Advanced PDAC carries a dismal prognosis with a 5-year survival rate of 3%. While treated as an even population, previous retrospective studies suggested significant different survival rates for patients (pts) with lung-only metastases (mets) when compared to other pts. This study aims to explore prospectively the difference in survival outcome based on initial site of metastases in synchronous metastatic PDAC. This is a prospective observational study including all adult pts with synchronous metastatic PDAC in BACAP (national Anatomo-Clinical Database on Pancreatic Adenocarcinoma). Data regarding pts demographics, tumor characteristics, and survival outcomes were analyzed. Primary endpoint was overall survival (OS), defined as the time from diagnosis to death or most recent follow-up. Overall, 504 pts were included [52.4% male, mean age 69 years] of which 31 (6.2%), 58 (11.5%), 363 (72%) and 51 (10.1%) pts had lung-only, peritoneal-only, liver-only and multi-site mets at diagnosis, respectively. Most patients (79.2%) received at least one line of chemotherapy. Patients with lung-only mets were older (38.7% were > 75 years old), mostly male (61.3%) and 22.6% received at least 3 lines of chemotherapy (vs 15.5% for other patients). Median OS was significantly different according to mets site (p=0.003) (Table), with a trend towards better PFS when lung-only mets: 6.3 vs 5.4, 4.5 and 2.4 mo when peritoneal-only, liver-only and multi-site mets, respectively (p=0188). Table: 1682PGroupNEvent (%)OS (mo)95% CILung-only2925 (86.2)11.7[9.3; 14.6]Peritoneal-only5849 (84.5)9.2[5.5; 12.9]Liver-only362334 (92.3%)7.2[6.1; 8.1]Multi-site5250 (96.2%)4.1[2.3; 5.0]Total501458 (91.4%)7.2[6.1 ;8.1]p=0.003 Open table in a new tab p=0.003 Pts with lung-only mets represented 6.2% of synchronous metastatic PDAC pts and exhibited improved survival. These results suggest that a subset of pts with synchronous metastatic PDAC could benefit from more aggressive locoregional treatments. Underlying biological mechanisms contributing to survival difference are under investigation.

Several studies have linked the E3 ubiquitin ligase TRIP12 (Thyroid hormone Receptor Interacting Protein 12) to the cell cycle. However, the regulation and the implication of this protein during the cell cycle are largely unknown. In this study, we show that TRIP12 expression is regulated during the cell cycle, which correlates with its nuclear localization. We identify an euchromatin-binding function of TRIP12 mediated by a N-terminal intrinsically disordered region. We demonstrate the functional implication of TRIP12 in the mitotic entry by controlling the duration of DNA replication that is independent from its catalytic activity. We also show the requirement of TRIP12 in the mitotic progression and chromosome stability. Altogether, our findings show that TRIP12 is as a new chromatin-associated protein with several implications in the cell cycle progression and in the maintenance of genome integrity.

Background MMR testing is performed to screen Lynch Syndrome, evaluate the prognosis of colorectal cancer (CRC) and predict the efficacy of PD1/PDL1 blockade in all tumor types. Two methods are available: immunohistochemistry (IHC) using antibodies against MMR proteins and molecular biology (MB) for assessing microsatellite instability (MSI). Classically, dMMR tumor corresponds to loss of expression of two proteins (MLH1 and PMS2 or MSH2 and MSH6) associated with MSI. Atypical profiles of dMMR tumors have sporadically been described. The aim of our study was to describe the frequency and characteristics of these atypical cases. Methods All MMR testing performed in our center between 2007 and 2017 were checked to select cases with both available IHC and MB. Then, all dMMR cases were reviewed to identify atypical cases which were defined by: isolated loss of expression of one protein, loss of expression of two proteins without MSI, normal expression of the four proteins with MSI, aberrant loss of proteins, or MSI-low. Biological data of atypical cases were controlled and clinical data were collected for each case. Results 4948 MMR tests were performed, 3800 had both available IHC and MB data, and 585 were dMMR (15 %). Among them, 97 cases were atypical and after biological control, 8 cases were re-classified typical; allowing to finally identify 89 atypical cases: 60 CRC, 10 endometrial carcinoma, 8 digestive non CRC and 11 others types of cancers. A strong correlation with genetic syndromes was observed for those atypical profiles. Table . 2015P Isolated PMS2 or MSH6 loss n = 53 Expression of the four proteins n = 5 MSH2/MSH6 or MLH1/PMS2 loss n = 16 Aberrant loss of proteins n = 15 MSI 43 3 - 13 MSI low 1 2 8 - MSS * 9 - 8 2 Clinical characteristics Predominantly CCR Genetic predisposition syndrome (73%) Exclusively CCR or endometrial Genetic predisposition syndrome (≥40%) Predominantly Non CRC (63%) None (* MSS: microsatellite stability) Conclusions Even using controlled IHC and MB, 15% of dMMR tumors have an atypical profile. These atypical cases mainly involve non CRC cancer with a strong prediction for Lynch syndrome. Their therapeutic impact particularly for immunotherapy should be now evaluated. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background Overall survival (OS) of locally advanced esophageal cancer remains poor with a 5-year survival of 15-34%. The standard treatment is definitive radiotherapy delivered with oxaliplatin-based chemotherapy (RCT). Majority of patients (pts) die due to non-complete response, local recurrence and/or metastatic progression and the efficacy of definitive RCT need to be increased. The immune checkpoint inhibitors, anti-programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1), demonstrated promising antitumor activity and manageable safety profile when used as monotherapy in metastatic esophageal squamous cell carcinoma. PD-L1 expression increased in esophageal cancer pts after neoadjuvant RCT but still associated with poor OS. The immune tumor microenvironment for tumor response has raised novel hypotheses regarding newer immunomodulatory approaches during radiotherapy, especially abscopal effect to improve local and distant outcome. Durvalumab (MEDI4736) is a selective high affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. We hypothesize that combining durvalumab with RCT can increase local response to treatment and prevent distant metastases. Trial design This multicentric, open-label, comparative phase II trial plans to randomize (1:1) 120 pts (≥18 years old, WHO Clinical trial identification NCT03777813. Legal entity responsible for the study Unicancer GI tumors. Funding AstraZeneca. Disclosure L. Quero: Research grant / Funding (institution): AstraZeneca. E.L. Cohen-Jonathan Moyal: Research grant / Funding (institution): AstraZeneca. A. Modesto: Research grant / Funding (institution): AstraZeneca. All other authors have declared no conflicts of interest.

BACKGROUND:The association between liver stiffness measurements (LSM) and mortality has not been fully described. In particular the effect of LSM on all-cause mortality taking sustained virological response (SVR) into account needs further study. METHODS:HIV/HCV participants in the French nation-wide, prospective, multicenter ANRS CO13 HEPAVIH cohort, with ≥1 LSM by FibroScan (FS) and a detectable HCV RNA when the first valid FS was performed were included. Cox proportional hazards models with delayed entry were performed to determine factors associated with all-cause mortality. LSM and SVR were considered as time dependent covariates. RESULTS:1,062 patients were included from 2005 to 2015 (69.8% men, median age 45.7 years (IQR 42.4-49.1)). 21.7% had baseline LSM >12.5 kPa. Median follow-up was 4.9 years (IQR 3.2-6.1). 727 (68.5%) were ever treated for HCV: 189 of them (26.0%) achieved SVR. 76 deaths were observed (26 liver-related, 10 HIV-related, 29 non-liver-non-HIV-related, 11 of unknown cause). At the age of 50, the mortality rate was 4.5% for patients with LSM ≤12.5 kPa and 10.8% for patients with LSM >12.5 kPa. LSM >12.5 kPa (adjusted Hazard Ratio [aHR] = 3.35 [2.06; 5.45], p<0.0001), history of HCV treatment (aHR = 0.53 [0.32; 0.90], p = 0.01) and smoking (past (aHR = 5.69 [1.56; 20.78]) and current (3.22 [0.93; 11.09]) versus never, p = 0.01) were associated with all-cause mortality independently of SVR, age, sex, alcohol use and metabolic disorders. CONCLUSION:Any LSM >12.5 kPa was strongly associated with all-cause mortality independently of SVR and other important covariates. Our results suggest that close follow-up of these patients should remain a priority even after achieving SVR.

L'AAP est l'intervention à visée curative dans les adénocarcinomes du très-bas rectum localement évolués et les carcinomes épidermoïdes de l'anus non répondeurs à la radiochimiothérapie. Nous y avons associé une reconstruction par colostomie périnéale avec irrigation antérograde et néoappendicostomie selon Malone. Notre objectif est de présenter les résultats carcinologiques et fonctionnels dans notre centre. Tous les patients opérés entre 1999 et 2016 d'une AAP avec Malone pour cancer ont été inclus. Le critère de jugement principal était la survie globale à 5 ans. Les critères secondaires étaient les résultats fonctionnels évalués par les scores CCIS et FIQL, et les complications post-opératoires. 80 patients ont été inclus avec un suivi médian de 91 mois (95 %IC[70,4 ;116,6]). Le taux de survie global à 5 ans était de 74,9 %. Le taux de complication post-opératoire était de 65,0 % (n = 52) dont 53,8 % (n = 43) de Dindo-Clavien ≤ II. Les taux de survie à 5 ans global et sans récidive étaient de 74,9 % et 74,8 %. À terme, le taux d'utilisation était de 82,5 % (n = 66). Le CCIS médian était 9,0 [1,0 ;18,0] et le FIQL 2,8 [1,3 ;4,0]. La colostomie périnéale avec procédé de Malone est une alternative fiable à la colostomie iliaque après AAP, avec des résultats carcinologiques équivalents et des résultats fonctionnels satisfaisants.

Background: Hepatitis C virus (HCV) and HIV infections are associated with higher risk of autoimmune diseases and T-cell dysfunction. Setting: We evaluate prevalence and factors associated with the presence of autoimmune antinuclear (ANA), anti-smooth muscle actin (aSMA), and anti-liver kidney microsome (aLKM1) antibodies (Ab) in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era. Methods: A cross-sectional observational study nested in the ANRS CO13 HEPAVIH cohort (NCT number: NCT03324633). We selected patients with both ANA testing and T-cell immunophenotyping determination during the cohort follow-up and collected aLKM1 and aSMA data when available. Logistic regression models were built to determine factors associated with the presence of autoAb. Results: Two hundred twenty-three HCV/HIV-coinfected patients fulfilled selection criteria. Prevalence of ANA and aSMA was 43.5% and 23.2%, respectively, and both were detected in 13.3% of patients. Isolated aSMA were detected in 9.9% and aLKM1 in 2 patients. In multivariable analysis, only a low nadir CD4 T-cell count was significantly associated with ANA detection. Conclusions: ANA and aSMA detection remain frequent in HCV/HIV-coinfected patients during the post-combined antiretroviral therapy era, despite fair immune restoration. These results advocate for a close monitoring of ANA before immune checkpoint inhibitor therapy in these patients with greater caution for those with a low nadir CD4 T-cell count.

Objectives Although common among patients coinfected with HIV and hepatitis C virus (HCV), sleep disturbances (SD) are still poorly documented in this population in the HCV cure era. This longitudinal study aimed at analysing SD in HIV-HCV coinfected patients and identifying their clinical and sociobehavioural correlates. Methods We used 5-year annual follow-up data from 1047 participants in the French National Agency for Research on Aids and Viral Hepatitis Cohort 13 'Hepatite et VIH' (ANRS C013 HEPAVIH) cohort of HIV-HCV coinfected patients to identify clinical (medical records) and behavioural (self-administered questionnaires) correlates of SD (mixed-effects logistic regression). SD were identified using one item documenting the occurrence of insomnia or difficulty falling asleep (ANRS 'Action Coordonnee 24' self-reported symptoms checklist), and two items documenting perceived sleep quality (Center for Epidemiologic Studies Depression and WHO Quality of Life HIV-specific brief scales). Results Seven hundred and sixteen (68.4%) patients with completed self-administered questionnaires reported SD at their most recent follow-up visit. In the multivariable model, hazardous alcohol consumption (Alcohol Use Disorders Identification Test-Consumption score 4 for men, 3 for women) (adjusted odds ratio =1.61; 95% confidence interval: 1.09-2.36), depressive symptoms (6.78; 4.36-10.55) and the number of other physical and psychological self-reported symptoms (1.10; 1.07-1.13) were associated independently with SD after adjustment for sex, age and employment status. HCV cure was not associated significantly with SD. Conclusion SD remain frequent in HIV-HCV coinfected patients and are associated with a series of modifiable behavioural risk factors. independent of HCV cure, improved screening and comprehensive management of alcohol use, physical and psychological self-reported symptoms and depression are essential in this population. Closer investigation of these risk factors of SDs may both increase sleep quality and indirectly improve patients' clinical outcomes. Copyright (C) 2019 Wolters Kluwer Health, Inc. All rights reserved.

Background: The consensus molecular subtypes (CMS) of colon cancer only accounts for inter-tumor heterogeneity so far. To overcome this limitation and describe intratumor heterogeneity, we split colon tumor transcriptomes as weighted linear combinations of the four CMS. This leads to identify pure samples, corresponding to a unique CMS, and mixed samples, corresponding to several CMS. Using the PETACC8 cohort, we evaluate the prognostic impact of this new weighted CMS classification. Methods: Paired Nanostring and Affymetrix data were available for the CIT training series (n = 198). NanoString expression data (172 genes) were available for 1779 samples from the PETACC8 trial validation cohort. A random forest classifier (rfc) of the CMS was trained on the Nanostring CIT data and then applied to PETACC8 samples. Using linear regressions, we identified for each sample the weighted linear combination of CMS centroids with minimal distance to its transcriptome profile. Results: Applying rfc to PETACC8 confirmed clinical and molecular data of the CMS classification previously published. Applying the weighted classifier to PETACC8 yielded 42.6% of pure tumors, displaying a unique CMS signature, and 57.4% of mixed tumors, displaying at least 2 CMS signatures (each weighting more than 20%). Mixed tumors were synthetized by their top 2 CMS components (major/minor). Therefore, we defined 16 subgroups with prevalence ranging from 2.1% to 18.3%. MMR deficiency and BRAF mutations were found enriched in pure CMS1, CMS1/CMS3 and CMS3/CMS1 mixed tumors. The pure CMS3 was the only subtype enriched for RAS mutations. For DFS univariate Cox analysis of this 16 subtype classification revealed a significant worse prognostic impact of CMS4 signature either pure or combined to any other CMS signature. The worst prognostic was observed in CMS3/CMS4 subtype (HR = 2.43 CI[1.6-3.7], followed by CMS1/CMS4 (HR = 2.36 CI[1.5-3.6] CMS4/CMS1 (HR = 2.3 CI[1.6-3.5]), CMS1/CMS3 (HR = 2 CI[1.3-3.1]) and CMS4/CMS3 (HR = 1.9 CI[1.2-3]) . These results were confirmed after adjusting for significant clinical variables. Conclusions: Taking into account the intra tumor heterogeneity brings additional information to colon cancer stage III prognostication. Legal entity responsible for the study: Fédération Francophone de Cancérologie Digestive. Funding: Merck KGA. Disclosure: All authors have declared no conflicts of interest.

Introduction: At the time of diagnosis, 14 to 17% of patients have synchronous colorectal liver metastases (CRLMs). Their presence is considered as a factor of poor prognosis and of early recurrence. Three types of treatment are possible: the "classic" strategy, the "combined" strategy, and the "reverse" strategy. The purpose of our study is to analyze the results of these three strategies on the overall survival rate, the survival rate without recurrence and the complication rate. Methods: All patients treated for CRLMs between October 2000 and May 2015 were included in a single center. Three groups were created based on their treatment: 1/ classic: treatment of primary tumor, then liver; 2/ combined: primary tumor and liver treatment during the same surgery; 3/ reverse: liver, then primary tumor. Results: 209 patients were included, 149 in the classic group, 34 in the combined group and 26 in the reverse group. The overall survival rate at 5 years was 44% without significant differences, with a median survival rate of 50 months. The survival rate without recurrence was 24% at 5 years, with a median survival rate without recurrence of 13 months, without significant difference. The complication rate was significantly higher in the combined group, while the hepatic resections were less extended. Conclusion: All three strategies are feasible with a comparable survival rate. However, the combined strategy does not give the best oncological results even if the patients have more limited hepatic resections, probably caused by an excess of major postoperative complications.

Germline mutations of the POLE gene are responsible for polymerase proofreading-associated polyposis syndrome (PPAP). These mutations were hypothesised to predispose to extra-gastrointestinal tumours (ovary, endometrium, brain), but this association has not been confirmed so far. We report a family with an autosomal dominant inheritance of PPAP due to a c.1089C>A; p.Asn363Lys mutation in the proofreading exonuclease domain of POLE. Ten patients presenting a history of colorectal tumours and three patients with polyposis are indexed in this family. Three carriers (including siblings and a distant cousin at 30, 45 and 52 respectively) and another member (at 37 not tested) presented glioblastoma. This is the second family reported to carry this mutation. Among the four glioblastomas in the family that we report, both show similar pathology: giant cell glioblastoma. These cases suggest that the c.1089C>A germline POLE mutation may confer an increased risk of brain cancer [incidence 17.4% (4/23) in mutation carriers combining the two families]. More observations are needed to support this hypothesis. It seems that not all mutations of POLE are equally associated with extra-gastrointestinal tumours. Although carriers of a mutation responsible for PPAP should benefit from screening for colorectal and uterine cancer, due to the rapid evolution of glioblastoma the value of neurological follow-up and brain imaging screening remains questionable. Nevertheless, considering the limitations of standard therapy for glioblastoma, mutation status could be useful for targeting therapy. The biological mechanism linking POLE mutation to glioblastoma remains to be determined.

Introduction: The Rubbia-Brandt classification showed that the Tumor Regression Grade had an influence on OS and DFS after resection of CRLM. This study evaluates the histological response and isolates the predictive factors of histological response and its impact on OS and DFS. Methods: 150 patients were included by a single center. Every slide was analyzed in double-blinded. Two groups were isolated, the responders (R) who had TRG between 1 and 3 and the non-responders (NR) who had TRG 4-5. Univariate and multivariate analysis were performed. Results: 74 patients were responders and 76 were non-responders. The predictive factors of non-response after NACT are (multivariate analysis): NACT cycles > 7, non-radiological response to NACT, absence of reverse strategy, repeated hepatectomy and colonic tumor. OS at 1, 3 and 5 years were 91%, 57% and 36%, respectively. DFS at 1, 3 and 5 years were 43%, 14% and 11%, respectively. Median OS and DFS of the responders were significantly higher (OS: 4.5 vs 2.8 years, p=0.006; DFS: 14 vs 8.3 months, p= 0.002). Without microscopic tumor emboli, the OS independent prognostic factors were: histological response, male, anti-angiogenic agents, two-steps protocol and N+ status. The DFS independent prognostic factors were: histological response, size > 3 cm, R1 resection and targeted therapy. Conclusion: The histological response must be specified in the anatomopathological reports because it has a major impact on OS and DFS. A non-radiological response and a number of NACT > 7 are the two most pertinent predictive factors of non-histological response.

Background: Currently, metastatic colorectal cancer is treated as a homogeneous disease and only RAS mutational status has been approved as a negative predictive factor in patients treated with cetuximab. The aim of this study was to evaluate if recently identified molecular subtypes of colon cancer are associated with response of metastatic patients to first line therapy.Patients and methods: We collected and analysed 143 samples of human colorectal tumours with complete clinical annotations, including the response to treatment. Gene expression profiling was used to classify patients in three to six classes using four different molecular classifications. Correlations between molecular subtypes, response to treatment, progression-free and overall survival were analysed.Results: We first demonstrated that the four previously described molecular classifications of colorectal cancer defined in non-metastatic patients also correctly classify stage IV patients. One of the classifications is strongly associated with response to FOLFIRI (P = 0.003), but not to FOLFOX (P = 0.911) and FOLFIRI + Bevacizumab (P = 0.190). In particular, we identify a molecular subtype representing 28% of the patients that shows an exceptionally high response rate to FOLFIRI (87.5%). These patients have a two-fold longer overall survival (40.1 months) when treated with FOLFIRI, as first-line regimen, instead of FOLFOX (18.6 months).Conclusions: Our results demonstrate the interest of molecular classifications to develop tailored therapies for patients with metastatic colorectal cancer and a strong impact of the first-line regimen on the overall survival of some.patients. This however remains to be confirmed in a large prospective clinical trial. (C) 2017 Elsevier Ltd. All rights reserved.