Nicolas Williet | Universite Jean Monnet - Saint-Etienne (original) (raw)

Papers by Nicolas Williet

Supplemental material, SupplTab1 for Folfirinox versus gemcitabine/nab-paclitaxel as first-line t... more Supplemental material, SupplTab1 for Folfirinox versus gemcitabine/nab-paclitaxel as first-line therapy in patients with metastatic pancreatic cancer: a comparative propensity score study by Nicolas Williet, Angélique Saint, Anne-Laure Pointet, David Tougeron, Simon Pernot, Astrid Pozet, Dominique Bechade, Isabelle Trouilloud, Nelson Lourenco, Vincent Hautefeuille, Christophe Locher, Jérome Desrame, Pascal Artru, Anne Thirot Bidault, Bertrand Le Roy, Denis Pezet, Jean-Marc Phelip and Julien Taieb in Therapeutic Advances in Gastroenterology

European Journal of Cancer, 2022

Background. The COVID-19 pandemic caused major oncology care pathway disruption. The CAPANCOVID s... more Background. The COVID-19 pandemic caused major oncology care pathway disruption. The CAPANCOVID study aimed to evaluate the impact on pancreatic adenocarcinoma (PA) – from diagnosis to treatment – of the reorganisation of the health care system during the first lockdown. Methods. This multicentre ambispective observational study included 833 patients diagnosed with PA between September 1st, 2019 and October 31st, 2020 from 13 French centres. Data were compared over three periods defined as before the outbreak of COVID-19, during the first lockdown (March 1st to May 11th, 2020) and after lockdown. Results. During the lockdown, mean weekly number of new cases decreased compared with that of pre-pandemic levels (13.2 vs. 10.8, -18.2%; p=0.63) without rebound in the post-lockdown period (13.2 vs. 12.9, -1.7%; p=0.97). The number of borderline tumours increased (13.6% to 21.7%) whereas the rate of metastatic diseases rate dropped (47.1% to 40.3%) (p=0.046). Time-to-diagnosis and -treatment were not different over periods. Waiting neoadjuvant chemotherapy in resectable tumours was significantly favoured (24.7% to 32.6%) compared with upfront surgery (13% to 7.8%) (p=0.013). The use of mFOLFIRINOX preoperative chemotherapy regimen decreased (84.9% to 69%; p=0.044). After lockdown, the number of borderline tumours decreased (21.7% to 9.6%) and advanced diseases increased (59.7% to 69.8%) (p=0.046). SARS-CoV-2 infected 39 patients (4.7%) causing 5 deaths (12.8%). Conclusion. This cohort study suggests the existence of missing diagnoses and of a shift in disease stage at diagnosis from resectable to advanced diseases with related therapeutic modifications whose prognostic consequences will be known after the planned follow-up.

Inflammatory Bowel Diseases, 2021

Background In cases of loss of response due to mechanistic failure under antitumor necrosis facto... more Background In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma—either ADA dose optimization or switching to vedolizumab or ustekinumab. Methods Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Results Adalimumab was optimized (n = 61 patients, 42 Crohn’s disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or u...

Cancers, 2021

Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces dispar... more Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces disparities and delays in the diagnosis and access to care. Our purposes were to describe the medical path of PDAC patients in the real-life setting and evaluate the overall survival at 1 year. We used the national hospital discharge summaries database system to analyze the management of patients with newly diagnosed PDAC over the year 2016 in Auvergne-Rhône-Alpes region (AuRA) (France). A total of 1872 patients met inclusion criteria corresponding to an incidence of 22.6 per 100,000 person-year. Within the follow-up period, 353 (18.9%) were operated with a curative intent, 743 (39.7%) underwent chemo- and/or radiotherapy, and 776 (41.4%) did not receive any of these treatments. Less than half of patients were operated in a high-volume center, defined by more than 20 PDAC resections performed annually, mainly university hospitals. The 1-year survival rate was 47% in the overall population. Thi...

Cancers, 2021

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line ther... more Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with either GN or FFX as the first-line therapy between 2010 and 2019. Coprimary objectives were progression-free survival (PFS) and overall survival (OS), both estimated using the Kaplan–Meier method. Results: A total of 147 patients (GN: n = 60; FFX: n = 87) were included. Tumor resection rates were similar between the two groups (16.7% vs. 16.1%; p = 1), with similar R0 resection rates (88.9%). Median PFS rates were not statistically different: 9 months (95% CI: 8–13.5) vs. 12.1 months (95% CI: 10.1–14.6; p = 0.8), respectively. Median OS rates were 15.7 months (95% CI: 12.6–20.2) and 16.7 months (95% CI: 14.8–20.4; p = 0.7), respectively. Abdominal pain at the...

Gastroenterology, 2018

manner. Knockdown of APE1 in dysplastic BE cells and EAC cells repressed MMP-14 cellular expressi... more manner. Knockdown of APE1 in dysplastic BE cells and EAC cells repressed MMP-14 cellular expression. Zymography assays indicated reduced MMP-14 activity and sequential impaired MMP-2 activation in APE1-knockdown cells. Further, endocytosis and recycling assays revealed lower levels of MMP-14 that enter recycling step (exocytosis) in APE1-knockdown cells. Immunoprecipitation and Proximity Ligation Assay identified that ARF6, known to regulate MMP-14 exocytosis, as a novel interacting partner of APE1. Furthermore, APE1 silencing or redox function inhibition significantly diminished ARF6 activity. Conclusion: Our findings demonstrate for the first time the role of APE1 redox functions in activation of ARF6-mediated MMP14 exocytosis and tumor invasion. We suggest redox-dependent activation of APE1-ARF6-MMP14 as a novel signaling axis in the invasion and progression of BE and EAC.

Supplemental digital content is available in the text. Objectives The total psoas area index (TPI... more Supplemental digital content is available in the text. Objectives The total psoas area index (TPI) is an emerging alternative to the total skeletal muscle area index as a prognostic factor but has never been evaluated in metastatic pancreatic cancer (mPC). Methods Areas were manually recorded, as previously described. Sex-specific cutoffs were identified by optimum stratification of TPI using log-rank χ2 statistic associated with mortality to define sarcopenic psoas. Progression-free survival (PFS) and overall survival (OS) were the primary objectives. Two period groups were used as internal validation. Results During the period study, 79 patients were treated for mPC. The TPI was correlated with PFS (hazards ratio, 0.81; P = 0.02) and OS (hazards ratio, 0.7; P < 0.001). Optimum thresholds defining sarcopenic psoas were less than 5.73 cm2/m2 in men and less than 4.37 cm2/m2 in women. Patients with sarcopenic psoas (62.0%) had shorter median PFS (2.9 months) compared with the othe...

British Journal of Cancer, 2021

BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resec... more BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group. METHODS: This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. RESULTS: We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /− CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001). CONCLUSIONS: FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in "real-life" patients now have to be confirmed in a Phase 3 randomised trial.

Digestive Diseases and Sciences, 2020

The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other w... more The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems. To compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens. This was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test. Sixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week. In IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient’s preference for the latter regimen, a modification of injection regimen should be systematically proposed.

European Journal of Cancer, 2020

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus... more Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis.

Gastroenterology, 2020

BACKGROUND & AIMS: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-... more BACKGROUND & AIMS: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly expanded; however, clinical trials excluded patients taking immunosuppressive medications such as those with inflammatory bowel disease (IBD). Therefore, we explored real-world effectiveness of coronavirus disease 2019 (COVID-19) vaccination on subsequent infection in patients with IBD with diverse exposure to immunosuppressive medications. METHODS: This was a retrospective cohort study of patients in the Veterans Health Administration with IBD diagnosed before December 18, 2020, the start date of the Veterans Health Administration patient vaccination program. IBD medication exposures included mesalamine, thiopurines, anti-tumor necrosis factor biologic agents, vedolizumab, ustekinumab, tofacitinib, methotrexate, and corticosteroid use. We used inverse probability weighting and Cox's regression with vaccination status as a time-updating exposure and computed vaccine effectiveness from incidence rates. RESULTS: The cohort comprised 14,697 patients, 7321 of whom received at least 1 vaccine dose (45.2% Pfizer, 54.8% Moderna). The cohort had median age 68 years, 92.2% were men, 80.4% were White, and 61.8% had ulcerative colitis. In follow-up data through April 20, 2021, unvaccinated individuals had the highest raw proportion of SARS-CoV-2 infection (197 [1.34%] vs 7 [0.11%] fully vaccinated). Full vaccination status, but not partial vaccination status, was associated with a 69% reduced hazard of infection relative to an unvaccinated status (hazard ratio, 0.31, 95% confidence interval, 0.17-0.56; P < .001), corresponding to an 80.4% effectiveness. CONCLUSIONS: Full vaccination (> 7 days after the second dose) against SARS-CoV-2 infection has an w80.4% effectiveness in a broad IBD cohort with diverse exposure to immunosuppressive medications. These results may serve to increase patient and provider willingness to pursue vaccination in these settings.

Gut, 2020

ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumo... more ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.DesignConsecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn’s disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable ph...

Clinical Gastroenterology and Hepatology, 2019

U stekinumab is approved for treatment of Crohn's disease (CD). 1,2 Few data are available to ass... more U stekinumab is approved for treatment of Crohn's disease (CD). 1,2 Few data are available to assess the usefulness of monitoring inflammatory biomarkers and therapeutic drug monitoring to predict response to ustekinumab. We conducted a prospective study to assess the relationships between these parameters and the clinical outcome at week 16 in active CD patients receiving ustekinumab.

Journal of Crohn's & colitis, Jan 31, 2018

Vedolizumab (VDZ), a humanized monoclonal antibody targeting α4β7 integrin, is effective in induc... more Vedolizumab (VDZ), a humanized monoclonal antibody targeting α4β7 integrin, is effective in induction and maintenance therapy in patients with inflammatory bowel disease (IBD) who have not adequately responded to standard therapies, and high levels of vedolizumab trough levels (VTL) have been associated with clinical remission. The α4β7 integrin binds to endothelial MAdCAM-1 and is up-regulated by retinoic acid (RA). To determine the relations between soluble MAdCAM-1 (sMAdCAM-1) and RA concentrations with clinical remission during VDZ maintenance therapy. In a retrospective study performed in IBD patients treated with VDZ we measured VTL, sMAdCAM-1 and RA concentrations. Among the 62 included patients (38 Crohn's disease) 24 relapsed and 38 stayed in remission between weeks 10 to 30 after VDZ initiation. During this maintenance therapy, median values of VTL and RA were 15.4 µg/mL and 0.97 ng/mL, whereas sMAdCAM-1 was undetectable (< 0.41 ng/mL) in 67.3% of samples. The posit...

Inflammatory bowel diseases, Jan 26, 2018

The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of... more The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD). In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks). At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti-TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the sec...

Digestive Diseases, 2018

Background and Aims: One of the reasons for the failure of infliximab (IFX) is immediate hypersen... more Background and Aims: One of the reasons for the failure of infliximab (IFX) is immediate hypersensitivity reactions (IHR). We aimed to report the efficacy and safety of a tolerance induction protocol in inflammatory bowel diseases (IBD) patients who had previously experienced IHR during IFX infusions. Patients and Methods: We reported all cases of IBD patients who had previously experienced IHR due to IFX and who were submitted to a standardized protocol of tolerance induction to IFX from 2010 to 2015. Results: IHR occurred in a majority of patients (69%) during the first 3 infusions and for half of them after a period of IFX withdrawn. Skin prick tests were negative and only 2 intradermal tests were positive. Basophil activation tests and antidrug antibody measurements were performed in 8 out of 16 patients and were positive in 3 and 4 patients respectively. Induction of tolerance was successful in 69% of patients and IFX was pursued with clinical efficacy > 1 year in 7 patients...

Oncotarget, 2018

Aims: To assess the interest of induction chemotherapy (ICT) intensification before chemoradiothe... more Aims: To assess the interest of induction chemotherapy (ICT) intensification before chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer. Methods: Charts of patients treated between February 2010 and November 2016 with consolidation capecitabin based-CRT were retrospectively reviewed in this bicentric study. Patients who underwent Gemcitabine as ICT (Group G) were compared to patients treated with intensive ICT (group I). Primary objectives were progression-free survival (PFS), defined as the time from the first day of ICT to progression or last follow-up, and Time without treatment (TWT), as the time from the last day of CRT to progression. Results: Patients' characteristics were balanced between group I (Folforinox: n = 24; GemOx: n = 6) and group G (n = 16) including mean age (63.7 vs 68.1 years), and performance status (PS 0-1 :90% vs 93.7%). Median PFS (17.8 months vs 12 months; p = 0.02) and TWT (7.4 months vs 2.5 months p = 0.01) were statistically better in group I vs group G. These results remained statistically and clinically significant by comparing Folfirinox subgroup to Gemcitabine. A trend to a better median overall survival was observed in group I (20.4 months) vs group G (18.3 months; p = 0.07). After adjusting for ICT duration, PS, and CA19.9 level, ICT intensification remains independently prognostic. Toxicity profile was in accordance with Literature. Conclusion: This study shows ICT intensification before CRT is an interesting approach in patients with locally advanced pancreatic cancer. Further studies are needed to confirm these results, and to assess the specific role of CRT in this setting.

Inflammatory bowel diseases, Jan 23, 2018

It has been demonstrated in many chronic conditions, including inflammatory bowel disease (IBD), ... more It has been demonstrated in many chronic conditions, including inflammatory bowel disease (IBD), that better patient knowledge about pathology and treatment improves the course and management of disease. The aim of this study was to develop an updated self-questionnaire to assess patients' level of knowledge of IBD. The IBD-INFO included 3 parts: an original part (Q1) and 2 parts from the translation of the preexisting questionnaires Crohn's and Colitis Knowledge score (CCKNOW) (Q2) and Crohn's and Colitis Pregnancy Knowledge score (CCPKNOW) (Q3). The reliability and discriminatory ability of the questionnaire were validated in 3 groups of non-IBD volunteers with various theoretical knowledge levels. The final questionnaire (64 validated questions) was then tested on 364 in- and out- IBD patients from 4 French university hospitals. The score for each part of the questionnaire was calculated, and factors associated with low scores were identified by univariate and multiva...

Supplemental material, SupplTab1 for Folfirinox versus gemcitabine/nab-paclitaxel as first-line t... more Supplemental material, SupplTab1 for Folfirinox versus gemcitabine/nab-paclitaxel as first-line therapy in patients with metastatic pancreatic cancer: a comparative propensity score study by Nicolas Williet, Angélique Saint, Anne-Laure Pointet, David Tougeron, Simon Pernot, Astrid Pozet, Dominique Bechade, Isabelle Trouilloud, Nelson Lourenco, Vincent Hautefeuille, Christophe Locher, Jérome Desrame, Pascal Artru, Anne Thirot Bidault, Bertrand Le Roy, Denis Pezet, Jean-Marc Phelip and Julien Taieb in Therapeutic Advances in Gastroenterology

European Journal of Cancer, 2022

Background. The COVID-19 pandemic caused major oncology care pathway disruption. The CAPANCOVID s... more Background. The COVID-19 pandemic caused major oncology care pathway disruption. The CAPANCOVID study aimed to evaluate the impact on pancreatic adenocarcinoma (PA) – from diagnosis to treatment – of the reorganisation of the health care system during the first lockdown. Methods. This multicentre ambispective observational study included 833 patients diagnosed with PA between September 1st, 2019 and October 31st, 2020 from 13 French centres. Data were compared over three periods defined as before the outbreak of COVID-19, during the first lockdown (March 1st to May 11th, 2020) and after lockdown. Results. During the lockdown, mean weekly number of new cases decreased compared with that of pre-pandemic levels (13.2 vs. 10.8, -18.2%; p=0.63) without rebound in the post-lockdown period (13.2 vs. 12.9, -1.7%; p=0.97). The number of borderline tumours increased (13.6% to 21.7%) whereas the rate of metastatic diseases rate dropped (47.1% to 40.3%) (p=0.046). Time-to-diagnosis and -treatment were not different over periods. Waiting neoadjuvant chemotherapy in resectable tumours was significantly favoured (24.7% to 32.6%) compared with upfront surgery (13% to 7.8%) (p=0.013). The use of mFOLFIRINOX preoperative chemotherapy regimen decreased (84.9% to 69%; p=0.044). After lockdown, the number of borderline tumours decreased (21.7% to 9.6%) and advanced diseases increased (59.7% to 69.8%) (p=0.046). SARS-CoV-2 infected 39 patients (4.7%) causing 5 deaths (12.8%). Conclusion. This cohort study suggests the existence of missing diagnoses and of a shift in disease stage at diagnosis from resectable to advanced diseases with related therapeutic modifications whose prognostic consequences will be known after the planned follow-up.

Inflammatory Bowel Diseases, 2021

Background In cases of loss of response due to mechanistic failure under antitumor necrosis facto... more Background In cases of loss of response due to mechanistic failure under antitumor necrosis factor agents, it is recommended to switch to another class of biologics. Two different strategies were compared in patients with inflammatory bowel disease (IBD) who were treated with nonoptimized adalimumab (ADA) and experienced a loss of response despite therapeutic trough levels of adalimuma—either ADA dose optimization or switching to vedolizumab or ustekinumab. Methods Patients under maintenance therapy with ADA monotherapy (40 mg every 14 days) and who experienced a secondary loss of response with trough levels > 4.9 μg/mL were included prospectively in this nonrandomized study. The primary end point was the survival rate without therapeutic discontinuation after ADA dose optimization or switching to another class of biologics. Results Adalimumab was optimized (n = 61 patients, 42 Crohn’s disease, 19 ulcerative colitis) or swapped for vedolizumab (n = 40, 20 ulcerative colitis) or u...

Cancers, 2021

Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces dispar... more Pancreatic ductal adenocarcinoma (PDAC) remains a major public health challenge, and faces disparities and delays in the diagnosis and access to care. Our purposes were to describe the medical path of PDAC patients in the real-life setting and evaluate the overall survival at 1 year. We used the national hospital discharge summaries database system to analyze the management of patients with newly diagnosed PDAC over the year 2016 in Auvergne-Rhône-Alpes region (AuRA) (France). A total of 1872 patients met inclusion criteria corresponding to an incidence of 22.6 per 100,000 person-year. Within the follow-up period, 353 (18.9%) were operated with a curative intent, 743 (39.7%) underwent chemo- and/or radiotherapy, and 776 (41.4%) did not receive any of these treatments. Less than half of patients were operated in a high-volume center, defined by more than 20 PDAC resections performed annually, mainly university hospitals. The 1-year survival rate was 47% in the overall population. Thi...

Cancers, 2021

Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line ther... more Background: Gemcitabine/nab-paclitaxel (GN) and FOLFIRINOX (FFX) are two standard first-line therapies for metastatic pancreatic cancer (PC) but have rarely been compared, especially in patients with locally advanced PC (LAPC). Methods: This is a retrospective European multicenter study including patients with LAPC treated with either GN or FFX as the first-line therapy between 2010 and 2019. Coprimary objectives were progression-free survival (PFS) and overall survival (OS), both estimated using the Kaplan–Meier method. Results: A total of 147 patients (GN: n = 60; FFX: n = 87) were included. Tumor resection rates were similar between the two groups (16.7% vs. 16.1%; p = 1), with similar R0 resection rates (88.9%). Median PFS rates were not statistically different: 9 months (95% CI: 8–13.5) vs. 12.1 months (95% CI: 10.1–14.6; p = 0.8), respectively. Median OS rates were 15.7 months (95% CI: 12.6–20.2) and 16.7 months (95% CI: 14.8–20.4; p = 0.7), respectively. Abdominal pain at the...

Gastroenterology, 2018

manner. Knockdown of APE1 in dysplastic BE cells and EAC cells repressed MMP-14 cellular expressi... more manner. Knockdown of APE1 in dysplastic BE cells and EAC cells repressed MMP-14 cellular expression. Zymography assays indicated reduced MMP-14 activity and sequential impaired MMP-2 activation in APE1-knockdown cells. Further, endocytosis and recycling assays revealed lower levels of MMP-14 that enter recycling step (exocytosis) in APE1-knockdown cells. Immunoprecipitation and Proximity Ligation Assay identified that ARF6, known to regulate MMP-14 exocytosis, as a novel interacting partner of APE1. Furthermore, APE1 silencing or redox function inhibition significantly diminished ARF6 activity. Conclusion: Our findings demonstrate for the first time the role of APE1 redox functions in activation of ARF6-mediated MMP14 exocytosis and tumor invasion. We suggest redox-dependent activation of APE1-ARF6-MMP14 as a novel signaling axis in the invasion and progression of BE and EAC.

Supplemental digital content is available in the text. Objectives The total psoas area index (TPI... more Supplemental digital content is available in the text. Objectives The total psoas area index (TPI) is an emerging alternative to the total skeletal muscle area index as a prognostic factor but has never been evaluated in metastatic pancreatic cancer (mPC). Methods Areas were manually recorded, as previously described. Sex-specific cutoffs were identified by optimum stratification of TPI using log-rank χ2 statistic associated with mortality to define sarcopenic psoas. Progression-free survival (PFS) and overall survival (OS) were the primary objectives. Two period groups were used as internal validation. Results During the period study, 79 patients were treated for mPC. The TPI was correlated with PFS (hazards ratio, 0.81; P = 0.02) and OS (hazards ratio, 0.7; P < 0.001). Optimum thresholds defining sarcopenic psoas were less than 5.73 cm2/m2 in men and less than 4.37 cm2/m2 in women. Patients with sarcopenic psoas (62.0%) had shorter median PFS (2.9 months) compared with the othe...

British Journal of Cancer, 2021

BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resec... more BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group. METHODS: This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. RESULTS: We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /− CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001). CONCLUSIONS: FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in "real-life" patients now have to be confirmed in a Phase 3 randomised trial.

Digestive Diseases and Sciences, 2020

The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other w... more The pharmacokinetic equivalence of dose intensification with adalimumab (ADA) 80 mg every other week (EOW) compared to weekly 40 mg has only been supported by modeling systems. To compare the trough levels of ADA (TLA) and the occurrence of anti-ADA antibodies (AAA) between these two treatment regimens. This was a prospective study including all consecutive patients with inflammatory bowel disease (IBD) who had reached a longstanding and deep remission under treatment with ADA 40 mg once a week. In these patients, the ADA regimen was changed from 40 mg/week to 80 mg EOW. TLA and AAA levels using a drug-tolerant assay were monitored before and ten weeks after from the change in the ADA regimen and the results compared by a Wilcoxon paired test. Sixty-two patients (60% CD, mean age 35 years) were included. Before and ten weeks after the changes of ADA regimen, the median TLA were (6.9 µg/mL versus 7.0 µg/mL, respectively; P = 0.34) and the AAA levels (3.4 µg/ml-eq versus 3.0 µg/ml-eq, respectively; P = 0.25.) were quite similar. Likewise, quartiles of TLA (Kendall test r = 0.91; P < 0.001) and AAA (r = 0.78; P < 0.001) did not differ before and after ADA regimen. When stratifying all the patients into 4 groups based on drug/antibody levels (immunogenic, subtherapeutic, therapeutic, or supratherapeutic), no patient needed for returning to the previous weekly regimen. In terms of acceptability, more than 60% of patients preferred an injection EOW compared once a week. In IBD patients who achieved a deep clinical remission under ADA 40 mg once a week, the pharmacokinetic of ADA was similar when ADA regimen was changed to 80 mg EOW. Given the patient’s preference for the latter regimen, a modification of injection regimen should be systematically proposed.

European Journal of Cancer, 2020

Background Cancer patients are thought to have an increased risk of developing severe Coronavirus... more Background Cancer patients are thought to have an increased risk of developing severe Coronavirus Disease 2019 (COVID-19) infection and of dying from the disease. In this work, predictive factors for COVID-19 severity and mortality in cancer patients were investigated. Patients and Methods In this large nationwide retro-prospective cohort study, we collected data on patients with solid tumours and COVID-19 diagnosed between March 1 and June 11, 2020. The primary endpoint was all-cause mortality and COVID-19 severity, defined as admission to an intensive care unit (ICU) and/or mechanical ventilation and/or death, was one of the secondary endpoints. Results From April 4 to June 11, 2020, 1289 patients were analysed. The most frequent cancers were digestive and thoracic. Altogether, 424 (33%) patients had a severe form of COVID-19 and 370 (29%) patients died. In multivariate analysis, independent factors associated with death were male sex (odds ratio 1.73, 95%CI: 1.18-2.52), ECOG PS ≥ 2 (OR 3.23, 95%CI: 2.27-4.61), updated Charlson comorbidity index (OR 1.08, 95%CI: 1.01-1.16) and admission to ICU (OR 3.62, 95%CI 2.14-6.11). The same factors, age along with corticosteroids before COVID-19 diagnosis, and thoracic primary tumour site were independently associated with COVID-19 severity. None of the anticancer treatments administered within the previous 3 months had any effect on mortality or COVID-19 severity, except cytotoxic chemotherapy in the subgroup of patients with detectable SARS-CoV-2 by RT-PCR, which was associated with a slight increase of the risk of death (OR 1.53; 95%CI: 1.00-2.34; p = 0.05). A total of 431 (39%) patients had their systemic anticancer treatment interrupted or stopped following diagnosis of COVID-19. Conclusions Mortality and COVID-19 severity in cancer patients are high and are associated with general characteristics of patients. We found no deleterious effects of recent anticancer treatments, except for cytotoxic chemotherapy in the RT-PCR-confirmed subgroup of patients. In almost 40% of patients, the systemic anticancer therapy was interrupted or stopped after COVID-19 diagnosis.

Gastroenterology, 2020

BACKGROUND & AIMS: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-... more BACKGROUND & AIMS: Vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly expanded; however, clinical trials excluded patients taking immunosuppressive medications such as those with inflammatory bowel disease (IBD). Therefore, we explored real-world effectiveness of coronavirus disease 2019 (COVID-19) vaccination on subsequent infection in patients with IBD with diverse exposure to immunosuppressive medications. METHODS: This was a retrospective cohort study of patients in the Veterans Health Administration with IBD diagnosed before December 18, 2020, the start date of the Veterans Health Administration patient vaccination program. IBD medication exposures included mesalamine, thiopurines, anti-tumor necrosis factor biologic agents, vedolizumab, ustekinumab, tofacitinib, methotrexate, and corticosteroid use. We used inverse probability weighting and Cox's regression with vaccination status as a time-updating exposure and computed vaccine effectiveness from incidence rates. RESULTS: The cohort comprised 14,697 patients, 7321 of whom received at least 1 vaccine dose (45.2% Pfizer, 54.8% Moderna). The cohort had median age 68 years, 92.2% were men, 80.4% were White, and 61.8% had ulcerative colitis. In follow-up data through April 20, 2021, unvaccinated individuals had the highest raw proportion of SARS-CoV-2 infection (197 [1.34%] vs 7 [0.11%] fully vaccinated). Full vaccination status, but not partial vaccination status, was associated with a 69% reduced hazard of infection relative to an unvaccinated status (hazard ratio, 0.31, 95% confidence interval, 0.17-0.56; P < .001), corresponding to an 80.4% effectiveness. CONCLUSIONS: Full vaccination (> 7 days after the second dose) against SARS-CoV-2 infection has an w80.4% effectiveness in a broad IBD cohort with diverse exposure to immunosuppressive medications. These results may serve to increase patient and provider willingness to pursue vaccination in these settings.

Gut, 2020

ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumo... more ObjectivesIn patients with IBD experiencing an immune-mediated loss of response (LOR) to antitumour necrosis factor (anti-TNF), algorithms recommend a switch of anti-TNF without immunosuppressive drug. The aim of our study was to compare in these patients two strategies: either switch to a second anti-TNF alone or with addition of azathioprine (AZA). After randomisation outcomes (time to clinical and pharmacokinetic failure) were compared between the two groups during a 2-year follow-up period.DesignConsecutive IBD patients in immune-mediated LOR to a first optimised anti-TNF given in monotherapy were randomised to receive either AZA or nothing with induction by a second anti-TNF in both arms. Clinical failure was defined for Crohn’s disease (CD) as a Harvey-Bradshaw index ≥5 associated with a faecal calprotectin level >250 µg/g stool and for UC as a Mayo score >5 with endoscopic subscore >1 or as the occurrence of adverse events requiring to stop treatment. Unfavourable ph...

Clinical Gastroenterology and Hepatology, 2019

U stekinumab is approved for treatment of Crohn's disease (CD). 1,2 Few data are available to ass... more U stekinumab is approved for treatment of Crohn's disease (CD). 1,2 Few data are available to assess the usefulness of monitoring inflammatory biomarkers and therapeutic drug monitoring to predict response to ustekinumab. We conducted a prospective study to assess the relationships between these parameters and the clinical outcome at week 16 in active CD patients receiving ustekinumab.

Journal of Crohn's & colitis, Jan 31, 2018

Vedolizumab (VDZ), a humanized monoclonal antibody targeting α4β7 integrin, is effective in induc... more Vedolizumab (VDZ), a humanized monoclonal antibody targeting α4β7 integrin, is effective in induction and maintenance therapy in patients with inflammatory bowel disease (IBD) who have not adequately responded to standard therapies, and high levels of vedolizumab trough levels (VTL) have been associated with clinical remission. The α4β7 integrin binds to endothelial MAdCAM-1 and is up-regulated by retinoic acid (RA). To determine the relations between soluble MAdCAM-1 (sMAdCAM-1) and RA concentrations with clinical remission during VDZ maintenance therapy. In a retrospective study performed in IBD patients treated with VDZ we measured VTL, sMAdCAM-1 and RA concentrations. Among the 62 included patients (38 Crohn's disease) 24 relapsed and 38 stayed in remission between weeks 10 to 30 after VDZ initiation. During this maintenance therapy, median values of VTL and RA were 15.4 µg/mL and 0.97 ng/mL, whereas sMAdCAM-1 was undetectable (< 0.41 ng/mL) in 67.3% of samples. The posit...

Inflammatory bowel diseases, Jan 26, 2018

The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of... more The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD). In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks). At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti-TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the sec...

Digestive Diseases, 2018

Background and Aims: One of the reasons for the failure of infliximab (IFX) is immediate hypersen... more Background and Aims: One of the reasons for the failure of infliximab (IFX) is immediate hypersensitivity reactions (IHR). We aimed to report the efficacy and safety of a tolerance induction protocol in inflammatory bowel diseases (IBD) patients who had previously experienced IHR during IFX infusions. Patients and Methods: We reported all cases of IBD patients who had previously experienced IHR due to IFX and who were submitted to a standardized protocol of tolerance induction to IFX from 2010 to 2015. Results: IHR occurred in a majority of patients (69%) during the first 3 infusions and for half of them after a period of IFX withdrawn. Skin prick tests were negative and only 2 intradermal tests were positive. Basophil activation tests and antidrug antibody measurements were performed in 8 out of 16 patients and were positive in 3 and 4 patients respectively. Induction of tolerance was successful in 69% of patients and IFX was pursued with clinical efficacy > 1 year in 7 patients...

Oncotarget, 2018

Aims: To assess the interest of induction chemotherapy (ICT) intensification before chemoradiothe... more Aims: To assess the interest of induction chemotherapy (ICT) intensification before chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer. Methods: Charts of patients treated between February 2010 and November 2016 with consolidation capecitabin based-CRT were retrospectively reviewed in this bicentric study. Patients who underwent Gemcitabine as ICT (Group G) were compared to patients treated with intensive ICT (group I). Primary objectives were progression-free survival (PFS), defined as the time from the first day of ICT to progression or last follow-up, and Time without treatment (TWT), as the time from the last day of CRT to progression. Results: Patients' characteristics were balanced between group I (Folforinox: n = 24; GemOx: n = 6) and group G (n = 16) including mean age (63.7 vs 68.1 years), and performance status (PS 0-1 :90% vs 93.7%). Median PFS (17.8 months vs 12 months; p = 0.02) and TWT (7.4 months vs 2.5 months p = 0.01) were statistically better in group I vs group G. These results remained statistically and clinically significant by comparing Folfirinox subgroup to Gemcitabine. A trend to a better median overall survival was observed in group I (20.4 months) vs group G (18.3 months; p = 0.07). After adjusting for ICT duration, PS, and CA19.9 level, ICT intensification remains independently prognostic. Toxicity profile was in accordance with Literature. Conclusion: This study shows ICT intensification before CRT is an interesting approach in patients with locally advanced pancreatic cancer. Further studies are needed to confirm these results, and to assess the specific role of CRT in this setting.

Inflammatory bowel diseases, Jan 23, 2018

It has been demonstrated in many chronic conditions, including inflammatory bowel disease (IBD), ... more It has been demonstrated in many chronic conditions, including inflammatory bowel disease (IBD), that better patient knowledge about pathology and treatment improves the course and management of disease. The aim of this study was to develop an updated self-questionnaire to assess patients' level of knowledge of IBD. The IBD-INFO included 3 parts: an original part (Q1) and 2 parts from the translation of the preexisting questionnaires Crohn's and Colitis Knowledge score (CCKNOW) (Q2) and Crohn's and Colitis Pregnancy Knowledge score (CCPKNOW) (Q3). The reliability and discriminatory ability of the questionnaire were validated in 3 groups of non-IBD volunteers with various theoretical knowledge levels. The final questionnaire (64 validated questions) was then tested on 364 in- and out- IBD patients from 4 French university hospitals. The score for each part of the questionnaire was calculated, and factors associated with low scores were identified by univariate and multiva...