Clear Cell Sarcoma Research Articles

Tolerability of ifosfamide-containing regimen in patients with high-risk renal and INI-1-deficient tumors.

Outcomes for children with high-risk renal (HRR) and INI-1-deficient (INI-) tumors are unacceptably poor. Concerns about excessive toxicity-as many are infants and/or undergo nephrectomy-have resulted in decreased chemotherapy dosing and omission of the nephrotoxic drug ifosfamide in collaborative group studies. As cause of death for children with these cancers remains overwhelmingly more from progressive disease rather than treatment toxicity, we examined the tolerability of an intensive ifosfamide-containing regimen. Retrospective review of children with HRR/INI- tumors treated at a single institution with vincristine, doxorubicin, cyclophosphamide alternating with ifosfamide, carboplatin, etoposide (VDC-ICE) from 2006-2016. The primary outcome was regimen tolerability, including kidney injury and grade 3-5 nonhematologic toxicities. Fourteen patients with a median age of 1.7years (range: 0.1-10.5) treated with VDC-ICE were identified. Diagnosis included malignant rhabdoid tumor (n=9) (primary renal [n=2]); diffuse anaplastic Wilms tumor (n=3); clear cell sarcoma of the kidney (n=1); and anaplastic chordoma (n=1). All children with primary renal tumors (43%) underwent complete (n=5) or partial nephrectomy (n=1) before chemotherapy. Nine (64%) completed all intended cycles of chemotherapy; n=5 (36%) did not due to disease progression. Unplanned hospitalizations occurred in 13 (93%) patients, most commonly for febrile neutropenia. No patient experienced severe organ toxicity, diminished renal function, treatment discontinuation due to toxicities, or treatment-related death. In children with HRR/INI- tumors, VDC-ICE chemotherapy was well-tolerated without excessive toxicities, even amongst young patients with solitary kidneys. Concerns about toxicity should not preclude an intensive ifosfamide-containing regimen from use in future trials in this population.

Malignant Gastrointestinal Neuroectodermal Tumor: A Case Report and Literary Review for a Rare Differential Diagnosis

Malignant gastrointestinal neuroectodermal tumor (GNET) is an infrequent soft-tissue sarcoma, formerly referred to as clear-cell sarcoma-like gastrointestinal tumor (CCSLGT) and frequently reported in the literature as clear-cell sarcoma of the gastrointestinal tract (CCS-GI); it is characterized by an absence of melanocytic differentiation and the presence of nontumoral osteoclast-like giant cells (OLGCs). The current study reports a case of a 79 year old woman admitted to the emergency department (ED) with symptoms of constipation and intestinal obstruction; a mass was found within the ileal wall necessitating of surgical approach. Immunohistochemically, tumor cells surprisingly had the hallmark of GNETs. Unfamiliarity with tumors with the features of GNETs can easily lead to a misdiagnosis by surgical pathologist. Therefore, comprehensive evaluation, including morphology and additional studies, is required for an appropriated diagnosis. Furthermore, without a high index of suspicion, there is actually no consensus on staging or treatment.

Metastatic sarcomas to pleural effusion: a 10-year large tertiary care center experience with emphasis on clinical features and cytomorphologic characteristics.

Metastatic sarcomas to pleural effusion are extremely rare, accounting for <1% of all malignant pleural effusions. We aim to present our experience with pleural effusion specimens containing metastatic sarcomas over a 10-year period. We performed a 10-year retrospective search of cytopathology archives to identify all pleural effusions that were involved by metastatic sarcoma. All available cytopathology and surgical pathology specimens were retrieved and reviewed. Twenty-eight pleural fluids from 22 patients with metastatic sarcoma were identified in our search. The patients' ages ranged from 12 to 73 years. The pleural fluid volumes ranged from 10 to 1500 ml. Rhabdomyosarcoma was the most commonly encountered metastatic sarcoma to pleural effusion (n = 7). Other metastatic sarcomas were as follows: epithelioid angiosarcoma (n = 4), Ewing sarcoma (n = 3), clear cell sarcoma (n = 2), high grade conventional osteosarcoma (n = 2), undifferentiated pleomorphic sarcoma (n = 1), epithelioid sarcoma, proximal type (n = 1), dedifferentiated liposarcoma (n = 1), and conventional chondrosarcoma (n = 1). The time between initial diagnosis and effusion varied from 3 months to 25 years. Two patients are alive with disease at 6 and 21 months of follow-up. All other patients were dead of disease and the survival after a malignant pleural effusion ranged from <1 month to 18 months. Metastatic bone and soft tissue sarcomas to pleural effusions are rare and their cytologic features can be mistaken for carcinoma, melanoma, or mesothelioma. Careful review of the patient's medical history, comparison of the previous pathology and the use of ancillary studies are crucial for the evaluation of pleural effusions involved by metastatic sarcomas.

Circulating tumor cells in clear cell sarcoma.

British Journal of HaematologyEarly View IMAGES IN HAEMATOLOGY Circulating tumor cells in clear cell sarcoma Yun Zhang, Yun Zhang orcid.org/0000-0001-5958-5494 Department of Clinical Laboratory, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorNa Guo, Na Guo Department of Blood Transfusion, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorNing Shen, Ning Shen Department of Medical Oncology, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorKechao Li, Kechao Li Department of Clinical Laboratory, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorJie Zheng, Jie Zheng orcid.org/0000-0001-9638-0199 Department of Hematology, The District People's Hospital of Zhangqiu, Jinan, Shandong Province, ChinaSearch for more papers by this authorTing Li, Ting Li orcid.org/0000-0002-2027-9462 Department of Flow Cytometry, Beijing Ludaopei Hospital, Beijing, ChinaSearch for more papers by this authorFang Long, Corresponding Author Fang Long [email protected] orcid.org/0000-0001-7429-1996 Department of Clinical Laboratory, Sichuan Provincial Maternity and Child Health Care Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan Province, ChinaSearch for more papers by this author Yun Zhang, Yun Zhang orcid.org/0000-0001-5958-5494 Department of Clinical Laboratory, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorNa Guo, Na Guo Department of Blood Transfusion, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorNing Shen, Ning Shen Department of Medical Oncology, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorKechao Li, Kechao Li Department of Clinical Laboratory, The District People’s Hospital of Zhangqiu, Jinan, ChinaSearch for more papers by this authorJie Zheng, Jie Zheng orcid.org/0000-0001-9638-0199 Department of Hematology, The District People's Hospital of Zhangqiu, Jinan, Shandong Province, ChinaSearch for more papers by this authorTing Li, Ting Li orcid.org/0000-0002-2027-9462 Department of Flow Cytometry, Beijing Ludaopei Hospital, Beijing, ChinaSearch for more papers by this authorFang Long, Corresponding Author Fang Long [email protected] orcid.org/0000-0001-7429-1996 Department of Clinical Laboratory, Sichuan Provincial Maternity and Child Health Care Hospital, The Affiliated Women's and Children's Hospital of Chengdu Medical College, Chengdu, Sichuan Province, ChinaSearch for more papers by this author First published: 25 April 2023 https://doi.org/10.1111/bjh.18803Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. Early ViewOnline Version of Record before inclusion in an issue RelatedInformation

Abstract 154: Establishment and characterization of a novel clear cell sarcoma organoid model derived from a human biopsy

Abstract Clear Cell Sarcoma (CCS) is an extremely aggressive, rare soft tissue cancer accounting for approximately 1% of all sarcomas. Often diagnosed in young adults with a median age of 25 years, CCS has a strong propensity for local recurrence and metastasis with an overall high mortality rate. Current treatment recommendations include radical surgical extirpation, followed by radiation or chemotherapy. Nonetheless, there is a need for extensive postoperative follow-up as the efficiency of adjuvant therapy in managing this disease remains poor. Consequently, it is imperative to identify clinically relevant models to advance our understanding of CCS tumor biology and facilitate the development of novel therapies. Compared to conventional preclinical tumor models, patient-derived organoids (PDOrgs) better recapitulate the patient tumor biology, genetic heterogeneity, and therapeutic responses. Here, we describe the development and validation of a human biopsy-derived CCS organoid model 1010561-T. 1010561-T was established from a male patient's metastatic paraspinal mass. This PDOrg demonstrates a moderate growth rate (doubling time of ~20 days) and pleomorphic traits, consisting mainly of solid, grape-like clusters, as well as elongated cells of mixed morphology. Furthermore, this model was successfully maintained over 7 months in culture and remained stable more than one year after cryopreservation. 1010561-T exhibits the cytogenetic hallmark of CCS which is the presence of a recurrent t(12;22)(q13;q12) chromosomal translocation, resulting in a fusion between the Ewing sarcoma gene and activating transcription factor 1 (EWS/ATF1 fusion). Reverse-transcription polymerase chain reaction (RT-PCR) confirmed that 1010561-T harbors a dual EWS/ATF1 fusion, namely EWS exon 8 to ATF1 codon 65 fusion (type 1) and EWS exon 7 to ATF1 codon 110 fusion (type 3). Quantitative RT-PCR and immunocytochemistry revealed strong expression of melanocytic differentiation markers typical of CCS including melanocyte inducing transcription factor (MITF), melan-A (MLANA), premelanosome protein (PMEL), and S100 calcium binding protein A11 (S100A11). Additionally, the gene expression profile of 1010561-T is in concordance with a well-established CCS cell line, SU-CCS-1. To our knowledge, 1010561-T is the first human CCS organoid model. It is, therefore, a valuable resource for advancing our understanding of the biology of this very rare disease, in addition to being a useful tool for validating new preclinical therapies that are undoubtedly needed to achieve better clinical outcomes for patients. To this end, 1010561-T will be transferred to the National Cancer Institute’s Patient-Derived Models Repository (https://pdmr.cancer.gov) where it will be made available to the scientific community. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201800001I. Citation Format: Petreena S. Campbell, Erik D. Harris, Nancy Moore, Ralph E. Parchment, Nathan P. Coussens, Beverly A. Teicher, Alice Chen, James H. Doroshow, Annamaria Rapisarda. Establishment and characterization of a novel clear cell sarcoma organoid model derived from a human biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 154.

Clinical relevance of BCOR internal tandem duplication and TP53 aberration in clear cell sarcoma of the kidney.

Clear cell sarcoma of the kidney (CCSK) is the second most common pediatric renal malignancy, characterized by BCOR internal tandem duplication (ITD), YWHAE rearrangement, BCOR-CCNB3 fusion, and lack of other consistent structural alteration. We accidentally identified TP53 deletion in CCSK, which was often associated with adverse clinical outcomes. In this study, we assessed the incidence as well as the clinical relevance of these molecules in CCSK patients. BCOR ITD, YWHAE rearrangement, BCOR-CCNB3 fusion and TP53 status were examined by polymerase chain reaction, fluorescence in situ hybridization, or Sanger sequencing in a cohort of 39 patients with CCSK. Among them, 34 cases (87.18%) had BCOR ITD, 1 (2.56%) had YWHAE rearrangement, and 1 (2.56%) had BCOR-CCNB3 gene fusion. The remaining 3 (7.69%) harbored none of these aberrations. BCOR ITD, YWHAE rearrangement and BCOR-CCNB3 were mutually exclusive. Furthermore, 25.64% of the cohort acquired TP53 aberration (10/39, 3 with both copy number deletion and point mutation, 6 with deletion only, and 1 with mutation only), all of which were associated with BCOR ITD. Patients with or without BCOR ITD or TP53 aberration did not differ in demographic characteristics such as sex, onset age, or tumor stage at diagnosis. However, the overall survival rates and progression-free survival rates of BCOR ITD or TP53 deletion groups showed obvious downward trends, albeit not all reaching statistical significance. Patients with both BCOR ITD and TP53 deletion had the poorest prognosis.

Functional genomics of human clear cell sarcoma: genomic, transcriptomic and chemical biology landscape for clear cell sarcoma.

Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults. To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines. Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability. These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCSis found.

Extraenteric Malignant Gastrointestinal Neuroectodermal Tumor—A Clinicopathologic and Molecular Genetic Study of 11 Cases

Malignant gastrointestinal neuroectodermal tumors (MGNETs), also known as “gastrointestinal clear cell sarcoma–like tumors”, are very rare, aggressive sarcomas characterized by enteric location, distinctive pathologic features, and EWSR1/FUS::ATF1/CREB1 fusions. Despite identical genetics, the clinicopathologic features of MGNET are otherwise quite different from those of clear cell sarcoma of soft parts. Only exceptional extraenteric MGNET (E-MGNET) has been reported. We report a series of 11 E-MGNETs, the largest to date. Cases diagnosed with MGNET and occurring in nonintestinal locations were retrieved. A clinical follow-up was obtained. The tumors occurred in 3 men and 8 women (range, 14-70 years of age; median, 33 years) and involved the soft tissues of the neck (3), shoulder (1), buttock (2), orbit (1), tongue/parapharyngeal space (1), urinary bladder (1), and falciform ligament/liver (1). Tumors showed morphologic features of enteric MGNET (small, relatively uniform, round to ovoid cells with round, regular nuclei containing small nucleoli growing in multinodular and vaguely lobular patterns, with solid, pseudoalveolar, and pseudopapillary architecture). Immunohistochemical results were S100 protein (11/11), SOX10 (11/11), synaptophysin (3/10), CD56 (7/9), CD117 (3/9), DOG1 (0/4), ALK (4/8), chromogranin A (0/10), HMB-45 (0/11), Melan-A (0/11), tyrosinase (0/4), and MiTF (0/11). Next-generation sequencing results were EWSR1::ATF1 (7 cases), EWSR1::CREB1 (3 cases), and EWSR1::PBX1 (1 case). The EWSR1::PBX1-positive tumor was similar to other cases, including osteoclast-like giant cells, and negative for myoepithelial markers. A clinical follow-up (range, 10-70 months; median, 34 months) showed 4 patients dead of disease (10.5, 12, 25, and 64 months after diagnosis), 1 patient alive with extensive metastases (43 months after diagnosis), 1 patient alive with persistent local disease (11 months after diagnosis), and 4 alive without disease (10, 47, 53, and 70 months after diagnosis). One case is too recent for the follow-up. The clinicopathologic and molecular genetic features of rare E-MGNET are essentially identical to those occurring in intestinal locations. Otherwise, typical E-MGNET may harbor EWSR1::PBX1, a finding previously unreported in this tumor type. As in enteric locations, the behavior of E-MGNET is aggressive, with metastases and/or death from disease in at least 50% of patients. E-MGNET should be distinguished from clear cell sarcoma of soft parts and other tumors with similar fusions. ALK expression appears to be a common feature of tumors harboring EWSR1/FUS::ATF1/CREB1 fusion but is unlikely to predict the therapeutic response to ALK inhibition. Future advances in our understanding of these unusual tumors will hopefully lead to improved nomenclature.

Clear cell sarcoma of soft tissue arising in the supraclavicular region: A cytological diagnosis

Clear cell sarcoma of soft tissue is a rare malignant neoplasm which constitutes about 1% of soft tissue tumors. It most commonly arises in the distal extremities of young adults. Peak incidence is in the third decade. More commonly seen in women than men. A 30 year old female presented with swelling in right supraclavicular region associated with pain since 3 months. CT scan findings revealed irregular and non-enhancing, hypodense lesion measuring 2.5x2x1cm in right supraclavicular region. Cytological features revealed abundant cellularity comprising of atypical cells mainly dispersed singly and arranged in loose cohesive groups. The cytoplasm was abundant, vacuolated at places, pleomorphic round to oval nucleus, placed centrally to eccentrically with prominent nucleoli. Diagnosis of malignant mesenchymal neoplasm was made on the basis of the cytomorphological details. Clear cell sarcoma was included in the differential diagnosis. Cytomorphological diagnosis was confirmed by histological and immunohistochemical diagnosis. When cytology of a soft tissue tumor shows high cellularity alongwith dispersion and loosely cohesiveness of cells, nuclear pleomorphism and conspicuous nucleoli, diagnosis of clear cell sarcoma may be considered.

Subtype-selective induction of apoptosis in translocation-related sarcoma cells induced by PUMA and BIM upon treatment with pan-PI3K inhibitors

Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have yet to be established. We previously reported that a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, ZSTK474, was effective for the treatment of sarcomas in a phase I clinical trial. We also demonstrated the efficacy of ZSTK474 in a preclinical model, particularly in cell lines from synovial sarcoma (SS), Ewing’s sarcoma (ES) and alveolar rhabdomyosarcoma (ARMS), all of which harbor chromosomal translocations. ZSTK474 selectively induced apoptosis in all these sarcoma cell lines, although the precise mechanism underlying the induction of apoptosis remained unclear. In the present study, we aimed to determine the antitumor effect of PI3K inhibitors, particularly with regards to the induction of apoptosis, against various TRS subtypes using cell lines and patient-derived cells (PDCs). All of the cell lines derived from SS (six), ES (two) and ARMS (one) underwent apoptosis accompanied by the cleavage of poly-(ADP-ribose) polymerase (PARP) and the loss of mitochondrial membrane potential. We also observed apoptotic progression in PDCs from SS, ES and clear cell sarcoma (CCS). Transcriptional analyses revealed that PI3K inhibitors triggered the induction of PUMA and BIM and the knockdown of these genes by RNA interference efficiently suppressed apoptosis, suggesting their functional involvement in the progression of apoptosis. In contrast, TRS-derived cell lines/PDCs from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. Thus, we conclude that PI3K inhibitors induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and the subsequent loss of mitochondrial membrane potential. This represents proof of concept for PI3K-targeted therapy, particularly such TRS patients.

Clear Cell Sarcoma of Soft Tissue: A Case Report

Introduction: Clear cell sarcoma (CCS), is an extremely rare type of sarcoma, frequently diagnosed in young adults, typically arises in the extremities of the limbs and has a predilection for occurring in the tendons and aponeuroses. In the past CCS was called malignant melanoma of the soft parts because the tumor shares clinical, histological and immunohistochemical similarities with amelanotic melanoma, but it is a unique lesion, distinct from melanoma. Case Report: A 33-year old woman with no significant history was referred with an unpainful bulky ulcerated tumor of the right ankle, appeared 05 years prior to presentation following a minimal trauma. The CT of the ankle revealed a bulky mass of the medial surface locally infiltrative associated to nodules of the surrounding adipose tissues and a unilamellar periosteal reaction without bone lysis or osteocondensation. MRI of the ankle showing a lobulated mass arising in the deep structures in iso-intense signal relative to adjacent muscle on T1 and heterogeneous high-signal intensity on T2 infiltrating surrounding adipose tissues without infiltration of muscles. Histological examination showed dermo-hypodermic malignant tumor proliferation. Round cells were arranged in nests separated by dense collagenous septa, with an abundant eosinophilic to clear cytoplasm. The immunohistochemical supplement were positive for Melan-A and HMB-45. Cytokeratin, Vimentin, Desmin and CD99 were negative. The extension assessment made of a head-chest-abdominal-pelvic CT scan showed multiple homolateral inguinal lymphadenopathies necrotic. No other metastasis was detected. The anatomo-clinical confrontation allowed to retain the diagnosis of CCS. Discussion: The tumor occurs most often in adolescents and young adults and was slightly more common in female than in male patients, CCS typically arises in the extremities of the limbs, its occurrence in the upper limbs is less common, described as a slowly growing mass painless. ..........

Molecular Signature of Biological Aggressiveness in Clear Cell Sarcoma of the Kidney (CCSK)

Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms' tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases.

Practice Pattern Variability in the Management of Regional Lymph Node Metastasis in Extremity and Trunk Soft Tissue Sarcoma: A Survey of the Society of Surgical Oncology and Musculoskeletal Tumor Society Membership.

Regional lymph node metastasis in extremity and trunk soft tissue sarcoma (ETSTS) is rare with no standardized management. We sought to determine management patterns for regional lymph node metastasis in ETSTS. A survey regarding the management of ETSTS lymph node metastasis was distributed to the membership of the Musculoskeletal Tumor Society (MSTS) and the Society of Surgical Oncology (SSO) in January 2022. The survey queried the type of training (surgical oncology, orthopedic oncology), details of their practice setting, and management decisions of hypothetical ETSTS scenarios that involved potential or confirmed lymph node metastasis. The survey was distributed to 349 MSTS members (open rate of 63%, completion rate 21%) and 3026 SSO members (open rate of 55%, completion rate 4.7%) and was completed by 214 respondents, of whom 73 (34.1%) and 141 (65.9%) were orthopedic oncology and surgical oncology fellowship-trained, respectively. The majority of respondents practiced in an academic setting (n=171, 79.9%) and treat >10 extremity sarcoma cases annually (n=138, 62.2%). In scenarios with confirmed nodal disease for clear cell and epithelioid sarcoma, surgical oncologists were inclined to perform lymphadenectomy, while orthopedic oncologists were inclined to offer targeted lymph node excision with adjuvant radiation (p<0.001). There was heterogeneity of responses regarding the management of nodal disease regardless of training background. Self-reported management of nodal disease in ETSTS was variable among respondent groups with differences and similarities based on training background. These data highlight the variability of practice for nodal disease management and the need for consensus-based guidelines.

Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma.

Chromothripsis is a catastrophic event of chromosomal instability that involves intensive fragmentation and rearrangements within localized chromosomal regions. However, its cause remains unclear. Here, we show that reduction and inactivation of Ran GTPase-activating protein 1 (RanGAP1) commonly occur in human osteosarcoma, which is associated with a high rate of chromothripsis. In rapidly expanding mouse osteoprogenitors, RanGAP1 deficiency causes chromothripsis in chr1q, instant inactivation of Rb1 and degradation of p53, consequent failure in DNA damage repair, and ultrafast osteosarcoma tumorigenesis. During mitosis, RanGAP1 anchors to the kinetochore, where it recruits PP1-γ to counteract the activity of the spindle-assembly checkpoint (SAC) and prevents TOP2A degradation, thus safeguarding chromatid decatenation. Loss of RanGAP1 causes SAC hyperactivation and chromatid decatenation failure. These findings demonstrate that RanGAP1 maintains mitotic chromosome integrity and that RanGAP1 loss drives tumorigenesis through its direct effects on SAC and decatenation and secondary effects on DNA damage surveillance.

Targeting epigenetic features in clear cell sarcomas based on patient-derived cell lines

BackgroundClear cell sarcomas (CCSs) are translocated aggressive malignancies, most commonly affecting young adults with a high incidence of metastases and a poor prognosis. Research into the disease is more feasible when adequate models are available. By establishing CCS cell lines from a primary and metastatic lesion and isolating healthy fibroblasts from the same patient, the in vivo process is accurately reflected and aspects of clinical multistep carcinogenesis recapitulated.MethodsIsolated tumor cells and normal healthy skin fibroblasts from the same patient were compared in terms of growth behavior and morphological characteristics using light and electron microscopy. Tumorigenicity potential was determined by soft agar colony formation assay and in vivo xenograft applications. While genetic differences between the two lineages were examined by copy number alternation profiles, nuclear magnetic resonance spectroscopy determined arginine methylation as epigenetic features. Potential anti-tumor effects of a protein arginine n-methyltransferase type I (PRMT1) inhibitor were elicited in 2D and 3D cell culture experiments using cell viability and apoptosis assays. Statistical significance was calculated by one-way ANOVA and unpaired t-test.ResultsThe two established CCS cell lines named MUG Lucifer prim and MUG Lucifer met showed differences in morphology, genetic and epigenetic data, reflecting the respective original tissue. The detailed cell line characterization especially in regards to the epigenetic domain allows investigation of new innovative therapies. Based on the epigenetic data, a PRMT1 inhibitor was used to demonstrate the targeted antitumor effect; normal tissue cells isolated and immortalized from the same patient were not affected with the IC50 used.ConclusionsMUG Lucifer prim, MUG Lucifer met and isolated and immortalized fibroblasts from the same patient represent an ideal in vitro model to explore the biology of CCS. Based on this cell culture model, novel therapies could be tested in the form of PRMT1 inhibitors, which drive tumor cells into apoptosis, but show no effect on fibroblasts, further supporting their potential as promising treatment options in the combat against CCS. The data substantiate the importance of tailored therapies in the advanced metastatic stage of CCS.

Evidence Based on an Integrative Analysis of Multi-Omics Data on METTL7A as a Molecular Marker in Pan-Cancer.

Methyltransferase-like protein 7A (METTL7A), an RNA N6-methyladenosine (m6A) methyltransferase, has attracted much attention as it has been found to be closely associated with various types of tumorigenesis and progression. This study provides a comprehensive assessment of METTL7A from a pan-cancer perspective using multi-omics data. The gene ontology enrichment analysis of METTL7A-binding proteins revealed a close association with methylation and lipid metabolism. We then explored the expression of METTL7A in normal tissues, cell lines, different subtypes and cancers, and found that METTL7A was differentially expressed in various cancer species, tumor molecular subtypes and immune subtypes. Evaluation of the diagnostic and prognostic value of METTL7A in pan-cancer revealed that METTL7A had high accuracy in tumor prediction. Moreover, the low expression of METTL7A significantly correlated with the poor prognosis, including kidney renal clear cell carcinoma (KIRC), mesothelioma and sarcoma, indicating that METTL7A could be a potential biomarker for tumor diagnosis and prognosis. We focused on KIRC after pre-screening and analyzed its expression and prognostic value in various clinical subgroups. We found that METTL7A was significantly related to tumor stage, metastasis stage, pathologic stage, primary therapy outcome, histologic grade and gender, and that low METTL7A expression was associated with poorer outcomes. Finally, we analyzed the immune infiltration and co-expressed genes of METTL7A as well as the differentially expressed genes in the high and low expression groups. In conclusion, METTL7A is a better molecular marker for pan-cancer diagnosis and prognosis and has high potential as a diagnostic and prognostic biomarker for KIRC.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignant tumors in children: Initial experience in a single institution.

Peritoneal malignant tumors in children are rare but commonly associated with disease progression and poor outcome. The successful treatment experience of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in adult peritoneal carcinoma has been applied to pediatric peritoneal malignancy in recent years. However, patients with desmoplastic small round cell tumor (DSRCT) accounted for the majority of patients treated with CRS and HIPEC in previous studies. The role of CRS and HIPEC remains controversial due to the rarity of the disease and the limited sample size of studies. Additionally, the cases using CRS and HIPEC except DSRCT were mainly small case reports with unclear outcomes. We present our experience in the treatment of pediatric peritoneal malignancies using CRS and HIPEC, with more emphasis on the safety, feasibility, and short-term outcome. A retrospective query from December 2019 to February 2022 identified 19 children with peritoneal malignancies who underwent CRS and HIPEC in our institution. Clinical characteristics, therapies, and outcomes were summarized and analyzed. The median age of the patients was 6.4 years (range, 0.7-13.9 years). The histologic types included rhabdomyosarcoma (7), Wilms tumor (2), clear cell sarcoma of the kidney (2), undifferentiated sarcoma (2), immature teratoma (1), peritoneal serous carcinoma (1), malignant rhabdoid of the kidney (1), malignant germ cell tumor (1), neuroblastoma (1), and epithelioid inflammatory myofibroblast sarcoma (1). Seven patients underwent initial operation, and 12 patients received reoperation for tumor recurrence. The median peritoneal carcinomatosis index was 5 (range, 2-21). There were no perioperative deaths or life-threatening complications of CRS and HIPEC. Two patients had grade 3 complications of wound infection and wound dehiscence. With a median follow-up time of 14 months (range, 1.5-31 months), 14 patients were alive, and 5 died of tumor recurrence. Of the 14 patients who were alive, 2 relapsed after CRS and HIPEC and then received radiotherapy and molecular-targeted therapy or chemotherapy. CRS and HIPEC are safe and feasible in children, without increasing serious complications in the peri- and postoperative periods. The complication is acceptable. The short-term outcome shows possible effectiveness in pediatric peritoneal malignant tumors. The long-term effectiveness needs to be verified by additional cases and long-term follow-ups.

Pediatric BCOR-Altered Tumors From Soft Tissue/Kidney Display Specific DNA Methylation Profiles

In the pediatric population, BCL6-correpresor gene (BCOR)–upregulated tumors include primitive myxoid mesenchymal tumors/undifferentiated sarcomas (PMMTI/UND), clear cell sarcomas of the kidney (CCSK), and high-grade neuroepithelial tumors (HG-NET). We investigated DNA methylation (DNAm) and copy number variation (CNV) profiling in these tumors (N = 34) using an Illumina EPIC BeadChip to better define the potential use of these tools to confirm diagnosis and predict outcomes. Twenty-seven tumors from 25 patients (age range, 0-10 years), showed molecular confirmation of genetic abnormalities as follows: BCOR internal tandem duplication in 14 PMMTI/UND, 8 CCSK, and 3 HG-NET and YWHAE fusions in 2 PMMTI/UND. The remaining 7 cases lacking informative molecular data were analyzed by immunophenotyping and were included in the study as a training cohort, clearly separated from the main study group. These were 4 PMMTI, 1 HG-NET, and 1 CCSK in which poor RNA preservation precluded the confirmation of BCOR rearrangements and 1 CCSK in which no rearrangements were found. DNAm data were compared with those of brain tumor and/or sarcoma classifier. Differentially methylated regions (DMRs) were analyzed in the 3 groups. Twenty-two cases of the 24 molecularly confirmed PMMTI/UND and CCSK and 3 of 6 of those with only immunophenotyping were classified within the methylation class “BCOR-altered sarcoma family” with optimal calibrated scores. PMMTI/UND and CCSK showed similar methylation profiles, whereas thousands of DMRs and significantly enriched pathways were evident between soft tissue/kidney tumors and HG-NET. The CNV analysis showed an overall flat profile in 19 of the 31 evaluable tumors (8/10 CCSK; 9/18 PMMTI/UND; 2/4 HG-NET). The most frequent CNVs were 1q gain and 9p and 10q loss. Follow-up time data were available for 20 patients: ≥2 CNV significantly correlated with a worse overall survival rate. In conclusion, soft tissue and kidney BCOR sarcomas matched with BCOR-altered sarcoma methylation class, whereas those from the brain matched with the central nervous system tumor classifier HG-NET BCOR, supporting the notion that DNAm profiling is an informative diagnostic tool. CNV alterations were associated with a more aggressive clinical behavior.

Secrete and Exude-Pancreatic Neuroendocrine Tumour

Pancreatic neuroendocrine tumour is derived from neuroendocrine cells of pancreas or hormone secreting cells within vicinity of pancreas and is categorized into indolent well differentiated neuroendocrine tumour (WDNET) and the aggressive, rapidly progressive poorly differentiated neuroendocrine carcinoma(PDNEC). Well differentiated neuroendocrine tumour (WDNET) demonstrates inactivation of MEN1, genetic mutation or loss of DAXX / ATRX, altered mTOR pathway, incrimination of PTEN, TSC2, PIK3CA genes with alteration of VHL. Poorly differentiated neuroendocrine carcinoma and mixed neuroendocrine / non neuroendocrine neoplasm delineates alterations within TP53, RB, KRAS, APC, BRAF or SMAD4 / DPC4 genes. Neuroendocrine tumour delineates an organoid architecture with solid nests, trabeculae, gyri, cords, festoons, ribbons, glandular, pseudoacinar or tubulo-acinar articulations. Miniature to intermediate tumour cells are permeated with eosinophilic, amphophilic, finely granular cytoplasm, centric, spherical to elliptical, uniform nuclei with finely stippled ‘salt and pepper’ nuclear chromatin, inconspicuous nucleoli and an abundant circumscribing vascular network. Pancreatic neuroendocrine tumour is immune reactive to CK8 / CK18, CAM 5.2, OSCAR, AE1 / AE3, synaptophysin, chromogranin A, INSM1, CD56, neuron specific enolase (NSE) or CD57. Pancreatic neuroendocrine tumour pancreas requires segregation from neoplasms such as acinar cell carcinoma, pancreatoblastoma, solid pseudo-papillary neoplasm, pancreatic ductal adenocarcinoma, paraganglioma, clear cell tumours as clear cell sarcoma, metastatic renal cell carcinoma, PEComa or solid variant of serous cystadenoma. Comprehensive surgical eradication is recommended for treating well differentiated neuroendocrine tumour. Poorly differentiated neuroendocrine tumour is appropriately treated with platinum based chemotherapy.

Çocuklarda Wilms tümörü dışındaki böbrek tümörlerinde risk grubunun sağkalıma etkisi

Purpose: The aim of this study was to evaluate tne effect of the risk group on the clinical features of the disease, treatment strategies and especially survival in children with Non-Wilms’ renal tumors (NWRTs). &#x0D; Materials and Methods: Patients diagnosed with NWRTs followed up and treated between January 2012 and January 2022 were included in the study (n=29; 16 boys and 13 girls). They were categorized into high- and low-risk groups based on their histological type. Patient records were reviewed retrospectively. Clinical characteristics, treatments, and outcomes of these patients were analyzed.&#x0D; Results: The high-risk group comprised clear cell sarcoma (CCSK) (n=8, 27.6%), malignant rhabdoid tumor (MRT) (n=3, 10.3%), renal cell carcinoma (n=2, 6.9%), non-Hodgkin lymphoma (n=1, 3.4%), and primitive neuroectodermal tumor (PNET) (n=1, 4%). The low-risk group comprised congenital mesoblastic nephroma (CMN) (n=9, 31%), angiomyolipoma (n=4, 3.8%), and hemangioma (n=1, 3.4%). Five patients died due to disease progression (mortality rate, 17%), all of whom belonged to the high-risk group (three patients with MRT, one with CCSK, one with PNET). The 5-year survival rate was 72% for the high risk group and 100% for the low risk group. &#x0D; Conclusion: Although low-risk tumors are associated with excellent outcomes, the outcomes vary in high-risk tumors. Physicians should be wary of high mortality rates in children with MRT, CCSK, and PNET, and should design multidisciplinary treatments for NWRTs.