Christine Clavel

Regression of high-grade cervical intraepithelial neoplasia with TG4001 targeted immunotherapy

OBJECTIVEnWe sought to evaluate the safety and efficacy of TG4001 in patients with human papillomavirus (HPV) 16-related cervical intraepithelial neoplasia (CIN) 2/3 at 6 and 12 months.nnnSTUDY DESIGNnIn all, 21 patients with HPV 16-related CIN 2/3 received 3 weekly subcutaneous injections of TG4001. Regression of the CIN 2/3 lesion and the clearance of HPV 16 infection were monitored by cytology, colposcopy, and HPV DNA/messenger RNA (mRNA) detection. A clinical response was defined by no CIN 2/3 found on conization, or no conization performed because not suspected at cytology or colposcopy.nnnRESULTSnTen patients (48%) were evaluated as clinical responders at month 6. Nine patients experienced an improvement of their HPV 16 infection, by mRNA ± DNA eradication. HPV 16 mRNA clearance was associated with CIN 2/3 cytologic and colposcopic regression in 7 of 10 patients. At month 12, 7 of 8 patients without conization reported neither suspicion of CIN 2/3 relapse nor HPV 16 infection. The remaining patient was lost to follow-up.nnnCONCLUSIONnThese promising data warrant further development of TG4001 in CIN 2/3 treatment.

Human papillomavirus type 16 E6 variants in France and risk of viral persistence.

BackgroundOnly a small portion of HPV 16 infections persist and can lead to cervical intraepithelial lesions and cancer. Factors that favour HPV persistence versus clearance are still poorly understood, but several studies have suggested that HPV intra-type variants may influence persistence and clinical outcome. The aim of this study was to assess the possible association between HPV 16 variants and the risk for viral persistence in the general population of France.MethodsOne hundred and forty two women infected with HPV 16 with normal cytology, without previous treatment for cervical lesions, and with a valid second follow-up visit 4 to 16u2009months later, were selected from patients participating in routine cervical cancer screening in the Reims HPV Primary Screening Cohort Study. HPV intra-type variants were determined by sequencing the HPV 16 E6 open reading frame, and were compared for viral persistence at the second visit using odds ratios (OR) to estimate relative risk.ResultsAlthough no statistically significant differences in risk for persistence were observed by the HPV 16 variant lineage, European variants containing the polymorphism 350u2009T (EUR-350u2009T) appeared to persist more often than those containing 350u2009G (EUR-350u2009G) (ORu2009=u20091.6, 95% CIu2009=u20090.8-3.4).ConclusionsNo strong differences were observed in the risk of viral persistence for the HPV 16 variants that predominate in France.

Deep brush‐based cytology in tonsils resected for benign diseases

A fraction of oropharyngeal cancer (OPC), especially in the tonsil, is caused by human papillomavirus (HPV), mainly HPV16. Noninvasive diagnostic methods to detect precancerous lesions in the tonsil would be useful, e.g., liquid‐based cytology (LBC). However, ill‐characterized precancerous lesions may be hidden in the depth of the tonsillar crypts. We therefore conducted a study on HPV and tonsillar precancerous lesions to evaluate, among other things, the utility of LBC obtained by deep brushing of the resected tonsils. Two hundred non‐paediatric patients (mean age: 30.3 years) who underwent tonsillectomy for infection‐related conditions (69%) or other conditions (mainly obstructive sleep apnoea, 31%) were included. An ultra‐sensitive Luminex bead‐based platform was used to test for the DNA of 21 mucosal HPV types; 56% of slides were unsatisfactory due to low number of squamous epithelial cells or the masking effect of a large number of lymphocytes. Three patients (1.5%; 95% CI: 0.5–4.3) showed suspicious cytological findings (atypical squamous cells‐cannot exclude high‐grade squamous intraepithelial lesion, ASC‐H) while 3 others were HPV‐positive (2 for HPV16 and 1 for HPV39). None of the ASC‐H patients and HPV‐positive patients showed dysplasia at histological examination. The rarity of HPV infection in the tonsil conflicts with the relatively frequent detection of the virus in the mouth. In conclusion, aggressive deep brushing of tonsils, while hardly applicable in vivo, is unlikely to be a reliable method to detect precancerous lesions. The absence of OPC screening modalities places the priority on multi‐purpose primary prevention strategies, i.e., HPV vaccination and reduction of smoking and drinking.

Prevalence of human herpesviruses infections in non-malignant tonsils: the SPLIT study: KOURIEH et al.

To assess the prevalence of all known human herpesviruses (HHV) in tonsils of an age‐stratified large sample of immunocompetent children and adults.

Rôle des oncoprotéines E6 et E7 d’HPV16 sur le phénotype invasif des cellules cancéreuses

Introductionxa0: Les papillomavirus humains a haut risque (HPV- HR) constituent un groupe de virus oncogenes a tropisme epithelial impliques dans 99xa0% des cancers du col de l’uterus et dans 20xa0% a 50xa0% des cancers des voies aerodigestives superieures. L’HPV de typexa016 est le genotype le plus frequemment retrouve dans ces cancers. Le processus de carcinogenese mediee par ces virus est directement lie a la surexpression des deux oncoproteines virales E6 et E7, qui degradent respectivement les proteines cellulaires p53 et pRB. Les actions conjuguees de ces oncoproteines ont pour effet de remettre les cellules differenciees en cycle tout en inhibant l’apoptose induite par cette proliferation non controlee. Le but de notre etude est de determiner l’implication dans le processus d’invasion tumorale des HPV-HR, notamment dans la regulation de l’expression des metallo-proteinases matricielles (MMP) et des molecules d’adherence. Methodesxa0: Dans une premiere approche des lignees pulmonaires 16HBE, A549, BZR de degre invasif croissant non infectees par HPV et des cellules CaSki infectees par HPV-16 ont ete transfectees par des plasmides codant E6 ou E7. L’expression de MMP2, et MT1-MMP a ete evaluee par RT-PCR semi-quantitative dans ces cellules. Nous avons, dans une seconde approche, inhibe les oncoproteines E6/E7 par technique d’ARN interference dans les cellules CaSki. La localisation des molecules d’adherence a ete etudiee par immunohistochimie, la capacite infiltrante des cellules traitees mesuree en chambre de Boyden inversee, enfin l’expression des MMP2 et MT1-MMP a ete quantifiee par PCR temps reel. Resultatsxa0: L’expression ou la surexpression des oncoproteines E6 ou E7 dans les lignees 16HBE, A549, BZR et CaSki n’a pas modifie l’expression des MMP2 et MT1-MMP. L’inhibition de l’oncoproteine E7 dans les cellules CaSki a entrainee une baisse de la capacite infiltrante des cellules, mais cet effet ne s’est accompagne ni de changement de localisation des molecules d’adherence ni de modification d’expression de MMP2. En revanche l’expression de la MT1-MMP etait augmentee par traitement d’ARN interferent anti-E7. Conclusionsxa0: Nos resultats demontrent donc que l’oncoproteine virale E7 joue un role dans la regulation du potentiel infiltrant des cellules tumorales CaSki. Travail soutenu par la Region Champagne-Ardenne

Clinical Aspects of Matrix Metalloproteinases

Tumor metastasis is ultimately responsible for most cancer deaths. Tumor invasion and metastasis represent a multistep process including basement membrane disruption, stromal infiltration, angiogenesis, intravasation and extravasation and invasion of target organs by tumor cells. All these events require degradation and remodeling of the extracellular matrix (ECM) by various proteolytic enzymes. Among these enzymes, matrix metalloproteinases (MMPs) play a key role at various levels. These enzymes are associated with degradation of a broad spectrum of ECM components. MMPs are also implicated in the remodeling the ECM by creating and maintaining a microenvironment that facilitates angiogenesis and growth of tumors. Thus, in the last years, the exploration of MMPs expression has led to a large bunch of studies on their biological activities and their clinical implications.