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Purpose: Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models. Patients and Methods: This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1. Results: Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8–5.4] and 10.8 months (95% CI, 5.9–NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (n = 14, 30%), hypertension (n = 11, 23%), and diarrhea (n = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; P = 0.002) and OS (3.7 months vs. not reached; P = 0.002). Increased tumor infiltration by CD8+ T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome. Conclusions: The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.

Left ventricular assist device (LVAD) implantation may be an attractive alternative therapeutic option for elderly patients with heart failure who are ineligible for heart transplantation.We aimed to describe the characteristics and outcomes of elderly patients (i.e. aged≥70 years) receiving an LVAD.This observational study was conducted in 19 centres between 2006 and 2016. Patients were divided into two groups-younger (aged70 years) and elderly (aged≥70 years), based on age at time of LVAD implantation.A total of 652 patients were included in the final analysis, and 74 patients (11.3%) were aged≥70 years at the time of LVAD implantation (maximal age 77.6 years). The proportion of elderly patients receiving an LVAD each year was constant, with a median of 10.6% (interquartile range 8.0-15.4%) per year, and all were implanted as destination therapy. Elderly and younger patients had similar durations of hospitalization in intensive care units and total lengths of hospital stays. Both age groups experienced similar rates of LVAD-related complications (i.e. stroke, bleeding, driveline infection and LVAD exchange), and the occurrence of LVAD complications did not impact survival in the elderly group compared with the younger group. Lastly, when compared with younger patients implanted as destination therapy, the elderly group also exhibited similar mid-term survival.This work strongly suggests that selected elderly adults can be scheduled for LVAD implantation.

Background Chemotherapy is effective in metastatic pancreatic adenocarcinoma (mPA), but new approaches are still needed to improve patients' survival and quality of life. We have previously published good efficacy and tolerability results on a sequential treatment strategy of gemcitabine followed by an intensified FOLFIRI (5FU+irinotecan) regimen. In the present study, we evaluated the same sequence but replaced gemcitabine by the new gemcitabine + nab-paclitaxel standard first-line combination. Patients and methods We randomised chemotherapy-naive patients with proven mPA, bilirubin levels ≤1.5 upper limit of normal values and performance status 0–2 to alternately receive gemcitabine + nab-paclitaxel for 2 months then FOLFIRI.3 for 2 months in arm A, or gemcitabine + nab-paclitaxel alone until progression in arm B. The primary objective was to increase the 6-month progression-free survival (PFS) rate from 40% (H0) to 60% (H1); using the binomial exact method, 124 patients were required. Analyses were carried out in preplanned modified intention-to-treat (mITT) and per-protocol (PP) populations. Results Between November 2015 and November 2016, 127 patients were enrolled. Main grade III–IV toxicities (% in arm A/B) were: diarrhoea (12.5/1.7), neutropenia (46.9/31, including febrile neutropenia: 1.6/0), skin toxicity (6.3/13.8), and peripheral neuropathy (6.3/8.6). No toxic deaths occurred. The objective response rate was 40.3% (95% confidence interval [CI]: 28.1–53.6) in arm A and 26.7% (95% CI: 16.1–39.7) in arm B. The primary end-point (6-month PFS rate) was 45.2% [one-sided 95% CI: 34.3–56.4] in arm A and 23.3% in arm B [one-sided 95% CI: 14.3–32.3] in the mITT population. In the PP population, median PFS and OS were 7.6 months and 6 months and 14.5 months and 12.2 months in arm A and B, respectively. Conclusions The FIRGEMAX strategy with gemcitabine + nab-paclitaxel alternating with FOLFIRI.3 every 2 months, appears feasible and effective, with manageable toxicities, in patients able to reach >2mo of treatment. Trial registration information EudraCT: 2014-004449-28: NCT: 0282701.

We investigated the clinical effects of bead size in irinotecan-loaded beads chemoembolization (DEBIRI) used for treating liver-dominant colorectal cancer. Between March 2009 and January 2018, all consecutive patients with colorectal cancer liver metastases referred for DEBIRI at our tertiary center were included in an observational study. Patients were treated exclusively with either 100-mg irinotecan-loaded DC beads of 70–150 μm (small bead group or SB) or 100–300 μm (large bead group or LB) in diameter, in addition to systemic therapy. Liver tumor response rate at 3 months, liver and overall progression-free survival (PFS) and overall survival were estimated. In total, 84 patients with liver-dominant progressive disease underwent 232 DEBIRI sessions. Fifty-four patients were treated in the SB group and 30 patients in the LB group. Liver progression-free rates at 3 months were 86.7% for the LB group and 79.6% for the SB group (NS). Median liver-PFS and overall PFS were, respectively, 7.15 months and 7.15 months for the LB group and 7.65 and 7.55 months for the SB group (NS). Median overall survival was 13.04 months for the LB group and 15.59 months for the SB group (p = 0.04). Specific treatment grade 3 + 4 toxicity occurrence was 5 (17%) in the LB group and 20 (37%) in the SB group. No significant difference in patient outcome was observed between DEBIRI bead sizes of 70–150 μm and 100–300 μm. A trend toward higher treatment-specific toxicity was observed with the smaller beads.

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes (CM) connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between CM. Yet no factor on its own is known to coordinate CM polarized organization. We have previously shown that PDZRN3, an ubiquitine ligase E3 expressed in various tissues including the heart, mediates a branch of the Planar cell polarity (PCP) signaling involved in tissue patterning, instructing cell polarity and cell polar organization within a tissue. PDZRN3 is expressed in the embryonic mouse heart then its expression dropped significantly postnatally corresponding with heart maturation and CM polarized elongation. A moderate CM overexpression of Pdzrn3 (Pdzrn3 OE) during the first week of life, induced a severe eccentric hypertrophic phenotype with heart failure. In models of pressure-overload stress heart failure, CM-specific Pdzrn3 knockout showed complete protection against degradation of heart function. We reported that Pdzrn3 signaling induced PKC ζ expression, c-Jun nuclear translocation and a reduced nuclear ß catenin level, consistent markers of the planar non-canonical Wnt signaling in CM. We then show that subcellular localization (intercalated disk) of junction proteins as Cx43, ZO1 and Desmoglein 2 was altered in Pdzrn3 OE mice, which provides a molecular explanation for impaired CM polarization in these mice. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of CM, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

The hypothermic circulatory arrest is a major limitation of the frozen elephant trunk (FET) technique, associated with a high incidence of postoperative mobility and mortality. The aim of this study was to evaluate the surgical outcomes of patients suffering from different aortic arch diseases treated with the release and perfuse technique (RPT).We retrospectively reviewed the records of patients who had undergone aortic arch repair with the RPT at our Institution between October 2019 and September 2021. Preoperative, intra-operative, and postoperative data were collected.A total of 18 patients undergoing aortic arch surgery with the use of RPT were analyzed. Twelve of them (67%) were males, and the median age of the entire cohort was 67 (56-73) years. The primary indications for surgery included acute type A aortic dissection (50%), chronic type B aortic dissection (33%), and chronic aneurysms (17%). The median cardiopulmonary bypass-, aortic cross-clamp- and circulatory arrest times were 163 (147-213) min, 69 (51-120) min, and 10 (8-13) min, respectively. The median intensive care unit and hospital stay were 4 (2-7) and 12 (11-16) days, respectively. One patient (6%) died during the first 30 days after surgery.Considering the anatomical limitations related to the use of this technique, the RPT can be safely performed and could represent a promising strategy to reduce the circulatory arrest time during aortic arch surgery. Nevertheless, further studies are required to demonstrate its efficacy.

International audience; After failure of first line FOLFOX-bevacizumab for metastatic colorectal cancer (mCRC), adding either bevacizumab or aflibercept to second-line FOLFIRI increases survival compared to FOLFIRI alone. In this French retrospective multicentre cohort, we included patients with a mCRC treated with either FOLFIRI-aflibercept or FOLFIRI-bevacizumab. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS), disease control rate (DCR: CR\,+\,PR\,+\,SD) and safety. We included 681 patients from 36 centers, 326 and 355 in the aflibercept and bevacizumab groups, respectively. Median age was 64.2\,years and 45.2% of patients were men. Most patients had RAS-mutated tumors (80.8%) and synchronous metastases (85.7%). After a median follow up of 31.2~months, median OS was 13.0~months (95% CI: 11.3-14.7) and 10.4~months (95% CI: 8.8-11.4) in the bevacizumab and aflibercept groups, respectively (P\

International audience; Aims: Despite regularly updated guidelines, there is still a delay in referral of advanced heart failure patients to mechanical circulatory support and transplant centres. We aimed to analyse characteristics and outcome of non-inotrope-dependent patients implanted with a left ventricular assist device (LVAD).Methods and results: The ASSIST-ICD registry collected LVAD data in 19 centres in France between February 2006 and December 2016. We used data of patients in Interagency Registry for Mechanically Assisted Circulatory Support Classes 4-7. The primary endpoint was survival analysis. Predictors of mortality were searched with multivariable analyses. A total of 303 patients (mean age 61.0 ± 9.9 years, male sex 86.8%) were included in the present analysis. Ischaemic cardiomyopathy was the leading heart failure aetiology (64%), and bridge to transplantation was the main implantation strategy (56.1%). The overall likelihood of being alive while on LVAD support or having a transplant at 1, 2, 3, and 5 years was 66%, 61.7%, 58.7%, and 55.1%, respectively. Age [hazard ratio (HR) 1.03, 95% confidence interval (CI) 1.00-1.05; P = 0.02], a concomitant procedure (HR 2.32, 95% CI 1.52-3.53; P < 0.0001), and temporary mechanical right ventricular support during LVAD implantation (HR 2.94, 95% CI 1.49-5.77; P = 0.002) were the only independent variables associated with mortality. Heart failure medications before or after LVAD implantation were not associated with survival.Conclusion: Ambulatory heart failure patients displayed unsatisfactory survival rates after LVAD implantation. A better selection of patients who can benefit from LVAD may help improving outcomes.

International audience; BACKGROUND: Chlordecone (CD), also known as Kepone, is an organochlorine insecticide that has been used in banana crops in the French West Indies. Due to long-term contamination of soils and water, the population is still exposed to CD. Exposure to CD in adulthood is associated with an increased risk of prostate cancer (PCa). OBJECTIVES: We examined the transgenerational effects of CD on murine prostate tissue. METHODS: We exposed pregnant Swiss mice to CD. The prostates from directly exposed (F1) and non-exposed (F3) male progeny were analyzed. We used immunofluorescence, RNA-seq and ChIP-seq techniques for the comprehensive analyses of chromatin states in prostate. RESULTS: We observed an increased prostatic intraepithelial neoplasia phenotype (PIN) in both F1 and F3 generations. Transcriptomic analysis in CD-derived F1 and F3 prostate using RNA-seq revealed that 970 genes in F1 and 218 in F3 genes were differentially expressed. The differentially expressed genes in both datasets could be clustered accordingly to common biological processes, "cell differentiation", "developmental process", "regulating of signaling", suggesting that in both generations similar processes were perturbed. We detected that in both datasets several Hox genes were upregulated; in F1, the expression was detected mainly in Hoxb and Hoxd, and in F3, in Hoxa family genes. Using a larger number of biological replicates and RT-qPCR we showed that genes implicated in testosterone synthesis (Akr1b3, Cyp11a1, Cyp17a1, Srd5a1) were dramatically upregulated in PIN samples; Cyp19a1, converting testosterone to estradiol was elevated as well. We found a dramatic increase in Esr2 expression both in F1 and F3 prostates containing PIN. The PIN-containing samples have a strong increase in expression of self-renewal-related genes (Nanog, Tbx3, Sox2, Sox3, Rb1). We observed changes in liver, F1 CD-exposed males have an increased expression of genes related to DNA repair, matrix collagen and inflammation related pathways in F1 but not in F3 adult CD-derived liver. The changes in RNA transcription were associated with epigenetic changes. Specifically, we found a global increase in H3K4 trimethylation (H3K4me3) and a decrease in H3K27 trimethylation (H3K27me3) in prostate of F1 mice. ChIP-seq analysis showed that 129 regions in F1 and 240 in F3 acquired altered H3K4me3 occupancy in CD-derived prostate, including highest increase at several promoters of Hoxa family genes in both datasets. The alteration in H3K4me3 in both generations overlap 73 genes including genes involved in proliferation regulation, Tbx2, Stat3, Stat5a, Pou2f3 and homeobox genes Hoxa13, Hoxa9. CONCLUSIONS: Our data suggest that developmental exposure to CD leads to epigenetic changes in prostate tissue. The PIN containing samples showed evidence of implication in hormonal pathway and self-renewal gene expression that have the capacity to promote neoplasia in CD-exposed mice.

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., More than half of the cases of metastatic colorectal cancer harbor a RAS mutation; however, the time to obtain RAS status might be long enough to consider delayed anti‐EGFR treatment. This article reports on the two main treatment strategies for these cases.

We developed a technology that extends the capabilities of functional ultrasound to whole-brain 4D neuroimaging. We implemented multiplane wave transmissions on matrix arrays at thousands of frames per second to provide volumetric recordings of cerebral blood volume changes at high spatiotemporal resolution. This approach is illustrated by several proofs-of-concept: real time multiple sensory stimuli, 4D functional connectivity and instantaneous tracking of epileptiform events within the whole brains of rodents.

Introduction The Patient-Generated Subjective Global Assessment (PG-SGA) is currently the standard nutritional assessment tool for patients with cancer. In a retrospective assessment of a prospective cohort, we showed that the Nutritional Risk Index (NRI) seemed to be associated with treatment toxicity and survival in patients with metastatic colorectal cancer (mCRC). Objective The objective of this study was to compare these two nutritional tools (PG-SGA and NRI) on their correlation with chemotherapy-related toxicity and survival in non–pre-treated patients with mCRC. Methods This prospective multicentre observational study enrolled non–pre-treated patients with mCRC. PG-SGA and NRI were performed at the onset of first-line chemotherapy. Treatment-related toxicities were registered according to National Cancer Institute Common Toxicity Criteria Adverse Event version 4.0. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment. Results A total of 168 patients were included from eight French centres. Patients were considered malnourished in 41% of cases according to PG-SGA and 56% of cases according to the NRI. In multivariate analysis, malnutrition according to PG-SGA was significantly associated with chemotherapy-related grade ≥2 clinical toxicities (odds ratio: 3.7; 95% confidence interval [CI]: 1.7–8.4; p = 0.001) and OS (hazard ratio [HR]: 2.6; 95% CI: 1.3–5.3; p = 0.006), but not with PFS (HR: 1.5; 95% CI: 0.8–2.6; p = 0.2). Conversely, malnutrition according to the NRI was not significantly associated with these tolerance and efficacy parameters. Conclusion Although more complex to perform in daily oncology practice, the PG-SGA score appears to be the best nutritional assessment tool because of its strong association with clinically relevant oncological outcomes such as OS and treatment-related toxicities in patients with mCRC.

To determine whether intraprocedural C-arm cone-beam CT (CBCT) parenchymal blood volume (PBV) can predict the response of colorectal cancer liver metastases (CRCLM) 2 months after irinotecan drug–eluting bead (DEBIRI) chemoembolization. This single-center observational study was compliant with the Helsinki Declaration and approved by our institutional review board. Thirty-four consecutive CRCLM patients referred for DEBIRI chemoembolization were enrolled between March 2015 and December 2016. Tumor size was assessed at baseline and 2 months after DEBIRI chemoembolization by multidetector CT (Response Evaluation Criteria in Solid Tumors RECIST 1.0), and PBV was measured before and after DEBIRI chemoembolization. Two independent readers reviewed all data. We determined the potential correlation (Spearman’s rank correlation) between intraprocedural PBV values and tumor response at 2 months. The relationship between tumor response and PBV was studied using a mixed model. A logistic regression model was applied to study the relationship between patient “Responder/Non-responder” and PBV. There was a strong correlation between baseline PBV or the percent change of PBV and the 2-month tumor response (rho = − 0.8587 (p = 0.00001) and rho = 0.8027 (p = 0.00001), respectively). The mixed model showed that an increase of 1 ml/1000 ml in PBV of a tumor before DEBIRI chemoembolization led to a 0.54 mm decrease in diameter (p

Objective: To explore the need for an extended diagnostic workup in patients with venous leg ulcers (VLUs) and to establish the prevalence of the underlying causes of VLU. Method: This retrospective cohort study analysed data from patients with VLU. The visual analogue scale (VAS) was used for pain assessment. The ankle-brachial index (ABI) was measured to exclude patients with arterial pathology. A duplex was performed. All patients received a wound treatment plan and ambulatory compression therapy. Continuous variables were presented as mean±standard deviation (SD) or median and interquartile range (IQR). Mann-Whitney U test and Kruskal-Wallis were used. When normally distributed, an independent sample t-test was used. Results: A total of 70 patients were recruited. Of these, 18 (25.7%) experienced a VLU once and 52 (74.3%) had a recurrent VLU. Treatment of the underlying lesions was performed in almost 30% of patients. Patients who were treated showed almost two times slower healing rates compared with those who were not treated for an underlying pathology. The mean time in patient referral exceeded two years, and patients who did not see their GP were treated by nurses who did not provide regular feedback the GP; as a result, compression therapy was not always adequate. Conclusion: Patients with a VLU showing no signs of healing after 2 months should be referred to a dedicated wound care centre to avoid delays.

Patient mortality at one year reaches 90% after out-of-hospital cardiac arrest and resuscitation. Temperature management is one of the main strategies proposed to improve patient outcome after resuscitation and preclinical studies have shown neuroprotective effects when hypothermia is achieved rapidly, although the underlying mechanisms have not yet been elucidated. State-of-the-art brain imaging technologies can bring new insights into the early cerebral events taking place post cardiac arrest and resuscitation. In this paper, we characterized cerebral hemodynamics in a post-cardiac arrest rabbit model using functional ultrasound imaging. Ultrasound datasets were processed to map the dynamic changes in cerebral blood flow and cerebral vascular resistivity with a 10 second repetition rate while animals underwent cardiac arrest and a cardiopulmonary resuscitation. We report that a severe transient hyperemia takes place in the brain within the first twenty minutes post resuscitation, emphasizing the need for fast post-cardiac arrest care. Furthermore, we observed that this early hyperemic event is not spatially homogeneous and that maximal cerebral hyperemia happens in the hippocampus. Finally, we show that rapid cooling induced by total liquid ventilation reduces early cerebral hyperemia, which could explain the improved neurological outcome reported in preclinical studies.

International audience; Background: Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.Methods: In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual.Findings: Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2·5%, 90% credible interval [CrI] -17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45).Interpretation: Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19.Funding: The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.

International audience; LVAD implantation in patients with a recently diagnosed cardiomyopathy has been poorly investigated. This work aims at describing the characteristics and outcomes of patients receiving a LVAD within 30 days following the diagnosis of cardiomyopathy. Patients from the ASSIST-ICD study was divided into recently and remotely diagnosed cardiomyopathy based on the time from initial diagnosis of cardiomyopathy to LVAD implantation using the cut point of 30 days. The primary end point of the study was all-cause mortality at 30-day and during follow-up. A total of 652 patients were included and followed during a median time of 9.1 (2.5 to 22.1) months. In this population, 117 (17.9%) had a recently diagnosed cardiomyopathy and had LVAD implantation after a median time of 15.0 (9.0 to 24.0) days following the diagnosis. This group of patients was significantly younger, with more ischemic cardiomyopathy, more sudden cardiac arrest (SCA) events at the time of the diagnosis and were more likely to receive temporary mechanical support before LVAD compared with the remotely diagnosed group. Postoperative in-hospital survival was similar in groups, but recently diagnosed patients had a better long-term survival after hospital discharge. SCA before LVAD and any cardiac surgery combined with LVAD implantation were identified as 2 independent predictors of postoperative mortality in recently diagnosed patients. In conclusion, rescue LVAD implantation for recently diagnosed severe cardiomyopathy is common in clinical practice. Such patients experience a relatively low postoperative mortality and have a better long-term survival compared with remotely diagnosed patients.

Background FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) + aflibercept improves median overall survival (OS) and progression-free survival (PFS) in patients with previously treated metastatic colorectal cancer (mCRC). Our aim was to investigate efficacy and tolerability of this combination in the first line. Patients and Methods Patients with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single-arm, multicenter trial. The primary endpoint was the 6-month PFS rate. Secondary endpoints were OS and tolerability. A 2-step Simon design was used with H0: 55% and H1= 75%. Data were analyzed in intention to treat. Results Forty-one patients were included, and 40 were analyzed (1 consent withdrawal) in 9 French centers between October 2014 and February 2017. The median age was 65 years (range, 46-81 years), 55% had ≥ 2 metastatic sites, and 50% and 15% had RAS and BRAF mutations, respectively. Twenty-two (54.5%; 95% confidence interval, 38.9%-68.5%) patients were alive and non-progressive at 6 months. FOLFIRI + aflibercept was considered ineffective, resulting in the cessation of inclusions. The median follow-up was 34 months. The overall response rate was 55%, and the disease control rate was 80%. The median duration of treatment was 5.3 months; the median PFS and OS were 8.2 and 18.6 months, respectively. Grade 3 to 4 adverse events were mainly gastrointestinal (47.5%) and vascular (32.5%). Of the patients, 87.5% had at least 1 dose modification. Conclusion Although the primary objective was not met, first-line FOLFIRI + aflibercept for mCRC leads to median PFS and OS close to those reported with classical doublet and targeted agents, but with significant toxicities needing dose reduction.

Modifications of the myocardial architecture can cause abnormal electrical activity of the heart. Fibro-fatty infiltrations have been implicated in various cardiac pathologies associated with arrhythmias and sudden cardiac death, such as arrhythmogenic right ventricular cardiomyopathy (ARVC). Here, we report the development of an MRI protocol to observe these modifications at 9.4 T. Two fixed ex vivo human hearts, one healthy and one ARVC, were imaged with an Iterative decomposition with echo asymmetry and least-square estimations (IDEAL) and a magnetization transfer (MT) 3D sequences. The resulting fat fraction and MT ratio (MTR) were analyzed and compared to histological analysis of the three regions (“ARVC triangle”) primarily involved in ARVC structural remodeling. In the ARVC heart, high fat content was observed in the “ARVC triangle” and the superimposition of the MTR and fat fraction allowed the identification of fibrotic regions in areas without the presence of fat. The healthy heart exhibited twice less fat than the ARVC heart (31.9%, 28.7% and 1.3% of fat in the same regions, respectively). Localization of fat and fibrosis were confirmed by means of histology. This non-destructive approach allows the investigation of structural remodeling in human pathologies where fibrosis and/or fatty tissue infiltrations are expected to occur.

International audience; We aimed at characterizing the impact of low and high body mass index (BMI) on outcomes after left-ventricular assist device (LVAD) surgery and define the predictors of mortality in patients with abnormal BMI (low/high). This study was conducted in 19 centers from 2006 to 2016. Patients were divided based on their baseline BMI into 3 groups of BMI: low (BMI ≤18.5 kg/m²); normal (BMI = 18.5 to 24.99 kg/m²) and high (BMI ≥25 kg/m²) (including overweight (BMI = 25 to 29.99 kg/m²), and obesity (BMI ≥30 Kg/m²)). Among 652 patients, 29 (4.4%), 279 (42.8%) and 344 (52.8%) had a low-, normal-, and high BMI, respectively. Patients with high BMI were significantly more likely men, with more co-morbidities and more history of ventricular/supra-ventricular arrhythmias before LVAD implantation. Patients with abnormal BMI had significantly lower survival than those with normal BMI. Notably, those with low BMI experienced the worst survival whereas overweight or obese patients had similar survival. Four predictors of mortality for LVAD candidates with abnormal BMI were defined: total bilirubin ≥16 µmol/L before LVAD, hypertension, destination therapy, and cardiac surgery with LVAD. Depending on the number of predictor per patients, those with abnormal BMI may be divided in 3 groups of 1-year mortality risk, i.e., low (0 to 1 predictor: 29% and 31%), intermediate (2 to 3 predictors, 51% and 52%, respectively), and high (4 predictors: 83%). In conclusion, LVAD recipients with abnormal BMI experience lower survival, especially underweight patients. Four predictors of mortality have been identified for LVAD population with abnormal BMI, differentiating those a low-, intermediate-, and high risks of death.

Purpose Daratumumab is the first anti-CD38 monoclonal antibody of the class approved for recurrent and refractory multiple myeloma. Grade 3 and 4 Infusion-Related Reactions (IRRs) are frequent during the first and second infusions. Due to the risks associated with severe IRRs, daratumumab is systematically administered over a period of 3.5 hours. The main objective of this study was to evaluate the safety of a 90-minute daratumumab infusion from the third infusion. Patients and methods All patients who had received two or more doses of daratumumab in monotherapy or in combination with standard infusion rates were included. We excluded patients enrolled in clinical trials. For the rapid infusion protocol, 20% of the dose was administered over 30 minutes and the remaining 80% over 60 minutes. Results From April 1 to May 31, 2019, 25 patients received 53 90-minute infusions of daratumumab. Premedication included corticosteroids, antipyretics, antihistamines, and if necessary a leukotriene receptor antagonist. No grade 3 or grade 4 IRRs were observed. Conclusion From the third infusion, we found that a rapid administration of daratumumab (90 vs 210 minutes) was well tolerated and safe. It would be interesting to test this regimen from the second infusion.

A combination of nab-paclitaxel plus gemcitabine (N+G) has recently become a standard first-line treatment in patients with metastatic pancreatic adenocarcinoma (MPA), but there are currently no published data concerning second-line treatment after N+G. The aim of this study was to evaluate the survival outcomes and tolerability of three usual fluoropyrimidine-based regimens FOLFOX, FOLFIRI and FOLFIRINOX after N+G failure in MPA patients.Patients receiving N+G as first-line regimen were prospectively identified in 11 French centers between January 2014 and January 2017. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were enrolled in the study. The primary endpoint was overall survival following the second-line regimen. Secondary endpoints were objective response, progression-free survival and safety.Out of 137 patients treated with N+G as first-line regimen, 61 (44.5%) received second-line chemotherapy, including FOLFOX (39.4%), FOLFIRI (34.4%) or FOLFIRINOX (26.2%). Baseline characteristics were not different between the 3 groups. In particular, median age was 71.7 years, sex ratio was 1/1, and performance status (PS) was 0 in 11.5% of case. Main grade 3 toxicities were neutropenia (4.9%) and nausea (3.3%), without major differences between the groups. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2.95 (95% CI: 2.3-5.4) and 5.97 months (95% CI: 4.0-8.0), respectively, with no difference between the 3 groups. Median OS from the start of first-line chemotherapy was 12.7 months (10.4-15.1) and was significantly better in patients receiving FOLFIRI after N+G failure, 18.4 months (95% CI: 11.7-24.1, P0.05), as compared with FOLFOX or FOLFIRINOX (10.4 and 12.3 months, respectively).This study suggests that second-line fluoropyrimidine-based regimens after N+G failure are feasible, have a manageable toxicity profile in selected patients with MPA, and are associated with promising clinical outcomes, in particular when combined with irinotecan. Randomized phase 3 trials are needed to confirm this trend.

Background Surgical management of aortic valve endocarditis in high risk patients is controversial and the ideal treatment has not been found yet. We describe a selected series of eight patients treated with rapid-deployment aortic valve prosthesis as a therapeutic solution for minimizing the risks associated with annulus manipulation in case of severe aortic infective endocarditis. Methods Eight consecutive patients (five men and three women) with a mean age of 74.3±7.2 years, mean logistic EuroSCORE II of 16.0%±0.1%, affected by aortic native (1 patient), or prosthetic valve endocarditis (7 patients), were treated with Edwards Intuity Elite implantation. Hemodynamic performance and infective data were collected pre-, intra-, and postoperatively with a mean follow-up of 2.7±0.7 years. Results One case of in-hospital mortality was noted. None of the patients had any embolic or infective complication postoperatively. The cardiopulmonary bypass and aortic cross-clamp times were 148.4±41.6 and 90.5±25.3 min, respectively. The postoperative echocardiographic controls indicated a mean transvalvular gradient of 16.7±3.0 mmHg and one case of paravalvular leaks (2 +). Two patients underwent epigastric permanent pacemaker implantation. During the follow-up, seven patients were alive, with no evidence of symptoms or recurrences of endocarditis or embolic episodes. No new paravalvular leaks were noted, and the mean gradient on the valves was 12.4±3.4 mmHg. Conclusions Rapid deployment aortic valve replacement in selected very high-risk patients affected by infective endocarditis could be a reasonable choice with acceptable results. However, further studies are needed to confirm these results.

Background For studying the effectiveness of treatment, it is important to check whether a new treatment is performed as originally described in the study-protocol. Objectives To evaluate whether an interdisciplinary graded exposure program, for adolescents with chronic musculoskeletal pain reporting pain-related fear, was performed according to protocol, and whether it is feasible to implement the program in rehabilitation care. Methods A process evaluation where quantitative and qualitative data on participant characteristics (adolescents, parents and therapists), attendance and participants’ opinion on the program were collected, by means of registration forms, questionnaires and group interviews. To evaluate treatment fidelity, audio and video recordings of program sessions were analyzed. Results Thirty adolescents were offered the program, of which 23 started the program. Adolescents attended on average 90% of the sessions. At least one parent per adolescent participated in the program. Analysis of 20 randomly selected recordings of treatment sessions revealed that treatment fidelity was high, since 81% of essential treatment elements were offered to the adolescents. The program was considered client-centered by adolescents and family-centered by parents. Treatment teams wished to continue offering the program in their center. Conclusion The interdisciplinary graded exposure program was performed largely according to protocol, and therapists, adolescents and their parents had a favorable opinion on the program. Implementation of the program in rehabilitation care is considered feasible. Trial registration Clinicaltrials.gov ID: NCT02181725 (7 February 2014).

Background Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection. Methods In the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session. Results Fifty-seven patients were enrolled. Grade 3–5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8–65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7–45.8), and median PFS 10.8 months (95% CI, 8.2–12.3). Conclusions Front-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal. Clinical trial registration NCT01839877.

AimsTo compare the stiffness index in patients with bicuspid aortic valve (BAV) with first-degree relatives at each segment of the thoracic ascending aorta and to compare segmental analysis of aortic stiffness in association with BAV morphotype and function.Methods219 patients with BAV and 148 first-degree relatives (without BAV) were consecutively included at a reference centre for BAV. Ultrasound assessment of aortic and carotid stiffness was based on the variation of the segmental arterial diameters during the cardiac cycle and on blood pressure.ResultsWithout adjustment, the ascending aorta of patients with BAV seemed stiffer at each segment compared with controls (stiffness index at the sinus of Valsalva: 17.0±10.9 vs 8.9±6.1, pConclusionStiffness increase at the sinus of Valsalva level is independent of aortic dilatation in patients with BAV, contrary to the classic relationship between stiffness and dilatation found on the other segments. The relationship between stiffness and clinical impact needs to be assessed at each aortic segment.

Background There is no consensus on screening strategy of high-grade intraepithelial neoplasia (HGAIN). Guidelines range from clinical examination with digital anorectal examination followed by standard anoscopy (SA), to anal cytology (Pap)+/− HPV genotyping. We compared screening strategy yields based on Pap, SA, and HPV-16 genotyping alone or in combination in HIV-MSM. Methods Pap, SA, and HPV-16 genotyping were performed in all HIV-MSM attending a first anal cancer screening consultation in Paris, France. High-resolution anoscopy, the gold standard to detect HGAIN, was performed in the case of HPV-16 positivity or abnormal cytology. Yield was defined as the number of patients with HGAIN relative to the total number of patients screened. Results On 212 patients, the complete strategy (SA + Pap + HPV genotyping) yield (12.7%) was significantly higher than that of SA (3.3%, p

Background Triplet chemotherapy, with docetaxel-5FU-oxaliplatin (TEFOX), has yielded promising results in patients with advanced and operable gastric adenocarcinoma. This may prove useful in treating signet ring cell carcinoma (SRCC), which is known to be chemoresistant and has a poor prognosis. We therefore evaluated TEFOX in patients with untreated advanced SRCC. Methods Patients with metastatic or locally advanced non-resectable SRCC were treated with TEFOX. Chemotherapy was administered every 14 days, with combined docetaxel (50 mg/m2) and oxaliplatin (85 mg/m2) followed by 5FU (2400 mg/m2). Results Among 65 patients enrolled, including 17 with linitis plastica, ORR and DCR were 66.1% and 87.6%, respectively. Median PFS and OS were 9.7 months (95% CI [6.9–11.4]) and 14.3 months (95% CI [11.6–21.6]) respectively. Twenty-six patients (40%) initially considered as unresectable had secondary resection (n = 24) or radiotherapy (n = 2) with curative intent, with median PFS and OS of 12.4 and 26.2 months, respectively. Conclusions TEFOX appears to be effective as first-line treatment in advanced gastric SRCC and has an acceptable safety profile. It allowed a curative intent approach in 40% of patients. Considering the low chemosensitivity of SRCC reported with other chemotherapy regimens and pending for randomised studies, TEFOX might be an option in advanced gastric SRCC.

Summary Introduction Hepatic arterial infusion (HAI) chemotherapy with oxaliplatin is an accepted option in the management of colorectal cancer (CRC) with dominant liver metastases (LM). However, despite prolonged control, some patients experience disease progression. On the other hand, oxaliplatin leads to dose-limiting toxicity. In these cases, the use of a second-line HAI with an alternative drug has never been reported to date. We evaluated treatment outcomes in patients receiving second-line HAI with 5-FU or mitomycin C, after first-line HAI of oxaliplatin in heavily pretreated patients. Material and methods Between March 2010 and June 2016, this observational study included 24 patients with unresectable CRC LM and treated with HAI of 5-FU (17 patients) or mitomycin C (7 patients), after HAI of oxaliplatin. Results Mean age was 61.7 years. Forty-two percent of patients (10/24) had extra-hepatic metastases and 75% (18/24) at least 8 liver metastases. Including HAI of oxaliplatin, all patients had previously received at least 2 lines of chemotherapy ± targeted agents (100%) and 96% (23/24) received concomitant systemic therapies together with HAI of 5-FU or mitomycin C. The overall objective response rate and disease control rate were, respectively, 42% (10/24) and 71% (17/24). Median progression-free survival and overall survival (OS) were, respectively, 5.6 and 25.8 months; hepatic progression-free survival was 8.5 months. Thirteen percent (3/24) of the patients received further curative intent treatment after HAI 5-FU and mitomycin C. No toxic death occurred and the toxicity profile was acceptable. Conclusions HAI of 5-FU or mitomycin C is an alternative option in patients with predominant CRC LM, when they experience disease progression or do not tolerate HAI of oxaliplatin.

Overuse of broad-spectrum antibiotics in emergency departments (EDs) results in antibiotic resistance. We determined whether procalcitonin (PCT) -guided therapy can be used to reduce antibiotic regimens in EDs by investigating efficacy, safety and accuracy.This was a non-inferiority multicentre randomized clinical trial, performed in two Dutch hospitals. Adult patients with fever ≥38.2°C (100.8°F) in triage were randomized between standard diagnostic workup (control group) and PCT-guided therapy, defined as standard workup with the addition of one single PCT measurement. The treatment algorithm encouraged withholding antibiotic regimens with PCT0.5 μg/L, and starting antibiotic regimens at PCT ≥0.5 μg/L. Exclusion criteria were immunocompromised conditions, pregnancy, moribund patients, patients72 h after surgery or requiring primary surgical intervention. Primary outcomes were efficacy, defined as number of prescribed antibiotic regimens; safety, defined as combined safety end point consisting of 30 days mortality, intensive-care unit admission, ED return visit within 2 weeks; accuracy, defined as sensitivity, specificity and area-under-the-curve (AUC) of PCT for bacterial infections. Non-inferiority margin for safety outcome was 7.5%.Between August 2014 and January 2017, 551 individuals were included. In the PCT-guided group (n = 275) 200 (73%) patients were prescribed antibiotic regimens, in the control group (n = 276) 212 (77%) patients were prescribed antibiotics (p 0.28). There was no significant difference in combined safety end point between the PCT-guided group, 29 (11%), and control group, 46 (16%) (p 0.16), with a non-inferiority margin of 0.46% (n = 526). AUC for confirmed bacterial infections for PCT was 0.681 (95% CI 0.633-0.730), and for CRP was 0.619 (95% CI 0.569-0.669).PCT-guided therapy was non-inferior in terms of safety, but did not reduce prescription of antibiotic regimens in an ED population with fever. In this heterogeneous population, the accuracy of PCT in diagnosing bacterial infections was poor. TRIAL REGISTRATION IN NETHERLANDS TRIAL REGISTER: http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4949.

Purpose The aim of this study was to assess the feasibility, safety and efficacy of percutaneous radiofrequency ablation of lung metastases from colorectal carcinoma using C-arm cone beam computed tomography (CBCT) guidance. Material and methods This single-center prospective observational study was performed from August 2013 to August 2016, and included consecutive patients referred for radiofrequency ablation of lung metastases from colorectal cancer. Radiofrequency ablation procedures were performed under C-arm CBCT guidance. Feasibility was assessed by probe accuracy placement, time to accurate placement and number of C-arm CBCT acquisitions to reach the target lesion. Safety was assessed by the report of adverse event graded using the common terminology criteria for adverse events (CTCAE-V4.0). Efficacy was assessed by metastases response rate using RECIST 1.1 and 18FDG-PET-CT tumor uptake at 6 months. Results Fifty-four consecutive patients (32 men, 22 women) with a mean age of 63 ± 8 (SD) years (range: 51–81 years) with a total of 56 lung metastasis from colorectal metastases were treated in a single session. The mean tumor diameter was 25.6 ± 4.5 (SD) mm (range: 17–31 mm). Median time to insert the needle into the target lesion was 10 min (range: 5–25 min). Median number of needles repositioning and C-arm CBCT acquisition per patient was 1 (range: 0–3) and 4 (range: 3–6) respectively. The accuracy for radiofrequency ablation probe placement was 2 ± 0.2 (SD) mm (range: 0–9 mm). Pneumothorax requiring chest tube placement occurred in one patient (CTCAE-V4.0 grade 3). At 6 months, all patients were alive with tumor response rate of −27% and had no significant activity on the 18FDG-PET CT follow-up. Conclusion Percutaneous radiofrequency ablation of lung metastases from colorectal cancer under C-arm CBCT guidance is feasible and safe, with immediate and short-term results similar to those obtained using conventional CT guidance.

IF 6.029; International audience; Background: The identification of dynamic biomarkers in advanced gastric and oesogastric junction adenocarcinoma (GOA) could help to tailor strategies for each patient. Enumeration of circulating tumour cells (CTCs) is approved by the US Food and Drug Administration in breast, colon and prostate cancer but is not in advanced GOA. Our study aims to establish the optimal threshold and the clinical significance of CTC count in advanced GOA before and during treatment.Methods: One hundred six patients with untreated advanced GOA were included in the ancillary study of the PRODIGE 17-ACCORD 20 trial. CTCs were detected in the peripheral blood using the CellSearch system on day 0 (D0) and day 28 (D28). The prognostic value of CTCs at D0 and D28 was analysed by testing several thresholds.Results: At baseline, median CTC count was 1 (range, 0-415). While CTCs >= 1, 2 or 3 at D0 were all significantly associated with worse overall survival (OS) and progression-free survival (PFS), CTCs >2 were the optimal threshold, on D0 or D28. CTCs >2 at D28 were also predictive of disease control. Taking into account both D0 and D28 CTC count defined 3 groups (low/low, high/low and low-high/high) with significantly different PFS (p = 0.0002) and OS (p = 0.003).Conclusion: Quantification of CTCs at baseline and during treatment may be a useful prognostic tool in advanced GOA, as it is associated with worse PFS and OS. A threshold >= 2 CTCs seems to have the best discriminant value. Change in CTC count between baseline and D28 could help to tailor treatment to each individual patient. (C) 2017 Elsevier Ltd. All rights reserved.

Introduction France deployed to Afghanistan from 2001 to 2014 within the International Security and Assistance Force. A French role 3 hospital was built in 2009 in the vicinity of Kabul International Airport (KaIA). The objectives of this study were to describe the epidemiology, management, and outcome of war-related craniocerebral injuries during the Afghan campaign in a French role 3 hospital. Methods From March 1, 2010 to September 30, 2012, we conducted a retrospective descriptive study in Kabul, Afghanistan. All patients presenting with a ballistic craniocerebral injury to the KaIA role 3 hospital were included. Results We analyzed 48 records. Mean age was 21.9 years (1–46 years) with a 37:11 (male:female) sex ratio and a majority Afghan population ( n = 41). Civilians represented 64.6% ( n = 31) of casualties. On the battlefield, mean Glasgow Coma Scale score was 9.4 [3–15]. On arrival at the KaIA field hospital, 20 of the 48 patients were hemodynamically unstable. All patients underwent a full-body computed tomography scan. The majority of our casualties had associated injuries. Neurosurgery was indicated for 42 (87.5%) patients. The surgery consisted of wound debridement plane by plane associated with decompressive craniectomy ( n = 11), debridement craniectomy ( n = 19), and craniotomy ( n = 12). A total of 32.4% wounded died at the point of injury, 8.4% at the emergency department, and 16.9% after surgery. Conclusions War casualties with ballistic head injuries were predominantly multitraumatized patients with hemodynamic compromise requiring neurosurgical damage control management and multidisciplinary care. The neurosurgeon has thus an essential role to play.

Summary Objectives We conducted a prospective study approved by the local ethics committee to determine the impact of a pharmaceutical intervention (PI) on pain, fatigue, quality of life (QoL) and coping strategies in patients with HMs starting chemotherapy sessions. Material and methods Patients received either usual care (UC) + PI (PI group) or UC alone (UC group). They had to complete 2 questionnaires, QLQ-C30 and MAC 21, at 3 different time points: before starting the 1st chemotherapy session (T1), during the intercure (T2) and the day before starting the 2nd chemotherapy session (T3). To determine predictive factors of pain, fatigue, QoL and coping scores at T3, a multivariate ANOVA was used. QoL and coping scores were analysed longitudinally using a linear mixed model. Results Sixty-eight patients were included in the PI (n = 34) or UC groups (n = 34). Ninety-two percent of the patients returned all the questionnaires. At inclusion, QoL was significantly better in the PI group (P = 0.047). At T3, the group had no influence on pain, fatigue, nor coping scores but a trend towards a better QoL was observed in the PI group (P = 0.090). Longitudinally, the PI group did not present significantly better scores on pain, fatigue but both a trend toward better Qol scores and lower anxious preoccupations scores. Conclusion A PI at the beginning of chemotherapy sessions did not have any significant impact on pain and fatigue but a trend towards better Qol scores and lower anxious preoccupations scores.

International audience; Objectives - This study aimed to evaluate incidence, clinical significance, and predictors of early ventricular arrhythmias (VAs) in left ventricular assist device (LVAD) recipients. Background - LVAD implantation is increasingly used in patients with end-stage heart failure. Early VAs may occur during the 30-day post-operative period, but many questions remain unanswered regarding their incidence and clinical impact. Methods - This observational study was conducted in 19 centers between 2006 and 2016. Early VAs were defined as sustained ventricular tachycardia and/or ventricular fibrillation occurring

Most western countries have guidelines on anal cancer screening for men who have sex with men (MSM) living with HIV. However, adherence to these guidelines has been studied poorly. This cross-sectional study reports anal cancer screening uptake and identifies the factors associated with a previous screening in MSM living with HIV in a Paris Hospital (France). A total of 410 outpatients completed a self-administered questionnaire on anal cancer screening. The median age was 50 years and the median time from HIV diagnosis was 14.2 years. Overall, 82.2% of patients were aware of anal cancer screening and, of these, 56.7% had already undergone a screening test. The absence of history of screening (43.3%) was most often explained by lack of time (31.3%) or information (28.2%). Among patients familiar with the anal screening procedure, those older than 50 years (adjusted odds ratio=2.4, 95% confidence interval=1.3-4.7, P=0.007) and informed by healthcare providers (adjusted odds ratio=8.2, 95% confidence interval=2.5-32.0, P=0.001) were more likely to have already been screened. To date, adherence to anal cancer screening in MSM living with HIV appears to be inadequate to enable diagnosis of cancer at its early stages. Encouraging physicians to inform MSM living with HIV about anal cancer screening, irrespective of their age, could be an effective strategy to improve anal cancer screening uptake.

The correlation between immune cells and the Lauren classification subtypes and their prognostic impact in advanced gastric cancer (AGC) are unknown. Circulating natural killer (NK) cells, CD4+ and CD8+ T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were quantified in peripheral blood mononuclear cells (PBMCs) from 67 patients with untreated AGC enrolled in the PRODIGE 17-ACCORD 20 trial. CD56+ cells (NK), CD8+, and FoxP3+ (Treg) tumor-infiltrating lymphocytes (TILs) were assessed in tumor samples. Circulating NK and Treg proportions were significantly lower in patients with diffuse/mixed-type AGC (n = 27) than those with intestinal type (n = 40; median 6.3% vs 11.5%; p = 0.02 and median 3.3% vs 5.2%; p = 0.03, respectively). Proportions of circulating MDSC, CD4+ and CD8+ T cells were not associated with one pathological type. Among tumor-infiltrating cells, CD8+ T cells, but not NK or FoxP3+ cells, were significantly lower in diffuse/mixed-type AGC (median 21 vs 59 cells/field; p = 0.009). Patients with high circulating NK cell counts (> 17%) had a better overall survival than those with 31 cells/field) had significantly longer overall survival (HR 0.44; 95% CI [0.21–0.92]; p = 0.02). The prognostic value of CD8+ TILs was maintained after adjustment for confounding factors, including the Lauren classification (HR = 0.42; 95% CI [0.18–0.96]; p = 0.039). Diffuse/mixed-type AGC has lower rates of CD8+ TILs and circulating NK cells and Tregs than the intestinal type. This “cold tumor” phenotype may be associated with a worse outcome.

Shear wave elastography and ultrafast imaging of the carotid artery pulse wave were performed in 27 normotensive participants and 29 age- and sex-matched patients with essential hypertension, and compared with reference techniques: carotid-femoral pulse wave velocity (cfPWV) determined via arterial tonometry and carotid stiffness (carPWV) determined via echotracking. Shear wave speed in the carotid anterior (a-SWS) and posterior (p-SWS) walls were assessed throughout the cardiac cycle. Ultrafast PWV was measured in early systole (ufPWV-FW) and in end-systole (dicrotic notch, ufPWV-DN). Shear wave speed in the carotid anterior appeared to be the best candidate to evaluate arterial stiffness from ultrafast imaging. In univariate analysis, a-SWS was associated with carPWV (r = 0.56, p = 0.003) and carotid-to-femoral PWV (r = 0.66, p0.001). In multivariate analysis, a-SWS was independently associated with age (R² = 0.14, p = 0.02) and blood pressure (R² = 0.21, p = 0.004). Moreover, a-SWS increased with blood pressure throughout the cardiac cycle and did not differ between normotensive participants and patients with essential hypertension when compared at similar blood pressures.

Background The primary objective was to evaluate the rates of older patients with colorectal cancer (CRC) who were eligible for a clinical trial, invited to participate, and, ultimately, included. The secondary objective was to assess the reasons for ineligibility, noninvitation, and noninclusion and factors associated. Materials and Methods The Sujets AGés dans les Essais Cliniques (SAGE; Older Subjects in Clinical Trials) multicenter prospective cohort was established in seven centers (10 departments of medical oncology, digestive oncology, and digestive surgery) between 2012 and 2016. All patients with CRC aged 65 or older were studied. The endpoints were clinical trial availability, patient's eligibility, invitation, and enrollment in a trial. Results We included 577 older patients (mean age ± SD: 75.6 ± 7 years; males: 56%; metastasis: 41%). Thirty-seven trials were ongoing (one trial for older patients). Of the 474 patients with at least one available trial for their cancer stage and site, 127 (27%) were eligible; 84 of these 127 (66%) were invited to participate, and 70 of these 84 (83%) were included. In a multivariate analysis, noninvitation was found to be associated with older age (p = .016): adjusted relative risk (95% confidence interval), 0.14 (0.02–0.60) for ≥80 vs. 65–69; 0.54 (0.18-1.04) for 75–79 vs. 65–69; 0.47 (0.17-0.93) for 70–74 vs. 65–69. Conclusion Three-quarters of older patients with CRC were ineligible for a clinical trial. One-third of the eligible patients were not invited to participate in a trial, and 17% of invited patients were not included. Few trials are reserved for older patients. Patients aged 80 or older were significantly less likely to be eligible for a trial and invited to participate. Clinical trial identification number: NCT01754636. Implications for Practice The results of this study suggest that barriers to participation of older patients in clinical trials are particularly marked at age 80 years or older. Secondly, the results emphasize the need for trials for older patients. Thirdly, there is also a need for more pragmatic “real-world” trials, rather than solely randomized trials performed in idealized settings with strictly selected patients. Large prospective observational cohorts with a precise follow-up of toxicity, functional decline, and quality of life may constitute one way of generating more data on the risk-benefit ratio for cancer treatments in older patients.

International audience; Glyphosate is the most widely used herbicide in the world. Several studies have investigated the effects of glyphosate and glyphosate-based-herbicides (GBHs) on male reproduction, but there is still little and conflicting evidence for its toxicity. In this study, we analyzed the effects of glyphosate, alone or in formula, on the male reproductive system. Pregnant mice were treated from E10.5 to 20 days postpartum (dpp) by adding glyphosate or a GBH (Roundup® 3 Plus) to their drinking water at 0.5 (the acceptable daily intake, ADI dose), 5 and 50 mg/kg/day. Male offspring derived from treated mice were sacrificed at 5, 20 and 35 days-old (d.o.) and 8 months-old (m.o.) for analysis. Our result showed that exposure to glyphosate, but not GBH, affect testis morphology in 20 d.o. and decrease serum testosterone concentrations in 35 d.o. males. We identified that the spermatozoa number decreased by 89% and 84% in 0.5 and 5 mg/kg/day of GBH and glyphosate groups, respectively. Moreover, the undifferentiated spermatogonia numbers were decreased by 60% in 5 mg/kg/day glyphosate group, which could be due to the alterations in the expression of genes involved in germ cell differentiation such as Sall4 and Nano3 and apoptosis as Bax and Bcl2. In 8 m.o. animals, a decreased testosterone level was observed in GBH groups. Our data demonstrate that glyphosate and GBHs could cause endocrine-disrupting effects on male reproduction at low doses. As glyphosate has effects at the ADI level, our data suggests that the current ADI for glyphosate could be overestimated.

Background In metastatic colorectal cancer (mCRC), circulating tumour DNA (ctDNA) monitoring can be used to genotype tumors and track clonal evolution. We investigated the clearance of RAS mutated clones under chemotherapy pressure by ctDNA analysis in patients with a RAS mutated mCRC. Methods Patients with a RAS mutated tumour included in the prospective PLACOL study, were monitored for ctDNA. Analyzes were based on optimized targeted next generation sequencing and/or droplet-based digital PCR (ddPCR). For plasma samples without detectable mutations, we tested the methylation status of WIF1 and NPY genes using methylation-ddPCR (met-ddPCR) to validate the presence of ctDNA. Results Among the 36 patients with positive plasma samples for RAS mutations at inclusion, 28 (77.8%) remained RAS positive at disease progression, and 8 (22.2%) became negative. Subsequent met-ddPCR for methylated markers showed that only 2 out of the 8 patients with RAS negative plasma had detectable ctDNA at progression. Therefore, only two samples among 36 were confirmed for clearance of RAS mutation in our series. Conclusions This study suggests that the clearance of RAS mutations in patients treated by chemotherapy for a RAS mutated mCRC is a rare event. Monitoring tumor mutations in plasma samples should be combined with a strict control of the presence of ctDNA. The therapeutic impacts of RAS clearance need to be further explored. Legal entity responsible for the study The authors. Funding The Ministere de l’Enseignement Superieur et de la Recherche, the Universite Paris-Descartes, the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Sante et de la Recherche Medicale (INSERM), the Institut National du Cancer (INCA, n° 2009-1-RT-03-US-1 and 2009-RT-03-UP5-1), the Association pour la recherche contre le cancer (ARC, no. SL220100601375), the Agence Nationale de la Recherche (ANR Nanobiotechnologies; no. ANR-10-NANO-0002-09), the SIRIC CARPEM, the ligue nationale contre le cancer (LNCC, Program “Equipe labelisee LIGUE”; no. EL2016.LNCC/VaT) and Advanced Merieux Research Grant and canceropole funding (no. 2011-1-LABEL-UP5-2). Disclosure H. Blons: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck; Advisory / Consultancy: Amgen; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pfizer. V. Taly: Advisory / Consultancy: Servier; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Raindance Technologies. W. Shu-Fang: Research grant / Funding (institution): Servier. S. Pernot: Advisory / Consultancy: Amgen; Advisory / Consultancy: Sanofi. J. Taieb: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sirtex; Advisory / Consultancy, Speaker Bureau / Expert testimony: Shire; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Servier; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre. P. Laurent-Puig: Advisory / Consultancy: Amgen; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly. A. Zaanan: Advisory / Consultancy: Amgen; Advisory / Consultancy: Baxter; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: MSD; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Roche; Advisory / Consultancy: Servier. All other authors have declared no conflicts of interest.

Aim of the study The optimal therapeutic strategy in patients with rectal cancer and synchronous unresectable metastases remains unknown. We evaluated the efficacy of FOLFIRINOX induction therapy in this setting. Patients and methods Chemotherapy-naive patients received at least 8 cycles of FOLFIRINOX. The primary end-point was the 4-month disease control (4 m DC) rate. Tumour responses were centrally reviewed and assessed by computed tomography scan for metastases (Response Evaluation Criteria in Solid Tumours criteria) and magnetic resonance imaging for rectal tumorus. With a Simon 2-stage design and a targeted (H1) 4 m DC > 75%, 65 patients were enrolled from July 2012 to February 2015: male, 78%; median age, 61 years; performance status, 0–1, 98%; liver metastases, 92%; ≥2 metastatic sites, 63%. Results Fifty-six (85%) of the 65 patients received the 8 planned FOLFIRINOX cycles. The primary objective was achieved (4 m DC rate: 94%; 95% confidence interval [CI], 86.3–97.8). Primary tumour symptoms decreased from 72% at baseline to 10% at 4 months. Response rate was 86%, and a >70% primary tumour volume decrease was seen in 63% of patients. Forty-four patients (68%) had at least one grade 3 side-effect; no toxic deaths occurred. Median follow-up was 35.0 months (95% CI, 31.3–43.7). Median progression-free survival and overall survival were 10.9 m (95% CI, 8.8–12.9) and 33.4 m (95% CI, 22.6–38.2), respectively. Conclusion Upfront FOLFIRINOX is feasible and allows good local and distant control. It therefore offers the opportunity to choose the best therapeutic strategy for each patient and to personalise treatment according to the local and distant efficacy results of this induction step. Trial registration Clinicaltrials.gov, NCT01674309 .

Background Docetaxel/cisplatin/infusional 5-fluorouracil (5-FU; DCF) is a standard chemotherapy regimen for patients with advanced gastric cancer (GC). This phase II study evaluated docetaxel/oxaliplatin (TE), docetaxel/oxaliplatin/5-FU (TEF), and docetaxel/oxaliplatin/capecitabine (TEX) in patients with advanced GC. Patients and methods Patients with metastatic or locally recurrent gastric adenocarcinoma (including carcinoma of the gastro-oesophageal junction) were randomly assigned (1 : 1 : 1) to TE, TEF, or TEX. Each regimen was tested at two doses before full evaluation at optimized dose levels. The primary end point was progression-free survival (PFS). Overall survival (OS), tumour response, and safety were also assessed. A therapeutic index (median PFS relative to the incidence of febrile neutropenia) was calculated for each regimen and compared with DCF (historical data). Results Overall, 248 patients were randomly assigned to receive optimized dose treatment. Median PFS was longer with TEF (7.66 [95% confidence interval (CI): 6.97–9.40] months) versus TE (4.50 [3.68–5.32] months) and TEX (5.55 [4.30–6.37] months). Median OS was 14.59 (95% CI: 11.70–21.78) months for TEF versus 8.97 (7.79–10.87) months for TE and 11.30 (8.08–14.03) months for TEX. The rate of tumour response (complete or partial) was 46.6% (95% CI 35.9–57.5) for TEF versus 23.1% (14.3–34.0) for TE and 25.6% (16.6–36.4) for TEX. The frequency and type of adverse events (AEs) were similar across the three arms. Common grade 3/4 AEs were fatigue (21%), sensory neuropathy (14%), and diarrhoea (13%). Febrile neutropenia was reported in 2% (TEF), 14% (TE), and 9% (TEX) of patients. The therapeutic index was improved with TEF versus TEX, TE, or DCF. Conclusion These results suggest that TEF is worthy of evaluation as an arm in a phase III trial or as a backbone regimen for new targeted agents in advanced GC. ClinicalTrials.gov Identifier Trial registration number: NCT00382720.

Background Allergic skin inflammation often presents in early childhood; however, little is known about the events leading to its initiation and whether it is transient or long-term in nature. Objective We sought to determine the immunologic rules that govern skin inflammation in early life. Methods Neonatal and adult mice were epicutaneously sensitized with allergen followed by airway allergen challenge. Epicutaneous application of labeled allergen allowed for determination of antigen uptake and processing by antigen-presenting cells. RNAseq and microbiome analysis was performed on skin from neonatal and adult specific pathogen-free and germ-free mice. Results A mixed TH2/TH17 inflammatory response in the skin and the lungs of adult mice was observed following sensitization and challenge. Comparatively, neonatal mice did not develop overt skin inflammation, but exhibited systemic release of IL-17a and a TH2-dominated lung response. Mechanical skin barrier disruption was not sufficient to drive allergic skin inflammation, although it did promote systemic immune priming. Skin of neonatal mice and adult germ-free mice was seeded with low numbers of antigen-presenting cells and impaired chemokine and alarmin production. Enhanced chemokine and alarmin production, and seeding of the skin with antigen-presenting cells capable of instructing recruited cells to elicit their effector function, was, at least in part, dependent on formation of the microbiome, and consequently contributed to the development of overt skin disease. Conclusions These data shed light on the principles that underlie allergic inflammation in different tissues and highlight a window of opportunity that might exist for early-life prevention of allergic diseases.

Summary Introduction Most liver metastases from colorectal cancer (CRC) are unresectable at diagnosis. Systemic chemotherapy allows secondary surgical resection in 10 to 20% of patients. Hepatic intra-arterial treatments could enhance response and resection rate. We therefore designed a prospective phase II trial testing the transarterial chemoembolization (TACE) using drug-eluting beads loaded with irinotecan (DEBIRI) with concomitant systemic FOLFOX regimen, the FFCD 1201 trial, in patients with liver limited metastatic CRC. Case report A 48-year old patient was operated from an occlusive sigmoid adenocarcinoma. Magnetic resonance imaging showed 6 bilobar liver metastasis. The patient was considered as non-eligible for surgery initially. Patient was included in the FFCD 1201 trial and received 5 cycles of FOLFOX and 2 sessions of DEBIRI, with a quite good tolerability. Post-treatment evaluation showed a partial response and sufficient tumor shrinkage to make liver metastasis resectable. Right hepatectomy associated with wedge resection in the left liver was performed and pathological findings showed a complete pathological response (CPR). Conclusion Combination of DEBIRI with FOLFOX could increase tumor shrinkage leading to secondary resection of liver metastases from CRC. This combination may also, as shown here for the first time in a patient with unresectable LM, induce CPR of all LM, known to be associated with better outcome. Our case also emphasizes the difficulty to morphologically assess pathological response and the need for new tool to better select patients who should be resected. Further results of the FFCD 1201 trial will bring more information on this new combination therapy.

Background Although no data have been reported beyond second-line therapy, aflibercept is approved in this setting in many countries. We conducted a multicenter study to analyze the efficacy and safety of a aflibercept–chemotherapy regimen beyond second-line therapy in patients with metastatic colorectal cancer. Patients and Methods Metastatic colorectal cancer patients treated with aflibercept beyond second-line therapy were included. Objective response rate, overall survival (OS), and progression-free survival (PFS) were assessed. Results A total of 130 patients were included. Median OS and PFS were 7.6 months (95% confidence interval, 6.2-9.3) and 3.3 months (95% confidence interval, 2.7-3.8), respectively. The best response rates were partial response 6.9%, stable disease 38.5%, progressive disease 42.5%, and not evaluable 12%. According to whether patients received previous FOLFIRI (leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin)-bevacizumab or not, OS was 7.7 and 8.1 months (P = .31), and PFS was 2.9 and 3.9 months (P = .02), respectively. Interestingly, PFS and OS were both significantly improved by 4% and 5% per month, respectively, without antiangiogenic treatment before the initiation of the aflibercept regimen. The negative effect of prior FOLFIRI–bevacizumab or shorter time since last bevacizumab was maintained in multivariate analysis for both OS and PFS. Conclusion The aflibercept–chemotherapy regimen is a therapeutic option in patients with chemorefractory disease beyond second-line therapy, in particular in patients with an antiangiogenic-free interval.

This study sought to describe the procedural and clinical outcomes of patients undergoing transcarotid (TC) transcatheter aortic valve replacement (TAVR) with the Edwards Sapien 3 device.The TC approach for TAVR holds the potential to become the optimal alternative to the transfemoral gold standard. Limited data exist regarding safety and efficacy of TC-TAVR using the Edwards Sapien 3 device.The French Transcarotid TAVR prospective multicenter registry included patients between 2014 and 2018. Consecutive patients treated in 1 of the 13 participating centers ineligible for transfemoral TAVR were screened for TC-TAVR. Clinical and echocardiographic data were prospectively collected. Perioperative and 30-day outcomes were reported according to the updated Valve Academic Research Consortium (VARC-2).A total of 314 patients were included with a median (interquartile range) age of 83 (78 to 88) years, 63% were males, Society of Thoracic Surgeons mortality risk score 5.8% (4% to 8.3%). Most patients presented with peripheral artery disease (64%). TC-TAVR was performed under general anesthesia in 91% of cases, mostly using the left carotid artery (73.6%) with a procedural success of 97%. Three annulus ruptures were reported, all resulting in patient death. At 30 days, rates of major bleeding, new permanent pacemaker, and stroke or transient ischemic attack were 4.1%, 16%, and 1.6%, respectively. The 30-day mortality was 3.2%.TC-TAVR using the Edwards Sapien 3 device was safe and effective in this prospective multicenter registry. The TC approach might be considered, in selected patients, as the first-line alternative approach for TAVR whenever the transfemoral access is prohibited. Sapien 3 device was safe and effective in our multicenter cohort.

Summary Background The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma. Methods We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m 2 docetaxel and 75 mg/m 2 cisplatin on day 1 and 750 mg/m 2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m 2 docetaxel and 40 mg/m 2 cisplatin on day 1 and 1200 mg/m 2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here. Findings Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3–4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3–4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded. Interpretation Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0–1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation. Funding Besancon University Hospital and Ligue contre le cancer Grand-Est.

Cancer chemotherapy is a high-risk process. To improve patient safety, a systematic pharmaceutical analysis of chemotherapy prescriptions is performed in our institution. The aim of this study was to assess the impact of pharmaceutical interventions (PIs) on the safety of patient chemotherapy prescriptions.This prospective cross-sectional study was conducted in an 800-bed university hospital with oncology departments. All chemotherapy prescriptions were included and PIs were collected prospectively during one month. The clinical impact of PIs was scored by an expert panel of oncologists and pharmacists, using the Hatoum scale. Univariate and multivariate analysis were conducted to identify factors associated with a higher frequency of PIs.Of 1346 prescriptions included, 129 required a PI (9.6% (95% CI: 8.1-11.4)). Most PIs were scored as having at least a significant impact for patient safety (69.8% (95% CI: 60.4-76.9)). The frequency of PIs was significantly associated with tumour site (p = 0.04) and weekday of prescription (p = 0.005). Multivariate analysis identified factors independently associated with PI performance, including pancreas and biliary tract cancers (odds ratio = 2.8 (95% CI: 1.4-5.3)), ovary cancers (odds ratio = 2.4 (95% CI: 1.2-4.8)) and head and neck cancers (odds ratio = 2.4 (95% CI: 1.1-5.1)) and the day 1 of the protocol with a cytotoxic agent (odds ratio = 3.7 (95% CI: 1.1-11.1)).Oncology pharmacists have a critical role in the safety of chemotherapy prescriptions. The coordination between healthcare professionals and access to patient data seem essential to improve the PIs' relevance and their clinical impact on patient safety.