Jean Iwaz

Long-term outcomes of chronic minimally conscious and vegetative states.

Objective: The present retrospective cohort study compares the long-term functional outcome, improvement or deterioration, of patients considered in a vegetative state (VS) or a minimally conscious state (MCS) 1 year after coma onset, then yearly for up to 5 years. Methods: We reviewed the clinical courses of 12 patients in VS and 39 in MCS. The outcomes were assessed at 2, 3, 4, and 5 years after injury using the 5 categories of the Glasgow Outcome Scale plus an additional category for patients in MCS. A logistic regression analysis investigated the relationships between each outcome and 10 predictor variables. Four of these variables were auditory evoked potentials recorded at the early stage of coma. Results: None of the patients in VS improved during the follow-up period: 1 was lost to follow-up, 9 died, and 2 remained in VS. Among patients in MCS, 3 were lost to follow-up, 14 died, 9 remained in MCS, and 13 emerged from MCS with severe disabilities. VS, age >39 years, and bilateral absence of cortical components of middle-latency auditory evoked potentials were significantly associated with deterioration. Conclusions: In contrast to patients in VS, a third of patients in MCS improved more than 1 year after coma onset. This emphasizes the need to define reliable boundaries between VS and MCS using repeated clinical evaluations and all imaging and neurophysiologic tools available today.

Ten-Year Survival Results of a Randomized Trial of Irradiation of Internal Mammary Nodes After Mastectomy

PURPOSE To evaluate the efficacy of irradiation of internal mammary nodes (IMN) on 10-year overall survival in breast cancer patients after mastectomy. METHODS AND PATIENTS This multicenter phase 3 study enrolled patients with positive axillary nodes (pN+) or central/medial tumors with or without pN+. Other inclusion criteria were age <75 and a Karnofsky index ≥70. All patients received postoperative irradiation of the chest wall and supraclavicular nodes and were randomly assigned to receive IMN irradiation or not. Randomization was stratified by tumor location (medial/central or lateral), axillary lymph node status, and adjuvant therapy (chemotherapy vs no chemotherapy). The prescribed dose of irradiation to the target volumes was 50 Gy or equivalent. The first 5 intercostal spaces were included in the IMN target volume, and two-thirds of the dose (31.5 Gy) was given by electrons. The primary outcome was overall survival at 10 years. Disease-free survival and toxicity were secondary outcomes. RESULTS T total of 1334 patients were analyzed after a median follow-up of 11.3 years among the survivors. No benefit of IMN irradiation on the overall survival could be demonstrated: the 10-year overall survival was 59.3% in the IMN-nonirradiated group versus 62.6% in the IMN-irradiated group (P=.8). According to stratification factors, we defined 6 subgroups (medial/central or lateral tumor, pN0 [only for medial/central] or pN+, and chemotherapy or not). In all these subgroups, IMN irradiation did not significantly improve overall survival. CONCLUSIONS In patients treated with 2-dimensional techniques, we failed to demonstrate a survival benefit for IMN irradiation. This study cannot rule out a moderate benefit, especially with more modern, conformal techniques applied to a higher risk population.

ReviewAdult-onset Still's disease

First described in 1971, adult-onset Stills disease (AOSD) is a rare multisystemic disorder considered as a complex (multigenic) autoinflammatory syndrome. A genetic background would confer susceptibility to the development of autoinflammatory reactions to environmental triggers. Macrophage and neutrophil activation is a hallmark of AOSD which can lead to a reactive hemophagocytic lymphohistiocytosis. As in the latter disease, the cytotoxic function of natural killer cells is decreased in patients with active AOSD. IL-18 and IL-1β, two proinflammatory cytokines processed through the inflammasome machinery, are key factors in the pathogenesis of AOSD; they cause IL-6 and Th1 cytokine secretion as well as NK cell dysregulation leading to macrophage activation. The clinico-biological picture of AOSD usually includes high spiking fever with joint symptoms, evanescent skin rash, sore throat, striking neutrophilic leukocytosis, hyperferritinemia with collapsed glycosylated ferritin (<20%), and abnormal liver function tests. According to the clinical presentation of the disease at diagnosis, two AOSD phenotypes may be distinguished: i) a highly symptomatic, systemic and feverish one, which would evolve into a systemic (mono- or polycyclic) pattern; ii) a more indolent one with arthritis in the foreground and poor systemic symptomatology, which would evolve into a chronic articular pattern. Steroid- and methotrexate-refractory AOSD cases benefit now from recent insights into autoinflammatory disorders: anakinra seems to be an efficient, well tolerated, steroid-sparing treatment in systemic patterns; tocilizumab seems efficient in AOSD with active arthritis and systemic symptoms while TNFα-blockers could be interesting in chronic polyarticular refractory AOSD.

Adult-onset still disease: manifestations, treatment, outcome, and prognostic factors in 57 patients.

AbstractWe conducted a retrospective observational study to describe a cohort and identify the prognostic factors in adult-onset Still disease (AOSD). Patients enrolled in this retrospective chart review fulfilled either Yamaguchi or Fautrel criteria. Candidate variables were analyzed with logistic unadjusted and adjusted regression models.Fifty-seven patients were seen in the internal medicine (75%) and rheumatology (25%) departments over a mean period of 8.4 years. The median time to diagnosis was 4 months. The course of AOSD was monocyclic in 17 patients, polycyclic in 25, and chronic in 15. The assessment of glycosylated ferritin (GF) in 37 patients was correlated with early diagnosis. Nine 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) scans identified the lymph nodes and glands as the main sites of hypermetabolism. Complications were frequent (n = 19), including reactive hemophagocytic syndrome (n = 8). None of the 3 deaths could be attributed to AOSD. Corticosteroid dependence, as predicted by a low GF level, occurred in 23 patients (45%). A quarter of the patients received tumor necrosis factor-&agr; blockers or anakinra with good tolerance. Fever >39.5°C was predictive of monocyclic AOSD, while arthritis and thrombocytopenia were associated with chronic and complicated AOSD, respectively. The youngest patients had the highest risks of resistance to first-line treatments.AOSD remains difficult to diagnose. Mortality is low despite frequent complications. GF and 18FDG-PET scans were of value in the diagnostic approach. The condition in highly symptomatic patients evolved to systemic AOSD, whereas more progressive patterns with arthritis predicted chronic AOSD.

Descriptive epidemiology of upper aerodigestive tract cancers in France: Incidence over 1980–2005 and projection to 2010

Over the 1998-2002 period, some French Départements have been shown to have the worlds highest incidence of upper aerodigestive tract (UADT) cancers in men. The objectives were to describe the changes in UADT cancer incidence in France over the 1980-2005 period, present projections for 2010, and describe the anatomical and histological characteristics of these tumours. The trend of cancer-incidence over 1980-2005 and projection up to 2010 were obtained using age-period-cohort models (data from eleven cancer registries) and incidence/mortality ratios in the area covered by these registries. The description of UADT cancers by anatomical and histological characteristics concerned data collected between 1980 and 2004 in eleven cancer registries. In men, cancer incidence decreased in all cancer sites and the world-standardized incidence rates decreased by 42.9% for lip-oral cavity-pharynx (LOCP) cancers and 50.4% for larynx cancer. In women, the world-standardized incidence rates increased by 48.6% for LOCP cancers and 66.7% for larynx cancer. Incidence increased the most for oropharynx, palate, and hypopharynx cancers. Incidence analysis by one-year cohorts revealed a progressive shift of the incidence peak towards younger and younger generations, with no change as yet in the mean age at diagnosis. In France, the incidence of these cancers is still higher than in other European and North American countries. This urges actions towards reducing the major risk factors for those cancers, namely alcohol and tobacco consumption, especially among young people, and reducing exposure to risk factors due to social inequalities.

Monitoring changes and predicting loss of ambulation in Duchenne muscular dystrophy with the Motor Function Measure

Aim  To assess changes in motor function in patients with Duchenne muscular dystrophy using the Motor Function Measure (MFM).

Creatinine‐ versus cystatine C‐based equations in assessing the renal function of candidates for liver transplantation with cirrhosis

Renal dysfunction is frequent in liver cirrhosis and is a strong prognostic predictor of orthotopic liver transplantation (OLT) outcome. Therefore, an accurate evaluation of the glomerular filtration rate (GFR) is crucial in pre‐OLT patients. However, in these patients plasma creatinine (Pcr) is inaccurate and the place of serum cystatine C (CystC) is still debated. New GFR‐predicting equations, based on standardized assays of Pcr and/or CystC, have been recently recommended in the general population but their performance in cirrhosis patients has been rarely studied. We evaluated the performance of the recently published Chronic Kidney Disease Epidemiology Collaboration equations (CKD‐EPI‐Pcr, CKD‐EPI‐CystC, and CKD‐EPI‐Pcr‐CystC) and the more classical ones (4‐ and 6‐variable MDRD and Hoek formulas) in cirrhosis patients referred for renal evaluation before OLT. Inulin clearance was performed in 202 consecutive patients together with the determination of Pcr and CystC with assays traceable to primary reference materials. The performance of the GFR‐predicting equations was evaluated according to ascites severity (no, moderate, or refractory) and to hepatic and renal dysfunctions (MELD score ≤ or >15 and KDOQI stages, respectively). In the whole population, CystC‐based equations showed a better performance than Pcr‐based ones (lower bias and higher 10% and 30% accuracies). CKD‐EPI‐CystC equation showed the best performance whatever the ascites severity and in presence of a significant renal dysfunction (GFR <60 mL/min/1.73 m2). Conclusion: Pcr‐based GFR predicting equations are not reliable in pre‐OLT patients even when an IDMS‐traceable enzymatic Pcr assay is used. Whenever a CystC‐assay traceable to primary reference materials is performed and when a true measurement of GFR is not possible, CystC‐based equations, especially CKD‐EPI‐CystC, may be recommended to evaluate renal function and for KDOQI staging. (Hepatology 2014;59:1522‐1531)

Cancer net survival on registry data: use of the new unbiased Pohar-Perme estimator and magnitude of the bias with the classical methods.

Net survival, the survival which might occur if cancer was the only cause of death, is a major epidemiological indicator required for international or temporal comparisons. Recent findings have shown that all classical methods used for routine estimation of net survival from cancer‐registry data, sometimes called “relative‐survival methods,” provide biased estimates. Meanwhile, an unbiased estimator, the Pohar‐Perme estimator (PPE), was recently proposed. Using real data, we investigated the magnitude of the errors made by four “relative‐survival” methods (Ederer I, Hakulinen, Ederer II and a univariable regression model) vs. PPE as reference and examined the influence of time of follow‐up, cancer prognosis, and age on the errors made. The data concerned seven cancer sites (2,51,316 cases) collected by FRANCIM cancer registries. Net survivals were estimated at 5, 10 and 15 years postdiagnosis. At 5 years, the errors were generally small. At 10 years, in good‐prognosis cancers, the errors made in nonstandardized estimates with all classical methods were generally great (+2.7 to +9% points in prostate cancer) and increased in age‐class estimations (vs. 5‐year ones). At 15 years, in bad‐ or average‐prognosis cancers, the errors were often substantial whatever the nature of the estimation. In good‐prognosis cancers, the errors in nonstandardized estimates of all classical methods were great and sometimes very important. With all classical methods, great errors occurred in age‐class estimates resulting in errors in age‐standardized estimates (+0.4 to +3.2% points in breast cancer). In estimating net survival, cancer registries should abandon all classical methods and adopt the new Pohar‐Perme estimator.

Unbiased estimates of long-term net survival of hematological malignancy patients detailed by major subtypes in France.

Long‐term population‐based survival data detailed by cancer subtype are important to measure the overall outcomes of malignancy managements. We provide net survival estimates at 1, 3, 5 and 10‐year postdiagnosis on 37,549 hematological malignancy (HM) patients whose ages were >15 years, diagnosed between 1989 and 2004 and actively followed until 2008 by French population‐based cancer registries. These are, to our knowledge, the first unbiased estimates of 10‐year net survival in HMs detailed by subtypes. HMs were classified according to the International Classification of Diseases‐Oncology 3. Net survival was estimated with the unbiased Pohar‐Perme method. The results are reported by sex and age classes. The changes of these indicators by periods of diagnosis were tabulated and the trends of the net mortality rates over time since diagnosis graphed. In all, 5‐ and 10‐year age‐standardized net survivals after HMs varied widely from 81 and 76% for classical Hodgkin lymphoma (CHL) to 18 and 14% for acute myeloid leukemia (AML). Even in HMs with the most favorable prognoses, the net survival decreased between 5‐ and 10‐year postdiagnosis. Women had better prognoses than men and age at diagnosis was an unfavorable prognostic factor for most HMs. In patients <55 years old, the net mortality rate decreased to null values 5‐year postdiagnosis in AML and 10‐year postdiagnosis in CHL, precursor non‐HL, chronic myelogenous leukemia, diffuse large B‐cell lymphoma and follicular lymphoma. The prognoses improved for various HMs over the study period. The obtained unbiased indicators are important to evaluate national cancer plans.

Impact of variability in adherence to HIV antiretroviral therapy on the immunovirological response and mortality

BackgroundSeveral previous studies have shown relationships between adherence to HIV antiretroviral therapy (ART) and the viral load, the CD4 cell count, or mortality. However, the impact of variability in adherence to ART on the immunovirological response does not seem to have been investigated yet.MethodsMonthly adherence data (November 1999 to April 2009) from 317 HIV-1 infected patients enrolled in the Senegalese ART initiative were analyzed. Latent-class trajectory models were used to build typical trajectories for the average adherence and the standardized variance of adherence. The relationship between the standardized variance of adherence and each of the change in CD4 cell count, the change in viral load, and mortality were investigated using, respectively, a mixed linear regression, a mixed logistic regression, and a Cox model with time-dependent covariates. All the models were adjusted on the average adherence.ResultsThree latent trajectories for the average adherence and three for the standardized variance of adherence were identified. The increase in CD4 cell count and the increase in the percentage of undetectable viral loads were negatively associated with the standardized variance of adherence but positively associated with the average adherence. The risk of death decreased significantly with the increase in the average adherence but increased significantly with the increase of the standardized variance of adherence.ConclusionsThe impacts of the level and the variability of adherence on the immunovirological response and survival justify the inclusion of these aspects into the process of patient education: adherence should be both high and constant.