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Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. Experimental Design: We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib. Results: A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. Conclusions: We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments. See related commentary by Zhou and Kim, p. 1170

Vaccination against coronavirus disease 2019 (COVID-19) relies on the in-depth understanding of protective immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). We characterized the polarity and specificity of memory T cells directed against SARS-CoV-2 viral lysates and peptides to determine correlates with spontaneous, virus-elicited, or vaccine-induced protection against COVID-19 in disease-free and cancer-bearing individuals. A disbalance between type 1 and 2 cytokine release was associated with high susceptibility to COVID-19. Individuals susceptible to infection exhibited a specific deficit in the T helper 1/T cytotoxic 1 (Th1/Tc1) peptide repertoire affecting the receptor binding domain of the spike protein (S1-RBD), a hotspot of viral mutations. Current vaccines triggered Th1/Tc1 responses in only a fraction of all subject categories, more effectively against the original sequence of S1-RBD than that from viral variants. We speculate that the next generation of vaccines should elicit Th1/Tc1 T-cell responses against the S1-RBD domain of emerging viral variants.Significance:This study prospectively analyzed virus-specific T-cell correlates of protection against COVID-19 in healthy and cancer-bearing individuals. A disbalance between Th1/Th2 recall responses conferred susceptibility to COVID-19 in both populations, coinciding with selective defects in Th1 recognition of the receptor binding domain of spike.See related commentary by McGary and Vardhana, p. 892.This article is highlighted in the In This Issue feature, p. 873

Supplementary Figure from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Supplementary Data from The Polarity and Specificity of Antiviral T Lymphocyte Responses Determine Susceptibility to SARS-CoV-2 Infection in Patients with Cancer and Healthy Individuals

Purpose:Immune checkpoint inhibitors (ICI) have revolutionized the treatment of patients with clear-cell renal cell carcinomas (ccRCC). Although analyses of transcriptome, genetic alterations, and the tumor microenvironment (TME) have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown.Experimental Design:We investigated the methylome of six ccRCC cohorts as well as one cell line dataset. Of note, we took advantage of the BIONIKK trial aiming to tailor treatments according to Paris Descartes 4-gene expression subgroups, and performed Illumina EPIC profiling for 46 samples related to patients treated with ipilimumab plus nivolumab, and 17 samples related to patients treated with sunitinib.Results:A group of tumors associated with enhancer demethylation was discovered, namely TED. TED was associated with tumors with sarcomatoid differentiation and poor clinical outcome. TED harbored TET1 promoter demethylation, activated the gene expression signature of epithelial–mesenchymal transition and IL6/JAK/STAT3 pathways, and displayed a TME characterized by both immune activation and suppressive populations, fibroblast infiltration, and endothelial depletion. In addition, TED was a predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, TED was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort.Conclusions:We report on the discovery of a novel epigenetic phenotype associated with resistance to ICIs that may pave the way to better personalizing patients’ treatments.See related commentary by Zhou and Kim, p. 1170

Figure S2. Focal copy number deletion identified by the GISTIC algorithm for a) 𝑇𝐸𝐷+ and b) 𝑇𝐸𝐷−, respectively, in the TCGA-KIRC cohort.

Supplementary Tables S1-S23

Supplementary Figure 1. Independent validation of C-CIMP A) Supervised clustering of TCGA samples in ccRCC validation dataset assessed by 27k Infinium arrays. The (beta value) level of DNA methylation is represented with a color scale. Each column represents a sample; each row a probe set. The transcriptomic subtype in TCGA, the copy number variation at 9p23.1 locus (CDKN2A), somatic mutation status of four genes (PBRM1, BAP1, SETD2 and VHL) are indicated by red, green and gray squares, with annotations in the legend. B) Kaplan-Meier curves showing distinct outcome of patients according to the three subgroups of DNA methylation classification, with patients belonging to C-CIMP subgroup having the worst outcome. Supplementary Figure 2. Expression vs DNA methylation between C-CIMP and no-CIMP subgroups using volcano and starburst plots. A) All CpG loci analyzed for C-CIMP association; x-axis: β-value difference in DNA methylation between C-CIMP and no-CIMP clusters; y-axis: p-value of the corrected FDR between the two groups; red: probes significantly different between the two subgroups. B) TCGA promoter DNA methylation vs. gene expression analyzed by RNAseq. Log-10 (FDR adjusted p-value) is plotted for DNA methylation (x-axis) and gene expression for each gene (y-axis). Green indicates genes that are downregulated for gene expression and which gain DNA methylation in C-CIMP cluster versus no-CIMP cluster. Red indicates genes that are upregulated for gene expression and gain DNA methylation. Supplementary Figure 3. Association between somatic mutations and DNA methylation subgroups. A) Mutational load is increased in C-CIMP as compared to no-CIMP and low-CIMP subgroups. B) Association between somatic mutations of BAP1 and SETD2 in C-CIMP subgroup as compared to low-CIMP and no-CIMP subgroups. Supplementary Figure 4. Predictive value of VEGF receptor methylation to predict response to sunitinib. Kaplan-Meier curves for progression-free survival of patients treated with sunitinib according to tumor methylation status of (A) FLT4, (B) FLT1, and (C) FLT3 genes in Beuselinck study. Supplementary Figure 5. C-CIMP subgroup in metastatic ccRCC A) Supervised clustering of DNA methylation in Beuselinck study was consistent with the three DNA methylation subgroups C-CIMP, low-CIMP and no-CIMP. B) Kaplan-Meier curves for progression-free survival of patients treated with sunitinib according to their CIMP status. Supplementary Figure 6. Correlation between methylome signature of NSD1 mutations of patients with Sotos syndrome and ccRCC. A) Supervised clustering of DNA methylation in TCGA ccRCC using genome-wide methylome signature of NSD1 mutations in Sotos syndrome. B) Kaplan-Meier curves for overall survival of patients with ccRCCs according to NSD1 mutations in genome-wide methylome signature. Note that the analyzed cohort encompasses 271 ccRCCs assessed by Infinium 450K arrays.

Supplementary Table 3: Ingenuity Pathway Analysis (IPA) for genes which gain promoter DNA methylation in C1 relative to C2 epi-cluster. Supplementary Table 4: Gene Ontology analysis for differentially methylated regions (DMR) between C1 and C2 epi-clusters, as assessed by GREAT online tool. Supplementary Table 5: List of motifs enriched in differentially methylated regions between C1 and C2 epi-clusters, as assessed by GREAT online tool. Supplementary Table 6: DAVID functional annotations analysis for enriched pathways related to genes which gain DNA methylation in renal cell carcinoma samples. Supplementary Table 7: List of gene promoters located in CG islands and which are assessed for DNA methylation using DREAM. The genes which showed the highest frequency of DNA methylation in our dataset are in the top. Furthermore, the frequency of gene promoters which gain DNA methylation in either RCC samples derived from the proximal or distal cells of the nephron are also reported. Supplementary Table 8: Validation dataset showing the prevalence of promoter DNA methylation for 25 genes in clear-cell renal cell carcinoma dataset of The Cancer Genome Atlas (TCGA) project. Those genes were both methylated and repressed in the TCGA dataset.

Unsupervised clustering of DNA methylation using 56 genes epi-signature in an independent data set encompassing 37 renal cell carcinomas cases. C2 contains the majority of oncocytoma and chromophobe RCC cases (n=11/13) as compared to C1 which encompasses the remaining RCC subtypes including clear-cell RCC (ccRCC) , papillary RCC (pRCC) and translocation RCC (tRCC).

Extensive dysregulation of chromatin-modifying genes in clear cell renal cell carcinoma (ccRCC) has been uncovered through next-generation sequencing. However, a scientific understanding of the cross-talk between epigenetic and genomic aberrations remains limited. Here we identify three ccRCC epigenetic clusters, including a clear cell CpG island methylator phenotype (C-CIMP) subgroup associated with promoter methylation of VEGF genes (FLT4, FLT1, and KDR). C-CIMP was furthermore characterized by silencing of genes related to vasculature development. Through an integrative analysis, we discovered frequent silencing of the histone H3 K36 methyltransferase NSD1 as the sole chromatin-modifying gene silenced by DNA methylation in ccRCC. Notably, tumors harboring NSD1 methylation were of higher grade and stage in different ccRCC datasets. NSD1 promoter methylation correlated with SETD2 somatic mutations across and within spatially distinct regions of primary ccRCC tumors. ccRCC harboring epigenetic silencing of NSD1 displayed a specific genome-wide methylome signature consistent with the NSD1 mutation methylome signature observed in Sotos syndrome. Thus, we concluded that epigenetic silencing of genes involved in angiogenesis is a hallmark of the methylator phenotype in ccRCC, implying a convergence toward loss of function of epigenetic writers of the H3K36 histone mark as a root feature of aggressive ccRCC. Cancer Res; 77(18); 4835–45. ©2017 AACR.

Supplementary Figure 2. Case study: 64-year old female with BRAF V600-mutant melanoma (A) Immunhistochemistry for Ki67 expression showing a reduction between baseline and cycle1/day15 in lymph node biopsies (B) Immunhistochemistry for pERK expression showing a reduction between baseline and cycle5/day1 in lymph node biopsies (C) FDG-PET uptake at baseline (D) FDG-PET metabolic partial response at day 15 of cycle 1 (E) CT scan images at baseline (F) CT scan images at day 1 of cycle 5 show a 80% reduction in target lesion size, indicating partial response

List of 369 probe sets defining the C-CIMP (CpG island methylator phenotype) in ccRCCs, including mean beta-values of those in C-CIMP (cluster 3) versus no-CIMP (cluster 2). Expression values as well as fold-changes of gene expression of those genes are also reported.

Purpose: DNA methylation is a heritable covalent modification that is developmentally regulated and is critical in tissue-type definition. Although genotype–phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morphological or ontology based phenotypes. Here, we test the hypothesis that DNA methylation signatures can discriminate between putative precursor cells in the nephron.Experimental Designs: We performed deep profiling of DNA methylation and transcriptome in diverse histopathological RCC subtypes and validated DNA methylation in an independent dataset as well as in The Cancer Genome Atlas Clear Cell and Chromophobe Renal Cell Carcinoma Datasets.Results: Our data provide the first mapping of methylome epi-signature and indicate that RCC subtypes can be grouped into two major epi-clusters: C1, which encompasses clear-cell RCC, papillary RCC, mucinous and spindle cell carcinomas and translocation RCC; C2, which comprises oncocytoma and chromophobe RCC. Interestingly, C1 epi-cluster displayed 3-fold more hypermethylation as compared with C2 epi-cluster. Of note, differentially methylated regions between C1 and C2 epi-clusters occur in gene bodies and intergenic regions, instead of gene promoters. Transcriptome analysis of C1 epi-cluster suggests a functional convergence on Polycomb targets, whereas C2 epi-cluster displays DNA methylation defects. Furthermore, we find that our epigenetic ontogeny signature is associated with worse outcomes of patients with clear-cell RCC.Conclusions: Our data define the epi-clusters that can discriminate between distinct RCC subtypes and for the first time define the epigenetic basis for proximal versus distal tubule derived kidney tumors. Clin Cancer Res; 22(24); 6236–46. ©2016 AACR.

Raw data for β-values of probe sets related to our 56 genes signature in an independent dataset encompassing 4 normal kidneys and 37 renal cell carcinomas belonging to diverse histopathological subtypes.

Supplementary Table 10: List of samples misclassified among the clear-cell renal cell carcinomas dataset with the corresponding new classification. Among those, many of them have been demonstrated to belong to the C4 cluster of long non-coding RNA classification. The first table reports the 5 misclassified TCGA clear-cell RCC (KIRC) using gene expression and which turned out to be chromophobe RCC (chRCC). The second table reports on misclassified TCGA KIRC cases with DNA methylation available. Supplementary Table 11: List of importance scores for genes used in the statistical model for predicting outcome of patients with clear-cell RCC. Supplementary Table 12: Associations (both training and validation datasets) between mutational load, TCGA clear-cell renal cell carcinomas transcriptomic subtypes classification and recurrent somatic mutations (VHL, PBRM1, BAP1 and KDM6A) identified in clear-cell renal cell carcinoma TCGA dataset with our 56 genes epi-signature. P-values less than 0.05 is considered as statistically significant.

List of 95 CpG located in promoter CG islands which are differentially methylated and expressed between C1 and C2 epi-clusters.

List of DNA methylation levels for each CpG sites detected by DREAM in the 2 normal kidneys and the 22 renal cell carcinomas samples. Each column represents one sample and each raw one CpG site with the relative annotations (coordinates, CpG islands or not, distance from transcription start site (TSS). The coordinates of each CpG sites are provided according to Hg18 version of the Human Genome.

Purpose: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor.Experimental Design: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non–small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added.Results: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications.Conclusions: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251–61. ©2014 AACR.

Resume Introduction L’Association d’enseignement et de recherche des internes en oncologie (AERIO) a mene une enquete nationale aupres des internes en « phase socle » de la promotion 2020 du diplome d’etudes specialisees d’oncologie. L’objectif etait de recueillir et decrire leurs motivations, ainsi que les objectifs et les obstacles de vie et de carriere de ces internes, lors de cette premiere annee de leur cursus. Methodes Un questionnaire comprenait 45 questions fermees reparties en six sections permettant de decrire : les caracteristiques demographiques de la population interrogee, l’engagement et les attentes cliniques et liees a la recherche des etudiants, leur formation, leurs objectifs de vie et de carriere, ainsi que leur engagement associatif. Resultats Soixante-dix-huit internes sur 119 ont participe (66 %), dont 68 (87 %) ayant complete le questionnaire dans son integralite. La population etait constituee en majorite de femmes (60 %) avec un âge median de 24 ans. Le choix entre oncologie option medicale ou option radiotherapie etait le plus souvent indetermine (87 %), 15 % des internes ont songe au droit au remord. Le temps de travail hospitalier moyen declare etait majoritairement situe entre 45 et 65 heures par semaine (83 %). Soixante-neuf pour cent souhaitaient s’investir dans la recherche clinique. Environ un interne sur deux (52 %) n’avait pas acces a la demi-journee de formation en autonomie. Conclusion Cette etude nationale a permis de decrire la perception des internes en phase socle d’oncologie vis a vis de leur formation, ainsi que leurs aspirations de carriere et leur rapport a la recherche.

Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

BackgroundIvuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.MethodsDose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1–3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every 4 weeks (Q4W)) intravenously. Dose-expansion: patients with melanoma (n=10) and NSCLC (n=20) who progressed on prior anti-programmed death receptor 1/programmed death ligand-1 and/or anti-cytotoxic T-lymphocyte-associated antigen 4 (melanoma) received ivuxolimab 30 mg Q2W intravenously plus utomilumab 20 mg Q4W intravenously. Adverse events (AEs) were graded per National Cancer Institute Common Terminology Criteria for Adverse Events V.4.03 and efficacy was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 and immune-related RECIST (irRECIST). Paired tumor biopsies and whole blood were collected to assess pharmacodynamic effects and immunophenotyping. Whole blood samples were collected longitudinally for immunophenotyping.ResultsDose-escalation: 57 patients were enrolled; 2 (3.5%) patients with melanoma (0.3 mg/kg+20 mg and 0.3 mg/kg+100 mg) achieved partial response (PR), 18 (31.6%) patients achieved stable disease (SD); the disease control rate (DCR) was 35.1% across all dose levels. Dose-expansion: 30 patients were enrolled; 1 patient with NSCLC achieved PR lasting >77 weeks. Seven of 10 patients with melanoma (70%) and 7 of 20 patients with NSCLC (35%) achieved SD: median (range) duration of SD was 18.9 (13.9–49.0) weeks for the melanoma cohort versus 24.1 (14.3–77.9+) weeks for the NSCLC cohort; DCR (NSCLC) was 40%. Grade 3–4 treatment-emergent AEs were reported in 28 (49.1%) patients versus 11 (36.7%) patients in dose-escalation and dose-expansion, respectively. There were no grade 5 AEs deemed attributable to treatment. Ivuxolimab area under the concentration–time curve increased in a dose-dependent manner at 0.3–3 mg/kg doses.ConclusionsIvuxolimab+utomilumab was found to be well tolerated and demonstrated preliminary antitumor activity in selected groups of patients.Trial registration numberNCT02315066.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients and Methods: Patients with advanced, treatment-naive, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

Resume La reforme du troisieme cycle des etudes de medecine mise en place en 2017 a cree le statut de « Docteur Junior » pour la derniere phase, appelee phase de consolidation. Elle a pour principe la mise en autonomie croissante et supervisee de l’etudiant de troisieme cycle, afin de mieux l’accompagner vers son statut de praticien senior. Des recommandations pour definir les missions specifiques a l’oncologie medicale paraissent indispensables a la bonne mise en place de la reforme. Ce document, realise conjointement par l’association pour l’enseignement et la recherche des internes en oncologie (AERIO) et le College national des enseignants en cancerologie (CNEC) est une reference nationale qui vise a orienter les pratiques locales, sans s’imposer a elles, en vue de l’arrivee des premiers Docteurs Juniors en oncologie medicale en novembre 2021. Les principaux roles du Docteur Junior y sont explicites : activite de reunion de concertation pluridisciplinaire, de consultation, d’hopital de jour, d’hospitalisation complete, d’enseignement, de recherche notamment clinique et de demarche qualite. L’option oncologie-radiotherapie n’est pas abordee dans ce document.

HIV testing is recommended at time of cancer diagnosis, HBV and HCV screening because of the risk of reactivation with certain anticancer drugs.This is a cross-sectional study. The objectives were to assess the screening practices in cancer patients and the satisfaction of professionals in the event of use of the CancerHIV network. A questionnaire drafted by the CancerHIV expert and the OncoPaca-Corse Regional Cancer Network (RCN) was distributed in the region at the end of 2018 (part 1: V1) before being extended to the national level via the CancerHIV network (part 2: V2). Participation reached 160 and 130 respondents (V1 and V2, respectively). At the initial cancer assessment, 23% of respondents declared that they systematically screened for HIV at V1 (V2: 17%), 25% for HBV (V2: 20%) and 24% for HCV (V2: 19%). Before immunotherapy, the rates were 54% for HIV in V1 (V2: 52%), 57% for HBV (V2: 60%) and 55% for HCV (V2: 57%). Among the respondents, satisfaction when requesting a regional or national remedy was high (almost 100%). Screening for HIV, HBV and HCV allows supervised prescription of immunosuppressive or cytotoxic treatment to a potentially immunosuppressed patient. This study, resulting of an original collaboration between a RCN and a national expert network, underlines the lack of screening at the 2 examined stages of patient care, and the need for raising practitioners' awareness to recommendations., Le dépistage de l’infection par le VIH est recommandé lors du bilan initial de tout cancer, celui de l’hépatite B et C en raison d’un risque de réactivation avec certains anticancéreux. Il s’agit d’une étude descriptive transversale. Les objectifs étaient d’évaluer les pratiques de dépistage chez des patients atteints de cancer et la satisfaction des professionnels en cas de recours au réseau CancerVIH. Un questionnaire élaboré par l’expert CancerVIH et le Réseau Régional de Cancérologie (RRC) OncoPaca-Corse a été diffusé fin 2018 en région (volet 1 : V1) avant une extension au niveau national via le réseau CancerVIH (volet 2 : V2). La participation a atteint 160 et 130 répondants (V1 et V2, respectivement). Au bilan initial de cancer, 23 % des répondants déclaraient dépister systématiquement le VIH au V1 (V2 : 17 %), 25 % le VHB (V2 : 20 %) et 24 % le VHC (V2 :19 %). Avant immunothérapie, les chiffres étaient de 54 % pour le VIH dans le V1 (V2 : 52 %), 57 % pour le VHB (V2 : 60 %) et 55 % pour le VHC (V2 : 57 %). Parmi les répondants, la satisfaction en cas de sollicitation du recours régional ou national était élevée (près de 100 %). Le dépistage du VIH, VHB et VHC permet la prescription encadrée d’un traitement immunosuppresseur ou cytotoxique à un patient potentiellement immunodéprimé. Cette enquête, fruit d’une collaboration originale entre RRC et réseau expert national, souligne l’insuffisance du dépistage aux 2 étapes de la prise en charge étudiées et la nécessité de sensibiliser les professionnels aux recommandations existantes.

To assess the feasibility and technical outcomes of pelvic bone cementoplasty using an electromagnetic navigation system (EMNS) in standard practice.Monocentric retrospective study of all consecutive patients treated with cementoplasty or reinforced cementoplasty of the pelvic bone with EMNS-assisted procedures. The endpoints were periprocedural adverse events, needle repositioning rates, procedure duration, and radiation exposure.A detailed description of the technical steps is provided. Thirty-three patients (68 years ± 10) were treated between February 2016 and February 2020. Needle repositioning was required for 1/33 patients (3%). The main minor technical adverse event was soft tissue PMMA cement leaks. No major adverse event was noted. The median number of CT acquisitions throughout the procedures was 4 (range: 2 to 8). Radiation exposure and mean procedure duration are provided.Electromagnetic navigation system-assisted percutaneous interventions for the pelvic bone are feasible and lead to low rates of minor technical adverse events and needle repositioning. Procedure duration and radiation exposure were low.• Initial experience for 33 patients treated with an electromagnetic navigation assistance for pelvic cementoplasty shows feasibility and safety. • The use of an electromagnetic navigation system does not expose to high procedure duration or radiation exposure. • The system is efficient in assisting the radiologist for extra-axial planes in challenging approaches.

Cancer-associated thrombosis (CAT) is a common complication resulting from various vascular mechanisms related to cancer, antitumoral therapy and patient status, and is associated with a poor prognosis. Anticoagulants recommended for CAT treatment or prevention mainly include low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs). Regarding thromboprophylaxis, a situation for which LMWH is a preferred option due to a lower risk of hemorrhage especially in patients with unresected gastro-intestinal and genito-urinary malignancies, the identification of patients at risk is a major issue. For patients with established CAT, the main issue is the choice of the most appropriate anticoagulant therapy. Because of the convenience of oral formulation, DOACs are an attractive option, and their efficacy has been shown in randomized trials. However, such studies are limited by selection biases, which make the analyzed population not representative of the real-life setting, as for instance cancers associated with a high risk of hemorrhage, or antitumoral therapies (e.g., tyrosine kinase inhibitors) known to interact with DOACs and then modifying their bioavailability. Caution associated with DOAC use is highlighted by most updated guidelines that recommend a case-by-case-based approach. The aim of the present paper is to help the oncologists make the most appropriate decision regarding the choice of anticoagulant therapy in a context of thromboprophylaxis or established CAT management in a patient with a solid tumor. The main issues are addressed through key practical questions, the answers of which are based on the current guidelines and additional published data or expert opinions.

Immune checkpoint inhibitors have revolutionized the treatment of patients with clear-cell renal carcinomas. Although, analyses of transcriptome, genetic alterations, and the tumor microenvironment have shed light into mechanisms of response and resistance to these agents, the role of epigenetic alterations in this process remains fully unknown. Herein, we investigated the methylome of six clear-cell renal cell carcinomas cohorts and discovered a group of tumors with enhancer demethylation, namely \(TED\). \(TED\) was associated with tumors with sarcomatoid differentiation and poor clinical outcome. \(TED\) harbored TET1 and JAK3 promoter demethylation, activated the gene expression signature of epithelial-mesenchymal transition and IL-6/JAK/STAT3 pathways, and displayed a tumor microenvironment characterized by immune exhaustion, fibroblasts infiltration, and endothelial depletion. In addition, \(TED\) was the only predictive factor of resistance to the combination of first-line ipilimumab-nivolumab in the BIONIKK clinical trial. Finally, \(TED\) was associated with activation of specific regulons, which we also found to be predictive of resistance to immunotherapy in an independent cohort. In conclusion, we report on the discovery of a novel epigenetic phenotype associated with resistance to immune checkpoint inhibitors that may pave the way to better personalizing patients’ treatments.