Is alpha-fetoprotein decline a prognostic factor of childhood non-seminomatous germ cell tumours? Results of the French TGM95 study.

PURPOSE: In adults' non-seminomatous germ cell tumours (NS-GCT), alpha-fetoprotein (AFP) decline was identified as an important prognostic factor. We investigated its prognostic value in the French TGM95 study for childhood NS-GCT. PATIENTS AND METHODS: Three risk groups were defined: low risk (LR: localised and completely resected pS1, AFP<15000 ng/ml), with a 'wait-and-see' strategy; intermediate-risk (IR: localised incompletely resected, AFP<15000 ng/ml) with 3-5 vinblastine-bleomycine-cisplatin courses; high risk (HiR: AFP≥15000 ng/ml and/or metastatic) with 4-6 etoposide-ifosfamide-cisplatin courses. The multivariable prognostic analysis for progression-free survival (PFS) included age (±10 years), primary tumour site (1-testis, 2-ovary, 3-extragonadal), extent of disease (1-pS1, 2-loco-regional dissemination, 3-metastasis) and AFP (±10,000 ng/ml). AFP decline prognostic value was investigated in IR + HiR groups using predicted time to normalisation (TTN), AFP change, and difference between observed and expected (based on AFP half-life) area under the curve (O-E AUC). RESULTS: From January 1995 to December 2005, 239 patients (median age = 3years, 60 LR, 65 IR, 114 HiR) were included. Main sites were testis (n = 66), ovary (n = 77) and sacrococcygeal (n = 57). Five-year PFS and OS were 85% (95% confidence interval [CI] = 80-89%) and 93% (89-95%), respectively. Age ≥ 10 years (hazard ratio [HR] = 4.6, 95% CI = 2.1-10.1, p = 0.0001) and extragonadal primary (HR = 6.3, 95% CI = 2.0-19.9, p = 0.005) were significant prognostic factors. In AFP decline analysis (n = 151, 17 events), TTN (p = 0.61) and AFP change (p = 0.10) were not prognostic, whereas we showed a significant effect of O-E AUC (HR = 2.1, 95% CI = 1.0-4.2, p = 0.05). CONCLUSION: Age ≥ 10 years and extragonadal tumours remain as poor prognostic factors. Contrary to adults, TTN is not reliable in paediatric NS-GCT. The prognostic value of O-E AUC should be investigated in larger studies.

Patterns of relapse in poor-prognosis germ-cell tumours in the GETUG 13 trial: Implications for assessment of brain metastases.

BACKGROUND: The GETUG 13 phase III trial tested personalised chemotherapy based on tumour marker decline in patients with poor-prognosis germ-cell tumour (GCT) and demonstrated that a dose-dense regimen improves progression-free survival in patients with an unfavourable decline. We investigated the pattern of relapse for patients included in GETUG 13. METHODS: We conducted an analysis of relapse events in patients from GETUG 13. Baseline procedures before inclusion in the trial comprised a thoraco-abdomino-pelvic computed tomography scan and a magnetic resonance imaging of the brain. RESULTS: With a median follow-up of 4.1 years (0.3; 8.8 years), a progression event was observed in 109/254 patients (43%). First event consisted in a marker progression only in 47 patients (43%), a radiographic progression only in 35 patients (32%), a mix progression on both markers and imaging in 12 patients (11%) and death in 15 patients (14%). In patients with radiographic progression only, brain was the predominant site (n = 19/35, 54%). Among patients with unfavourable decline who experienced a radiographic progression (as first and subsequent progression event, n = 58), brain was a site of progression in 28 patients (48%): 12/30 (40%) in patients treated with cisplatin, bleomycin and etoposide and 16/28 (57%) in those treated with dose-dense chemotherapy. CONCLUSIONS: Brain metastases develop often, early and frequently as the only site of relapse in the course of poor-prognosis GCT. This raises the question of early detection and optimal treatment of brain metastases in these patients, e.g. by integrating a systematic brain MRI after 2-3 months of chemotherapy.

Reassessing the clinical spectrum associated with hereditary leiomyomatosis and renal cell carcinoma syndrome in French FH mutation carriers.

We addressed uncertainties regarding hereditary leiomyomatosis and renal cell carcinoma (HLRCC) by exploring all French cases, representing the largest series to date. Fumarate hydratase (FH) germline testing was performed with Sanger sequencing and qPCR/MLPA. Enzyme activity was measured when necessary. We carried out whenever possible a pathology review of RCC and S-(2-succino)-cysteine (2SC)/fumarate hydratase immunohistochemistry. We estimated survival using non-parametric Kaplan-Meier. There were 182 cases from 114 families. Thirty-seven RCC were diagnosed in 34 carriers (19%) at a median age of 40. Among the 23 RCC with pathology review, 13 were papillary type 2. There were 4 papillary RCC of unspecified type, 3 unclassified, 2 tubulocystic, and 1 collecting duct (CD) RCC, all 2SC+ and most (8/10) FH-. Of the remaining 14, papillary type 2, papillary unspecified, CD, and clear cell histologies were reported. The vast majority of RCC (82%) were metastatic at diagnosis or rapidly became metastatic. Median survival for metastatic disease was 18 months (95%CI: 11-29). 133 cases (73%) had a history of cutaneous leiomyomas, 3 developed skin leiomyosarcoma. Uterine leiomyomas were frequent in women (77%), but no sarcomas were observed. Only 2 cases had pheochromocytomas/paraganglioma. CONCLUSION: Our findings have direct implications regarding the identification and management of HLRCC patients.

PD-L1 protein expression assessed by immunohistochemistry is neither prognostic nor predictive of benefit from adjuvant chemotherapy in resected non-small cell lung cancer.

Background: The expression of programmed death (PD) ligand 1 (PD-L1) protein expression assessed by immunohistochemistry (IHC) has been correlated with response and survival benefit from anti-PD-1/PD-L1 immune checkpoint inhibitor therapies in advanced non-small cell lung carcinoma (NSCLC). The efficacy of several agents appears correlated with PD-L1 expression. It remains controversial whether PD-L1 is prognostic in NSCLC. We assessed the prognostic value of PD-L1 IHC and its predictive role for adjuvant chemotherapy in early stage NSCLC. Patients and methods: Tumor sections from three pivotal adjuvant chemotherapy trials (IALT, JBR.10, CALGB 9633) using the E1L3N antibody were studied in this pooled analysis. PD-L1 staining intensity and percentage in both tumor cells (TCs) and immune cells (ICs) were scored by two pathologists. The average or consensus PD-L1 expression levels across intensities and/or percent cells stained were correlated with clinicopathological and molecular features, patient survivals and potential benefit of adjuvant chemotherapy. Results: Results from 982 patients were available for analysis. Considering staining at any intensities for overall PD-L1 expression, 314 (32.0%), 204 (20.8%) and 141 (14.3%) tumor samples were positive for PD-L1 staining on TCs using cut-offs at ≥1%, ≥10% and ≥25%, respectively. For PD-L1 expressing ICs, 380 (38.7%), 308 (31.4%) and 148 (15.1%) were positive at ≥ 1%, ≥10% and 25% cut-offs, respectively. Positive PD-L1 was correlated with squamous histology, intense lymphocytic infiltrate, and KRAS but not with TP53 mutation. EGFR mutated tumors showed statistically non-significant lower PD-L1 expression. PD-L1 expression was neither prognostic with these cut-offs nor other exploratory cut-offs, nor were predictive for survival benefit from adjuvant chemotherapy. Conclusions: PD-L1 IHC is not a prognostic factor in early stage NSCLC patients. It is also not predictive for adjuvant chemotherapy benefit in these patients.

Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study).

BACKGROUND: A marginal interaction between sex and the type of alkylating agent was observed for event-free survival in the Euro-EWING99-R1 randomized controlled trial (RCT) comparing cyclophosphamide and ifosfamide in Ewing sarcoma. To further evaluate this interaction, we performed an individual patient data meta-analysis of RCTs assessing cyclophosphamide versus ifosfamide in any type of cancer. METHODS: A literature search produced two more eligible RCTs (EICESS92 and IRS-IV). The endpoints were progression-free survival (PFS, main endpoint) and overall survival (OS). The hazard ratios (HRs) of the treatment-by-sex interaction and their 95% confidence interval (95% CI) were assessed using stratified multivariable Cox models. Heterogeneity of the interaction across age categories and trials was explored. We also assessed this interaction for severe acute toxicity using logistic models. RESULTS: The meta-analysis comprised 1,528 pediatric and young adult sarcoma patients from three RCTs: Euro-EWING99-R1 (n = 856), EICESS92 (n = 155), and IRS-IV (n = 517). There were 224 PFS events in Euro-EWING99-R1 and 200 in the validation set (EICESS92 + IRS-IV), and 171 and 154 deaths in each dataset, respectively. The estimated treatment-by-sex interaction for PFS in Euro-EWING99-R1 (HR = 1.73, 95% CI = 1.00-3.00) was not replicated in the validation set (HR = 0.97, 95% CI = 0.55-1.72), without heterogeneity across trials (P = 0.62). In the pooled analysis, the treatment-by-sex interaction was not significant (HR = 1.31, 95% CI = 0.89-1.95, P = 0.17), without heterogeneity across age categories (P = 0.88) and trials (P = 0.36). Similar results were observed for OS. No significant treatment-by-sex interaction was observed for leucopenia/neutropenia (P = 0.45), infection (P = 0.64), or renal toxicity (P = 0.20). CONCLUSION: Our meta-analysis did not confirm the hypothesis of a treatment-by-sex interaction on efficacy or toxicity outcomes.

[Individual patient data meta-analyses of randomized trials for the treatment of non-metastatic head and neck squamous cell carcinomas: Principles, results and perspectives]. / Méta-analyses d'essais randomisés sur données individuelles dans le traitement des cancers ORL non métastatiques : principes, résultats, perspectives.

Meta-analyses are considered as an important pillar of evidence-based medicine. The aim of this review is to describe the main principles of a meta-analysis and to use examples of head and neck oncology to demonstrate their clinical impact and methodological interest. The major role of individual patient data is outlined, as well as the superiority of individual patient data over meta-analyses based on published summary data. The major clinical breakthrough of head and neck meta-analyses are summarized, regarding concomitant chemotherapy, altered fractionated chemotherapy, new regimens of induction chemotherapy or the use of radioprotectants. Recent methodological developments are described, including network meta-analyses, the validation of surrogate markers. Lastly, the future of meta-analyses is discussed in the context of personalized medicine.

Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma.

BACKGROUND: To examine the association between hypertension (HTN), angiotensin system inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU). METHODS: We retrospectively reviewed all patients with mRCC who received SU as first-line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre-existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HRs) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, International mRCC Database Consortium risk group and histology. RESULTS: Among 213 patients with a 3.6-year median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the two exposures (P < 0.0001). Hypertensive patients have longer OS (median: 41.6 versus 16.4 months, P < 0.0001) and longer PFS (median: 12.9 versus 5.6 months, P < 0.0001) than non-hypertensive patients (n = 79). ASI users (n = 105) had more HTN_PRE compared with those (n = 108) who did not (65% versus 19%, P < 0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (P = 0.05) and marginally with PFS (P = 0.06) while ASI intake was significantly associated with better OS [HR = 0.40; 95% CI (0.24-0.66), P < 0.001] and PFS [HR = 0.55 (0.35-0.86), P = 0.009]. The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment. CONCLUSION: Concomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients.

Efficacy of phase 1 trials in malignant pleural mesothelioma: description of a series of patients at a single institution.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a locally aggressive disease with a poor prognosis. After failure of first line platinum-based chemotherapy, there is no widely approved salvage regimen. New strategies for treatment are needed and phase 1 trials appear as a rationale alternative. MATERIALS AND METHODS: MPM patients were enrolled in 20 different phase 1 trials between March 2005 and January 2012, and their data analyzed retrospectively. The primary endpoint was response rate and secondary endpoints were toxicity profile, overall survival (OS) and progression free survival (PFS). OS and PFS were estimated using Kaplan-Meier and their association with baseline characteristics was investigated through a log-rank test. The drugs described were divided into 5 groups based on their mechanism of action. RESULTS: Forty-five patients were analyzed with a median follow up of 20.5 months. The best tumor response was as follows: 4% of patients had a RECIST partial response, 60% had stable disease, 24% had progressive disease and 11% were not evaluable. Grade ≥3 toxicities were observed in 19 (42%) patients. Median OS and PFS were estimated to 6 months (95% CI=[4.2-10.5]) and 2 months (95% CI=[1.3-2.7]), respectively. The cellular motility inhibitors group appeared as the most promising class to be developed in a phase 2 setting. CONCLUSION: Including MPM patients in phase I trials beyond first line of treatment can result in modest clinical benefits with an acceptable toxicity profile. Several molecular pathways involved in MPM have been identified and further novel biologic therapies need to be tested.

Prediction of fluid responsiveness by a continuous non-invasive assessment of arterial pressure in critically ill patients: comparison with four other dynamic indices.

BACKGROUND: We evaluated the ability of an infrared photoplethysmography arterial waveform (continuous non-invasive arterial pressure, CNAP) to estimate arterial pulse pressure variation (PPV). We compared the ability of non-invasive PPV to predict fluid responsiveness with invasive PPV, respiratory variation of pulse contour-derived stroke volume, and changes in cardiac index induced by passive leg raising (PLR) and end-expiratory occlusion (EEO) tests. METHODS: We measured the responses of cardiac index (PiCCO) to 500 ml of saline in 47 critically ill patients with haemodynamic failure. Before fluid administration, we recorded non-invasive and invasive PPVs, stroke volume variation, and changes in cardiac index induced by PLR and by 15 s EEO. Logistic regressions were performed to investigate the advantage of combining invasive PPV, stroke volume variation, PLR, and EEO when predicting fluid responsiveness. RESULTS: In eight patients, CNAP could not record arterial pressure. In the 39 remaining patients, fluid increased cardiac index by ≥15% in 17 'responders'. Considering the 195 pairs of measurements, the bias (sd) between invasive and non-invasive PPVs was -0.6 (2.3)%. The areas under the receiver operating characteristic (ROC) curves for predicting fluid responsiveness were 0.89 (95% confidence interval, 0.78-1.01) for non-invasive PPV compared with 0.89 (0.77-1.01), 0.84 (0.70-0.96), 0.95 (0.88-1.03), and 0.97 (0.91-1.03) for invasive pulse pressure, stroke volume variations, PLR, and EEO tests (no significant difference). Combining multiple tests did not significantly improve the area under the ROC curves. CONCLUSIONS: Non-invasive assessment of PPV seems valuable in predicting fluid responsiveness.

Expression of miR-487b and miR-410 encoded by 14q32.31 locus is a prognostic marker in neuroblastoma.

BACKGROUND: Combination of age at diagnosis, stage and MYCN amplification stratifies neuroblastoma into low-risk and high-risk. We aimed to establish whether a microRNA (miRNA) signature could be associated with prognosis in both groups. METHODS: Microarray expression profiling of human miRNAs and quantitative reverse-transcriptase PCR of selected miRNAs were performed on a preliminary cohort of 13 patients. Results were validated on an independent cohort of 214 patients. The relationship between miRNA expression and the overall or disease-free survival was analysed on the total cohort of 227 patients using the log-rank test and the multivariable Cox proportional hazard model. RESULTS: A total of 15 of 17 miRNAs that discriminated high-risk from low-risk neuroblastoma belonged to the imprinted human 14q32.31 miRNA cluster and two, miR-487b and miR-410, were significantly downregulated in the high-risk group. Multivariable analyses showed miR-487b expression as associated with overall survival and disease-free survival in the whole cohort, independently of clinical covariates. Moreover, miR-487b and miR-410 expression was significantly associated with disease-free survival of the non-MYCN-amplified favourable neuroblastoma: localised (stage 1, 2 and 3) and stage 4 of infant <18 months. CONCLUSION: Expression of miR-487b and miR-410 shows predictive value beyond the classical high-/low-risk stratification and is a biomarker of relapse in favourable neuroblastoma.

Markov modelling of HIV infection evolution in the HAART era.

The aim was to investigate the impact of the main prognostic factors on HIV evolution. A multi-state Markov model was applied in a cohort of 2126 patients to estimate impact of these factors on patients' clinical and immunological evolutions. Clinical progression and immunological deterioration shared most of their prognostic factors: male gender, intravenous drug use, weight loss, low haemoglobin level (<110 g/l), CD8 cell count (<500/mm(3)) and HIV viral load (>5 log(10) copies/ml). Highly active retroviral therapy reduced the risks of clinical progression and immune deterioration whatever patients' CD4 cell count. Risk reductions were 41-60% for protease inhibitor-based and 27-68% for non-nucleoside reverse transcriptase inhibitor-based regimens. Three-year transition probabilities showed that only patients with a CD4 cell count >or=350 CD4/mm(3) could in most cases maintain their immunity. This model provides 'real life' transition probabilities from one immunological stage to another, allowing decision analyses that could help determine the beneficial therapeutic strategies for HIV-infected patients.

Clinical parameters to predict response to interferon in relapsing multiple sclerosis.

BACKGROUND: To identify clinical parameters of response to beta-interferon (IFN-beta) in relapsing-remitting multiple sclerosis (RRMS) from an East France cohort. METHODS: Data from 2,645 patients, identified by Burgundy and Lorraine multiple sclerosis (MS) networks, were computerized by a neurologist using the European Database for MS software. Patient inclusion criteria were: clinically or laboratory-supported definite RRMS according to Poser's diagnostic criteria and treatment with IFN-beta for at least 6 months. Four criteria were chosen to predict a response to IFN-beta. The first criterion was any patient who had a lower annualized relapse rate under IFN-beta therapy than during the year preceding treatment; the second criterion was a lower relapse rate than during the 2 years preceding treatment. The third was any patient free of relapse during the first 2 years of IFN-beta therapy. The last criterion concerned the variation in the degree of disability measured by the Disability Status Scale during the first year of treatment. Multivariate logistic regression analyses were performed. RESULTS: 751 RRMS cases were included. A higher relapse rate in the year preceding IFN-beta onset, an older age at MS onset and having a polysymptomatic onset of MS were significantly associated with a response for the first criterion. With the 3 other criteria, no parameter predicting response was identified. CONCLUSION: Only the relapse rate in the year before initiation of IFN-beta treatment appears to be able to predict response to treatment but not the one of 2 years before.

[A prospective auto-controlled study to evaluate the interest of selected sperm morphology to inseminate oocytes during IVF]. / Evaluation d'une procédure d'insémination des ovocytes en FIV classique tenant compte de la morphologie des spermatozoïdes sélectionnés.

OBJECTIVES: Since we observed in our laboratory a significant decrease of the fertilization rate in the classical IVF procedure compared to ICSI, we wanted to evaluate a new insemination procedure, using sperm morphology of selected semen as a criterion taken into account to calculate the number of mobile sperm to inseminate. PATIENTS AND METHODS: Therefore, we designed a prospective autocontrolled study which took place from September 2006 to May 2007. All IVF attempts resulting from infertile couples were included in the study if a previous analysis (lesser than one year) of sperm parameters performed in our laboratory was assessed as normal. The retrieved oocytes were separated into two groups (sibling ovocytes), inseminated randomly either with the usual procedure (control group) or with the tested protocol (tested group). Fertilization rate was the primary end point to evaluate this assay. Polyspermy rates were also compared. Subsequently, embryonic quality and development were assessed to eliminate an oxidative stress impact. Paired Student t-test was applied for statistical analysis. RESULTS: In all, 130 couples were included. The diploid fertilization rate was significantly increased in the tested group compared to the control group (66.9% vs 61.3%; p=0.017). No statistically significant difference was showed between the polyspermy rate and numbers of (i) good quality embryos and (ii) blastomeres per embryo into the two groups. DISCUSSION AND CONCLUSION: Compared with the conventional insemination procedure, the fertilization rate benefited from the tested insemination method in our laboratory without damaging embryonic growth. In the limit of our procedure, selected sperm morphology should be used to inseminate an appropriate number of spermatozoa within oocytes, even in case of normal semen values.

Disability evolution in multiple sclerosis: how to deal with missing transition times in the Markov model?

Markov modeling of disability progression in multiple sclerosis requires knowledge of all times of transitions from a given level of disability to the next level, but such data are often missing. We address methodological challenges due to partly missing transition times. To estimate the effects of prognostic factors on the risk of transitions between three consecutive disability levels, two methods were used to deal with missing data. Listwise deletion limited the analysis to subjects with complete data. Multiple imputation of missing data revealed that data were missing at random (MAR mechanism) and imputed the missing transition times from the Weibull model. The results were then compared with the full data set with the actual times established through chart review. Multiple imputation estimates were systematically closer to those from the full data set than the listwise deletion estimates.

The prognostic value of initial relapses on the evolution of disability in patients with relapsing-remitting multiple sclerosis.

The evolution of multiple sclerosis (MS) and the resulting disability are unpredictable. To identify clinical variables that could be potential prognostic factors, we followed a cohort of 288 patients diagnosed as having relapsing-remitting MS between 1990 and 2003. The end point was the first occurrence of a non-reversible EDMUS-GS score >or=3 (moderate disability). The impact of the number of MS attacks during the first 2 years of the disease as well as the first interattack interval were assessed in two Cox models, one using a fixed-in-time covariate, the other using a time-dependent covariate. Older age at onset and a higher number of MS attacks during the first 2 years of MS proved to be predictors of unfavourable prognosis. The first interattack interval had no influence on the evolution of the disability, conversely to the first relapse which had a short-term impact on the prognosis. We confirmed that the age at onset and the number of MS attacks during the first 2 years of MS are predictors of the evolution of the disability and demonstrated the importance of using time-dependent covariates.

A population-based assessment of the prognostic value of the CD19 positive lymphocyte count in B-cell chronic lymphocytic leukemia using Cox and Markov models.

No population-based study has assessed the prognostic impact on survival of the CD19 positive lymphocyte count, evaluated by immunophenotyping at diagnosis, in B-cell chronic lymphocytic leukemia (B-CLL). Aiming at addressing this issue, we investigated the clinical outcome of a well-defined population of B-CLL patients. Survival of B-CLL patients, diagnosed between 1990 and 1999 and recorded by the Registry of Hematological Malignancies of the Côte d'Or, was analysed applying Cox's regression model to the 237 included cases and to the 195 Binet stage A patients. To assess simultaneously the predictive value of each parameter on the risk of disease progression and on the risk of death, we completed this analysis by applying a three-states homogeneous Markov model to the whole study population. Analysis of the entire population showed that age (p < 0.001), Binet stage (p = 0.008) and CD19 positive lymphocyte count (p = 0.038) were three independent prognostic factors. However, in stage A patients, only progression into a more advanced stage, analysed as a time-dependent variable, and age had a clear impact on survival (p < 0.001 for both). Markov model revealed that an increased CD19 positive lymphocyte count increased the risk of disease progression in stage A patients (p = 0.002) but did not have direct impact on survival of either stage A patients with stable disease or stage B or C patients. An increased CD19 positive lymphocyte count at diagnosis is a marker of an increased risk of disease progression in stage A patients. Thus, it can be a useful tool for the clinical management of these patients.

Measuring the contribution of pharmacological treatment to advice to stay active in patients with subacute low-back pain: a randomised controlled trial.

PURPOSE: In clinical guidelines for acute and subacute low-back pain, pharmacological treatment is recommended for short-term symptomatic relief. The objective was to study the effect of the guidelines' advise to remain active, alone and with the addition of the drug adenosine tri-phosphate (ATP), in patients with subacute low-back pain. METHODS: A drug-guidelines effectiveness trial was undertaken simultaneously to an experimental drug efficacy placebo controlled trial in subacute (4-12 weeks) non-specific low-back pain patients. The 132 participating primary care physicians across France were randomised to participate to either trial. In the drug-guidelines trial, all physicians received a quick consultation card containing the key elements of the clinical guidelines and a brochure that gave their patients practical tips to remain active. Patients were then randomised to receive Atepadene, containing 90 mg of ATP by mouth daily for 30 days (guidelines plus ATP group), or nothing beside the rescue drug that was made available to all patients (guidelines alone group). The principal outcome was functional improvement on the Roland-Morris Disability Questionnaire (RDQ) at 90 days. RESULTS: In the drug-guidelines effectiveness trial, 157 patients were randomised. The rate of improvement in the RDQ over the 90 days of follow-up was superior in the group guidelines plus ATP (8.3 points, 95% confidence interval (CI): 7.3-9.3) than in the group guidelines alone (6.5 points, 95%CI: 5.3-7.7) (p = 0.02). In terms of probability of improving between two to five points on the RDQ at 90 days this difference translated in a 2 to 13 times higher probability compared to the group guidelines alone (odds ratios ranging from 2.1, 95%CI: 0.9-5.0 to 12.9, 95%CI: 1.6-103.4). Patients in the group guidelines plus ATP were also three times less likely to report a condition that had worsened or remained unimproved at 90 days (p = 0.02). CONCLUSION: This drug-guidelines effectiveness trial showed a modest advantage of combined specific pharmacologic and non-pharmacological treatments on absolute improvement on the RDQ. A threefold reduction in the risk of chronicity was observed, an important goal in low-back pain guidelines.

Improving model robustness with bootstrapping -- application to optimal discriminant analysis for ordinal responses (ODAO).

OBJECTIVE: Recent results published by Coste et al. in discriminant analysis with ordinal responses showed the superiority of optimal discriminating analysis for ordinal responses (ODAO) both in terms of classification and simplicity of implementation compared to classic methods (Fisher's discrimination, logistic regression) applied to medical data (prognostics of burns) and to simulated data. Nevertheless, the solutions obtained by ODAO may be sensitive to re-sampling (i.e the estimated coefficients by ODAO may show excessive sensitivity to the training sample). This study proposes some solutions to control the fluctuations of sampling and to ensure model stability. METHODS: We used intensive computational methods and bootstrapping, at the outset of model building in order to reduce the sampling variability of estimated coefficients. Thus, the estimation of the coefficients was not based on the minimization of a classification criterion of the training sample, but on the minimization of an aggregate criterion of bootstrapped replications of a classification criterion. Five aggregate criteria were studied. RESULTS: The improvement in terms of robustness appeared in 30% of the test cases with moderate training sample size and 55% of those with small training sample size. CONCLUSION: Simulated test cases showed that bootstrapping can help construct more robust models in difficult classification situations and small training samples which are particularly frequent.

Law and standards faced to market rules in health information security.

This paper presents the main differences existing in the elaboration process of law and standard and analyses their potential conflicts. It also describes the respective force of law and standards in three main areas: legal threat versus financial threat, conflict versus cooperation and finally their respective position faced to oligarchic power.