Desmoplastic Small Round Cell Tumor Research Articles

Case Report: A pericardial effusion secondary to cardiac desmoplastic small round cell tumor

Desmoplastic small round cell tumor (DSRCT) is an aggressive malignancy usually described in the abdomen and pelvis of adolescent males but rarely in the chest. A 71-year-old male presented with chest pain and was found to have pericardial effusion with cardiac tamponade. He underwent pericardiocentesis and pericardial window. Pericardial fluid and cardiac biopsy results confirmed DSRCT. The patient received the P6 protocol with a good but brief response. He had multiple hospitalizations in the following months for pericardial fluid recollection. Repeat imaging showed mediastinal metastasis. He is currently undergoing second-line chemotherapy treatment. We describe a unique case of primary DSRCT invading the pericardium and myocardium and exhibiting extensive mediastinal metastasis. This is the fourth report of cardiac DSRCT in the literature.

Desmoplastic Small Round Cell Tumor of the Head and Neck: A Potential Diagnostic Pitfall.

Primary desmoplastic small round cell tumor (DSRCT) in the head and neck region is extremely rare. There is limited information about its clinicopathological characteristics, prognosis, and treatment modalities. The purpose of this study is to provide a comprehensive review of DSRCT occurring primarily in the head and neck, to demonstrate its peculiar morphology and immunohistochemical expression, and to address the differential diagnoses. A total of 25 cases were collected after a thorough review of the relevant literature. DSRCT was most frequently reported in the major salivary glands, followed by the eyes. Furthermore, some cases were misinterpreted as poorly differentiated carcinoma, Ewing sarcoma, and olfactory neuroblastoma. Diagnosing DSRCTs in the head and neck can be very challenging due to their rarity in this location, overlapping morphology, and immunohistochemistry. In these cases, following a systemic approach helps to solve diagnostic problems.

Anesthesia and pain management of pediatric cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy has shown to improve survival in patients with extensive or refractory abdominal tumors of many different histologies. Postoperative pain control can be challenging as the surgical procedure is performed through a midline laparotomy incision from xiphoid to symphysis pubis, and patients are usually nothing by mouth for the first 8-10 postoperative days. We present the anesthetic management and postoperative pain control strategies for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy using a multimodal, opioid-sparing, and total intravenous anesthetic technique with a tunneled thoracic epidural. A single institution retrospective review of anesthetic management, intraoperative fluid and blood administration, and postoperative pain control for pediatric patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy between July 2018 and December 2020 was conducted. We employed a novel anesthetic and analgesia protocol consisting of premedication with gabapentin followed by intraoperative infusions of propofol, dexmedetomidine, ketamine, and cisatracurium. A tunneled thoracic epidural catheter was placed for management of pain. We reviewed and analyzed the first 25 patient records. The most common diagnosis was desmoplastic small round cell tumor (n=12). Median age of patients was 14 years (range 21 months-22 years). All patients were extubated in the operating room and no patients required reintubation. There were no incidences of acute kidney injury. Epidural infusions were used for a median of 8 days (range 2-14 days). Median postoperative intravenous opioid use (morphine equivalent) through postoperative day 10 was 0.02 mg/kg/day (range 0-0.86 mg/kg/day) administered for a median of 2 days (range 0-17 days). Nine patients (36%) did not require any intravenous opioids in the postoperative period. Utilizing a multimodal, opioid-sparing, total intravenous anesthetic technique in conjunction with a tunneled thoracic epidural catheter, we were able to avoid the need for postoperative mechanical ventilation and minimize both intraoperative and postoperative opioid requirements.

Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Standard of Care and Treatment Recommendations from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma.

Response to chemotherapy combined with anlotinib plus anlotinib maintenance in intra-abdominal desmoplastic small round cell tumors (IADSRCT): a case report and literature review

BackgroundIntra-abdominal desmoplastic small round cell tumors (IADSRCT) are rare and aggressive neoplasia that are resistant to chemotherapy. Anlotinib is an oral multi-target tyrosine kinase inhibitor that also has anti-angiogenic and anti-proliferative properties. In this article, we report on a case showing effective and durable responses to chemotherapy combined with anlotinib in a young man with IADSRCT.Case presentationA 27-year-old man was admitted to our hospital complaining of a palpable periumbilical mass that had been present for longer than 4 months. The diagnosis of IADSRCT was confirmed by biopsy and immunohistochemistry. An extensive unresectable metastasis was found on the initial diagnosis. The patient received six cycles of chemotherapy combined with anlotinib, and maintenance therapy with anlotinib was recommended. Hematochezia, proteinuria and hypertension were observed, however, long-term maintenance therapy was well tolerated. A partial response was observed after two cycles of combined therapy and the patient was still alive with stable disease at the time of reporting.ConclusionsChemotherapy combined with anlotinib plus anlotinib maintenance showed promising efficacy and manageable toxicity in the treatment of advanced IADSRCT.

Desmoplastic Small Round Cell Tumor of Small Intestine: A Case Report and Review of Literature

Desmoplastic Small Round Cell Tumor of Small Intestine: A Case Report and Review of Literature

Malignant rhabdoid tumor: Cyto-histologic correlation and immunohistochemical characterization of a rare pediatric malignancy and its differential diagnoses

Malignant rhabdoid tumor of the kidney (MRTK) is a rare aggressive pediatric renal tumor which can be diagnosed via fine-needle aspiration (FNA) cytology and core biopsy. The diagnosis of MRTK is challenging, and requires morphologic, immunohistochemical and clinical correlation to distinguish it from other entities. The differential diagnosis includes Wilms tumor, desmoplastic small round cell tumor, rhabdomyosarcoma, synovial sarcoma, renal medullary carcinoma, and epithelioid sarcoma. Here we describe a case of MRTK diagnosed on renal cytology and core biopsy with immunohistochemistry and follow by nephrectomy with gross and morphologic findings.

Shattering Glass Ceilings: Three Black Women Surgeons Ascend to Chairs of Departments of Surgery.

Shattering Glass Ceilings: Three Black Women Surgeons Ascend to Chairs of Departments of Surgery.

A case report of pericardial desmoplastic small round cell tumor

A case report of pericardial desmoplastic small round cell tumor

Liver metastasis in soft tissue sarcoma at initial presentation.

We reviewed all patients with STS diagnosed between 2010 and 2018 in the Surveillance, Epidemiology, and End Resultsdatabase. Incidence of liver metastasis at initial presentation and high incidence of liver metastasis by histological subtype were investigated. In addition, risk factors for liver metastasis were investigated by multiple logistic regression analysis. After excluding patients without information about liver metastasis, cause of death or primary liver tumor, 47 260 patients were included in this study. Of those, 1471 patients (3.2%) showed liver metastasis at initial presentation. The histological subtype showing the highest incidence of liver metastasis was desmoplastic small round cell tumor (30.3%), followed by malignant hemangioendothelioma (11.5%) and angiomyoliposarcoma (10.5%). Deep-rooted tumor, location in the body wall, retroperitoneum, or thorax/peritoneum, high histological grade, and higher T stage were associated with higher incidences of liver metastasis at initial presentation. Risk factors for liver metastasis were deep location, trunk development, larger tumor size, high histological grade, and specific histological subtypes.

Rare Histologies and Infrequent Indications for Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

This single-centre study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with rare histologies and uncommon tumour origins. Prospectively collected data from the data registry of a single institution was retrospectively investigated. We present a series of selected patients who underwent CRS and HIPEC between 2011 and 2021 for peritoneal metastases arising from infrequent tumour entities. The study included 76 patients. From the wide range of histologies, seven groups were formed: Cancer of unknown primary, uncommon ovarian cancer types, other gynaecological tumours (endosalpingiosis, endometrial and cervical cancer), small bowel carcinoma, recurrent peritoneal mesothelioma, desmoplastic small round-cell tumour, and other rare malignancies. The median peritoneal cancer index was 8. Fifty-five patients with primary and 22 patients with recurrent disease were examined. Complete macroscopic tumour resection was achieved in 84% of cases. The median survival was 68.53 months considering the entire cohort, whilst the longest survival rate was registered in the group with rare ovarian cancer, and the shortest in the group of patients with small round-cell tumour, at 112.3 and 11.4 months, respectively (small round-cell tumour versus rare ovarian cancer, hazard ratio=15.6817; 95% confidence interval=2.6585-92.5030; p=0.0024). Based on the encouraging results in some test groups, especially in rare ovarian cancer, CUP, small bowel cancer and recurrent mesothelioma, multicenter prospective studies examining such rare tumour histologies are needed to reach a higher number of cases and, thus, explore the impact of multimodal therapy on these patients.

Beyond Wilms tumor: imaging findings and outcomes of rare renal tumors in children.

Compared to Wilms, non-Wilms renal tumors in children are less well understood due to their rare occurrence which limits precise definition of the typical imaging patterns. This study aims to identify distinctive imaging findings, demographic characteristics and prognosis of pediatric non-Wilms renal tumors. From January 2007 to December 2018, 207 patients with a diagnosis of primary kidney neoplasia were yielded from our radiology archive, 171 of whom were diagnosed with Wilms tumor, 4 with angiomyolipoma and one with nephrogenic rest. The remaining 31 patients with a diagnosis of primary kidney neoplasia were enrolled in this retrospective study. Imaging data, age, gender, prognosis and findings regarding follow-up were noted. Eight patients had renal cell carcinoma, seven had clear cell sarcoma, six had mesoblastic nephroma, four had rhabdoid tumor, three had desmoplastic small round cell tumor, two had cystic nephroma and one had metanephric stromal tumor. The age of diagnosis was > 8years for renal cell carcinoma and desmoplastic small round cell tumor, < 5years for rhabdoid tumor and < 7months for mesoblastic nephroma. There was no gender preference for any tumor type. The prognosis for rhabdoid tumor was extremely poor in that all the patients followed up in our institute were deceased, whereas no recurrence was found in other tumors. Translocation type renal cell carcinoma had lower T2-weighted signal intensity, mesoblastic nephroma was a predominantly cystic mass, clear cell sarcoma was generally larger at presentation and extensive amorphous calcifications were seen in desmoplastic small round cell tumor. For the differential diagnosis of pediatric non-Wilms renal tumors, age is the most important factor, followed by propensity to metastasize/aggressive behavior of the mass. Knowledge of specific imaging findings of these tumors may help to narrow the differential diagnosis.

Abstract 6277: Identification of ATR inhibitors as therapeutic opportunities in Desmoplastic small round cell tumors

Abstract Introduction: Desmoplastic small round cell tumor (DSRCT) is a rare and very aggressive subtype of sarcoma, affecting predominantly young males. DSRCT is molecularly characterized by the t(11;22)(q24;q12) chromosomal translocation, which fuses EWSR1 to WT1 and encodes an aberrant chimeric transcription factor. A few additional secondary mutations have been reported, notably in genes encoding proteins involved in chromatin remodeling and DNA repair. No therapeutic advance have been done in the past 20 years, and the five-year overall survival is still below 15% in metastatic cases, despite aggressive poly-chemotherapy and extensive surgical debulking. Thus, we aimed to identify actionable targeted dependencies to propose novel therapeutic approaches, using drug screening and molecular biology. Material and Methods: Drug sensitivity screen evaluating 80 cancer-relevant small molecule inhibitors in dose-response was performed on the JN-DSRCT-1 (JN1) cell line. Revalidation was performed on JN1 and in a Champions Oncology PDX-derived in-house-generated DSRCT cell line (R) using multiple clinical compounds. Mechanistic dissection was performed using flow cytometry, immunofluorescence, western blotting, DNA fiber assay, RT-qPCR, and dot blot to evaluate markers of DNA damage response, replication stress and cell-autonomous innate immune signaling. Results: The drug screen identified that JN1 cells were particularly sensitive to one ATR inhibitor (ATRi) and multiple PARPi inhibitors (PARPi), which scored #6, 7, 9 and 20 of the hits. Sensitivity to ATRi was revalidated in the JN1 and R cell lines, whereas sensitivity to PARPi was only revalidated in the JN1 cell line - consistent with the very low PARP1 expression in that cell line. Sensitivity to ATRi and PARPi was partially reversed upon EWS-WT1 silencing. Combination experiments revealed that both drugs were synergistic in the JN1 cell line. Exposure to PARP inhibitor increased the number of γH2AX and RAD51 foci, suggesting that JN1 cells were not deficient in homologous recombination. Further, PARPi or ATRi exposure decreased replication fork speed and increased R-loops accumulation, whereas EWS-WT1 silencing increased replication fork speed. Resistance to PARPi and to ATRi was restored upon exogenous expression of the R-loop resolution enzyme RNAseH1. The combination of PARPi and ATRi also induced micronuclei formation and activated the cGAS-STING cytosolic innate immune sensing pathway, together with increased expression of CCL5, CXCL10 and PD-L1. Conclusion: DSRCT cells are sensitive to ATR and PARP inhibitors, through a mechanism that, at least in part, may involve enhanced replication stress and increased R-loop formation. Our data provide the preclinical rationale for assessing ATRi combined with PARPi in patients with DSRCT, as a cytotoxic therapy or as an immunomodulatory approach to enhance cell-autonomous immunogenicity. Citation Format: Asuka KAWAI-KAWACHI, Madison LENORMAND, Clémence HENON, Thomas EYCHENNE, Leo COLMET-DAAGE, Nicolas DORVAULT, Marlene GARRIDO, Clémence ASTIER, Carine NGO, Helen PEMBERTON, Aditi GULATI, Stephen PETTITT, Roman CHABANON, Christopher J LORD, Sophie POSTEL-VINAY. Identification of ATR inhibitors as therapeutic opportunities in Desmoplastic small round cell tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6277.

Abstract 902: Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells

Abstract Desmoplastic Small Round Cell Tumor (DSRCT) is a rare and aggressive form of pediatric cancer caused by a translocation between chromosomes 11 and 22, creating the novel EWSR1-WT1 fusion gene. Current therapy including surgery and the P6 chemotherapy regimen is insufficient, leading to a 5-year survival rate of only 15-25%. One potential explanation for this poor prognosis is the existence of a cancer stem cell (CSC) population with the ability to resist chemotherapy and cause both tumor recurrence and metastasis. While a CSC population has been identified in the closely related Ewing Sarcoma, most commonly caused by the EWSR1-FLI1 fusion gene, no CSC population has yet been identified in DSRCT. In this study, novel culture conditions were developed that enabled the formation of tumorspheres in vitro in the two commonly available DSRCT cell lines: JN-DSRCT-1 and BER-DSRCT. These novel culture conditions led to upregulation of stemness genes at the RNA and protein level including NANOG and SOX2, two genes that are associated with poor survival outcomes in TCGA sarcomas data. CCK-8 assay demonstrated an increased chemoresistance for tumorspheres versus normal adherent culture especially for doxorubicin, which was confirmed by reduction in PARP cleavage. This chemoresistance may be partially explained by a more quiescent CSC state as shown by reduced cell proliferation and a lower percentage of cells in the S and G2/M phases. However, cells grown in tumorspheres still robustly formed tumors in vivo, thus demonstrating the two hallmark CSC traits of chemoresistance and tumor formation. RNA-seq was performed to elucidate key differences between the adherent and sphere culture conditions and identify potential targets for the therapeutically important CSC-like population. Overrepresentation analysis and gene set enrichment analysis both showed upregulation of pathways related to chromatin assembly and disassembly, suggesting epigenetic changes as DSRCT cells move to a more stem-like state. RNA-seq further revealed kinases upregulated in tumorspheres including B-lymphocyte kinase (BLK) which previous studies have demonstrated is oncogenic, regulated by EWSR1-WT1, and not necessary for normal survival. BLK knockdown reduced CSC-like properties including abrogation of tumorsphere formation and reduction in the levels of SOX2 and NANOG. Together, this work for the first time identifies a CSC-like population in DSRCT and BLK as a potential DSRCT CSC target. Citation Format: Justin W. Magrath, Alifiani B. Hartono, Sean B. Lee. Identification, characterization, and targeting of desmoplastic small round cell tumor cancer stem cell-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 902.

Abstract 704: Development of a patient-derived xenograft (PDX) modeling program to enable pediatric precision medicine

Abstract Background: Recapitulation of the full spectrum of genomic changes driving patient tumors have resulted in increased use of patient-derived xenograft (PDX) models in studies of basic cancer biology and preclinical drug development. Given the translational potential of PDXs and limited availability of pediatric cancer models, we established a PDX program to expand the existing collection of pediatric PDXs in the community and enable pre- and post-clinical studies. Methods: PDX generation requests were integrated into clinical workflows to maximize identification of eligible patients for informed consent and tissue collection at Memorial Sloan Kettering Cancer Center. Methodologies for tissue procurement and cryopreservation were optimized to facilitate implantation into host immunodeficient mice and enable multi-institutional tissue exchange for model building. A bioinformatics pipeline was established to allow molecular validation of engrafted PDXs using a next-generation targeted gene panel (MSK-IMPACT) evaluating concordance based on acquired mutations, copy number alterations and clonal structure. Results: Between November 2016 - October 2021, 379 PDX models were developed (265 distinct models) representing 69 discrete diagnoses. Sarcoma represents the most common model type (50 discrete osteosarcoma, 20 desmoplastic small round cell tumor, 14 Ewing sarcoma, 24 rhabdomyosarcoma, 2 CIC/DUX4 and 2 BCOR-rearranged sarcoma) followed by neuroblastoma (n=35), leukemia (n=44), and Wilms tumor (n=15). While the majority of PDXs were established from recurrent or metastatic tissue, 7 paired diagnostic/pre-therapy and post-therapy or relapse models were generated. Genomic characterization of PDXs demonstrate excellent concordance and recapitulation of single nucleotide variants (90%), structural (88%) and copy number variants (94%) between patient tumor and matched PDX. Discrepancies between matched patient/PDX pairs are due to sub-clonal heterogeneity in source tumors with clonal outgrowth in the PDX. Analysis of serial PDX passages also demonstrate stable recapitulation of the genomic profile. Establishment of a diverse PDX collection allowed preclinical evaluation of 10 targeted agents across a spectrum of pediatric tumors and provided the preclinical rationale for 3 investigator-initiated pediatric clinical trials. Conclusions: Investment in the development of a phenotypically diverse and biologically faithful collection of pediatric PDX models enables the goals of precision medicine. Optimization of PDX workflows and methods has also enabled the development of a pediatric PDX consortium (PROXC - Pediatric Research in Oncology Xenografting Consortium) to further support the development of pre- and post-clinical studies for pediatric cancer. Citation Format: Filemon S. Dela Cruz, Joseph G. McCarter, Daoqi You, Nancy Bouvier, Xinyi Wang, Kristina C. Guillan, Armaan H. Siddiquee, Katie B. Souto, Hongyan Li, Teng Gao, Dominik Glodzik, Daniel Diolaiti, Neerav N. Shukla, Joachim Silber, Umeshkumar K. Bhanot, Faruk Erdem Kombak, Diego F. Coutinho, Shanita Li, Juan E. Arango Ossa, Juan S. Medina-Martinez, Michael V. Ortiz, Emily K. Slotkin, Michael D. Kinnaman, Sameer F. Sait, Tara J. O'Donohue, Marissa Mattar, Maximiliano Meneses, Michael P. LaQuaglia, Todd E. Heaton, Justin T. Gerstle, Nicola Fabbri, Chelsey M. Burke, Irene M. Rodriquez-Sanchez, Christine A. Iacobuzio-Donahue, Julia L. Glade Bender, Ryan D. Roberts, Jason T. Yustein, Nino C. Rainusso, Brian D. Crompton, Elizabeth Stewart, Alejandro Sweet-Cordero, Leanne C. Sayles, Andrika D. Thomas, Michael H. Roehrl, Elisa de Stanchina, Elli Papaemmanuil, Andrew L. Kung. Development of a patient-derived xenograft (PDX) modeling program to enable pediatric precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 704.

Desmoplastic small round cell tumor: Analysis of surveillance, epidemiology, and end results (SEER) database 1975 to 2018.

e23540 Background: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a poor prognosis. The incidence and prognosis of patients with DSRCT have been inadequately understood. Survival analysis for DSRCT has been sparsely investigated in a population-based study. Methods: We conducted a retrospective cohort study using the SEER 9 Registry (1975-2018). Site recode International Classification of Diseases for Oncology (ICD-O-3) 8806/3 was used via SEER*Stat software to select DSRCT cases. SEER*Stat software estimated annual percent changes, and Poisson regression estimated risk ratios. Cox regression models were constructed to estimate the hazard ratio for survival at five years. The period-specific rates were portrayed as rate per 1,000,000. Results: The male and female age adjusted DSRCT incidence rates were 0.22 and 0.05, respectively (p &lt; 0.05). Incidence rate of DSRCT has been rising in the last two decades from 1975–2000 to 2001-2018 (0.013 vs. 0.31,p &lt; 0.05). Males have a higher age adjusted DSRCT incidence rate (0.22 vs. 0.05,p &lt; 0.05), and non-metropolitan counties had a higher incidence rate than metro counties (1.14 vs. 0.14,p &lt; 0.05). The observed survival at 12, 36, and 60 months was 81%, 39.9%, and 23.4%, respectively. There was no significant difference in survival between females and males. Ages greater than 70 years had poor survival compared to ages less than 60 years (p &lt; 0.001). Compared to surgery with chemotherapy, surgery combined with radiotherapy and chemotherapy was associated with a 62% lower risk of mortality (p&lt; 0.001). Conclusions: This study reveals that DSRCT incidence has been increasing since 2000, is more common in white males. Gender may not affect survival in DSRCT, and surgery combined with chemoradiotherapy is associated with improved survival outcomes compared to surgical management with chemotherapy alone. Further comparative data would be beneficial to confirm reported findings.[Table: see text]

Nested set information derived from fusion genes in Ewing sarcoma and other cancers.

e23521 Background: Ewing family tumors including Ewing sarcoma (ES) and desmoplastic small round cell tumor (DSRCT) are characterized by EWSR1 and ETS fusion partners including EWS-FLI1, EWS-ERG, EWS-WT1, and others. Since 2019 our Next Generation Sequencing (NGS) sarcoma panel (N = 338) identified both fusion partners and exons containing the EWS breakpoint in ES and DSRCT. Hence, it should be possible to learn more about the exact breakpoints of EWS fusion genes. The molecular diversity and functionality of these fusion transcripts, especially the exact sequence, which could be identical, similar, or unique, may have significant biological implications for diagnostics and treatment options. We have used in-frame analysis of EWS gene fusion breakpoints to identify corresponding polypeptides spanning the breakpoints of the most common EWS gene fusions to provide useful insights about ES and DSRCT. Methods: Pathology reports and EWS gene fusions were analyzed using the Cleveland Clinic NGS panel which is based on anchored multiplex polymerase chain reaction (PCR) enriched for 34 gene targets. The amplicons were subjected to massively parallel sequencing with 151x2 cycle pair-end reads. An informatics pipeline was used for read alignment (GRCh37 as reference genome), fusion identification, and annotation. The DNA sequence across fusion junction and translational amino acid sequences were extracted for comparison in a preliminary teaching set (37/338 EWS fusions). Results: EWS-FLI1 fusions at exon 7-7 (chr22:29683123-chr11:128675261) and exon 7-6 (chr22:29683123-chr11:128651853) were the most common fusion genes in ES (N = 24/32;75%). Other ES gene fusions included exons 10-6, 7-10, 9-8, 7-2 EWS-FEV, 7-8 EWS-ERG, 7-9 EWS-ERG, and 10-9 EWS-ERG. EWS-WT1 gene fusions (chr22:29683123-chr11:32414301) in DSRCT exon 7-7 occurred in 4 of 5 cases (80%). In frame analysis of the common gene fusions in 75% of ES and DSRCT (total n = 37) yielded identical corresponding polypeptides that span the breakpoint (table). Conclusions: Analysis of ES and DSRCT fusion genes provides evidence that cancer-specific fusion genes are associated with common identical breakpoints and corresponding in-frame polypeptides. Our results show that the identification of in-frame polypeptides from the fusion gene sequencing can identify potential nested sets of cancer-specific mRNAs and polypeptides. This information may become relevant for diagnostic and therapeutic targets future vaccines and diagnostics against ES and DSRCT as well as other cancers characterized by fusion genes or frameshift mutations. [Table: see text]

A phase I/II study of prexasertib in combination with irinotecan in patients with relapsed/refractory desmoplastic small round cell tumor and rhabdomyosarcoma.

11503 Background: Prexasertib (PRX) is an inhibitor of CHK1, prevents DNA repair leading to mitotic catastrophe, and can enhance the activity of DNA-damaging chemotherapy. Translocation driven sarcomas exhibit high levels of replication stress and have demonstrated susceptibility to CHK1 inhibition in preclinical models. Desmoplastic small round cell tumor (DSRCT) and rhabdomyosarcoma (RMS) are aggressive sarcomas of children, adolescents and young adults for which novel therapies are urgently required. Methods: We conducted a phase I/II trial of PRX with irinotecan (irino) in patients ≥ 12 months of age with relapsed or refractory DSRCT or RMS. Eligible patients could have any number of prior therapies, including irino. Dose level 1 was PRX 80 mg/m2 on day 1 + irino 20 mg/m2 for 10 days. Dose levels 2 and 2A were PRX 105 or 150 mg/m2 (&gt;21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 10 (level 2) or 5 (level 2A) days. All cycles were 21 days. The primary objectives were to determine the RP2D of PRX with irino, and to determine the best overall response rate (ORR) in 6 months at the RP2D (RECIST v1.1) in DSRCT, with 3 or more responses out of 16 considered promising. Results: 21 patients were enrolled (DSRCT: 19; 2 RMS:2). The RP2D was dose level 2A. Treatment was well tolerated with the most common adverse events being neutropenia (48%), nausea (48%), and fatigue (52%). Cytopenias were managed with the aid of growth factor support in all patients once the RP2D was established. The DSRCT expansion enrolled 13 of 16 planned patients due to discontinuation of PRX supply prior to study completion. Four patients remain on therapy at the time of this submission. Responses in DSRCT patients at all dose levels are shown in Table. Sixteen of 21 enrolled patients, and 5 of 6 patients achieving PR had previously received irino. The median (range) number of cycles was 7 (2-26). Both RMS patients treated at the RP2D experienced SD as best response. The estimated ORR at the RP2D was 23%, and lower boundary of the one-sided 90% confidence interval was 9%, exceeding the unpromising rate of 5%. The two-sided 90% confidence interval was 7 to 49%. In addition, 3 patients had a PR at doses lower than the RP2D, bringing the ORR for all dose levels (n = 19) to 32% (90%CI: 15 to 53%). Conclusions: The RP2D of PRX in combination with irino is PRX 105 or 150 mg/m2 (&gt;21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 5 days in 21 day cycles with myelosuppression successfully managed with growth factor support. The study met its primary objective to consider PRX + irino promising in DSRCT and should be further investigated. Clinical trial information: NCT04095221. [Table: see text]

The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma

Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.

Chylothorax and chylous ascites during RET tyrosine kinase inhibitor therapy.

9080 Background: Spontaneous, atraumatic chylous effusions are rare. Investigators have observed a higher than anticipated incidence of chylothorax and chylous ascites in patients (pts) treated with RET tyrosine kinase inhibitors (TKIs). A systematic analysis of the occurrence of chylous effusions during RET TKI therapy and management strategies was thus performed. Methods: In this multicenter, retrospective study, the frequency of biochemically confirmed chylothorax or chylous ascites in pts treated with multikinase inhibitors (MKIs) with anti-RET activity or selective RET TKIs was determined. Clinicopathologic features and management of pts with chylous effusions were assessed. Results: A pan-cancer cohort of 7517 pts treated with at least 1 of 17 MKIs and selective RET TKIs and an independent cohort of 96 pts treated with the selective RET TKIs, selpercatinib or pralsetinib, were identified. Across cohorts, chylous effusions were identified in 22 pts and were most common with selpercatinib (7%; 15/217), followed by the MKIs agerafenib (4%; 1/24), cabozantinib (0.3%; 3/918), and lenvatinib (0.3%; 3/1185). Chylous effusions were not noted in 28 pts treated with pralsetinib. The distribution of malignancies included lung adenocarcinoma (54%) medullary thyroid carcinoma (23%), renal cell carcinoma (19%), and desmoplastic small round cell tumor (4%). Of the 22 pts, 12 had chylothorax, 5 had chylous ascites, and 5 had both. The cumulative incidence of chylous effusions from TKI initiation at 12 months was 3.09%. Median fluid triglyceride level was lower in chylothorax than in chylous ascites [397 mg/dL (IQR 282-4000) vs. 3786 mg/dL (IQR 676-6596), p = 0.035]. Median pleural fluid triglyceride level was higher with selpercatinib compared to MKIs [4,000 mg/dL (IQR 356-4425) vs. 287 mg/dL (IQR 216-395); p = 0.017]. Malignant cells were identified in the effusions from 12% (2/17) and 10% (1/10) of pts with chylothoraces and chylous ascites, respectively. Median time to disease progression from radiographic index and biochemical index across the full cohort was 1.5 years (IQR: 0.6-2.4) and 1.0 year (IQR: 0.1-1.2), respectively. Anatomic chyle leak was not identified in 6 pts who underwent lymphangiography. After initial drainage, additional drainage procedures were required in all cases with chylothorax and 50% of cases with chylous ascites. Chylous effusions prompted TKI dose reduction in 47% (7/15) of pts treated with selpercatinib and 14% (1/7) treated with MKI; none discontinued TKI due to chylous effusions. Conclusions: Chylous effusions can emerge on treatment with certain MKIs or selective RET TKIs. Recognition of this potential side effect is key to prevent misattribution of worsening effusions to progressive malignancy and to motivate a better understanding of its biology and management.