Publications by authors named "Julie Henriques"

27 Publications

  • Page 1 of 1

Panel gene profiling of small bowel adenocarcinoma: Results from the NADEGE prospective cohort.

Int J Cancer 2021 Apr 4;148(7):1731-1742. Epub 2021 Jan 4.

Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, Paris, France.

Small bowel adenocarcinoma (SBA) is a rare tumour. Large genomic analyses with prognostic assessments are lacking. The NADEGE cohort has enrolled 347 patients with all stage SBA from 2009 to 2012. Next-generation sequencing investigates the presence of 740 hotspot somatic mutations in a panel of 46 genes involved in carcinogenesis. The mismatch repair (MMR) status was assessed by immunochemistry. We have collected 196 tumour samples and 125 had conclusive results for mutation analysis. The number of mutations was 0 in 9.6% of tumours, only 1 in 32.0%, 2 in 26.4% and ≥3 in 32.0%. Overall, at least one genomic alteration was observed in 90.4% of tumour. The most frequent genomic alteration was in KRAS (44.0%), TP53 (38.4%), PIK3CA (20.0%), APC (18.4%), SMAD4 (14.4%) and ERBB2 (7.2%) genes. KRAS mutations were more frequent in synchronous metastatic tumours than in localised tumours (72.7% vs 38.2%, P = .003). There was no significant difference in the mutation rates according to primary location for the most frequently altered gene. ATM, FGFR3 and FGFR1 gene alterations were associated with Lynch syndrome and IDH1 mutations with Crohn disease. dMMR tumours were associated with younger age, localised tumours, less KRAS but more SMARCB1 mutations. No genomic alteration was associated with overall survival. There is a trend for better survival in patient with dMMR tumours. In conclusion, there is a different genomic alteration profile in SBA according to predisposing diseases. No association between genomic alterations and prognoses was observed except for a trend of better prognoses associated with dMMR.
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http://dx.doi.org/10.1002/ijc.33392DOI Listing
April 2021

Association of Bevacizumab Plus Oxaliplatin-Based Chemotherapy With Disease-Free Survival and Overall Survival in Patients With Stage II Colon Cancer: A Secondary Analysis of the AVANT Trial.

JAMA Netw Open 2020 10 1;3(10):e2020425. Epub 2020 Oct 1.

Department of Medical Oncology, Franco-British Hospital-Fondation Cognacq-Jay, Levallois-Perret, France.

Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial.

Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC.

Design, Setting, And Participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019.

Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab.

Main Outcomes And Measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC.

Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4.

Conclusions And Relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited.

Trial Registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).
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http://dx.doi.org/10.1001/jamanetworkopen.2020.20425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573695PMC
October 2020

Prognostic value of the early change in neutrophil-to-lymphocyte ratio in metastatic pancreatic adenocarcinoma.

Clin Res Hepatol Gastroenterol 2020 Oct 11:101541. Epub 2020 Oct 11.

Sorbonne Université, 4 Place Jussieu, 75005, Paris, France; Department of Hepato-Gastroenterology, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital 75013, APHP, Paris, France. Electronic address:

In metastatic pancreatic adenocarcinoma, a high neutrophil-to-lymphocyte ratio (NLR) at diagnosis is a marker of poor prognosis. The prognostic role of baseline NLR and NLR change during first-line chemotherapy were determined. We conducted a retrospective study by using data from a single-center prospective cohort and a randomized open-label, multicenter, randomized trial. Two hundred and twelve patients were analyzed. Baseline NLR>5 was an independent marker of poor prognosis for overall survival (HR=2.01, 95% CI 1.33-3.05; P=0.001) and progression-free survival (PFS; HR=1.80, 95% CI 1.23-2.65; P=0.0026). According to NLR dynamics (n=172), patients with NLR≤5 on days 1 and 15 had a significantly better prognosis than those with NLR≤5 on day 1 and NLR>5 on day 15 (HR=2.23, 95% CI 1.18-4.21; P=0.013), NLR >5 on day 1 and NLR ≤5 on day 15 (HR=3.25, 95% CI 1.86-5.68; P<0.001), and NLR>5 on days 1 and 15 (HR=3.37, 95% CI 1.93-5.90; P<0.001). Over time, bad responders (PFS <6 months) had significantly higher mean NLR than good responders (PFS>6 months; group effect: P<0.0001). Seven out of eight patients with baseline NLR>5 had circulating tumor DNA. This study confirmed the independent prognostic value of baseline NLR >5 in metastatic pancreatic cancer. The change in NLR early during chemotherapy was also a prognostic indicator in patients with NLR ≤5.
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http://dx.doi.org/10.1016/j.clinre.2020.08.016DOI Listing
October 2020

Exposure-response analysis of Raltitrexed assessing liver toxicity.

Br J Clin Pharmacol 2021 Mar 4;87(3):1327-1337. Epub 2020 Sep 4.

INSERM, EFS BFC, Université Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, F-25000, France.

Aim: Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m every 3 weeks. However, every 2 weeks administration at 2 mg/m demonstrated a favourable toxicity profile.

Method: We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m ) and every 3 weeks TOMOX (RTX 3 mg/m ).

Results: A three-compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48-10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates-based dose was calculated, leading to less variability in AUC than observed with the actual BSA-based or fixed doses.

Conclusion: These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.
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http://dx.doi.org/10.1111/bcp.14519DOI Listing
March 2021

Efficacy of anti-EGFR in MSI metastatic colorectal cancer depending on sporadic or familial origin.

J Natl Cancer Inst 2020 May 16. Epub 2020 May 16.

Gastroenterology Department, Poitiers University Hospital and University of Poitiers, Poitiers, France.

Anti-EGFR efficacy in patients with microsatellite instability (MSI) metastatic colorectal cancer (mCRC) according to sporadic versus familial origin is unknown. We retrospectively analyzed 128 patients with MSI mCRC treated with first-line chemotherapy ± anti-EGFR. Among them, 61 and 67 patients were respectively categorized as familial and sporadic based on mismatch repair protein immunostaining, BRAF mutational status and MLH1 promoter methylation status. We observed that addition of anti-EGFR to chemotherapy was associated with a statistically significant improvement of progression-free survival (PFS) for familial (median: 5.0 versus 10.2 months; HR = 0.47; 95% CI, 0.23-0.94; P=.03) but not for sporadic (median: 4.4 versus 5.4 months; HR = 0.80; 95% CI, 0.39-1.60; P=.52) MSI mCRC patients. In multivariate analysis, the survival benefit of adding anti-EGFR to chemotherapy remained statistically significant for familial MSI cases (P=.04). These findings deserve to be confirmed in a prospective study and could help decision-making in MSI mCRC without access or resistant to immunotherapy.
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http://dx.doi.org/10.1093/jnci/djaa072DOI Listing
May 2020

Guidelines for time-to-event end-point definitions in adjuvant randomised trials for patients with localised colon cancer: Results of the DATECAN initiative.

Eur J Cancer 2020 05 12;130:63-71. Epub 2020 Mar 12.

Sorbonne Université, Department of Medical Oncology, AP-HP, Hôpital Saint-Antoine, F-7512, Paris, France.

Background: The variability of definitions for time-to-event (TTE) end-points impacts the conclusions of randomised clinical trials (RCTs). The Definition for the Assessment of Time-to-event Endpoints in CANcer (DATECAN) initiative aims to provide consensus definitions for TTE end-points used in RCTs. Here, we formulate guidelines for adjuvant colon cancer RCTs.

Methods: We performed a literature review to identify TTE end-points and events included in their definition in RCT publications. Then, a consensus was reached among a panel of international experts, using a formal modified Delphi method, with 2 rounds of questionnaires and an in-person meeting.

Results: Twenty-four experts scored 72 events involved in 6 TTE end-points. Consensus was reached for 24%, 57% and 100% events after the first round, second round and in-person meeting. For RCTs not using overall survival as their primary end-point, the experts recommend using disease-free survival (DFS) rather than recurrence-free survival (RFS) or time to recurrence (TTR) as the primary end-point. The consensus definition of DFS includes all causes of death, second primary colorectal cancers (CRCs), anastomotic relapse and metastatic relapse as an event, but not second primary non-CRCs. Events included in the RFS definition are the same as for DFS with the exception of second primary CRCs. The consensus definition of TTR includes anastomotic or metastatic relapse, death with evidence of recurrence and death from CC cause.

Conclusion: Standardised definitions of TTE end-points ensure the reproducibility of the end-points between RCTs and facilitate cross-trial comparisons. These definitions should be integrated in standard practice for the design, reporting and interpretation of adjuvant CC RCTs.
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http://dx.doi.org/10.1016/j.ejca.2020.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409551PMC
May 2020

Prognostic Value of Tumor Deposits for Disease-Free Survival in Patients With Stage III Colon Cancer: A Post Hoc Analysis of the IDEA France Phase III Trial (PRODIGE-GERCOR).

J Clin Oncol 2020 05 13;38(15):1702-1710. Epub 2020 Mar 13.

Sorbonne Université, Paris, France.

Patients And Methods: A post hoc analysis of all pathologic reports from patients with stage III CC included in the IDEA France phase III study (ClinicalTrials.gov identifier: NCT00958737) investigating the duration of adjuvant fluorouracil, leucovorin, and oxaliplatin or capecitabine and oxaliplatin therapy (3 6 months) was performed. The primary objective was to determine the prognostic impact of TD on disease-free survival (DFS). The effect of the addition of TD to LNM count on pN restaging was also evaluated. A multivariable analysis was performed to establish the association between TD and DFS.

Results: Of 1,942 patients, 184 (9.5%) had TDs. The pN1a/b and pN1c populations showed similar DFS. TD-positive patients had worse prognosis compared with TD-negative patients, with 3-year DFS rates of 65.6% (95% CI, 58.0% to 72.1%) and 74.7% (95% CI, 72.6% to 76.7%; = .0079), respectively. On multivariable analysis, TDs were associated with a higher risk of recurrence or death (hazard ratio [HR], 1.36; = .0201). Other adverse factors included pT4 and/or pN2 disease (HR, 2.21; < .001), the 3 months of adjuvant treatment (HR, 1.29; = .0029), tumor obstruction (HR, 1.28; = .0233), and male sex (HR, 1.24; = .0151). Patients restaged as having pN2 disease (n = 35, 2.3%) had similar DFS as patients initially classified as pN2.

Conclusion: The presence of TDs is an independent prognostic factor for DFS in patients with stage III CC. The addition of TD to LNM may help to better define the duration of adjuvant therapy.
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http://dx.doi.org/10.1200/JCO.19.01960DOI Listing
May 2020

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

Oncologist 2020 02 2;25(2):e266-e275. Epub 2019 Oct 2.

Department of Gastroenterology, Cochin Hospital, Paris, France.

Background: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting.

Materials And Methods: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR).

Results: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007).

Conclusion: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF.

Implications For Practice: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.
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http://dx.doi.org/10.1634/theoncologist.2019-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011620PMC
February 2020

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study.

Int J Cancer 2020 07 13;147(1):285-296. Epub 2020 Feb 13.

Sorbonne University and Medical Oncology Department, Saint Antoine Hospital, Paris, France.

Mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI) colorectal cancers (CRC) represent about 5% of metastatic CRC (mCRC). Prognosis and chemosensitivity of dMMR/MSI mCRC remain unclear. This multicenter study included consecutive patients with dMMR/MSI mCRC from 2007 to 2017. The primary endpoint was the progression-free survival (PFS) in a population receiving first-line chemotherapy. Associations between chemotherapy regimen and survival were evaluated using a Cox regression model and inverse of probability of treatment weighting (IPTW) methodology in order to limit potential biases. Overall, 342 patients with dMMR/MSI mCRC were included. Median PFS and overall survival (OS) on first-line chemotherapy were 6.0 and 26.3 months, respectively. For second-line chemotherapy, median PFS and OS were 4.4 and 21.6 months. Longer PFS (8.1 vs. 5.4 months, p = 0.0405) and OS (35.1 vs. 24.4 months, p = 0.0747) were observed for irinotecan-based chemotherapy compared to oxaliplatin-based chemotherapy. The association was no longer statistically significant using IPTW methodology. In multivariable analysis, anti-VEGF as compared to anti-EGFR was associated with a trend to longer OS (HR = 1.78, 95% CI 1.00-3.19, p = 0.0518), whatever the backbone chemotherapy used. Our study shows that dMMR/MSI mCRC patients experienced short PFS with first-line chemotherapy with or without targeted therapy. OS was not different according to the chemotherapy regimen used, but a trend to better OS was observed with anti-VEGF. Our study provides some historical results concerning chemotherapy in dMMR/MSI mCRC in light of the recent nonrandomized trials with immune checkpoint inhibitors.
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http://dx.doi.org/10.1002/ijc.32879DOI Listing
July 2020

Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients.

Int J Cancer 2020 Aug 22;147(4):967-977. Epub 2020 Jan 22.

Department of Oncology, Saint Antoine Hospital, APHP, Paris, France.

Small bowel adenocarcinoma (SBA) is a rare tumour. We conducted a prospective cohort to describe the prevalence, survival and prognostic factors in unselected SBA patients. The study enrolled patients with all stages of newly diagnosed or recurrent SBA at 74 French centres between January 2009 and December 2012. In total, 347 patients were analysed; the median age was 63 years (range 23-90). The primary tumour was in the duodenum (60.6%), jejunum (20.7%) and ileum (18.7%). The prevalence of predisposing disease was 8.7%, 6.9%, 1.7%, 1.7% and 0.6% for Crohn disease, Lynch syndrome, familial adenomatous polyposis, celiac disease and Peutz-Jeghers syndrome, respectively. At diagnosis, 58.9%, 5.5% and 35.6% of patients had localised and resectable, locally advanced unresectable and metastatic disease, respectively. Crohn disease was significantly associated with younger age, poor differentiation and ileum location, whereas Lynch syndrome with younger age, poor differentiation, early stage and duodenum location. Adjuvant chemotherapy (oxaliplatin-based in 89.9%) was performed in 61.5% of patients with locally resected tumours. With a 54-months median follow-up, the 5-year overall survival (OS) was 87.9%, 78.2% and 55.5% in Stages I, II and III, respectively. The median OS of patients with Stage IV was 12.7 months. In patients with resected tumours, poor differentiation (p = 0.047) and T4 stage (p = 0.001) were associated with a higher risk of death. In conclusion, our study showed that the prognosis of advanced SBA remains poor. Tumour characteristics differed according to predisposing disease. In SBA-resected tumours, the prognostic factors for OS were grade and T stage.
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http://dx.doi.org/10.1002/ijc.32860DOI Listing
August 2020

High IGF1R protein expression correlates with disease-free survival of patients with stage III colon cancer.

Cell Oncol (Dordr) 2020 Apr 10;43(2):237-247. Epub 2019 Dec 10.

Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, UMR_S938, F-75012, Paris, France.

Purpose: The aim of this study was to investigate the association between expression of insulin-like growth factor-1 receptor (IGF1R) and its ligand, IGF-II, and disease-free survival (DFS) in patients with stage III colon cancer (CC).

Methods: In this retrospective study we included consecutive patients who underwent curative surgery for stage III CC. IGF1R and IGF-II/IGF2 status were evaluated in tumour samples by immunohistochemistry and quantitative real-time PCR (qRT-PCR). Associations of markers with DFS were analysed using Cox proportional hazards models.

Results: Hundred and fifty-one CC patients were included (median age, 66.6 years; female, 54.3%). Low levels of IGF1R and IGF-II protein expression were observed in 16.1% and 10.7% of the cases, respectively. No significant differences in clinicopathological characteristics between patients with tumours expressing low IGF1R or IGF-II protein levels and those with high levels were observed. A low IGF1R protein expression was found to be significantly associated with a shorter DFS (HR 3.32; 95% CI, 1.7-6.31; p = 0.0003), while no association was observed between IGF-II protein expression and DFS (HR 0.91; 95% CI, 0.28-2.96; p = 0.87). In a multivariate analysis, IGF1R protein status remained an independent prognostic factor for DFS (HR 2.73; 95% CI, 1.40-5.31; p = 0.003). Furthermore, we found that neither IGF1R nor IGF2 mRNA expression levels as measured by qRT-PCR correlated with the respective protein expression levels as assessed by immunohistochemistry. Neither of the mRNA expression levels was significantly associated with DFS.

Conclusions: From our data we conclude that low IGF1R protein expression represents a poor prognostic biomarker in stage III colon cancer.
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http://dx.doi.org/10.1007/s13402-019-00484-6DOI Listing
April 2020

RECIST and CHOI criteria in the evaluation of tumor response in patients with metastatic colorectal cancer treated with regorafenib, a prospective multicenter study.

Cancer Imaging 2019 Dec 9;19(1):85. Epub 2019 Dec 9.

GERCOR (Groupe Cooperateur Multidisciplinaire en Oncologie), 151 rue du Faubourg Saint Antoine, 75011, Paris, France.

Background: To evaluate the objective response rate (ORR) at 2 months of treatment with regorafenib according to RECIST 1.1, Choi, and modified Choi (mChoi) criteria in patients with metastatic colorectal cancer (mCRC).

Methods: Baseline and 2-month contrast-enhanced computed-tomography (CECT) scans of 55 patients with mCRC, prospectively enrolled in phase II TEXCAN trial, were centrally assessed. The primary endpoint was 2-month ORR by RECIST 1.1, Choi, and mChoi criteria. Final outcome was overall survival (OS).

Results: Of 55 patients included in this study (Intention-to-treat [ITT1] population), 35 had CECT at 2 months (ITT2 population). According to RECIST 1.1 criteria, 20 (57%) patients were SD and 15 were PD (43%) in the ITT2 population. According to Choi criteria, 18 (51%) patients were responders and 17 (48%) were non-responders. Median OS was 5.3 months (95% CI 3.7-8.6) in the ITT1 population and 8.9 months (95% CI 5.1-12.6) in the ITT2 population. In the ITT2 population, median OS was 16 months (95% CI 6.6-17.5) in SD patients (n = 20) and 4.6 months (95% CI 3.3-5.8) in PD patients (n = 15), according to RECIST 1.1 criteria (HR = 6.48). Median OS was 7.9 months (95% CI 4.2-17.5) in responders (n = 18) and 9.9 months (95% CI 3.7-NA) in non-responders (n = 17) according to Choi criteria (HR = 1.06). All patients except one were classified as non-responders with mChoi criteria.

Conclusion: At 2 months, unlike RECIST 1.1, Choi and mChoi criteria could not identify mCRC patients with regorafenib survival benefit.

Trial Registration: ClinicalTrials.gov Identifier: NCT02699073.Registered March 4, 2016, Retrospectively registered.
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http://dx.doi.org/10.1186/s40644-019-0271-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902493PMC
December 2019

[Adjuvant hormonal therapy for early breast cancer: Assessment of patients' satisfaction].

Bull Cancer 2019 Dec 12;106(12):1104-1114. Epub 2019 Oct 12.

CHU de Besançon, pôle pharmaceutique, 3, boulevard Fleming, 25030 Besançon cedex, France; Université Bourgogne Franche-Comté, fédération Hospitalo-Universitaire INCREASE, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, EFS BFC, UMR1098, Inserm, 8, rue du Dr Jean-François-Xavier-Girod, 25000 Besançon, France. Electronic address:

Introduction: Since the cancer plan, evaluation of professional practices is essential to ensure the implementation of high-quality health care. Assess patient satisfaction is one of the pillars of high-quality health care. The main objective of the study was to assess the satisfaction of patients with early breast cancer taking a hormonal therapy, the secondary objective was to identify factors associated with their satisfaction.

Methods: The modified EORTC OUT-PATSAT-35 questionnaire was sent to a sample of patients in Franche-Comté in order to evaluate nine dimensions of satisfaction among which interpersonal skills, provided information, and overall satisfaction. For each dimension, a satisfaction score between 0 (no satisfaction) and 100 (highest satisfaction) was measured. Logistic regression analyses were used to study the factors associated with satisfaction.

Results: The mean overall satisfaction score for the 280 patients who answered was 73 [0-100]. Practicing an extra-professional activity was associated with higher satisfaction for several dimensions (odds ratio between 2.80 and 4.12, P<0.05) whereas it was decreased in the case of a modified appetite (odds ratio between 0.27 and 0.52, P<0.05). No link has been shown between satisfaction and adherence.

Discussion: The patients were satisfied and several factors impacting their satisfaction were identified, based on a questionnaire that must evolve to take into account the ambulatory aspect of their care. During the consultations, particular attention will be paid to these factors.
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http://dx.doi.org/10.1016/j.bulcan.2019.08.019DOI Listing
December 2019

6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial.

Lancet 2019 06 6;393(10191):2591-2598. Epub 2019 Jun 6.

Department of Statistics, University of Rouen, Rouen, France.

Background: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events.

Methods: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901.

Findings: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group.

Interpretation: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months.

Funding: The French National Cancer Institute.
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http://dx.doi.org/10.1016/S0140-6736(19)30653-1DOI Listing
June 2019

Absorbable Polyglactin vs. Non-Cross-linked Porcine Biological Mesh for the Surgical Treatment of Infected Incisional Hernia.

J Gastrointest Surg 2020 02 22;24(2):435-443. Epub 2019 Jan 22.

Department of General, Digestive and Endocrine Surgery, Robert-Debré University Hospital, University of Reims Champagne-Ardenne, Reims, France.

Background: The use of absorbable meshes during contaminated or infected incisional hernia (IH) repair is associated with high morbidity and recurrence rates. Biological meshes might be more appropriate but have been described in highly heterogeneous series. This study aimed at comparing the efficacy of absorbable vs. biological meshes for the treatment of contaminated or infected IH in a homogeneous series with a standardized technique.

Methods: Data of all patients operated on between 2008 and 2015 for contaminated or infected IH, using an absorbable (A) Vicryl® or a biological (B) Strattice® mesh, were reviewed. Patient characteristics, infectious complication rates, and recurrence-free outcome (RFO) were compared between the two groups. A propensity score methodology was applied to a Cox regression model to deal with unbalanced characteristics between groups.

Results: Patient demographics in A (n = 57) and in B (n = 24) were similar except that B patients had larger parietal defects (p < 0.001) and higher Center for Disease Control (CDC) wound class (p = 0.034). Patients in A had statistically significantly more postoperative early (61.4% vs. 33.3%, p = 0.03) and late (31.2% vs. 8.3%, p = 0.046) infectious complications. Six-, 12-, and 36-month RFO rates were 77%, 47%, and 24%, and 96%, 87%, and 82% in A and B, respectively, p < 0.001. Raw multivariable Cox regression analysis found that B (HR = 0.1, 95% CI [0.03-0.34], p < 0.001) was independently associated with prolonged RFO (HR = 0.091, 95% CI [0.045-0.180], p < 0.001).

Conclusion: Biological meshes seem to be superior to absorbable meshes in patients with contaminated or infected incisional hernia. These results need to be confirmed by prospective randomized trials.
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http://dx.doi.org/10.1007/s11605-018-04095-8DOI Listing
February 2020

Peritoneal dialysis after kidney transplant failure: a nationwide matched cohort study from the French Language Peritoneal Dialysis Registry (RDPLF).

Nephrol Dial Transplant 2019 05;34(5):858-863

Department of Nephrology, Dialysis and Renal Transplantation, University of Franche-Comté, Besançon, France.

Background: Failed kidney transplant is becoming a frequent cause of dialysis initiation. Although studies have shown no difference between peritoneal dialysis (PD) and haemodialysis (HD) in terms of patients and technique survival, PD remains quite rarely used in this condition. Studies in larger multicentre matched cohorts are missing.

Methods: We conducted a retrospective study about 328 patients registered in the French Language Peritoneal Dialysis Registry (RDPLF) who started PD after kidney transplant failure (Tx group) between January 2002 and December 2012 who were compared with 656 matched never-transplanted patients having started PD during the same period (control group). Patients and PD technique survival as well as peritonitis episodes were analysed.

Results: Over the study period, patients' survival was similar between the two groups (P = 0.34). The mean time on PD was significantly shorter for patients in the Tx group [17 months (range 14-20)] compared with the control group [21 months (range 19-23)] (P = 0.003). The main cause of transfer to HD was for both group adequacy and/or ultrafiltration failure. Peritonitis rates were similar in the two groups: 43.6% (n = 143) versus 40.1% (n = 263) in the Tx and control group, respectively (P = 0.3). In multivariate Cox analysis, kidney transplant failure (P < 0.0001), younger age (P = 0.02) and male gender (P = 0.01) were associated with a higher risk of transfer to HD. Using multivariate competing risk analysis, kidney transplant failure was again observed as a predictive factor (P < 0.0001), but not age and gender. The only other significant predictive factor observed was peritonitis episodes experienced during PD treatment (P = 0.002).

Conclusions: Comparing the Tx and control groups, we report similar patient survival and peritonitis rates but a higher PD technique failure in the Tx group.
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http://dx.doi.org/10.1093/ndt/gfy290DOI Listing
May 2019

Switch from abiraterone plus prednisone to abiraterone plus dexamethasone at asymptomatic PSA progression in patients with metastatic castration-resistant prostate cancer.

BJU Int 2019 02 4;123(2):300-306. Epub 2018 Sep 4.

Department of Medical Oncology, Institut Mutualiste Montsouris, Paris, France.

Objective: To evaluate the effects of switching from prednisone (P) to dexamethasone (D) at asymptomatic prostate-specific antigen (PSA) progression in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).

Materials And Methods: Among 93 patients treated with AA between January 2013 and April 2016 in our institution, 48 consecutive asymptomatic patients with mCRPC, who experienced biochemical progression on treatment with AA+P 10 mg/day, were included. A corticosteroid switch to AA+D 0.5 mg/day at PSA increase was administered until radiological and/or clinical progression. The primary endpoint was progression-free-survival (PFS). A prognostic score based on independent prognostic factors was defined.

Results: The median time to PSA progression on AA+P was 8.94 months. The median PFS on AA+D and AA+corticosteroids (P then D) was 10.35 and 20.07 months, respectively. A total of 56.25% of patients showed a decrease or stabilization in PSA levels after the switch. In univariate analysis, three markers of switch efficiency were significantly associated with a longer PFS: long hormone-sensitivity duration (≥5 years; median PFS 16.62 vs 4.17 months, hazard ratio [HR] 0.30, 90% confidence interval [CI] 0.16-0.56); low PSA level at the time of switch (<50 ng/mL; median PFS 15.21 vs 3.86 months, HR 0.33, 90% CI 0.18-0.60); and short time to PSA progression on AA+P (<6 months; median PFS 28.02 vs 6.65 months, HR 0.41 (90% CI 0.21-0.81). In multivariate analysis, hormone sensitivity duration and PSA level were independent prognostic factors.

Conclusion: A steroid switch from P to D appears to be a safe and non-expensive way of obtaining long-term responses to AA in selected patients with mCRPC. A longer PFS has been observed in patients with previous long hormone sensitivity duration, and/or low PSA level and/or short time to PSA progression on AA+P.
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http://dx.doi.org/10.1111/bju.14511DOI Listing
February 2019

Fluctuation of the left ventricular ejection fraction in patients with HER2-positive early breast cancer treated by 12 months of adjuvant trastuzumab.

Breast 2018 Oct 15;41:1-7. Epub 2018 Jun 15.

Centre Paul Strauss, Strasbourg, France. Electronic address:

Background: Cardiac toxicity with a decrease of the left ventricular ejection fraction (LVEF) is the main side effect induced by trastuzumab. This study reports the fluctuation of LVEF over the 12 months of adjuvant trastuzumab in PHARE trial (NCT00381901).

Methods: LVEF assessment was performed every 3 months while patients received trastuzumab and after completion of treatment over the first 2 years and then every 6 months afterwards. The fluctuations of LVEF over time were described and a logistic regression model was performed investigating associated factors to LVEF perfect recovery at baseline value.

Results: A total of 1631 patients who received 12 months of trastuzumab from PHARE trial, were considered in the analysis. A total of 13 881 LVEF measurements were assessed. Baseline mean LVEF was 66.08% (standard error (SE): 0.15) and the mean relative LVEF decrease observed at 12-month was 3.61% (SE: 0.31). No clinical characteristic was significantly associated to LVEF fluctuation. After completion of trastuzumab, the relative difference progressively disappeared with beyond 30 months a relative difference value of 0.08% (SE: 0.42). Nevertheless, at 30 months, 48.53% of patients with available measures (379/781) did not fully recover their baseline LVEF value.

Conclusion: The LVEF decreased during treatment with trastuzumab and rose up after the completion of treatment without coming back to the initial values for a substantial subset. These results would suggest investigating some strategies aimed to improve the ability to achieve a full recovery.
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http://dx.doi.org/10.1016/j.breast.2018.06.001DOI Listing
October 2018

Adjuvant hormonal therapy for early breast cancer: an epidemiologic study of medication adherence.

Breast Cancer Res Treat 2018 May 23;169(1):153-162. Epub 2018 Jan 23.

Department of Pharmacy, Besançon University Hospital, Boulevard Fleming, 25030, Besançon Cedex, France.

Purpose: The aim of this study was to determine the prevalence of adherence to adjuvant hormonal therapy (AHT) and to identify risk factors for medication non-adherence in clinical practice in patients with early-stage hormone receptor (HR)-positive breast cancer (BC) previously treated with chemotherapy.

Methods: We carried out a cross-sectional, observational, prospective, and multicenter survey based on a structured self-report postal questionnaire (35 items investigating six areas). A sample of 474 patients was drawn from 676 patients potentially eligible. The structured and validated Morisky Medication Adherence Scale-4 items was used for measuring medication adherence. An analysis of risk factors for non-adherence to AHT was performed using a two-step approach: univariate, then multivariate analysis.

Results: A total of 280 patients out of the 428 analyzed patients participated in the survey, yielding a response rate of 65.4% [60.9-69.9]. The prevalence of adherence to AHT was estimated at 68.6% [63.1-74.0], corresponding to a high level of adherence. Three risk factors for non-adherence to AHT were identified: > 2 medications to treat comorbidities (p-value = 0.003), age less than 65 years (p-value = 0.008), and patient management in a university hospital setting (p-value = 0.014).

Conclusions: Non-adherence is a common, complex, and multidimensional healthcare problem. This better understanding and knowledge of risk factors will allow healthcare providers (such as oncologists, general practitioners, pharmacists) to more easily identify patients at risk for non-adherence and help them provide appropriate information about AHT and its management, thus improving medication adherence in their patients.
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http://dx.doi.org/10.1007/s10549-018-4676-3DOI Listing
May 2018

Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes.

Breast Cancer Res 2017 Aug 22;19(1):98. Epub 2017 Aug 22.

Centre de Recherche en Cancérologie de Lyon, INSERM U1052 - Centre Léon Bérard, 28 rue Laennec, 69373, Lyon, France.

Background: Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer.

Methods: A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS.

Results: The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1-97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival.

Conclusions: In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients' outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis.

Trial Registration: PHARE cohort: NCT00381901 , Sept. 26, 2006 - SIGNAL cohort: INCa RECF1098, Jan. 28, 2009.
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http://dx.doi.org/10.1186/s13058-017-0888-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5568360PMC
August 2017

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort.

Eur J Cancer 2017 08 16;81:151-160. Epub 2017 Jun 16.

Oncologie Sénologie, ICM Institut Régional du Cancer, 34298 Montpellier Cedex, France.

Aim: Adjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab.

Methods: A population combining patients from Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan-Meier method, and comparisons between groups were based on the log rank test.

Results: The SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86-1.19) and similar DFS (HR = 1.08; 95% CI: 0.96-1.21).

Conclusion: These results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.
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http://dx.doi.org/10.1016/j.ejca.2017.05.020DOI Listing
August 2017

Nonlinear Memory Capacity of Parallel Time-Delay Reservoir Computers in the Processing of Multidimensional Signals.

Neural Comput 2016 07 12;28(7):1411-51. Epub 2016 May 12.

Faculty of Mathematics and Statistics, Universität Sankt Gallen, CH-9000, Sankt Gallen, Switzerland, and Centre National de la Recherche Scientifique, France

This letter addresses the reservoir design problem in the context of delay-based reservoir computers for multidimensional input signals, parallel architectures, and real-time multitasking. First, an approximating reservoir model is presented in those frameworks that provides an explicit functional link between the reservoir architecture and its performance in the execution of a specific task. Second, the inference properties of the ridge regression estimator in the multivariate context are used to assess the impact of finite sample training on the decrease of the reservoir capacity. Finally, an empirical study is conducted that shows the adequacy of the theoretical results with the empirical performances exhibited by various reservoir architectures in the execution of several nonlinear tasks with multidimensional inputs. Our results confirm the robustness properties of the parallel reservoir architecture with respect to task misspecification and parameter choice already documented in the literature.
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http://dx.doi.org/10.1162/NECO_a_00845DOI Listing
July 2016

Replicability and impact of statistics in the detection of neural responses of consciousness.

Brain 2016 06 26;139(Pt 6):e30. Epub 2016 Mar 26.

Centre d'Investigation Clinique CIC 1431, Inserm, CHRU Besançon, F-25000 Besançon, France Neurosciences intégratives et cliniques EA 481, Univ. Franche-Comté, Univ. Bourgogne Franche-Comté, F-25000 Besançon, France Service de Neurologie, CHRU Besançon, F-25000 Besançon, France.

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http://dx.doi.org/10.1093/brain/aww065DOI Listing
June 2016

Bedside Evaluation of the Functional Organization of the Auditory Cortex in Patients with Disorders of Consciousness.

PLoS One 2016 20;11(1):e0146788. Epub 2016 Jan 20.

INSERM CIC 1431 Centre d'Investigation Clinique en Innovation Technologique, CHU de Besançon, Besançon, France.

To measure the level of residual cognitive function in patients with disorders of consciousness, the use of electrophysiological and neuroimaging protocols of increasing complexity is recommended. This work presents an EEG-based method capable of assessing at an individual level the integrity of the auditory cortex at the bedside of patients and can be seen as the first cortical stage of this hierarchical approach. The method is based on two features: first, the possibility of automatically detecting the presence of a N100 wave and second, in showing evidence of frequency processing in the auditory cortex with a machine learning based classification of the EEG signals associated with different frequencies and auditory stimulation modalities. In the control group of twelve healthy volunteers, cortical frequency processing was clearly demonstrated. EEG recordings from two patients with disorders of consciousness showed evidence of partially preserved cortical processing in the first patient and none in the second patient. From these results, it appears that the classification method presented here reliably detects signal differences in the encoding of frequencies and is a useful tool in the evaluation of the integrity of the auditory cortex. Even though the classification method presented in this work was designed for patients with disorders of consciousness, it can also be applied to other pathological populations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146788PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720275PMC
July 2016

Optimal nonlinear information processing capacity in delay-based reservoir computers.

Sci Rep 2015 Sep 11;5:12858. Epub 2015 Sep 11.

Centre National de la Recherche Scientifique, Laboratoire de Mathématiques de Besançon, UMR CNRS 6623, Université de Franche-Comté, UFR des Sciences et Techniques. 16, route de Gray. F-25030 Besançon cedex. France.

Reservoir computing is a recently introduced brain-inspired machine learning paradigm capable of excellent performances in the processing of empirical data. We focus in a particular kind of time-delay based reservoir computers that have been physically implemented using optical and electronic systems and have shown unprecedented data processing rates. Reservoir computing is well-known for the ease of the associated training scheme but also for the problematic sensitivity of its performance to architecture parameters. This article addresses the reservoir design problem, which remains the biggest challenge in the applicability of this information processing scheme. More specifically, we use the information available regarding the optimal reservoir working regimes to construct a functional link between the reservoir parameters and its performance. This function is used to explore various properties of the device and to choose the optimal reservoir architecture, thus replacing the tedious and time consuming parameter scannings used so far in the literature.
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http://dx.doi.org/10.1038/srep12858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4566100PMC
September 2015

Stochastic nonlinear time series forecasting using time-delay reservoir computers: performance and universality.

Neural Netw 2014 Jul 21;55:59-71. Epub 2014 Mar 21.

Centre National de la Recherche Scientifique, Laboratoire de Mathématiques de Besançon, Université de Franche-Comté, UFR des Sciences et Techniques. 16, route de Gray. F-25030 Besançon Cedex, France. Electronic address:

Reservoir computing is a recently introduced machine learning paradigm that has already shown excellent performances in the processing of empirical data. We study a particular kind of reservoir computers called time-delay reservoirs that are constructed out of the sampling of the solution of a time-delay differential equation and show their good performance in the forecasting of the conditional covariances associated to multivariate discrete-time nonlinear stochastic processes of VEC-GARCH type as well as in the prediction of factual daily market realized volatilities computed with intraday quotes, using as training input daily log-return series of moderate size. We tackle some problems associated to the lack of task-universality for individually operating reservoirs and propose a solution based on the use of parallel arrays of time-delay reservoirs.
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http://dx.doi.org/10.1016/j.neunet.2014.03.004DOI Listing
July 2014

Comparison of methods to correct survival estimates and survival regression analysis on a large HIV African cohort.

PLoS One 2012 23;7(2):e31706. Epub 2012 Feb 23.

Service de Biostatistique, Hospices Civils de Lyon, Lyon, France.

Objective: The evaluation of HIV treatment programs is generally based on an estimation of survival among patients receiving antiretroviral treatment (ART). In large HIV programs, loss to follow-up (LFU) rates remain high despite active patient tracing, which is likely to bias survival estimates and survival regression analyses.

Methods: We compared uncorrected survival estimates derived from routine program data with estimates obtained by applying six correction methods that use updated outcome data by a field survey targeting LFU patients in a rural HIV program in Malawi. These methods were based on double-sampling and differed according to the weights given to survival estimates in LFU and non-LFU subpopulations. We then proposed a correction of the survival regression analysis.

Results: Among 6,727 HIV-infected adults receiving ART, 9% were LFU after one year. The uncorrected survival estimates from routine data were 91% in women and 84% in men. According to increasing sophistication of the correction methods, the corrected survival estimates ranged from 89% to 85% in women and 82% to 77% in men. The estimates derived from uncorrected regression analyses were highly biased for initial tuberculosis mortality ratios (RR; 95% CI: 1.07; 0.76-1.50 vs. 2.06 to 2.28 with different correction weights), Kaposi sarcoma diagnosis (2.11; 1.61-2.76 vs. 2.64 to 3.9), and year of ART initiation (1.40; 1.17-1.66 vs. 1.29 to 1.34).

Conclusions: In HIV programs with high LFU rates, the use of correction methods based on non-exhaustive double-sampling data are necessary to minimise the bias in survival estimates and survival regressions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031706PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285641PMC
August 2012