Targeting the Clear Cell Sarcoma Oncogenic Driver Fusion Gene EWSR1::ATF1 by HDAC Inhibition.

Clear cell sarcoma (CCS), a rare but extremely aggressive malignancy with no effective therapy, is characterized by the expression of the oncogenic driver fusion gene EWSR1::ATF1. In this study, we performed a high-throughput drug screening, finding that the histone deacetylase inhibitor vorinostat exerted an antiproliferation effect with the reduced expression of EWSR1::ATF1. We expected the reduced expression of EWSR1::ATF1 to be due to the alteration of chromatin accessibility; however, assay for transposase-accessible chromatin using sequencing and a cleavage under targets and release using nuclease assay revealed that chromatin structure was only slightly altered, despite histone deacetylation at the EWSR1::ATF1 promoter region. Alternatively, we found that vorinostat treatment reduced the level of BRD4, a member of the bromodomain and extraterminal motif protein family, at the EWSR1::ATF1 promoter region. Furthermore, the BRD4 inhibitor JQ1 downregulated EWSR1::ATF1 according to Western blotting and qPCR analyses. In addition, motif analysis revealed that vorinostat treatment suppressed the transcriptional factor SOX10, which directly regulates EWSR1::ATF1 expression and is involved in CCS proliferation. Importantly, we demonstrate that a combination therapy of vorinostat and JQ1 synergistically enhances antiproliferation effect and EWSR1::ATF1 suppression. These results highlight a novel fusion gene suppression mechanism achieved using epigenetic modification agents and provide a potential therapeutic target for fusion gene-related tumors. Significance: This study reveals the epigenetic and transcriptional suppression mechanism of the fusion oncogene EWSR1::ATF1 in clear cell sarcoma by histone deacetylase inhibitor treatment as well as identifying SOX10 as a transcription factor that regulates EWSR1::ATF1 expression.

Positive response of a recurrent clear cell sarcoma to anlotinib combined with chemotherapy: A case report.

RATIONALE: Renal clear cell sarcoma is a rare and highly invasive malignant renal tumor that easily relapses after treatment. Recurrent recurrent clear cell carcinoma (CCSK) responds poorly to chemotherapy and has no established standardized treatment, and need to be explored potentially useful treatments. PATIENT CONCERNS: A 18-years-old patient with renal clear cell sarcoma recurrence after open radical nephrectomy. DIAGNOSIS: Recurrent clear cell sarcoma. INTERVENTIONS: After chemotherapy alone failed, the patient received 6 courses of anlotinib combined with chemotherapy. The tumor had significantly reduced in size and the recurrent tumor and part of the liver were resected. OUTCOMES: No tumor recurrence or metastasis was detected during the follow-up 8 months after the operation. LESSONS: This is the first report describing the use of anlotinib in treating CCSK. We believe that anlotinib combined with chemotherapy may be a useful treatment option for patients with recurrent CCSK.

Clear cell sarcoma of soft tissue with plasmacytoid morphology: A rare case report.

RATIONALE: Clear cell sarcoma of soft tissue (CCSST) is a rare malignant tumor that occurs in the extremities of young adults. CCSST has been documented to have atypical histopathological features, such as epidermotropism or myxoid differentiation, which may set pitfalls in the differential diagnosis. We report a case of CCSST with plasmacytoid morphology which has never been described. PATIENT CONCERNS: A 15-year-old male, presented with a 5-cm mass in his left inguinal area. DIAGNOSIS: Positron emission tomography-computed tomography examination showed nodules in the left groin and the lung, the latter was considered metastasis. A core needle biopsy with the diagnosis of CCSST with plasmacytoid morphology was made according to histology, immunostaining, and molecular analysis. INTERVENTIONS: The patient received chemotherapy of doxorubicin and ifosfamide. OUTCOMES: The patient failed to respond to the standard chemotherapy and deceased twelve months after diagnosis. LESSONS: This special case of CCSST with plasmacytoid features demonstrated a morphological variation never been documented and may easily lead to misdiagnosis. For such cases, molecular analysis is essential to provide solid evidence for accurate diagnosis.

Systemic treatment of advanced clear cell sarcoma: results from a retrospective international series from the World Sarcoma Network.

BACKGROUND: Clear cell sarcoma (CCS) is a translocated aggressive malignancy with a high incidence of metastases and poor prognosis. There are few studies describing the activity of systemic therapy in CCS. We report a multi-institutional retrospective study of the outcomes of patients with advanced CCS treated with systemic therapy within the World Sarcoma Network (WSN). MATERIALS AND METHODS: Patients with molecularly confirmed locally advanced or metastatic CCS treated with systemic therapy from June 1985 to May 2021 were included. Baseline demographic and treatment information, including response by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, was retrospectively collected by local investigators. Descriptive statistics were carried out. RESULTS: Fifty-five patients from 10 institutions were included. At diagnosis, the median age was 30 (15-73) years and 24% (n = 13/55) had metastatic disease. The median age at diagnosis was 30 (15-73) years. Most primary tumours were at aponeurosis (n = 9/55, 16%) or non-aponeurosis limb sites (n = 17/55, 31%). The most common fusion was EWSR1-ATF1 (n = 24/55, 44%). The median number of systemic therapies was 1 (range 1-7). The best response rate was seen for patients treated with sunitinib (30%, n = 3/10), with a median progression-free survival of 4 [95% confidence interval (CI) 1-7] months. The median overall survival for patients with advanced/metastatic disease was 15 months (95% CI 3-27 months). CONCLUSIONS: Soft tissue sarcoma-type systemic therapies have limited benefit in advanced CCS and response rate was poor. International, multicentre prospective translational studies are required to identify new treatments for this ultra-rare subtype, and access to early clinical trial enrolment remains key for patients with CCS.

Oral recombinant methioninase combined with paclitaxel arrests recalcitrant ovarian clear cell carcinoma growth in a patient-derived orthotopic xenograft (PDOX) nude-mouse model.

PURPOSE: Advanced ovarian clear cell carcinoma (OCCC) is a recalcitrant disease, often resistant to the first-line platinum-based therapy. Using a novel patient-derived orthotopic xenograft (PDOX) nude-mouse model of OCCC, we tested whether oral-recombinant methioninase (o-rMETase) could enhance the efficacy of paclitaxel (PTX). METHODS: The OCCC PDOX model was established and passaged in nude mice. The OCCC PDOX models were randomized into 5 groups. G1: untreated control; G2: paclitaxel (PTX) (20 mg/kg, intraperitoneal (i.p.) injection, weekly); G3: o-rMETase (100 units, oral, daily); G4: PTX (20 mg/kg, i.p. injection, weekly) + carboplatinum (CBDCA) (40 mg/kg, i.p. injection weekly); G5: PTX (20 mg/kg, i.p. injection, weekly) + o-rMETase (100 units, oral, daily). The treatment period was 2 weeks. RESULTS: The combination of PTX and o-rMETase arrested OCCC tumor growth (relative tumor volume: 1.09 ± 0.63 (mean ± SD)) compared with the untreated control (relative tumor volume: 3.92 ± 1.04 (mean ± SD)) (p < 0.0001). There was no significant difference in relative tumor volume between PTX plus o-rMETase and PTX plus CBDCA (relative tumor volume: 1.39 ± 0.37 (mean ± SD)) (p = 0.93). CONCLUSION: PTX plus o-rMETase arrested the OCCC tumor growth. o-rMETase is readily administered and can greatly enhance first-line therapy of a recalcitrant cancer. The novel and effective treatment strategy in the present report has future clinical potential for patients with OCCC, especially for patients who cannot well tolerate platinum-based therapy.

Clear cell sarcoma of soft tissue with eccrine differentiation: A case report and review of the literature.

Clear cell sarcoma of soft tissue (CCSST) is a deep soft tissue tumor presenting in the extremities of young adults. Histopathologically, nests and sheets of polygonal cells with clear to eosinophilic cytoplasm separated by fibrous septa as well as occasional "wreath-like" giant cells are visualized. However, CCSST has been noted to have atypical histopathological features, such as epidermotropism or myxoid differentiation, or occurrence at unusual sites. Here, we present a case of eccrine ductal differentiation in CCSST. The patient, a 21-year-old woman, presented with a lump of 10-year duration sized 3 × 5 cm on the plantar surface of the fourth and fifth interdigital spaces. There had been an increase in size as well as pain and redness over 6 years. Besides the characteristic findings, there were ductal structures in continuity with the upper dermis indicative of ductal differentiation. The tumor stained positively for S100, HMB45, and succinic dehydrogenase; ducts stained positively for epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA). CCSST was confirmed with cytogenetic analysis showing the translocation associated with EWSR1-ATF1 fusion gene. Therefore, ductal differentiation is a unique finding that should be considered when evaluating for CCSST.

Efficacy of Gemcitabine-based Chemotherapy in Clear Cell Sarcoma of Soft Tissue.

BACKGROUND/AIM: Clear cell sarcoma (CCS) is an aggressive sarcoma subtype, resistant to conventional anthracycline-based chemotherapy and radiation. The diagnosis is often challenging due to similarities with malignant melanoma. PATIENTS AND METHODS: We aimed to analyse the activity of gemcitabine-based chemotherapy in a cohort of patients with CCS treated at the Royal Marsden Hospital. RESULTS: Five patients with metastatic CCS received gemcitabine as first- or second-line systemic therapy. The median time-to-progression was 10 weeks. The median number of cycles of gemcitabine-based therapy was 3 (range=2-7 cycles). Median overall survival in our cohort was 66 months from the initial diagnosis but in the metastatic setting, the overall survival was reduced to 28 months. CONCLUSION: Gemcitabine-based therapy has modest activity in CCS. There remains a significant unmet medical need for novel, effective therapies for this disease.

Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling.

Clear cell sarcoma (CCS) is a rare but chemotherapy-resistant and often fatal high-grade soft-tissue sarcoma (STS) characterized by melanocytic differentiation under control of microphthalmia-associated transcription factor (MITF). Eribulin mesilate (eribulin) is a mechanistically unique microtubule inhibitor commonly used for STS treatment, particularly liposarcoma and leiomyosarcoma. In this study, we examined the antitumor efficacy of eribulin on four human CCS cell lines and two mouse xenograft models. Eribulin inhibited CCS cell proliferation by inducing cell-cycle arrest and apoptosis, shrunk CCS xenograft tumors, and increased tumor vessel density. Eribulin induced MITF protein upregulation and stimulated tumor cell melanocytic differentiation through ERK1/2 inactivation (a MITF negative regulator) in vitro and in vivo Moreover, tumor reoxygenation, probably caused by eribulin-induced vascular remodeling, attenuated cell growth and inhibited ERK1/2 activity, thereby upregulating MITF expression and promoting melanocytic differentiation. Finally, downregulation of MITF protein levels modestly debilitated the antiproliferative effect of eribulin on CCS cells. Taken together, eribulin suppresses CCS through inhibition of cell proliferation and promotion of tumor differentiation by acting both directly on tumor cells and indirectly through tumor reoxygenation.

Novel therapy for pediatric and adolescent kidney cancer.

Pediatric and adolescent renal tumors account for approximately 7% of all new cancer diagnoses in the USA each year. The prognosis and treatment are varied based on factors including the underlying histology and tumor stage, with survival rates ranging from greater than 90% in favorable histology Wilms tumor to almost universally fatal in other disease types, including those patients with advanced stage malignant rhabdoid tumor and renal medullary carcinoma. In recent years, our understanding of the underlying genetic drivers of the different types of pediatric kidney cancer has dramatically increased, opening the door to utilization of new targeted biologic agents alone or in combination with conventional chemotherapy to improve outcomes. Several ongoing clinical trials are investigating the use of a variety of targeted agents in pediatric patients with underlying genetic aberrations. In this manuscript, the underlying biology and early phase clinical trials relevant to pediatric renal cancers are reviewed.

Clear cell sarcoma of the kidney in a 62-year-old patient presenting with generalized pruritus.

BACKGROUND: Clear cell sarcoma of the kidney (CCSK) is the second most common renal tumor in children following Wilms' tumor. CCSK is extremely rare in adults, with only 25 adult cases reported in the medical literature. CASE PRESENTATION: We reported a 62-year-old man with a right renal mass presenting only with generalized pruritus who underwent radical right nephrectomy. With immunostaining, tumor cells were positive for expressed vimentin, neural cell adhesion molecule (NCAM, CD56), and Ki-67 and focally positive for p53, CD10 and Bcl-2. The histopathological diagnosis was CCSK. Two weeks after the operation, the generalized pruritus ended. One month after the operation, the patient started treatment with a regimen combining doxorubicin, vincristine, cyclophosphamide, and etoposide. At the 20-month follow-up visit, there was no evidence of local recurrence or metastases. CONCLUSIONS: In a patient presenting with generalized pruritus, further evaluation for an underlying malignancy should be considered. It is difficult to distinguish CCSK from undifferentiated renal neoplasms. Immunohistochemistry could help to make exact histopathological diagnoses. The BCL-6 corepressor (BCOR) gene could play a significant role in CCSK tumorigenesis and be a good marker for CCSK diagnosis. Surgery with combination chemotherapy and radiation therapy could be used to treat CCSK in older patients.

Impact of cyclophosphamide and etoposide on outcome of clear cell sarcoma of the kidney treated on the National Wilms Tumor Study-5 (NWTS-5).

PURPOSE: To improve the event-free survival (EFS) and overall survival (OS) for patients with clear cell sarcoma of the kidney (CCSK) by incorporating cyclophosphamide and etoposide into treatment on National Wilms Tumor Study (NWTS)-5. PATIENTS AND METHODS: Patients less than 16 years of age with a centrally confirmed pathological diagnosis of CCSK were eligible for treatment on this prospective single-arm study conducted between August 1995 and June 2002. Staging consisted of CT scans of chest, abdomen, pelvis, bone scan, skeletal survey, and CT or MRI of the head. Treatment consisted of vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide for 24 weeks and radiation to sites of disease. RESULTS: One hundred eight eligible patients were enrolled on study (69% males, 63% Caucasian), with a median age of 22 months. Stage distribution was as follows: stage I, 12; II, 44; III, 45; IV, 7. Median follow-up was 9.7 years. Five-year EFS and OS were 79% (95% CI: 71%-88%) and 90% (95% CI: 84%-96%). Five-year EFS for stage I-IV was 100%, 88%, 73%, and 29%, respectively. Twenty of the 23 disease-related events occurred within three years of initial treatment. The most common site of recurrence was brain (12/23). CONCLUSION: The outcome for patients with CCSK treated on NWTS-5 was similar to NWTS-4 and accomplished over a shorter treatment duration. Stage was highly predictive of outcome. Brain metastases occurred more frequently than on NWTS-4. Regimen I showed more benefit for patients with stage I and II disease as compared with higher stages of disease where new therapies are needed.

Therapeutic potential of CPI-613 for targeting tumorous mitochondrial energy metabolism and inhibiting autophagy in clear cell sarcoma.

Clear cell sarcoma (CCS) is an aggressive type of soft tissue tumor that is associated with high rates of metastasis. In the present study, we found that CPI-613, which targets tumorous mitochondrial energy metabolism, induced autophagosome formation followed by lysosome fusion in HS-MM CCS cells in vitro. Interestingly, CPI-613 along with chloroquine, which inhibits the fusion of autophagosomes with lysosomes, significantly induced necrosis of HS-MM CCS cell growth in vitro. Subsequently, we established a murine orthotropic metastatic model of CCS and evaluated the putative suppressive effect of a combination of CPI-613 and chloroquine on CCS progression. Injection of HS-MM into the aponeuroses of the thigh, the most frequently affected site in CCS, resulted in massive metastasis in SCID-beige mice. By contrast, intraperitoneal administration of CPI-613 (25 mg/kg) and chloroquine (50 mg/kg), two days a week for two weeks, significantly decreased tumor growth at the injection site and abolished metastasis. The present results imply the inhibitory effects of a combination of CPI-613 and chloroquine on the progression of CCS.

Malignant gastrointestinal neuroectodermal tumor (clear cell sarcoma-like tumor of the gastrointestinal tract) of the small intestine in a 12-year-old boy.

The aim of this paper is a clinical and anatomopathological demonstration of a malignant lesion, a gastrointestinal neuroectodermal tumor (GNET), as an exceedingly rare cause of ileus in the pediatric population. Specifically, we present the case of a 12-year-old boy who showed dramatic weight loss, hypochromic anemia, fever, dehydration, exaggerated granulation of the terminal ileum, and mechanical ileus due to the obstruction by an intramural tumor of the small intestine. A 50cm-long part of the small intestine with pathological stricture was surgically removed, sampled and routinely fixed and stained with hematoxylin and eosin. The additional immunostains that were preformed were: PAS, S-100, HMB-45, NSE, LCA, CK AE1 / AE3, desmin, SMA, vimentin, CD99, NSE, synaptophysin, WT-1, calretinin, and DOG-1. Moreover, fluorescent in situ hybridization (FISH) with the EWSR1 Break Apart FISH Probe was applied. The neoplasm was composed of nests and alveolar patterns of frankly malignant clear cells with immunoreactivity to S-100, vimentin, and CD 99. The FISH technique detected chromosomal breaking at 22q12. The tumor metastasized to both the mesenteric lymph nodes and a number of hepatic segments. With several chemotherapy protocols, repeat laparotomies, and liver thermal ablations, the patient had a 1.5-year-long survival from the moment of diagnosis. The diagnosis of this malignancy requires both histopathological evaluation and molecular analysis, and the follow-up is based on careful clinical imaging of the neoplastic spread in order to apply proper surgical and oncological treatments. In conclusion, the clinical course of GNET was highly aggressive.

Establishment and proteomic characterization of patient-derived clear cell sarcoma xenografts and cell lines.

Clear cell sarcoma (CCS) is an aggressive mesenchymal malignancy characterized by the unique chimeric EWS-ATF1 fusion gene. Patient-derived cancer models are essential tools for the understanding of tumorigenesis and the development of anti-cancer drugs; however, only a limited number of CCS cell lines exist. The objective of this study was to establish patient-derived CCS models. We established patient-derived CCS models from a 43-yr-old female patient. We prepared the patient-derived xenografts (PDXs) from tumor tissues obtained through biopsy or surgery and isolated stable cell lines from PDXs and the original tumor tissue. The presence of gene fusions was examined by RT-PCR, and Sanger sequencing. The established cell lines were characterized by short tandem repeat, viability, colony and spheroid formation, and invasion analyses. Differences in gene enrichment between the primary tumor and cell lines were examined by mass spectrometry and KEGG pathway analysis. The cell lines were maintained for more than 80 passages, and had tumorigenic characteristics such as colony and spheroid formation and invasion. Mass spectrometric proteome analysis demonstrated that the cell lines were enriched for similar but distinct molecular pathways, compared to those in the xenografts and original tumor tissue. Next, tyrosine kinase inhibitors were screened for their suppressive effects on viability. We found that ponatinib, vandetanib, and doxorubicin suppressed the growth of cell lines, and had equivalent IC50 values. Further in-depth investigation and understanding of drug-sensitivity mechanisms will be important for the clinical applications of our cell lines.

Informe de evaluación científica en la evidencia disponible: sarcoma del tejido blando / Scientific evaluation report on the available evidence: soft tissue sarcoma

INTRODUCCIÓN: Este informe evalúa imatinib para pacientes con dermatofibrosarcoma protuberans de carácter irresecable, recidivante o metastásico que no son de elección para cirugía, los cuales no están cubiertos por la Ley 20.850. El dermatofibrosarcoma protuberans (DFSP) es un sarcoma de tejido blando infiltrante, poco frecuente y agresivo (2). Se presenta clínicamente en forma de placa indurada de crecimiento lento sobre la que aparecen nódulos a medida que el tumor progresa, se localiza inicialmente en la piel, desde donde invade tejidos más profundos. La prevalencia se estima en 1 entre 10.000, y la incidencia anual es alrededor de 1 entre 200.000. Es más frecuente en adultos y jóvenes, pero también se presenta en niños. El pronóstico general del DFSP es bueno, con una tasa de supervivencia a 10 años del 99,1%. La edad mayor de 50 años es un factor de riesgo de recurrencia local. Los pacientes con enfermedad metastásica viven en promedio dos años después del momento del diagnóstico. Se considerarán para su evaluación aquellas solicitudes realizadas conforme al Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con sistema de protección financiera, según lo establecido en los artículos 7° y 8° de la Ley N° 20.850. Estas solicitudes no son vinculantes para el Ministerio de Salud, debiendo, sin embargo, tomar especialmente en cuenta aquellas solicitudes y opiniones que hayan sido realizadas por sus comisiones técnicas asesoras y por las asociaciones de pacientes incluidas en el Registro de Asociaciones de Pacientes que crea la Ley 20.850. De igual forma, para ser incorporadas en el proceso de evaluación científica de la evidencia, cada intervención debe cumplir con los criterios establecidos en el Artículo 6o del Reglamento mencionado, según lo indicado en el Numeral 9 del presente informe. TECNOLOGÍAS SANITARIA DE INTERÉS: El imatinib mesilato es una terapia molecularmente dirigida de administración oral; funciona como inhibidor de tirosina kinasa con actividad contra varias vías de señalización, entre las cuales se cuenta la del receptor del factor de crecimiento plaquetario activado. Como la activación de esta vía de señalización es un evento genético muy frecuente en DFSP, podría tener actividad en esta enfermedad, lo cual sería de utilidad en el pequeño número de pacientes con enfermedad irresecable. EFICACIA DE LOS TRATAMIENTOS: Dado que el grado de la certeza en la evidencia es muy baja para una patología poco frecuente no cumple con el Título III De las Evaluaciones Favorables de la Norma Técnica N° 0192 del Ministerio de Salud, sobre el proceso de evaluación científica de la Evidencia establecido en el artículo 7° de la ley N°20.850, por lo que no se continúa con la evaluación. ALTERNATIVAS DISPONIBLES: 1. Radioterapia, se utiliza para tumores irresecables, aunque con mayor frecuencia como terapia adyuvante después de la cirugía. 2. Quimioterapia para aliviar los síntomas. 3. Cirugía de las metástasis como tratamiento paliativo. RESULTADOS DE LA BÚSQUEDA DE EVIDENCIA: No se identificaron revisiones sistemáticas evaluando imatinib en DFSP. ­ Tampoco se identificaron ensayos relevantes en la búsqueda adicional. Una búsqueda en revisiones no sistemáticas y mediante la técnica de cross-citation se identificó un reporte de dos estudios no aleatorizados. CONCLUSIÓN: Para dar cumplimiento al artículo 28° del Reglamento que establece el proceso destinado a determinar los diagnósticos y tratamientos de alto costo con Sistema de Protección Financiera, según lo establecido en los artículos 7°y 8° de la ley N°20.850, aprobado por el decreto N°13 del Ministerio de Salud, se concluye que el presente informe de evaluación se considera no favorable, de acuerdo a lo establecido en el Título III. de las Evaluaciones Favorables de la Norma Técnica N° 0192 de este mismo ministerio.

Activity and safety of crizotinib in patients with advanced clear-cell sarcoma with MET alterations: European Organization for Research and Treatment of Cancer phase II trial 90101 'CREATE'.

BACKGROUND: Clear-cell sarcoma (CCSA) is an orphan malignancy, characterized by a specific t(12;22) translocation, leading to rearrangement of the EWSR1 gene and overexpression of MET. We prospectively investigated the efficacy and safety of the tyrosine kinase inhibitor crizotinib in patients with advanced or metastatic CCSA. PATIENTS AND METHODS: Patients with CCSA received oral crizotinib 250 mg twice daily. Primary end point was objective response rate (ORR), secondary end points included duration of response, disease control rate (DCR), progression-free survival (PFS), progression-free rate (PFR), overall survival (OS), OS rate and safety. The study design focused on MET+ disease with documented rearrangement of the EWSR1 gene by fluorescence in situ hybridization. RESULTS: Among 43 consenting patients with the local diagnosis of CCSA, 36 had centrally confirmed CCSA, 28 of whom were eligible, treated and assessable. Twenty-six out of the 28 patients had MET+ disease, of whom one achieved a confirmed partial response and 17 had stable disease (SD) (ORR 3.8%, 95% confidence interval: 0.1-19.6). Further efficacy end points in MET+ CCSA were DCR: 69.2% (48.2% to 85.7%), median PFS: 131 days (49-235), median OS: 277 days (232-442). The 3-, 6-, 12- and 24-month PFR was 53.8% (34.6-73.0), 26.9% (9.8-43.9), 7.7% (1.3-21.7) and 7.7% (1.3-21.7), respectively. Among two assessable MET- patients, one had stable disease and one had progression. The most common treatment-related adverse events were nausea [18/34 (52.9%)], fatigue [17/34 (50.0%)], vomiting [12/34 (35.3%)], diarrhoea [11/34 (32.4%)], constipation [9/34 (26.5%)] and blurred vision [7/34 (20.6%)]. CONCLUSIONS: The PFS with crizotinib in MET+ CCSA is similar to results achieved first-line in non-selected metastatic soft tissue sarcomas with single-agent doxorubicin. The PFS is similar to results achieved with pazopanib in previously treated sarcoma patients. CLINICAL TRIAL NUMBER: EORTC 90101, EudraCT number 2011-001988-52, NCT01524926.

Trabectedin is a promising antitumor agent potentially inducing melanocytic differentiation for clear cell sarcoma.

Clear cell sarcoma is an aggressive soft tissue sarcoma and highly resistant to conventional chemotherapy and radiation therapy. This devastating disease is defined by EWSR1-ATF1 fusion gene resulting from chromosomal translocation t(12;22)(q13;q12) and characterized by melanocytic differentiation. A marine-derived antineoplastic agent, trabectedin, inhibits the growth of myxoid liposarcoma and Ewing sarcoma by causing adipogenic differentiation and neural differentiation, respectively. In this study, we examined the antitumor effects and mechanism of action of trabectedin on human clear cell sarcoma cell lines. We showed that trabectedin decreased the cell proliferation of five clear cell sarcoma cell lines in a dose-dependent manner in vitro and reduced tumor growth of two mouse xenograft models. Flow cytometry and immunoblot analyses in vitro and immunohistochemical analysis in vivo revealed that trabectedin-induced G2/M cell cycle arrest and apoptosis. Furthermore, trabectedin increased the expression of melanocytic differentiation markers along with downregulation of ERK activity in vitro and the rate of melanin-positive cells in vivo. These results suggest that trabectedin has potent antitumor activity against clear cell sarcoma cells by inducing cell cycle arrest, apoptosis, and, in part, by promoting melanocytic differentiation through inactivation of ERK signaling. Our present study indicates that trabectedin is a promising differentiation-inducing agent for clear cell sarcoma.

A giant clear cell sarcoma on right scapular: A case report.

Clear-cell sarcoma is a rare and malignant soft tissue tumor most commonly located at the distal end of extremities and rarely at the trunk. Data on the clinical features of the tumor is limited, complicating the analysis of prognosis and establishment of treatment protocols. In our study, we present a case diagnosed with clear-cell sarcoma in his right scapula and treated with tumor resection and chemotherapy, combination of dacarbazine, pharmorubicin and cisplatin. The patient died due to multiple organ failure eight months after operation. Early diagnosis, attentive care, and extended surgical resection combined with adjuvant therapy is of essence in treatment of clear-cell sarcoma.