Publications by authors named "Shintaro Iwata"

69 Publications

Establishment and Characterization of NCC-DDLPS4-C1: A Novel Patient-Derived Cell Line of Dedifferentiated Liposarcoma.

J Pers Med 2021 Oct 24;11(11). Epub 2021 Oct 24.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.

Dedifferentiated liposarcoma (DDLPS) is a highly malignant sarcoma characterized by the co-amplification of and . Although systemic chemotherapy is recommended for unresectable or metastatic cases, DDLPS is insensitive to conventional chemotherapy, leading to an unfavorable prognosis. Therefore, novel treatment methods are urgently required. Patient-derived cell lines are essential in preclinical studies. Recently, large-scale screening studies using a number of cell lines have been actively conducted for the development of new therapeutic drugs. However, the DDLPS cell line cannot be obtained from public cell banks owing to its rarity, hindering screening studies. As such, novel DDLPS cell lines need to be established. Accordingly, this study aimed to establish a novel DDLPS cell line from surgical specimens. The cell line was named NCC-DDLPS4-C1. NCC-DDLPS4-C1 cells retained copy number alterations corresponding to the original tumors. Further, the cells demonstrated constant growth, spheroid formation, and equivalent invasiveness to MG63 osteosarcoma cells. We also conducted drug screening and integrated the results with those of the previously reported DDLPS cell lines. Consequently, we identified the histone deacetylase inhibitor romidepsin as a novel candidate drug. In conclusion, the NCC-DDLPS4-C1 cell line is a useful tool for the basic study of DDLPS.
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http://dx.doi.org/10.3390/jpm11111075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618493PMC
October 2021

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

Cell Rep 2021 Nov;37(8):110047

University of Toronto Musculoskeletal Oncology Unit, Sinai Health System; Department of Surgery, University of Toronto, Toronto, ON, Canada.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.
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http://dx.doi.org/10.1016/j.celrep.2021.110047DOI Listing
November 2021

Clinical analysis of multimodal treatment for localized synovial sarcoma: A multicenter retrospective study.

J Orthop Sci 2021 Oct 27. Epub 2021 Oct 27.

Dept. Orthopedic Surgery, Tokyo Women's Medical University, Tokyo, Japan.

Introduction: Several prognostic factors for survival in synovial sarcoma have been proposed, but the role of adjuvant chemotherapy and radiotherapy is a matter of debate. The study aim was to clarify the effect of high-dose ifosfamide-containing chemotherapy and adjuvant radiotherapy for patients with localized synovial sarcoma.

Materials And Methods: Five tertiary musculoskeletal oncology hospitals participated in this retrospective study. The records of the patient diagnosed with synovial sarcoma without metastasis at diagnosis from 1990 to 2011 have been collected and reviewed. Overall, distant failure-free, and local failure-free survivals were calculated, and prognostic factors for each survival were evaluated by performing univariate and multivariate analyses.

Results: A total of 162 patients were enrolled in this study with a median follow-up period of 67 months (range, 5-267 months) for all surviving patients. The 5-year overall, distant failure-free, and local failure-free survival rates were 79.7%, 66.3%, and 98.4%, respectively. Univariate analyses demonstrated that high-dose ifosfamide-containing chemotherapy was significantly associated with better overall (p = 0.014) and distant failure-free survival (p = 0.0043) than that of low-dose or no ifosfamide-containing chemotherapy if we analyzed only patients with tumors >5 cm in size. Addition of radiotherapy was not a significant prognostic factor for overall survival in the univariate and multivariate analyses, but it did improve the overall survival of the patients with R1 resection (p = 0.053).

Conclusion: Patients with localized synovial sarcoma >5 cm in size had better overall and distant failure-free survival after receiving adjuvant chemotherapy containing high-dose ifosfamide comparing to low-dose or no ifosfamide-containing chemotherapy. The addition of adjuvant radiotherapy was beneficial for the patients who received R1 resection. Alternatively, adjuvant radiotherapy could be avoided for patients who achieved an R0 margin.
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http://dx.doi.org/10.1016/j.jos.2021.09.012DOI Listing
October 2021

Establishment and characterization of NCC-LGFMS1-C1: a novel patient-derived cell line of low-grade fibromyxoid sarcoma.

Hum Cell 2021 Nov 17;34(6):1919-1928. Epub 2021 Sep 17.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Low-grade fibromyxoid sarcoma (LGFMS) is a rare soft-tissue sarcoma genetically characterized by the presence of the FUS-CREB3L2 gene fusion. While LGFMS exhibits indolent features during its early stages, the rates of recurrence, metastasis, and death from the disease are high. Presently, the role of FUS-CREB3L2 gene fusions in the unique features of LGFMS is not clear, and there is no modality to improve the clinical outcomes of patients with LGFMS; thus, extensive studies on LGFMS are required. Patient-derived cancer cell lines are critical tools for cancer research. However, no cell line has been established for LGFMS. Here, we aimed to develop a novel cell line for LGFMS and successfully established it using surgically resected tumor tissues. The cells, named NCC-LGFMS1-C1, possessed the same fusion genes as their original tumor and visible copy number variations. The cells had a fibroblastic appearance, formed spheroids when they were seeded in a low-attachment dish, and exhibited constant growth and invasion. Additionally, we demonstrated the feasibility of high-throughput drug screening using these cells. In conclusion, the NCC-LGFMS1-C1 cell line is a useful tool for studying LGFMS.
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http://dx.doi.org/10.1007/s13577-021-00612-1DOI Listing
November 2021

Prognostic impact of IDH mutations in chondrosarcoma.

J Orthop Sci 2021 Sep 13. Epub 2021 Sep 13.

Department of Musculoskeletal Oncology and Rehabilitation, National Cancer Center Hospital, Tokyo, Japan. Electronic address:

Background: Mutant isocitrate dehydrogenase (IDH) in chondrosarcoma produces the oncometabolite 2-hydroxyglutarate (2-HG) and contributes to malignant progression, and is therefore a potential therapeutic target for chondrosarcoma. Robust historical control data are important in clinical trials of rare cancers such as chondrosarcoma in order to show a clear benefit of new drugs. However, it remains controversial whether IDH mutation status is associated with the clinical outcome of chondrosarcoma, and this hinders the development of mutant IDH inhibitors in clinical trials.background METHODS: We investigated the relationship between IDH gene status and clinicopathological data in 38 chondrosarcoma patients from whom frozen tumor samples were obtained at the time of biopsy or surgery. Targeted next-generation sequencing was also performed to compare genetic alterations between patients with and without IDH mutations.methods RESULTS: The results revealed 15 cases (40%) of heterozygous IDH1 mutations and five cases (13%) of IDH2 mutations. IDH-mutant chondrosarcoma was associated with worse overall survival than IDH-wild-type chondrosarcoma (IDH1/2 Mut vs. IDH Wt, P = 0.006; IDH1 Mut vs. IDH Wt, P = 0.030; IDH2 Mut vs. IDH Wt, P < 0.0001). IDH mutation was also a significant poor prognostic factor both in univariate (P = 0.026) and multivariate (P = 0.048) analyses. Targeted next-generation sequencing revealed that characteristic mutations in chondrosarcoma, including TP53 and COL2A1, were more common in the IDH-mutant group than in the IDH-wild-type group.results CONCLUSION: This study is the first to report in detail the characteristics and clinical courses of IDH-mutant chondrosarcoma patients in Japan. Our data suggested that IDH-mutant chondrosarcomas might have a worse prognosis than that of IDH-wild-type chondrosarcoma, possibly through the more aggressive characters after metastasis. This information will be useful for designing clinical trials of mutant IDH inhibitors for treatment of advanced chondrosarcoma.

Conclusion:
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http://dx.doi.org/10.1016/j.jos.2021.07.024DOI Listing
September 2021

Establishment and characterization of NCC-MFS4-C1: a novel patient-derived cell line of myxofibrosarcoma.

Hum Cell 2021 Nov 12;34(6):1911-1918. Epub 2021 Aug 12.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Myxofibrosarcoma (MFS) is an aggressive sarcoma with a highly complex karyotype. Complete resection is the only curative treatment for MFS because it is refractory to chemotherapy. To improve clinical outcomes, it is critical to develop novel treatments for MFS. Although patient-derived cell lines play a key role in cancer research, only 12 MFS cell lines have been reported to date, and considering the diversity of the disease, more cell lines need to be established. Hence, in the present study, we established a novel MFS cell line, NCC-MFS4-C1, using a surgically resected tumor tissue from a patient with MFS. NCC-MFS4-C1 cells exhibited copy number alterations similar to those of the original tumors and showed constant proliferation, spheroid formation, and aggressive invasion. By screening a drug library, we found that actinomycin D, bortezomib, docetaxel, eribulin, and romidepsin significantly reduced the proliferation of NCC-MFS4-C1 cells. Therefore, the NCC-MFS4-C1 cell line may be a useful resource for researching MFS.
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http://dx.doi.org/10.1007/s13577-021-00589-xDOI Listing
November 2021

Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study.

Invest New Drugs 2021 12 12;39(6):1559-1567. Epub 2021 Jun 12.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background osteosarcoma is a rare, primary malignant bone tumour with limited available treatments for advanced or recurrent disease, resulting in a poor prognosis for patients. TAS-115 is a novel tyrosine kinase inhibitor under investigation in a phase I study in patients with solid tumours. We report data of osteosarcoma patients in the expansion cohort of this ongoing study. Patients and methods an analysis of this multicentre, open-label study was performed 6 months after the final patient was enrolled, and included patients aged ≥15 years, with unresectable or recurrent osteosarcoma, and who had refractory to standard therapy or for whom no standard therapy was available. TAS-115 650 mg/day was orally administered in a 5 days on/2 days off schedule. Results a total of 20 patients with osteosarcoma were enrolled. The most common adverse drug reactions (ADRs) were neutrophil count decreased (75%), aspartate aminotransferase increased (50%), and platelet count decreased (50%); 85% of patients had grade ≥ 3 ADRs. Long-term disease control (>1 year) with TAS-115 was achieved in three patients. The best overall response was stable disease (50%); no patient achieved a complete or partial response. Median progression-free survival was 3 months; 4-month and 12-month progression-free rates were 42% and 31%, respectively. Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013).
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http://dx.doi.org/10.1007/s10637-021-01107-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8541973PMC
December 2021

CDK4 overexpression is a predictive biomarker for resistance to conventional chemotherapy in patients with osteosarcoma.

Oncol Rep 2021 Jul 26;46(1). Epub 2021 May 26.

Division of Oncogenomics, Chiba Cancer Center Research Institute, Chuoh-ku, Chiba 260‑8717, Japan.

Osteosarcoma (OS) is the most common malignant bone tumor, and its sensitivity to preoperative chemotherapy is a significant prognostic factor. The present study aimed to identify potential genomic markers for the prediction of chemosensitivity in patients with OS using a genomic approach. A total of 50 pediatric and adolescent patients diagnosed with high‑grade OS were selected. Each pre‑therapeutic biopsy sample was subjected to comparative genomic hybridization array analysis and targeted exome sequencing. Although no recurrent gene mutation was observed in chemoresistant tumors, copy number analysis detected recurrent gain of chromosome 12q14.1, which was significantly more frequent (5/21; 24%) in the poor responder cohort than in the good responder cohort (0/29; 0%; P<0.01). Subsequent expression analysis revealed that was the only gene in the 12q14.1 gained region with an expression level that was positively associated with copy number gains. In order to elucidate the effect of CDK4 on drug sensitivity, CDK4‑overexpressing OS cell lines were treated with cisplatin (CDDP); significant attenuation of CDDP sensitivity, demonstrated by increased cell viability and decreased expression of cleaved caspase‑9, was induced by enforced expression of CDK4. In addition, treatment with CDK4/6 inhibitor palbociclib in CDK4‑overexpressing U2OS cells facilitated apoptosis and a significant decrease in cell viability in a dose‑dependent manner. In conclusion, the results of the present study showed that higher expression and amplification of in tumors is a predictive biomarker for resistance to conventional chemotherapy in patients with OS and that palbociclib is a promising drug for this therapeutically challenging cohort.
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http://dx.doi.org/10.3892/or.2021.8086DOI Listing
July 2021

Establishment and characterization of NCC-MFS3-C1: a novel patient-derived cell line of myxofibrosarcoma.

Hum Cell 2021 Jul 15;34(4):1266-1273. Epub 2021 May 15.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Myxofibrosarcoma (MFS) is one of the most aggressive sarcomas with highly complex karyotypes and genomic profiles. Although a complete resection is required in the treatment of MFS, it is often not achieved due to its strong invasive nature. Additionally, MFS is refractory to conventional chemotherapy, leading to poor prognosis. Therefore, it is necessary to develop novel treatment modalities for MFS. Patient-derived cell lines are important tools in basic research and preclinical studies. However, only 10 MFS cell lines have been reported to date. Furthermore, among these cell lines, merely two MFS cell lines are publicly available. Hence, we established a novel MFS cell line named NCC-MFS3-C1, using a surgically resected tumor specimen from a patient with MFS. NCC-MFS3-C1 cells had copy number alterations corresponding to the original tumor. NCC-MFS3-C1 cells demonstrate constant proliferation, spheroid formation, and aggressive invasion. In drug screening tests, the proteasome inhibitor bortezomib and the histone deacetylase inhibitor romidepsin demonstrated significant antiproliferative effects on NCC-MFS3-C1 cells. Thus, the NCC-MFS3-C1 cell line is a useful tool in both basic and preclinical studies for MFS.
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http://dx.doi.org/10.1007/s13577-021-00548-6DOI Listing
July 2021

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma.

Cancers (Basel) 2021 Apr 11;13(8). Epub 2021 Apr 11.

Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1, Shikata-cho, Kita-ku, Okayama 700-8558, Japan.

The lack of noninvasive biomarkers that can be used for tumor monitoring is a major problem for soft-tissue sarcomas. Here we describe a sensitive analytical technique for tumor monitoring by detecting circulating extracellular vesicles (EVs) of patients with synovial sarcoma (SS). The proteomic analysis of purified EVs from SYO-1, HS-SY-II, and YaFuSS identified 199 common proteins. DAVID GO analysis identified monocarboxylate transporter 1 (MCT1) as a surface marker of SS-derived EVs, which was also highly expressed in SS patient-derived EVs compared with healthy individuals. MCT1CD9 EVs were also detected from SS-bearing mice and their expression levels were significantly correlated with tumor volume ( = 0.003). Furthermore, serum levels of MCT1CD9 EVs reflected tumor burden in SS patients. Immunohistochemistry revealed that MCT1 was positive in 96.7% of SS specimens and its expression on the cytoplasm/plasma membrane was significantly associated with worse overall survival ( = 0.002). Silencing of MCT1 reduced the cellular viability, and migration and invasion capability of SS cells. This work describes a new liquid biopsy technique to sensitively monitor SS using circulating MCT1CD9 EVs and indicates the therapeutic potential of MCT1 in SS.
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http://dx.doi.org/10.3390/cancers13081823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069269PMC
April 2021

Benefit of surgical resection of distant metastasis in soft tissue sarcoma: a systematic review.

Jpn J Clin Oncol 2021 Jul;51(7):1088-1093

Division of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan.

Objective: The aim of this systematic review was to evaluate the efficacy of metastasectomy for patients with advanced soft tissue sarcoma and to develop a recommendation outlining clinical guidelines for soft tissue sarcoma.

Methods: We searched the pertinent literature from January 1985 to December 2017. Two reviewers evaluated and screened the literature independently for eligibility and extracted data. We evaluated the quality of body of evidence and made a recommendation according to the Grading of Recommendations Development and Evaluation methodology.

Results: Among 244 identified studies, only 10 were finally included in this review and no randomized controlled trial reports were present. The median survival period after metastasectomy ranged from 9.6 to 39.6 months, and the 5-year survival rate ranged from 8 to 52%. The complication rate ranged from 7.3 to 25%, and the perioperative mortality rate was 0-1%. The guidelines committee proposed 'Metastasectomy can be offered for malignant soft tissue tumours with distant metastases'. This recommendation gained 100% consensus among the members of the guidelines group.

Conclusions: Although the level of evidence is very low, many retrospective studies support a clinical advantage for metastasectomy, and surgical indications should be carefully considered for patients with metastasis from soft tissue sarcoma. Metastasectomy is an option for patients with metastasis and should be done only if it can be performed safely and if potential advantages outweigh disadvantages.
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http://dx.doi.org/10.1093/jjco/hyab049DOI Listing
July 2021

Is perioperative chemotherapy recommended in childhood and adolescent patients with synovial sarcoma? A systematic review.

Jpn J Clin Oncol 2021 May;51(6):927-931

Department of Musculoskeletal Oncology, National Cancer Center Hospital Tokyo, Japan.

Objective: Synovial sarcoma is the most common soft tissue sarcomas among childhood and adolescents, accounting for 8-10% of all soft tissue sarcoma. Synovial sarcoma is considered a relatively chemosensitive tumor compared with other soft tissue sarcomas. However, the role of perioperative chemotherapy in synovial sarcoma remains controversial. The purpose of this systematic review is to evaluate the role of perioperative chemotherapy in childhood and adolescent patients with synovial sarcoma.

Methods: We evaluated studies published between 1 January 1990 and 31 December 2017. The following databases were searched: MEDLINE, Cochrane database (via PubMed) and Ichushi (in Japanese).

Results: The search yielded 216 articles in English and Japanese. After the initial screening, based on the title and abstract, 160 articles were excluded. As a second screening, we then assessed the full text of the remaining 56 articles for eligibility. Finally, 10 articles were included in the systematic review. Surgical resection with R0 margin alone was recommended because of the excellent results of two prospective studies. Meta-analysis was performed using data from two retrospective studies of 261 patients. Perioperative chemotherapy did not have a significant effect on survival and event-free survival.

Conclusions: We weakly do not recommend perioperative chemotherapy in patients with non-metastatic synovial sarcoma ≤ 5 cm when R0 resection is acquired. There was no consensus concerning the role of perioperative chemotherapy in patients with synovial sarcoma > 5 cm or those with ≤5 cm who undergo R1 or R2 resection.
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http://dx.doi.org/10.1093/jjco/hyab039DOI Listing
May 2021

[Ⅲ. Early Phase Drug Development and Precision Medicine for Osteosarcoma].

Authors:
Shintaro Iwata

Gan To Kagaku Ryoho 2021 Mar;48(3):351-355

Dept. of Musculoskeletal Oncology and Rehabilitation, National Cancer Center Hospital.

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March 2021

Prognostic factors and impact of surgery in patients with metastatic soft tissue sarcoma at diagnosis: A population-based cohort study.

Jpn J Clin Oncol 2021 May;51(6):918-926

Department of Orthopedic Surgery, The University of Tokyo, Tokyo, Japan.

Background: Approximately 10% of the patients with soft tissue sarcoma show metastasis at initial diagnosis, and hence, poorer prognosis. However, the prognostic factors and whether definitive surgery for the primary lesion improves overall survival, especially when complete resection of metastasis is difficult, remain unclear.

Methods: This retrospective analysis was based on the Bone and Soft Tissue Tumor Registry in Japan. Patients with soft tissue sarcoma having metastasis at diagnosis were enrolled, excluding those with Ewing's sarcoma, rhabdomyosarcoma and several other sarcomas with unique behavior and treatment strategies. Overall survival was estimated using the Kaplan-Meier method and compared among the common histologic subtypes. Multivariate analysis with the Cox regression model was used to identify the prognostic factors.

Results: In total, 1184 patients were included, with a median follow-up duration of 10 months (range: 1-83). The median overall survival was 21 months (95% confidence interval: 18.2-23.8). The multivariate analyses indicated that tumor size, grade and histologic subtypes significantly correlated with overall survival. Moreover, surgery for the primary lesion, in addition to surgery for metastases and chemotherapy, showed significant association with better survival.

Conclusions: The prognostic factors in patients with metastatic soft tissue sarcoma at diagnosis are generally similar to those in patients with localized disease. The overall survival in patients differed significantly according to histologic subtype. Surgical resection of primary lesions, especially those with a wide margin, may be an independent prognostic factor. Further studies are needed identify which subgroup of patients would benefit the most from primary lesion surgery.
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http://dx.doi.org/10.1093/jjco/hyab033DOI Listing
May 2021

Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature.

Cancer Med 2021 04 13;10(8):2645-2659. Epub 2021 Mar 13.

Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy.

Background: This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions.

Methods: Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method.

Results: Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported.

Conclusion: Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.
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http://dx.doi.org/10.1002/cam4.3807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026938PMC
April 2021

Establishment and characterization of NCC-SS4-C1: a novel patient-derived cell line of synovial sarcoma.

Hum Cell 2021 May 20;34(3):998-1007. Epub 2021 Feb 20.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Synovial sarcoma (SS) is defined as a monomorphic blue spindle cell sarcoma showing variable epithelial differentiation, and is characterized by a specific fusion gene, SS18-SSX. Although SS is rare, it accounts for approximately 8% of all soft tissue sarcomas, which occupies a significant proportion of soft tissue tumors. The prognosis of SS is unfavorable, with 5-year survival rate of 50-60%, and only a few anti-cancer agents are recommended for its treatment. Thus, we need to urgently establish novel treatment methods. Patient-derived cell lines are essential tools in basic research and pre-clinical studies. However, there are only 4 publicly available SS cell lines. Therefore, we established a novel SS cell line, NCC-SS4-C1, using surgically resected tumor tissues of a patient with SS. The cell line maintained the characteristic fusion gene, SS18-SSX1, and copy number alteration, in concordance with the original tumor. The cells also exhibited moderate cell proliferation, invasion ability, and spheroid formation ability. Moreover, a drug-screening test using 4 SS cell lines, including NCC-SS4-C1, demonstrated the significant anti-proliferative effects of ALK and HDAC inhibitors. Thus, we concluded that the NCC-SS4-C1 cell line is a useful tool for basic and pre-clinical studies of SS.
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http://dx.doi.org/10.1007/s13577-021-00509-zDOI Listing
May 2021

Comprehensive molecular and clinicopathological profiling of desmoid tumours.

Eur J Cancer 2021 03 11;145:109-120. Epub 2021 Jan 11.

Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. Electronic address:

Previous studies have not clearly identified a prognostic factor for desmoid tumours (DT). Whole-exome sequencing (WES) and/or RNA sequencing (RNA-seq) were performed in 64 cases of DT to investigate the molecular profiles in combination with the clinicopathological characteristics. CTNNB1 mutations with specific hotspots were identified in 56 cases (87.5%). A copy number loss in chromosome 6 (chr6) was identified in 14 cases (21.9%). Clustering based on the mRNA expression profiles was predictive of the patients' prognoses. The risk score generated by the expression of a three-gene set (IFI6, LGMN, and CKLF) was a strong prognostic marker for recurrence-free survival (RFS) in our cohort. In risk groups stratified by the expression of IFI6, the hazard ratio for recurrence-free survival in the high-risk group relative to the low-risk group was 12.12 (95% confidence interval: 1.56-94.2; p = 8.0 × 10). In conclusion, CTNNB1 mutations and a chr6 copy number loss are likely the causative mutations underlying the tumorigenesis of DT while the gene expression profiles may help to differentiate patients who would be good candidates for wait-and-see management and those who might benefit from additional systemic or radiation therapies.
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http://dx.doi.org/10.1016/j.ejca.2020.12.001DOI Listing
March 2021

Surgical resection of the primary lesion for osteosarcoma patients with metastasis at initial diagnosis.

Jpn J Clin Oncol 2021 Mar;51(3):416-423

Department of Orthopedic Surgery, The University of Tokyo, Tokyo, Japan.

Background: Approximately 10-20% of osteosarcoma patients present with metastasis on diagnosis. Completely resecting the lesion is associated with better prognosis. However, evidence regarding optimal surgical strategies for patients with unresectable metastasis is limited.

Methods: This retrospective analysis was based on the Japanese Nationwide Bone and Soft Tissue Tumor registry. In total, 335 patients diagnosed with osteosarcoma with metastasis were included. Factors affecting overall survival were identified using multivariate analysis. Kaplan-Meier method was used to compare the overall survival by the status of surgical intervention. Two hundred and four patients who did not undergo surgery for metastasis were divided into two groups, depending on whether they underwent surgery for the primary lesion. The background differences between these two groups were adjusted with propensity score matching, with 43 patients per group. The overall survival was calculated using the Kaplan-Meier method and compared with a log-rank test.

Results: Factors positively impacting overall survival were age <40, female sex, extremity origin, surgery for the primary lesions, surgery for metastasis and radiotherapy without surgery. For patients with unresectable metastasis, after propensity score matching, the survival rate was higher in the group that underwent primary lesion surgery than the group without surgery. Their median survival was 19 (95% confidence interval: 11.7-26.3) and 11 months (95% confidence interval: 4.5-17.5) (P = 0.02), respectively.

Conclusions: Surgical resection of the primary osteosarcoma lesion did not worsen prognosis, even in patients with unresectable metastasis. Further study is needed to identify which patient group will benefit from primary lesion resection.
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http://dx.doi.org/10.1093/jjco/hyaa204DOI Listing
March 2021

ASO Author Reflections: Venous Thromboembolism in a Patient with Musculoskeletal Tumor: Fact or Fiction?

Authors:
Shintaro Iwata

Ann Surg Oncol 2021 Jul 18;28(7):3928-3929. Epub 2020 Nov 18.

Department of Musculoskeletal Oncology and Rehabilitation, National Cancer Center Japan, Tokyo, Japan.

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http://dx.doi.org/10.1245/s10434-020-09359-9DOI Listing
July 2021

Symptomatic Venous Thromboembolism in Patients with Malignant Bone and Soft Tissue Tumors: A Prospective Multicenter Cohort Study.

Ann Surg Oncol 2021 Jul 9;28(7):3919-3927. Epub 2020 Nov 9.

Division of Orthopedic Surgery, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan.

Background: A prospective cohort study was conducted to determine the incidence and risk factors of symptomatic venous thromboembolism (sVTE) during the perioperative period in patients with malignant bone and soft tissue tumors.

Methods: Patients with newly diagnosed primary malignant bone and soft tissue tumors for whom definitive surgery was planned were consecutively registered among 27 tertiary hospitals specializing in musculoskeletal oncology. Clinicopathological information on each patient was collected prospectively, and careful follow-up was conducted for 6 months after surgery. The study endpoint was the occurrence of sVTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE).

Results: Eleven of 929 patients developed sVTE, including 8 patients with DVT, 2 with PE, and 1 with both, making the incidence of sVTE 1.18%. The median time until the development of sVTE after tumor resection was 11 days, ranging from - 7 to 95 days. Multiple logistic regression analyses revealed that ischemic heart disease as a comorbidity, maximum tumor diameter exceeding 8 cm, and elevated preoperative platelet count were independent risk factors for sVTE.

Conclusions: The incidence of sVTE in this series of patients with bone and soft tissue sarcomas was 1.18%, which was relatively lower than in previous retrospective studies. We identified the risk factors for sVTE specific to patients with malignant bone and soft tissue tumors, and these included ischemic heart disease, tumor size, and elevation of the preoperative platelet count.
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http://dx.doi.org/10.1245/s10434-020-09308-6DOI Listing
July 2021

Prognostic factors of metastatic myxoid liposarcoma.

BMC Cancer 2020 Sep 14;20(1):883. Epub 2020 Sep 14.

Department of Orthopaedic Surgery, Teikyo University School of Medicine, Tokyo, Japan.

Background: Myxoid liposarcoma (MLS) has the tendency to metastasize extrapulmonary. Although prognostic factors at the initial diagnosis of MLS have been reported, those at diagnosis of metastasis remain unclear. The purpose of this study was to investigate the prognostic factors for disease-specific survival at the initial diagnosis of metastasis.

Methods: This retrospective observational study was conducted at three cancer centers and two university hospitals in Japan. Of 274 MLS patients pathologically diagnosed between 2001 and 2015, 48 metastatic patients were examined.

Results: Lung metastases were detected in nine patients (18.8%) and extrapulmonary metastases in 45 (93.8%). Interval from primary diagnosis to the first metastasis was significantly shorter in patients with lung metastases than without (p = 0.007). Median disease-specific survival after diagnosis of metastases was 52.5 months in all patients. In multivariable analysis, liver metastasis (hazard ratio (HR), 2.71 [95% confidence interval (CI), 1.00-7.09]) and no evidence of disease (NED) achieved by radical treatment (resection with or without radiation therapy, or radiation therapy ≥60 Gy) or semi-radical (radiation therapy ≥40 Gy) treatment were significantly related to survival (HR, 0.36; 95%CI [0.13-0.95]). The number of metastases (odds ratio (OR), 0.44; 95%CI [0.25-0.78]) and abdominal/retroperitoneal metastases (OR, 0.09; 95%CI [0.008-0.95]) were the significant inhibitory factors of achieving NED.

Conclusions: This is the first study to statistically demonstrate the importance of achieving NED with surgical resection or radiation therapy for longer survival in metastatic MLS patients. As number of metastases was a significant factor for achieving NED, early detection of metastases might be important.
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http://dx.doi.org/10.1186/s12885-020-07384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491192PMC
September 2020

[Sarcoma].

Gan To Kagaku Ryoho 2020 Jul;47(7):1016-1019

Rare Cancer Center, National Cancer Center.

Challenges in the treatment of sarcoma as a rare cancer include(1)inexperience of sarcoma physicians due to the small number of patients,(2)insufficient information due to the lack of evidence,(3)lack of opportunities to provide information to non-specialists and to educate young physicians,(4)low adherence to standard treatments presented in clinical practice guidelines,(5)insufficient number of researchers engaged in basic research on rare cancers and their research funds, and(6) low number of clinical trials for the development of orphan drugs. This paper describes the current status and future prospects for the centralization and networking of sarcoma treatment, problems in pathological diagnosis, clinical evidence creation, information provision and human resource development, and information dissemination and consultation support to sarcoma patients.
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July 2020

Establishment and characterization of NCC-ssRMS1-C1: a novel patient-derived spindle-cell/sclerosing rhabdomyosarcoma cell line.

Hum Cell 2020 Jul 16;33(3):886-893. Epub 2020 Apr 16.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Spindle-cell/sclerosing rhabdomyosarcoma (ssRMS) is a rare subtype of rhabdomyosarcoma, characterized by unique pathological features. Although distinctive molecular backgrounds such as frequent mutations in MyoD1 have been reported, optimized therapy has not been fully developed, and further investigations are required. Patient-derived cancer models are critical tools for basic and pre-clinical studies. However, there is no model for ssRMS. Thus, this study aimed to develop a novel cell line from the tumor tissue of a patient with ssRMS. Using surgically resected tissue, we successfully established this cell line, named NCC-ssRMS1-C1. These cells exhibited spindle-shape morphology, consistent with the pathological observations of the original tumor tissue. Genetic studies demonstrated that NCC-ssRMS1-C1 cells retained original copy number alterations and the typical point mutation in MyoD1. Malignant phenotypes such as proliferation, spheroid formation, and invasion were confirmed in vitro by studying NCC-ssRMS1-C1 cells. Upon screening an anti-cancer agent library, sensitivity to conventional chemotherapeutic agents such as actinomycin D was revealed. We conclude that the NCC-ssRMS1-C1 cell line will be a useful resource for basic and pre-clinical studies.
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http://dx.doi.org/10.1007/s13577-020-00359-1DOI Listing
July 2020

Establishment and characterization of NCC-SS3-C1: a novel patient-derived cell line of synovial sarcoma.

Hum Cell 2020 Jul 9;33(3):877-885. Epub 2020 Apr 9.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

Synovial sarcoma is a rare malignancy of mesenchymal origin, characterized by a chromosomal translocation, t(X;18) (p11.2;q11.2). Wide surgical resection with radiation and cytotoxic chemotherapy is established as a standard treatment; however synovial sarcoma remains a high-grade sarcoma with poor prognosis, and novel anti-cancer agents and immunological approaches are currently being developed. The patient-derived cell line is a critical tool for basic and pre-clinical research. However, only a few patient-derived synovial sarcoma cell lines are publicly available from cell banks. Thus, the aim of this study was to establish and characterize a novel cell line for synovial sarcoma. Using a surgically resected tumor tissue from a 48-year-old female patient, we successfully established a cell line, named NCC-SS3-C1. NCC-SS3-C1 cells harbor an SS18-SSX1 fusion gene and exhibit moderate growth, spheroid formation, and invasion. We examined a range of proliferation-inhibiting effects of small molecule anti-cancer compounds, including FDA-approved anti-cancer drugs, using NCC-SS3-C1 cells, and identified anti-cancer drugs which inhibited the proliferation of NCC-SS3-C1 cells at the low concentration. We concluded that NCC-SS3-C1 would be a useful tool for basic and pre-clinical synovial sarcoma research.
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http://dx.doi.org/10.1007/s13577-020-00354-6DOI Listing
July 2020

Establishment and characterization of patient-derived cancer models of malignant peripheral nerve sheath tumors.

Cancer Cell Int 2020 19;20:58. Epub 2020 Feb 19.

1Department of Innovative Seeds Evaluation, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan.

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are a rare subtype of soft-tissue sarcoma, derived from a peripheral branch or the sheath of the sciatic nerve, brachial plexus, or sacral plexus. The clinical outcomes for MPNST patients with unresectable or metastatic tumors are dismal, and novel therapeutic strategies are required. Although patient-derived cancer cell lines are vital for basic research and preclinical studies, few MPNST cell lines are available from public cell banks. Therefore, the aim of this study was to establish cancer cell lines derived from MPNST patients.

Methods: We used tumor tissues from five patients with MPNSTs, including one derived from a rare bone tissue MPNST. The tumor tissues were obtained at the time of surgery and were immediately processed to establish cell lines. A patient-derived xenograft was also established when a sufficient amount of tumor tissue was available. The characterization of established cells was performed with respect to cell proliferation, spheroid formation, and invasion. The mutation status of actionable genes was monitored by NCC Oncopanel, by which the mutation of 114 genes was assessed by next-generation sequencing. The response to anti-cancer agents, including anti-cancer drugs approved for the treatment of other malignancies was investigated in the established cell lines.

Results: We established five cell lines (NCC-MPNST1-C1, NCC-MPNST2-C1, NCC-MPNST3-C1, NCC-MPNST4-C1, and NCC-MPNST5-C1) from the original tumors, and also established patient-derived xenografts (PDXs) from which one cell line (NCC-MPNST3-X2-C1) was produced. The established MPNST cell lines proliferated continuously and formed spheroids while exhibiting distinct invasion abilities. The cell lines had typical mutations in the actionable genes, and the mutation profiles differed among the cell lines. The responsiveness to examined anti-cancer agents differed among cell lines; while the presence of an actionable gene mutation did not correspond with the response to the anticipated anti-cancer agents.

Conclusion: The established cell lines exhibit various characteristics, including proliferation and invasion potential. In addition, they had different mutation profiles and response to the anti-cancer agents. These observations suggest that the established cell lines will be useful for future research on MPNSTs.
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http://dx.doi.org/10.1186/s12935-020-1128-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031935PMC
February 2020

Establishment and characterization of NCC-CDS2-C1: a novel patient-derived cell line of CIC-DUX4 sarcoma.

Hum Cell 2020 Apr 2;33(2):427-436. Epub 2020 Jan 2.

Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.

CIC-DUX4 sarcoma (CDS), an aggressive soft tissue sarcoma, is characterized by a CIC and DUX4 rearrangement. It has a dismal clinical course and high metastatic rate and shows chemotherapy resistance; therefore, a novel therapeutic strategy is required. Patient-derived cell lines are indispensable tools for basic and preclinical research. However, only a few patient-derived CDS cell lines have been currently reported. Therefore, in this study, we aimed to establish and characterize a novel cell line of CDS. We successfully established the NCC-CDS2-C1 cell line by using surgically resected tumor tissue from a patient with CDS. The NCC-CDS2-C1 cells harbored a CIC-DUX4 fusion gene without insertion and exhibited rapid growth, spheroid formation, and invasion. We screened the antiproliferative effects of small anticancer agent compounds, which included FDA-approved anticancer drugs, on NCC-CDS2-C1 cells in comparison with those on the two previously reported patient-derived CDS cell lines, NCC-CDS1-X1-C1 and NCC-CDS1-X3-C1. The response profile of NCC-CDS2-C1 was similar to but distinct from those of the other cell lines for the small anticancer agent compounds. Therefore, we conclude that the NCC-CDS2-C1 cell line will be a useful tool for basic and preclinical studies of CDS.
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http://dx.doi.org/10.1007/s13577-019-00312-xDOI Listing
April 2020

Integrated exome and RNA sequencing of dedifferentiated liposarcoma.

Nat Commun 2019 12 12;10(1):5683. Epub 2019 Dec 12.

Laboratory of DNA Information Analysis, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.

The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management.
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http://dx.doi.org/10.1038/s41467-019-13286-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908635PMC
December 2019

Efficacy and safety of trabectedin for patients with unresectable and relapsed soft-tissue sarcoma in Japan: A Japanese Musculoskeletal Oncology Group study.

Cancer 2020 03 11;126(6):1253-1263. Epub 2019 Dec 11.

Department of Orthopaedic Surgery, The University of Tokyo Hospital, Tokyo, Japan.

Background: Although initial trabectedin (1.2 mg/m ) is safe and effective for patients with translocation-related sarcoma (TRS) in Japan, its efficacy in other types of soft-tissue sarcomas (STSs) remains unknown. This study retrospectively investigated its efficacy and safety through postmarketing surveillance of trabectedin in patients with unresectable and relapsed STS.

Methods: One hundred forty patients received intravenous trabectedin (1.2 mg/m on day 1 every 21 days) over the course of 24 hours. The primary endpoint was the efficacy and safety of trabectedin.

Results: Grade 3 or higher adverse events occurred in 100 patients (71%) and included hepatotoxicity (37.8%), neutropenia (32.8%), and rhabdomyolysis (3.6%). Patients at high risk for grade 3 or higher rhabdomyolysis (36%) were classified by height (≥170.3 cm) and age (≤32 years) through a classification and regression tree model (area under the curve, 0.9). The overall median progression-free survival (PFS) was 3.7 months; with respect to the histological type, the median PFS was 17.4 months for myxoid liposarcoma, 4.9 months for leiomyosarcoma, 5.6 months for synovial sarcoma, and 3.7 months for dedifferentiated liposarcoma. Histological type (liposarcoma/leiomyosarcoma [L-sarcoma] and TRS) and grade 3 neutropenia (but not grade 4) were associated with significantly improved PFS after trabectedin treatment (P = .003, P = .04, and P = .001). The median growth modulation index (GMI) was 0.91; 37 patients (36.7%) experienced a GMI > 1.33, and among patients with solitary fibrous tumors and undifferentiated pleomorphic sarcoma, 60% and 42.9%, respectively, had a GMI > 1.33. The median overall survival (OS) was 16.4 months. A GMI > 1.33 was associated with significantly improved OS (P = .0006).

Conclusions: Initial trabectedin at 1.2 mg/m has clinically meaningful benefits for patients with L-sarcoma and certain histological subtypes of TRS.
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http://dx.doi.org/10.1002/cncr.32661DOI Listing
March 2020

Expanding the Phenotypic Spectrum of Mesenchymal Tumors Harboring the EWSR1-CREM Fusion.

Am J Surg Pathol 2019 12;43(12):1622-1630

Departments of Diagnostic Pathology.

ATF1, CREB1, and CREM constitute the CREB family of transcription factors. The genes encoding these factors are involved in gene fusion events in human tumors. EWSR1-ATF1 and EWSR1-CREB1 are the 2 most characterized fusions, whereas EWSR1-CREM has been less studied. To better understand the phenotypic spectrum of mesenchymal tumors associated with the EWSR1-CREM fusion, we investigated archival cases using fluorescence in situ hybridization and/or RNA sequencing. Among 33 clear cell sarcomas of soft tissue tested, we found 1 specimen, a hand tumor bearing the rearrangements of EWSR1 and CREM, with classic histology and immunophenotype. None of 6 clear cell sarcoma-like tumors of the gastrointestinal tract tested harbored the EWSR1-CREM fusion. Among 11 angiomatoid fibrous histiocytomas, we found that 3 tumors of myxoid variant harbored the rearrangements of EWSR1 and CREM. All 3 tumors occurred in middle-aged men and involved the distal extremities (N=2) and the lung (N=1). Prominent lymphoid cuff, fibrous pseudocapsule, and amianthoid fiber were present in 3, 2, and 2 tumors, respectively, whereas none showed pseudoangiomatoid spaces. All 3 tumors were immunohistochemically positive for epithelial membrane antigen and desmin. These cases suggested a closer relationship between angiomatoid fibrous histiocytoma and a recently proposed novel group of myxoid tumors with CREB family fusions. Our cohort also included 2 unclassifiable sarcomas positive for EWSR1-CREM. One of these was an aggressive pediatric tumor of the abdominal cavity characterized by proliferation of swirling spindle cells immunopositive for cytokeratin and CD34. The other tumor derived from the chest wall of an adult and exhibited a MUC4-positive sclerosing epithelioid fibrosarcoma-like histology. Our study demonstrates that a wider phenotypic spectrum is associated with the EWSR1-CREM fusion than previously reported.
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http://dx.doi.org/10.1097/PAS.0000000000001331DOI Listing
December 2019
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