Raphael Porcher

Quadriceps strength predicts mortality in patients with moderate to severe Chronic Obstructive Pulmonary Disease

Background: Prognosis in chronic obstructive pulmonary disease (COPD) is poorly predicted by indices of air flow obstruction, because other factors that reflect the systemic nature of the disease also influence prognosis. Objective: To test the hypothesis that a reduction in quadriceps maximal voluntary contraction force (QMVC) is a useful predictor of mortality in patients with COPD. Methods: A mortality questionnaire was sent to the primary care physician of 184 patients with COPD who had undergone quadriceps strength measurement over the past 5 years. QMVC was expressed as a percentage of the patient’s body mass index. The end point measured was death or lung transplantation, and median (range) follow-up was 38 (1–54) months. Results: Data were obtained for 162 patients (108 men and 54 women) with a mean (SD) percentage of forced expiratory volume in 1 s (FEV1) predicted of 35.6 (16.2), giving a response rate of 88%. Transplant-free survival of the cohort was 93.5% at 1 year and 87.1% at 2 years. Cox regression models showed that the mortality risk increased with increasing age and with reducing QMVC. Only age (HR 1.72 (95% CI 1.14 to 2.6); p = 0.01) and QMVC (HR 0.91 (95% CI 0.83 to 0.99); p = 0.036) continued to be significant predictors of mortality when controlled for other variables in the multivariate analysis. Conclusion: QMVC is simple and provides more powerful prognostic information on COPD than that provided by age, body mass index and forced expiratory volume in 1 s.

Rituximab efficacy and safety in adult splenectomy candidates with chronic immune thrombocytopenic purpura - results of a prospective multicenter phase 2 study

Whether rituximab could effectively and safely avoid splenectomy for adults with chronic immune thrombocytopenic purpura (ITP) remains unresolved. A multicenter, prospective, open-label, single-arm, phase 2 trial was conducted to assess rituximab safety and efficacy in adult splenectomy candidates with chronic ITP. Sixty patients with chronic (>or= 6 months) ITP and platelet counts less than 30 x 10(9)/L received a weekly intravenous infusion of rituximab (375 mg/m(2)) for 4 weeks. All other ITP treatments were stopped. A good response was defined as a platelet count 50 x 10(9)/L or more, with at least a doubling of the initial value at 1 and 2 years after the first rituximab infusion. Patients who required another treatment during follow up were considered nonresponders. Sixteen patients experienced transient side effects that necessitated treatment discontinuation for only 1. Good 1-year responses were obtained in 40% of the patients (24/60 [95% confidence interval: 28%-52%]). At 2 years, 33.3% (20/60 patients) had good responses and 6.7% (4/60) had sustained platelet counts of 30 x 10(9)/L or more without treatment. Thirty-six (60%) patients failed to respond; 25 underwent splenectomy. Based on these results, rituximab was an apparently safe and effective splenectomy-avoiding option in some adults with chronic ITP. This trial is registered at http://clinicaltrials.gov as NCT00225875.

Identification of Prognostic Factors in 61 Patients With Posttransplantation Lymphoproliferative Disorders

PURPOSE Prognostic studies of posttransplantation lymphoproliferative disorders (PTLDs) are hindered by the small number of cases at each transplant center. We analyzed prognostic factors and long-term outcome according to clinical manifestations, pathologic features, and treatment and investigated the prognostic value of the non-Hodgkins lymphoma International Prognostic Index (IPI) in 61 patients with PTLD. PATIENTS AND METHODS We studied 61 patients in two institutions who developed PTLD and analyzed factors influencing the complete remission and survival rates. RESULTS In univariate analysis, factors predictive of failure to achieve complete remission were performance status (PS) > or = (P =.0001) and nondetection of Epstein-Barr virus (EBV) in the tumor (P =.01). Only a negative link with PS > or = 2 was observed in multivariate analysis. In univariate analysis, factors predictive of lower survival were PS > or = 2, the number of sites (one v > one), primary CNS localization, T-cell origin, monoclonality, nondetection of EBV, and treatment with chemotherapy. The IPI failed to identify a patient subgroup with better survival and was less predictive of the response rate than was a specific index using two risk factors (PS and number of involved sites), which defined three groups of patients: low-risk patients whose median survival time has not yet been reached, intermediate-risk patients with a median survival time of 34 months, and high-risk patients with a median survival time of 1 month. CONCLUSION PS and the number of involved sites defined three risk groups in our population. The value of these prognostic factors needs to be confirmed in larger cohorts of patients treated in prospective multicenter studies.

Prospective evaluation of a 21-sample needle biopsy procedure designed to improve the prostate cancer detection rate.

OBJECTIVES To evaluate prospectively the diagnostic yield of a 21-sample ultrasound-guided needle biopsy procedure for prostate cancer in patients with elevated serum prostate-specific antigen and/or abnormal digital rectal examination findings. METHODS Between December 2000 and May 2002, 303 patients underwent 21-sample needle biopsy under local anesthesia, comprising sextant biopsies at a 45 degrees angle, 3 biopsies in each peripheral zone at an 80 degrees angle, 3 biopsies in each transition zone (TZ), and 3 biopsies in the midline peripheral zone. Morbidity was assessed clinically. A short questionnaire was filled out by 90 consecutive patients. RESULTS The cancer detection rate using 6 biopsy samples (sextant biopsies only), 12 samples (sextant plus lateral biopsies), 18 samples (sextant plus lateral plus TZ biopsies), and 21 samples (sextant plus lateral plus TZ, plus midline biopsies) was 22.7%, 28.3%, 30.7%, and 31.3%, respectively. The 21-sample procedure statistically improved the cancer detection rate by 37.9% relative to the 6-sample procedure. The improvement was most marked in patients with a prostate volume of more than 40 cm(3) (48.3%), patients with Stage T1c prostate disease (44.9%), patients undergoing repeat biopsy (66.2%), and patients with prostate-specific antigen levels greater than 10 ng/mL (38.5%). Adverse effects were infrequent (3%), consisting of prostatitis in 3 patients, acute urinary retention in 6 patients, and rectal bleeding requiring hospitalization in 1 patient taking aspirin. Using the questionnaire, 84% of patients reported macroscopic hematuria for an average of 3.4 days and hematospermia for 12.8 days, and 45% reported minor rectal bleeding lasting 1.1 days. The mean pain score, with a visual analog scale ranging between 0 (no pain) and 10 (intense pain), was 4.56. CONCLUSIONS A 21-sample needle biopsy procedure increased the prostate cancer detection rate relative to a 6-sample procedure, without increasing morbidity. Patients with elevated prostate-specific antigen values should undergo sextant biopsies and at least 6 additional biopsies in the peripheral zone and 6 in the TZ.

Kinetics of Response to Long-Term Treatment Combining Pentoxifylline and Tocopherol in Patients With Superficial Radiation-Induced Fibrosis

PURPOSE Significant regression of radiation (RT) -induced fibrosis (RIF) has been achieved after treatment combining pentoxifylline (PTX) and alpha-tocopherol (vitE). In this study, we focus on the maximum response, how long it takes to achieve response, and changes after treatment discontinuation. PATIENTS AND METHODS Measurable superficial RIF was assessed in patients treated by RT for breast cancer in a long-treatment (24 to 48 months) PTX-vitE (LPE) group of 37 patients (47 RIFs) and in a short-treatment (6 to 12 months) PTX-vitE (SPE) group of seven patients (eight RIFs). Between April 1995 and April 2000, women were treated with a daily combination of PTX (800 mg) and VitE (1,000 IU). RESULTS Combined PTX-vitE was continuously effective and resulted in exponential RIF surface area regression (-46% for LPE and -68% for SPE at 6 months, -58% for LPE and -69% for SPE at 12 months, -63% for LPE and -62% for SPE at 18 months, and -68% for LPE at 24 and 36 months). The mean estimated maximal treatment effect was 68% RIF surface area regression. The mean time to this effect was 24 months and was shorter (16 months) in more recent RIF (< 6 years since RT) than in older RIF (28 months; P = .0003). Symptom severity (Subjective Objective Medical Management and Analytic Evaluation score) was halved in both groups. After treatment discontinuation, mean RIF surface area at 1 year had increased by +40% in the SPE group (rebound) and +8.5% in the LPE group. CONCLUSION Under combined PTX-vitE treatment, RIF regression was exponential, with a two-thirds maximum response after a mean of 2 years. There was a risk of a rebound effect if treatment was too short. Long treatment (>/= 3 years) is recommended in patients with severe RIF.

Factors affecting lymphocyte subset reconstitution after either related or unrelated cord blood transplantation in children - a Eurocord analysis

Immune recovery after cord blood transplantation (CBT) is of concern owing to the low number of lymphocytes transferred with the graft and their immaturity. Risk factors influencing lymphocyte subset reconstitution related to disease, patient, donor and transplant were studied in 63 children (< 16 years), given either related (n = 14) or unrelated (n = 49) CBT for malignant (n = 33) or non‐malignant diseases (n = 30). Only children with sustained myeloid engraftment were analysed. Absolute numbers of T (CD3+, CD4+, CD8+), B and natural killer (NK) cells were reported 2–3, 6, 9, 12 and 12–24 months after CBT. Median patient age was 4·0 years (0–15) and median follow‐up was 23 months (1·7–61·0). Twenty‐six patients received human leucocyte antigen (HLA)‐matched CBT and 37 received HLA‐mismatched CBT. The median number of nucleated cells (NCs) collected/recipient weight was 6·1 × 107/kg. In this selected population, the estimate 2 year survival was 85%. Lymphocyte reconstitution (defined as the median time to reach the normal value of age‐matched healthy children) was 3, 6 and 8 months for NK, B and CD8+ cells, while it was 11·7 months for both CD3+ and CD4+ lymphocytes. In the multivariate analysis, factors favouring T‐cell recovery were: related donor (P = 0·002); higher NCs/kg (P = 0·005) and recipient cytomegalovirus (CMV)‐positive serology (P = 0·04). Presence of acute graft‐versus‐host disease (GVHD) delayed T‐cell recovery (P = 0·04). To summarize, in children with sustained myeloid engraftment the concern that lymphocyte recovery after CBT could be delayed does not appear to be substantiated by our results.

Survival after bilateral versus single-lung transplantation for idiopathic pulmonary fibrosis.

Context Patients with end-stage lung disease caused by idiopathic pulmonary fibrosis often have bilateral lung transplantation, but the benefits of this procedure over single-lung transplantation are unclear. Contribution In this comparison of outcomes for patients who received 1 or 2 lungs, overall survival did not differ but causes of death did. Bilateral transplantation seemed to increase mortality in the first year and decrease mortality thereafter. Caution Unmeasured variables associated with transplantation might have contributed to the studys findings. Implication Single and bilateral lung transplantation carry different short- and long-term benefits and harms for patients with idiopathic pulmonary fibrosis. The Editors Idiopathic pulmonary fibrosis (IPF) often progresses to end-stage lung disease and is the second most common reason for lung transplantation (1, 2), accounting for more than 25% of lung transplantation procedures (2). The procedure can involve single or bilateral lung transplantation (13). Single-lung transplantation was considered the procedure of choice after the first report of successful transplantation for patients with IPF by the Toronto Group (4, 5). However, patients with IPF are having bilateral lung transplantation with greater frequency, and the procedure now accounts for almost 50% of all lung transplantations in patients with IPF (2). The reason for this progressive shift toward bilateral transplantation is unclear. Because no randomized, controlled studies have addressed this issue, current evidence comes from observational studies and yields conflicting results (69). Using data from the United Network for Organ Sharing (UNOS), we aimed to compare survival rates after single and bilateral lung transplantation for patients with IPF by using multivariate model risk adjustment, propensity score risk adjustment, and propensity-based matching techniques to account for confounding factors. Methods Patients The UNOS supplied all data as a standard analysis and research file, based on Organ Procurement and Transplantation Network data as of February 2009, and included coded transplant-center identifiers. The registry contains data on all patients who had lung transplantation in the United States since the registrys inception in 1987. Before May 2005, recipients were allocated organs on the basis of wait-list times. Since May 2005, priority on the waiting list has been determined by the Lung Allocation Score, which ranks patients according to the difference between survival benefit and survival on the waiting list (10). All adult patients were eligible for the study if they had cadaveric single or bilateral lung transplantation for IPF (code 1604 of the UNOS data set) and the date of transplantation, date of last follow-up, and vital status at last follow-up were known. We collected data on donor, surgery, and recipient characteristics at the time of transplantation from the UNOS registry. We excluded variables for which data were sparse or those that described clinically uncommon or rare characteristics, and we calculated several variables from those that were available (such as donor and recipient body mass indexes and mismatches of sex and blood type). The Appendix Table lists the variables we included in the analyses. Appendix Table. Variables Tested for Association With Survival After Lung Transplantation Outcomes The primary outcome was recipient survival. We assessed cause of death of the lung recipient as a secondary end point. Statistical Analysis We adjusted for confounding factors by using multivariate model risk adjustment, propensity-score risk adjustment, and matching on the propensity score. Multivariate model risk adjustment is a conventional modeling approach that incorporates all known confounders, including interactions, into a regression model. Controlling for these confounders produces a risk-adjusted treatment effect and removes overt bias due to these factors. We used Cox proportional hazards regression models to compare mortality rates between the single and bilateral lung transplantation groups, adjusted for covariates. We used purposeful selection of covariates, as described by Hosmer and Lemeshow (11), to select the multivariate model. The first step was the inclusion of all variables significant at the 20% level in the bivariate analysis, as well as all variables known to be clinically relevant (12). The second step was to remove, one by one, variables that did not significantly contribute to the multivariate model on the basis of the Wald test P value and the change in the coefficient of the remaining variables. We assessed the scale of the continuous covariates by using residual analysis (13). We only considered first-order interactions with surgical procedure. We took transplant center effects into account by including centers in the multivariate analyses as a random effect with a Gaussian distribution. Residual plots supported a linear relation between all continuous covariates and the log hazard for death. No significant interaction was retained in the final model; interactions between age at transplantation and procedure and between systolic pulmonary artery pressure and procedure were not significant. The final model included recipient variables (age, body mass index, functional status, and mean pulmonary artery pressure), donor variables (body mass index and cytomegalovirus status), and procedure-related variables (transplantation year, surgical procedure, lung transplantation center, and lung transplantation center volume). In our analyses of cause of death, we used the cumulative incidence estimator and the proportional subdistribution hazard model described by Fine and Gray (14) to account for competing causes. Propensity scores estimate the probability that a patient with specific pretreatment characteristics will receive a treatment, in this case bilateral rather than single-lung transplantation (15, 16). Within propensity score strata, covariates in both groups tend to be similarly distributed. We computed propensity scores by using logistic regression, in which surgical procedure was the dependent variable and the variables listed in the Appendix Table were independent variables. We judged the success of the propensity score modeling by assessing balance on baseline characteristics within deciles of propensity score or after matching propensity scores for patients in the single and bilateral lung transplantation groups, and found balanced distribution of variables within deciles. We used Cox proportional hazards regression to estimate the effect of bilateral lung transplantation on survival, adjusting for the propensity score (on the linear predictor scale) and surgical procedure. In another analysis, we took only data with propensity score overlap into account and adjusted the estimates on the deciles of the propensity score. We used a 1:1 matching algorithm without replacement to match patients, with calipers defined to have a maximum width of 0.25 SD of the logit of the estimated propensity score. We used marginal Cox models, accounting for correlation within matched pairs, to compare the single and bilateral lung transplantation groups in terms of adjusted survival (17). We used several statistical methods to assess whether the effect of surgical procedure was constant over time (proportional hazards assumption), including residual plots (as described by Grambsch and Therneau [18]) and fitting of additive regression models (as described by Aalen [19]). For variables involved in the multivariate model risk adjustment and propensity score analysis, we imputed missing data by using the multiple imputations by chained equation method (20), which resulted in 20 imputed data sets. We independently analyzed each of the 20 data sets. We averaged estimates of the variables to give a single mean estimate and adjusted SEs according to the Rubin rules (2022). The Appendix lists the steps of the imputation procedure. All analyses were performed by using R, version 2.5 (R Foundation for Statistical Computing, Vienna, Austria), and Stata, version 10.2 (StataCorp, College Station, Texas), for Windows XP. Propensity-score matching was done by using the Matching package for R. Role of the Funding Source This study received no funding. The authors had full access to all data in the study and had final responsibility for the decision to submit for publication. Results The UNOS database included data for 33252 patients registered on a waiting list for lung transplantation in the United States during the study period; 18333 (55.1%) had lung transplantation. Of these, 3411 (18.6%) had received a diagnosis of IPF at the time of transplantation. We excluded 11 patients who received grafts from nonheart-beating donors, 25 patients who were younger than 18 years at the time of transplantation, and 48 patients whose survival time was unknown. The final analysis included the remaining 3327 patients who had lung transplantation in 88 U.S. centers (median, 120 lung transplantations per center [25th to 75th percentile, 22 to 323 transplantations per center]). The number of patients who had lung transplantation for IPF increased over time, from 59 in 1992 to 409 in 2008; 2146 (64.5%) had single-lung transplantation and 1181 (35.5%) had bilateral lung transplantation. The proportion of patients who had bilateral lung transplantation also increased over time, from 6 of 59 total procedures (10.2%) in 1992 to 223 of 409 procedures (54.5%) in 2008 (Appendix Figure 1). Appendix Figure 2 shows the proportion of bilateral lung transplantation by transplant-ation center volumes for IPF and all indications and suggests that high-volume centers were more likely than low-volume centers to perform bilateral lung transplantation. Appendix Figure 1. Rates of single and bilateral lung transplantation over time in patients with idiopathic pulmonary fibrosis. Data are from the United

Individual Smallest Detectable Difference in Bone Mineral Density Measurements

Bone mineral density (BMD) measurement is a major outcome measure in osteoporosis. The BMD changes observed must exceed the variability inherent in the measurement process to be considered related to disease progression. The objective of the study was to estimate short‐term variability of BMD measurement and to propose a cut‐off value for the smallest detectable BMD changes for an individual. To estimate the short‐term variability, 70 healthy postmenopausal women aged 53 ± 4 years (group 1) and 57 elderly osteoporotic postmenopausal women aged 80 ± 6 years (group 2) had two repeated BMD measurements of the lumbar spine (L2–L4) and the proximal femur with dual‐energy X‐ray absorptiometry, with complete repositioning within 1 h. Cut‐offs derived from short‐term variability were either estimated from the coefficient of variation (CV) (which is a function of the measured value) or from the standard deviation (SD), and applied to 330 postmenopausal women (group 3) who had BMD measurements at baseline and 2 years later. The short‐term intrasubject variability was greater at the lumbar spine in group 2 versus group 1 (0.0123 vs. 0.0059 g/cm2, p < 10–4), whereas it was not at the femoral neck (0.0098 vs. 0.0076 g/cm2, p = 0.28). There was no statistically significant correlation between short‐term intrasubject variability (SD) and BMD as demonstrated with an analysis of covariance (p values ranging from 0.17 to 0.90). Cut‐offs estimated with SD and CV were individually applied to group 3 patients. Using these two cut‐offs, discrepancies in assessment of progression were observed in 1.7–8.6% of cases. Short‐term BMD variability is constant in a wide range of BMD values. Consequently, to determine cut‐off values for the smallest detectable differences in BMD at the individual level, precision errors should be based on SD (expressed in absolute units) rather than on CV (expressed in percentage).

Quantitative and individualized assessment of the learning curve using LC-CUSUM.

Current methods available for assessing the learning curve, such as a predefined number of procedures or direct observation by a tutor, are unsatisfactory. A new tool, the cumulative summation test for learning curve (LC‐CUSUM), has been developed that allows quantitative and individual assessment of the learning curve.

Long-Term Impact of a Multifaceted Prevention Program on Ventilator-Associated Pneumonia in a Medical Intensive Care Unit

BACKGROUND Ventilator-associated pneumonia (VAP), the most common hospital-acquired infection in intensive care units, increases mortality and health care costs. We describe the long-term impact of a multifaceted program for decreasing VAP rates that markedly improved compliance with 8 targeted preventive measures. METHODS We compared VAP rates during a 45-month baseline period and a 30-month intervention period in a cohort of patients who received mechanical ventilation for > 48 h. VAP was diagnosed on the basis of quantitative cultures of distal specimens. VAP incidence density rates were expressed as total VAP episodes over total mechanical ventilation duration and as first VAP episodes over mechanical ventilation duration at VAP or hospital discharge. We used segmented regression analysis and a Cox proportional hazard model to assess the impact of the program on first VAP occurrence. RESULTS Baseline and intervention VAP rates were 22.6 and 13.1 total VAP episodes over total mechanical ventilation duration per 1000 ventilation-days, respectively, and 26.1 and 14.9 first VAP episodes over mechanical ventilation duration at VAP or hospital discharge per 1000 procedure-days, respectively (P < .001). VAP rates decreased by 43% in both statistical analyses and remained significant after adjustment for confounders (Cox adjusted hazard ratio, 0.58; 95% confidence interval, 0.46-0.72; P < .001). Daily VAP hazard rates on ventilation days 5, 10, and 15 were 2.6%, 3.5%, and 3.4%, respectively, during the baseline period and 1.4%, 2.3%, and 2%, respectively, during the intervention period. CONCLUSION Our preventive program produced sustained VAP rate decreases in the long term. However, VAP rates remained substantial despite high compliance with preventive measures, suggesting that eliminating VAP in the intensive care unit may be an unrealistic goal.