Les adénocarcinomes à cellules indépendantes : une entité particulière au sein des cancers gastriques ?

Background: Specific prognosis and chemoresistance of signet-ring cell (SRC) gastric adenocarcinoma have been reported and debated, questioning utility of perioperative chemotherapy for these tumors. Objective: To assess the impact of SRC on survival in resected gastric adenocarcinoma and to assess if prognostic factors of SRC and Non-SRC adenocarcinoma including the use of perioperative chemotherapies do differ. Methods: 1799 adenocarcinoma consecutively treated from 1997 to 2010 in 19 French centers by subtotal or total gastrectomy were included in a retrospective study. A D2 lymphadenectomy was performed for antropyloric tumors and a modified D2 for upper tumors. The diagnosis of SRC was based on the presence, on resected specimen, of isolated carcinoma cells containing mucin. Results: A total gastrectomy was performed in 979 (54,4%) patients. SRC type was diagnosed in 899 (50%) patients. Patients with SRC tumor were more frequently female, younger, malnourished, with lower ASA score and had more extended tumors than Non-SRC patients. Median survival in patients with Non-SRC carcinoma was of 51 months compared to 26 months in patients with SRC carcinoma (p 60 years, linitis and involvement of adjacent organs. Contrary to Non-SRC tumors, pre and postoperative chemotherapies did not significantly impact survival of resected SRC adenocarcinoma. Conclusion: SRC-type exhibit worse prognosis, its own prognostic factors and seems poorly sensitive to perioperative chemotherapies. Non-SRC and SRC adenocarcinoma should be considered as different entities in future therapeutic trials.Contexte : Le mauvais pronostic des adénocarcinomes gastriques à cellules indépendantes (ADCI) reste discuté et la potentielle chimiorésistance de ce type histologique, évoquée par certains travaux, remet en question l'utilité d'une chimiothérapie péri-opératoire pour ces tumeurs. Objectifs : Évaluer l'impact sur la survie, du type histologique ADCI, chez des patients opérés d'un adénocarcinome gastrique et identifier si les facteurs pronostiques indépendants, incluant la réalisation d'une chimiothérapie péri-opératoire, diffèrent entre les tumeurs ADCI et non-ADCI. Méthodes : 1799 patients consécutifs opérés d'un adénocarcinome gastrique entre 1997 et 2010 dans 19 centres français ont été inclus dans cette étude multicentrique rétrospective. Un curage ganglionnaire de type D2 modifié (D1,5) était réalisé pour les tumeurs du fundus et de type D2 était réalisé pour les tumeurs antro-pyloriques. Le diagnostic d'ADCI reposait sur la présence, sur la pièce, de cellules tumorales isolées contenant de la mucine. Résultats: Une gastrectomie totale était réalisée chez 979 (54,4%) patients. Une tumeur de type ADCI a été diagnostiquée chez 899 (50%) patients. Les patients ayant un ADCI étaient plus fréquemment des femmes, d'âge jeune, dénutris, avec un score ASA plus faible et une tumeur plus évoluée que les patients présentant une tumeur non-ADCI. La survie médiane des patients non-ADCI était de 51 mois contre 26 mois pour les patients ADCI (p<0,001). En analyse multivariée, le type histologique ADCI restait un facteur indépendant de mauvais pronostic (HR=1,182). Les facteurs pronostiques propres au type histologique ADCI, non retrouvés dans le groupe non-ADCI, étaient un âge supérieur à 60 ans, un aspect de linite, et l'envahissement d'organes adjacents à l'estomac. À l'inverse des tumeurs non-ADCI, le fait de recevoir une chimiothérapie pré- ou postopératoire n'influençait pas significativement la survie globale des patients opérés d'un ADCI Conclusion: Le type histologique ADCI est de mauvais pronostic, possède ses facteurs pronostiques propres et semble peu sensible aux chimiothérapies périopératoires. Les tumeurs ADCI et non-ADCI devraient donc être considérées comme des entités distinctes dans les futurs essais thérapeutiques

Stoma-free survival after anastomotic leak following rectal cancer resection : worldwide cohort of 2470 patients

Funding Information: The TENTACLE-Rectum study was funded by Medtronic External Research Program. The authors declare no other conflict of interest.Peer reviewedPublisher PD

VEGF-A directly impacts immune system in tumor microenvironment : modulative effects by anti-angiogenic treatments

L'évolution d'une cellule humaine vers une cellule tumorale est dépendante de l'acquisition successive d'anomalies leur conférant un avantage de croissance et leur permettant une expansion clonale. Parmi ces anomalies, la capacité d'échapper à la surveillance continue du système immunitaire s'est révélée être indispensable. Pour y aboutir, les cellules tumorales développent différents mécanismes parmi lesquels l'instauration d'un microenvironnement immunosuppresseur favorisant l'accumulation de cellules immunorégulatrices, telles que les lymphocytes T régulateurs(Treg), ainsi que l'inhibition des fonctions des lymphocytes T CD8+ effecteurs. Cette perte de fonction, appelée "exhaustion" ou épuisement, passe notamment par l'expression à leur surface de molécules de co-stimulation inhibitrices telles que PD-1, Tim3, CTLA4 et LAG3. Au sein de ce microenvironnement tumoral, le vascular endothelial growth factor (VEGF)-A a longtemps été étudié pour ses propriétés pro-angiogéniques, aboutissant au développement de traitements anti-angiogéniques. Cependant, le VEGF-A possède également des propriétés immunomodulatrices favorisant l'échappement des cellules tumorales à la surveillance par le système immunitaire en inhibant la maturation des cellules dendritiques, en induisant l'accumulation de cellules myéloïdes suppressives (MDSC) et en favorisant l'accumulation de Treg en périphérie. Mais l'action directe du VEGF-A sur les lymphocytes T CD8+ et Treg infiltrant la tumeur, n'a jamais été étudiée. L'objectif de ce travail était donc d'évaluer l'effet directe de la voie VEGF-A/VEGFR sur les lymphocytes cytotoxiques CD8+ mais également les Treg intratumoraux, tout d'abord dans des modèles précliniques murins puis chez l'homme. Dans un premier temps, nous avons montré, dans un modèle murin, que le VEGF-A, présent au sein du microenvironnement tumoral, augmentait l'expression de PD-1 mais également Tim3, CTLA4 et LAG3 à la surface des lymphocytes T CD8+ infiltrant la tumeur, participant ainsi de façon directe à l'épuisement de ces lymphocytes intratumoraux. Au contraire, un traitement par anti-angiogénique ciblant la voie VEGF-A/VEGFR limitait l'expression de ces molécules de co-stimulation inhibitrices à la surface de ces mêmes lymphocytes et par conséquent restaurait une immunité antitumorale. Nous avons ensuite confirmé ces résultats chez l'homme, en montrant qu'une stimulation in vitro des lymphocytes T CD8+ humains permettait une augmentation de l'expression des molécules de co-stimulation inhibitrices(PD-1 et Tim3), dépendante de l'expression de VEGFR2 et de la concentration de VEGF-A dans le milieu de culture. In vivo, nous avons également observé une corrélation entre le phénotype épuisé(PD-1+/Tim3+) des lymphocytes T CD8+ intratumoraux et la concentration intratumorale de VEGF, dans des adénocarcinomes gastriques opérés, après analyse en immunofluorescence. Parallèlement à l'effet direct du VEGF-A sur l'épuisement et la perte de fonction des lymphocytes T CD8+ intratumoraux, nous avons également montré que le VEGF-A agissait sur les Treg intratumoraux. Ainsi, dans un modèle murin de cancer colorectal, un traitement par anti-angiogénique ciblant la voie VEGF-A/VEGFR réduisait la proportion de Tregs intratumoraux de façon significative. De plus, l'inhibition de la voie VEGF-A/VEGFR modifiait aussi le phénotype de ces Tregs, avec une diminution de l'expression de PD-1 et de Tim3 à leurs surfaces. Cette modification de phénotype n'était observée que sur les Tregs exprimant des récepteurs de type 2 au VEGF. L'ensemble de ces résultats semble donc confirmer l'effet immunomodulateur du VEGF-A en démontrant pour la première fois son impact direct sur l'épuisement des lymphocytes T CD8+ infiltrant la tumeur, mais également sur le recrutement et les propriétés immunosuppressive des Tregs intratumoraux.Tumor development is dependent on the successive acquisition of cellular abnormalities conferring growth advantage and allowing clonal expansion. Among these abnormalities, the ability to avoid the surveillance of the immune system has been shown to be essential and constitute a "hallmark" for cancer. To achieve this, tumor develop numerous mechanisms, including the development of an immunosuppressive microenvironment that promotes accumulation of immunoregulatory cells, such as regulatory T cells (Treg), as well as inhibition of intratumoral effector CD8+ T cells. This loss of function, named exhaustion, is characterized by expression of immune inhibitory receptors, such as PD-1, CTLA-4, Tim3 and a progressive loss of function. Within this tumor microenvironment, vascular endothelial growth factor (VEGF)-A has long been studied for its proangiogenic properties, leading to the development of anti-angiogenic therapy, but VEGF-A exhibits also immunomodulatory properties that promote escape to the surveillance of immune system., including accumulation of myeloid-derived suppressor cells (MDSC) and Treg. However, direct role of VEGF-A on intratumoral CD8+ T cells and intratumoral Treg was never assessed. The aim of this study was to assess the impact of VEGF-A/VEGFR blockade on CD8+ T cells but also on intratumoral Treg, first in murine preclinical models and then in humans. First, we demonstrated in a mouse model of colorectal cancer (CT26 tumor) that VEGF-A, produced by tumor cells, increases PD-1 expression on CD8+ T cells but also increases expression of other inhibitory receptors, such as Tim3, CTLA-4 and LAG3. Thus, tumor-derived VEGF-A directly promotes CD8+ T cells exhaustion in tumor. On the contrary, VEGFR-A/VEGFR blockade with anti-VEGF-A antibody or tyrosine kinase inhibitor targeting VEGFR results in a significant reduction of PD-1, Tim3, CTLA-4 and LAG3 expression on intratumoral CD8+ T cells, restoring antitumor immunity. These results were then confirmed in humans. Thus, after in vitro stimulation of human CD8+ T cells, we demonstrated that inhibitory receptors (PD-1 and Tim3) expression was correlated with VEGFR2 expression on CD8+ T cells and with VEGF-A concentration in culture milieu. In gastric adenocarcinoma, we also observed a significant correlation between exhausted phenotype (PD-1+/Tim3+) on intratumoral CD8+ T cells and intratumoral VEGF-A expression, using immunofluorescence staining. In addition to the direct impact of VEGF-A on exhaustion and loss of function of intratumoral CD8+ T cells, we also showed that VEGF-A acts on intratumoral regulatory T cells. Thus, in a mouse model of colorectal cancer (CT26 tumor), VEGF-A/VEGFR blockade with anti-VEGF-A antibody reduces significantly the proportion of Treg cells among CD4+ T cells infiltrating the tumor. Moreover, VEGF-A/VEGFR blockade also altered the phenotype of intratumoral Treg, with a decrease in PD-1 and Tim3 expression, resulting in modifications of their properties. These modifications observed on their phenotype was only observed on Treg expressing type 2 VEGF-receptor (VEGFR2). Therefore these results confirm the immunomodulatory effects of VEGF-A/VEGFR pathway and demonstrate for the first time its direct impact on intratumoral CD8+ T cells exhaustion, but also its effect on recruitment and immunosuppressive properties of intratumoral Treg

Colorectal screening: We have not caught up. A surge of colorectal cancer after the coronavirus disease 2019 (COVID-19) pandemic?

International audienc

Postoperative outcomes after laparoscopic or open gastrectomy. A national cohort study of 10,343 patients

International audienceBackgroundLaparoscopy for gastric cancer has not been as popular compared with other digestive surgeries, with conflicting reports on outcomes. The aim of this study focuses on the surgical techniques comparing open and laparoscopy by assessing the morbi-mortality and long-term complications after gastrectomy.MethodsA retrospective study (2013–2018) was performed on a prospective national cohort (PMSI). All patients undergoing resection for gastric cancer with a partial gastrectomy (PG) or total gastrectomy (TG) were included. Overall morbidity at 90 post-operative days and long-term results were the main outcomes. The groups (open and laparoscopy) were compared using a propensity score and volume activity matching after stratification on resection type (TG or PG).ResultsA total of 10,343 patients were included. The overall 90-day mortality and morbidity were 7% and 45%, with reintervention required in 9.1%. High centre volume was associated with improved outcomes. There was no difference in population characteristics between groups after matching. An overall benefit for a laparoscopic approach after PG was found for morbidity (Open = 39.4% vs. Laparoscopy = 32.6%, p = 0.01), length of stay (Open = 14[10–21] vs. Laparoscopy = 11[8–17] days, p<0.0001). For TG, increased reintervention rate (Open = 10.8% vs. Laparoscopy = 14.5%, p = 0.04) and increased oesophageal stricture rate (HR = 2.54[1.67–3.85], p<0.001) were encountered after a laparoscopic approach. No benefit on mortality was found for laparoscopic approach in both type of resections after adjusted analysis.ConclusionsLaparoscopy is feasible for PG with a substantial benefit on morbidity and length of stay, however, laparoscopic TG should be performed with caution, with of higher rates of reintervention and oesophageal stricture

Centralization and Oncologic Training Reduce Postoperative Morbidity and Failure-to-rescue Rates After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies: Study on a 10-year National French Practice.

International audienceObjective: Evaluate at a national level the postoperative mortality (POM), major morbidity (MM) and failure-to-rescue (FTR) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) across time and according to hospital-volume.Background: CRS/HIPEC is an effective therapeutic strategy commonly used to treat peritoneal surface malignancies. However, this aggressive approach has the reputation to be associated with a high POM and MM.Methods: All patients treated with CRS/HIPEC between 2009 and 2018 in France were identified through a national medical database. Patients and perioperative outcomes were analyzed. A cut-off value of the annual CRS/HIPEC caseload affecting the 90-day POM was calculated using the Chi-squared Automatic Interaction Detector method. A multivariable logistic model was used to identify factors mediating 90-day POM.Results: A total of 7476 CRS/HIPEC were analyzed. Median age was 59 years with a mean Elixhauser comorbidity index of 3.1, both increasing over time (P 70 years (P = 0.002), Elixhauser comorbidity index ≥8 (P = 0.006), lower gastro-intestinal origin, (P < 0.010), MM (P < 0.001), and <45 procedures/yr (P = 0.002).Conclusion: In France, CRS/HIPEC is a safe procedure with an acceptable 90-day POM that could even be improved through centralization in high-volume centers

Does An Ileo-anal Anastomosis Decrease the Rate of Successful Pregnancy Compared to an Ileorectal Anastomosis? A National Study of 1,491 Patients

International audienceObjective: Report the rate of successful pregnancy in a national cohort of women with either an ileal pouch anal (IPAA) or ileo-rectal (IRA) anastomosis constructed after colectomy for inflammatory bowel disease (IBD) or polyposis.Summary Background Data: Fertility after IPAA is probably impaired. All available data are corroborated by only small sample size studies. It is not known whether construction of IPAA versus IRA influences the odds of subsequently achieving a successful pregnancy, especially with increased utilization of the laparoscopic approach.Methods: All women (age: 12-45 y) undergoing IRA or IPAA in France for polyposis or IBD, between 2010-2020, were included. A control population was defined as women aged from 12 to 45 years undergoing laparoscopic appendicectomy during the same period. The odds of successful pregnancy were studied using an adjusted survival analysis.Results: 1,491 women (IPAA=872, 58%; IRA=619, 42%) were included. A total of 220 deliveries (15%) occurred during the follow-up period of 71 months [39-100]. After adjustment, the odds of successful pregnancy was not significantly associated with type of anastomosis (after IPAA: HR=0.79, 95%CI=0.56-1.11, P=0;17). The laparoscopic approach increased the odds of achieving successful pregnancy (HR=1.79, 95%CI=1.20-2.63, P=0.004). IRA and IPAA significantly impacted fertility when compared to the control population (P<0.001).Conclusions: In this large cohort study, total colectomy for polyposis or IBD was associated with reduced fertility compared to the general population. No difference in odds of achieving successful pregnancy was found between IRA and IPAA after adjustment. This analysis suggests laparoscopic surgery may be associated with greater likelihood of pregnancy

Effective initial management of anastomotic leak in the maintenance of functional colorectal or coloanal anastomosis

International audiencePurposeThe present study assessed the factors associated with the maintenance of a functional anastomosis in a large consecutive series of patients with anastomotic leakage (AL).MethodsAll consecutive patients presenting with AL after colorectal or coloanal anastomosis (2012–2019) were analyzed. The primary end point was a functional anastomosis without a stoma at 1 year.ResultsA total of 156 patients were included. AL was initially treated by antibiotics (38%), drainage (43%) or urgent surgery (19%). Initial treatment of AL was not adequate in 24.3%, and reintervention in the form of drainage or surgery was required. A total of 60.9% of patients had a functional anastomosis without a stoma 1 year after surgery. Factors associated with the risk of anastomotic failure at 1 year were diabetes (odds ratio [OR] = 4.24 [95% confidence interval {CI} 1.39–14.24] p = 0.014), neoadjuvant chemoradiotherapy (OR = 3.03 [95% CI 1.14–8.63] p = 0.03) and Grade B (OR = 6.49 [95% CI 2.23–21.74] p = 0.001) or C leak (OR = 35.35 [95% CI 9.36–168.21] p < 0.001). Among patients treated initially by drainage, side-to-end or J-pouch anastomoses were significantly associated with revision of the anastomosis compared to end-to-end (OR = 12.90, p = 0.04).ConclusionAfter acute AL following coloanal or colorectal anastomosis, 60.9% of patients had a functional anastomosis without a stoma at the 1 year of follow-up. The type of treatment of AL influenced the risk of anastomotic failure