of WDL .

PMID: 15041220 (None)   Terms:
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0		Characterization of large chromosome markers in a malignant fibrous histiocytoma by spectral karyotyping , comparative genomic hybridization ( CGH ) , and array CGH .
1		In this study , we characterized the chromosomal composition of an intra-abdominal soft tissue sarcoma diagnosed as a malignant fibrous histiocytoma ( MFH ) .
2		By applying a combination of spectral karyotyping , G-banding , and comparative genomic hybridization ( CGH ) , this case was shown to carry large chromosome markers with material mainly from chromosomes 6 and 8 .
3	Μ	Further characterization of this unique tumor revealed high-level amplifications at the 6q21 approximately q23 , 8p21 approximately pter , 8q24 approximately qter , and 12q13 approximately q21 regions .
4	Μ	Using array CGH , these amplified regions were found to include MASL1 in 8p , as well s MDM2 and CDK4 in 12q , which have been shown to be amplified in MFH .
5		Similarly , gains of 6q and 8q have also been seen in MFH .
6		In conclusion , our study demonstrates the occurrence of large chromosome markers in MFH and suggests that the regions 6q21 approximately q23 , 8p21 approximately pter , 8q24 approximately qter , and 12q13 approximately q21 might harbor oncogenes that could play a role in MFH 's tumorigenesis .
7		In addition , gain of 12q13 approximately q21 , which is typical of well-differentiated liposarcoma , may also occur in MFH , supporting the previously suggested overlap in genetic etiologies between these two tumor types .

PMID: 14736600 (None)   Terms:
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0		[ Atypical lipomatous tumour of the vulva . About one case ] .
1		Liposarcoma of the vulva is a rare entity .
2		This unusual localization with atypical clinical and histological appearance may induce diagnostic and treatment delay .
3		We report the 13th case shown in the literature in a 31-year-old woman initially treated for a vulvar lipoma .
4		Arguments based on clinical short term recurrence , histological infiltrating adipocytes , and cytogenentical findings evoked well-differentiated liposarcoma .
5		Even though cytogenetic abnormalities , involving MDM2 and CDK4 genes , have been found , a certainty in malignity diagnosis could be difficult .
6		In these cases , treatment decision may be uneasy .
7		This case report recalls difficulties encountered in uterine hypercellular leiomyomas .

PMID: 14694526 (None)   Terms:
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0		Evaluation of MDM2 and CDK4 amplification by real-time PCR on paraffin wax-embedded material : a potential tool for the diagnosis of atypical lipomatous tumours/well-differentiated liposarcomas .
1		Atypical lipomatous tumours/well-differentiated liposarcomas and dedifferentiated liposarcomas are characterized by 12q13-15 region amplification .
2		In contrast , this molecular event has not been reported in benign lipomas .
3		Within the 12q13-15 chromosomal region , the MDM2 , SAS , HMGA2 , and CDK4 genes are the most frequent targets of amplification .
4		A series of lipomas ( 36 cases ) and liposarcomas ( 48 cases ) was analysed for MDM2 and CDK4 gene amplification by real-time PCR .
5	Μ	MDM2 and CDK4 gene amplification was detected in 2.8% and 5.6% of lipomas and 98.2% and 82.4% of liposarcomas , respectively .
6		Moreover , co-amplification of the two genes as well as a higher-level amplification was observed more frequently in dedifferentiated liposarcomas than in atypical lipomatous tumours/well-differentiated liposarcomas .
7		Real-time PCR proved to be a fast and reliable method to characterize lipomas and liposarcomas by quantification of MDM2 and CDK4 gene amplification .
8		It is applicable to paraffin wax-embedded tissues and could be useful when histological diagnosis is difficult .

PMID: 12640106 (Patient)   Terms:
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0		Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas : a review of 25 cases initially diagnosed as malignant fibrous histiocytoma .
1		Forty-four samples from 25 cases of retroperitoneal sarcoma initially diagnosed as malignant fibrous histiocytoma were histologically reviewed .
2		Immunohistochemistry for mdm2 and cdk4 was performed on 20 cases .
3		Comparative genomic hybridization was performed on 18 samples from 13 patients .
4		Seventeen cases were reclassified as dedifferentiated liposarcoma .
5		Twenty-one of 32 samples from these patients showed areas of well-differentiated liposarcoma , allowing the diagnosis of dedifferentiated liposarcoma .
6		Immunohistochemistry performed in 15 of these cases showed positivity for mdm2 and cdk4 .
7	Μ	Comparative genomic hybridization analysis performed on 15 samples from 11 of these patients showed an amplification of the 12q13-15 region .
8		Eight cases were reclassified as poorly differentiated sarcoma .
9		Twelve samples from these patients showed no area of well-differentiated liposarcoma .
10		Immunohistochemistry showed positivity for mdm2 and cdk4 in one of six of these patients and showed positivity for CD34 in another one .
11	Μ	Comparative genomic hybridization analysis performed on three samples from two of these patients showed no amplification of the 12q13-15 region but showed complex profiles .
12		This study shows that most so-called malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcoma and that a poorly differentiated sarcoma in this area should prompt extensive sampling to demonstrate a well-differentiated liposarcoma component , immunohistochemistry for mdm2 and cdk4 , and if possible , a cytogenetic or a molecular biology analysis .

PMID: 12242528 (Patient)   Terms:
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0		Atypical lipomatous tumor in a 14-year-old patient : distinction from lipoblastoma using FISH analysis .
1		Liposarcomas are rare in young age .
2		We present the rare case of an atypical lipomatous tumor ( synonym : well-differentiated lipoma-like liposarcoma ) in a 14-year-old girl with the differential diagnosis of lipoblastoma which was excluded by fluorescence in situ hybridization ( FISH ) analysis .
3		The tumor presented as a soft tissue mass at the dorsal part of the right thigh measuring up to 18 cm .
4		Microscopically the lesion consisted of atypical adipocytes with hyperchromatic nuclei and additional multivacuolated lipoblasts .
5		Interphase dual-color FISH performed with chromosome 8 centromeric and YAC164H5 ( mapping to exons 2-5 of the PLAG1 gene ) probes revealed no rearrangement of PLAG1 oncogene or polysomy of chromosome 8 .
6	Μ	Additional FISH using an MDM2 gene probe and an BAC534N15 probe ( containing sequences specific for the CDK4 gene ) showed amplification of the CDK4 gene .
7		These findings indicate that this tumor was no lipoblastoma but an atypical lipomatous tumor , which is of clinical relevance .
8		In young individuals the distinction between lipoblastoma and liposarcoma is often impossible by light microscopy alone .
9		This case shows that FISH can serve as a decisive tool in the differential diagnosis of lipoblastoma and lipoma-like liposarcoma apart from its role in distinction between lipoblastoma and myxoid/round cell liposarcoma .

PMID: 12036902 (Cell)   Terms:
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0		Microarray-based copy number and expression profiling in dedifferentiated and pleomorphic liposarcoma .
1		Sixteen dedifferentiated and pleomorphic liposarcomas were LONGTOKEN , cDNA-derived microarrays for expression profiling , and by quantitative PCR .
2		Matrix-CGH revealed copy number gains of numerous oncogenes , i.e. , CCND1 , MDM2 , GLI , CDK4 , MYB , ESR1 , and AIB1 , several of which correlate with a high level of transcripts from the respective gene .
3		In addition , a number of genes were found differentially expressed in dedifferentiated and pleomorphic liposarcomas .
4		Application of dedicated clustering algorithms revealed that both tumor subtypes are clearly separated by the genomic profiles but only with a lesser power by the expression profiles .
5		Using a support vector machine , a subset of five clones was identified as "class discriminators." Thus , for the distinction of these types of liposarcomas , genomic profiling appears to be more advantageous than RNA expression analysis .

PMID: 11734312 (Patient)   Terms:
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0		A well-differentiated liposarcoma with a new type of chromosome 12-derived markers .
1		Well-differentiated liposarcomas ( WDLPS ) are cytogenetically characterized by the presence of supernumerary ring or giant rod marker chromosomes .
2		These supernumerary chromosomes are composed of amplified sequences from chromosome 12 ( 12q14 approximately 15 ) in association with amplified segments from various other chromosomes , and contain alterations of the alpha satellite sequences .
3		We report a case of WDLPS of the lipoma-like and sclerosing subtype that contains a novel type of supernumerary marker chromosome .
4		Instead of rings or giant rods , these cells had three apparently identical copies of a subtelocentric supernumerary marker with a size and shape similar to C - group chromosomes .
5	Μ	Fluorescence in situ hybridization analysis revealed that the markers were composed of amplified material from 12q14 approximately 15 , including the genes MDM2 and CDK4 .
6		Similar to the rings and giant rods observed in other WDLPS cases , these unusual markers had no alpha satellite repeats at the primary constriction site , but centromeric activity could be demonstrated by using anti-centromere protein C antibodies .
7		These findings show that the supernumerary markers of WDLPS may be variable in size and shape , but consistently share the same genomic structure , specifically 12q amplified sequences together with centromere alterations , and underline the importance of molecular methods in the diagnosis of adipose tissue tumors .

PMID: 11505267 (Patient)   Terms:
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0		MDM2+/CDK4+/p53+ oral liposarcoma : case report and review of the literature .
1		Although liposarcoma is one of the most common soft tissue sarcomas , its location in the oral cavity is very rare .
2		To our knowledge , only 43 cases of liposarcoma originating in the oral tissues have been reported in the English-language literature .
3		In this article , we report a case of well-differentiated liposarcoma affecting the cheek of a 28-year-old man and review the oral liposarcoma literature .
4		Immunohistochemical analysis of the tumor revealed an MDM2+/CDK4+/p53+ immunophenotype that is consistent with the immunohistochemical profile of well-differentiated liposarcoma originating in other areas of the body .
5		Quantitative polymerase chain reaction analysis of the DNA levels of the MDM2 ( human homologue of the murine double-minute type 2 ) , CDK4 ( cyclin-dependent kinase 4 ) , and SAS ( sarcoma amplified sequence ) , genes was performed , revealing only SAS gene amplification .
6		The possibility of misdiagnosis of oral liposarcoma because of its sometimes inconspicuous clinical and microscopic features is emphasized .
7		Careful pathologic examination of liposarcoma is essential for discrimination from benign adipose tissue neoplasms and for precise histologic classification , both of major prognostic significance .
8		Possible implications of molecular and cytogenetic analysis for unraveling the pathogenesis and determining the prognosis of liposarcoma are discussed .

PMID: 11369052 (None)   Terms:
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0		Dedifferentiation of a well-differentiated liposarcoma to a highly malignant metastatic osteosarcoma : amplification of 12q14 at all stages and gain of 1q22-q24 associated with metastases .
1		Well-differentiated liposarcomas ( WDLPS ) , especially those located in the retroperitoneum , may occasionally undergo dedifferentiation .
2		Although this process is associated with a more aggressive clinical course , dedifferentiated liposarcomas rarely produces metastases .
3		The case reported here is rather uncommon : A retroperitoneal WDLPS gave lung metastases that were diagnosed as highly malignant osteosarcomas .
4		We used comparative genomic hybridization ( CGH ) , fluorescence in situ hybridization ( FISH ) , and Southern blot analyses to characterize the copy number changes and genetic aberrations occurring at different stages of the disease .
5	Μ	In the primary tumor , the only detectable aberration was amplification of 12q13-q14 , which was present only in a fraction of the cells and revealed by FISH analysis .
6		High-level amplification of 12q13-q14 , involving CDK4 , MDM2 , and HMGIC , was seen both in the relapse and the metastases .
7		The second most common change , gain or high-level amplification of 1q22-q24 , was detectable by CGH only in the osteogenic metastases , as was loss of the distal 2q .
8		FISH analyses revealed considerable heterogeneity in the samples , and the percentage of cells showing aberrations was significantly higher in the metastatic samples .
9	Μ	In particular , increased copy numbers of 789f2 , a marker for 1q21 amplification in sarcomas , was observed in more than 65% of the cells in the metastatic samples , but in less than 10% of the cells from the recurrent samples .
10		These observations could indicate that 1q amplification , in particular , may be indicative of a more malignant phenotype and ability of metastasis in WDLPS , as has also been suggested by others .

PMID: 10755400 (Patient)   Terms:
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0		The expression of MDM2/CDK4 gene product in the differential diagnosis of well differentiated liposarcoma and large deep-seated lipoma .
1		Ordinary lipomas are cytogenetically characterized by a variety of balanced rearrangements involving chromosome segment 12q13-15 , whereas well differentiated liposarcomas ( WDL ) show supernumerary ring and giant marker chromosomes , known to contain amplified 12q sequences .
2		The tight correlation between the presence of ring chromosomes and both amplification and overexpression of MDM2 and CDK4 genes suggests the exploration of the possibility that immunocytochemistry ( ICC ) might assist in the differential diagnosis of lipoma-like well differentiated liposarcomas ( LL-WDL ) and large deep-seated lipomas ( LDSL ) .
3		For this purpose , 21 cases of the former and 19 cases of the latter tumours were analysed by ICC and , according to the availability of material , by molecular and cytogenetic approaches .
4		All lipomas displayed a null MDM2/CDK4 phenotype , whereas all LL-WDL showed MDM2/CDK4 or CDK4 phenotypes .
5		Southern blot analysis performed on 16 suitable cases , complemented by fluorescence in situ hybridization and classical cytogenetic analysis in 11 cases , was consistent with , and further supported the immunophenotyping data .
6		In conclusion , MDM2/CDK4 product -based immunophenotyping appears to represent a valuable method for the categorization of arguable LDSL .

PMID: 10981874 (Patient)   Terms:
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0		Morphologic-cytogenetic analysis of dedifferentiated liposarcomas with an extensive misleading leiomyosarcomatous component .
1		This report describes two cases of recurrent retroperitoneal dedifferentiated liposarcoma characterized by an extensive leiomyomatous component that prevented the correct diagnosis before the last recurrence .
2		Strong immunoreactivity with smooth muscle and desmin antibodies and ultrastructural features consistent with leiomyosarcoma were observed in the spindle - cell and/or myxoid-like components in all four recurrences in case 1 , and in the spindle - cell component of the primary tumor and the first recurrence in case 2 .
3		In case 1 , the correct diagnosis was suggested by the cytogenetic evidence of ring markers , a hallmark of well-differentiated/dedifferentiated liposarcoma .
4		In case 2 , tumor type was yielded mainly by the morphology of the second recurrence , which consisted entirely of a well-differentiated liposarcoma , a sclerosing inflammatory variant , as confirmed by the karyotype .
5		Reevaluation of the first two surgical specimens of each case revealed small areas consistent with well-differentiated liposarcoma that had been previously overlooked .
6		Despite the smooth-muscle antigen profile , both cases retained an mdm2+/p53+/cdk4+ immunophenotype consistent with the genotype .

PMID: 10862042 (None)   Terms:
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0		Locus -specific multifluor FISH analysis allows physical characterization of complex chromosome abnormalities in neoplasia .
1		Novel techniques in molecular cytogenetics have radically improved the ability to characterize genetic changes in neoplastic cells .
2		In parallel , a rapid development in high-throughput genomics has resulted in detailed physical maps of the human genome .
3		Combining these two fields , we have developed a method for the simultaneous visualization of several physically defined segments along a chromosome .
4		Seven YAC clones and one subtelomeric cosmid clone from chromosome 12 were labeled with unique combinations of four fluors and hybridized to metaphase chromosomes from neoplastic cells .
5		In a uterine leiomyoma and a myxoid liposarcoma with translocations 12 ; 14 and 12 ; 16 , the breakpoints in chromosome 12 could be localized to the HMGIC and CHOP regions , respectively .
6		In the other tumors , more complex aberrations were visualized , including two inversions in 12q with a common breakpoint between MDM2 and D12S332 in a pleomorphic adenoma , amplification of MDM2 and CDK4 in ring chromosomes from a malignant fibrous histiocytoma , and amplification of KRAS2 together with other unbalanced rearrangements in two pancreatic adenocarcinomas .
7		Combinatorially labeled single-copy probes may thus simultaneously provide physical localization of breakpoints and an overview of complex structural rearrangements .
8		Genes Chromosomes Cancer 28 : 347-352 , 2000 .

PMID: 9862519 (Patient)   Terms:
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0		Limited role of TP53 and TP53-related genes in myxoid liposarcoma .
1		AIMS :
2		Circumstantial evidence suggests that genetic changes may lead to tumor progression within the myxoid liposarcoma tumors ( MLTs ) carrying non-random chromosomal translocation t ( 12 ; 16 ) .
3		METHODS :
4		To address this subject an immunophenotypic analysis , applying antibodies against proteins encoded by TP53 , MDM2 and CDK4 genes , complemented by molecular analysis of eight suitable cases , was performed on 104 consecutive cases .
5		Chromosomal translocations were assessed either by cytogenetic analysis or by RT-PCR in 9 suitable cases and chimeric transcripts were found in all cases but two pleomorphic liposarcomas .
6		RESULTS :
7		Based on immunophenotyping and tumor site , the case material consisted of three groups .
8		The first one was made up of 92 non-retroperitoneal cases carrying a null p53 , mdm2 , cdk4 immunophenotype , which remained unchanged over the time of recurrences and along the gamut of histologic subtypes .
9	Μ	The second group was represented by five p53+ , mdm2 - , cdk4 - non-retroperitoneal cases , 4 of which were further analysed by PCR-SSCP for p53 mutation .
10		The immunophenotypic profile of these cases , complemented by the molecular findings , supported a role of TP53 in tumor progression in three high-grade MLTs .
11		The third group , consisting of 7 retroperitoneal cases , showed a heterogeneous immunophenotype , sharing immunophenotypic and molecular features with the well-differentiated/evoluted ( dedifferentiated ) liposarcoma group .
12		CONCLUSIONS :
13	✓	TP53 mutations seem to play a role in tumor progression in a few cases of MLTs ( 28% ) showing more aggressive histologic characteristics .	GM-INV-RO
14		The unexpected finding that a number of retroperitoneal LMTs display the immunophenotypic profile of the well differentiated/evoluted ( dedifferentiated ) liposarcomas , deserves further investigation .

PMID: 9713346 (Patient)   Terms:
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0		Molecular abnormalities in liposarcoma : role of MDM2 and CDK4-containing amplicons at 12q13-22 .
1		It has recently been shown that mdm2 overexpression with stabilization of p53 represents a characteristic of retroperitoneal well-differentiated-dedifferentiated , here renamed evolved ( WD-E ) , liposarcomas at the immunocytochemical , molecular , and cytogenetic level .
2		This make-up appears to be confined to half the cases in non-retroperitoneal well-differentiated liposarcomas .
3		Since in different tumours MDM2 amplification involves amplicons encompassing flanking genes , such as CDK4 , the possibility was investigated that in these tumours , CDK4 could act as an alternative or additional gene involved in the transformation mechanism .
4		Forty-one retroperitoneal (R) /non-retroperitoneal ( NR ) well-differentiated-dedifferentiated ( WD-DD ) and 33 myxoid/round cell liposarcomas were reanalysed by immunocytochemical , molecular ( nine cases ) and fluorescence in situ hybridization ( FISH ) ( one case ) techniques .
5		The results showed that all but one R WD-E cases carried the mdm2+ , p53+ , cdk4+ immunophenotype .
6		In NR-WD liposarcomas , this immunophenotype was shared in five cases and the remainder showed mdm2+ , p53 - , cdk4+ in four and mdm2 - , p53 - , cdk4+ in one case , showing ring chromosomes by FISH analysis .
7	✓	TP53 mutations are confirmed to be closely correlated with NR-DD liposarcomas and no CDK4 involvement was found in the myxoid/round cell liposarcoma group .	GM-ASS-DS
8		As well as confirming the synergistic effect of MDM2 and CDK4 , these results are consistent with the concept that amplicons excluding MDM2 may contribute to transformation and support a role of CDK4 in opposing p53 function , particularly in NR WD liposarcoma .

PMID: 9703873 (Patient)   Terms:
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0		Amplification of the CDK4 gene in sarcomas : tumor specificity and relationship with the RB gene mutation .
1		Amplification of the CDK4 gene , which encodes a key molecule in the cell cycle , has been shown in some types of human neoplasms , including bone and soft tissue tumors .
2		It is also reported that the CDK4 gene is coamplified with other sequences in the 12q13-15 region , including the MDM2 and SAS genes .
3		Using 146 DNA samples derived from a variety of bone and soft tissue tumors , we have studied the pattern of amplification of these three genes , CDK4 , MDM2 , and SAS , to investigate whether there are any tumor type specific patterns of amplification .
4	Μ	Amplification of atleast one of these three genes was found in 18 tumors , and five different patterns of amplification were observed .
5	Μ	Amplification of all of these three genes was detected in 9 cases .
6	Μ	Amplification of the CDK4 gene without MDM2 amplification was observed in osteosarcomas and a chondrosarcoma but not in soft tissue tumors , whereas amplification of MDM2 gene alone was observed in malignant fibrous histiocytomas ( MFHs ) , liposarcomas , and lipomas , but not in bone tumors .
7		These results suggested that the CDK4 region is the primary target for amplification in bone tumors , whereas the MDM2 region is in soft tissue tumors .
8	Μ	We also investigated the relationship of CDK4 amplification with retinoblastoma ( RB ) gene mutations in osteosarcomas , for which we have already performed the mutation analyses in detail .
9	Μ	Interestingly , contrary to the prevailing theory that CDK4 amplification is an alternative mechanism for RB gene mutation , we found that three of four cases with amplification of the CDK4 gene showed loss of expression of the RB protein , one of which was proved to have an gross DNA alteration in the RB locus .
10		This redundancy of mutations may indicate that the amplification of CDK4 may have some roles other than the inactivation of the RB protein in the development of osteosarcomas .

PMID: 9403703 (Patient)   Terms:
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0		Molecular aberrations of the G1-S checkpoint in myxoid and round cell liposarcoma .
1	Μ	Myxoid and round cell liposarcoma represents a morphological spectrum in which tumor progression from low-grade myxoid to high-grade round cell areas is frequently observed .
2		A distinctive t ( 12 ; 16 ) ( q13 ; p11 ) reciprocal translocation rearranges the CHOP gene localized to 12q13 in most cases .
3		Data concerning the occurrence of cell cycle aberrations in this subset of mesenchymal malignancies are very limited .
4		Therefore , we analyzed a histologically homogeneous series of 21 cases of myxoid and round cell liposarcoma .
5		The p53 pathway was studied by investigating the TP53 gene and protein , mdm2 protein , and p21Waf1 protein .
6		The Rb-cyclin D pathway was analyzed by studying the pRb protein , the p16MTS1 gene , cyclin D1 , cyclin D3 , p27Kip1 , cdk4 , and cdk6 proteins .
7		In contrast with the rare involvement of the TP53 gene in well differentiated liposarcoma , aberrations of the TP53 gene were observed in approximately 30% of cases of myxoid and round cell liposarcoma .
8		Notably , mdm2 overexpression was seen in 56% of cases and correlated with histological grade , therefore indicating a possible role in tumor progression .
9		Abnormalities involving the Rb-cyclin D pathway were observed in more than 90% of cases .
10		pRb loss was present in one-third of cases and , at variance with that observed in other subsets of sarcoma , overexpression of cyclin Ds represented a rare event .
11		Interestingly , upregulation of either cdk4 or cdk6 was demonstrated in 85% of cases .

PMID: 9205100 (Patient)   Terms:
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0		HMGIC , the gene for an architectural transcription factor , is amplified and rearranged in a subset of human sarcomas .
1	Μ	Amplified segments of the long arm of chromosome 12 are frequently observed in human sarcomas .
2		In most cases there are separate amplified regions around the MDM2 and CDK4 genes .
3		Here we show recurrent amplification of a third region encompassing HMGIC , a human architectural transcription factor gene .
4	Μ	Reduced amplification frequency of sequences flanking the gene was observed , indicating that inclusion of this third region in the amplicons is also selected for .
5		In three samples only the 5' part of HMGIC was amplified , suggesting preferential loss of the 3' part of the gene preceding or during amplification .
6		In several other samples rearrangement of the gene was observed .
7		Expression analysis showed transcripts of aberrant sizes , lacking 3' sequences , and 3' RACE of one sample revealed replacement of exons 4 and 5 with ectopic sequences .
8	Μ	This truncation of HMGIC resembles that reported for translocations of HMGIC in benign tumors , including lipomas , and it is striking that the gene was frequently amplified or rearranged in well differentiated liposarcomas , the malignant counterpart of lipomas .
9		It seems conceivable that high levels of either full length or truncated hmgic could be relevant for the etiology of these tumors .

PMID: 8993982 (Patient)   Terms:
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0		Complexity of 12q13-22 amplicon in liposarcoma : microsatellite repeat analysis .
1		The 12q13-22 amplicon from four liposacroma specimens evaluated by comparative genomic hybridization was studied analyzing 55 microsatellite markers by PCR .
2	Μ	All four specimens were informative in atleast 34 loci ; an amplification or allelic imbalance was identified with four to 17 markers .
3		The amplicons were discontinuous ; there were non-amplified marker loci between the amplified marker loci .
4		These findings indicate the presence of separate amplicons in the 12q13-22 region .
5	Μ	Evidence of the concomitant gain of one allele and loss of the other allele was found with several markers in one tumor and with one marker in two tumor specimens .
6	Μ	Southern blotting showed amplification of CDK4 and MDM2 in all four specimens .

PMID: 7592643 (Cell)   Terms:
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0		Deletion in human chromosome region 12q13-15 by integration of human papillomavirus DNA in a cervical carcinoma cell line .
1		In human cervical carcinomas papillomavirus DNA is frequently integrated in the cell genome .
2		We have cloned the integration site of human papillomavirus-18 DNA in human chromosome region 12q13-15 present in the SW756 cervical carcinoma cell line .
3		Viral DNA is broken from nucleotides 2643 to 3418 in the E1 and E2 open reading frames , resulting in a deletion of 775 bases of viral DNA .
4		Cloning and sequence analysis of the rearranged and germline alleles shows that there is no homology between the target cellular and viral DNA , suggesting it is a nonhomologous recombination .
5		The target cellular region is called papillomavirus associated locus 2 ( PAL2 ) .
6		The 5' - and 3'-flanking probes derived from the hybrid viral-cellular clone detect completely different germline restriction fragments in DNA from cells with normal chromosome 12 .
7		There is no overlap between the restriction maps of the target germline clones obtained with 5' - and 3'-flanking probes .
8		Probes from these germline clones beyond the breakpoint position do not detect any DNA rearrangement in SW756 cells DNA .
9		These data prove that there is a deletion of cellular DNA as consequence of the integration , with an estimated minimum size of 14 kilobases .
10		Both cellular flanking probes are outside the amplicon of this chromosome region identified in the OSA and RMS13 sarcoma cell lines , comprising SAS-CHOP-CDK4-MDM2 genes and where translocation breakpoints are located in liposarcomas .
11		The integration at 12q13-15 might have been selected by its contribution to the tumor phenotype .

PMID: 7656201 (Patient)   Terms:
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0		Characterization of the 12q13-15 amplicon in soft tissue tumors .
1		Amplification of the genes MDM2 , SAS , and CDK4 , all located on the long arm of chromosome 12 , has recently been demonstrated in human soft tissue tumors .
2		To determine the extent of the amplification unit , we examined 16 soft tissue tumor samples , including pleomorphic liposarcoma , malignant fibrous histiocytoma ( MFH ) , and atypical lipoma , by Southern blot analysis using 13 chromosome 12 probes .
3		All tumors had previously been shown to have 3 - to 20-fold amplification of MDM2 .
4		In five samples , all MFH , only MDM2 was amplified , whereas in the remaining 11 samples , two to five additional genes were amplified .
5		The amplicon included markers both proximal and distal to MDM2 , but was in all but one atypical lipoma confined to the chromosome region 12q13-15 .
6		Discontinuous amplicons were found in two of the tumors .
7		This study indicates that MDM2 , or possibly an as-yet-unidentified gene in its proximity , is the target gene of the 12q13-15 amplification in soft tissue tumors .

PMID: 7640224 (Patient)   Terms:
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0		Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas--relationship to amplification and mRNA levels of CDK4 and CCND1 .
1	Μ	Homozygous deletions of the putative tumour-suppressor gene CDKN2 , which encodes an inhibitor of cdk4 , have been detected in a high percentage of cancer cell lines of various histological types .
2		In the present study , 109 human sarcomas were examined for homozygous deletions and for mRNA expression levels of the CDKN2 gene .
3	Μ	Altogether , deletions were found in only eight ( 7% ) of the cases , but , interestingly , in two ( of eight ) malignant Schwannomas and in two ( of five ) rhabdomyosarcomas .
4		In comparison , such deletions were seen in only one ( of 21 ) osteosarcomas and in none of 20 MFHs and 21 liposarcomas .
5		Notably , highly elevated CDKN2 mRNA levels were found in 33% of the sarcomas , whereas no detectable transcript was present in 12 normal tissues .
6	Μ	Amplifications of CDK4 and CCND1 ( cyclin D1 ) were observed in 11% and 4% of the sarcomas respectively , but never in tumours with CDKN2 deletions .
7		The level of CDK4 mRNA expression was increased in nine tumours in addition to the 12 samples with CDK4 amplification .
8	Μ	Increased levels of the cyclin D1 transcript was found in 37 cases , four with and 33 without amplification .
9		The data indicate that aberrations of these functionally related genes , or in regulation of the expression of the kinase , the activator or the inhibitor , may participate in sarcoma development .
10		Furthermore , the data suggest that homozygous CDKN2 deletions may be of dissimilar significance in different sarcoma subtypes .

PMID: 7664245 (Cell)   Terms:
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0		Identification of two distinct chromosome 12-derived amplification units in neuroblastoma cell line NGP .
1		The neuroblastoma cell line NGP contains two homogeneously staining regions ( hsr ) .
2		One of these hsrs contains MYCN sequences .
3	Μ	Reverse painting experiments demonstrated that the second HSR consisted of two chromosome 12-derived amplification units , located at 12q14-15 and 12q24 .
4	Μ	Southern blot and fluorescence in situ hybridization ( FISH ) analysis showed amplification of genes located at 12q14-15 : SAS , MDM2 , and CDK4 , GLI , CHOP , CDK2 , and A2MR were found not to be amplified .
5	Μ	FISH further demonstrated amplification of RSN , a gene located at 12q24 .
6		The finding of two distinct chromosome 12 amplification units in a neuroblastoma cell line NGP is reminiscent of recent findings in well-differentiated liposarcoma ( WDLPS ) and other sarcomas .
7		The second amplification unit on chromosome 12 in NGP is located more distal ( 12q24 ) than the one observed in WDLPS ( 12q21 ) .
8		The mechanism and biologic significance of this amplification process in neuroblastoma and WDLPS remain to be elucidated .

PMID: AACR_2015-3093 (Cell)   Terms: in vivo, in vitro, xenograft
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0	✓	CDK4 amplification reduces sensitivity to CDK4/6 inhibition in fusion-positive rhabdomyosarcoma .
1		Rhabdomyosarcoma ( RMS ) is the most common pediatric soft tissue sarcoma and includes an aggressive , PAX3-FOXO1 fusion-positive subtype .
2	Μ	Amplification of chromosomal region 12q13-q14 , which contains the CDK4 proto-oncogene , was identified in a subset of fusion-positive RMS .
3		Other tumor types with CDK4 amplification or overexpression , including liposarcoma and neuroblastoma , are sensitive to CDK4/6 inhibition , suggesting that CDK4/6-targeted therapies may provide a new treatment strategy in fusion-positive RMS .
4		To evaluate the role of CDK4 in chromosomal region 12q13-14 amplification in fusion-positive RMS and the potential clinical utility of CDK4/6 inhibition in this disease setting , we examined the biological consequences of CDK4 knockdown , CDK4 overexpression , and pharmacologic CDK4/6 inhibition in fusion-positive RMS in vitro and in vivo .
5		Knockdown of CDK4 abrogated proliferation and transformation of 12q13-14-amplified and non-amplified fusion-positive RMS cells via G1-phase cell cycle arrest .
6		This arrest was associated with reduced RB phosphorylation and E2F-responsive gene expression .
7	Μ	Significant differences in E2F target expression , however , were not observed in RMS cells overexpressing CDK4 or in fusion-positive tumors harboring 12q13-14 amplification relative to control cells or tumors lacking amplification , respectively .
8		Treatment with the small molecule CDK4/6 inhibitor LEE011 phenocopied CDK4 knockdown , decreasing viability , RB phosphorylation , and E2F-responsive gene expression and inducing G1-phase cell cycle arrest .
9	✓	All fusion-positive RMS cell lines showed sensitivity to CDK4/6 inhibition , with evidence of differential antitumor activity resulting from an inverse relationship between CDK4 expression and inhibitor vulnerability .
10		This variable responsiveness to LEE011 was recapitulated in xenograft models of CDK4-amplified and non-amplified fusion-positive RMS .
11	✓	Our findings demonstrate that CDK4 is necessary for RB-E2F -mediated G1-phase cell cycle progression , proliferation , and transformation in fusion-positive RMS regardless of CDK4 amplification status .	GE-INV-RO
12	✓	Our studies further indicate that single-agent LEE011 is active in the setting of fusion-positive RMS and suggest that CDK4 amplification may be a marker of reduced sensitivity whereas low CDK4 expression may be associated with higher susceptibility to CDK4/6 inhibition .
13		Collectively , our data provide preclinical evidence supporting further investigation of CDK4/6-targeted therapies in treatment regimens for fusion-positive RMS .

PMID: AACR_2017-4188 (Cell)   Terms: In vitro, in vivo, xenograft, in vitro
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0		Multitargeted tyrosine kinase inhibitor identified as potential therapeutic intervention for liposarcoma using high-throughput profiling. .
1		Liposarcoma is a rare fat cell adult tumor with high risk of recurrence and metastasis , largely underserved by research community and till now limited progress has been made in treatment of this aggressive disease .
2		We used a strategy to identify effective and potential therapeutic kinase inhibitors , irrespective of the activated kinase pathway , using small molecule kinase inhibitor panel .
3		We screened liposarcoma cell lines of different histotypes to a panel of small molecule kinase inhibitors and analyzed using cell proliferation assay .
4		In vitro cell proliferation assay , colony formation , cell cycle analysis , apoptosis assay and western blotting analysis were performed to investigate the effect and mechanism of inhibitor treatment on liposarcoma .
5		Liposarcoma xenograft model system was also employed to investigate anti-tumor in vivo effects of inhibitor treatment .
6		We observed that cell lines demonstrated diverse in vitro drug sensitivity patterns to various kinase inhibitors .
7	Μ	Most of the cell lines showed very high sensitivity towards inhibitors targeting proteasome , protein kinase C , Hsp90 , PI3K , mTOR and CDKs .
8		Among the receptor tyrosine kinase inhibitors ; Ponatinib , Dasatinib , and Sunitinib are the top most sensitive drugs affecting liposarcoma cells lines’ viability irrespective of subtypes and all these are already approved by the U .
9		S .
10		Food and Drug Administration to treat various cancers .
11		We studied multi-targeted tyrosine kinase inhibitor ponatinib as an effective potential drug molecule in liposarcoma .
12		We demonstrated that ponatinib treatment in liposarcoma cell lines reduced the levels of phosphorylated KIT compared to total KIT protein levels in dose dependent manner .
13		Further , western blotting experiments revealed effect of ponatinib treatment on KIT downstream signalling by inhibiting the phosphorylation of AKT , ERK1/2 , STAT3 , mTOR , P70S6K and RB without affecting their total protein levels .
14		Significant reduction in cell number and colonies with ponatinib treatment implicates anti-neoplastic effects in liposarcoma .
15		Ponatinib treatment causes cell cycle arrest at G0/G1 phase by regulating CDK4 and cyclinD1 proteins levels .
16		It also induces apoptosis of treated cells by downregulating AKT and ERK signaling pathway leading to dephosphorylation of BAD .
17		Similar growth inhibiting effect of ponatinib was demonstrated in in vivo liposarcoma xenograft model .
18		In vitro drug sensitivity profiling of liposarcoma highlighted Ponatinib , an oral FDA approved drug , as potential therapeutic drug candidate for treatment and management of this deadly tumor .

PMID: AACR_2014-5136 (Cell)   Terms:
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0		HDACi inhibits liposarcoma via targeting of the MDM2-p53 signaling axis and PTEN , irrespective of p53 mutational status .
1		Liposarcoma ( LPS ) is the most common sarcoma of humans .
2		There are no systemic therapeutic regimens known to improve survival when complete surgical resection is not feasible , underscoring the need for an improved molecular understanding of LPS to stimulate the development of effective targeted therapies .
3		The MDM2-p53 pathway plays a prominent role in WDLPS pathogenesis , with the vast majority of human tumors harboring either MDM2 amplifications or p53 mutations .
4		Nutlin-3 , a small-molecular antagonist of MDM2 , inhibits cell proliferation via blocking the interaction of MDM2-p53 in LPS with wild-type p53 .
5		We wonder whether MDM2 overexpression due to amplification or/and mutant p53 still plays a crucial oncogenic role in LPS containing p53 mutation .
6	✓	Herein , we developed isogenic liposarcoma lines in which the parental forms were MDM2 amplification and p53 wild-type , whereas sublines had mutation p53 expression , showed Nutlin-3 resistance .
7		mRNA sequencing and immunoblotting showed that MDM2 and CDK4 were overexpression in the parental lines and sublines , whereas MDM2 and CDK4 expression was low in mesothelioma and GIST cell lines .
8		HDAC inhibitor ( HDACi , SAHA and LBH589 ) treatment resulted in the dephosphorylation and degradation of MDM2 and p53 , but little affected CDK4 and JUN expression , irrespective of p53 mutational status in LPS with MDM2 amplification , and in a mesothelioma cell line JMN1B with p53 mutation , but not two mesothelioma lines containing normal MDM2 level and wild-type p53 .
9		Our findings indicate that regulation of wild-type 53 degradation by HDACi is MDM2 amplification -dependent .
10		HDAC inhibition by SAHA and LBH589 had a substantially effect on LPS and mesothelioma proliferation and survival associated with upregulation of the PTEN and p21 , inhibition of cell proliferation marker cyclin A and PCNA expression , induction of G1 or G2 phase arrest ; induction of apoptosis showing an increase of caspase 3/7 activity and expression , PARP cleavage , and the sub-G1 apoptotic population .
11		Moreover , we characterize biological functions of MDM2-p53 axis in nutlin-3-sensitive and nutlin-3-resistant LPS , showing MDM2 knockdown in the four LPS lines and p53 knockdown in the three mutant -p53 LPS lines resulted in anti-proliferative effects .
12		Additive effects were obtained through a coordinated attack on MDM2 and p53 , as demonstrated by immunoblots , cell viability and cell cycle analyses , showing that MDM2 and p53 knockdown , in LPS cell lines containing the p53 mutation , induced greater cell apoptosis and anti-proliferative effects , compared to either intervention alone , which is comparable to the effects seen after HDAC inhibition by SAHA and LBH589 .
13		These compelling pro-apoptotic and anti-proliferative responses indicate that HDAC inhibition warrants clinical evaluation as a novel therapeutic strategy in LPS , including nutlin-3 resistant sublines with the p53 mutation .
14		Note : This abstract was not presented at the meeting .

PMID: ASCO_187921-199 (None)   Terms:
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0		Phase 2 trial of the novel multi - receptor tyrosine kinase inhibitor sitravatinib in well-differentiated/dedifferentiated liposarcoma. .
1		Alternative treatment strategies to overcome MAPK inhibitor resistance in melanoma .

PMID: ASCO_133596-144 (Patient)   Terms: NCT01209598, NCT01037790, NCT01209589, Clinical trial
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0		Characterization of isolated , uncomplicated neutropeniarelated to the CDK4/6 inhibitor palbociclib. .
1		Background : Palbociclib (P) , an oral , selective , reversible CDK4/6 inhibitor induces transient G1 arrest in hematopoietic stem/progenitor cells ( HSPC ) , without DNA damage or apoptosis in preclinical studies .
2		In patients ( pts ) with advanced malignancy , P had activity in several tumor types , but neutropenia was dose-limiting .
3		We sought to characterize the incidence and patterns of myelosuppression to determine if the mechanisms observed preclinically were reflected in the clinical experience .
4		Methods : Data from 2 phase 2 studies of single agent P in pts with advanced RB+ tumors ( UPenn , NCT01037790 ) and liposarcoma ( MSKCC , NCT01209598 ) were analyzed .
5		Dose ( 125 mg P ) , schedule ( 3 wks on/1 wk off ) and safety assessments ( baseline , weekly cycle 1 and d 1 of subsequent cycle ) were identical .
6		Both trials required P be held for > grade ( Gr ) 3 myelosuppression until resolved to < Gr 2 .
7		Results : 140 patients with breast ( 36% ) , sarcoma ( 21% ) , germ cell ( 21% ) , colon ( 13% ) , gastric ( 7% ) tumors were enrolled .
8		Neutropenia , anemia and thrombocytopenia rates in cycle 1 by Gr are shown .
9		Mean absolute neutrophil count was 4.98 , 4.24 , 2.15 , 1.62 and 1.86 at weeks 1 , 2 , 3 , 4 and 5 , respectively , reflecting time to nadir .
10		Time to Gr3 neutropenia was 3 wks in 11% , 4 wks in 30% , 5 wks in 14% .
11		Recovery occurred after brief dose delay .
12		Neutropenia led to dose interruption in 19% of pts in cycle 1 and 8% had Gr3 neutropenia on day 1/cycle 2 .
13		Despite the high rate of Gr 3/4 neutropenia ( 39% ) , only 1 episode of neutropenic fever occurred ( in setting of disease progression ) , with no infections or use of G-CSF .
14		Mucositis was rare and
15		Concurrent Gr3 anemia or thrombocytopenia were rare ( 6% and 15% respectively ) .
16		Conclusions : Frequent , isolated and uncomplicated neutropenia in patients receiving P is consistent with preclinically observed quiescence but not death of HSPC and little effect on differentiated myeloid cells .
17		The lack of clinical morbidity or pancytopenia suggests that P-induced neutropenia is short lasting , reversible and may be managed conservatively .
18		PK data will be reported to confirm the relationship between ANC and drug exposure .
19		Clinical trial information : NCT01037790 , NCT01209589 .

PMID: AACR_2015-495 (Patient)   Terms:
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0		Amplification of chromosomal regions 12q13-14 and 12q15 defines a distinct subgroup of high-risk neuroblastoma patients and is associated with atypical clinical features .
1		Neuroblastoma is a pediatric cancer of the sympathetic nervous system with wide heterogeneity regarding clinobiological subtypes , ranging from patients with tumors of spontaneous regression to patients with aggressive tumors with fatal outcome despite multimodal treatment .
2		MYCN-amplification and 11q-deletion are important , although incomplete , markers of high-risk neuroblastoma .
3		Thus , characterization of additional genomic alterations that can be used as prognostic and/or predictive markers is of clinical importance in order to provide best possible treatment .
4	Μ	From genomic profiles generated through high-density SNP microarrays we identified a group of neuroblastomas ( 14 primary tumors and two cell lines ) with regional high grade amplification of one or multiple loci on the long arm of chromosome 12 , commonly involving either chromosomal region 12q13-14 , 12q15 or both .
5		Amplification of these regions has also been reported in other malignancies such as liposarcoma , glioma and lung cancer .
6		The two different 12q regions contains the potential oncogenic target genes ; CKD4 ( 12q13-14 ) and MDM2 ( 12q15 ) , involved in cell cycle progression and p53 regulation respectively .
7		The CDK4 and MDM2 regions were co-amplified in 13/16 neuroblastoma samples while two tumors had CDK4 amplification in absence of MDM2 amplification and one tumor had MDM2 amplification without CDK4 amplification .
8		Exome sequencing was performed for seven of the primary tumors with 12q-amplification .
9	Μ	No novel protein altering single nucleotide variant ( SNV ) were detected within the amplicons with exception of a rare INHBE K222Q mutation in one patient .
10		The exome sequencing also indicated that two tumors had a substantial number of additional rearrangements at subclonal level within the amplified regions , including a break of MDM2 in intron 8 for one of these patients .
11		Interestingly , the majority of the 12q-amplified neuroblastoma was of abdominal origin , some with renal location with initial suspicion of Wilms tumor .
12		Atypical metastatic pattern were also seen in this patient group showing low degree of bone marrow involvement favoring other metastatic sites such as lung , otherwise an uncommon localization in neuroblastoma .
13		The consistent co-amplification of two separate chromosome 12 regions in this subset of neuroblastoma suggests that these regions contain one or more genes with importance in tumor development .
14		Our study indicates that CDK4 appears as main target in this 12q-amplified neuroblastoma subgroup although other genes such as MDM2 and FRS2 also could provide proliferative advantages .
15		The 12q-amplified neuroblastoma exhibit distinct clinical features and can benefit from targeted therapy using a small molecule CDK4/CDK6 inhibitor such as LEE011 ( Novartis ) .

PMID: AACR_2017-2253 (None)   Terms:
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0		5 Gene prognostic signature for dedifferentiated liposarcomas. .
1		Introduction : Liposarcomas , despite being rare consist of a number of entities spanning low to high grade sarcomas .
2		De-differentiated liposarcoma ( DDLS ) is associated with increased frequency of recurrence and lower overall survival .
3	Μ	We aimed to identify gene expression changes associated with OS in DDLS .
4		Secondary aims was to postulate a mechanism for DDLS .

PMID: AACR_2013-4203 (None)   Terms:
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0		Overexpression of miR-26a-2 in human liposarcoma is correlated with poor patient survival. .
1		Approximately 90% of well-differentiated/de-differentiated LPS (WDLPS/DDLPS) , the most common LPS subtype , have chromosomal amplification at 12q13-q15 .
2		Many protein -coding genes in the region , such as MDM2 and CDK4 , have been studied as potential therapeutic targets for LPS treatment with minimal success .
3	Μ	Within this amplicon near the MDM2 gene , our SNP array analysis identified frequent amplification of miR-26a-2 .
4		Besides being in the amplicon , we found that miR-26a-2 is overexpressed significantly in WDLPS/DDLPS , as well as in myxoid/round cell LPS ( MRC ) .
5		Furthermore , Kaplan-Meier survival analysis showed that overexpression of miR-26a-2 significantly correlated with poor patient survival in both types of LPS .
6		Based on these findings , we hypothesized that miR-26a-2 plays an important role in LPS tumorigenesis , regardless of LPS subtypes .
7		Overexpression of miR-26a-2 in LPS cells could help the growth and survival of cancer cells in a cell type-specific manner , including faster cell proliferation , faster cell migration , enhanced clonogenicity , suppressed adipocyte differentiation , and/or resistance to apoptosis .
8		Inhibition of miR-26a-2 in LPS cells using anti-miR-26a-2 resulted in the opposite responses .
9		To explain further the effect of miR-26a-2 overexpression in LPS cells , we performed in sillico analysis and identified 93 candidate targets of miR-26a-2 .
10		Among these candidate genes , we found that RCBTB1 ( RCC1 and BTB domain containing protein 1 ) was located at 13q12.3-q14.3 , a recurrent region of loss of heterozygosity ( LOH ) in human LPS .
11		Indeed , overexpression of RCBTB1 made cells more susceptible to apoptosis .
12		Likewise , inhibition of RCBTB1 made cells more resistant to apoptosis .
13		In conclusion , our study reveals , for the first time , the contribution that miR-26a-2 makes to LPS tumorigenesis , partly through inhibiting RCBTB1 .
14		Our study shows that miR-26a-2 is a novel therapeutic target for human LPS .

PMID: ASCO_166807-176 (Patient)   Terms: clinical trial
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0		Clinical next-generation sequencing in sarcomas. .
1		Background : There are currently no FDA approved targeted therapies for sarcomas except GIST .
2		Complicating this is the extreme diversity , heterogeneity , and rarity of these neoplasms .
3		Few therapeutic options exist for relapsed and refractory sarcomas .
4		In clinical practice many oncologists refer patients for genomic profiling hoping for guidance on treatment options after standard therapy .
5		We analyzed clinical next generation exome sequencing ( NGS ) results in patients with advanced sarcomas to discover potentially actionable aberrations and their frequency in a clinical setting .
6		Methods : We reviewed charts of patients with advanced sarcoma referred to investigational cancer therapeutics department and had CLIA certified comprehensive genomic profiling of 200 - 315 cancer genes in atleast 50ng of DNA .
7		Actionable aberrations were defined as those identifying anti-cancer drugs on the market , in registered clinical trials , or in the Drug - Gene Interaction Database .
8		Results : Among the 98 patients analyzed median age was 33.5 years ( range 10-76 ) , M : F ratio 47 : 51 .
9		Common sarcoma types were de-differentiated lipo ( N = 20 ; 20% ) , leiomyo ( n = 11 ; 11% ) , osteo ( n = 9 ; 9% ) , well-differentiated lipo ( n = 7 ; 7% ) , rhabdomyo ( n = 6 ; 6% ) , carcino , GIST , spindle cell , and unclassified ( N = 5 each ; 5% ) .
10		Seventy percent ( 69/98 ) of patients had > 1 potentially actionable genomic aberration .
11		The most common aberrations involved CDK4 amplification ( n = 22 ; 22% ) , CDKN2A/B loss or mutation ( n = 16 ; 16 % ) , and MDM2 amplification ( n = 21 ; 21% , non-liposarcoma = 4 ) , .
12		Other notably targetable mutations occurring more rarely included PIK3CA , NOTCH2 , NTRK1/3 , KDR and PDGFR .
13		Novel fusions were characterized ( KIAA1549 : BRAF and DCTN1-ALK ) that molecularly matched to therapy with patient benefit .
14		Interesting cases included a patient with 3 EWS rearrangements ( EWSR1-FLI1 , CENPP-EWSR1 , ETS1-EWSR1 ) and re-classification of an unclassified sarcoma to Ewings .
15		Conclusions : Incorporating NGS into sarcoma management may allow for more precise diagnosis and sub-classification of this diverse and rare disease .
16		Matching patients to inhibitors targeting CDK , MDM2 , PIK3CA , NOTCH2 , and NTRK available in basket clinical trials are opportunities for translation of biology into clinical benefit .

PMID: ASCO_134972-144 (Patient)   Terms:
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0		Diversity and heterogeneity in molecular analysis of advanced sarcomas : The clinical , regulatory , and financial challenge for drug development and precision medicine. .
1		Background : Therapeutic options are limited for advanced sarcomas .
2		Search for molecular alterations could lead to identification of novel therapies for refractory sarcoma patients .
3		Rarity poses an extreme challenge in drug development .
4		Methods : We reviewed the charts of patients with advanced sarcoma patients who were referred to the phase 1 clinic at MD Anderson Cancer center and had molecular profiling done by commercially available CLIA certified labs .
5		We analyzed the preliminary responses to matched therapy in these patients .
6		Results : Among the 57 pts analyzed , median age =48 years ( M : F = 25 : 32 ) , median ECOG PS = 1 , median no .
7		of prior therapies = 3 .
8		Most common subtypes were leiomyosarcoma ( n = 13 ; 22% ) , rhabdomyosarcoma ( n = 8 ; 14 % ) , liposarcoma ( n = 7 ; 12 % ) , osteosarcoma ( n = 7 ; 12 % ) , clear cell sarcoma ( n = 3 ) , and synovial sarcoma ( n = 3 ) .
9		Forty-five/57 ( 78% ) patients had > 1 genomic aberration .
10		Each pts aberration profile was distinct .
11		For instance , in osteosarcoma no 2 ps had the same profile .
12		In other soft tissue sarcomas , aberrations involved CDKN2A/B loss or mutation ( n = 10 ; 22 % ) , TP53 alterations ( n = 15 ; 33% ) , CDK4 amplification ( n = 8 ; 17% ) , MDM2 amplification ( n = 7 ; 15% ) , and RB1 loss/mutation ( n = 6 ; 13% ) .
13		In addition , novel aberrations : KIAA1549-BRAF fusion protein in a spindle cell sarcoma , CD30 + in osteosarcoma , and PTPRD mutation in Ewings sarcoma were identified .
14		Molecularly matched therapy are ongoing ( Table ) .
15		Conclusions : Based on the uniqueness and distinct biology of sarcoma , we conclude that the established model for drug development in sarcoma of one size fits all approach does not fit the reality of sarcoma biology .
16		New creative models for precision medicine with regulatory approval , establishment of levels of evidence , modification of reimbursement policies by health care payers and innovative dynamic ways to collect N of 1 clinical data in real time with open access are warranted .

PMID: ASCO_193380-199 (None)   Terms:
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0		Genetic landscape of soft - tissue sarcomas : Moving toward personalized medicine. .
1		Background : Patients with advanced soft - tissue sarcomas have a very poor outcome with a median overall survival of less than 18 months .
2		Identification of molecular abnormalities for which targeted therapies are available or can be developed is critical for improving their outcomes .
3	Μ	Methods : We have analyzed the mutational and copy number profiles of patients with sarcoma sequenced through the AACR Project GENIE Consortium in order to identify the proportion of cases bearing actionable mutation .
4		Results : 587 patients ( pts ) were included in the study ( 295 males ) .
5		331 pts ( 56% ) had complex genomics sarcomas , 144 ( 25% ) translocation-related sarcomas and 112 ( 19% ) others sarcomas ( inactivating mutation , simple amplicon ) .
6		The five most frequent histology were : Leiomyosarcoma ( n = 112 ; 191% ) ; Undifferentiated Pleomorphic Sarcomas ( n = 74 , 126% ) , dedifferentiated liposarcoma ( n = 55 , 94 % ) , angiosarcoma ( n = 43 , 73% ) , synovial sarcoma ( n = 38 , 65% ) .
7		430 pts ( 73% ) had atleast one mutation .
8	Μ	The ten most frequently mutated genes were : TP53 ( 347% ) ; ATRX ( 91% ) , RB1 ( 84% ) , KMT2D ( 58% ) , NF1 ( 53% ) , ATM ( 51% ) , PI3KCA ( 49% ) , ERBB4 ( 42% ) , PTEN ( 4% ) , and ARID1A ( 37% ) .
9		504 patients ( 859% ) presented atleast one copy number alteration .
10	Μ	The 5 five most frequently amplified genes were : MDM2 ( 20% ) , CDK4 ( 167% ) , GLI1 , MAP2KA , and TERT ( 32% for each gene ) , and the most frequently deleted were RB1 ( 127% ) , CDKN2A ( 103% ) , CDKN2B ( 97% ) , TP53 ( 9.5% ) , PTEN ( 85 ) .
11		92.5% of pts had atleast one targetable mutation , copy number alteration and/or fusion gene ( Leiomyosarcoma n = 100/17% , UPS n = 74/12% , dedifferentiated diposarcoma n = 54/9% , angiosarcoma n = 41/7% , synovial Sarcoma n = 36/6% ) , with incidences reported that will be reported in details at the meeting .
12		Conclusions : This is the first large report of genomic landscape including mutation and copy number profiling through NGS of soft - tissue sarcomas .
13		Our results indicate a significant proportion of actionable mutations and represent a rationale for the MULTISARC study : the first study implementing Exome Seq and RNA Seq for clinical decision making in patients with advanced STS .
14		The design of this study supported by the French government and launched in 09/2017 will be presented at the meeting .

PMID: AACR_2015-1759 (Cell)   Terms: Phase I, clinical trial, in vivo, in vitro, xenograft, tumor xenograft
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0		Preclinical activity of selinexor , an inhibitor of XPO1/CRM1 , in sarcoma .
1		ObjectiveExportin 1/Chromosomal Region Maintenance Protein 1 (XPO1/CRM1) transports proteins bearing nuclear export signals from the cell nucleus to the cytoplasm .
2		SINE are a family of small-molecules that selectively inhibit nuclear export through covalent binding to Cysteine 528 (Cys528) in the cargo binding pocket of XPO1 .
3		This leads to forced nuclear retention of cargo proteins that include major tumor suppressor proteins such as p53 , FOXO , pRB and IkB .
4		Preclinical and clinical studies have demonstrated selinexor activity in hematologic malignancies as well as in certain solid tumors , and it is currently in Phase I and II clinical trials for advanced cancers .
5		In this study , we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes .
6		Materials and MethodsThe efficacy of selinexor was tested in vitro and in vivo using 17 cell lines and 10 sarcoma xenograft models including gastrointestinal stromal tumor ( GIST ) , liposarcoma ( LPS ) , leiomyosarcoma , rhabdomyosarcoma , undifferentiated sarcomas , and alveolar soft part sarcoma ( ASPS ) .
7		Following exposure of cell lines to selinexor , effects on cell viability , cell cycle , and RNA and protein expression were determined .
8		In sarcoma xenograft studies , selinexor was administered twice a week by oral gavage and changes in tumor size were recorded .
9		ResultsMost sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM ( median : 66.1 nM ) .
10		The ASPS cell lines were exceptionally resistant to selinexor with IC50 greater than 2 M .
11		Selinexor suppressed sarcoma tumor xenograft growth , including models of ASPS that were resistant in vitro .
12		Cell lines from several sarcoma subtypes with defined molecular backgrounds , such as GIST with KIT mutations and dedifferentiated LPS with MDM2 and CDK4 amplification , were treated with selinexor to investigate its mechanism of action .
13		Selinexor induced G1 arrest in GIST cells without attenuation of phosphorylation of KIT , AKT , or MAPK , in contrast to imatinib .
14		In LPS cell lines selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation status and induced G1-arrest irrespective of RB expression .
15		Selinexor increased p53 and p21 expression at the protein but not RNA levels , indicating a post-transcriptional effect .
16		ConclusionsSelinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models .
17		Selinexor induced G1-arrest independent of known molecular mechanisms in GIST and LPS .
18		These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes .