Randomized phase 2 trial of intravenous oncolytic virus JX-594 combined with low-dose cyclophosphamide in patients with advanced soft-tissue sarcoma

JX-594 is an oncolytic vaccinia virus genetically modified to replicate selectively in tumor cells. Metronomic chemotherapy has shown preclinical synergy with oncolytic viruses. We report here the results of the METROMAJX which is a randomized phase II clinical trial investigating the combination of JX-594 combined with metronomic cyclophosphamide (arm 1) or metronomic cyclophosphamide (arm 2) in patients with advanced STS. A two-stage Simon design was used. JX-594 was administered intra-venously at the dose 1.109 every 2 weeks for the first 3 injections and then every 3 weeks. Cyclophosphamide was given orally at the dose of 50 mg BID 1 week on 1 week off. The primary endpoint was the 6-month non progression rate. 20 patients were included (arm 1:15, arm 2:5). The two most frequent toxicities were grade 1 fatigue and fever and grade 2 fatigue and grade 2 lymphopenia in arms 1 and 2, respectively. In arm 1, 12 patients were assessable for the efficacy analysis. None of them were progression-free at 6 months indicating that the first stage of the Simon's design was not satisfied. One patient out 4 assessable for efficacy was progression-free at 6 months in arm 2. High throughput analysis of sequential plasma samples revealed an upregulation of protein biomarkers reflecting immune induction such as CXCL10 and soluble CD8 antigen in arm 1. Systemic treatment with JX-594 is safe in patients with advanced STS. Further investigations are needed to improve immune response to oncolytic viruses and define their therapeutic potential in patients with STS

Determinants of the access to remote specialised services provided by national sarcoma reference centres

BACKGROUND: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients. METHODS: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery. RESULTS: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities. CONCLUSIONS: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis

BAFfling pathologies: Alterations of BAF complexes in cancer

International audienceTo activate or repress specific genes, chromatin is constantly modified by chromatin-remodeling complexes. Among these complexes, the SWItch/Sucrose Non-Fermenting (SWI/SNF) complex, also referred to as BRG1-Associated Factor (BAF) complex, moves the nucleosome along chromatin using energy provided by ATP hydrolysis. In mammalian organisms, the SWI/SNF complex is composed of 10-15 subunits, depending on cell type, and a defect in one of these subunits can have dramatic consequences. In this review we will focus on the alterations identified in the SWI/SNF (BAF) complex subunits that lead to cancerous pathologies. While SMARCB1 was the first mutated subunit to be reported in a majority of malignant rhabdoid tumors, the advent of next-generation sequencing allowed the discovery of mutations in various SWI/SNF subunits within a broad spectrum of cancers. In most cases, the mutation leads to a loss of expression or to a truncated subunit unable to perform its function. Even though it is now commonly acknowledged that approximately 20% of all cancers present a mutation in a SWI/SNF subunit, some cancers are associated to a specific alteration of a SWI/SNF subunit, which acts either as tumor suppressor genes or as oncogenes, and therefore constitute diagnostic or prognostic biomarkers. Consistently, therapeutic strategies targeting SWI/SNF subunits or the genes affected downstream have been revealed to treat cancers

Aspects morphologiques et moléculaires des tumeurs malignes associées à une dérégulation des complexes BAF

International audienceBAF complexes are chromatin remodelling complexes made up of 15 subunits which overview transcription regulation. A subset of their subunits are notoriously linked to cancer, with the examples of SMARCB1, SMARCA4, ARID1A/1B and PBRM1. The complexes act as tumor suppressor genes, commonly mutated in a wide array of malignancies with an overrepresentation of sarcomas and tumors of the central nervous system. The recurrent inactivation of their genes points towards their driving role in the tumorigenesis of SMARCB1 in malignant rhabdoid tumors and SMARCA4 in small cell carcinoma of the ovary, hypercalcemic type. These tumors are morphologically similar composed of solid sheets of cells displaying vesicular nuclei dotted with clear chromatin and conspicuous nucleoli. Genomically, they share simple diploid profiles with no other alterations than in the culprit gene. Other mesenchymal tumors, distinct from malignant rhabdoid tumors are associated with BAF alterations, namely epithelioid sarcomas, SMARCA4-deficient thoracic sarcomas. BAF subunits are mostly inactivated through mutations or deletions but also occur through translocations in medullary carcinoma of the kidney and synovial sarcomas. Apart from tumors displaying recurrent alterations of the complexes, some variants or tumor variants display BAF alterations, including epithelioid malignant peripheral nerve sheet tumors and poorly differentiated chordomas. Lastly, some malignancies display low frequency of BAF alterations, in keeping with their passenger role in tumorigenesis with the example of dedifferentiated carcinomas, especially in colon, lung and uterus. BAF complexes alterations correlate with morphological features recognizable by microscopy, paving the way for their routine diagnosis and potential therapeutic prospects

Imaging features of SMARCA4-deficient thoracic sarcomas: a multi-centric study of 21 patients

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A Deep Attention-Multiple Instance Learning Framework to Predict Survival of Soft-Tissue Sarcoma from Whole Slide Images

International audienceSoft-tissue sarcomas are heterogeneous cancers of the mesenchymal lineage that can develop anywhere in the body. A precise prediction of sarcomas patients’ prognosis is critical for clinicians to define an adequate treatment plan. In this paper, we proposed an end-to-end Deep learning framework via Multiple Instance Learning (MIL), Deep Attention-MIL framework, for the survival predictions: Overall survival (OS), Metastasis-free survival (MFS), and Local-recurrence free survival (LRFS) of sarcomas patients, by studying the features from Whole Slide Images (WSIs) of their tumors. The Deep Attention-MIL framework consists of three steps: tiles selection from the WSIs to choose the relevant tiles for the study; tiles feature extraction by using a pre-trained deep learning model; and a Deep Attention-MIL model to predict the risk score for each patient via MIL approach. The risk scores outputted from the Deep Attention-MIL model are used to divide the patients into low/high-risk groups and predict survival time. The framework was trained and validated on a local dataset including 220 patients, then it was used to predict the survival for 48 patients in an external validation dataset. The experiments showed the proposed framework yielded satisfactory and promising results and contributed to accurate cancer survival predictions on both the validation and external testing datasets: By using the WSIs feature only, we obtained an average C-index (of 5-fold cross-validation) of 0.6901, 0.7179, and 0.6211 for OS, MFS, and LRFS tasks on the validation dataset, respectively. On the external testing dataset, these scores are 0.6294, 0.682, and 0.76 for the three tasks (OS, MFS, LRFS), respectively. By adding the clinical features, these scores have been improved both on validation and external testing datasets. We obtained an average C-index of 0.7835/0.6378, 0.7389/0.6885, and 0.6883/0.7272 for the three tasks (OS, MFS, LRFS) on validation/external testing datasets

Golfe Normano-Breton. Bilan des connaissances

Ce document a été élaboré dans le cadre de la préparation d'un programme d' "étude régionale intégrée" du golfe normano-breton. Réalisé dans des délais très courts, il ne constitue pas un inventaire exhaustif des travaux effectués dans le golfe mais une illustration par grands secteurs disciplinaires de l'état actuel des connaissances. Son objectif est de cerner les domaines à développer dans le cadre d'une programmation poly-disciplinaire orientée vers la gestion de l'espace littoral. La présentation par disciplines fondamentales de l'océanographie (physique, sédimentologie, biologie) est associée à un bilan de l'utilisation du milieu, faisant apparaître la diversité et la complexité des problèmes à résoudre. En effet, point privilégié entre la Manche Est, la Manche Ouest et le continent, le golfe est le siège d'une activité humaine intense et diversifiée : conchyliculture, pêche, extraction d'agrégats, rejets industriels (La Hague, et prochainement Flamanville), tourisme, activité portuaire ... Par ailleurs de nombreux projets d'aménagement sont à l'étude depuis ces dernières années : usine marémotrice, schéma d'aménagement conchylicole et aquacole, insularité du Mont St Michel, Parc National des Chausey .. . Ce dossier fait apparaître un certain nombre de voies scientifiques à developper dans des délais relativement brefs si l'on veut maitriser la connaissance des phénomènes naturels indispensables à une gestion globale de cette zone

SRF-FOXO1 and SRF-NCOA1 Fusion Genes Delineate a Distinctive Subset of Well-differentiated Rhabdomyosarcoma

International audienceRhabdomyosarcoma (RMS) encompasses a heterogenous collection of tumors in which new groups have recently been identified that improved the World Health Organization (WHO) classification. While performing RNA-sequencing in our routine practice, we identified 3 cases of well-differentiated RMS harboring new fusion genes. We also analyzed these tumors through array-comparative genomic hybridization. Clinically, these tumors were deep paraspinal tumors, occurring in neo-nat and young children. The patients underwent resection and adjuvant therapy. At the time of last follow-up (ranging from 12 to 108 mo), they were alive without disease. Histologically, these tumors consisted of well-differentiated rhabdomyoblastic proliferations with nuclear atypia, infiltrative borders, and a specific growth pattern. These tumors harbored new fusion genes involving SRF and either FOXO1 or NCOA1. We compared the expression profiles of these 3 tumors to the expression data of a series of 33 skeletal muscle tumors including embryonal RMSs, alveolar rhandomyosarcomas, RMSs with VGLL2 fusions, RMSs with the myoD1 mutation, EWSR1/FUS-TFCP2 epithelioid and spindle cell RMSs of the bone, and rhabdomyomas with PTCH1 loss. According to clustering analyses, the 3 SRF-fused tumors formed a distinct group with a specific expression profile different from that of the other types of skeletal muscle tumors. Array-comparative genomic hybridization showed a recurrent gain of chromosome 11. These 3 tumors define a new group of RMS associated with a fusion of the SRF gene. FOXO1 rearrangements, usually used to confirm the diagnosis of alveolar RMS and identify poor-outcome RMSs, were identified in a nonalveolar RMS for the first time

Clinicopathologic and Molecular Features of a Series of 41 Biphenotypic Sinonasal Sarcomas Expanding Their Molecular Spectrum

International audienceBiphenotypic sinonasal sarcoma (BSNS) is a locally aggressive tumor occurring in the sinonasal region. It harbors both myogenic and neural differentiation and is characterized by PAX3 rearrangement with MAML3 as the most frequent fusion partner, but the partner of PAX3 remains unidentified in a subset of cases. About 70 cases have been reported so far. In this study, we report a series of 41 cases with clinical, pathologic, and molecular description. Twenty-five (61%) patients were female individuals, and the median age was 49 years. Tumors arose predominantly in the nasal cavity and ethmoidal sinuses. Local recurrences occurred in 8 cases of the 25 (32%). Histologic features were characteristic of BSNS, with 5 cases showing focal rhabdomyoblastic differentiation. Immunohistochemistry showed a constant positivity of S100 protein and PAX3 and negativity of SOX10. MyoD1 was focally positive in 91% of cases, whereas only 20% were positive for myogenin. Molecular analysis showed a PAX3-MAML3 transcript in 37 cases (90%). RNA sequencing was performed in the 4 negative cases for PAX3-MAML3 fusion, and it showed that 1 case harbored a PAX3-FOXO1 fusion, as previously described in the literature, and 2 novel fusions: PAX3-WWTR1 fusion in 2 cases and PAX3-NCOA2 fusion in 1 case. RNA sequencing results were confirmed by fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and Sanger sequencing. The PAX3-NCOA2-positive case showed focal rhabdomyoblastic differentiation. In conclusion, we report 2 novel fusions (PAX3-WWTR1 and PAX3-NCOA2) in BSNS and show that MyoD1 is more sensitive than myogenin for demonstrating myogenic differentiation in this tumor

Pembrolizumab in soft-tissue sarcomas with tertiary lymphoid structures: a phase 2 PEMBROSARC trial cohort

Immune checkpoint inhibitors (ICIs) show limited clinical activity in patients with advanced soft-tissue sarcomas (STSs). Retrospective analysis suggests that intratumoral tertiary lymphoid structures (TLSs) are associated with improved outcome in these patients. PEMBROSARC is a multicohort phase 2 study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS (NCT02406781). The primary endpoint was the 6-month non-progression rate (NPR). Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and safety. The 6-month NPR and ORRs for cohorts in this trial enrolling all comers were previously reported; here, we report the results of a cohort enrolling patients selected based on the presence of TLSs (n = 30). The 6-month NPR was 40% (95% confidence interval (CI), 22.7-59.4), so the primary endpoint was met. The ORR was 30% (95% CI, 14.7-49.4). In comparison, the 6-month NPR and ORR were 4.9% (95% CI, 0.6-16.5) and 2.4% (95% CI, 0.1-12.9), respectively, in the all-comer cohorts. The most frequent toxicities were grade 1 or 2 fatigue, nausea, dysthyroidism, diarrhea and anemia. Exploratory analyses revealed that the abundance of intratumoral plasma cells (PCs) was significantly associated with improved outcome. These results suggest that TLS presence in advanced STS is a potential predictive biomarker to improve patients' selection for pembrolizumab treatment