Histopathology of prostate tissue after vascular-targeted photodynamic therapy for localized prostate cancer

Low-risk prostate adenocarcinoma is classically managed either with active surveillance or radical therapy (such as external radiotherapy or radical prostatectomy), but both have significant side effects. Vascular-targeted photodynamic therapy (VTP) is a focal therapy proposed as an alternative approach for localized, low-volume, and low-Gleason score (≤6) carcinomas. We report histological modifications observed in prostate biopsies of 56 patients, performed 6 months after VTP using the photosensitizer TOOKAD® Soluble (WST11) and low-energy laser administered in the tumor area transperineally by optic fibers. In 53 patients, we observed sharply demarcated hyaline fibrotic scars, with or without rare atrophic glands, sometimes reduced to corpora amylacea surrounded by giant multinuclear macrophages. Mild chronic inflammation, hemosiderin, and coagulative necrosis were also observed. When residual cancer was present in a treated lobe (17 patients), it was always located outside the scar, most often close to the prostate capsule, and it showed no therapy-related modification. Histopathological interpretation of post-WST11 VTP prostate biopsies was straightforward, in contrast with that of prostate biopsies after radio or hormonal therapy, which introduces lesions difficult to interpret. VTP resulted in complete ablation of cancer in the targeted area

Nicotinamide N-méthyltransférase (NNMT) : biomarqueur potentiel de l’agressivité du carcinome rénal à cellules claires

Objectifs NNMT (nicotinamide N-méthyltransférase) est une enzyme de la voie des pyridines. Les études d’analyse protéomique ont démontré sa surexpression dans le carcinome rénal à cellules claires (CRCC). Des études de validation immunohistochimiques ont montré son association avec les tumeurs à risque d’évolution défavorable. Nous avons voulu étudier le lien entre la survie de patients atteints de CRCC et l’expression tissulaire de NNMT comme potentiel biomarqueur. Méthodes Nous avons inclus de manière prospective au sein de la base de données nationale UroCCR 137 patients opérés d’un CRCC. Nous avons étudié l’intensité du marquage cellulaire intracytoplasmique de NNMT (cotée de 0 à 3) évaluée par le même pathologiste pour l’ensemble des tumeurs et nous avons étudié la corrélation entre cette donnée de pathologie cellulaire et la survie (globale et sans récidive) des patients en fonction de l’âge et de l’agressivité tumorale définie grâce au score SSIGN (pTNM, taille tumorale, grade histopronostique de Fuhrman et présence de nécrose). Le test du log rank et le modèle de Cox étaient utilisés. Résultats Nous avons inclus dans notre étude 126 patients (onze patients avec des données manquantes). L’intensité du marquage tissulaire intracytoplasmique de NNMT était cotée à 0 (absente) dans 7 cas, à 1 (faible) dans 20 cas, à 1,5 dans 28 cas, à 2 (intermédiaire) dans 27 cas, à 2,5 dans 19 cas et à 3 (élevée) dans 25 cas. Un score SSIGN ≤ 6 était retrouvé dans 89 cas et un score SSIGN > 6 dans 38 cas. Durant la première année de suivi, une intensité cellulaire de NNMT > 2,5 était associée à un pronostic défavorable indépendamment du score SSIGN (p = 10–3). Ce seuil d’intensité cellulaire était associé à des tumeurs de score SSIGN > 6 (p = 0,01) de moins bon pronostic. Conclusion Nous avons démontré qu’une intensité intracytoplasmique élevée de NNMT, évaluée en anatomocytopathologie, était associée à une évolution péjorative des patients atteints d’un CRCC durant la première année de suivi indépendamment de l’agressivité de leur tumeur. Il s’agit d’un biomarqueur corrélé à des tumeurs agressives de score SSIGN > 6 ce qui souligne le rôle potentiel de NNMT comme biomarqueur histopronostique du CRCC. NNMT pourrait présenter un intérêt dans la sélection des patients nécessitant un traitement adjuvant

Relationship Between the Expression of O-Methylguanine-DNA Methyltransferase (MGMT) and p53, and the Clinical Response in Metastatic Pancreatic Adenocarcinoma Treated with FOLFIRINOX

BACKGROUND: To date, no predictive biomarker for the efficacy of FOLFIRINOX in metastatic pancreatic adenocarcinoma has been demonstrated. Deficiency in O-methylguanine-DNA methyltransferase (MGMT) has been associated with a therapeutic response in endocrine tumors of the pancreas and the lack of expression of protein 53 (p53) could interfere with the action of MGMT. OBJECTIVE: The aim of our study was to assess the prevalence of MGMT and p53 in patients with metastatic pancreatic adenocarcinoma treated with FOLFIRINOX as a first-line treatment and to investigate their association with therapeutic response and survival. PATIENTS AND METHODS: The immunohistochemical expression of MGMT was recorded as present or absent and the expression of p53 was semi-quantitatively scored in 30 patients with metastatic pancreatic adenocarcinoma, at Angers Hospital in France between September 2011 and June 2015. Clinical and radiologic data were collected retrospectively. RESULTS: The presence or absence of MGMT expression entailed no significant differences in response rate. Median values of progression-free survival (PFS) and overall survival (OS) were lower in patients with MGMT expression, but sample size is too small to conclude that there is a statistically significant difference. No significant relationship for response rate and PFS was observed in relation with p53 expression. By contrast, patients with a strong tumor expression of p53 had a significantly lower OS compared to patients with no or weak expression of the protein (p = 0.027). There was a positive correlation between the expression of p53 and MGMT (p = 0.08). CONCLUSIONS: These preliminary findings suggest that for patients treated with FOLFIRINOX as a first-line treatment for metastatic pancreatic adenocarcinoma, the immunohistochemical evaluation of MGMT could not predict the clinical outcome; however, the survival was not significant probably because of the under-powered study (due to small sample size). A strong tumor expression of p53 is associated with a poor prognosis of OS

Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41

Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10(-7)). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine famil

Evaluation of identified genomic profiles in ovarian carcinomas by a phenotypic, histological and biostatistical approach

L’objet de ce travail est d’étudier par une approche phénotypique immunohistochimique une cohorte de carcinomes ovariens (OC) en ciblant les principales protéines dérégulées en lien avec les mutations ou anomalies génétiques connues. Les OC regroupent 5 types histologiques principaux avec des caractéristiques cliniques, phénotypiques et génomiques distinctes : les carcinomes séreux de bas et haut grade (LGSC et HGSC), les carcinomes endométrioïdes, les carcinomes à cellules claires (CCC) et les carcinomes mucineux. L'expression de 17 anticorps dont BRCA, p53, PTEN, HNF1B, ARID1A, - Caténine, HER2, BRAF, KRAS, C-MYC, PD-L1 ont été évalués par tissu micro-array. Une analyse descriptive en cluster est réalisée avec élaboration de courbes de survie globale (SG) et survie sans progression correspondantes (SSP). Sur 286 OC étudiés, une partie du panel testé a des taux d’anomalie observée cohérents avec les données de la littérature. Une proportion faible des OC exprime PD-L1 essentiellement des HGSC et de CCC. Une différence significative de SSP pour p53 et C-MYC est observée en analyse multivariée avec une courbe de SSP plus péjorative pour les patientes p53+ / C-MYC-. L’analyse par cluster a permis d’identifier 4 groupes de patientes : cluster 1 b-Caténine+/KRAS+ ; cluster 2 hypermuté au profil p53+/ C-MYC+/KRAS+ /HNF1+ /PTEN- ; cluster 3 : déficient Rb et le cluster 4 ARID1A déficient. Il n’a pas été montré de différence significative en SSP et SG entre ces 4 clusters, toutefois une inflexion des courbes semble suggérer que le cluster Rb déficient aurait une meilleure SG et SSP tandis que le groupe ARID1A déficient, au contraire semblerait avoir le plus mauvais pronostic.The purpose of this work is to investigate a cohort of ovarian carcinomas (OC) using an immunohistochemical approach by focusing main deregulated proteins in relation to genetic mutations or abnormalities in OC. OCs include 5 main histological types with distinct clinical, phenotypic and genomic characteristics: low- and high-grade serous carcinomas (LGSC and HGSC), endometrioid carcinomas, clear cell carcinomas (CCC) and mucinous carcinomas. The expression of 17 antibodies including BRCA, p53, PTEN, HNF1B, ARID1A, -Catenin, HER2, BRAF, KRAS, C-MYC, PD-L1 were evaluated by tissue microarray. A descriptive cluster analysis is performed to establish groups of markers with greatest potential for prognostic discrimination. The corresponding overall survival (OS) and progression-free survival (PFS) curves were elaborated. In totally, 286 OCs studied. A part of the testing panel showed abnormality rates consistent with literature data. A small proportion of OCs expressed PD-L1, mainly HGSC and CCC. A significant difference in PFS for p53 and C-MYC is observed in multivariate analysis with a more pejorative PFS curve for p53+ / C-MYC- patients. Cluster analysis identified 4 groups of patients: cluster 1 -Catenin+/KRAS+; cluster 2 hypermutated with p53+/ C-MYC+/KRAS+ /HNF1+ /PTEN- profile; cluster 3: Rb deficient and cluster 4 ARID1A deficient. There was no significant difference in PFS and OS between these 4 clusters, however an inflection of t curves seems to suggest that Rb-deficient cluster could have a better OS and PFS while the ARID1A deficient group

PD-L1 expression with QR1 and E1L3N antibodies according to histological ovarian cancer subtype: A series of 232 cases

International audienceTherapeutic strategies for epithelial ovarian cancers are evolving with the advent of immunotherapy, such as PD-L1 inhibitors, with encouraging results. However, little data are available on PDL-1 expression in ovarian cancers. Thus, we set out to determine the PD-L1 expression according to histological subtype. We evaluated the expression of two PD-L1 clones-QR1 and E1L3N-with two scores, one based on the percentage of labeled tumor cells (tumor proportion score, TPS) and the other on labeled immune cells (combined proportion score, CPS) in a consecutive retrospective series of 232 ovarian cancers. PD-L1 expression was more frequent in high grade serous carcinoma (27.5% with E1L3N clone and 41.5% with QR1 clone), grade 3 endometrioid carcinoma (25% with E1L3N clone and 50% with QR1 clone), and clear-cell carcinomas (27.3% with E1L3N clone and 29.6% with QR1 clone) than other histological subtypes with CPS score. Using the CPS score, 17% of cases were labeled with E1L3N vs 28% with QR1. Using the TPS score, 14% of cases were positive to E1L3N vs 17% for QR1. For TPS and CPS, respectively, 77% and 78% of the QR1 cases were concordant with E1L3N for the thresholds of 1%. Overall and progression-free survival between PD-L1 positive and PD-L1 negative patients were not different across all histological types, and each subtype in particular for serous carcinomas expressing PD-L1. Expression of PD-L1 is relatively uncommon in epithelium ovarian tumors. When positive, usually <10% of tumor cells are labeled. QR1 clone and CPS appear the best tools to evaluate PD-L1 expression

Severe Viral Hepatitis in a Patient with Chronic Lymphocytic Leukemia (CLL) Complicated with Autoimmune Haemolytic Anemia (AIAH), Treated with Steroids

International audienceInfectious complications are a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL) due to impaired immunity secondary to the disease itself and to the immunosuppressive therapies administered to these patients. We report a 78-year-old woman with CLL who was treated with steroids for autoimmune hemolytic anemia (AIHA). A few weeks later, she was admitted for severe acute hepatitis with disseminated intravascular coagulation (DIC). Despite the symptomatic treatment of DIC, standard reanimation and probabilistic antibiotics, the patient died within 24h with severe hepatic failure. Autopsy was in favor of a disseminated viral infection with esophageal, hepatic and pulmonary cytopathologic lesions with acidophilic intranuclear inclusions suggestive of herpes virus, even though HSV 1 and 2, CMV and HHV6 PCRs were negative. This case of severe viral hepatitis with esophagitis occurring three weeks after the introduction of high-dose steroid treatment for AIHA in a CLL patient calls for anti-herpetic prophylaxis in such patients, immunodepressed by their diseases and the treatment they receive