A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine.

Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits

Detection of oncogenic virus genomes and gene products in lung carcinoma

We investigated a series of 122 cases of small cell lung carcinomas and non-small cell lung carcinomas for the presence of several viruses that are known to be oncogenic in humans. Thus, viral genomes (DNA) and/or RNA transcripts and/or proteins of human papillomaviruses (HPV) 16, 18, 31, 33, 51, Epstein–Barr virus (EBV), human herpesvirus 8 (HHV-8), human cytomegalovirus (HCMV) and simian virus 40 (SV40) were investigated on tissue sections (prepared in tissue microarrays) with different techniques of immunohistochemistry and in situ hybridisation. None of the cases displayed a single positive tumour cell for all the viruses tested whatever the technique applied. Of note, in five cases of tumours with lymphoid infiltrates, we detected scattered EBV (EBER)-positive bystander lymphocytes. In three cases, a faint nuclear staining was found with the anti-latent nuclear antigen/LANA1 (HHV-8) antibody. These cases were checked by PCR with two sets of primers (orf 26 and orf 75) and remained negative for this latter virus. Taken together, our data strongly suggest that the conventional human oncogenic viruses (HPV, EBV, HCMV, HHV-8 and SV40) are unlikely to play some role in the development of lung carcinomas

T1 Vertebra Pedicular Osteoid Osteoma: Minimally Invasive Surgical Resection Aided by New Integrated Navigation to 3D Imaging Device

We hereby describe a minimally invasive resection of a T1 pedicular osteoid osteoma next to the vertebral canal. The patient had an 18-month report of painful radiculopathy. We performed the surgery under 3D imaging guidance using navigation with an all-in-one device. Full procedure irradiation was 1.17 mSv for a 181-picture acquisition. Complete operative time incision to closure was 58 minutes. Despite sparing the vertebral stability without any fixation, the tumor resection was well-margined, thanks to the focused guidance. After surgery, the patient had complete relief of his symptoms at the 6-month follow-up. 3D imaging system coupled to navigation made the procedure safe without consuming time. The single Surgivisio® device allows comfortable 3D minimally invasive spine navigation surgery with the ergonomics of a C-arm

Prevalence and distribution of HPV genotypes and cervical-associated lesions in sexually active young French women following HPV vaccine

International audienceBackgroundDespite the availability of safe and effective HPV vaccines in France, more than 80% of girls remain unvaccinated.SettingA regional university hospital referral center in France.ObjectiveTo estimate the overall prevalence and distribution of HPV in vaccinated, sexually active young French women who were screened for cervical cancer by cytology and HPV testing.MethodsHigh-risk HPV (HR-HPV) prevalence, genotype-specific prevalence and extent of multiple infections were assessed in 125 cervical samples from females with available vaccine data using hc2 assay and INNO-LiPA assay. HPV status was analyzed in accordance with cytological data.ResultsIn our series, mean age was 23 years, overall prevalence of HR-HPV was 52% and was correlated with the lesion grade. The diversity of HPV genotypes was broad. Single HR-HPV infections were identified in 11%, 21% and 47% of women with NILM, ASC-US/-H and LSIL respectively. Multiple infections with HR-HPV were detected in 28% of the specimens. Only 24.5% of women with NILM presented infections with 2 genotypes or more, vs 28% of women with ASC-US/-H and 35% of women with LSIL. The overall prevalence of genotypes covered by the quadrivalent vaccine was low (5.9%); with 4.2%, 0%, 0.8% and 0.8% for HPV 16, HPV 18, HPV 6 and HPV 11 respectively.ConclusionAmong HPV-vaccinated young women, HR-HPV are detected at a high rate, and an association with the grade of cytological abnormalities was observed. However, HPV 16 and 18, both targeted by the vaccines, are remarkably rare among young French women since program implementation

Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study.

Epithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD-L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM. Immunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression-free survival (PFS). Inter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1-5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS. E1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM

Mucinous Neoplasms Of The Appendix And Peritoneum: Virtual Microscopy For Histomorphologic Assessment And Interobserver Diagnostic Reproducibility : SY02.06 | Telepathology

INTRODUCTION / BACKGROUND: Among gastrointestinal (GI) tumours, pseudomyxoma peritonei (PMP) from appendiceal origin has unique clinical and morphologic features. Due to the relative paucity of patients and the absence of therapeutic consensus, evaluation and refinement of the morphologic criteria used for assessment of the disease are still difficult. As a result, a uniformly accepted classification is still lacking. In collaboration with NJ Carr, who initiated the conference consensus process, in Basingstoke, and on behalf of the French group RENA-PATH, 11 experienced GI pathologists agreed to participate to a virtual workshop, in order to assess inter-observer variability in PMP diagnosis and staging. AIMS: The goal of the study was to evaluate, for appendiceal and peritoneal mucinous neoplasms, the degree of concordance in the identification of diagnostic histological criteria by experienced pathologists, and to assess the degree of inter-individual variation in the application of WHO classification (2010) and TNM staging system (7th edition). METHODS: A single section stained with hematoxylin and eosin from 9 resected cases of mucinous neoplasms was selected by members of RENA-PATH. All digitalized at a maximum resolution (X40) using an HAMMAMATSU scanner system, to ensure that all participants evaluate exactly the same tumour areas; 1 to 16 questions were prepared for each case. On Teleslide web platform, interactive services provided by TRIBVN. All submitted cases were then reviewed by a panel of 11 pathologists with specific expertise and interest in PMP. Data were analyzed using SAS program. RESULTS: Whole slide set evaluated by all participants; no abstention or “unknown diagnosis” for any submitted case. Agreement for classification, WHO 2010: -Appendiceal mucinous neoplasms: LAMN 83 %; mucinous adenocarcinoma 92%. -Peritonei mucinous carcinoma: Low grade 91.7%; high grade 91.7%. -Disagreement on the concept of High Grade AMN defined by low power architecture of LAMN + high grade cytology. -Agreement for using pTNM classification (82%) in PMP. -Pushing Invasion (PI) and dissection by acellular mucin (DAM) in appendix wall are not reproducible criteria and need to be better defined. -Criteria need to be redefined to use HAMN according to a majority of participants. -The identification of signet ring cells is not reproducible; the lesion needs to be better defined. -Invasion of organs and pattern of invasion (broatfront invasion / classic by irregular glands or single cells with desmoplasia) are not reproducible criteria. -Improvement in staging assessment is neede

Impact of Cytomegalovirus infection on the outcome of patients with cirrhosis: a preliminary study

International audienc

HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53

Background:Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established. The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy.Methods:Human papillomavirus DNA was determined using an INNO-LiPA-based assay in tumour tissue of 107 patients with locally advanced SCCAC. Patients were treated with radiotherapy, with or without concurrent chemotherapy consisting of a fluoropyrimidine and mitomycin C. Expression of p16 and p53 was determined using immunohistochemistry. Exons 2-11 of TP53 in tumour tissue were sequenced.Results:DNA of high-risk HPV types was detected in 93 out of 107 tumours (87%), all of which overexpressed p16 (HPV+/p16+). Of 14 HPV-negative (HPV-) tumours (13%), 10 (9%) were p16-negative (HPV-/p16-) and 4 (4%) overexpressed p16 (HPV-/p16+). Patients with HPV-/p16-disease had inferior 3-year locoregional control (LRC) (15%) compared with patients with HPV+/p16+ tumours (82%,