Systemic chemotherapy in the treatment of anal canal carcinoma

Les carcinomes épidermoïdes du canal anal sont très généralement diagnostiqués à un stade d’extension locale ou locorégionale. Seuls 5 % sont métastatiques au moment du diagnostic. Les formes évoluées sont donc beaucoup plus rares que les formes locorégionales et correspondent le plus souvent à des évolutions métastatiques métachrones de maladies initialement localisées. La chimiothérapie systémique a une place à la fois dans le traitement des formes localisées, en association à la radiothérapie, et dans le traitement des formes métastatiques. Cet article a pour objectif de préciser les indications actuelles et les modalités de la chimiothérapie dans le traitement de ces cancers à partir d’une synthèse des données publiées et en prenant en compte les recommandations des différents sociétés savantes.Epidermoid carcinomas of the anal canal are rare and usually localized at the time of diagnosis. Only few patients develop distant metastases. Systemic chemotherapy has a key role in the treatment of these patients, either in combination with radiotherapy for locally advanced or alone for disseminated diseases. The aim of this article is examine the indications and the modalities of the chemotherapy in all stages of anal canal cancer through a updated systematic review of published data and taking into account current available guidelines

Complex interplay between β-catenin signalling and Notch effectors in intestinal tumorigenesis

International audienceAims The activation of β-catenin signalling is a key step in intestinal tumorigenesis. Interplay between the β-catenin and Notch pathways during tumorigenesis has been reported, but the mechanisms involved and the role of Notch remain unclear. Methods Notch status was analysed by studying expression of the Notch effector Hes1 and Notch ligands/receptors in human colorectal cancer (CRC) and mouse models of Apc mutation. A genetic approach was used, deleting the Apc and RBP-J or Atoh1 genes in murine intestine. CRC cell lines were used to analyse the control of Hes1 and Atoh1 by β-catenin signalling. Results Notch signalling was found to be activated downstream from β-catenin. It was rapidly induced and maintained throughout tumorigenesis. Hes1 induction was mediated by β-catenin and resulted from both the induction of the Notch ligand/receptor and Notch-independent control of the Hes1 promoter by β-catenin. Surprisingly, the strong phenotype of unrestricted proliferation and impaired differentiation induced by acute Apc deletion in the intestine was not rescued by conditional Notch inactivation. Hyperactivation of β-catenin signalling overrode the forced differention induced by Notch inhibition, through the downregulation of Atoh1, a key secretory determinant factor downstream of Notch. This process involves glycogen synthase kinase 3 β (GSK3β) and proteasome-mediated degradation. The restoration of Atoh1 expression in CRC cell lines displaying β-catenin activation was sufficient to increase goblet cell differentiation, whereas genetic ablation of Atoh1 greatly increased tumour formation in Apc mutant mice. Conclusion Notch signalling is a downstream target of β-catenin hyperactivation in intestinal tumorigenesis. However, its inhibition had no tumour suppressor effect in the context of acute β-catenin activation probably due to the downregulation of Atoh1. This finding calls into question the use of γ-secretase inhibitors for the treatment of CRC and suggests that the restoration of Atoh1 expression in CRC should be considered as a therapeutic approach

MRI-Based Radiomics Input for Prediction of 2-Year Disease Recurrence in Anal Squamous Cell Carcinoma

International audiencePurpose: Chemo-radiotherapy (CRT) is the standard treatment for non-metastatic anal squamous cell carcinomas (ASCC). Despite excellent results for T1-2 stages, relapses still occur in around 35% of locally advanced tumors. Recent strategies focus on treatment intensification, but could benefit from a better patient selection. Our goal was to assess the prognostic value of pre-therapeutic MRI radiomics on 2-year disease control (DC). Methods: We retrospectively selected patients with non-metastatic ASCC treated at the CHU Bordeaux and in the French FFCD0904 multicentric trial. Radiomic features were extracted from T2-weighted pre-therapeutic MRI delineated sequences. After random division between training and testing sets on a 2:1 ratio, univariate and multivariate analysis were performed on the training cohort to select optimal features. The correlation with 2-year DC was assessed using logistic regression models, with AUC and accuracy as performance gauges, and the prediction of disease-free survival using Cox regression and Kaplan-Meier analysis. Results: A total of 82 patients were randomized in the training (n = 54) and testing sets (n = 28). At 2 years, 24 patients (29%) presented relapse. In the training set, two clinical (tumor size and CRT length) and two radiomic features (FirstOrder_Entropy and GLCM_JointEnergy) were associated with disease control in univariate analysis and included in the model. The clinical model was outperformed by the mixed (clinical and radiomic) model in both the training (AUC 0.758 versus 0.825, accuracy of 75.9% versus 87%) and testing (AUC 0.714 versus 0.898, accuracy of 78.6% versus 85.7%) sets, which led to distinctive high and low risk of disease relapse groups (HR 8.60, p = 0.005). Conclusion: A mixed model with two clinical and two radiomic features was predictive of 2-year disease control after CRT and could contribute to identify high risk patients amenable to treatment intensification with view of personalized medicine

Prediction of survival with second-line therapy in biliary tract cancer: Actualisation of the AGEO CT2BIL cohort and European multicentre validations

BACKGROUND: The benefit of second-line chemotherapy (L2) over standard first-line (L1) gemcitabine plus cisplatin (GEMCIS) or oxaliplatin (GEMOX) chemotherapy in advanced biliary tract cancer (aBTC) is unclear. Our aim was to identify and validate prognostic factors for overall survival (OS) with L2 in aBTC to guide clinical decisions in this setting. METHODS: We performed a retrospective analysis of four prospective patient cohorts: a development cohort (28 French centres) and three validation cohorts from Italy, UK and France. All consecutive patients with aBTC receiving L2 after GEMCIS/GEMOX L1 between 2003 and 2016 were included. The association of clinicobiological data with OS was investigated in univariate and multivariate Cox analyses. A simple score was derived from the multivariate model. RESULTS: The development cohort included 405 patients treated with L1 GEMOX (91%) or GEMCIS. Of them, 55.3% were men, and median age was 64.8 years. Prior surgical resection was observed in 26.7%, and 94.8% had metastatic disease. Performance status (PS) was 0, 1 and 2 in 17.8%, 52.4% and 29.7%, respectively. Among 22 clinical parameters, eight were associated with OS in univariate analysis. In multivariate analysis, four were independent prognostic factors (p < 0.05): PS, reason for L1 discontinuation, prior resection of primary tumour and peritoneal carcinomatosis. The model had the Harrell's concordance index of 0.655, a good calibration and was validated in the three external cohorts (N = 392). CONCLUSION: We validated previously reported predictive factors of OS with L2 and identified peritoneal carcinomatosis as a new pejorative factor in nearly 800 patients. Our model and score may be useful in daily practice and for future clinical trial design

Molecular analysis of consequences of activation of Wnt/b-catenin pathway : description of autophagy during intestinal carcinogenesis

Plus de 80% des cancers colorectaux sont initiés par la perte de fonction du gène Apc. Afin d’identifier de nouvelles cibles thérapeutiques, nous avons utilisé des modèles murins présentant des mutations du gène Apc et recherché par des analyses de puces à ADN de nouveaux événements moléculaires impliqués au cours de la carcinogenèse intestinale.Cette approche nous a permis d’identifier une activation de la signalisation Notch tout au long du processus tumoral. Toutefois, cette activation n’est pas un élément clé de la progression tumorale puisque son inhibition n’empêche pas le phénotype tumoral induit par la perte du gène Apc. En parallèle, nos travaux ont permis d’identifier une induction de l’autophagie tout au long de la carcinogenèse intestinale. L’activation de ce processus biologique ouvre, quant à lui, de nouvelles perspectives thérapeutiques dans le traitement du CCR.Over 80% of colorectal cancers are linked to an Apc mutation. To identify new therapeutic targets, we used mouse models with Apc mutations and performed microarray experiments to identify key molecular events involved in intestinal carcinogenesis. This approach allowed usto identify an activation of the Notch signaling all along tumor progression. However, this induction is dispensable for tumor development since its inhibition did not prevent the Apc phenotype. In addition, we have identified an induction of autophagy throughout intestinal carcinogenesis which appears to be an attractive therapeutic target in the treatment of CRC patients

Cancers superficiels de l’estomac : épidémiologie, diagnostic et prise en charge

Stomach cancers are diagnosed at an early stage in less than 10% of cases in Europe. They are superficial tumours, involving the mucosa and the submucosa only. Node involvement is the most important prognostic factor for these tumours. To determine the optimal therapeutic strategy, it is necessary to carry out a precise work-up involving an endoscopy, with chemical or virtual colorations and an echo-endoscopy. Gastric surgery is the reference treatment. Nowadays, endoscopic tumour resection is a validated curative alternative. High quality medical expertise is needed for those tumours with a good prognosis, after evaluating risk for node involvement, and should be followed by Helicobacter pylori eradication and regular endoscopic surveillance

Analyse moléculaire des conséquences de l'activation de la voie Wnt/b-caténine (mise en évidence del'autophagie au cours de la carcinogenèse intestinale.)

Plus de 80% des cancers colorectaux sont initiés par la perte de fonction du gène Apc. Afind identifier de nouvelles cibles thérapeutiques, nous avons utilisé des modèles murinsprésentant des mutations du gène Apc et recherché par des analyses de puces à ADN denouveaux événements moléculaires impliqués au cours de la carcinogenèse intestinale.Cette approche nous a permis d identifier une activation de la signalisation Notch tout au longdu processus tumoral. Toutefois, cette activation n est pas un élément clé de la progressiontumorale puisque son inhibition n empêche pas le phénotype tumoral induit par la perte dugène Apc. En parallèle, nos travaux ont permis d identifier une induction de l autophagie toutau long de la carcinogenèse intestinale. L activation de ce processus biologique ouvre, quant àlui, de nouvelles perspectives thérapeutiques dans le traitement du CCR.Over 80% of colorectal cancers are linked to an Apc mutation. To identify new therapeutictargets, we used mouse models with Apc mutations and performed microarray experiments toidentify key molecular events involved in intestinal carcinogenesis. This approach allowed usto identify an activation of the Notch signaling all along tumor progression. However, thisinduction is dispensable for tumor development since its inhibition did not prevent the Apcphenotype. In addition, we have identified an induction of autophagy throughout intestinalcarcinogenesis which appears to be an attractive therapeutic target in the treatment of CRCpatients.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

Cancers superficiels de l’œsophage : épidémiologie, diagnostic et traitement

In Europe, oesophageal cancers are diagnosed at an early stage in less than 10% of the cases. They are superficial tumours whose invasion is limited to the mucosae and the submucosa. Synchronous node invasion is the most important prognosis factor. Oesophagectomy is the benchmark treatment. Nowadays, endoscopic resection is a validated curative therapeutic alternative. Accurate endoscopic evaluation using chemical or virtual colouring as well as an echoendoscopy, followed by an expert pathological review, must be conducted beforehand. It can be realised for good prognosis tumours after evaluation of the synchronous node invasion or its risk. After completion, regular endoscopic follow-ups are compulsory to detect local relapse