Novel mutations in antiviral multiresistant HSV‐2 genital lesion: A case report

HSV‐2 antiviral resistance mainly occurs in immunocompromised patients and especially in HIV‐positive individuals receiving long‐term antiviral treatment. Those situations can be challenging as few alternatives are available for HSV infection management. To describe clinical and virological significance of two novel potential HSV‐2 resistance mutations after treating an obese patient with a pseudotumoral genital HSV‐related lesion. Consecutive different antiviral treatments were used: valacyclovir (VACV) then foscarnet (FOS) then topical cidofovir (CDV) and finally imiquimod. Under VACV, genotypic resistance testing revealed a novel mutation within viral thymidine kinase (TK, gene UL23) not previously reported but probably accounting for antiviral resistance: W89G, similar to W88R mutation reported in HSV‐1 TK, known to be associated with ACV resistance for HSV‐1. Under FOS, while initial mutations were still present, a second genotypic resistance testing performed on persisting lesions showed a novel mutation within viral DNA polymerase (DNA pol, gene UL30): C625R. All three antivirals used in this case are small molecules and pharmacokinetics of VACV, FOS, and CDV have not been evaluated in animals and there are very few studies in human. As small molecules are poorly bound to proteins and distribution volume is increased in obese patients, there is risk of underdosage. This mechanism is suspected to be involved in emergence of resistance mutation and further data is needed to adapt, closely to patient profile, antiviral dosage. This report describes a chronic HSV‐2 genital lesion, with resistance to current antivirals and novel mutations within viral TK and DNA pol which may confer antiviral resistance

Impact of vulvar reconstruction on the accuracy of a nomogram for predicting local recurrence after surgery for vulvar cancer

International audienceBACKGROUND DATA: Vulvar carcinoma is a rare disease accounting for 3%-5% of all gynaecological cancers. Although surgery is the standard treatment at an early stage, the outcomes are highly correlated with clear resection margins. Therefore, surgical defects can be important and require reconstruction. The aim of this study was to evaluate vulvar reconstructions using a previously validated nomogram predicting the risk of local recurrence at 2 years. METHODS: Patients who underwent surgery for vulvar cancer between 1998 and 2017 were extracted from eight FRANCOGYN centres. We estimated the probability of local recurrence at 2 years using a previously validated nomogram and compared it with actual relapse in patients with or without vulvar reconstruction. Patients were clustered into tiertiles according to their nomogram score: low-, intermediate-, and high-risk for local relapse probability. RESULTS: We reviewed 254 patients, of whom 49 underwent immediate vulvar reconstruction. The predicted and actual probability of two-year local relapse were 20.1% and 15.7%, respectively, with a concordance index of 0.75. In the low- and intermediate-risk groups, the difference between predicted and observed recurrence was less than 10% in patients with or without vulvar reconstruction. For the high-risk group, the difference reached 25% and observed recurrence probability was lower in patients who underwent vulvar plasty compared with those who did not (20.0% vs. 36.2%, respectively). Local recurrence-free survival rates following vulvar reconstruction were comparable at two years (82.1% vs. 84.8%, respectively, p = 0.26). CONCLUSION: Vulvar reconstruction after surgical resection for vulvar cancer is safe. Vulvar reconstruction should be considered in aggressive cases to decrease local recurrence

Transcriptomic Profiling of Upper Tract Urothelial Carcinoma: Bladder Cancer Consensus Classification Relevance, Molecular Heterogeneity, and Differential Immune Signatures

International audienceAnalyses of large transcriptomics data sets of muscle-invasive bladder cancer (MIBC) have led to a consensus classification. Molecular subtypes of upper tract urothelial carcinomas (UTUCs) are less known. Our objective was to determine the relevance of the consensus classification in UTUCs by characterizing a novel cohort of surgically treated ≥pT1 tumors. Using immunohistochemistry (IHC), subtype markers GATA3-CK5/6-TUBB2B in multiplex, CK20, p16, Ki67, mismatch repair system proteins, and PD-L1 were evaluated. Heterogeneity was assessed morphologically and/or with subtype IHC. FGFR3 mutations were identified by pyrosequencing. We performed 3'RNA sequencing of each tumor, with multisampling in heterogeneous cases. Consensus classes, unsupervised groups, and microenvironment cell abundance were determined using gene expression. Most of the 66 patients were men (77.3%), with pT1 (n = 23, 34.8%) or pT2-4 stage UTUC (n = 43, 65.2%). FGFR3 mutations and mismatch repair-deficient status were identified in 40% and 4.7% of cases, respectively. Consensus subtypes robustly classified UTUCs and reflected intrinsic subgroups. All pT1 tumors were classified as luminal papillary (LumP). Combining our consensus classification results with those of previously published UTUC cohorts, LumP tumors represented 57.2% of ≥pT2 UTUCs, which was significantly higher than MIBCs. Ten patients (15.2%) harbored areas of distinct subtypes. Consensus classes were associated with FGFR3 mutations, stage, morphology, and IHC. The majority of LumP tumors were characterized by low immune infiltration and PD-L1 expression, in particular, if FGFR3 mutated. Our study shows that MIBC consensus classification robustly classified UTUCs and highlighted intratumoral molecular heterogeneity. The proportion of LumP was significantly higher in UTUCs than in MIBCs. Most LumP tumors showed low immune infiltration and PD-L1 expression and high proportion of FGFR3 mutations. These findings suggest differential response to novel therapies between patients with UTUC and those with MIBC. Copyrigh