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Purpose Studies performed in spontaneously breathing patients with mild to moderate respiratory failure suggested that prone position (PP) in COVID-19 could be beneficial. Materials and methods Consecutive critically ill patients with COVID-19 were enrolled in four ICUs. PP sessions lasted at least 3 h each and were performed twice daily. A Cox proportional hazard model identified factors associated with the need of intubation. A propensity score overlap weighting analysis was performed to assess the association between spontaneous breathing PP (SBPP) and intubation. Results Among 379 patients, 40 underwent SBPP. Oxygenation was achieved by high flow nasal canula in all but three patients. Duration of proning was 2.5 [1.6;3.4] days. SBPP was well tolerated hemodynamically, increased PaO2/FiO2 (78 [68;96] versus 63 [53;77] mm Hg, p = 0.004) and PaCO2 (38 [34;43] versus 35 [32;38] mm Hg, p = 0.005). Neither day-28 survival (HR 0.51, 95% CI 0.16–1.16] nor risk of invasive ventilation [sHR 0.96; 95% CI 0.49;1.88] differed between patients who underwent PP and others. Conclusions SBPP in COVID-19 is feasible and well tolerated in severely hypoxemic patients. It did not induce any effect on risk of intubation and day-28 mortality.

International audience; ImportanceCompared with standard cytotoxic therapies, randomized immune checkpoint inhibitor (ICI) phase 3 trials reveal delayed benefits in terms of patient survival and/or long-term response. Such outcomes generally violate the assumption of proportional hazards, and the classical Cox proportional hazards regression model is therefore unsuitable for these types of analyses.ObjectiveTo evaluate the ability of the flexible parametric cure model (FPCM) to estimate treatment effects and long-term responder fractions (LRFs) independently of prespecified time points.Evidence ReviewThis systematic review used reconstructed individual patient data from ICI advanced or metastatic melanoma and lung cancer phase 3 trials extracted from the literature. Trials published between January 1, 2010, and October 1, 2019, with long-term follow-up periods (maximum follow-up, ≥36 months in first line and ≥30 months otherwise) were selected to identify LRFs. Individual patient data for progression-free survival were reconstructed from the published randomized ICI phase 3 trial results. The FPCM was applied to estimate treatment effects on the overall population and on the following components of the population: LRF and progression-free survival in non–long-term responders. Results obtained were compared with treatment effects estimated using the Cox proportional hazards regression model.FindingsIn this systematic review, among the 23 comparisons studied using the FPCM, a statistically significant association between the time-to-event component and experimental treatment was observed in the main analyses and confirmed in the sensitivity analyses of 18 comparisons. Results were discordant for 4 comparisons that were not significant by the Cox proportional hazards regression model. The LRFs varied from 1.5% to 12.7% for the control arms and from 4.6% to 38.8% for the experimental arms. Differences in LRFs varied from 2% to 29% and were significantly increased in the experimental compared with the control arms, except for 4 comparisons.Conclusions and RelevanceThis systematic review of reconstructed individual patient data found that the FPCM was a complementary approach that provided a comprehensive and pertinent evaluation of benefit and risk by assessing whether ICI treatment was associated with an increased probability of patients being long-term responders or with an improved progression-free survival in patients who were not long-term responders.

The Netrin-1 receptor UNC5B is an axon guidance regulator that is also expressed in endothelial cells (ECs), where it finely controls developmental and tumor angiogenesis. In the absence of Netrin-1, UNC5B induces apoptosis that is blocked upon Netrin-1 binding. Here, we identify an UNC5B splicing isoform (called UNC5B-Δ8) expressed exclusively by ECs and generated through exon skipping by NOVA2, an alternative splicing factor regulating vascular development. We show that UNC5B-Δ8 is a constitutively pro-apoptotic splicing isoform insensitive to Netrin-1 and required for specific blood vessel development in an apoptosis-dependent manner. Like NOVA2, UNC5B-Δ8 is aberrantly expressed in colon cancer vasculature where its expression correlates with tumor angiogenesis and poor patient outcome. Collectively, our data identify a mechanism controlling UNC5B’s necessary apoptotic function in ECs and suggest that the NOVA2/UNC5B circuit represents a post-transcriptional pathway regulating angiogenesis., Nature Communications, 12, ISSN:2041-1723

International audience; Recently, there has been a lot of development in relative survival field. In the absence of data on the cause of death, the research has tended to focus on the estimation of survival probability of a cancer (as a disease of interest). In many cancers, one nonfatal event that decreases the survival probability can occur. There are a few methods that assess the role of prognostic factors for multiple types of clinical events while dealing with uncertainty about the cause of death. However, these methods require proportional hazard or Markov assumptions. In practice, one or both of these assumptions might be violated. Violation of the proportional hazard assumption can lead to estimates that are biased, and difficult to interpret and violation of Markov assumption results in inconsistent estimators. In this work, we propose a semi-parametric approach to estimate the possibly time-varying regression coefficients in the likely non-Markov relative survival progressive illness-death model. The performance of the proposed estimator is investigated through simulations. We illustrate our approach using data from a study on rectal cancer resected for cure conducted in two French population-based digestive cancer registries.

International audience; In a previous phase II study (THERAPY), cetuximab and trastuzumab combination, as second-line after progression with gemcitabine, showed disease stabilization in 27% of 33 patients with pancreatic carcinoma. In the present phase II multicenter study, we assessed the efficacy and tolerance of gemcitabine, trastuzumab plus erlotinib as first-line treatment of metastatic pancreatic cancer. The primary endpoint was disease control rate (DCR, RECIST v.1); secondary endpoints were progression-free (PFS), overall (OS) survival and toxicity (NCI-CTCAE v3.0). Ancillary study addressed the predictive value of both EGFR/HER2 expression and KRAS mutational status. Sixty-three patients from four centers were included (62 evaluable for toxicity, 59 for efficacy), median age was 62 years (35-77), 59.7% men. The median treatment duration was 16.1 weeks (2.1-61). Eleven patients (19%) reported a partial tumor response, and 33 (56%) disease stabilization. DCR was 74.6% (95%CI: 61.8-85.0; 44/59 patients). After a median follow-up of 23.3 months (0.6-23.6), median PFS was 3.5 months (95%CI: 2.4-3.8) and median OS 7.9 months (95%CI: 5.1-10.2). PFS was significantly longer in patients with grade ≥ 2 cutaneous toxicities vs patients with grade 0-1 toxicities (HR = 0.55, 95%CI: 0.33-0.92, P = .020). Expression of EGFR and HER2 was correlated with PFS and OS in multivariate analysis; HER2 expression was correlated with the tumor response. Main severe toxicities were neutropenia (32%), cutaneous rash (37%) and thrombosis/embolisms (35.5%). This triplet combination is effective in terms of disease control, PFS and OS, and acceptable for safety. A larger study to investigate this combination compared to the standard regimen should be discussed.

This phase III trial included patients with ultra-low rectal adenocarcinoma that initially required abdominoperineal resection. The surgical decision was based on clinical tumour status after preoperative treatment. The overall sphincter-saving resection rate was 85 per cent, with 72 per cent rate of intersphincteric resection. Long-term results showed that changing the initial abdominoperineal resection indication into a sphincter-saving resection according to tumoral response is oncologically safe. Saving the sphincter

International audience; Available data comparing the long-term results of hybrid minimally invasive esophagectomy (HMIE) with that of open esophagectomy are conflicting, with similar or even better results reported for the minimally invasive esophagectomy group.Objective: To evaluate the long-term, 5-year outcomes of HMIE vs open esophagectomy, including overall survival (OS), disease-free survival (DFS), and pattern of disease recurrence, and the potential risk factors associated with these outcomes.Design, setting, and participants: This randomized clinical trial is a post hoc follow-up study that analyzes the results of the open-label Multicentre Randomized Controlled Phase III Trial, which enrolled patients from 13 different centers in France and was conducted from October 26, 2009, to April 4, 2012. Eligible patients were 18 to 75 years of age and were diagnosed with resectable cancer of the middle or lower third of the esophagus. After exclusions, patients were randomized to either the HMIE group or the open esophagectomy group. Data analysis was performed on an intention-to-treat basis from November 19, 2019, to December 4, 2020.Interventions: Hybrid minimally invasive esophagectomy (laparoscopic gastric mobilization with open right thoracotomy) was compared with open esophagectomy.Main outcomes and measures: The primary end points of this follow-up study were 5-year OS and DFS. The secondary end points were the site of disease recurrence and potential risk factors associated with DFS and OS.Results: A total of 207 patients were randomized, of whom 175 were men (85%), and the median (range) age was 61 (23-78) years. The median follow-up duration was 58.2 (95% CI, 56.5-63.8) months. The 5-year OS was 59% (95% CI, 48%-68%) in the HMIE group and 47% (95% CI, 37%-57%) in the open esophagectomy group (hazard ratio [HR], 0.71; 95% CI, 0.48-1.06). The 5-year DFS was 52% (95% CI, 42%-61%) in the HMIE group vs 44% (95% CI, 34%-53%) in the open esophagectomy group (HR, 0.81; 95% CI, 0.55-1.17). No statistically significant difference in recurrence rate or location was found between groups. In a multivariable analysis, major intraoperative and postoperative complications (HR, 2.21; 95% CI, 1.41-3.45; P < .001) and major pulmonary complications (HR, 1.94; 95% CI, 1.21-3.10; P = .005) were identified as risk factors associated with decreased OS. Similarly, multivariable analysis of DFS identified overall intraoperative and postoperative complications (HR, 1.93; 95% CI, 1.28-2.90; P = .002) and major pulmonary complications (HR, 1.85; 95% CI, 1.19-2.86; P = .006) as risk factors.Conclusions and relevance: This study found no difference in long-term survival between the HMIE and open esophagectomy groups. Major postoperative overall complications and pulmonary complications appeared to be independent risk factors in decreased OS and DFS, providing additional evidence that HMIE may be associated with improved oncological results compared with open esophagectomy primarily because of a reduction in postoperative complications.

Background The 2018–2019 Ebola virus disease (EVD) outbreak in North Kivu and Ituri provinces in the Democratic Republic of the Congo (DRC) is the largest ever recorded in the DRC. It has been declared a Public Health Emergency of International Concern. The outbreak emerged in a region of chronic conflict and insecurity, and directed attacks against health care workers may have interfered with disease response activities. Our study characterizes and quantifies the broader conflict dynamics over the course of the outbreak by pairing epidemiological and all available spatial conflict data. Methods We build a set of conflict variables by mapping the spatial locations of all conflict events and their associated deaths in each of the affected health zones in North Kivu and Ituri, eastern DRC, before and during the outbreak. Using these data, we compare patterns of conflict before and during the outbreak in affected health zones and those not affected. We then test whether conflict is correlated with increased EVD transmission at the health zone level. Findings The incidence of conflict events per capita is ~ 600 times more likely in Ituri and North Kivu than for the rest of the DRC. We identified 15 time periods of substantial uninterrupted transmission across 11 health zones and a total of 120 bi-weeks. We do not find significant short-term associations between the bi-week reproduction numbers and the number of conflicts. However, we do find that the incidence of conflict per capita was correlated with the incidence of EVD per capita at the health zone level for the entire outbreak (Pearson’s r = 0.33, 95% CI 0.05–0.57). In the two provinces, the monthly number of conflict events also increased by a factor of 2.7 in Ebola-affected health zones (p value Conclusion We characterized the association between variables documenting broad conflict levels and EVD transmission. Such assessment is important to understand if and how such conflict variables could be used to inform the outbreak response. We found that while these variables can help characterize long-term challenges and susceptibilities of the different regions they provide little insight on the short-term dynamics of EVD transmission.

International audience; Salmonella is an intracellular bacterium found in the gastrointestinal tract of mammalian, avian, and reptilian hosts. Mouse models have been extensively used to model in vivo distinct aspects of human Salmonella infections and have led to the identification of several host susceptibility genes. We have investigated the susceptibility of Collaborative Cross strains to intravenous infection with Salmonella enterica serovar Typhimurium as a model of human systemic invasive infection. In this model, strain CC042/GeniUnc (CC042) mice displayed extreme susceptibility with very high bacterial loads and mortality. CC042 mice showed lower spleen weights and decreased splenocyte numbers before and after infection, affecting mostly CD8+ T cells, B cells, and all myeloid cell populations, compared with control C57BL/6J mice. CC042 mice also had lower thymus weights with a reduced total number of thymocytes and double-negative and double-positive (CD4+, CD8+) thymocytes compared to C57BL/6J mice. Analysis of bone marrow-resident hematopoietic progenitors showed a strong bias against lymphoid-primed multipotent progenitors. An F2 cross between CC042 and C57BL/6N mice identified two loci on chromosome 7 (Stsl6 and Stsl7) associated with differences in bacterial loads. In the Stsl7 region, CC042 carried a loss-of-function variant, unique to this strain, in the integrin alpha L (Itgal) gene, the causative role of which was confirmed by a quantitative complementation test. Notably, Itgal loss of function increased the susceptibility to S. Typhimurium in a (C57BL/6J × CC042)F1 mouse background but not in a C57BL/6J mouse inbred background. These results further emphasize the utility of the Collaborative Cross to identify new host genetic variants controlling susceptibility to infections and improve our understanding of the function of the Itgal gene.

International audience; Objective: Weight loss has been identified as a negative prognostic factor in amyotrophic lateral sclerosis, but there is no evidence regarding whether a high-caloric diet increases survival. Therefore, we sought to evaluate the efficacy of a high-caloric fatty diet (HCFD) for increasing survival.Methods: A 1:1 randomized, placebo-controlled, parallel-group, double-blinded trial (LIPCAL-ALS study) was conducted between February 2015 and September 2018. Patients were followed up at 3, 6, 9, 12, 15, and 18 months after randomization. The study was performed at 12 sites of the clinical and scientific network of German motor neuron disease centers (ALS/MND-NET). Eligible patients were randomly assigned (1:1) to receive either HCFD (405kcal/day, 100% fat) or placebo in addition to riluzole (100mg/day). The primary endpoint was survival time, defined as time to death or time to study cutoff date.Results: Two hundred one patients (80 female, 121 male, age = 62.4 ± 10.8 years) were included. The confirmatory analysis of the primary outcome survival showed a survival probability of 0.39 (95% confidence interval [CI] = 0.27-0.51) in the placebo group and 0.37 (95% CI = 0.25-0.49) in the HCFD group, both after 28 months (point in time of the last event). The hazard ratio was 0.97, 1-sided 97.5% CI = -∞ to 1.44, p = 0.44.Interpretation: The results provide no evidence for a life-prolonging effect of HCFD for the whole amyotrophic lateral sclerosis population. However, post hoc analysis revealed a significant survival benefit for the subgroup of fast-progressing patients. ANN NEUROL 2020;87:206-216.

Objective: the aim of this study was to analyze the association between a history of cancer and 90-day mortality following cardiac surgery with cardiopulmonary bypass. Material and methods: an observational monocentric study with data collected from a prospective institutional database was conducted. History of cancer was preoperatively identified, and relevant information was retrospectively collected from medical records. Ninety-day survival of patients with and without cancer was compared using a univariate Cox model and then adjusted using a multivariable Cox model. Results: between 2005 and 2017,12143 patients underwent cardiac surgery with CPB including 4681 (39%) isolated coronary artery bypass surgery. Median EuroSCORE II was 3.1 [IQR:1.5-6.4]. Nine hundred thirty patients (7.7%) had a diagnosis of cancer out of which 469 (50%) were diagnosed = 5 years before the index surgery; 103 (11%) patients had hemopathy and 825 (89%) solid cancers. The 90-day mortality was significantly higher among patients with cancer: 94/930 (10%) vs 814/11203 (7%) (HR = 1.34 [1.08-1.66], p

International audience; Background : Although prognosis of Chronic Granulomatous Disease (CGD) has greatly improved, few studies have focused on its long-term outcome. We studied the clinical course and sequelae of CGD patients diagnosed before age 16, at various adult time points. Method : Cross-sectional French nationwide retrospective study of patients screened through the National Reference Center for Primary Immunodeficiencies (CEREDIH) registry. Results : Eighty CGD patients (71 males [88.7%], 59 X-linked [73.7%], median age 23.9 years [minimum, 16.6; maximum, 59.9]) were included, Median ages at diagnosis and last follow-up were 2.52 and 23.9 years, respectively. Seven patients underwent hematopoietic stem cell transplantation. A total of 553 infections requiring hospitalization occurred in 2017 patient-years. The most common site of infection was pulmonary (31%). Aspergillus spp. (17%) and Staphylococcus aureus (10.7%) were the commonest pathogens. A total of 224 inflammatory episodes occurred in 71 patients, mainly digestive (50%). Their characteristics as well as their annual frequency did not vary before and after age 16. Main sequelae were a small adult height and weight and mild chronic restrictive respiratory failure. At age 16, only 53% of patients were in high school. After age 30 years, 9/13 patients were working. Ten patients died during adulthood. Conclusions : Adult CGD patients displayed similar characteristics and rates of severe infections and inflammatory episodes that those of childhood. The high rate of handicap has become a matter of medical and social consideration. Careful follow-up in centers of expertise is strongly recommended and an extended indication of curative treatment by HSCT should be considered.

IF 7.702; International audience; The survival of patients with diffuse large B-cell lymphoma has increased during the last decade as a result of addition of anti-CD20 to anthracycline-based chemotherapy. Although the trend is encouraging, there are persistent differences in survival within and between the USA and European countries suggesting that non-biological factors play a role. Our aim was to investigate the influence of such factors on relative survival of patients with diffuse large B-cell lymphoma. We conducted a retrospective, multicenter, registry-based study in France on 1165 incident cases of diffuse large B-cell lymphoma between 2002 and 2008. Relative survival analyses were performed and missing data were controlled with the multiple imputation method. In a multivariate analysis, adjusted for age, sex and International Prognostic Index, we confirmed that time period was associated with a better 5-year relative survival. The registry area, the medical specialty of the care department (onco-hematology versus other), the time to travel to the nearest teaching hospital, the place of treatment (teaching versus not-teaching hospital -borderline significance), a comorbidity burden and marital status were independently associated with the 5-year relative survival. Adjusted for first-course treatment, inclusion in a clinical trial and treatment discussion in a multidisciplinary meeting were strongly associated with a better survival outcome. In contrast, socio-economic status (determined using the European Deprivation Index) was not associated with outcome. Despite therapeutic advances, various non-biological factors affected the relative survival of patients with diffuse large B-cell lymphoma. The notion of lymphoma-specific expertise seems to be essential to achieve optimal care management and reopens the debate regarding centralization of these patients' care in hematology/oncology departments.

International audience; Few data are currently available regarding the efficacy and safety of T-DM1 in breast cancer (BC) patients with unselected brain metastases (BM), since most clinical trials have excluded BM patients or have only included highly selected patients. HER2 + BC patients with BM treated with T-DM1 in 5 French centers were included in this retrospective study. Clinical management was performed according to the product guidelines. Efficacy was evaluated recording tumor response rates, progression-free (PFS) and overall survival, treatment compliance, and safety. Thirty nine patients received T-DM1, among whom 82 % presented with concomitant extra-cerebral disease. Median number of previous metastatic chemotherapy and HER2-directed targeted therapy regimens was 2 (range 0-8) and 1 (0-7), respectively. Thirty six patients had received BM loco-regional treatment (72 % whole-brain radiation therapy). After a median follow-up of 8.1 months (1.4-39.6), 24 patients had progressed (first site of progression: brain 14; meningeal 2; outside of the central nervous system 5; both intra- and extra-cerebral 3), 12 patients had died (disease progression), and 27 patients were still alive. Median number of T-DM1 cycles was 8 (1-43). There were 17 partial responses (44 %) and 6 patients achieved disease stabilization (59 % clinical benefit rate). Median PFS was 6.1 months (95 %CI 5.2-18.3), with one- and two-year PFS rates of 33 and 17 %, respectively. Treatment was well tolerated, without unexpected toxicities, treatment delay, or dose reduction. In this retrospective study, T-DM1 appeared to be an effective and well-tolerated therapeutic option in unselected HER2 + BC patients with BM. These findings require a prospective validation.

International audience

Background The prevalence of and mortality from HIV-associated tuberculosis (HIV/TB) in hospital inpatients in Africa remains unacceptably high. Currently, there is a lack of tools to identify those at high risk of early mortality who may benefit from adjunctive interventions. We therefore aimed to develop and validate a simple clinical risk score to predict mortality in high-burden, low-resource settings. Methods and findings A cohort of HIV-positive adults with laboratory-confirmed TB from the STAMP TB screening trial (Malawi and South Africa) was used to derive a clinical risk score using multivariable predictive modelling, considering factors at hospital admission (including urine lipoarabinomannan [LAM] detection) thought to be associated with 2-month mortality. Performance was evaluated internally and then externally validated using independent cohorts from 2 other studies (LAM-RCT and a Médecins Sans Frontières [MSF] cohort) from South Africa, Zambia, Zimbabwe, Tanzania, and Kenya. The derivation cohort included 315 patients enrolled from October 2015 and September 2017. Their median age was 36 years (IQR 30–43), 45.4% were female, median CD4 cell count at admission was 76 cells/μl (IQR 23–206), and 80.2% (210/262) of those who knew they were HIV-positive at hospital admission were taking antiretroviral therapy (ART). Two-month mortality was 30% (94/315), and mortality was associated with the following factors included in the score: age 55 years or older, male sex, being ART experienced, having severe anaemia (haemoglobin < 80 g/l), being unable to walk unaided, and having a positive urinary Determine TB LAM Ag test (Alere). The score identified patients with a 46.4% (95% CI 37.8%–55.2%) mortality risk in the high-risk group compared to 12.5% (95% CI 5.7%–25.4%) in the low-risk group (p < 0.001). The odds ratio (OR) for mortality was 6.1 (95% CI 2.4–15.2) in high-risk patients compared to low-risk patients (p < 0.001). Discrimination (c-statistic 0.70, 95% CI 0.63–0.76) and calibration (Hosmer-Lemeshow statistic, p = 0.78) were good in the derivation cohort, and similar in the external validation cohort (complete cases n = 372, c-statistic 0.68 [95% CI 0.61–0.74]). The validation cohort included 644 patients between January 2013 and August 2015. Median age was 36 years, 48.9% were female, and median CD4 count at admission was 61 (IQR 21–145). OR for mortality was 5.3 (95% CI 2.2–9.5) for high compared to low-risk patients (complete cases n = 372, p < 0.001). The score also predicted patients at higher risk of death both pre- and post-discharge. A simplified score (any 3 or more of the predictors) performed equally well. The main limitations of the scores were their imperfect accuracy, the need for access to urine LAM testing, modest study size, and not measuring all potential predictors of mortality (e.g., tuberculosis drug resistance). Conclusions This risk score is capable of identifying patients who could benefit from enhanced clinical care, follow-up, and/or adjunctive interventions, although further prospective validation studies are necessary. Given the scale of HIV/TB morbidity and mortality in African hospitals, better prognostic tools along with interventions could contribute towards global targets to reduce tuberculosis mortality., Author summary Why was this study done? HIV-associated tuberculosis (TB) is very common in hospitals in sub-Saharan Africa, and is a major cause of morbidity and mortality. There is a lack of tools to identify which patients are more likely to die early; therefore, these patients cannot be targeted for more intensive clinical care or other treatments in addition to TB antibiotics and antiretroviral drugs. A new urine TB diagnostic test (detecting a substance called lipoarabinomannan [LAM]) can identify patients at higher risk of dying and, along with other simply measured clinical signs or symptoms, may be useful for predicting which patients are most likely to do poorly. What did the researchers do and find? We used data from HIV-positive adults admitted to hospital in Malawi and South Africa and diagnosed with TB to develop a simple clinical risk score to identify patients with a 50% chance of dying within 2 months. The score included 6 factors that can be measured at admission to hospital, including the results of the urine TB test, presence of anaemia, and some demographic factors. We then tested the performance of the risk score using data from studies of different patients from sub-Saharan Africa, and it performed similarly. The score was able to identify patients at higher risk of dying during admission to hospital, and after discharge from hospital. What do these findings mean? This score could be used to identify patients admitted to hospital and diagnosed with HIV-associated TB who may benefit most from more intensive clinical care, additional treatments, and/or closer follow-up after discharge. It could also be used as a research tool to study new drugs or strategies aimed at reducing mortality from with HIV-associated TB. This is the first such tool to our knowledge in this patient population, and future studies could optimise such predictive tools, in particular if appropriate new interventions and/or diagnostics become available.

Background Inflammatory breast cancer (IBC) is a rare and rapidly progressive form of invasive breast cancer. The aim of this study was to explore the clinical evolution, stromal tumour-infiltrating lymphocytes (sTIL) infiltration and programmed death-ligand 1 (PD-L1) expression in a large IBC cohort. Patients and methods Data were collected prospectively from patients with IBC as part of an international collaborative effort since 1996. In total, 143 patients with IBC starting treatment between June 1996 and December 2016 were included. Clinicopathological variables were collected, and sTIL were scored by two pathologists on standard H&E stained sections. PD-L1 expression was assessed using a validated PD-L1 (SP142) assay. A validation cohort of 64 patients with IBC was used to test our findings. Results Survival outcomes of IBC remained poor with a 5-year overall survival (OS) of 45.6%. OS was significantly better in patients with primary non-metastatic disease who received taxane-containing (neo)adjuvant therapy (P = 0.01), had a hormone receptor-positive tumour (P = 0.001) and had lower cN stage at diagnosis (P = 0.001). PD-L1 positivity on immune cells (42.9%) was higher in IBC than in non-IBC in both our patient samples and the validation cohort. Furthermore, PD-L1 expression predicted pCR (P = 0.002) and correlated with sTIL infiltration (P

[Background] In an early-phase study involving patients with advanced non–small-cell lung cancer (NSCLC), the response rate was better with nivolumab plus ipilimumab than with nivolumab monotherapy, particularly among patients with tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC., [Methods] In this open-label, phase 3 trial, we randomly assigned patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more., [Results] Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P=0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy., [Conclusions] First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; CheckMate 227 ClinicalTrials.gov number, NCT02477826. opens in new tab.), Funded by Bristol-Myers Squibb and Ono Pharmaceutical.

Background: adenoid cystic carcinoma (ACC) of the head and neck are uncommon malignant tumors arising from the salivary glands. These tumors have a high propensity for perineural spread, liable for skull base invasion. Objectives: the purpose of this study was to identify imaging and pathological features of perineural invasion (PNI) in ACC of the midface, to define its prognostic value, then to describe the natural history of these tumors. Design: a single-centre retrospective study was managed between 1999 and 2018, at Gustave Roussy Cancer Campus; all the patients with an ACC of the midface were included. PNI was assessed on the first imaging (RMI and CT), and on the histopathological analysis of the resection specimens. The predictive factors of PNI, the overallsurvival (OS) and the disease-free survival (DFS) were analyzed. Results: fifty-five patients were included; 63% had a neural invasion on first imaging. A named nerve involvement was detected by histopathologic examination in 23% of ACC treated surgically. Predictive factors of PNI was an abnormal imaging at diagnosis (p=0,007), and the microscopic infiltration of the nerves sheaths (p=0,03). Mean follow-up was 73 months. The ten-year OS and DFS rates were 69% and 29%, respectively. Our study showed that surgical resection with positive margins on the skull base, particularly on the nerve V2, would not impact significantly patients prognosis, provided that an adjuvant radiotherapy is applied. Conclusions: neurotropism of midface ACC increases the risk of dissemination to the skull base. The treatment recommended for these tumors remains the combination of surgery and adjuvant radiotherapy.; Introduction : les carcinomes adénoïdes kystiques (CAK) de la tête et du cou sont des entités rares d’origine salivaire ayant la particularité de présenter un fort potentiel neurotrope, responsable d’extensions vers la base du crâne. Objectif : le but de cette étude est de rechercher les caractéristiques radio-histologiques des invasions périnerveuses (IPN) des CAK du massif facial, d’évaluer la valeur pronostique puis de décrire l’histoire naturelle de ces tumeurs. Matériel et méthode : cette étude rétrospective, menée entre 1999 et 2018, à Gustave Roussy a inclus les patients présentant un CAK au niveau du massif facial. Une IPN était recherchée à l’imagerie initiale (IRM et TDM) et sur l’analyse histologique des pièces opératoires. Les facteurs prédictifs d’IPN ainsi que le taux de survie globale (SG) et sans récidive (SSR) étaient analysés. Résultats : parmi les 55 patients inclus, 63% présentaient une atteinte périneurale radiologique. D’autre part, 23% des patients opérés présentaient un envahissement histologique d’un tronc nerveux. Les facteurs prédictifs d’IPN étaient une imagerie anormale (p=0,007) et la présence d’engainements périnerveux (p=0,03). Le suivi moyen était de 73 mois avec une SG de 82% et 69% ainsi qu’une SSR de 51% et 29% à 5 et 10 ans respectivement. Il semblerait qu’une résection insuffisante au niveau basicrânien, notamment sur le V2, n’impacte pas significativement le pronostic lorsqu’elle est suivie d’une radiothérapie complémentaire. Conclusion : Le neurotropisme des CAK du massif facial augmente le risque d’extension à la base du crâne. La chirurgie avec irradiation complémentaire reste néanmoins le gold standard thérapeutique pour ces tumeurs.

Despite several clinical trials implemented, no antiviral drug could demonstrate efficacy against Ebola virus. In non-human primates, early initiation of polymerase inhibitors favipiravir and remdesivir improves survival, but whether they could be effective in patients is unknown. Here we analyze the impact of antiviral therapy by using a mathematical model that integrates virological and immunological data of 44 cynomolgus macaques, left untreated or treated with favipiravir. We estimate that favipiravir has a ~50% efficacy in blocking viral production, which results in reducing virus growth and cytokine storm while IFNα reduces cell susceptibility to infection. Simulating the effect of delayed initiations of treatment, our model predicts survival rates of 60% for favipiravir and 100% for remdesivir when treatment is initiated within 3 and 4 days post infection, respectively. These results improve the understanding of Ebola immuno-pathogenesis and can help optimize antiviral evaluation in future outbreaks., Optimization of antiviral therapy can be crucial in the management of Ebola virus outbreaks. Here, Madelain et al. use an integrative mathematical model to correlate the dose and the time of treatment initiation with survival rate, enhanced immune response and viral clearance.

International audience; No abstract available

International audience; Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib's efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome-overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)-were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3-85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3-51), 18 months (3-72), and 24 months (3-100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.

International audience; PURPOSE:Over the past 3 decades, no major treatment breakthrough has been reported for advanced bladder cancer. Recent Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors in the management of advanced bladder cancer represent new therapeutic opportunities. This review examines the available data of the clinical trials leading to the approval of ICIs in the management of metastatic bladder cancer and the ongoing trials in advanced and localized settings.METHODS:A literature search was performed on PubMed and ClinicalTrials.gov combining the MeSH terms: 'urothelial carcinoma' OR 'bladder cancer', and 'immunotherapy' OR 'CTLA-4' OR 'PD-1' OR 'PD-L1' OR 'atezolizumab' OR 'nivolumab' OR 'ipilimumab' OR 'pembrolizumab' OR 'avelumab' OR 'durvalumab' OR 'tremelimumab'. Prospectives studies evaluating anti-PD(L)1 and anti-CTLA-4 monoclonal antibodies were included.RESULTS:Evidence-data related to early phase and phase III trials evaluating the 5 ICIs in the advanced urothelial carcinoma are detailed in this review. Anti-tumour activity of the 5 ICIs supporting the FDA approval in the second-line setting are reported. The activity of PD(L)1 inhibitors in the first-line setting in cisplatin-ineligible patients are also presented. Ongoing trials in earlier disease-states including non-muscle-invasive and muscle-invasive bladder cancer are discussed.CONCLUSIONS:Blocking the PD-1 negative immune receptor or its ligand, PD-L1, results in unprecedented rates of anti-tumour activity in patients with metastatic urothelial cancer. However, a large majority of patients do not respond to anti-PD(L)1 drugs monotherapy. Investigations exploring the potential value of predictive biomarkers, optimal combination and sequences are ongoing to improve such treatment strategies.

The width of resection margin is still a matter of debate in case of colorectal liver metastasis resection. The aim of this study was to determine the risk factors for R1 resection. Once risk factors had been identified, patients were matched according to Fong’s prognostic criteria, in order to evaluate whether R1 resection still remained a negative prognostic factor impacting overall and disease-free survival. A total of 1784 hepatectomies were analyzed from a multicentric retrospective cohort of hepatectomies. Patients were compared before and after a 1:1 propensity score analysis in order to compare R0 versus R1 resections according to Fong criteria. Primary tumor nodes found positive after colorectal resection (RR = 1.20, p = 0.02), operative time (> 240 min) (RR = 1.26, p = 0.05), synchronous liver metastasis (RR = 1.27, p = 0.02), pedicle clamping (> 40 min) (RR = 1.52, p = 0.001), lesion size larger than 50 mm (RR = 1.54, p = 0.001), rehepatectomy (RR = 1.68, p = 0.001), more than 3 lesions (RR = 1.69, p = 0.0001), and bilateral lesions (RR = 1.74, p = 0.0001) were identified as risk factors in multivariate analysis. After a 1:1 PSM according to Fong criteria, R1 resection still remained a negative prognostic factor impacting overall and disease-free survival, with 1-, 3-, 5-year OS at 94, 81, and 70% in R0 and 92, 75, and 58% in R1, respectively, (p = 0.008), and disease-free survival (DFS) with 1-, 3-, 5-year survival at 64, 41, and 28% in R0 versus 51, 28, and 18% in R1 (p = 0.0002), respectively. Even after using PSM as an oncological prognostic criterion, R1 resection still impacts overall and disease-free survival negatively.

International audience; Canine distemper (CD) is the most deadly disease in dogs with mortality rates reaching 50%. The pathological agent, the CD virus (CDV), generally causes a severe systemic disease, although the nervous form can coexist with the acute catarrhal form in the same individual. In this study, we describe an outbreak of 18 cases of CD that occurred in 2015 in a German Shepherd dog population in northwestern Gabon. In addition, we determined the sequence of the CDV genotype associated with this fatal distemper infection in Gabon and compared it with other published CDV sequences. The CDV was detected using RT-PCR on cDNA from RNA of harvested brains and other organs. The identification was confirmed by sequencing amplicons. Moreover, we obtained the whole genome sequence using high-throughput sequencing. Phylogenetic analysis revealed that Gabonese CDV strain clustered with European strains belonging to the Europe genotype. This study provided the first molecular detection of the CDV strain associated with this fatal distemper infection in Central Africa region.

International audience; Clinical data and experimental studies suggest that bronchial epithelium could serve as a portal of entry for invasive fungal infections. We therefore analyzed the interactions between molds and the bronchial/bronchiolar epithelium at the early steps after inhalation. We developed invasive aspergillosis (Aspergillus fumigatus) and mucormycosis (Lichtheimia corymbifera) murine models that mimic the main clinical risk factors for these infections. Histopathology studies were completed with a specific computer-assisted morphometric method to quantify bronchial and alveolar spores and with transmission electron microscopy. Morphometric analysis revealed a higher number of bronchial/bronchiolar spores for A. fumigatus than L. corymbifera. The bronchial/bronchiolar spores decreased between 1 and 18 hours after inoculation for both fungi, except in corticosteroid-treated mice infected with A. fumigatus, suggesting an effect of cortisone on bronchial spore clearance. No increase in the number of spores of any species was observed over time at the basal pole of the epithelium, suggesting the lack of transepithelial crossing. Transmission electron microscopy did not show spore internalization by bronchial epithelial cells. Instead, spores were phagocytized by mononuclear cells on the apical pole of epithelial cells. Early epithelial internalization of fungal spores in vivo cannot explain the bronchial/bronchiolar epithelium invasion observed in some invasive mold infections. The bioimaging approach provides a useful means to accurately enumerate and localize the fungal spores in the pulmonary tissues.

International audience; To investigate the associations of leptin, adiponectin and high-sensitive (hs) C-reactive protein (CRP) with risk and prognosis of amyotrophic lateral sclerosis (ALS). Data from a population-based case-control study in Southern Germany (10/2010-6/2014) of 289 ALS patients (mean age of 65.7 (SD 10.5) years, 59.5% men) and 506 controls were included. During median follow-up of 14.5 months of 279 ALS patients 104 (53.9% men, 68.9 (10.3) years) died. Serum samples were measured for leptin, adiponectin and hs-CRP. Conditional logistic regression was used to estimate ALS risk. Survival models were used to appraise the prognostic value. ALS patients were characterized by lower levels of school education, BMI and smoking prevalence. Adjusted for covariates, leptin was inversely associated with ALS risk (top vs. bottom quartile: OR 0.49; 95% CI 0.29-0.80), while for adiponectin a positive association was found (OR 2.89; 95% CI 1.78-4.68). Among ALS patients increasing leptin concentrations were associated with longer survival (p for trend 0.002), while for adiponectin no association was found (p for trend 0.55). For hs-CRP no association was found. Leptin and adiponectin, two key hormones regulating energy metabolism, were strongly and independently related with ALS risk. Leptin levels were further negatively related with overall survival of ALS patients.

Background We performed a randomized, non-comparative phase II study evaluating docetaxel in combination with either daily continuous (protracted IV) 5-fluorouracil or cisplatin administered weekly, concurrent to radiotherapy in the treatment of locally advanced pancreatic carcinoma. Results of the docetaxel plus cisplatin regimen are reported. Methods Forty chemotherapy-naive patients with locally advanced pancreatic carcinoma were randomly assigned to receive 5-fluorouracil and docetaxel or docetaxel 20 mg/m2 and cisplatin 20 mg/m2/week, plus concurrent radiotherapy for 6 weeks. The radiation dose to the primary tumour was 54 Gy in 30 fractions. The trial's primary endpoint was the 6-month crude non-progression rate. Results 51 patients from 7 centres were included in the docetaxel–cisplatin treatment group. Six-month non-progression rate was 39% (95% confidence interval: 26–53). Median overall survival was 9.6 months (95% confidence interval: 2.4–60.7); 6 complete and 8 partial responses were obtained. Six patients survived more than 2 years after their inclusion in the trial. Grade ≥3 toxicity was reported in 63% of patients; no treatment-related death occurred. Severe toxicities were mainly anorexia (22%), vomiting (20%) and fatigue (24%). Conclusions Despite inadequate efficacy according to the main end point, this regimen gave a satisfactory rate of objective response (27%) with tolerable toxicity.

International audience; BACKGROUND: Cancer patients with CD4 lymphopenia have an increased risk of severe toxicity after administration of cytotoxic chemotherapy. The impact of CD4 lymphopenia on long term overall survival (OS) of cancer patients was explored in this work. PATIENTS AND METHODS: The first prospective series (test series) included 219 patients with solid tumours, lymphomas or myelomas receiving chemotherapy within an oncology department in 1999 and 2000. A phenotypic analysis of lymphocyte subsets by flow cytometry was performed before chemotherapy on day 1. The prognostic value of total, CD4, CD8 and CD56 lymphocyte count for OS was tested in a multivariate analysis. The prognostic value of low CD4 counts was then tested in a validation series of 269 patients with metastatic solid tumours in second line treatment included in a prospective observational study in the Centre Leon Berard. RESULTS: In the test series, all patients with metastatic cancers and CD4 lymphopenia ≤ 200/μL (12% of metastatic patients) died within 18 months with a median OS of 5.9 months. CD4 count was an independent prognostic factor for OS and PFS in multivariate analysis. In the validation series, 83 (30%) of patients had CD4 count ≤ 200/μL: their median overall survival was 3.9 months with an 18-month survival rate of 6%. CD4 count was also an independent prognostic factor for overall survival in this series. CONCLUSIONS: CD4 lymphopenia

International audience; Infectious diseases are one of the most common threats for both domestic and wild animals, but little is known about the effects on the physiological condition and survival of wild animals. Here, we have tested for the first time in a wild vertebrate facing a viral disease possibly due to herpesvirus (i) whether nestlings with either low levels of oxidative damage or high levels of antioxidant protection are less susceptible to develop visible clinical signs, (ii) whether the disease is associated with the nestlings' oxidative status, (iii) whether the association between the disease and oxidative status is similar between males and females (iv), and whether cloacal and tracheal swabs might be used to detect herpesvirus. To address our questions, we took advantage of a population of Magnificent frigatebirds (Fregata magnificens) whose nestlings have experienced high mortality rates in recent times. Our work shows that (i) blood lipid oxidative damage is associated with observable clinical signs and survival probabilities of nestling frigatebirds, and (ii) that high glutathione levels in red blood cells are associated with the emergence of visible clinical signs of the disease. Our work provides evidence that differences in the oxidative status of nestlings might underlie individual health and survival.

Background Epstein-Barr virus (EBV) displays oncogenic properties, particularly in the immunocompromised host. Notably, hematopoietic stem cell transplantation (HSCT) recipients with a detectable blood EBV viral load (BEBVL) are considered at higher risk of post-transplant lymphoproliferative diseases (PTLD). Therefore, BEBVL is monitored after HSCT, and preemptive rituximab may be used in patients with high values. However, little is known about post-HSCT BEBVL dynamics, and the threshold that should lead to anti-CD20 therapy is poorly defined. Methods We retrospectively analyzed the post-HSCT BEBVL of 332 adult HSCT recipients in our center from 2005 to 2013, including the effect of rituximab. Results Detection of BEBVL > 100, 1000, 5000, 10,000, and 50,000 copies/mL occurred in respectively 77.7%, 69.6%, 37.0%, 27.1%, and 7.5% of the patients after a respective median time of 9, 14, 15, 16, and 14 weeks. No BEBVL threshold was associated with an overall survival difference. Seventy-eight patients received rituximab, with a BEBVL decrease in most. Among patients with detectable BEBVL, long-term survival did not differ in rituximab-treated and non-treated, except for patients with BEBVL ≥50,000. Only 1 case of PTLD was observed. Conclusions BEBVL is frequently detectable after HSCT, but suggests no strong association with survival. Preemptive rituximab therapy threshold remains to be defined. This article is protected by copyright. All rights reserved.

Background Already since the 1990s, promoter CpG island methylation markers have been considered promising diagnostic, prognostic, and predictive cancer biomarkers. However, so far, only a limited number of DNA methylation markers have been introduced into clinical practice. One reason why the vast majority of methylation markers do not translate into clinical applications is lack of independent validation of methylation markers, often caused by differences in methylation analysis techniques. We recently described RET promoter CpG island methylation as a potential prognostic marker in stage II colorectal cancer (CRC) patients of two independent series. Methods In the current study, we analyzed the RET promoter CpG island methylation of 241 stage II colon cancer patients by direct methylation-specific PCR (MSP), nested-MSP, pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM). All primers were designed as close as possible to the same genomic region. In order to investigate the effect of different DNA methylation assays on patient outcome, we assessed the clinical sensitivity and specificity as well as the association of RET methylation with overall survival for three and five years of follow-up. Results Using direct-MSP and nested-MSP, 12.0 % (25/209) and 29.6 % (71/240) of the patients showed RET promoter CpG island methylation. Methylation frequencies detected by pyrosequencing were related to the threshold for positivity that defined RET methylation. Methylation frequencies obtained by pyrosequencing (threshold for positivity at 20 %) and MS-HRM were 13.3 % (32/240) and 13.8 % (33/239), respectively. The pyrosequencing threshold for positivity of 20 % showed the best correlation with MS-HRM and direct-MSP results. Nested-MSP detected RET promoter CpG island methylation in deceased patients with a higher sensitivity (33.1 %) compared to direct-MSP (10.7 %), pyrosequencing (14.4 %), and MS-HRM (15.4 %). While RET methylation frequencies detected by nested-MSP, pyrosequencing, and MS-HRM varied, the prognostic effect seemed similar (HR 1.74, 95 % CI 0.97–3.15; HR 1.85, 95 % CI 0.93–3.86; HR 1.83, 95 % CI 0.92–3.65, respectively). Conclusions Our results show that upon optimizing and aligning four RET methylation assays with regard to primer location and sensitivity, differences in methylation frequencies and clinical sensitivities are observed; however, the effect on the marker’s prognostic outcome is minimal. Electronic supplementary material The online version of this article (doi:10.1186/s13148-016-0211-8) contains supplementary material, which is available to authorized users.

International audience; Reintroduction of amiodarone in patients with a history of amiodarone-induced thyrotoxicosis (AIT) is rarely used. To date, the risk of AIT recurrence after amiodarone reintroduction is unpredicted. The aim of the study was to evaluate the risk of AIT recurrence. Retrospectively, from 2000 to 2011, all euthyroid patients with a history of AIT with amiodarone reintroduction were included. Type and severity of the first AIT, amiodarone chronology, and thyroid function evolution after reintroduction of amiodarone were investigated: 46 of 172 patients with AIT history needed amiodarone reintroduction. At first AIT episode, the mean age was 62.2 ± 16 years with male gender predominance; 65% of patients were classified as type 1 AIT. AIT recurred in 14 patients (30%), 12 patients developed hypothyroidism (26%), and 20 patients remained euthyroid (44%). Characteristics of type 1 AIT during the first episode, namely briefer exposure period to amiodarone and longer duration of treatment to normalize thyroid hormones, were predictive of AIT recurrence; 73% of patients (8 of 11) with previous episode of type 1 AIT, who did not receive a preventive thioamide treatment, developed a second episode of AIT. Thioamide preventive treatment could be useful to prevent type 1 AIT recurrence. In conclusion, AIT recurrence after amiodarone reintroduction is 4 times more frequent in patients with type 1 AIT history. Thyroid ablation before amiodarone reintroduction in patients with a history of type 1 AIT is preferred. Preventive thioamide treatment could be suggested in patients with type 1 AIT history pending for surgery.

International audience; This study aimed to compare the relative survival of patients with invasive breast cancer between women from French Guiana (a French territory in South America) and metropolitan France. No study hadever compared survival of breast cancer on the basis of immigrant status in France. Our study underlined that access to care for migrants is challenging whichwgenerates health inequalities. Background The prognosis of breast cancer in French Guiana is worse than in France with 23 deaths per 100 incident cases against 17 per 100 in metropolitan France. This study aimed to compare relative survival of patients with invasive breast cancer (IBC) between women from French Guiana and metropolitan France and to determine risk factors influencing breast cancer survival in French Guiana.Materials and methods Data were collected from the Cancer registry of French Guiana. We comparedthe relative survival of women with IBC between French Guiana and metropolitan France. We used Cox's proportional hazard regression to evaluate the effect of prognostic factors on cancer-specific mortality in French Guiana. Results We included all 269 cases of IBC in women diagnosed in French Guiana between 2003 and 2009. The overall 5-year relative survival rate of patients with IBC was 79% in French Guiana and 86% in metropolitan France. The place of birth (foreign country versus French territory), the tumor stage at the time of diagnosis, the mode of diagnosis (symptoms versus screening), the presence of hormone receptors in the tumor and the histologic type were the variables associated with survival differences. None of the other study variables were significantly associated with prognosis. Conclusion Access to care for migrants is challenging,which leads to health inequalities. Early detection through prevention programs is crucial to increaseIBC survival notably for foreign-born patients.

Purpose Acute promyelocytic leukemia (APL) is rare in children. All-trans-retinoic acid (ATRA) combined with chemotherapy, the reference treatment of APL, is generally considered to produce similar results in children and adults. However, previously published childhood APL studies have generally analyzed all patients age < 18 years as a group, without further dividing according to age. Patients and Methods We compared disease characteristics and outcomes of children (age ≤ 12 years), adolescents (13 to 18 years), and adults (> 18 years) included in two multicenter APL clinical trials (APL 93 and 2000 trials). Results Of the 833 patients age ≤ 60 years included in the two trials, 26 (3%), 58 (7%), and 749 (90%) were children, adolescents, and adults, respectively. Children had significantly higher baseline WBC counts (P < .001). The complete remission (CR) rate (92%, 100%, and 94.5%, respectively) and 5-year cumulative incidence of relapse (CIR; 28%, 20%, and 23%, respectively) did not differ between children, adolescents, and adults, whereas adolescents had significantly better overall survival (OS; 5-year OS, 93.6% v 80.4% in adults and 80.4% in children; P = .03). However, in children age ≤ 4 years, the 5-year CIR was 52%, compared with 17.6% in children age 5 to 12 years (P = .006), although most of the younger children who relapsed experienced durable salvage with autologous or allogeneic stem-cell transplantation. Conclusion Adolescents and children age > 4 years with APL treated with ATRA and chemotherapy have outcomes at least as favorable as those of adults. Younger children seem to experience more relapses and may require reinforcement of first-line treatment.

International audience; UNLABELLED: Radioembolization of liver cancers using (90)Y-loaded microspheres is experiencing more widespread use. However, few data are available concerning the doses delivered to the tumors and the healthy liver. This retrospective study was conducted to calculate the tumor dosimetry (planned tumor dose [T(plan) D]) and nontumor dosimetry in patients treated by (90)Y-loaded glass microspheres and determine whether tumor dosimetry could predict response and survival. METHODS: Thirty-six patients with hepatocellular carcinoma (HCC), including 16 with portal vein thrombosis (PVT), were treated with (90)Y-loaded glass microspheres. The T(plan) D and the dose delivered to the injected healthy liver were calculated using a quantitative analysis of the (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) SPECT/CT exam. Responses were assessed after 3 mo, using the criteria of the European Association for the Study of the Liver. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier tests. RESULTS: The response rate was 69% for the overall population and 75% for the PVT patients. The dose delivered to the tumor was the only parameter associated with response with multivariate analysis (P = 0.019). A threshold T(plan) D value of 205 Gy was predictive of response, with a sensitivity of 100% and an accuracy of 91%. Quantitative (99m)Tc-MAA SPECT/CT allowed us to increase the injected activity for 4 patients with large lesions. PFS was only 5.2 mo and OS 9 mo when using a T(plan) D of less than 205 Gy versus 14 mo (P = 0.0003) and 18 mo (P = 0.0322), respectively, with a T(plan) D of 205 Gy or more. CONCLUSION: Quantitative (99m)Tc-MAA SPECT/CT is predictive of response, PFS, and OS. Dosimetry based on (99m)Tc-MAA SPECT/CT can be used for the selection of patients and for an adaptation of treatment planning, especially in selected patients (particularly in the case of large tumors). These results also confirm the efficacy and safety of (90)Y-loaded microspheres in treating HCC, even in the presence of PVT (and especially when (99m)Tc-MAA uptake is seen inside the PVT).

International audience; Invasive aspergillosis (IA) during induction chemotherapy of acute myeloid leukemia (AML) could worsen the prognosis. Our objective was to study how the development of IA during AML interferes with the therapeutic strategy and to evaluate its impact on the short- and long-term survival. Newly diagnosed AML patients between the years 2004 and 2007 were retrospectively analyzed. The outcome was death of the patient. A Cox proportional hazards model with the diagnosis of IA and post-induction response evaluation as the main exposure was fitted. Overall, 262 patients were analyzed and 58 IA were observed. The 2-year survival of patients having had remission of AML was 54% and, for patients with failure of chemotherapy, it was 5% (p < 0.001). The 2-year survival of patients having had IA was 14%, and without IA, it was 32% (p = 0.01). Multivariate analysis showed that IA was associated with a higher risk of death in case of remission compared to no IA (hazard ratio [HR] = 1.66 [1.05-2.65], p = 0.031) and also in case of failure (HR = 6.43, p < 0.001). IA was associated with an increased risk of death for patients if they were either in remission or in failure after induction chemotherapy.

Several risk factors are associated with increased mortality in patients with chronic graft-versus-host disease (cGVHD), but there is considerable variability in the reported factors. Therefore, we evaluated patient, transplantation, and cGVHD characteristics to develop a risk score in 5343 patients with cGVHD. Ten variables were identified as being significant in multivariate analysis of overall survival and nonrelapse mortality (NRM): age, prior acute GVHD, time from transplantation to cGVHD, donor type, disease status at transplantation, GVHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score, and platelet count. These 10 variables were used to build a cGVHD risk score, and 6 risk groups (RGs) were identified. The 5-year NRM was 5% (1%-9%) in RG1, 20% (19%-23%) in RG2, 33% (29%-37%) in RG3, 43% (40%-46%) in RG4, 63% (53%-74%) in RG5, and 72% (59%-85%) in RG6. The 5-year overall survival was highest at 91% (95% confidence interval [CI]:85%-97%) in RG1, followed by 67% (65%-69%) in RG2, 51% (46%-55%) in RG3, 40% (37%-43%) in RG4, 21% (12%-30%) in RG5, and 4% (0%-9%) in RG6 (all P < .01). This analysis demonstrates the usefulness of data from a large registry to develop risk-score categories for major transplantation outcomes. Validation of this cGVHD risk score is needed in a different population to ensure its broad applicability.

Purpose: Gene expression studies provide molecular insights improving the classification of patients with high-grade gliomas. We have developed a risk estimation strategy based on a combined analysis of gene expression data to search for robust biomarkers associated with outcome in these tumors. Experimental Design: We performed a meta-analysis using 3 publicly available malignant gliomas microarray data sets (267 patients) to define the genes related to both glioma malignancy and patient outcome. These biomarkers were used to construct a risk-score equation based on a Cox proportional hazards model on a subset of 144 patients. External validations were performed on microarray data (59 patients) and on RT-qPCR data (194 patients). The risk-score model performances (discrimination and calibration) were evaluated and compared with that of clinical risk factors, MGMT promoter methylation status, and IDH1 mutational status. Results: This interstudy cross-validation approach allowed the identification of a 4-gene signature highly correlated to survival (CHAF1B, PDLIM4, EDNRB, and HJURP), from which an optimal survival model was built (P < 0.001 in training and validation sets). Multivariate analysis showed that the 4-gene risk score was strongly and independently associated with survival (hazard ratio = 0.46; 95% CI, 0.26–0.81; P = 0.007). Performance estimations indicated that this score added beyond standard clinical parameters and beyond both the MGMT methylation status and the IDH1 mutational status in terms of discrimination (C statistics, 0.827 versus 0.835; P < 0.001). Conclusion: The 4-gene signature provides an independent risk score strongly associated with outcome of patients with high-grade gliomas. Clin Cancer Res; 17(2); 317–27. ©2011 AACR.

Objective: Diffuse coronary artery disease makes cardiac surgeons hesitant regarding whether coronary artery bypass grafting (CABG) surgery is feasible or not. Coronary artery reconstruction using the internal thoracic artery (ITA) allows bypassing of coronary arteries with diffuse atheromatous plaques without systematically resorting to endarterectomy. The aim of the present study was to evaluate the medium-term results of coronary artery reconstruction. Methods: All patients undergoing coronary artery reconstruction using the ITA between 1999 and 2002 (233 patients) were included in the study. The mean age was 61.9 ± 9.8 years. Two hundred and eighty-one coronary artery reconstructions using the ITA were performed (mean length 3.6 ± 2 cm) for 514 CABGs. Coronary artery reconstruction using the ITA was associated with endarterectomy in 48 cases (17%). Results: In-hospital mortality was 2.6%. Follow-up data were compiled in December 2008. Mean follow-up was 73.4 ± 16.7 months. The actuarial survival rate at 7 years was 89.3 ± 2.1%, and 88% of patients were free of major cardiac events at 7 years. Conclusions: Coronary artery reconstruction gives comparable medium-term results to conventional coronary surgery, even though it is indicated for patients with more severe lesions.

International audience; BACKGROUND: The aim was to identify predictors of outcome in patients with localized prostate cancer treated with external beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT). Materials and methods: A total of 448 patients with prostate cancer received EBRT alone (n = 361, group 1) or ADT followed by EBRT (n = 87, group 2). In group 2, ADT was initiated 3 months before EBRT. After baseline prostate-specific antigen (PSA) determination (PSA(preRT)), PSA was assessed during the 6th week of the EBRT course (PSA(6wRT)) in group 1. In group 2, PSA was measured again 3 months after the start of ADT, before EBRT (PSA(ADT-preRT)). RESULTS: In group 1, median PSA(6wRT)/PSA(preRT) was 0.72 and median prostate-specific antigen velocity (PSAV) was -1.5 ng/ml/month. In the multivariate analysis, prognostic groups and PSA(6wRT)/PSA(preRT) (or PSAV) independently predicted biochemical failure (BF), clinical failure (CF), and prostate cancer-specific survival. In group 2, the median PSA(ADT-preRT) was 1.3 ng/ml. In the high-risk group, an undetectable PSA(ADT-preRT) (< or =0.2 ng/ml) predicted BF (P < 0.01) and CF (P = 0.007). CONCLUSION: A PSA decline 6 weeks after the start of EBRT when used as monotherapy and 3 months after the start of ADT in patients treated with combined ADT and EBRT is predictive of progression and specific survival.

International audience; In aortic stenosis (AS), the increased afterload results in progressive structural and functional changes that precede the development of symptoms. We hypothesized that the detection of abnormalities in left ventricular long-axis function could identify patients with asymptomatic AS at increased risk of events. We prospectively examined the outcome of 126 patients with asymptomatic AS who underwent a comprehensive echocardiographic examination, including tissue Doppler imaging. B-type natriuretic peptide (BNP) was measured in all patients. During a median follow-up period of 20.3 + or - 17.8 months, 6 patients died, 8 developed symptoms but did not undergo surgery, and 48 underwent aortic valve replacement. On multivariate Cox regression analysis, the parameters associated with the predefined outcome were gender (p = 0.048), left atrial area index (p = 0.011), systolic annular velocity (p = 0.016), E/Ea ratio (p = 0.024), late diastolic annular velocity (p = 0.023), and BNP (p = 0.012). Using receiver operating characteristics curve analysis, a left atrial area index of > or = 12.4 cm(2)/m(2), systolic annular velocity of < or = 4.5 cm/s, E/Ea ratio >13.8, late diastolic annular velocity of < or = 9 cm/s, and BNP of > or = 61 pg/ml were identified as the best cutoff values to predict events. In conclusion, in asymptomatic AS, tissue Doppler imaging and BNP measurements provide prognostic information beyond that from clinical and conventional echocardiographic parameters.

International audience; We have evaluated the efficacy of intracerebral (i.c.) convection-enhanced delivery (CED) of cisplatin in combination with photon irradiation for the treatment of F98 glioma-bearing rats. One thousand glioma cells were stereotactically implanted into the brains of Fischer rats and 13 days later cisplatin (6 microg/20 microl) was administered i.c. by CED at a flow rate of 0.5 microl/min. On the following day the animals were irradiated with a single 15 Gy dose of X-rays, administered by a linear accelerator (LINAC) or 78.8 keV synchrotron X-rays at the European Synchrotron Radiation Facility (ESRF). Untreated controls had a mean survival time (MST) + or - standard error of 24 + or - 1 days compared to >59 + or - 13 days for rats that received cisplatin alone with 13% of the latter surviving >200 days. Rats that received cisplatin in combination with either 6 MV (LINAC) or 78.8 keV (synchrotron) X-rays had almost identical MSTs of >75 + or - 18 and >74 + or - 19 days, respectively with 17 and 18% long-term survivors. Microscopic examination of the brains of long-term surviving rats revealed an absence of viable tumor cells and cystic areas at the presumptive site of the tumor. Our data demonstrate that i.c. CED of cisplatin in combination with external X-irradiation significantly enhanced the survival of F98 glioma-bearing rats. This was independent of the X-ray beam energy and probably was not due to the production of Auger electrons as we previously had postulated. Our data provide strong support for the approach of concomitantly administering platinum-based chemotherapy in combination with radiotherapy for the treatment of brain tumors. Since a conventional LINAC can be used as the radiation source, this should significantly broaden the clinical applicability of this approach compared to synchrotron radiotherapy, which could only be carried out at a very small number of specialized facilities.

International audience; BACKGROUND: Use of cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has the potential to increase survival in patients with advanced non-small-cell lung cancer. We therefore compared chemotherapy plus cetuximab with chemotherapy alone in patients with advanced EGFR-positive non-small-cell lung cancer. METHODS: In a multinational, multicentre, open-label, phase III trial, chemotherapy-naive patients (>or=18 years) with advanced EGFR-expressing histologically or cytologically proven stage wet IIIB or stage IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio to chemotherapy plus cetuximab or just chemotherapy. Chemotherapy was cisplatin 80 mg/m(2) intravenous infusion on day 1, and vinorelbine 25 mg/m(2) intravenous infusion on days 1 and 8 of every 3-week cycle) for up to six cycles. Cetuximab-at a starting dose of 400 mg/m(2) intravenous infusion over 2 h on day 1, and from day 8 onwards at 250 mg/m(2) over 1 h per week-was continued after the end of chemotherapy until disease progression or unacceptable toxicity had occurred. The primary endpoint was overall survival. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00148798. FINDINGS: Between October, 2004, and January, 2006, 1125 patients were randomly assigned to chemotherapy plus cetuximab (n=557) or chemotherapy alone (n=568). Patients given chemotherapy plus cetuximab survived longer than those in the chemotherapy-alone group (median 11.3 months vs 10.1 months; hazard ratio for death 0.871 [95% CI 0.762-0.996]; p=0.044). The main cetuximab-related adverse event was acne-like rash (57 [10%] of 548, grade 3). INTERPRETATION: Addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced non-small-cell lung cancer. FUNDING: Merck KGaA.

BACKGROUND: Relative to radical nephrectomy (RN), partial nephrectomy (PN) performed for renal cell carcinoma (RCC) may protect from non-cancer-related deaths. The authors tested this hypothesis in a cohort of PN and RN patients. METHODS: The Surveillance, Epidemiology, and End Results-9 database allowed identification of 2198 PN (22.4%) and 7611 RN (77.6%) patients treated for T1aN0M0 RCC between 1988 and 2004. Analyses matched for age, year of surgery, tumor size, and Fuhrman grade addressed the effect of nephrectomy type (RN vs PN) on overall mortality (Cox regression models) and on non-cancer-related mortality (competing-risks regression models). RESULTS: Relative to PN, RN was associated with 1.23-fold (P = .001) increased overall mortality rate, which translated into a 4.9% and 3.1% absolute increase in mortality at 5 and 10 years after surgery, respectively. Similarly, non-cancer-related death rate was significantly higher after RN in competing-risks regression models (P < .001), which translated into a 4.6% and 4.5% absolute increase in non-cancer-related mortality at 5 and 10 years after surgery, respectively. CONCLUSIONS: Relative to PN, RN predisposes to an increase in overall mortality and non-cancer-related death rate in patients with T1a RCC. In consequence, PN should be attempted whenever technically feasible. Selective referrals should be considered if PN expertise is unavailable Cancer 2009. © 2009 American Cancer Society.

International audience; The present study is aimed to compare survival and prognostic changes over time between elderly (70-84 years) and middle-aged cancer patients (55-69 years). We considered seven cancer sites (stomach, colon, breast, cervix and corpus uteri, ovary and prostate) and all cancers combined (but excluding prostate and non-melanoma skin cancers). Five-year relative survival was estimated for cohorts of patients diagnosed in 1988-1999 in a pool of 51 European populations covered by cancer registries. Furthermore, we applied the period-analysis method to more recent incidence data from 32 cancer registries to provide 1- and 5-year relative survival estimates for the period of follow-up 2000-2002. A significant survival improvement was observed from 1988 to 1999 for all cancers combined and for every cancer site, except cervical cancer. However, survival increased at a slower rate in the elderly, so that the gap between younger and older patients widened, particularly for prostate cancer in men and for all considered cancers except cervical cancer in women. For breast and prostate cancers, the increasing gap was likely attributable to a larger use of, respectively, mammographic screening and PSA test in middle-aged with respect to the elderly. In the period analysis of the most recent data, relative survival was much higher in middle-aged patients than in the elderly. The differences were higher for breast and gynaecological cancers, and for prostate cancer. Most of this age gap was due to a very large difference in survival after the 1st year following the diagnosis. Differences were much smaller for conditional 5-year relative survival among patients who had already survived the first year. The increase of survival in elderly men is encouraging but the lesser improvement in women and, in particular, the widening gap for breast cancer suggest that many barriers still delay access to care and that enhanced prevention and clinical management remain major issues.

International audience; AIMS: Mitral regurgitation (MR) is common and independently predicts mortality in patients with left ventricular (LV) systolic dysfunction. Its management remains challenging because of the complexity and variety of potential mechanisms implicated. We sought to determine which LV functional characteristics are the most important determinants of the severity of the MR associated with dilated cardiomyopathies. METHODS AND RESULTS: We performed echocardiographic studies in 87 consecutive patients with dilated cardiomyopathy. The degree of MR was quantified according to guidelines. LV, left atrial and mitral annulus dimensions, mitral valve tenting, estimated filling pressures, regional myocardial contractility, and dyssynchrony (using regional strain (epsilon) analysis) were recorded too. Determinants of significant MR was thus assessed using multivariate models. Mitral regurgitant volume correlated with mitral annulus diameter (P

International audience; In diseases caused by a deleterious gene mutation, knowledge of age-specific cumulative risks is necessary for medical management of mutation carriers. When pedigrees are ascertained through at least one affected individual, ascertainment bias can be corrected by using a parametric method such as the Proband's phenotype Exclusion Likelihood, or PEL, that uses a survival analysis approach based on the Weibull model. This paper proposes a nonparametric method for penetrance function estimation that corrects for ascertainment on at least one affected: the Index Discarding EuclideAn Likelihood or IDEAL. IDEAL is compared with PEL, using family samples simulated from a Weibull distribution and under alternative models. We show that, under Weibull assumption and asymptotic conditions, IDEAL and PEL both provide unbiased risk estimates. However, when the true risk function deviates from a Weibull distribution, we show that the PEL might provide biased estimates while IDEAL remains unbiased.

In international comparisons of cancer registry based survival it is common practice to restrict the analysis to first primary tumours and exclude multiple cancers. The probability of correctly detecting subsequent cancers depends on the registry's running time, which results in different proportions of excluded patients and may lead to biased comparisons. We evaluated the impact on the age-standardised relative survival estimates of also including multiple primary tumours. Data from 2,919,023 malignant cancers from 69 European cancer registries participating in the EUROCARE-4 collaborative study were used. A total of 183,683 multiple primary tumours were found, with an overall proportion of 6.3% over all the considered cancers, ranging from 0.4% (Naples, Italy) to 12.9% (Iceland). The proportion of multiple tumours varied greatly by type of tumour, being higher for those with high incidence and long survival (breast, prostate and colon-rectum). Five-year relative survival was lower when including patients with multiple cancers. For all cancers combined the average difference was -0.4 percentage points in women and -0.7 percentage points in men, and was greater for older registries. Inclusion of multiple tumours led to lower survival in 44 out of 45 cancer sites analysed, with the greatest differences found for larynx (-1.9%), oropharynx (-1.5%), and penis (-1.3%). Including multiple primary tumours in survival estimates for international comparison is advisable because it reduces the bias due to different observation periods, age, registration quality and completeness of registration. The general effect of inclusion is to reduce survival estimates by a variable amount depending on the proportion of multiple primaries and cancer site. (C) 2008 Elsevier Ltd. All rights reserved.

We analysed 1.6 million population-based EUROCARE-4 cancer cases (26 cancer sites, excluding sex-specific sites, and breast) from 23 countries to investigate the role of sex in cancer survival according to age at diagnosis, site, and European region. For 15 sites (salivary glands, head and neck, oesophagus, stomach, colon and rectum, pancreas, lung, pleura, bone, melanoma of skin, kidney, brain, thyroid, Hodgkin disease and non-Hodgkin's lymphoma) age- and region-adjusted relative survival was significantly higher in women than men. By multivariable analysis, women had significantly lower relative excess risk (RER) of death for the sites listed above plus multiple myeloma. Women significantly had higher RER of death for biliary tract, bladder and leukaemia. For all cancers combined women had a significant 5% lower RER of death. Age at diagnosis was the main determinant of the women's advantage, which, however, decreased with increasing age, becoming negligible in the elderly, suggesting that sex hormone patterns may have a role in women's superior ability to cope with cancer. (C) 2008 Elsevier Ltd. All rights reserved.