Publications by authors named "Joris Giai"

26 Publications

  • Page 1 of 1

Muscle elasticity in patients with neonatal brachial plexus palsy using shear-wave ultrasound elastography. Preliminary results.

J Pediatr Orthop B 2021 Jul;30(4):385-392

Department of Pediatric Orthopedics and Reconstructive Surgery.

Ultrasound shear wave elastography (SWE) is a noninvasive, reliable and reproducible method, used for the qualitative and quantitative evaluation of tissues. The aim of this study was to compare muscle elasticity between the healthy and the involved sides in children with neonatal brachial plexus palsy (NBPP) using the elastography tool and to assess whether the difference was correlated with the Mallet grading system. We repeatedly measured the shear modulus coefficient of several muscles around the shoulder in stretched or passively relaxed positions on 14 patients. We evaluated the abductor muscles (supraspinatus and deltoid), the infraspinatus, the pectoralis major and the latissimus dorsi. We found a mean shear modulus significantly higher in most studied muscles in the pathologic side (P < 0.001), especially in the stretched position (P < 0.001). Moreover, the shear modulus increases with the degradation of the Mallet score for the abduction and external rotation tasks. SWE seems to be a reliable and reproducible tool to assess muscle elasticity in NBPP.
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http://dx.doi.org/10.1097/BPB.0000000000000781DOI Listing
July 2021

Superselective Ischemia in Robotic Partial Nephrectomy Does Not Provide Better Long-term Renal Function than Renal Artery Clamping in a Randomized Controlled Trial (EMERALD): Should We Take the Risk?

Eur Urol Focus 2021 Apr 27. Epub 2021 Apr 27.

Urology Department, Grenoble University Hospital, Grenoble, France.

Background: Superselective clamping of tumor-targeted arteries aims to eliminate ischemia of the remnant kidney while keeping tumor bed bloodless during excision.

Objective: To evaluate the impact of superselective clamping on long-term renal function, compared with renal artery early unclamping.

Design, Setting, And Participants: A randomized monocentric single-blind trial (1:1) was conducted from February 2018 to August 2019. Patients with a single renal tumor were candidates for a robot-assisted partial nephrectomy (RAPN) in a referral center. EMERALD (NCT03679572) was powered to include 50 patients with an interim analysis after 30 cases.

Intervention: Superselective RAPN (SS-RAPN) with near-infrared fluorescence (NIRF) or conventional RAPN with renal artery early unclamping.

Outcome Measurements And Statistical Analysis: The primary endpoint was the percent change of estimated glomerular filtration rate (eGFR) in the operated kidney after 6 mo (combination of eGFR and relative function on Tc-DMSA scintigraphy). Secondary endpoints assessed feasibility and safety of the technique.

Results And Limitations: Relative eGFR reduction in the operated kidney at 6 mo did not differ significantly (-21.4% vs -23.4%, p=0.66). This absence of difference remained after adjusting on percentage of kidney volume preserved, which was an independent predictor of functional preservation. There were no significant differences in terms of blood loss, change in hemoglobin, postoperative complications, transfusion, and conversion to radical nephrectomy (two vs zero) or to open surgery (one vs zero). Despite a good accrual, the steering committee interrupted the trial after the interim analysis for futility given the absence of trend in favor of SS-RAPN.

Conclusions: SS-RAPN using NIRF does not provide better renal function preservation than renal artery clamping, questioning the interest of this technique at a higher risk of bleeding.

Patient Summary: In this randomized controlled trial, superselective clamping of tumor feeding arteries did not show any advantage in terms of long-term renal function compared with conventional artery clamping.
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http://dx.doi.org/10.1016/j.euf.2021.04.009DOI Listing
April 2021

Correcting the bias of the net benefit estimator due to right-censored observations.

Biom J 2021 Apr 22;63(4):893-906. Epub 2021 Feb 22.

Neurobiology Research Unit, Rigshospitalet, Copenhagen, Denmark.

Generalized pairwise comparisons (GPCs) are a statistical method used in randomized clinical trials to simultaneously analyze several prioritized outcomes. This procedure estimates the net benefit (Δ). Δ may be interpreted as the probability for a random patient in the treatment group to have a better overall outcome than a random patient in the control group, minus the probability of the opposite situation. However, the presence of right censoring introduces uninformative pairs that will typically bias the estimate of Δ toward 0. We propose a correction to GPCs that estimates the contribution of each uninformative pair based on the average contribution of the informative pairs. The correction can be applied to the analysis of several prioritized outcomes. We perform a simulation study to evaluate the bias associated with this correction. When only one time-to-event outcome was generated, the corrected estimates were unbiased except in the presence of very heavy censoring. The correction had no effect on the power or type-1 error of the tests based on the Δ. Finally, we illustrate the impact of the correction using data from two randomized trials. The illustrative datasets showed that the correction had limited impact when the proportion of censored observations was around 20% and was most useful when this proportion was close to 70%. Overall, we propose an estimator for the net benefit that is minimally affected by censoring under the assumption that uninformative pairs are exchangeable with informative pairs.
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http://dx.doi.org/10.1002/bimj.202000001DOI Listing
April 2021

Net benefit in the presence of correlated prioritized outcomes using generalized pairwise comparisons: A simulation study.

Stat Med 2021 02 2;40(3):553-565. Epub 2020 Nov 2.

Hospices Civils de Lyon, Pôle Santé Publique, Service de Biostatistique - Bioinformatique, Lyon, France.

Background: The prioritized net benefit (Δ) is a measure of the benefit-risk balance in clinical trials, based on generalized pairwise comparisons (GPC) using several prioritized outcomes. Its estimation requires the classification as Wins or Losses of all possible pairs of patients, one from the experimental treatment (E) group and one from the control treatment (C) group. In this simulation study, we assessed the impact of the correlation between prioritized outcomes on Δ, its estimate, bias, size, and power.

Methods: The theoretical Δ value was derived for the specific case of two correlated binary outcomes when a normal copula is used. Focusing on one efficacy and one toxicity outcome, two situations frequently met in practice were simulated: binary efficacy outcome with binary toxicity outcome, or time to event efficacy outcome with categorical toxicity outcome. Several scenarios of efficacy and toxicity were generated, with various levels of correlation.

Results: When E was more effective than C, positive correlations were mainly associated with a decrease in the proportion of Losses, while negative correlations were associated with a decrease in the proportion of Wins on the toxicity outcome. This resulted in an increase of with the intensity of the positive correlation without adding any bias. Results were similar whatever the type of outcomes generated but led to power alteration.

Conclusion: Correlations between outcomes analyzed with GPC led to substantial but predictable modifications of Δ and its estimate. Correlations should be taken into consideration when performing sample size estimations in clinical trials.
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http://dx.doi.org/10.1002/sim.8788DOI Listing
February 2021

Analysis of Preoperative CT Scan Can Help Predict Technical Failure of Endovascular Treatment of TASC C-D Aortoiliac Chronic Total Occlusions.

Ann Vasc Surg 2021 Apr 3;72:276-283. Epub 2020 Sep 3.

Vascular and Endovascular Surgery Department, Hospices Civils de Lyon, Lyon, France; Claude Bernard Lyon 1 University, Lyon, France.

Background And Aims: To evaluate if features of occlusion analyzable on preoperative computed tomography scan could predict risks of technical failure or iliac rupture of endovascular treatment of TransAtlantic InterSociety Consensus C-D aortoiliac chronic total occlusion.

Methods And Results: All patients treated by endovascular techniques for a TransAtlantic InterSociety Consensus C-D aortoiliac chronic total occlusion between 2009 and 2016 were included (107 patients, 148 iliac arteries). We evaluated the location of the occlusion and the importance of the arterial calcifications. For this factor, patients were divided into 3 groups: the Black occlusion group with mild or no calcifications, the white occlusion group with moderate no protrusive calcifications, and the white protrusive occlusion group with heavy endoluminal calcifications. Technical failure occurred in 11 iliac arteries and peroperative iliac rupture in 6. The location in the external iliac artery is the most significate risk factor of technical failure in univariate (OR = 9.93; P = 0.0012) and multivariate analysis (OR = 15.26; P = 0.0006). The presence of heavy endoluminal calcifications is a further significate risk factor (OR = 13.88; P = 0.0365). Rupture rate was comparable between the 3 groups.

Conclusions: Preoperative computed tomography scan can predict risk of technical failure but not of iliac rupture.
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http://dx.doi.org/10.1016/j.avsg.2020.08.108DOI Listing
April 2021

Cytological features and nuclear scores: Diagnostic tools in preoperative fine needle aspiration of indeterminate thyroid nodules with RAS or BRAF K601E mutations?

Cytopathology 2021 01 12;32(1):37-44. Epub 2020 Oct 12.

Centre de Biologie et Pathologie Sud, Centre Hospitalier Lyon Sud, Pierre Bénite, France.

Introduction: The cytological diagnosis of follicular-patterned thyroid lesions is challenging, especially since the World Health Organisation classification has recognised non-invasive follicular thyroid neoplasm with papillary-like features. These entities are often classified as indeterminate on cytology. Molecular testing has been proposed to help classify indeterminate nodules. RAS and K601E BRAF mutations are mostly encountered in follicular-patterned lesions, but their diagnostic value is not well established. Nuclear scores have also been proposed to help classify indeterminate lesions.

Objective: To investigate the correlation between cytological features and histology and to assess nuclear scores in a series of indeterminate RAS or BRAF K601E positive thyroid nodules.

Methods: The cytological parameters of 69 indeterminate RAS or BRAF K601E-positive thyroid nodules were evaluated. The Strickland and Maletta scores and a new nuclear score were assessed. Diagnosis of malignant, benign or indolent neoplasms was confirmed in each case by histology. Malignant and indolent nodules were considered surgical nodules, and adenomas non-surgical nodule.

Results: Surgical nodules were associated with the presence of ground glass nuclei (P = .001), grooves (P < .001) or irregular nuclear membranes (P = .01) on cytology. Nuclear scores were more often ≥2 in surgical nodules compared to benign ones (P < .001), with high sensitivity, but a low negative predictive value.

Conclusions: Analysis of nuclear features is useful to distinguish non-surgical from surgical nodules in indeterminate FNAs. Although nuclear scores are not ideal rule-out tests for indeterminate RAS or BRAF K601E positive nodules, they seem useful to screen non-molecular tested or non-mutated indeterminate FNAs. This work shows that meticulous analysis of nuclear features on cytological specimens can be useful to distinguish non-surgical nodules (adenoma) from surgical nodules in indeterminate FNAs. Although nuclear scores are not rule-out tests for indeterminate RAS or BRAF K601E positive nodules, they are useful in screening non-molecular tested or non-mutated indeterminate FNAs for surgery.
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http://dx.doi.org/10.1111/cyt.12904DOI Listing
January 2021

Severity and long-term complications of surgical site infections after orthognathic surgery: a retrospective study.

Sci Rep 2020 07 21;10(1):12015. Epub 2020 Jul 21.

Department of Maxillofacial Surgery and Facial Plastic Surgery, Lyon Sud Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Pierre Bénite, France.

Surgical site infections (SSI) occur in 1.4% to 33.4% of cases after orthognathic surgery. This type of complication is a major concern to surgical teams, but there is no consensus for the prevention and treatment of SSI in orthognathic surgery. The purpose of this descriptive study was to evaluate the severity and the consequences of postoperative infections. The charts of all the patients operated on by the orthognathic surgery team between January 2015 and July 2017 were collected. All types of orthognathic procedures (Le Fort I maxillary osteotomy, bilateral sagittal split mandibular osteotomy, and genioplasty) were screened, and patients diagnosed with SSI were included. Demographic data, timing and severity of the infection, as well as long-term complications were recorded. Five hundred and twelve patients were screened. Forty-one patients (8%) presenting with SSI were included. There were 18 men and 23 women. The site of the infection was mandibular for 38 patients (92.7%) and maxillary for 3 patients (7.3%). The average time between surgery and infection was 31.5 days. Twenty-four patients received isolated oral antibiotics for inflammatory cellulitic reaction (58.8%), 15 patients had a localized collection treated by incision and drainage under local anesthesia (36.6%), and 2 patients had an extensive collection requiring surgical drainage under general anesthesia (4.9%). Five patients (12.2%) needed hardware removal for plate loosening, and 2 patients (4.9%) developed chronic osteomyelitis. Infection following orthognathic surgery is easily treated most of the time with no long-term complications. In cases of patients with potential risk factors for severe infection, antibiotics may be given with curative intents.
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http://dx.doi.org/10.1038/s41598-020-68968-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374733PMC
July 2020

Externally Controlled Trials: Are We There Yet?

Clin Pharmacol Ther 2020 11 15;108(5):918-919. Epub 2020 Jun 15.

Grenoble University Hospital, Grenoble, France.

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http://dx.doi.org/10.1002/cpt.1881DOI Listing
November 2020

Esophageal Motility Disorders Associated With Death or Allograft Dysfunction After Lung Transplantation? Results of a Retrospective Monocentric Study.

Clin Transl Gastroenterol 2020 03;11(3):e00137

Hospices Civils de Lyon, Digestive Physiology, Hopital E Herriot, Lyon, France.

Objectives: Pathological gastroesophageal reflux (GER) is a known risk factor for bronchiolitis obliterans syndrome (BOS) after lung transplantation. This study aimed at determining whether functional esophageal evaluation might predict BOS occurrence and survival in this setting.

Methods: Ninety-three patients who underwent esophageal high-resolution manometry and 24-hour pH-impedance monitoring within the first year after lung transplantation were retrospectively included. A univariable analysis was performed to evaluate the parameters associated with GER disease and BOS occurrence. The Cox regression model was used to identify the prognostic factors of death or retransplantation.

Results: Thirteen percent of patients exhibited major esophageal motility disorders and 20% pathological GER. GER occurrence was associated with younger age, cystic fibrosis, and hypotensive esophagogastric junction. Within a median follow-up of 62 months, 10 patients (11%) developed BOS, and no predictive factors were identified. At the end of the follow-up, 10 patients died and 1 underwent retransplantation. The 5-year cumulative survival rate without retransplantation was lower in patients with major esophageal motility disorders compared with that in those without (75% vs 90%, P = 0.01) and in patients who developed BOS compared with that in those without (66% vs 91%; P = 0.005). However, in multivariable analysis, major esophageal motility disorders and BOS were no longer significant predictors of survival without retransplantation.

Discussion: Major esophageal motility disorders and BOS were associated with allograft survival in lung transplantation in the univariable analysis. Although the causes of this association remain to be determined, this observation confirms that esophageal motor dysfunction should be evaluated in the context of lung transplantation.
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http://dx.doi.org/10.14309/ctg.0000000000000137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7145052PMC
March 2020

Role of ultrasonography in the assessment of correct endotracheal tube placement in neonates.

Acta Paediatr 2020 05 4;109(5):1057-1059. Epub 2019 Dec 4.

Neonatal Intensive Care Unit, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.

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http://dx.doi.org/10.1111/apa.15097DOI Listing
May 2020

Prediction of ventricular arrhythmias in patients with a spontaneous Brugada type 1 pattern: the key is in the electrocardiogram.

Europace 2019 Sep;21(9):1400-1409

Service de Rythmologie, Centre National de Référence des Troubles du Rythme Cardiaque Héréditaires de Lyon, Hôpital Cardiologique Louis Pradel, Hospices Civils de Lyon, Avenue du Doyen Jean Lépine, 69500 Bron, France & Université de Lyon, Lyon, France.

Aims: There is currently no reliable tool to quantify the risks of ventricular fibrillation or sudden cardiac arrest (VF/SCA) in patients with spontaneous Brugada type 1 pattern (BrT1). Previous studies showed that electrocardiographic (ECG) markers of depolarization or repolarization disorders might indicate elevated risk. We aimed to design a VF/SCA risk prediction model based on ECG analyses for adult patients with spontaneous BrT1.

Methods And Results: This retrospective multicentre international study analysed ECG data from 115 patients (mean age 45.1 ± 12.8 years, 105 males) with spontaneous BrT1. Of these, 45 patients had experienced VF/SCA and 70 patients did not experience VF/SCA. Among 10 ECG markers, a univariate analysis showed significant associations between VF/SCA and maximum corrected Tpeak-Tend intervals ≥100 ms in precordial leads (LMaxTpec) (P < 0.001), BrT1 in a peripheral lead (pT1) (P = 0.004), early repolarization in inferolateral leads (ER) (P < 0.001), and QRS duration ≥120 ms in lead V2 (P = 0.002). The Cox multivariate analysis revealed four predictors of VF/SCA: the LMaxTpec [hazard ratio (HR) 8.3, 95% confidence interval (CI) 2.4-28.5; P < 0.001], LMaxTpec + ER (HR 14.9, 95% CI 4.2-53.1; P < 0.001), LMaxTpec + pT1 (HR 17.2, 95% CI 4.1-72; P < 0.001), and LMaxTpec + pT1 + ER (HR 23.5, 95% CI 6-93; P < 0.001). Our multidimensional penalized spline model predicted the 1-year risk of VF/SCA, based on age and these markers.

Conclusion: LMaxTpec and its association with pT1 and/or ER indicated elevated VF/SCA risk in adult patients with spontaneous BrT1. We successfully developed a simple risk prediction model based on age and these ECG markers.
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http://dx.doi.org/10.1093/europace/euz156DOI Listing
September 2019

Off-label drug prescriptions in French general practice: a cross-sectional study.

BMJ Open 2019 04 9;9(4):e026076. Epub 2019 Apr 9.

Univ. Lyon, Université Claude Bernard Lyon 1, Université Saint-Étienne, Collège universitaire de médecine générale, F-69008 Lyon, F-42023 Saint-Étienne, Département de médecine générale, Lyon, France.

Objectives: Off-label drug prescribing is a public health and economic issue. The aim of this study was to describe off-label prescription in general practice in France, in terms of frequency and nature, and to identify its main determining factors.

Design: Multicentre cross-sectional study SETTING: Twenty-three training general practice offices PARTICIPANTS: All the voluntary patients coming for a medical consultation or visited at home over a cumulative period of 5 days per office between November 2015 and January 2016.

Methods: Eleven interns, acting as observers, collected data. Two reviewers analysed the drugs prescribed by the trainers, in order to identify those prescribed off-label in terms of their indication or the age of the patient. We used a univariate, then a multivariate model, based on hierarchical mixed-effects logistic regression.

Results: Among the 4932 drug prescriptions registered, 911 (18.5%[95% CI17.4% to 19.6%]) were off-label, of which 865 (17.6%) due to the indication of the drug and 58 (1.2%) due to the age of the patient. The prescription never mentioned the off-label use, neither was the patient informed of it, as required by the French law. With the multivariate analysis, variables contributing to off-label prescription were the number of drugs (OR=1.05 for each additional drug), the initiation of new drug therapy (OR=1.26) and the non-specific goal of the prescription (OR=1.43); the age of the patient ≤14 years (OR=1.42); the rural location of the physician's practice (OR=1.38) and the low frequency of the visits of national health insurance representatives (OR=0.93).

Conclusion: Almost one out of five drugs prescribed in French general practice was off-label. It seems necessary to better train physicians in clinical pharmacology, to provide them with more effective drug prescription software, to reinforce postmarketing surveillance and to clearly define off-label use by consensus.
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http://dx.doi.org/10.1136/bmjopen-2018-026076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500201PMC
April 2019

Managing Missing Data in the Hospital Survey on Patient Safety Culture: A Simulation Study.

J Patient Saf 2021 03;17(2):e98-e106

Service de biostatistique, Hospices Civils de Lyon, Laboratoire de biométrie et biologie évolutive, UMR 5558 CNRS, Lyon.

Background: Case-wise analysis is advocated for the Hospital Survey on Patient Safety culture (HSOPS).

Objectives: Through a computer-intensive simulation study, we aimed to evaluate the accuracy of various imputation methods in managing missing data in the HSOPS.

Methods: Using the original data from a cross-sectional survey of 5064 employees at a single university hospital in France, we produced simulation data on two levels. First, we resampled 1000 completed data based on the original 3045 complete responses using a bootstrap procedure. Second, missing values were simulated in these 1000 completed case data for comparison purposes, using eight different missing data scenarios. Third, missing values were imputed using five different imputation methods (1, random imputation; 2, item mean; 3, individual mean; 4, multiple imputation, and 5, sparse nonnegative matrix factorization. The performance for each imputation method was assessed using the root mean square error and dimension score bias.

Results: The five imputation methods yielded close root mean square errors, with an advantage for the multiple imputation. The bias differences were greater regarding the dimension scores, with a clear advantage for multiple imputation. The worst performance was achieved by the mean imputation methods.

Discussion And Conclusions: We recommend the use of multiple imputation to handle missing data in HSOPS-based surveys, whereas mean imputation methods should be avoided. Overall, these results suggest the possibility of optimizing the HSOPS instrument, which should be reduced without loss of overall information.
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http://dx.doi.org/10.1097/PTS.0000000000000595DOI Listing
March 2021

Assessing Long-Term Survival Benefits of Immune Checkpoint Inhibitors Using the Net Survival Benefit.

J Natl Cancer Inst 2019 11;111(11):1186-1191

Background: The treatment effect in survival analysis is commonly quantified as the hazard ratio, and tested statistically using the standard log-rank test. Modern anticancer immunotherapies are successful in a proportion of patients who remain alive even after a long-term follow-up. This new phenomenon induces a nonproportionality of the underlying hazards of death.

Methods: The properties of the net survival benefit were illustrated using the dataset from a trial evaluating ipilimumab in metastatic melanoma. The net survival benefit was then investigated through simulated datasets under typical scenarios of proportional hazards, delayed treatment effect, and cure rate. The net survival benefit test was computed according to the value of the minimal survival difference considered clinically relevant. As comparators, the standard and the weighted log-rank tests were also performed.

Results: In the illustrative dataset, the net survival benefit favored ipilimumab [Δ(0) = 15.8%, 95% confidence interval = 4.6% to 27.3%, P = .006]. This favorable effect was maintained when the analysis was focused on long-term survival differences (eg, >12 months, Δ(12) = 12.5% (95% confidence interval = 4.4% to 20.6%, P = .002). Under the scenarios of a delayed treatment effect and cure rate, the power of the net survival benefit test compared favorably to the standard log-rank test power and was comparable to the power of the weighted log-rank test for large values of the threshold of clinical relevance.

Conclusion: The net long-term survival benefit is a measure of treatment effect that is meaningful whether or not hazards are proportional. The associated statistical test is more powerful than the standard log-rank test when a delayed treatment effect is anticipated.
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http://dx.doi.org/10.1093/jnci/djz030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855951PMC
November 2019

The Benefit-Risk Balance of Nab-Paclitaxel in Metastatic Pancreatic Adenocarcinoma.

Pancreas 2019 02;48(2):275-280

International Drug Development Institute, San Francisco, CA.

Objectives: The benefit-risk balance of 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin versus gemcitabine assessed using generalized pairwise comparison was strongly positive. We sought to assess the benefit-risk balance of nab-paclitaxel plus gemcitabine using the data of the MPACT trial, as it is an alternative to 5-fluorouracil, oxaliplatin, irinotecan, and leucovorin.

Methods: This statistical method allows for the simultaneous analysis of several prioritized outcomes. The first priority outcome was survival time (overall survival). The second priority outcome was toxicity. The overall treatment effect was quantified using the overall net benefit. Multiple sensitivity analyses were performed to assess the consistency of the results according to possible patients' preferences.

Results: In this trial, 861 patients received nab-paclitaxel plus gemcitabine or gemcitabine alone. The overall net benefit favored strongly and significantly the combination group. When only large survival differences were considered clinically relevant, the net benefit was not in favor of the combination group.

Conclusions: The overall net benefit is a clinically intuitive way of comparing patients with respect to all important efficacy and toxicity outcomes. The nab-paclitaxel plus gemcitabine combination has a positive benefit-risk balance, but it might not be suitable for patients who would consider losing several months of survival to avoid a significant toxic event.
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http://dx.doi.org/10.1097/MPA.0000000000001234DOI Listing
February 2019

On-Demand Sildenafil as a Treatment for Raynaud Phenomenon: A Series of n-of-1 Trials.

Ann Intern Med 2018 11 30;169(10):694-703. Epub 2018 Oct 30.

Université Grenoble Alpes and Grenoble Alpes University Hospital, Grenoble, France (M.R., O.G., C.K., M.M., A.L., S.B., C.S., A.P., C.C., B.I., P.C., J.C.).

Background: Treatment of Raynaud phenomenon (RP) with phosphodiesterase-5 inhibitors has shown moderate efficacy. Adverse effects decrease the risk-benefit profile of these drugs, and patients may not be willing to receive long-term treatment. On-demand single doses before or during exposure to cold may be a good alternative.

Objective: To assess the efficacy and safety of on-demand sildenafil in RP.

Design: Series of randomized, double-blind, n-of-1 trials. (ClinicalTrials.gov: NCT02050360).

Setting: Outpatients at a French university hospital.

Participants: Patients with primary or secondary RP.

Intervention: Each trial consisted of a multiple crossover study in a single patient. Repeated blocks of 3 periods of on-demand treatment were evaluated: 1 week of placebo, 1 week of sildenafil at 40 mg per dose, and 1 week of sildenafil at 80 mg per dose, with a maximum of 2 doses daily.

Measurements: Raynaud Condition Score (RCS) and frequency and daily duration of attacks. Skin blood flow in response to cooling also was assessed with laser speckle contrast imaging. Mixed-effects models were used and parameters were estimated in a Bayesian framework to determine individual and aggregated efficacy.

Results: 38 patients completed 2 to 5 treatment blocks. On the basis of aggregated data, the probability that sildenafil at 40 mg or 80 mg was more effective than placebo was greater than 90% for all outcomes (except for RCS with sildenafil, 80 mg). However, the aggregated effect size was not clinically relevant. Yet, substantial heterogeneity in sildenafil's efficacy was observed among participants, with clinically relevant efficacy in some patients.

Limitation: The response to sildenafil was substantially heterogeneous among patients.

Conclusion: Despite a high probability that sildenafil is superior to placebo, substantial heterogeneity was observed in patient response and aggregated results did not show that on-demand sildenafil has clinically relevant efficacy. In this context, the use of n-of-1 trials may be an original and relevant approach in RP.

Primary Funding Source: GIRCI (Groupement Interrégional de Recherche Clinique et d'Innovation) Auvergne Rhône-Alpes (academic funding) and Pfizer.
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http://dx.doi.org/10.7326/M18-0517DOI Listing
November 2018

INN or brand name drug prescriptions: a multilevel, cross-sectional study in general practice.

Eur J Clin Pharmacol 2019 Feb 27;75(2):275-283. Epub 2018 Oct 27.

Collège universitaire de médecine générale, Univ. Lyon, Université Claude Bernard Lyon 1, Université Saint-Etienne, F-42023, Saint-Etienne, France.

Purpose: The prescription in International Nonproprietary Names (INN) is a legal obligation for all physicians in France since January 2015. The objective of this study was to analyze the frequency and main factors of INN drug prescribing in general practice.

Methods: Multicenter cross-sectional study conducted with 11 interns acting as observers of 23 GP trainers between November 2015 and January 2016. Two evaluators analyzed all GPs' drug prescriptions to identify INN or brand name prescriptions.

Results: The database included 4957 drugs prescribed during 1647 visits. Of these, 1462 (29.5% [95% CI 28.2-30.8%]) were prescribed only in INN. According to the multivariate analyses, the factors favoring INN prescribing were as follows: at the drug level, its initial prescribing (OR = 1.4), a nonspecific prescribing objective (OR = 1.6), its listing in the generic drug index with (OR = 7.7) or without (OR = 2.9) efficiency objective included in the payment for public health objectives (PPHO) program, and the oral route of administration (OR from 0.4 for the percutaneous route to 0.2 for the pulmonary route); at the patient level, the male gender (OR = 1.3), the age of 15 years or more (OR = 1.9), and the absence of a long-term condition (OR = 1.3); at the physician level, the reception of a public healthcare insurance representative (OR = 4.1), the nonreception of pharmaceutical sales representatives (OR = 3.0), and the urban practice environment (OR = 2.8).

Conclusions: In 2015, less than one third of drugs were prescribed in INN only in general practice. The use of various incentives and regulatory measures is likely to favor the prescription of INNs by practitioners.
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http://dx.doi.org/10.1007/s00228-018-2580-8DOI Listing
February 2019

Radical Prostatectomy after Vascular Targeted Photodynamic Therapy with Padeliporfin: Feasibility, and Early and Intermediate Results.

J Urol 2019 02;201(2):315-321

Department of Urology, Lyon Sud University Hospital, Lyon.

Purpose: Vascular targeted photodynamic therapy with TOOKAD® is a new therapeutic option for localized prostate cancer management. The objectives of this study were to assess the feasibility of radical prostatectomy after vascular targeted photodynamic therapy and describe functional and oncologic outcomes.

Materials And Methods: We retrospectively included in study 45 patients who underwent salvage radical prostatectomy after vascular targeted photodynamic therapy for recurrent prostate cancer at a total of 14 surgical centers in Europe between October 2008 and March 2017. Of the 42 radical prostatectomies performed 16 were robot-assisted, 6 were laparoscopic and 20 were open surgery. Primary end points were morbidity and technical difficulties. Secondary end points were early and intermediate postoperative functional and oncologic outcomes.

Results: Median operative time was 180 minutes (IQR 150-223). Median blood loss was 200 ml (IQR 155-363). According to the surgeons the surgery was easy in 29 patients (69%) and difficult in 13 (31%). Nerve sparing was feasible in 14 patients (33%). Five postoperative complications (12%) were found, including 2 Clavien I, 2 Clavien II and 1 Clavien IIIB complications. Of the cases 13 (31%) were pT3 and 21 (50%) were pT2c. Surgical margins were positive in 13 patients (31%). Prostate specific antigen was undetectable at 6 to 12 months in 37 patients (88%). Nine patients underwent complementary radiotherapy. Four patients had final prostate specific antigen greater than 0.2 ng/ml at a median followup of 23 months (IQR 12-36). At 1 year 27 patients (64%) were completely continent (no pads) and 10 (24%) had low incontinence (1 pad). Four patients (11%) recovered potency without treatment and 23 (64%) recovered potency with appropriate treatment.

Conclusions: Salvage radical prostatectomy after vascular targeted photodynamic therapy treatment was feasible and safe without difficulty for most of the surgeons.
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http://dx.doi.org/10.1016/j.juro.2018.08.084DOI Listing
February 2019

Mandibular Advancement Means Lower Facial Enlargement: A 2-Dimensional and 3-Dimensional Analysis.

J Oral Maxillofac Surg 2018 12 16;76(12):2646.e1-2646.e8. Epub 2018 Aug 16.

Professor, Department of Maxillofacial Surgery and Plastic Facial Surgery, Lyon Sud Hospital, Hospices Civils de Lyon, Claude Bernard Lyon 1 University, Pierre-Bénite, France.

Purpose: Bilateral sagittal split osteotomy (BSSO) is frequently used to treat Class II malocclusion for functional and esthetic purposes, with expected changes in the profile. The goal of this study was to assess transversal changes in mandibular advancement by comparing 3-dimensional (3D) photogrammetric modifications and 2-dimensional (2D) radiographic enlargement.

Materials And Methods: A cohort study was conducted of patients who underwent an isolated advancement BSSO (Obwegeser-Dal Pont II type) for a Class II malocclusion. All patients had 3D photogrammetric and 2D radiographic evaluations before and after surgery. Frontal cephalograms were used to measure the evolution of bigonial distance (BGD) and 3D photographs were used to measure the evolution of cutaneous BGD (CBGD).

Results: Fourteen patients were included. Mean mandibular advancement was 6 mm. BGD (+6.1 mm; P < 10) and CBGD (+4.2 mm; P = .0017) were significantly increased. The mean ratio of soft tissue response to transversal skeletal changes was 0.81.

Conclusion: This 2D and 3D analysis of transversal modifications shows that advancement with the BSSO is responsible for marked lower third facial enlargement. This parameter must be taken into account during the preoperative esthetic assessment to ensure the provision of pertinent information to the patient and the consideration of complementary surgical correction.
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http://dx.doi.org/10.1016/j.joms.2018.07.034DOI Listing
December 2018

Involvement in Root Cause Analysis and Patient Safety Culture Among Hospital Care Providers.

J Patient Saf 2017 Dec 27. Epub 2017 Dec 27.

Background: The experience feedback committee (EFC) is a tool designed to involve medical teams in patient safety management, through root cause analysis within the team.

Objective: The aim of the study was to determine whether patient safety culture, as measured by the Hospital Survey on Patient Safety Culture (HSOPS), differed regarding care provider involvement in EFC activities.

Methods: Using the original data from a cross-sectional survey of 5064 employees at a single university hospital in France, we analyzed the differences in HSOPS dimension scores according involvement in EFC activities.

Results: Of 5064 eligible employees, 3888 (76.8%) participated in the study. Among the respondents, 440 (11.3%) participated in EFC activities. Experience feedback committee participants had a more developed patient safety culture, with 9 of the 12 HSOPS dimension scores significantly higher than EFC nonparticipants (overall effect size = 0.31, 95% confidence interval = 0.21 to 0.41, P < 0.001). A multivariate analysis of variance indicated that all 12 dimension scores, taken together, were significantly different between EFC participants and nonparticipants (P < 0.0001), independently of sex, hospital department, and healthcare profession category. The largest differences in scores related to the "feedback and communication about error," "organizational learning," and "Nonpunitive response to error" dimensions. The analysis of the subgroup of professionals who worked in a department with a productive EFC, defined as an EFC implementing at least five actions per year, showed a higher patient safety culture level for seven of the 12 HSOPS dimensions (overall effect size = 0.19, 95% confidence interval = 0.10 to 0.27, P < 0.001).

Discussion And Conclusions: Participation in EFC activities was associated with higher patient safety culture scores. The findings suggest that root cause analysis in the team's routine may improve patient safety culture.
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http://dx.doi.org/10.1097/PTS.0000000000000456DOI Listing
December 2017

Inconsistencies Between Two Cross-Cultural Adaptations of the Hospital Survey on Patient Safety Culture Into French.

J Patient Saf 2017 Nov 15. Epub 2017 Nov 15.

From the *Quality of Care Unit, Grenoble University Hospital; †Grenoble Alps University, TIMC UMR 5525 CNRS, France; ‡Service de Biostatistique, Hospices Civils de Lyon, Laboratoire de Biométrie et Biologie Evolutive, Lyon, France; §Division of Clinical Epidemiology, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; and ∥INSERM CIC 1406, Grenoble, France.

Objectives: Two cross-cultural adaptations of the 12-dimension Hospital Survey on Patient Safety Culture (HSOPSC) into French coexist: the Occelli and Vlayen versions. The objective of this study was to assess the psychometric properties of the Occelli version in comparison with those reported for the Vlayen and the original US versions of this instrument.

Methods: Using the original data from a cross-sectional study of 5,064 employees at a single university hospital in France, we examined the acceptability, internal consistency, factorial structure, and construct validity of the Occelli version of the HSOPSC.

Results: The response rate was 76.8% (n = 3888). Our study yielded lower missing value rates (median, 0.4% [range, 0.0%-2.4%] versus 0.8% [range, 0.2%-11.4%]) and lower dimension scores (median, 3.19 [range, 2.67-3.54] versus 3.42 [range, 2.92-3.96]) than those reported for the Vlayen version. Cronbach alphas (median, 0.64; range, 0.56-0.84) compared unfavorably with those reported for the Vlayen (median, 0.73; range, 0.57-0.86) and original US (median, 0.78; range, 0.63-0.84) versions. The results of the confirmatory factor analysis were consistent between the Vlayen and Occelli versions, making it possible to conduct surveys from the 12-dimensional structure with both versions.

Conclusions: The inconsistencies observed between the Occelli and Vlayen versions of the HSOPSC may reflect either differences between the translations or heterogeneity in the study population and context. Current evidence does not clearly support the use of one version over the other. The two cross-cultural adaptations of the HSOPSC can be used interchangeably in French-speaking countries.
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http://dx.doi.org/10.1097/PTS.0000000000000443DOI Listing
November 2017

Hospital survey on patient safety culture (HSOPS): variability of scoring strategies.

Int J Qual Health Care 2017 Oct;29(5):685-692

Quality of Care Unit, Grenoble University Hospital, F-38043 Grenoble, France.

Objective: To assess the variability of safety culture dimension scores and their associated rankings depending on three different scoring strategies using the Hospital Survey On Patient Safety Culture (HSOPS).

Design: Cross-sectional study using a self-administered questionnaire.

Setting: The study was conducted in an 1836-bed acute-care French university hospital with an annual volume of 135 999 stays, between April 2013 and November 2014.

Participants: All caregivers and technical-administrative staff with at least 6 months of employment, spending at least half of their working time in the hospital, were asked to participate.

Intervention: None.

Main Outcome Measure: The variability of the HSOPS results using three different scoring methods: the percentage of positive responses recommended by the Agency for Healthcare Research and Quality, the averaged individual means and the averaged individual sums.

Results: The response rate was 78.6% (n = 3978). The percentage of positive responses resulted in lower scores compared to averaged individual means and averaged individual sums in the six least developed dimensions, and gave more widely spread scores and greater 95CIs in the six most developed dimensions. Department rankings also varied greatly depending on the scoring methods.

Conclusion: The values of the HSOPS scores and their corresponding rankings greatly depended on the computation method. This finding shows how important it is to agree on the use of the same scoring strategies, before broadly comparing results within and across organizations.
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http://dx.doi.org/10.1093/intqhc/mzx086DOI Listing
October 2017

Spontaneous Cerebrospinal Fluid Rhinorrhea: Association with Body Weight and Imaging Data.

J Neurol Surg B Skull Base 2017 Oct 8;78(5):419-424. Epub 2017 Jun 8.

Joseph Fourier University, UFR Medecine, Grenoble, France.

 Spontaneous cerebrospinal fluid rhinorrhea (SCSFR) might be the only clinical manifestation of idiopathic intracranial hypertension (IIH), which has been historically related to overweight. Our goal was to search for an association between SCSFR and increased body weight on the one hand and SCSFR and imaging findings suggestive of IIH on the other hand.  We retrospectively collected clinical and radiological data of patients operated on endoscopically for SCSFR in our institution from 1993 to 2013. Analyzed factors were body mass index (BMI), extended sphenoid sinus pneumatization on computed tomography, and empty sella and distention of the optic nerve sheath on magnetic resonance imaging.  There were 15 patients: 8 females/7 males; mean age 50 years. Primary surgical success rate was 86.7%. Regarding body weight, 80% were overweight (BMI ≥ 25) versus 32% in the French general population (  < 0.001). Among patients with SCSFR, 20% were obese (BMI ≥ 30) versus 15% in French individuals without SCSFR (  = 0.483). Increased pneumatization of sphenoid sinuses was observed in 92.9 versus 27.5% in the general population (  < 0.0001). Empty sella was found in 46.2 versus 3% in the general population (  < 0.00001). Dilation of the optic nerve sheath was observed in 46.2 versus 15% in the general population (  < 0.01).  We found statistically significant associations between SCSFR and overweight, increased pneumatization of sphenoid sinuses, empty sella, and dilation of optic nerve sheath, but not with obesity, which did not have any additional impact of CSF leak than did overweight.
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http://dx.doi.org/10.1055/s-0037-1603731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5582967PMC
October 2017

Lactic Acidosis in Diabetic Population: Is Metformin Implicated? Results of a Matched Case-Control Study Performed on the Type 2 Diabetes Population of Grenoble Hospital University.

J Diabetes Res 2016 29;2016:3545914. Epub 2016 Feb 29.

Centre Régional de Pharmacovigilance, Pôle Santé Publique, Centre Hospitalier Universitaire de Grenoble, 38000 Grenoble, France.

Introduction: To evaluate the strength of association between lactic acidosis (LA) and well-recognized risk factors for LA, particularly the weight of metformin.

Methods: This study is a matched case-control analysis concerning the type 2 diabetes population from Grenoble Hospital University. Cases of LA were defined biologically with pH < 7.35 and lactates > 5 mmol/L. They were matched to 2 controls defined as type 2 diabetic inpatients who did not present a LA during the study period. We performed a conditional logistic regression.

Results: We included 302 cases and 604 controls; mean age was 69.5 years (SD 11.93). Intercurrent diseases were significantly associated with LA. Chronic medical conditions had a minor impact on LA incidence, except hepatocellular dysfunction. Metformin was significantly associated with a higher LA probability in case of acute kidney injury (AKI) (OR = 1.79; p value = 0.020) but not in patients without AKI.

Discussion And Conclusions: According to this study, metformin, compared to acute medical conditions, seemed not to be associated with LA in patients with type 2 diabetes; however in case of AKI, metformin may be associated with LA.
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http://dx.doi.org/10.1155/2016/3545914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789438PMC
December 2016

Study of inter- and intra-observer reproducibility in the interpretation of [(18)F]choline PET/CT examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment.

EJNMMI Res 2014 30;4:25. Epub 2014 May 30.

Service de Médecine Nucléaire, Centre Hospitalier Universitaire Nord Grenoble, Boulevard de la Chantourne, la Tronche, 38700, France.

Background: The aim of this study was to investigate the reproducibility of intra- and inter-observer interpretation of [(18)F]choline positron emission tomography/computed tomography examinations in patients suffering from biochemically recurrent prostate cancer following curative treatment.

Methods: A total of 60 patients with biochemical recurrence after curative treatment were included in this bicentric study. The interpretations were based on a systematic analysis of several anatomic regions and all the four nuclear medicine physicians used identical result consoles. The examinations were interpreted with no knowledge of the patients' clinical context. Two months later, a second interpretation of all these examinations was performed using the same method, in random order.

Results: To evaluate local recurrences, when the prostate is in place, the results showed moderate inter- and intra-observer reproducibility: concordance of all 4 physicians has a Fleiss' kappa coefficient of 0.553 with a confidence interval of (0.425 to 0.693). For patients who had had a prostatectomy, there was excellent concordance for the negative examinations. For the lymphatic basin, inter- and intra-observer reproducibility was excellent with a Fleiss' kappa coefficient of 0.892 with a confidence interval of (0.788 to 0.975). The lymphatic sub-group analysis was also good. For the lymphatic groups in the right or left hemi-pelves, all Fleiss' kappa and Cohen's kappa coefficients are varying from 0.760 to 1 with narrow confidence intervals from (0.536 to 0.984) to (1 to 1) in favour of good/excellent inter-observer reproducibility. To evaluate bone metastasis, inter-observer reproducibility was good with a Fleiss' kappa coefficient of 0.703 and a confidence interval of (0.407 to 0.881).

Conclusion: Our study is at time the only one on the reproducibility of interpretation of [(18)F]choline positron emission tomography/computed tomography examinations, which is a key examination for the treatment of patients suffering biochemical recurrence of prostate cancer. Interpretation of the [(18)F]choline positron emission tomography/computed tomography examination is not so useful at prostate level in patients not previously treated with prostatectomy but has a great interest on patients treated by prostatectomy. It showed good concordance in the interpretation of sub-diaphragmatic lymphatic recurrences as well as in bone metastasis.
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http://dx.doi.org/10.1186/s13550-014-0025-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077623PMC
July 2014

Sensitivity of a colorectal cancer screening program based on a guaiac test: a population-based study.

Clin Res Hepatol Gastroenterol 2014 Feb 27;38(1):106-11. Epub 2013 Jul 27.

Registre du cancer de l'Isère, CHU de Grenoble, pavillon E, BP 217, 38043 Grenoble cedex 9, France. Electronic address:

Background: The main objective of this study was to estimate the sensitivity of a colorectal cancer-screening program based on a guaiac fecal occult blood (FOB) test. The secondary objective was to determine whether the sensitivity varied by sex and if the difference between males and females could be explained by differences in age group at the time of the test, round of screening, how the test was provided to the participant, tumor location, and the presence of theoretical screening program exclusion criteria.

Methods: For the 2002-2006 period, we retrospectively analyzed data from the organized colorectal screening program in Isère, France, which was designed for asymptomatic individuals aged 50-74. Sensitivity was assessed considering the number of interval cancers diagnosed in the 2 years following the test. A logistical regression analysis was done to evaluate the factors associated with the sensitivity of the screening program.

Results: A total of 506 participants were included in the analysis. The overall sensitivity of the screening program was 48.4%, being 58.3% for males and 32.5% for females. In multivariate analysis, sensitivity for males was still higher than for females (OR=2.1 [95% CI, 1.4-3.4]) after adjusting for age group, presence of exclusion criteria, the way the test was given, the round of participation, and the tumor location. A total of 183 (36.2%) study subjects presented with at least one exclusion criterion for the screening program.

Conclusion: The sensitivity of the colorectal cancer-screening program based on a guaiac test was insufficient, being higher for males than for females. This difference in sensitivity was not entirely explained by differences in age, characteristics of screening participation, and tumor location.
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http://dx.doi.org/10.1016/j.clinre.2013.06.011DOI Listing
February 2014