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The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants, based on a central pathological review of the cases. From March 2005 to February 2007, pathology reports and tumor blocks were prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year. Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000), liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000). The observed incidence of sarcomas was higher than expected. This study is the first detailed investigation of the crude incidence of histological and molecular subtypes of sarcomas.

Advances in molecular genetics of sarcoma have enabled the identification of type-specific aberrations. We aimed to assess the clinical effect of systematic implementation of molecular assays to improve sarcoma misdiagnosis. In this multicentre, observational study, we recruited patients from 32 centres of the French Sarcoma Group/Reference Network in Pathology of Sarcomas. Eligibility criteria included: biopsy or surgical resection; suspicion of: dermatofibrosarcoma protuberans (cohort 1), dedifferentiated liposarcoma (cohort 2), Ewing's sarcoma family of tumours (cohort 3), synovial sarcoma (cohort 4), alveolar rhabdomyosarcoma (cohort 5), and myxoid or round cell liposarcoma (cohort 6); review by one sarcoma-expert pathologist; availability of frozen material (except for cohort 1 of patients with dermatofibrosarcoma protuberans because anti-CD34 immunohistochemistry is performed on paraffin-embedded tissue); and patient information. For each case, the pathologist made one primary diagnosis followed by up to two differential diagnoses, based on histological characteristics only. Each diagnosis was classified as certain, probable, or possible. For each case to determine the molecular classification, we did fluorescence in-situ hybridisation on paraffin-embedded samples. We also did comparative genomic hybridisation and quantitative PCR (cohort 2) or reverse transcriptase PCR (cohorts 3–6) on frozen and paraffin-embedded samples. We made a final diagnosis based on the molecular results. The clinical effect of diagnosis correction was assessed by a board of experts. Between June 22, 2009, and Oct 30, 2012, 395 patients were enrolled in the study, of which 384 were eligible for inclusion. The diagnosis was eventually modified by molecular genetics for 53 patients: eight (16%) of 50 patients with dermatofibrosarcoma (cohort 1), seven (23%) of 30 patients with dedifferentiated liposarcoma (cohort 2), 13 (12%) of 112 with Ewing's sarcoma family of tumours (cohort 3), 16 (16%) of 97 patients with synovial sarcoma (cohort 4), seven (15%) of 46 patients with alveolar rhabdomyosarcoma (cohort 5), and two (4%) of 49 patients with myxoid or round cell liposarcoma (cohort 6), with an effect on primary management or prognosis assessment in 45 cases. Molecular genetic testing should be mandatory for diagnostic accuracy of sarcoma and appropriate clinical management, even when histological diagnosis is made by pathologist experts in this field. French National Cancer Institute and Nice University Hospital.

Background Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody (OTSA-101) targeting FZD10 , overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions. Methods Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of 111 In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using 90 Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of 90 Y-OTSA-101 for radionuclide therapy. Results From January 2012 to June 2015, 20 pts. (median age 43 years [21–67]) with advanced SS were enrolled. Even though 111 In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with 90 Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient. Conclusions Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with 111 In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for 90 Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of 90 Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index. Trial registration The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.

Circulating tumor cells (CTCs) analysis is a promising new diagnostic field to estimate risk and monitor treatment efficacy, metastatic relapse, and progression in cancer patients. The study aim was to isolate and characterize CTCs in blood samples of Ewing sarcoma (ES) patients exploiting two main characteristics: CD99 expression and presence of chromosomal translocations. The method isolated CTCs from peripheral blood (PB) of ES patients. Cell-surface CD99 was a useful marker for CTCs determined using immunomagnetic separation with microbeads and CD99 monoclonal antibody. We tested sensitivity and specificity by detecting CTCs in blood collected from healthy donors and randomly during therapy from 18 ES patients. Evidence of CTCs was confirmed by detection of specific molecular markers using quantitative and digital reverse transcription-polymerase chain reaction targeting type 1 and type 2 or -related gene transcripts type 1 and type 9e. Feasibility of finding CTCs in PB of ES patients by immunoseparation with CD99 antibody and magnetic microbeads was demonstrated for the first time. At molecular analysis, three PB specimens tested positive for chimeric type 2 and one PB for chimeric type 2. CTCs detection was found above a limit of detection of 1 cell/mL of PB. CTCs in PB of ES patients can be identified by this method and in ES CTCs analysis can be used as a liquid biopsy approach for prognostic and predictive purposes. The potential clinical implications of CTCs in PB samples detected by the platform for CTC isolation with molecular confirmation during therapy require further evaluation.

BackgroundHead and neck squamous cell carcinoma (HNSCC) exhibits low response rates to immunotherapies, with only about 15–25% of patients responding to monotherapy and 30–45% to combination therapy. This limited effectiveness is attributed to significant intertumor and intratumor heterogeneity, which affects the immunological activity of individual tumors and their regions, thereby influencing immunotherapy outcomes. Various biomarkers at the gene and protein expression levels have been identified to predict the response to immunotherapy in HNSCC.MethodsIn this study, we evaluated intertumor heterogeneity using a 27-gene expression signature to stratify tumors by their immunologic activity status. We investigated intertumor heterogeneity at the molecular and cellular level and further analyzed intratumor spatial heterogeneity within and across these subgroups by using spatial multiomics approaches.ResultsImmunologically active tumors showed increased interferon-γ and interferon-α signaling and upregulation of major histocompatibility complex-I signaling and genes involved in antigen presentation. Chemokines such as CXCL8 and CXCL9, which are crucial for immune cell recruitment, were differentially regulated. The spatial analysis revealed that active tumors tended to show higher autocorrelation of homogeneous regions with immune cell infiltration compared with inactive tumors. Proximity measures showed an increased colocalization of immune cells, particularly CD8+ T cells, T helper cells, and regulatory T cells, near tumor cells in active tumors. Despite this high immune infiltration, HNSCC often has an immunosuppressive microenvironment, which we observed as a colocalization of programmed cell death protein-1+ (PD-1+) cytotoxic T cells and cytotoxic T cells, indicating regional differences in active and exhausted cell ratios. Furthermore, upregulation of JAK-STAT3 signaling in active tumors was potentially associated with immune evasion.ConclusionsThe spatial analysis at multiple omics levels allowed for a detailed investigation of molecular and cell type markers to further distinguish between immunologically active and immunosuppressive microenvironments and their spatial heterogeneity. Our study demonstrates that, besides gene expression signatures, cell colocalization signatures can infer immunological activity in HNSCC, thus predicting immunotherapy response.

Desmoplastic small round cell tumor (DSRCT) is a rare and highly aggressive mesenchymal tumor that develops in the abdominal cavity of young men adults. Patients typically present with symptoms of abdominal sarcomatosis. Diagnosis is based on histological analysis of biopsies which typically show small round blue cells in nests separated by an abundant desmoplastic stroma. DSRCT is associated with a unique chromosomal translocation t(11:22) (p 13; q 12) that involves the EWSR1 and WT1 genes. The prognosis is particularly poor; median survival ranges from 17 to 25 months, largely due to the presentation of the majority of patients with metastatic disease. Management of DSRCT remains challenging and current schemes lack a significant cure rate despite the use of aggressive treatments such as polychemotherapy, debulking surgery and whole abdominal radiation. Several methods are being evaluated to improve survival: addition of chemotherapy and targeted therapies to standard neoadjuvant protocol, completion of surgical resection with HIPEC, postoperative IMRT, treatment of hepatic metastases with [90Y]Yttrium microsphere liver embolization.

Background: Limited information is available on the applicative value of liquid biopsy (LB) in rare tumors, including Ewing’s sarcoma (ES). The accepted precision diagnostics standards would greatly benefit from a non-invasive LB test monitoring pathognomonic gene rearrangements in the bloodstream. Methods: Tissue and blood samples were collected from six and four ES patients, respectively. Plasma was cleared by two successive rounds of centrifugation and stored frozen until RNA extraction by the QIAmp CNA kit. RNA was retro-transcribed and subjected to real-time quantitative polymerase chain reaction (RT-qPCR) and digital polymerase chain reaction (dPCR). Reactions were set up using two custom primer sets identifying types 1 and 2 EWS-FLI1 fusion transcripts. Results: The two prevalent types of EWS-FLI1 rearrangements could be identified using only two sets of polymerase chain reaction primers, regardless of patient-specific EWS-FLI1 DNA breakpoints. RT-qPCR and dPCR discriminated the two variants in five tumor tissue RNAs and in four circulating tumor RNAs (ctRNAs). Of note, EWS-FLI1 molecular diagnosis was possible using blood samples even when tumor tissue was not available. ctRNA levels correlated (p < 0.05) with volume-based positron emission tomography (PET) parameters (metabolic tumor volume and total lesion glycolysis), and allowed the fine tracking of disease course after surgery, during adjuvant as well as neoadjuvant chemotherapy, and at follow up in one patient. Conclusions: To our knowledge, this is one of the few single-marker LB assays in solid tumors specifically designed to detect rearranged RNAs in blood, and the first study describing EWS circulating tumor RNAs in ES patients. Altogether, our results support the idea that LB may have a considerable impact on ES patient monitoring and management.

Background Tumor genotype plays a crucial role in clinical management of GIST. Whether genetic polymorphism of KIT may influence GIST patient outcome is unclear. Methods We investigated the biological and clinical significance of the presence of KIT exon 10 variant (c.1621 A > C), KIT L541 , in a transfected cell line (3 T3 L541) and in two retrospectively collected series of 109 GIST patients in total. The control group consisted of 60 healthy donors collected at the French department of blood transfusion. Results In the 3 T3 L541 cell line, KIT L541 protein exhibited a spontaneous phosphorylation status comparable to that of wild-type KIT but displayed a phosphorylation pattern of AKT and ERK1/2 that was found similar to that of the classical mutated forms of the KIT receptor. Of 109 patients enrolled in this retrospective translational research study, 24 (22 %) harboured KIT L541 , similarly to the control group of healthy donors ( n  = 10 of 60, 17 %). A higher prevalence of the variant KIT L541 was observed in patients with metastatic status at diagnosis ( KIT L541 correlated nine of 22 versus 15 of 87, p  = 0.02). In addition, patients with KIT L541 and localized GIST had a higher rate of relapse at 5 years and lower relapse free survival at 5 years in univariate, as well as in multivariate analysis. Response rate and duration of response to imatinib was similar in KIT L541 and KIT M541 patients. Conclusion KIT L541 genotype is associated with a higher risk of metastasis at diagnosis and a higher risk of relapse in GIST patients.

Desmoid tumor is a rare connective tissue tumor with locoregional aggressiveness but unpredictable behavior. The miRNA profile was ascertained for 26 patients included in the Desminib phase II trial and an independent validation cohort of 15 patients. Predictive and prognostic supervised analysis on the Desminib cohort failed to identify miRNAs differentially expressed between progressive and non‐progressive patients under imatinib treatment or between progressive and non‐progressive patients after discontinuation of imatinib. However, an unsupervised hierarchical clustering of the Desminib cohort identified two groups (A and B) of 13 patients each, where only the number of previous lines of treatment before inclusion in the study differed significantly between the two groups. Time to progression after discontinuation of imatinib was longer in group B than in group A. Fifteen miRNAs were highly statistically differentially expressed between groups A and B, targeting more than 3000 genes, including AGO1, BCL2, CDK6, SMAD4, PTEN, CCND1, VEGFA, and RB1. These results were confirmed in the independent validation cohort: hierarchical clustering of these 15 miRNAs identified two groups, in which time to recurrence was statistically different (28.8 months vs 68.8 months). These results provide the first indication of the prognostic value of miRNA expression profiling with a possible direct impact on patient management. A more precise miRNA signature must now be determined to select patients who would not benefit from surgical resection of their tumor and who ought to be monitored without treatment. This study was conducted to define the potential predictive and/or prognostic value of a miRNA expression profile of desmoid tumors. The results bring the first demonstration of the prognostic value of miRNA profile in DT. The results were obtained in a cohort of patients included in a clinical phase II trial and validated in an independent cohort. The implication of such a discovery will be important in the management of patients with tumors particularly over‐treated.

Production of high levels of IL-6 is often correlated with resistance to cytotoxics or ionizing radiations, in cancer cell lines as in various cancer patients. We investigated whether monoclonal antibodies directed against IL-6 may enable to reverse resistance of cancer cell lines. We exposed ten haematological cancer cells from lymphoma, myeloma, or leukemia origins to cytotoxics or ionizing radiations and assessed the effects of anti-IL-6 antibody addition on cell proliferation, apoptosis, or IL-6 signaling. A strong correlation between IL-6 secretion, measured by ELISA, and resistance to doxorubicin as ionizing radiations was observed in the multiple myeloma U266 and the Burkitt's lymphoma Daudi and Namalwa cells. Although an anti-IL-6 antibody combined to both treatments efficiently blocked IL-6 signaling in U266 cells, expressing the IL-6 receptor gp80, it did not increase treatment-induced anti-proliferative and pro-apoptotic effects on these cells, as well as on Daudi and Namalwa cells. This lack of effect could be related to diverse factors: 1) a higher release of the soluble form of IL-6 receptor gp80 in response to doxorubicin and irradiation from all cell lines, 2) an impaired level of the IL-6 pathway inhibitor SOCS3 in Daudi cells, and 3) an increased release of IL-10 and TNFalpha, two cytokines involved in cell radio- and chemoresistance. These data support the fact that IL-6 is not the preponderant actor of cell resistance to cytotoxics and ionizing radiations, which seems to be regulated by a complex network of proteins.