Desmoplastic Round Cell Tumor Research Articles

Epigenetic determinants of fusion-driven sarcomas: paradigms and challenges.

We describe exciting recent advances in fusion-driven sarcoma etiology, from an epigenetics perspective. By exploring the current state of the field, we identify and describe the central mechanisms that determine sarcomagenesis. Further, we discuss seminal studies in translational genomics, which enabled epigenetic characterization of fusion-driven sarcomas. Important context for epigenetic mechanisms include, but are not limited to, cell cycle and metabolism, core regulatory circuitry, 3-dimensional chromatin architectural dysregulation, integration with ATP-dependent chromatin remodeling, and translational animal modeling. Paradoxically, while the genetic requirements for oncogenic transformation are highly specific for the fusion partners, the epigenetic mechanisms we as a community have uncovered are categorically very broad. This dichotomy prompts the question of whether the investigation of rare disease epigenomics should prioritize studying individual cell populations, thereby examining whether the mechanisms of chromatin dysregulation are specific to a particular tumor. We review recent advances focusing on rhabdomyosarcoma, synovial sarcoma, alveolar soft part sarcoma, clear cell sarcoma, undifferentiated round cell sarcoma, Ewing sarcoma, myxoid/round liposarcoma, epithelioid hemangioendothelioma and desmoplastic round cell tumor. The growing number of groundbreaking discoveries in the field, motivated us to anticipate further exciting advances in the area of mechanistic epigenomics and direct targeting of fusion transcription factors in the years ahead.

Abstract P087: Targeting LSD1 protein scaffolding function in FET-rearranged sarcomas with SP-2577

Abstract The RNA-binding proteins, FUS, EWSR1, and TAF15 (FET protein family) are frequently fused to transcription factors, and the resulting oncogenic fusion proteins characterize various sarcomas. These fusion proteins act as aberrant transcription factors and promote oncogenic gene expression profiles. FET family rearranged sarcomas include Ewing Sarcoma, desmoplastic round cell tumors, myxoid liposarcoma, and clear cell sarcoma, amongst others. A growing body of work suggests that, independently of Lysine Specific Demethylase 1 (LSD1) demethylase activity, LSD1’s association with FET family oncogenic transcription factors is critical for FET-rearranged sarcoma development and progression. Extensive ongoing work aims to characterize the functional relationship of LSD1 and EWS/FLI, as well as the anti-tumor effect of disrupting that interaction. SP-2577 is an oral, first-in-class, small molecule with reversible, noncompetitive inhibition of LSD1 demethylase activity (IC50: 25–50 nM) and, importantly, also disrupts LSD1 protein-protein interactions. In vitro and in vivo data demonstrate SP-2577, or analogs, reverses EWS/ETS-mediated transcriptional regulation at both up- and downregulation target genes, leading to significant tumor growth inhibition in Ewing Sarcoma mouse xenograft studies. In this study, we set out to expand our understanding of SP-2577’s efficacy in diverse FET-rearranged malignancies including desmoplastic small round cell tumor (DSCRT: EWSR1/WT1), myxoid liposarcoma (ML: FUS/DDIT3), and clear cell sarcoma (CCS: EWS/ATF1). To examine whether these additional FET-rearranged sarcomas are sensitive to LSD1 scaffolding inhibition, we measured viability of Ewing sarcoma cells A673, TC32, TTC-446, and SK-N-MC, clear cell sarcoma cell lines SU-CCS-1, DTC-1, myxoid liposarcoma cell lines DL-221, 402-91, and 1765-92, and DSCRT patient derived xenograft organoids from SJDSRCT046151, X0069, SJDSRCT046155 after 96 hours of treatment with the clinical compound SP-2577, a first generation compound SP-2509, an inactive control, SP2513, and, a TCP-scaffold based, irreversible inhibitor of LSD1, OG-L002. While SP-2513 and OG-L002 had no activity against these cells SP-2509 and SP-2577 demonstrated potent activity across cell lines in vitro. Preliminary in vivo assessment of SP-2577 efficacy in DSCRT PDX SJDSRCT046151 resulted in a significant delay in time to event (p<0.02). Together, these data demonstrate that the unique scaffolding inhibition function of SP-2577 is essential for reducing cell viability through LSD1 targeting. Currently, we are elucidating changes to the transcriptome and proteome following SP-2577 treatment, in vitro. These data, in combination with results from the ongoing dose expansion phase 1 trial of SP-2577 in select sarcoma patients, may offer further mechanistic insight into the dependency of FET-rearranged sarcomas on LSD1 scaffolding functions and potentially lead to identifying biomarkers of sensitivity and response. Citation Format: Galen Rask, Emily R. Theisen, Aundrietta D. Duncan, Daniela Y. Santiesteban. Targeting LSD1 protein scaffolding function in FET-rearranged sarcomas with SP-2577 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P087.

Real-World Experience in Toxicity with Bevacizumab in Indian Cancer Patients.

Background Bevacizumab, a humanized monoclonal antibody, known to block the binding of all known vascular endothelial growth factor-A isomers to their receptors, is used in solid cancers, especially in advanced settings where its role is proven to be stronger than localized stages. Furthermore, various studies have suggested that adding bevacizumab to first-line standard therapy in advanced solid cancers, such as colorectal cancer, lung cancer, ovarian cancer, renal cancer, and breast cancer, significantly prolongs progression-free survival, overall survival, and response rates. However, this ability is limited and variable in cancer subtype. The toxicity profile of bevacizumab is outspread, ranging from mild gastrointestinal side effects, proteinuria to life-threatening hemorrhagic tendency, ischemic thromboembolism, and intestinal perforation. However, it has never been studied in Indian subset of patients till date. Materials and Methods We performed an institutional retrospective study of 41 patients with a pathologically proven ovarian, colorectal, lung, mesothelioma, melanoma, round cell tumors, and GBMs who received bevacizumab (2.5 mg/kg/week [5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks]) with or without chemotherapy, between January 2016 and January 2019 at our center in North India. Results Forty-one patients, including 12 (29) advanced ovarian cancer, 12 (29) colon cancer, 10 (24) rectal cancer, 1 (2) appendicular cancer, 1 (2) mesothelioma, 1 (2) melanoma, 1 (2) desmoplastic round cell tumor, and 3 (7) GBM, were treated with bevacizumab. The incidence of arterial thrombus and hemorrhage was 2 and 10%, respectively, whereas venous thrombus and fistula were not seen and not related to age. No fatal adverse event was recorded. The global incidence of severe (grade 3/4) arterial hypertension (HTN) was 49%. It was safely managed in all cases, and no grade 4 (life-threatening complication) occurred. The incidence of severe HTN was significantly higher in elderly patients than in younger ones (72 vs. 40%), proteinuria was found to be more frequent in the younger age group as compared with older age group (7 vs. 3%). Also to note, the incidence of congestive heart failure and subacute intestinal obstruction was found in 5% of patients, wherein all four patients belonged to the older subgroup. Furthermore, Grade 3 hypersensitivity reaction was found in one patient in the younger subgroup which warranted immediate termination of bevacizumab.

EWSR1 fusions: Ewing sarcoma and beyond.

EWSR1 fusions: Ewing sarcoma and beyond.

Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is a relatively recently identified, rare, aggressive cancer that arises from the peritoneal lining of the abdominal cavity and predominantly affects male adolescents and young adults. DSRCT is included in the Ewing family of tumors and harbors a unique translocation between EWSR and WT1 genes. Patients characteristically present with advanced disease, including widespread involvement of the abdominal cavity and pelvis, with frequent extraperitoneal metastases involving liver, spleen, and thoracic lymph nodes. Five-year overall survival remains approximately 15 to 20% in recent series despite aggressive multimodal therapy. Neoadjuvant chemotherapy, complete resection, defined as less than 1 cm3 of residual tumor, and consolidative whole abdominopelvic radiotherapy (WAP-RT) appear to play important role in curative treatment. The rarity of DSRCT makes large randomized trials difficult and consensus statements about clinical approach impossible. However, this chapter summarizes the best available data on the pathogenesis, diagnosis, and treatment of DSRCT; highlights the major advances made in these areas; and discusses the addition of local therapy to the treatment paradigm. This review contains 3 figures, 1 table, and 51 references. Key Words: DSRCT, peritoneal malignancy, desmoplastic round cell tumor, surface malignancies of the peritoneum, desmoplastic small round cell tumor of the abdomen, surgical oncology, rare malignancies, surgical therapy of abdominal malignancies

Desmoplastic Small Round Cell Tumor

Desmoplastic small round cell tumor (DSRCT) is a relatively recently identified, rare, aggressive cancer that arises from the peritoneal lining of the abdominal cavity and predominantly affects male adolescents and young adults. DSRCT is included in the Ewing family of tumors and harbors a unique translocation between EWSR and WT1 genes. Patients characteristically present with advanced disease, including widespread involvement of the abdominal cavity and pelvis, with frequent extraperitoneal metastases involving liver, spleen, and thoracic lymph nodes. Five-year overall survival remains approximately 15 to 20% in recent series despite aggressive multimodal therapy. Neoadjuvant chemotherapy, complete resection, defined as less than 1 cm3 of residual tumor, and consolidative whole abdominopelvic radiotherapy (WAP-RT) appear to play important role in curative treatment. The rarity of DSRCT makes large randomized trials difficult and consensus statements about clinical approach impossible. However, this chapter summarizes the best available data on the pathogenesis, diagnosis, and treatment of DSRCT; highlights the major advances made in these areas; and discusses the addition of local therapy to the treatment paradigm. This review contains 3 figures, 1 table, and 51 references. Key Words: DSRCT, peritoneal malignancy, desmoplastic round cell tumor, surface malignancies of the peritoneum, desmoplastic small round cell tumor of the abdomen, surgical oncology, rare malignancies, surgical therapy of abdominal malignancies

Feasibility of Administering A Modified Outpatient Regimen of Vincristine, Doxorubicin, Cyclophosphamide Alternating with Ifosfamide, and Etoposide (VAC/IE) For High-Risk Desmoplastic Small Round Blue Cell Tumor and the Role of Tumor Profiling in Selecting Treatments

Feasibility of Administering A Modified Outpatient Regimen of Vincristine, Doxorubicin, Cyclophosphamide Alternating with Ifosfamide, and Etoposide (VAC/IE) For High-Risk Desmoplastic Small Round Blue Cell Tumor and the Role of Tumor Profiling in Selecting Treatments

Programmed Death Ligand 1 (PD-L1) Expression in Malignant Mesenchymal Tumors.

Programmed death ligand 1 (PD-L1) found on tumor cells has recently been reported to have a key role in the development and dissemination of many tumors, such as lung and breast carcinomas. In this study, we retrospectively analyzed PD-L1 expression among different types of sarcomas. Tissue microarrays of 3-4 mm diameter were composed from paraffin blocks of 222 various sarcomas. Slides prepared from microarrays were stained for PD-L1 antibody (Cell Signaling, E1L3N®) using Leica Bond Autostainer. Any membranous staining over 5% of the cells was regarded as positive. Quantitative real-time PCR with TaqMan gene expression assays for PDL1 was performed using whole sections from FFPE tissue of PD-L1 positive cases, by normalizing absolute values to β-actin. Relative expression level of mRNA of PDL1 was calculated and scored using Log102(threshold cycle of b-actin - threshold cycle of PDL1). Immunohistochemically, PD-L1 expression was present in 34 of 222 (15%) sarcomas. 5/13 (39%) undifferentiated pleomorphic sarcomas, 6/18 (33%) malignant peripheral nerve sheath tumors, 5/16 (31%) dedifferentiated liposarcomas, 4/19 (21%) rhabdomyosarcomas, 2/16 (13%) epithelioid sarcomas, 2/15 (13%) leiomyosarcomas, 3/26 (12%) synovial sarcomas, 1/18 (6%) myxoid liposarcoma, 1/2 (50%) extraskeletal myxoid chondrosarcoma, 1/3 (33%) alveolar soft part sarcoma, 1/3 (33%) parachordoma/myoepithelioma, 1/5 (20%) pleomorphic liposarcoma, 1/7 (14%) angiosarcoma, 1/8 (13%) Ewing sarcoma showed PD-L1 expression. Cases of solitary fibrous tumor/hemangiopericytoma (18), desmoplastic round cell tumor (14), Ewing-like sarcoma (6), epithelioid hemangioendothelioma (5), clear cell sarcoma (4), myxofibrosarcoma (4), low grade fibromyxoid sarcoma (2) were all negative. Tumor-infiltrating hematopoietic cells were positive for PD-L1 in 32 cases (15%) with only 2 cases overlapping with PD-L1 staining in tumoral cells. Sixteen of 34 (47%) immunohistochemically PD-L1 positive cases showed significant but low-level PD-L1 mRNA overexpression. We have shown PD-L1 expression in a subset of sarcomas, both at the protein and mRNA level. High-grade pleomorphic sarcomas tend to show more frequent PD-L1 expression. Clinical trials are necessary to further assess the effect of anti PD-L1 drugs on sarcomas showing PD-L1 expression.

18F-FDG-PET/CT of peritoneal tumors: a pictorial essay.

Cancer imaging on the peritoneum is quite difficult on PET/CT because of the particular anatomical features of this membrane. The abdominal cavity can be the seat of very different primary or secondary tumoral lesions, with heterogeneous aggressiveness and variable fluorine-18 fluorodeoxyglucose uptake and patterns. We aimed to depict a spectrum of appearances with abnormal fluorine-18 fluorodeoxyglucose uptakes localized on the peritoneum in frequent conditions such as peritoneal carcinomatosis and in rarer disease such as desmoplastic round cell tumor.

Trabectedin in advanced desmoplastic round cell tumors: a retrospective single-center series.

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy that occurs with unpredictable chemosensitivity and limited treatment options in the advanced setting. Prognosis is poor, and exploring new treatment options for such diseases is difficult because of its rarity. Clinical activity of trabectedin for advanced DSRCT was scarcely reported in the literature. Here, we report a series of six patients treated with trabectedin for an unresectable DSRCT. After receiving trabectedin, two patients had stable disease with a time to progression of 3 and 3.5 months; four patients experienced disease progression after one cycle, two of them could receive one and two patients another line regiment. Four patients experienced grade 3-4 adverse events, two grade 3 thrombocytopenia, and one neutropenic fever. Prognosis was poor with a median overall survival of 4 (range: 2-14) months. In our experience, trabectedin had limited activity in advanced DSRCT. Further studies are warranted to find effective treatments.

Desmoplastic Small Round Cell Tumor: A Rare but Aggressive Tumor in Young Women

ABSTRACT Desmoplastic small round cell tumor (DSRCT) is a rare malignant neoplasm. It is primarily found in young men, with a reported male to female ratio of 4:1. The tumor typically develops in the abdominal cavity, invading the omentum with multiple peritoneal implants involving the diaphragm, splenic hilum, mesentery of the small and large bowel, and the pelvic peritoneum. Most of them have widespread disease at presentation, with an organ of origin difficult to ascertain. We report a case of desmoplastic round cell tumor in a 17-year-old teenage girl. Immunohistochemistry helped in the diagnosis. She received multimodality treatment. How to cite this article Nandini G, Harish K, Swamy ACV, Subramanian M, Padma K. Desmoplastic Small Round Cell Tumor: A Rare but Aggressive Tumor in Young Women. J South Asian Feder Obst Gynae 2016;8(3):239-242.

A report of a case of desmoplastic small round cell tumor of peritoneum

Desmoplastic round cell tumor (DSRCT) is a rare subtype of small round blue cell tumors typically arising from the peritoneum. An 18-year-old male patient presented with palpable nontender abdominal mass associated with dragging sensation. Imaging revealed a large heterogenous soft tissue mass in the pelvis and lower abdomen along with irregular peritoneal thickening. Histopathology and immunohistochemistry suggested DSRCT. Neoadjuvant chemotherapy followed by laparotomy with debulking surgery of the pelvic mass was done after 5 months of starting chemotherapy. Follow-up contrast enhanced computed tomography abdomen showed a reduction of the size of residual disease. However, follow-up magnetic resonance imaging done after 3 months of surgery showed disease recurrence. The tumor should be suspected in young males when imaging is showing a pelvic mass along with multiple peritoneal soft tissue deposits.

Multiple EWSR1-WT1 and WT1-EWSR1 copies in two cases of desmoplastic round cell tumor

To provide new insights into the genomic profile of desmoplastic round cell tumors (DSRCT), we applied fluorescence in situ hybridization (FISH) and metaphase comparative genomic hybridization (M-CGH) to two newly diagnosed cases. FISH detected multiple subclones bearing one to three copies of der(11)t(11;22)(p13;q12) and/or der(22)t(11;22)(p13;q12) in both patients. This peculiar genomic imbalance might result from derivative chromosome duplication due to non-disjunction and/or mitotic recombination between normal and derivative chromosomes 11 and 22. Concomitant loss of normal chromosomes (i.e., 11 in patient 1 and 22 in patient 2) caused loss of the WT1 or EWSR1 wild-type allele. M-CGH identified other genomic imbalances: gain at chromosome 3 in both cases and chromosome 5 polysomy in patient 1. Common genomic events (i.e., trisomy 3 and extra EWSR1-WT1 and WT1-EWSR1 copies) probably contributed to disease pathogenesis and/or evolution of DSRCT. Our study demonstrated that an integrated molecular cytogenetic approach identified EWSR1-WT1 cooperating molecular events and genetic markers for prognosis. Thus, FISH and M-CGH might well be applied in a large series of patients to elucidate the genomic background of DSRCT.

Abstract 2416: Weekly EZN-2208 (pegylated SN-38) in combination with bevacizumab in patients with refractory solid tumors.

Abstract Background: Anti-angiogenic therapies such as bevacizumab (Bev) have been shown to up-regulate hypoxia-inducible factor-1α (HIF-1α), a possible mechanism of resistance. Camptothecin analogues, including SN-38, have been shown to reduce the expression and transcriptional activity of HIF-1α in preclinical models. Thus, co-administration of pegylated SN 38 (EZN 2208) could offset the induction of HIF-1α following administration of Bev, resulting in synergistic anti-tumor effects. We are conducting a trial of the combination of EZN 2208 (E) with Bev in patients with refractory solid tumors to determine the safety and tolerability of the combination, and to evaluate modulation of HIF-1α protein in tumor biopsies following administration of study drugs. Methods: Eligible pts have refractory advanced solid tumors that have progressed following standard therapy; ≥ 18 yrs of age; ECOG PS 0-2; adequate organ function. Bev at 5mg/kg is administered on D-7 and D15 for cycle 1 only and on D1, 15 for each subsequent cycle; q28d cycles. E(9mg/kg) is administered on D1, 8, and 15. Tumor biopsies and dynamic contrast enhanced MRI (DCE-MRI) are obtained on D1 prior to EZN administration (7 days post Bev) and on C2D15 post Bev and E. An additional DCE-MRI is also performed at baseline prior to Bev on D-7. Tumor biopsies are analyzed for HIF-1α protein levels using a validated immunoassay, and HIF-1α response genes, Hexokinase 2(HK), vascular endothelial growth factor A(VEGF), pyruvate dehydrogenase kinase, isozyme 1(PDK1), carbonic anhydrase IX(CA9), solute carrier family 2 (GLUT1), are assessed using RTPCR. Results: Twelve pts have been enrolled to date; median age 50 (range 27-76 yrs); median # prior therapies 3 (1-6); Dx: Soft tissue sarcoma (4), colorectal cancer (2), parotid gland cancer (1), malignant hurthle cell tumor (1), HCC (1), melanoma (1), gastrointestinal stromal tumor (1), Head and neck cancer (1). Grade 3/4 toxicities (#pts): neutropenia (8), leucopenia (3), lymphopenia (2), hypertension (1). Eight pts are evaluable for response; prolonged stable disease was observed in 2 pts: HCC 16 cycles, desmoplastic round cell tumor 7 cycles. HIF-1α protein and mRNA levels of HIF-1α dependent genes were assessed in 5 pts who had paired biopsies. Reduction in HIF-1α protein levels compared to baseline (post Bev alone) was seen in 4 of 5 pts (range 24% - 64%), with evidence of modulation of mRNA in 3 of 5 pt tumors evaluated. Quantitative analysis of DCE MRI from 3 pts revealed changes in Ktrans and kep maps following drug administration. Correlation of observed changes with tumor response is ongoing. Conclusions: This clinical trial provides preliminary proof of mechanism demonstrating modulation of HIF-1α levels in tumors following administration of a camptothecin analog, EZN 2208. Accrual is ongoing to establish safety, efficacy, and further proof of target modulation. Citation Format: Woondong Jeong, Sook Ryun Park, Annamaria Rapisarda, Michelle Eugeni, Robert Kinders, Alice Chen, Giovanni Melillo, Baris Turkbey, James H. Doroshow, Shivaani Kummar. Weekly EZN-2208 (pegylated SN-38) in combination with bevacizumab in patients with refractory solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2416. doi:10.1158/1538-7445.AM2013-2416

Clinical activity of sunitinib in patients with advanced desmoplastic round cell tumor: a case series

Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy with poor outcome occurring in adolescents and young adults. Therapeutic options for patients with advanced disease are limited. Preclinical studies have shown that VEGFR-2 and VEGFA are overexpressed in DSRCT and that DSRCT xenografts were highly responsive to anti-VEGF agents such as bevacizumab. We report here the clinical activity of sunitinib in eight patients with DSCRT. Our data suggest that sunitinib may be associated with clinical benefit even in heavily pretreated patients.

Apport des analyses moléculaires à la classification anatomopathologique des sarcomes

Conventional histology and immunohistochemistry remain the basic tools for the diagnosis and classification of sarcomas. However, molecular biology can enrich the pathologists analysis: the identification of a specific molecular abnormality can confirm diagnosis, rule out a differential diagnosis, and sometimes provide prognostic information. About 15% of sarcomas bear a specific translocation, such as rearrangements of SS18 (SYT) [synovial sarcoma], DDIT3 (CHOP) [myxoid liposarcoma], FUS (TLS) [low-grade fibromyxoid sarcoma, myxoid liposarcoma], FOXO1 (FHKR) [alveolar rhabdomyosarcoma], PDGFB (dermatofibrosarcoma protuberans), and ALK (inflammatory myofibroblastic tumor). Rearrangements of the EWSR1 gene are less specific as found in many sarcomas (Ewing sarcoma, desmoplastic round cell tumor, clear cell sarcoma, myxoid liposarcoma, andmyoepithelioma). The search for an amplification of MDM2 gene is a sensitive and specific tool for the diagnosis of atypical lipomatous tumors/welldifferentiated liposarcomas and dedifferentiated liposarcomas (ALT/WDL). The same molecular abnormality can be observed in several tumor types, emphasizing the importance of integrating the results of any molecular study within clinical, morphological, and immunohistochemical context: ASPSCR1 (ASPL)-TFE3 translocation can be observed in alveolar soft tissue sarcoma but also in juvenile renal carcinomas, ETV6 (TEL)-NTRK3 (TRKC) translocation in infantile fibrosarcoma and secretory breast carcinoma, ALK rearrangements in inflammatory myofibroblastic tumors, anaplastic lymphomas, and lung adenocarcinomas. In some cases immunochemistry can highlight the consequence of a molecular abnormality: MDM2 overexpression in ALT/WDL, loss of INI1 expression in rhabdoid tumors and epithelioid sarcoma, and overexpression of ALK in inflammatory myofibroblastic tumors.

Paratesticular desmoplastic small round cell tumour: an unusual tumour with an unusual fusion; cytogenetic and molecular genetic analysis combining RT-PCR and COBRA-FISH

Desmoplastic small round cell tumour is a rare malignant tumour with a male to female ratio of 4:1. It manifests mostly at serosal sites. Here we present a case of a 28-year-old male patient, who presented with a fast growing paratesticular mass. On biopsy nests and cords of small round cells, without a clear morphological lineage of differentiation were seen. Occasionally desmoplatic small round cell tumour shows different lines of differentiation. An unequivocal histological diagnosis might be difficult in such cases. Here we demonstrate by a combination of methods the characteristic immunohistochemical profile and - albeit unusual - molecular background and discuss the eventual link with Ewing sarcoma.Immunohistochemical studies showed a membranous staining of Keratine AE1/3 and a dot-like staining of Desmine, confirming its diagnosis. Using COBRA-FISH following a metaphase approach we demonstrated a balanced translocation, t(11;22)(p13;q12) and in RT-PCR formation of the EWSR1-WT1 fusion product, a specific translocation of desmoplastic round cell tumour. The fusion involves exon 9 of EWSR1 to exon 8 of WT1, an unusual fusion product, though earlier described in a case of a desmoplastic small round cell tumour of the hand. The EWSR1-WT1 chimera seems to function as an oncogenic transcription factor. Here the zinc finger domain of the WT1 acts with affinity with certain promoter domains influencing the expression of various downstream proteins such as: PDGFA, PAX2, insulin-like growth factor 1 receptor, epidermal growth factor receptor, IL2 receptor beta, BAIAP3, MLF1, TALLA-1, LRRC15 and ENT. We discuss their potential oncogenic roles and potential therapeutic consequences.

WT1 Expression in the Female Genital Tract

The Wilms tumor gene 1 (WT1) has been reported in normal tissues and many neoplasms of the female genital tract. This review discusses WT1 expression in the female genital tract and its potential utility in the differential diagnosis of neoplasms that occur at this location. WT1 is of value in the differential diagnosis of synchronous serous carcinomas arising in the ovary/fallopian tube/peritoneum and endometrium, as strong WT1 positivity in both tumors points toward an extrauterine origin. In addition, WT1 can be used to distinguish sex cord stromal tumors (WT1 positive) from endometrioid carcinomas (OECs). WT1 expression is not helpful in the differential diagnosis of ovarian serous carcinomas (OSCs) and transitional carcinomas, as both are typically positive and has limited value in the distinction of serous tumors arising in the ovary/fallopian tube/peritoneum from mesotheliomas. WT1 is also not helpful to differentiate small cell carcinoma of hypercalcemic type from juvenile granulosa cell tumor, a common diagnostic problem. Intra-abdominal desmoplastic round cell tumor reacts to WT1 (C-terminal) in contrast to all other tumors discussed which helps to separate this rare tumor from most other small round cell tumors that may involve, primarily or secondarily, the ovary with the exception of small cell carcinoma of hypercalcemic type that typically reacts with the N-terminal of WT1.

Analysis of Prognostic Factors of Pediatric-Type Sarcomas in Adult Patients

Objective: Pediatric-type sarcomas such as Ewing’s sarcoma (EWS)/primitive neuroectodermal tumor family and rhabdomyosarcoma are relatively uncommon in adult patients. Optimal treatment strategies for this population and prognosis in adult patients compared with pediatric patients remain controversial. Methods: We retrospectively reviewed pediatric-type sarcoma patients older than 15 years at a single institution. Results: A total of 84 consecutive patients between 1995 and 2009 were identified at the Samsung Medical Center, Seoul, Korea. Median age was 30 years with a range of 15–74 years. Forty-seven patients (56.0%) were diagnosed with Ewing’s sarcoma/primitive neuroectodermal tumor family, 34 (40.5%) with rhabdomyosarcoma and 3 (3.6%) with desmoplastic round-cell tumor. Median follow-up duration was 5.9 years. Median overall survival for all patients was 33.1 months (95% CI 13.5–52.7) and median event-free survival for all patients was 14.4 months (95% CI 5.9–22.9 months). Multivariate analysis revealed that localized disease was a significant independent prognostic factor for longer overall survival (hazard ratio 0.30, 95% CI 0.14–0.66, p = 0.003), and favorable primary tumor sites were associated with longer event-free survival (hazard ratio 0.33, 95% CI 0.11–0.98, p = 0.045). Conclusion: We identified the prognostic variables which may facilitate risk-adapted therapies for this rare adult sarcoma group, which should be further investigated.

A phase I dose-escalation study of azacitidine in combination with temozolomide in patients with soft tissue sarcomas.

10073 Background: The response rate in patients with soft tissue sarcomas (STS) treated with the DNA-alkylator temozolomide (TZ) is 15%. DNA methylation dependent silencing of mismatch repair proteins may contribute to TZ resistance by eliminating the tumor cell’s ability to link the recognition of DNA damage caused by alkylating agents with an apoptotic response. Preclinical studies have shown that gene silencing may be reversed with a DNA methyl transferase inhibitor (e.g, azacitidine (AZ)). We hypothesized that sequential AZ treatment followed by TZ would reverse the silencing of mismatch repair proteins in tumors cell, thereby increasing the apoptotic effect of TZ. Methods: Patients with unresectable or metastatic STS, life expectancy >3 months, KPS ≥ 60%, and sufficient hematologic, hepatic, and renal function were enrolled. A standard 3+3 design was used to determine the MTD with levels 1-3 dosed with AZ (SQ days 1-5) 25 mg/m2, 50 mg/m2, and 75 mg/m2 respectively, and TZ (PO days 8-12) constant at 200 mg/m2. Results: Twelve patients (9 male 3 female) were enrolled: 3 in cohort 1, 3 in cohort 2, and 6 in cohort 3. Ages ranged from 41-81, with a median of 57. Diagnoses included: liposarcoma (5), synovial cell sarcoma (1), granular cell tumor (1), desmoplastic round cell tumor (1), pleomorphic sarcoma (1), endometrial stromal sarcoma (1), and leiomyosarcoma (2). The most common toxicities were nausea, thrombocytopenia, hypoalbuminemia, hyperglycemia, and elevated alkaline phosphatase. One DLT (grade 4 neutropenia) was observed at dose level 3. The recommended Phase II dose was determined to be AZ 75 mg/m2 and TZ200 mg/m2. All 6 patients treated on the lower dose levels showed progressive disease after 2 cycles. Of those treated at the highest dose, 2 patients demonstrated progressive disease, 2 demonstrated stable disease and 1 demonstrated a partial response. Conclusions: The combination of TZ plus AZ was well tolerated, and the recommended Phase II dose for the combination is consistent with the conventional single agent doses. An expansion study is being implemented to allow for further analysis of the safety and efficacy of this combination of drugs in patients with STS.