Dedifferentiated Liposarcoma Research Articles

"Incidental Discovery of Dedifferentiated Liposarcoma of the Anterior Mediastinum: A Case Report"

Knauss HM1, Glosser LD1, Shi SX2* and Taleb M3 Author Affiliations 1Department of Medical Education, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA 2Clinical Neuroscience Research Center, Department of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, LA, USA 3Department of Pulmonary/Critical Care Medicine, University of Toledo Medical Center, Toledo, OH, USA Received: August 30, 2021 | Published: September 07, 2021 Corresponding author: Shi SX, Clinical Neuroscience Research Center, Department of Neurosurgery and Neurology, Tulane University School of Medicine, New Orleans, LA, USA DOI: 10.26717/BJSTR.2021.38.006178

1531P Multi-omic characterization of dedifferentiated liposarcoma: Towards a new model of oncogenesis?

Dedifferentiated liposarcomas (DDLPS) are one of the most frequent sarcoma subtypes, characterized by the coexistence of one low-grade, adipocytic, well-differentiated (WD) component and one high-grade, undifferentiated (DD) component. The molecular mechanisms determining the existence of these two distinct cell populations are poorly understood. We performed a multi-omics characterization of DDLPS to decipher the molecular and micro environmental characteristics of WD and DD components.

Giant De-Differentiated Liposarcoma of the Ascending Colon – A Rare Entity

Background: Liposarcoma is one of the common malignant mesenchymal tumors of the retroperitoneum and soft tissue of the extremities. Liposarcoma primarily arising from the colon is extremely rare. De-differentiated liposarcoma, a high grade variant has high local recurrence and distant metastatic potential. At present no standard treatment guidelines are established for the colonic liposarcoma in view of the rarity of the condition. Case Presentation: In this article we report a case of 46-year-old female who presented with a large right sided abdominal lump. On cross sectional imaging, she was found to have a large heterogenous exophytic mass arising from the ascending colon. Colonoscopy showed a submucosal lesion of the ascending colon with luminal narrowing. She underwent a right radical hemicolectomy. Histopathology of the resected specimen was reported as a de-differentiated liposarcoma arising from the ascending colon, which is an extremely rare occurrence. Patient made an uneventful recovery and is under follow-up. Conclusion: Liposarcoma is a rare disease of large intestine. It should be considered in the differential diagnosis when there is a large, submucosal colonic swelling with no lymph nodal or peritoneal disease. Complete surgical resection with clear margins is the standard of treatment. Evidence on the benefits of adjuvant chemotherapy and radiotherapy in improving survival in liposarcoma of colon is currently evolving.

Biology and Management of Dedifferentiated Liposarcoma: State of the Art and Perspectives.

Dedifferentiated liposarcoma (DDL) is defined as the transition from well-differentiated liposarcoma (WDL)/atypical lipomatous tumor (ALT) to non-lipogenic sarcoma, which arises mostly in the retroperitoneum and deep soft tissue of proximal extremities. It is characterized by a supernumerary ring and giant marker chromosomes, both of which contain amplified sequences of 12q13-15 including murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) cell cycle oncogenes. Detection of MDM2 (and/or CDK4) amplification serves to distinguish DDL from other undifferentiated sarcomas. Recently, CTDSP1/2-DNM3OS fusion genes have been identified in a subset of DDL. However, the genetic events associated with dedifferentiation of WDL/ALT remain to be clarified. The standard treatment for localized DDL is surgery, with or without radiotherapy. In advanced disease, the standard first-line therapy is an anthracycline-based regimen, with either single-agent anthracycline or anthracycline in combination with the alkylating agent ifosfamide. Unfortunately, this regimen has not necessarily led to a satisfactory clinical outcome. Recent advances in the understanding of the pathogenesis of DDL may allow for the development of more-effective innovative therapeutic strategies. This review provides an overview of the current knowledge on the clinical presentation, pathogenesis, histopathology and treatment of DDL.

Radical Hemiscrotectomy and En Bloc Orchidectomy: Surgical Technique and Perioperative and Oncologic Outcomes of a Supra-Regional UK Referral Centre

Background and PurposeHemiscrotectomy with en bloc orchidectomy represents a radical primary, completion, or salvage option in men with inguinoscrotal cancers. We describe our surgical technique and peri-operative and oncological outcomes.Patients and MethodsRetrospective cohort study of 16 men treated at a supra-regional referral centre with open radical hemiscrotectomy with or without en bloc orchidectomy between 2010 and 2020. Peri-operative and survival outcomes were analysed.ResultsRadical hemiscrotectomy with or without en bloc orchidectomy was performed on 16 patients comprising 7 well-differentiated liposarcomas, 4 dedifferentiated liposarcomas, 2 leiomyosarcomas, 1 mesothelioma, 1 rhabdomyosarcoma and 1 mammary type myofibroblastoma. Primary hemiscrotectomy was performed in four, completion hemiscrotectomy in nine and salvage hemiscrotectomy in three. The median hospital stay was 2 days [interquartile range (IQR) 2–4]. Four patients (25%) had post-operative complications including wound infection or haematoma. During a median follow-up of 18 months (IQR 2–66), one patient (6%) died following a recurrence in the pelvis and retroperitoneum.Discussionand ConclusionsIf careful dissection is performed, radical hemiscrotectomy and en bloc orchidectomy is a radical but safe procedure with a short hospital stay. Haematoma and infection represent the main complications, and within limited follow-up most men showed no recurrence.

BCL7B is a potential novel diagnosis and prognosis biomarker for sarcomas using bioinformatics analysis.

BCL7B plays a potential role in the progression of various cancers, while its role in sarcomas is unknown. We aimed to evaluate BCL7B's diagnostic and prognostic value, and potential BCL7B-related mechanisms in sarcomas based on The Cancer Genome Atlas (TCGA) database. We collected patients with sarcoma from TCGA. Wilcoxon rank sum test was used to compare the expression of BCL7B in sarcoma samples with different clinical-pathologic features. Univariate Cox regression analysis and multivariate Cox regression analysis were used to evaluate prognosis factors for sarcoma. Gene set enrichment analysis (GSEA) was conducted to elucidate the significant functions and pathways associated with BCL7B. BCL7B was a potential biomarker for distinguishing normal and tumor tissues with the analysis of ROC curve (AUC = 0.588). Low BCL7B expression was significantly correlated with tumor multifocal (OR = 0.39 for yes vs no), larger residual tumor (OR = 0.40 for R1,R2 vs RO), male gender (OR = 0.48 for male vs female) and White race (OR = 0.29 for White vs Asian, Black or African American). High BCL7B expression was correlated with leiomyosarcoma histological type (OR = 6.08 for leiomyosarcoma vs dedifferentiated liposarcoma, pleomorphic sarcoma). Univariate and multivariate Cox regression analysis showed that low BCL7B expression was independently associated with poor overall survival (P = .008). GSEA showed that GPCR (G protein-coupled receptors) ligand binding, secreted factors, class A1 rhodopsin-like receptors, extracellular matrix organization, core matrisome, Fc epsilon receptor I mediated NF-κB activation, and WNT signaling pathway were differentially enriched in BCL7B low expression phenotype (|NES| > 1, adjusted P value <.05, and FDR value <0.25). BCL7B may play an important role in sarcoma progression and may be a potential biomarker for prognosis and diagnosis in sarcomas.

Bone and soft tissue sarcomas in cerebrospinal fluid and effusion: A 20-year review at our institution.

The literature on bone and soft tissue sarcomas (BSTSs) involving effusions and cerebrospinal fluid (CSF) is very limited. A computerized search for fluid cytology with a sarcoma diagnosis from 2000 to 2020 was performed. All available cases, including the clinical follow-up, were reviewed. A total of 57 fluids specimens from 36 BSTSs were identified (9 rhabdomyosarcomas, 6 angiosarcomas, 5 epithelioid hemangioendotheliomas, 3 dedifferentiated liposarcomas, 2 chondrosarcomas, 1 extraskeletal myxoid chondrosarcoma, 3 Ewing sarcomas, 2 undifferentiated sarcomas, 3 osteosarcomas, 1 synovial sarcoma, and 1 hybrid low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma). There were 22 males and 14 females. The age range was 4 to 82 years (median, 45 years). Sites of involvement included pleural fluid (n = 38), peritoneal fluid (n = 14), and CSF (n = 5). Twenty-four cytology cases were available for review. The cytologic features were nonspecific and ranged from dyshesive to clusters of round, epithelioid, pleomorphic, and occasionally spindle-shaped malignant cells that could easily mimic other non-BSTS malignant tumors. The diagnosis of BSTS was made by comparison with a prior specimen and/or ancillary studies (molecular or immunohistochemical stains). The prognosis was poor because 95% of the patients died of their disease. The incidence of BSTS in fluid cytology is extremely rare, and it can have cytologic features similar to those of non-BSTS malignancies. Although, in most cases, a comparison with a prior known BSTS specimen may suffice, the use of ancillary studies is extremely helpful in arriving at the correct diagnosis. However, in cases with no known prior malignancy, including BSTS in the differential diagnosis is prudent for preventing misdiagnosis.

Clinicopathologic Characteristics and Clinical Outcome of Localized Liposarcoma: A Single-Center Experience over 25 Years and Evaluation of PD-L1 Expression.

PurposeFor liposarcoma (LPS), clinical course and proper treatment strategies have not been well-established. Recently, immune-checkpoint inhibitors have shown potential efficacy in LPS. We aimed to describe the clinical course of LPS and evaluate the clinical impact of programmed death-ligand 1 (PD-L1).Materials and MethodsWe reviewed all consecutive patients (n=332) who underwent curative-intent surgery for localized LPS at Asan Medical Center between 1989 and 2017. PD-L1 testing was performed in well-differentiated and dedifferentiated LPS.ResultsThe median age was 56 years with males comprising 60.8%. Abdomen-pelvis (47.6%) and well-differentiated (37.7%) were the most frequent primary site and histologic subtype, respectively. During a median follow-up of 81.2 months, recurrence was observed in 135 (40.7%), and 86.7% (117/135) were loco-regional. Well-differentiated subtype (hazard ratio [HR], 0.38), abdomen-pelvis origin (HR, 2.43), tumor size larger than 5 cm (HR, 1.83), positive resection margin (HR, 2.58), and postoperative radiotherapy (HR, 0.36) were significantly related with recurrence-free survival as well as visceral involvement (HR, 1.84) and multifocality (HR, 3.79) in abdomen-pelvis LPS. PD-L1 was positive in 31.5% (23/73) and 51.3% (39/76) of well-differentiated and dedifferentiated LPS, respectively, but had no impact on survival outcomes.ConclusionClinical course of LPS was heterogeneous according to histology and anatomic location. Clear resection margin was important to lower recurrence and postoperative radiotherapy might have additional benefit. A decent portion of well-differentiated and dedifferentiated LPS were positive for PD-L1, but its prognostic role was unclear. Further research is needed to determine clinical implications of PD-L1, especially for advanced-stage LPS with unmet needs for effective systemic treatment.

Abstract 625: Co-amplification of CDK4 and MDM2 plus HMGA2 fusion in a patient with myogenic differentiation dedifferentiated liposarcoma

Abstract BACKGROUND: Dedifferentiated liposarcoma (DDLPS) with myogenic differentiation is a rare subtype of soft tissue sarcoma, and its pathogenesis remains unclear. The morphological resemblance with myofibroblastic sarcoma and rhabdomyosarcoma may easily result in misdiagnosis. Some studies have shown that myogenic differentiation is considered as a poor prognostic factor for DDLPS; consequently, it is of great clinical significance for its accurate diagnosis. Next-generation sequencing (NGS) can be performed to better explore the molecular characteristics and targeted therapies of myogenic differentiation DDLPS. Here, we reported a rare case of myogenic differentiation DDLPS harboring co-amplification of CDK4 and MDM2 plus HMGA2 gene fusion, which was clarified via NGS. CASE PRESENTATION: A 61-year-old male patient presented with local soft tissue thickening in the right groin and scrotum by PET-CT. Pathological examination revealed a 5.8*4.5*3.5cm mass in the right groin with an enveloping appearance and gray-brown section. Microscopic examination showed the parenchymal mass was composed of spindle cells. Immunohistochemistry (IHC) reported that spindle cells were diffusely positive for desmin and vimentin; focally positive for epithelial membrane antigen, smooth muscle actin and actin; and negative for ALK, S-100, myogenin, CD30, CK, h-caldesmon, MyoD1, STAT6, SOX-10 and β-catenin. The approximate Ki-67 label index was 40%. Combining with the morphology and IHC, the patient was diagnosed with myogenic differentiated soft tissue sarcoma. After surgical resection, NGS was performed on resected tissues to further identify the subtype due to its high aggressiveness. Fresh surgical tissues were tested by the NGS-based 825-gene DNA panel and 395-gene RNA panel. The tumor samples contained three somatic mutations: ELAC2 p.H194R (14.4%), HRH2 p.S325F (18.1%), and KEL p.G167D (19.3%). Copy number analysis revealed copy number gains for CDK4, MDM2 and IGF1R in the patient. He also carried HMGA2(E3)-CCDC91(E2), FRS2(E3)-BCAT1(E3) and ATG5(E5)-DSG3(E13) gene fusion. CDK4 and MDM2 gene amplification is the clinical diagnostic marker of DDLPS, this patient was finally diagnosed as DDLPS with myogenic differentiation. Additionally, HMGA2 gene fusion was firstly reported in myogenic differentiation DDLPS, which was often discussed in lipoma before. CONCLUSION: To date, limited scientific literature is available for a comprehensive understanding of the genetic characteristics of myogenic differentiation DDLPS. For the first time, we reported a case of myogenic differentiation DDLPS with simultaneous CDK4, MDM2 amplification and HMGA2 gene fusion, which may be the potential tumorigenic mechanism of myogenic differentiation DDLPS. Citation Format: Gang Huang, Xianan Li, Chunyang Wang, Qifan He, Xiaojuan Wang. Co-amplification of CDK4 and MDM2 plus HMGA2 fusion in a patient with myogenic differentiation dedifferentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 625.

Abstract 2438: Genetic activation of JUN fuels the core regulatory circuitry of de-differentiated liposarcoma

Abstract Background: As a high-grade neoplasm of connective tissues, de-differentiated liposarcoma (DDLPS) is featured by genomic amplification of MDM2, CDK4 and JUN. Super-enhancer-driven master transcription factors (RUNX1, FOSL2 and MYC) establish a core feed-forward transcriptional circuit underpinning the DDLPS malignancy. However, an important question remains unanswered: how do genomic insults interact with epigenetic dysregulation in this disease? Methods: We performed ChIP-seq analysis to map loading of transcription factors and histone marks on chromatin in DDLPS cells. Functional assays following genetic manipulation of target genes were conducted to explore their disease relevance. Results: Genomic activation of JUN represents a promising prognostic marker for DDLPS. Meanwhile, JUN locus engaged excessive H3K27ac signals in both DDLPS tissues and cells, while a markedly lower level of H3K27ac deposition was observed in normal adipose tissues, adipocytes and MSCs. JUN formed a complex with FOSL2 and other co-factors in active chromatin, especially super-enhancers. Silencing of either JUN or its co-factors disrupted the core regulatory circuitry, which was accompanied by strong deleterious impacts on both cell viability and tumorigenicity. As BET bromodomain proteins dictate transcriptionally active chromatin, targeted degradation of BET proteins by PROTAC compounds exerted potent inhibitory effects on both JUN cistrome and DDLPS development. Conclusion: Our study reveals that amplification and overexpression of JUN contribute to DDLPS development. DDLPS-associated genomic abnormalities collaborate with BET proteins to fuel disease-driving core regulatory circuitry. Citation Format: Ye Chen, Pushkar Dakle, Tuan Zea Tan, Ruby Yu-Tong Lin, Mark E. Puhaindran, Sigal Gery, Liang Xu, Phillip H. Koeffler. Genetic activation of JUN fuels the core regulatory circuitry of de-differentiated liposarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2438.

Abstract 1067: PDK-1 targeting with SNS-510 in sarcoma

Abstract Soft tissue sarcomas are heterogeneous mesenchymal neoplasms and account for 1% of all cancers in adults. Over 50 sarcomas subtypes have been classified and many have limited treatment options some of which include surgery, chemotherapy and radiation. 3-phosphoinositide dependent protein kinase 1 (PDK1) is overexpressed in many cancers, suggesting a role for PDK1 in cancer progression. In addition, PDK1 has been identified as a key modifier of acquired resistance to CDK4/6 inhibitors. In order to interrogate this in sarcoma, we elected to test SNS-510 a potent, orally bioavailable PDK1 inhibitor against a broad range of sarcoma cell lines (leiomyosarcoma, dedifferentiated liposarcoma, Ewing's sarcoma, osteosarcoma, chondrosarcoma and synovial sarcoma) as well as dedifferentiated liposarcoma cell lines with acquired resistance to ribociclib, which are also cross resistant to palbociclib. All the cell lines expressed PDK1 and, as measured by WST-8 cell proliferation assay, nearly all the cell lines were sensitive to the drug, with IC50s generally between 250 to 500nM. Leiomyosarcoma cell lines (SK-LMS, SK-UT1, SK-UT1b) were seen to be most sensitive to SNS-510 with IC50s determined to be between 50-100nM. In contrast, synovial sarcoma cell lines (SYO-1 and HSSY-II) exhibited relative resistance to SNS-510 with IC50s determined to be &amp;gt; 500nM. As assessed by western blot, SNS-510 exhibited a dose dependent inhibition of the PDK-1/RSK2/AKT pathway with inhibition of p-RSK2(244), p-AKT(308), and pS6(235/236). SNS-510 induced a dose-dependent G1 cell cycle arrest. This was associated with inhibition of p-RB(780) and suppression of cyclin D1 and cyclin E1. The exception to this was the synovial cell lines for which there was no inhibition of p-RB despite inhibition of p-RSK, p-AKT and p-S6. When combined with palbociclib in both the CDK4/6 sensitive (LS141 and DDLS) and CDK4/6 resistant liposarcoma cells (RES.LS141 and RES.DDLS), we observed enhanced inhibition of proliferation with a synergistic effect, as defined by the Chou-Talalay method. These results would suggest a role for PDK-1 targeting with SNS-510 in sarcoma and consideration of combination strategies, especially with CDK4/6 inhibitors in both CDK4/6 sensitive and resistant dedifferentiated liposarcoma. Citation Format: Elgilda Musi, Pietro Taverna, Gary K. Schwartz. PDK-1 targeting with SNS-510 in sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1067.

Abstract 475: Improving liposarcoma diagnosis through cross-flow microfiltration

Abstract Introduction: Dedifferentiated liposarcoma (DDLPS) is frequently diagnosed late and patients typically respondpoorly to treatments bringing to an overall survival rate of only 10% at 10 years. Prognosis isenhanced by early detection of recurrent lesions, but current diagnostic methods rely on invasivetissue biopsies combined with whole or part-body imaging. These diagnostic and prognosticchallenges prompted us to explore the use of circulating biomolecules as potential biomarkersaccessible through bodily fluids. Extracellular Vesicles (EVs) are membrane vesicles containingproteins and nucleic acids that circulate in the blood, so they are an emerging class of easilyaccessible blood biomarkers. We recently identified extracellular vesicle EV-MDM2 as liquidbiopsy biomarker for disease identification in DDLPS. Unfortunately, due to these challenges forisolation and capture of EVs, despite the potential diagnostic and prognostic utility, the practicalrelevance of using EVs for routine analysis remains limited. Methods: A microfluidic device was fabricated via standard soft lithography in PDMS(polydimethylsiloxane). A 5 x 5 mm2 nanocapillary array membrane (nominal capillary diameterof 0.2 µm) was sandwiched between two microchannels for a vertically aligned configuration withan injection and separation channel (each 500 µm wide and 150 µm high) perpendicular to eachother. The separation channel surface was functionalized with the anti-CD63 antibody forcapturing EVs. Results: We present here a facile approach to fabricate and operate a micro-nanofluidic device that usescross-flow filtration to isolate and capture liposarcoma derived EVs. Our methodology integratesthe unit operations of size based separation with immunoaffinity-based capture of extracellularvesicles in the same device. The eluted media collected showed ~84% extracellular vesiclerecovery from the liposarcoma cell conditioned media and ~38% extracellular vesicle recoveryfrom dedifferentiated liposarcoma patient serum when compared to extracellular vesicle isolationand subsequent quantification by ultracentrifugation. The results reported here also show a five-fold increase in amount of critical liposarcoma relevant extracellular vesicle cargo obtained in30 minutes presenting a significant advance over existing state-of-art. Conclusion: In conclusion we developed a cross-flow filtration micro-nanofluidic device for isolation, selectivecapture and release of liposarcoma EVs. Citation Format: Lucia Casadei, Patricia Sarchet, Adarsh Choudhury, Shaurya Prakash, Raphael Pollock. Improving liposarcoma diagnosis through cross-flow microfiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 475.

Comprehensive serum and tissue microRNA profiling in dedifferentiated liposarcoma.

Sarcoma is a rare cancer with several subtypes; therefore, our understanding of the pathogenesis of sarcoma is limited, and designing effective treatments is difficult. Circulating microRNAs (miRNAs), including exosomal miRNAs, have attracted attention as biomarkers in cancer. However, the roles of miRNAs and exosomes in sarcoma remain unclear. The present analysis of tissue and serum miRNA expression in osteosarcoma, Ewing's sarcoma and dedifferentiated liposarcoma (DDLPS) identified miR-1246, −4532, −4454, −619-5p and −6126 as biomarkers for DDLPS. These miRNAs were highly expressed in human DDLPS cell lines and exosomes, suggesting that they are secreted from DDLPS tissues. The present results suggested that specific miRNAs may be used as biomarkers for early diagnosis or treatment targets in DDLPS.

Atypical spindle cell lipomatous tumour – A case report

The atypical spindle cell lipomatous tumour (ASLT) is a relatively new entity proposed by Mentzel et al. in 2010. The clinicopathological characteristics were further detailed in a large series of 232 cases by Marino-Enriquez et al. in 2017. These lesions presented as a persistent or enlarging mass with a medium size of 5 cm and a wide anatomic distribution. A spectrum of cytological atypia present in these lesions could be alarming. The cellular cases with marked nuclear atypia and frequent lipoblasts could be mistaken as atypical lipomatous tumour/ dedifferentiated liposarcoma. Lack of MDM2 amplification is an important biological characteristic different from its morphology mimic. Despite the concerning histomorphology, none of those 232 patients in the 2017 series developed metastasis or died of disease. The local recurrence rate was 13%. We hereby present such an interesting case in which an 81-year-old male presented with an 8 cm mass at the right shoulder. The cut surfaces of the mass showed fatty tissue with variegated and gelatinous areas. Microscopic examination revealed an admixture of variably sized adipocytes, univacuolated or multivacuolated lipoblasts and spindle cells. Many spindle cells were bland while the remainders were irregular, pleomorphic and hyperchromatic. Multinucleated cells reminiscent of floret giant cells were also present. The stroma was variable ranging from myxoid to collagenous nature. CD34 was diffusely positive among the spindle cells and pleomorphic cells. S100 was positive among the adipocytic cells and negative among the spindle cells. MDM2 and CDK4 immunostains were negative. FISH analysis showed no evidence of MDM2 amplification. The poster will demonstrate the morphological spectra of ASLT and the awareness of this entity will avoid a malignant misdiagnosis.

Gene Expression Changes Associated with Dedifferentiation in Liposarcoma Predict Overall Survival.

Simple SummaryPrevious studies have performed integrative analyses of genomic aberrations in soft tissue sarcomas. Utilising clinical information, groups have proposed nomograms for prediction of survival and recurrence in retroperitoneal sarcomas. Expanding on clinical nomogram prediction models with molecular classification of tumours may allow us to further identify clinical phenotypes within this heterogeneous group. We showed that a five-gene molecular prognostic panel can provide additional prognostic information in patients with retroperitoneal DDLS, independent of clinical features. A combined clinical and molecular prediction model may offer the best way to prognosticate patients for patient counselling and therapeutic decision making.Up to 10% of well-differentiated liposarcoma (WDLS) progress to dedifferentiated liposarcoma (DDLS). We aimed to identify gene expression changes associated with dedifferentiation and whether these were informative of tumour biology of DDLS. We analysed datasets from the Gene Expression Omnibus (GEO, ID = GSE30929) database to identify differentially expressed genes between WDLS (n = 52) and DDLS (n = 39). We validated the signature on whole and laser-capture microdissected samples from patients with tumours consisting of mixed WDLS and DDLS components. A subset of this signature was applied to an independent dataset from The Cancer Genome Atlas (TCGA, n = 58 DDLS) database to segregate samples based on gene expression and compared for recurrence and overall survival (OS). A 15-gene signature consisting of genes with increased expression in DDLS compared to WDLS was generated. This signature segregated WDLS and DDLS samples from patients with mixed component tumours and across multiple recurrences. A further subset of this signature, consisting of five genes (AQP7, ACACB, FZD4, GPD1, LEP), segregated DDLS in a TCGA cohort with a significant difference in OS (p = 0.019) and recurrence-free survival (RFS) (p = 0.061). The five-gene model stratified DDLS into prognostic groups and outperformed clinical factors in existing models in retroperitoneal DDLS.

Retroperitoneal Dedifferentiated Liposarcoma.

We aimed to test the hypothesis that in retroperitoneal dedifferentiated liposarcoma (DDLS) the presence of the dedifferentiated (DD) component at the resection margin is associated with adverse outcome. We retrospectively searched the archive for primary resections of retroperitoneal DDLS performed at our institution between 1990 and 2017. Slides were rereviewed for diagnosis, Fédération Nationale des Centres de Lutte Contre le Cancer grade, myogenic differentiation, and the presence of the well-differentiated (WD) or DD component at the resection margin. The medical records were reviewed for patient age, sex, tumor size, tumor focality, adjuvant/neoadjuvant therapy, local recurrence, distant metastases, local recurrence-free survival (LRFS), overall survival (OS), and follow-up duration. The presence of the DD component at the resection margin was associated with worse LRFS compared with cases without the DD component at the margin (P = .002). However, OS was not significantly affected (P = .11). LRFS is significantly shorter in cases with the DD component at the margin compared with cases without DD tumor at the margin, while there is no association with OS. We recommend reporting the presence or absence of DD tumor at the margin in retroperitoneal DDLS, as it adds meaningful prognostic information.

Prognostic groups in retroperitoneal well-differentiated and dedifferentiated liposarcomas

Prognostic groups in retroperitoneal well-differentiated and dedifferentiated liposarcomas

Hypofractionated radiation therapy and wound healing after massive sarcoma resection: Case report and review of the literature.

IntroductionLarge high-grade sarcomas are commonly managed with five weeks of pre-operative radiation with chemotherapy followed by surgical resection. Wound complications occur in about one out of three patients with this regimen. Hypofractionated radiation therapy (HFRT) is a developing pre-operative approach that delivers radiation over a shorter duration of 5–10 treatments.Presentation of caseTwo patients underwent HFRT with neoadjuvant chemotherapy followed by tumor resection. The first patient had high-grade de-differentiated liposarcoma, and the second patient a high-grade myxofibrosarcoma. Neither patient developed post-operative wound complications despite the massive tumor size.DiscussionLess is understood regarding rates and risk factors associated with wound complications using this shortened radiation approach. With attention to surgical detail, and advancing radiation delivery technologies, rates of complications can be minimized.ConclusionWe discuss our experience with a neoadjuvant hypofractionated chemoradiation protocol in two patients with large volume sarcomas resected from the chest wall and the thigh who did not develop acute wound complications. Further evaluation of this shortened regimen is warranted.

Outcomes in the dedifferentiated liposarcoma cohort of SAR-096, a phase II trial of ribociclib in combination with everolimus in advanced dedifferentiated liposarcoma (DDL), and leiomyosarcoma (LMS).

11515 Background: Dedifferentiated liposarcoma (DDL) is characterized by ring chromosomes of chromosone12, which includes amplification of MDM2 and CDK4. Exposure to CDK4 inhibitors in Rb+ leiomyosarcoma (LMS) cell lines leads to decreased cell proliferation, and increased senescence, and G0/G1-phase arrest. When combined, ribociclib a CDK4 inhibitor and everolimus, an mTOR inhibitor show synergistic growth inhibition in multiple tumor models. We hypothesized that this combination could lead to increased disease control in patients with DDL. Methods: This study enrolled patients (pts) into one of two cohorts: DDL or Rb+ LMS. LMS pts were required to have 1 prior line of therapy; DDL pts required no prior therapy. There were no limits to prior therapies in either group. Measurable disease by RECIST 1.1 was also required. Ribociclib was given at 300 mg daily for 21/28 days and everolimus was given continuously at 2.5 mg daily in 28 day cycles. The primary endpoint was progression free rate at 16 weeks. A Simon two-stage design was utilized and if at least 8 out of 24 pts were progression free at 16 weeks, the treatment was declared promising for the cohort. Here in we present data on the DDL cohort. Results: To date, 21 DDS pts, median age of 63 (range 40-79), of which 43% (n = 9) female were treated. Median prior lines of therapy was 1 (range 0-6). Of 19 pts with complete data, 8 (42%) met the primary endpoint of non-progression at 16 weeks. Confirmed partial response was seen in 2 pts (10%). Median PFS was 16 weeks, and stable disease occurring as best response in 11 (55%) pts. Grade 3-4 toxicities were uncommon except for lymphopenia (24%) and neutropenia (33%); no episode of neutropenic fever were observed. There was one death on study secondary to myocardial infarction, considered possibly related to therapy. Results of optional tissue biopsies pre and on therapy obtained to assess pharmacodynamic changes in PTEN, pAKT, CDK4, Rb and pS6 will be presented. Conclusions: The combination of ribociclib and everolimus demonstrates activity in DDL with prolonged stable disease (&gt;16 weeks) meeting the primary protocol endpoint. Notably partial responses were also observed. The combination was well tolerated with acceptable side effects. Updated outcomes will be presented. Clinical trial information: NCT03114527.

Molecular predictors of response to selinexor in advanced unresectable de-differentiated liposarcoma (DDLS).

11509 Background: Patients (pts) with recurrent inoperative DDLS have a poor prognosis and limited treatment options. Selinexor is an oral, selective inhibitor of nuclear export (SINE) compound approved for previously treated pts with myeloma and diffuse large B-cell lymphoma. SEAL was a Phase 2-3 randomized, double-blind, study of selinexor versus placebo in pts with progressive DDLS and 2-5 prior systemic therapies. SEAL showed significantly prolonged progression-free survival (PFS, HR = 0.70, p = 0.0228) with well managed toxicity. A biomarker predictive of clinical activity could be used to optimize selection of pts with DDLS for selinexor. Methods: Pts were randomized 2:1 for Phase 3: 188 received twice weekly selinexor (60mg) and 97 received placebo. Three exploratory biomarker analyses (RNA sequencing of biopsies) from selinexor-treated pts were performed: discovery set of sensitive (n = 8) or resistant (n = 9) tumors; a validation set of pts with favorable (n = 19) or poor (n = 14) tumor control based on PFS, and paired lesions from a pt who harbored both a responsive and resistant lesion. Tumor biopsies from 24 pts on placebo with short ( &lt; 5 months, n = 18) and long ( &gt; 6 months, n = 6) PFS were RNA sequenced. Gene expressions were compared using a negative binomial distribution with DeSeq2. Pathway analyses were performed using Gene Set Enrichment Analysis (GSEA) with MSigDB Cancer Gene Neighborhoods. Results: RNA sequencing analysis comparing 17 sensitive and resistant tumors identified 114 differentially expressed genes (adjusted p-values &lt; 0.05). Expression of CALB1, which encodes the calcium-binding protein calbindin, was significantly lower in sensitive tumors (adjusted P [Padj] = 7.5x10-20), and expression of GRM1, which encodes a metabotropic glutamate receptor that activates phospholipase C, was higher in selinexor sensitive tumors (Padj= 0.003). These findings were confirmed in an independent validation set (Padj = 0.01 – 0.02). In the pt with paired sensitive and resistant lesions, CALB1 expression was 52-fold lower in the sensitive tumor. In a comparison of placebo-treated pts, neither CALB1 or GRM1 was differentially expressed between pts with short or long PFS, indicating they are markers of response to selinexor treatment, rather than general markers of disease aggressiveness. Gene set enrichment analyses revealed that selinexor sensitive tumors in the discovery and validation sets showed upregulation of cancer genes related to SNRK and the netrin 1 receptor tumor suppressor DCC. The resistant tumors showed upregulated EIF3S2 translation initiator-related genes. Conclusions: Selinexor sensitive DDLS tumors showed low expression of CALB1 and high GRM1. If validated, pts with DDLS whose tumors match this expression profile are especially likely to benefit from selinexor. Clinical trial information: NCT02606461.