Safety and Patient-Reported outcomes of atezolizumab plus chemotherapy with or without bevacizumab in stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies (GFPC 06-2018 study).

BACKGROUND: In an open-label multicenter non-randomized non-comparative phase II study in patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC), oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine-kinase inhibitor and no prior chemotherapy (NCT04042558), atezolizumab, carboplatin, pemetrexed with or without bevacizumab showed some promising result. Beyond the clinical evaluation, we assessed safety and patient-reported outcomes (PROs) to provide additional information on the relative impact of adding atezolizumab to chemotherapy with and without bevacizumab in this population. MATERIALS: Patients received platinum-pemetrexed-atezolizumab-bevacizumab (PPAB cohort) or, if not eligible, platinum-pemetrexed-atezolizumab (PPA cohort). The incidence, nature, and severity of adverse events (AEs) were assessed. PROs were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-Core 30 and EORTC QLQ-Lung Cancer 13). RESULT: Overall, 68 (PPAB) and 72 (PPA) patients were evaluable for safety. Grade 3-4 AEs occurred in 83.8% (PPAB) and 63.9% (PPA). Grade 3-4 atezolizumab-related AEs occurred in 29.4% and 19.4%, respectively. Grade 3-4 bevacizumab-related AEs occurred in 36.8% (PPAB). Most frequent grade 3-4 AEs were neutropenia (19.1% in PPAB; 23.6% in PPA) and asthenia (16.2% in PPAB; 9.7% in PPA). In PPAB, we observed a global stability in global health security (GHS) score, fatigue and dyspnea with a constant tendency of improvement, and a significant improvement in cough. In PPA, we observed a significant improvement in GHS score with a significant improvement in fatigue, dyspnea and cough. At week 54, we observed an improvement from baseline in GHS score for 49.2% of patients. In both cohorts, patients reported on average no clinically significant worsening in their overall health or physical functioning scores. CONCLUSION: PPAB and PPA combinations seem tolerable and manageable in patients with stage IIIB/IV non-squamous NSCLC with oncogenic addiction (EGFR mutation or ALK/ROS1 fusion) after targeted therapies.

Multidimensional penalized splines for survival models: illustration for net survival trend analyses.

BACKGROUND: In descriptive epidemiology, there are strong similarities between incidence and survival analyses. Because of the success of multidimensional penalized splines (MPSs) in incidence analysis, we propose in this pedagogical paper to show that MPSs are also very suitable for survival or net survival studies. METHODS: The use of MPSs is illustrated in cancer epidemiology in the context of survival trends studies that require specific statistical modelling. We focus on two examples (cervical and colon cancers) using survival data from the French cancer registries (cases 1990-2015). The dynamic of the excess mortality hazard according to time since diagnosis was modelled using an MPS of time since diagnosis, age at diagnosis and year of diagnosis. Multidimensional splines bring the flexibility necessary to capture any trend patterns while penalization ensures selecting only the complexities necessary to describe the data. RESULTS: For cervical cancer, the dynamic of the excess mortality hazard changed with the year of diagnosis in opposite ways according to age: this led to a net survival that improved in young women and worsened in older women. For colon cancer, regardless of age, excess mortality decreases with the year of diagnosis but this only concerns mortality at the start of follow-up. CONCLUSIONS: MPSs make it possible to describe the dynamic of the mortality hazard and how this dynamic changes with the year of diagnosis, or more generally with any covariates of interest: this gives essential epidemiological insights for interpreting results. We use the R package survPen to do this type of analysis.

Comparison of 2 Methods for Estimating Multiple Sclerosis-Related Mortality.

BACKGROUND AND OBJECTIVES: Determining whether multiple sclerosis (MS) causes death is challenging. Our objective was to contrast 2 frameworks to estimate probabilities of death attributed to MS (PMS) and other causes (Pother): the cause-specific framework (CSF), which requires the causes of death, and the excess mortality framework (EMF), which does not. METHODS: We used data from the Observatoire Français de la Sclérose en Plaques (OFSEP, n = 37,524) and from a comparative subset where causes of death were available (4,004 women with relapsing-onset MS [R-MS]). In CSF, the probabilities were estimated using the Aalen-Johansen method. In EMF, they were estimated from the excess mortality hazard, which is the additional mortality among patients with MS as compared with the expected mortality in the matched general population. PMS values were estimated at 30 years of follow-up, (1) with both frameworks in the comparative subset, by age group at onset, and (2) with EMF only in the OFSEP population, by initial phenotype, sex, and age at onset. RESULTS: In the comparative subset, the estimated 30-year PMS values were greater using EMF than CSF: 10.9% (95% CI 8.3-13.6) vs 8.7% (6.4-11.8) among the youngest and 20.4% (11.3-29.5) vs 16.2% (8.7-30.2) for the oldest groups, respectively. In the CSF, probabilities of death from unknown causes ranged from 1.5% (0.7-3.0) to 6.4% (2.5-16.4), and even after their reallocation, PMS values remained lower with CSF than with EMF. The estimated probabilities of being alive were close using the 2 frameworks, and the estimated POther (EMF vs CSF) was 2.6% (2.5-2.6) vs 2.1% (1.2-3.9) and 18.1% (16.9-19.3) vs 26.4% (16.5-42.2), respectively, for the youngest and oldest groups. In the OFSEP population, the estimated 30-year PMS values ranged from 7.5% (6.4-8.7) to 24.0% (19.1-28.9) in patients with R-MS and from 25.4% (21.1-29.7) to 36.8% (28.3-45.3) in primary progressive patients, depending on sex and age. DISCUSSION: EMF has the great advantage of not requiring death certificates, their quality being less than optimal. Conceptually, it also seems more relevant because it avoids having to state, for each individual, whether death was directly or indirectly caused by MS or whether it would have occurred anyway, which is especially difficult in such chronic diseases.

Trends in incidence of invasive vaginal cancer in France from 1990 to 2018 and survival of recently diagnosed women - A population-based study.

OBJECTIVE: The aim of this study was to analyze trends in the incidence of vaginal cancer in France over a 28-year period and to present survival for recently-diagnosed women. METHODS: French cancer registries provided data on invasive vaginal cancers diagnosed from 1990 to 2015 and followed up through June 2018. Trends in incidence were analyzed using a Poisson model with a bidimensional penalized spline of age and year at diagnosis. Net survival analysis was restricted to recently-diagnosed cases (2010-2015) and used a novel approach based on a bidimensional penalized spline of age and time-since-diagnosis to model excess mortality hazard. RESULTS: With 162 new cases estimated in France in 2018, vaginal cancer represented 0.9 % of genital cancers in French women. In 2018, the world population age-standardized incidence rate was 0.2 per 100,000 person-years, median age at diagnosis was 75 years. The standardized incidence rate decreased significantly by 3 % per year (95 % CI, -3.8; -2.2) between 1990 and 2018 (0.4 cases per 100,000 person-year in 1990, vs 0.2 in 2018). Age-standardized net survival at 1 and 5 years after diagnosis was respectively 74 % and 45 %. CONCLUSIONS: This study confirms that vaginal cancer is still a rare malignancy in France with 5-year net survival that remains low. We observed a consistent decrease in the incidence rate between 1990 and 2018. It may be too early to attribute these trends to a positive impact of vaccination campaigns against hrHPV infection, since vaginal cancer mainly affects older women and HPV vaccination has only been available since the early 2000s, and only targets young girls.

Protocol for a prospective quasi-experimental study on SARS-CoV-2 transmission during outdoor sports events in France: the COVID-ESO project.

INTRODUCTION: The spread of SARS-CoV-2 and its variants in the community remains a major concern despite the application of control measures including the banning of mass sporting events. The circulation of SARS-CoV-2 within the general population, and potentially within the population practicing outdoor sports activities, suggests contexts conducive to the transmission of the virus. We hypothesise that outdoor sports events (OSEs) do not present a higher risk of SARS-CoV-2 contamination. The objective of the COVID-ESO project is to measure if individuals participating in OSE present a similar risk of SARS-CoV-2 transmission compared with individuals not participating in OSE, in France. METHODS AND ANALYSIS: The COVID-ESO project is a prospective, quasi-experimental study to be conducted in volunteer individuals likely to participate in OSE. Six events are targeted across France to be included. Three sport trials will be eligible for the study: running, cycling and triathlon. Each individual participating in the OSE will choose one of his or her usual training partner to be eligible for the unexposed control group. Individuals will be matched (1:1) on age, sex and the district of residence. Individuals assigned to the exposed group will participate in the OSE, whereas individuals assigned to the unexposed group will not participate in the OSE. All individuals will be asked to perform saliva tests on the day of the event and 7 days after the event. A questionnaire including sociodemographic, clinical and exposure data to SARS-CoV-2 will be sent by email for both groups on the day before the event and 7 days after the event. Differences in SARS-CoV-2 infection rates between the exposed versus the unexposed group will be analysed by fitting a conditional logistic regression model, adjusted for potential confounders. As the sport events unfold, data will be analyzed by performing sequential meta-analyses. ETHICS AND DISSEMINATION: This protocol has been approved by the ethical committee. Ethical approval has been obtained for the Clinical research and committee of South West of France, 10 June 2021. COMITE DE PROTECTION DES PERSONNES DU SUD-OUEST ET OUTRE-MER 4 under the reference number 21.03.23.71737/CPP2021-04-045 a COVID/2021-A00845-36. Findings generated from this study will be shared to national health and sport authorities.

Selected and simplified FDI criteria for assessment of restorations.

OBJECTIVES: Assess the quality of dental restorations with simplified FDI criteria and examine its relationships with other general characteristics of restored teeth. METHODS: The study involved 76 dentists from private and hospital practices. Assessments of successes and failures of previous restorations used a simplified rating with FDI criteria 3 to 8, 11, 12, and 14. The results were examined versus tooth location, number of restored surfaces, type of restoration, and filling material. RESULTS: The dentists examined 4,612 dental restorations, of which 4,185 direct fillings mainly with resin composite materials (2,555). Of all restorations, 2,048 (44.4%) were considered as failures, of which 1,489 had one or two criteria for 'clinically unsatisfactory/poor restoration'. As simplified, the esthetic criterion 'color match' was the most frequent criterion for failure (912 cases). The rate of restoration failures was found associated with the number of surfaces restored and the use of glass-ionomer cement. Results are not comparable with others obtained with original FDI criteria. CONCLUSIONS: Assessing dental restorations with the original FDI criteria leads generally to much more failure statements than practitioners' decisions to reintervene. Though requiring some adjustment (e.g., regarding 'color match'), the simplified assessment proved convenient and amenable to standardization. CLINICAL SIGNIFICANCE: Regardless of the type of practice, selecting, understanding, and optimal interpreting of FDI criteria for failure is essential to help practitioners faced with daily dilemmas of replacement vs. repair of failed dental restorations. Standardization of simplified criteria is desirable to help comparing research data.

Needs for re-intervention on restored teeth in adults: a practice-based study.

OBJECTIVES: Evaluate the need for re-intervention on dental coronal restorations in adults seen in a network of general dental practitioners (ReCOL).  MATERIALS AND METHODS: This observational, cross-sectional, multicenter study involved 40 practitioners and 400 patients. Coronal restoration failures (needing re-intervention for unsatisfactory outcomes) were assessed with a simplified rating scale of seven criteria from the FDI World Dental Federation. The oral health status, the risk factors, and Oral Health Impact Profile-14 were also examined. Previous restoration characteristics (extent, technique, material) were analyzed according to the need for re-intervention (yes/no), the age group, and the risk profile. Qualitative variables were compared between "re-intervention" and "no re-intervention" group using Fisher exact test. RESULTS: The need for re-intervention was estimated at 74% (95% CI: 70; 79); it increased with age (49 to 90%), unfavorable risk profile (82 vs. 62%), and extent of the filling (32, 39, 44, and 44% on 1, 2, 3 surfaces, and crowns, respectively). More posterior than anterior teeth were restored (median per patient: 6 vs. 1) or needed re-intervention (median per patient: 1 vs. 0). CONCLUSIONS: The needs for re-intervention in adults are still high within a context of ever-changing materials and techniques, simplified and rationalized decision-makings, and demands for patient involvement. CLINICAL RELEVANCE: Meeting these needs requires the following: (i) consensus definitions and assessment methods for "failure" and (ii) reliable feedbacks on materials, procedures, and satisfaction. Building large and detailed databases fed by networks of motivated practitioners will help analyzing complex success/failure data by artificial intelligence and guiding treatment and research.

Diverging incidence trends of oral tongue cancer compared to other head and neck cancers in young adults in France.

While head and neck cancer incidence decreased worldwide due to reduced tobacco and alcohol consumption, oral tongue cancer (OTC) incidence has been reported to be increasing in several countries. Our study examines the incidence trends of OTC in France from 1990 to 2018, globally and by age; and compares the incidence trends with the evolution of the incidence of other human papilloma virus-unrelated head and neck squamous cell carcinoma, that is, cancers of the remaining subsites of the oral cavity (RSOCC) and laryngeal cancers for the period 1990 to 2018. World age-standardized incidence rates of oral tongue cancers (C02), cancers of the remaining subsites of the oral cavity (RSOCC, C03-06) and laryngeal cancers (C32) were estimated using the French National Network of Cancer Registries for the period 1990 to 2018. Trends in national incidence rates were estimated from a mixed-effect Poisson model including age and year effects using penalized splines and a district-random effect. In women aged 30 and 40, a significant increase in OTC incidence was observed, while ROSCC showed a nonsignificant incidence decrease. In young men aged 25, a marginally significant increase of OTC incidence years was observed, while incidence rates of RSOCC significantly declined. The results suggest a tendency towards diverging incidence trends for OTC compared to RSOCC and laryngeal cancer in young adults. The observed trends may reflect changes in underlying exposures or emerging exposures not yet identified, and stress the need to further investigate the etiology of oral tongue cancers.

Multidimensional penalized splines for incidence and mortality-trend analyses and validation of national cancer-incidence estimates.

BACKGROUND: Cancer-incidence and mortality-trend analyses require appropriate statistical modelling. In countries without a nationwide cancer registry, an additional issue is estimating national incidence from local-registry data. The objectives of this study were to (i) promote the use of multidimensional penalized splines (MPS) for trend analyses; (ii) estimate the national cancer-incidence trends, using MPS, from only local-registry data; and (iii) propose a validation process of these estimates. METHODS: We used an MPS model of age and year for trend analyses in France over 1990-2015 with a projection up to 2018. Validation was performed for 22 cancer sites and relied essentially on comparison with reference estimates that used the incidence/health-care ratio over the period 2011-2015. Alternative estimates that used the incidence/mortality ratio were also used to validate the trends. RESULTS: In the validation assessment, the relative differences of the incidence estimates (2011-2015) with the reference estimates were <5% except for testis cancer in men and < 7% except for larynx cancer in women. Trends could be correctly derived since 1990 despite incomplete histories in some registries. The proposed method was applied to estimate the incidence and mortality trends of female lung cancer and prostate cancer in France. CONCLUSIONS: The validation process confirmed the validity of the national French estimates; it may be applied in other countries to help in choosing the most appropriate national estimation method according to country-specific contexts. MPS form a powerful statistical tool for trend analyses; they allow trends to vary smoothly with age and are suitable for modelling simple as well as complex trends thanks to penalization. Detailed trend analyses of lung and prostate cancers illustrated the suitability of MPS and the epidemiological interest of such analyses.

Trends in probabilities of death owing to cancer and owing to other causes in patients with colon cancer.

BACKGROUND: It is of interest to both the clinicians and patients to estimate the probability of death owing to cancer in the presence of other causes as time elapses since diagnosis. The objective of this study was to depict for patients diagnosed with colon cancer between 1990 and 2010 in France, the probability of surviving up to 10 years after diagnosis and to disentangle the probability of death owing to cancer from that of death owing to other causes. PATIENTS AND METHODS: Individuals with cancer were described, up to 10 years after diagnosis, as belonging to one of three categories: those who died owing to a cause related to cancer, those who died owing to another cause and those who survived. Net survival, crude probabilities of death related to colon cancer, death related to another cause and survival were estimated by modeling excess mortality hazard. RESULTS: In women of all ages, 5 and 10-year net survival improved over calendar time. The 10-year probability of survival decreased when age increased in both sexes. It was higher in women than in men, and this difference increased with age. Crude probabilities of death related to colon cancer decreased between 1990 and 2010 for men and women, although this was not observed in the eldest men. CONCLUSION: Crude probability of death related to colon cancer is an important indicator for patients and health policy makers. Results of cancer screening should be faced to trends in probability of death related to colorectal cancer.

Optimism Bias Correction in Omics Studies with Big Data: Assessment of Penalized Methods on Simulated Data.

Big Data generated by omics technologies require simultaneous analyses of large numbers of variables. This leads to complex model selection and parameter estimates that show optimism bias. This study on simulated data sets examined optimism-bias correction by penalty regression methods in case-control studies that involve clinical and omics variables. Least absolute shrinkage and selection operator (LASSO)-based methods (LASSO-penalized logistic regression, adaptive LASSO, and regularized LASSO for selection + ridge regression) were evaluated using power, the false positive rate (FPR), false discovery rate (FDR), and by estimated versus theoretical parameter comparisons. The "ordinary" LASSO overcorrects the optimism bias. The adaptive LASSO with LASSO estimation of the weights was unable to provide a sufficient correction. Importantly, the adaptive LASSO with ridge estimation of the weights showed the best parameter estimation. The regularized LASSO selection showed a slight optimism bias that decreased with the increase in the training set size. The optimism bias decreased with the increase of the number of variables selected among truly differentially expressed variables; however, power, FPR, and FDR were correlated. A compromise between model selection and estimation accuracy should be found. These results might prove useful because Big Data analyses are becoming commonplace in omics/multiomics studies in integrative biology, precision medicine, and planetary health.

Effect of Buparlisib, a Pan-Class I PI3K Inhibitor, in Refractory Follicular and Poorly Differentiated Thyroid Cancer.

BACKGROUND: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway is frequent in advanced follicular (FTC) and poorly differentiated thyroid (PDTC) carcinomas and has been implicated in oncogenesis and tumor progression. This study investigated the efficacy and safety of buparlisib, a pan-PI3K inhibitor in radioiodine refractory FTC and PDTC. METHODS: The primary endpoint of this open-label, multicenter, phase 2 pilot study was progression-free survival (PFS) at 6 months. The sample size was determined considering that a PFS ≤50% at 6 months would denote an absence of benefits (null hypothesis). Secondary endpoints were objective response rate, PFS at 12 months, overall survival at 6 and 12 months, and safety based on the frequency and severity of adverse events (AEs). RESULTS: Forty-three patients (19M/24 F; median age: 67 years) with metastatic, radioiodine refractory, progressive disease received buparlisib, 100 mg, daily. Histology was PDTC in 25 (58%), FTC in 17 (40%), and Hürthle cell carcinoma in 1 (2%). RAS mutation was found in 44% (12/27) and activation of the PI3K pathway in 35% (8/23) of tested tumors. The probability of PFS was 41.7% [95% confidence interval (CI) 7.7-55.5] at 6 months and 20.9% [CI 0-35.7] at 12 months, lower than the 50% expected PFS. At 6 months, 25.6% patients had stable disease, 48.8% were progressive and 25.6% had stopped treatment due to AE. The response to therapy was not influenced by age, sex, histology, or genetic alterations. The overall survivals at 6 and 12 months were 85.9% [CI 76-97] and 78.7 % [CI 67-92], respectively. The mean tumor growth rate decreased from 3.78 mm/month [CI 2.61-4.95] before treatment to 0.8 mm/month [CI -0.2-1.88] during treatment (p < 0.02). Severe grade 3-4 AEs occurred in 27 patients (63%), including hepatitis (25%), hyperglycemia (21%), mood disorders (12%), and skin toxicity (12%), with favorable outcome after temporary or permanent treatment discontinuation or dose reduction. CONCLUSIONS: Buparlisib did not result in significant efficacy in advanced FTC and PDTC. However, the decrease in tumor growth rate may suggest incomplete inhibition of oncogenic pathways and/or escape mechanisms. This should lead to evaluate combined therapy associating inhibitors of both the PI3K and mitogen-activated protein kinase pathways.

Predicting thyroid nodule malignancy at several prevalence values with a combined Bethesda-molecular test.

Investigation of thyroid nodules using fine-needle aspiration cytology (FNAC) gives indeterminate results in up to 30% of samples using the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). We present a combined Bethesda-molecular predictor of nodule malignancy to improve the accuracy of the preoperative diagnosis of thyroid nodules. To detect a molecular signature of thyroid nodule malignancy, a molecular test was performed on FNACs from 128 thyroid nodules from prospectively included patients, collected in a tertiary center. The test relied on a transcriptomic array of 20 genes selected from a previous study. An optimal set of seven genes was identified using a logistic regression model. Comparison between the combined predictor (TBSRTC + molecular) and TBSRTC alone used the area under the ROC curve (AUC). Performance of the combined predictor was calculated according to various malignancy prevalence values and benefit-to-harm ratios (B/Hr) (favoring sensitivity or specificity). In our population (36% malignancy prevalence) and with a B/Hr of 1, the combined predictor achieved 95% specificity and 76% sensitivity. The AUC was 93.5%; higher than that of TBSRTC (P = 0.004). Among indeterminate nodules (30% malignancy prevalence), sensitivity and specificity were 52.2% and 96.2%, respectively, with a B/Hr of 1, or 95.7% and 64.2% with a B/Hr of 4 (favoring sensitivity), allowing avoidance of 64% of unnecessary surgeries at the cost of only one false-positive result. In conclusion, this predictor could improve the detection of thyroid nodule malignancy, taking into account malignancy prevalence and B/Hr, and reduce the number of unnecessary thyroidectomies.

Risk of Recurrence in Pituitary Neuroendocrine Tumors: A Prospective Study Using a Five-Tiered Classification.

Background: Most pituitary neuroendocrine tumors (PitNETs) show benign behavior, but a substantial number are invasive, recur, or resist medical treatment. Based on a retrospective case-control study, we recently proposed a classification of PitNETs of prognostic relevance. This prospective study aims to test the value of this classification in an independent patient cohort. Methods: All patients who underwent PitNET surgery from 2007 to 2012 in one single center were included. Using a grading system based on invasion on magnetic resonance imaging, immunocytochemical profile, Ki-67, mitotic index, and p53 positivity, tumors were classified. Progression-free survival of the graded tumors was calculated by the Kaplan-Meier method and compared using the log-rank test. A multivariate analysis, using a Cox regression model, was also performed. Results: In total, 365 patients had grade 1a PitNETs (51.2%), followed by grade 2a (32.3%), 2b (8.8%), and 1b tumors (7.7%). Of 213 patients with a follow-up, 42% had recurrent (n = 52) or progressive disease (n = 37) at 3.5 years. Grade was a significant predictor of progression-free survival (P < 0.001). Multivariate analysis indicated grade (P < 0.001), age (P = 0.035), and tumor type (P = 0.028) as independent predictors of recurrence and/progression. This risk was 3.72-fold higher for a grade 2b tumor compared with grade 1a tumor. Conclusions: Our data suggest that classification of PitNETs into five grades is of prognostic value to predict postoperative tumor behavior and identifies patients who have a high risk of early recurrence or progression. It therefore will allow clinicians to adapt their therapeutic strategies and stratify patients in future clinical trials.

Circulating Klotho Associates With Cardiovascular Morbidity and Mortality During Hemodialysis.

Background: Klotho gene was identified as an aging suppressor. In animals, klotho overexpression extends life span, and defective klotho results in rapid aging and early death. The kidney is the main contributor to circulating klotho levels, and, during chronic kidney disease, renal klotho gene expression is drastically reduced in animals and humans as well. Objective: We aimed to determine the consequences of a serum klotho (seKL) defect on cardiovascular morbidity and mortality during chronic dialysis. Design: The ARNOGENE study was designed to prospectively follow a cohort of hemodialysis patients for 2 years without specific intervention. A total of 769 patients was recruited and followed from the end of 2008 until January 2011. A total of 238 patients was analyzed due to a technical sample conservation issue with other samples. Results: The median seKL was markedly reduced, 360.4 ng/L (interquartile range 176.5) as compared with nondialysis chronic kidney disease patients or healthy volunteers. Patients with a seKL above the first quartile (≥280 ng/L) had a significantly reduced occurrence of outcome combining cardiovascular events and cardiovascular death [odds ratio (OR) = 0.39; 0.19 to 0.78, P = 0.008] compared with patient with klotho <280 ng/L. This effect persisted (OR = 0.86; 0.76 to 0.99, P = 0.03) after adjustment on age, sex, diabetes, cardiac insufficiency, dialysis vintage, and serum hemoglobin, albumin, fibroblast growth factor-23, phosphate, and calcium. Conclusions: These results suggest that, during chronic hemodialysis, conservation of seKL >280 ng/L is associated with a better 2-year cardiovascular protection. Thus, a preserved klotho function supports cardiovascular protection and may represent a prognostic tool and therapeutic target for cardiovascular disease.

Restricted mean survival time over 15 years for patients starting renal replacement therapy.

Background: The restricted mean survival time (RMST) estimates life expectancy up to a given time horizon and can thus express the impact of a disease. The aim of this study was to estimate the 15-year RMST of a hypothetical cohort of incident patients starting renal replacement therapy (RRT), according to their age, gender and diabetes status, and to compare it with the expected RMST of the general population. Methods: Using data from 67 258 adult patients in the French Renal Epidemiology and Information Network (REIN) registry, we estimated the RMST of a hypothetical patient cohort (and its subgroups) for the first 15 years after starting RRT (cRMST) and used the general population mortality tables to estimate the expected RMST (pRMST). Results were expressed in three different ways: the cRMST, which calculates the years of life gained under the hypothesis of 100% death without RRT treatment, the difference between the pRMST and the cRMST (the years lost), and a ratio expressing the percentage reduction of the expected RMST: (pRMST - cRMST)/pRMST. Results: Over their first 15 years of RRT, the RMST of end-stage renal disease (ESRD) patients decreased with age, ranging from 14.3 years in patients without diabetes aged 18 years at ESRD to 1.8 years for those aged 90 years, and from 12.7 to 1.6 years, respectively, for those with diabetes; expected RMST varied from 15.0 to 4.1 years between 18 and 90 years. The number of years lost in all subgroups followed a bell curve that was highest for patients aged 70 years. After the age of 55 years in patients with and 70 years in patients without diabetes, the reduction of the expected RMST was >50%. Conclusion: While neither a clinician nor a survival curve can predict with absolute certainty how long a patient will live, providing estimates on years gained or lost, or percentage reduction of expected RMST, may improve the accuracy of the prognostic estimates that influence clinical decisions and information given to patients.

[Cost-effectiveness analysis of various strategies of end-stage renal disease patients' care in France]. / Évaluation médico-économique des stratégies de prise en charge de l'insuffisance rénale chronique terminale en France.

End-stage renal disease is a chronic state that may continue for many years before death. Patients may receive various modalities of renal replacement therapy that vary over time, which we describe as a treatment trajectory. The French health insurance system pays dialysis facilities and professionals various fixed fees according to the dialysis modalities they provide; fees are highest for hospital-based haemodialysis care, which treats around 58% of all dialysis patients. As in other European countries, a variety of dialysis modalities are used in France, and their weight and distribution differ from region to region. This study hypothesizes that some patients currently treated in hospital-based haemodialysis could be treated with another RRT modality without any increase in mortality risk. The aim of this study was to propose new care strategies so as to evaluate the medico-economic impact of replacing some hospital-based HD care by various other modalities for French health insurance. Care strategies were modelled using a statistical tool that predicts course and trajectories of a hypothetical cohort of news patients over a 15-year period. The results confirmed that the development of kidney transplantation in six sub-cohorts (according to age and diabetes status) is an efficient strategy, compared to all evaluated strategies. Strategies considering joint development of peritoneal dialysis and hospital-based haemodialysis are efficient for patients over 45 years but their feasibility has to be evaluated. Other alternative strategies also need to be considered because they are as effective and less costly than the current care practices.

Oversizing the tibial component in TKAs: incidence, consequences and risk factors.

PURPOSE: The incidence of anteroposterior overhang of the tibial component after TKA and its effect on clinical outcome were investigated, and the morphometric characteristics of the knees in which tibial baseplates were oversized were identified. METHOD: One hundred and fourteen consecutive TKAs were retrospectively assessed. The dimensions of the tibia were measured on a pre-operative CT scan and were compared with those of the implanted tibial component. We analysed the effect of anteroposterior and mediolateral size variations on clinical outcomes 1 year after surgery. RESULTS: An anteroposterior overhang was observed in 87 % of cases on the lateral plateau, in 88 % on the central plateau and in 25 % on the medial tibial plateau. The mean post-pre-operative size differences were 3.2 ± 2.7, 2.8 ± 2.7 and -1.6 ± 2.3 mm, respectively. (Positive value means oversizing). A mediolateral overhang of the tibial component was found in 61 % of the patients. Oversizing was significantly greater and more frequent in females. Patients oversized in the anteroposterior dimension had lower post-operative pain scores. Patients with mediolateral oversizing had decreased flexion 1 year after surgery. Anteroposterior oversizing was observed more frequently in patients with asymmetric tibial plateaus, while mediolateral oversizing was observed more frequently in patients with small tibias. CONCLUSIONS: This study demonstrates that the incidence of oversized tibial plateau components is surprisingly high and that functional outcomes are lower in the case of mediolateral or anteroposterior oversizing. The risk of oversizing could be predicted as it occurs predominantly in patients with asymmetric proximal tibia and/or small tibia. LEVEL OF EVIDENCE: IV.

Economic impact of a modification of the treatment trajectories of patients with end-stage renal disease.

BACKGROUND: This study assumed that some patients currently treated at hospital-based haemodialysis centres can be treated with another renal replacement therapy (RRT) modality without any increase in mortality risk and sought to evaluate the monthly cost impact of replacing hospital-based haemodialysis, for which fees are highest, by different proportions of other modalities. METHODS: We used a deterministic model tool to predict the outcomes and trajectories of hypothetical cohorts of incident adult end-stage renal disease (ESRD) patients for 15 years of RRT (10 different modalities). Our estimates were based on data from 67 258 patients in the REIN registry and 65 662 patients in the French national health insurance information system. Patients were categorized into six subcohorts, stratified for age and diabetes at ESRD onset, and analyses run for each subcohort. We simulated new strategies of care by changing any or all of the following: initial distributions in treatment modalities, transition rates and some costs. Strategies were classified according to their monthly per-patient cost compared to current practices (cost-minimization analysis). RESULTS: Simulations of the status quo for the next 15 years predicted a per-patient monthly cost of €2684 for a patient aged 18-45 years without diabetes and €7361 for one older than 70 years with diabetes. All of the strategies we analysed had monthly per-patient costs lower than the status quo, except for daily home HD. None impaired expected survival. Savings varied by strategy. CONCLUSIONS: Alternative strategies may well be less expensive than current practices. The decision to implement new strategies must nonetheless consider the number of patients concerned, feasibility of renal care reorganization, and investment costs. It must also take into account the role of patients' choice and the availability of professionals.

Pelvic-floor muscle rehabilitation in erectile dysfunction and premature ejaculation.

BACKGROUND: In men, involuntary or voluntary ischiocavernosus muscle contractions after erection lead to intracavernous blood pressures far higher than the systolic pressure, which builds and maintains penile rigidity. Thus, erectile dysfunction may be partly due to ischiocavernosus muscle atrophy and may be treated by rehabilitation interventions. OBJECTIVE: The purpose of this study was to determine whether pelvic-floor muscle strengthening interventions could be associated with increases in intracavernous pressure that would increase penile rigidity. DESIGN: An observational study was conducted. METHODS: One hundred twenty-two men with isolated erectile dysfunction and 108 men with isolated premature ejaculation participated (no neuromuscular diseases or previous perineal rehabilitation). Thirty-minute sessions of voluntary contractions coupled with electrical stimulation were designed to increase ischiocavernosus muscle strength (monitored through intracavernous pressure increase). A linear mixed-effects model per group analyzed separately, then jointly, the maximum change in pressure (ΔP) and the maximum baseline (ie, respectively, the average contraction-generated difference in intracavernous pressure and the intracavernous pressure plateau at full erection, both measured during the highest moving average of the best 2 minutes of each session). RESULTS: Over 20 sessions, the maximum ΔP increased in erectile dysfunction as well as in premature ejaculation (87% and 88%, respectively, in men with positive trends). The maximum baseline also increased (99% and 72%, respectively, in men with positive trends). The joint modeling indicated that the mean expected progressions of the intracavernous pressure after 5 sessions in erectile dysfunction and premature ejaculation were 62.85 and 64.15 cm H2O, respectively. LIMITATIONS: Indirect measurements were obtained of intracavernous pressure and ischiocavernosus muscle force. CONCLUSIONS: Pelvic-floor muscle rehabilitation was found to be beneficial in erectile dysfunction. However, its effects on symptoms of premature ejaculation, despite intracavernous pressure gains, were much more difficult to assess. The definitive proof of its benefits requires rather difficult-to-design clinical trials.