Publications by authors named "Fabien Subtil"

67 Publications

Trajectory clustering using mixed classification models.

Stat Med 2021 Apr 7. Epub 2021 Apr 7.

Université de Lyon, Lyon, France.

Trajectory classification has become frequent in clinical research to understand the heterogeneity of individual trajectories. The standard classification model for trajectories assumes no between-individual variance within groups. However, this assumption is often not appropriate, which may overestimate the error variance of the model, leading to a biased classification. Hence, two extensions of the standard classification model were developed through a mixed model. The first one considers an equal between-individual variance across groups, and the second one considers unequal between-individual variance. Simulations were performed to evaluate the impact of these considerations on the classification. The simulation results showed that the first extended model gives a lower misclassification percentage (with differences up to 50%) than the standard one in case of presence of a true variance between individuals inside groups. The second model decreases the misclassification percentage compared with the first one (up to 11%) when the between-individual variance is unequal between groups. However, these two extensions require high number of repeated measurements to be adjusted correctly. Using human chorionic gonadotropin trajectories after curettage for hydatidiform mole, the standard classification model classified trajectories mainly according to their levels whereas the two extended models classified them according to their patterns, which provided more clinically relevant groups. In conclusion, for studies with a nonnegligible number of repeated measurements, the use, in first instance, of a classification model that considers equal between-individual variance across groups rather than a standard classification model, appears more appropriate. A model that considers unequal between-individual variance may find its place thereafter.
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http://dx.doi.org/10.1002/sim.8975DOI Listing
April 2021

Heterogeneity of contact patterns with Ebola virus disease cases.

J Infect 2021 Mar 18. Epub 2021 Mar 18.

Université de Lyon, Lyon, France. Université Claude Bernard Lyon 1, Villeurbanne, France. Service de Biostatistique-Bioinformatique, Pôle Santé Publique, Hospices Civils de Lyon, Lyon, France. Équipe Biostatistique-Santé, Laboratoire de Biométrie et Biologie Évolutive, CNRS UMR 5558, Villeurbanne, France.

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http://dx.doi.org/10.1016/j.jinf.2021.03.009DOI Listing
March 2021

Value of a patient-reported-outcome measure of carcinoid syndrome symptoms.

Eur J Endocrinol 2021 May;184(5):711-722

Service d'Oncologie Médicale et Hépatogastroentérologie, Hospices Civil de Lyon, Lyon, France.

Objective: Literature on patient-reported outcomes (PRO) of carcinoid syndrome symptoms (CSS) is scarce. We used a patient-reported outcome measure (PROM) to evaluate CSS, the domains of daily life impacted by CSS, the main symptoms that affect daily life, its change according to clinical, biological and morphological evolution, and the risk factors for a poor PRO-CSS score.

Methods: Patients completed the PRO-CSS, EORTC-QLQ30, and GI-NET21 questionnaires at the time of their clinical, laboratory, and morphological assessments in a multicentre French cohort study from February 2019 to May 2020.

Results: In total, 147 patients with metastatic ileal (n =126), lung (n =20), or unknown primitive neuroendocrine tumour but high 5-hydroxyindole-3-acetic acid level (n =1) were included; 42 (32%) received an above-label dose of somatostatin analogues. Fifty-one (35%) patients had a poor PRO-CSS score. Travelling and food restriction were the two main domains affected. Diarrhoea (mean: 2.3/5 on Likert scale), imperiousness (mean of 2.5/5), fatigue (2.2/5), abdominal pain (1.7/5), and flushing episodes (1.5/5) were the main symptoms affecting daily life. The PRO-CSS score was not correlated to the clinical assessment performed by physicians at the baseline and during the follow-up. Patients with a poor PRO-CSS score had a higher tumour burden.

Conclusions: PROM-CSS may help physicians make an objective assessment of CSS and its impact in daily practice; this tool could become a key evaluation criterion in clinical trials focusing on CSS.
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http://dx.doi.org/10.1530/EJE-20-1138DOI Listing
May 2021

First-line treatment of double-hit and triple-hit lymphomas: Survival and tolerance data from a retrospective multicenter French study.

Am J Hematol 2021 03 29;96(3):302-311. Epub 2020 Dec 29.

Department of Hematology and Medical Oncology, Centre Léon Bérard, Lyon, France.

Historically, double or triple hit lymphoma (DHL and THL) have poor outcomes with conventional chemotherapy, but there is currently no guideline. We report the French experience in managing DHL and THL in first line using collective data on both survival and tolerance. All consecutive patients with newly diagnosis of large B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangements, as determined by FISH between January 2013 and April 2019 were included. Based on the eligibility criteria, 160 patients were selected among the 184 patients identified. With a median follow-up of 32 months, 2- and 4-year progression free survival (PFS) rates were 40% and 28% with R-CHOP compared with 57% and 52% with intensive chemotherapy (P = .063). There was no difference in overall survival (OS). For advanced stages, PFS was significantly longer with intensive chemotherapy than with R-CHOP (P = .029). There was no impact of autologous stem cell transplantation among patient in remission. For patients with central nervous system (CNS) involvement, the 2-year PFS and OS rate was 21% and 39%, vs 57% and 75% without CNS disease (P = .007 and P < .001). By multivariate analysis, elevated IPI score and CNS disease were strongly and independently associated with a poorer survival, whereas treatment was not significantly associated with OS. This is the largest series reporting the treatment of DHL and THL in Europe. The PFS was significantly longer with an intensive regimen for advanced stage, but no difference in OS, supporting the need for a prospective randomized trial.
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http://dx.doi.org/10.1002/ajh.26068DOI Listing
March 2021

A fixed-duration, measurable residual disease-guided approach in CLL: follow-up data from the phase 2 ICLL-07 FILO trial.

Blood 2021 Feb;137(8):1019-1023

Department of Hematology, Centre Hospitalier Régional Universitaire (CHRU) Nancy, Unité 1256, INSERM Lorraine University, Nancy, France.

Trials assessing first-line, fixed-duration approaches in chronic lymphocytic leukemia (CLL) are yielding promising activity, but few long-term data are available. We report follow-up data from a phase 2 trial (ICLL07 FILO) in previously untreated, medically fit patients (N = 135). Patients underwent obinutuzumab-ibrutinib induction for 9 months; then, following evaluation (N = 130 evaluable), those in complete remission and with bone marrow measurable residual disease (BM MRD) <0.01% (n = 10) received ibrutinib for 6 additional months; those in partial remission and/or with BM MRD ≥0.01%, the majority (n = 120), also received 4 cycles of immunochemotherapy (fludarabine/cyclophosphamide-obinutuzumab). Beyond end of treatment, responses were assessed every 3 month and peripheral blood MRD every 6 months. At median follow-up 36.7 months from treatment start, progression-free and overall survival rates (95% confidence interval) at 3 years were 95.7% (92.0% to 99.5%) and 98% (95.1% to 100%), respectively. Peripheral blood MRD <0.01% rates were 97%, 96%, 90%, 84%, and 89% at months 16, 22, 28, 34, and 40, respectively. No new treatment-related or serious adverse event occurred beyond end of treatment. Thus, in previously untreated, medically fit patients with CLL, a fixed-duration (15 months), MRD-guided approach achieved high survival rates, a persistent MRD benefit beyond the end of treatment, and low long-term toxicity. This trial was registered at www.clinicaltrials.gov as #NCT02666898.
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http://dx.doi.org/10.1182/blood.2020008164DOI Listing
February 2021

[What are the factors associated with mandibular asymmetries? A case-control study].

Orthod Fr 2020 10;91(3):225-238

Département d'Orthopédie Dento-Faciale, Faculté d'Odontologie, rue Guillaume Paradin, 69372 Lyon cedex 08, France.

The treatment of mandibular asymmetry often requires a late surgical orthodontic protocol that certainly allows an improvement but no complete correction. Ideal would be to control the etiological factors which are still controversial. The aim of the study is to identify per and postnatal factors associated with the development of mandibular asymmetry. This case-control study was performed with a cohort of 100 individuals divided in two subgroups. A subgroup of 50 subjects with mandibular asymmetry and another subgroup of 50 subjects without mandibular asymmetry. The subjects included in the study had to be from 6 to 16 years old, have a complete orthodontic file and no congenital syndrom or pathology. The following factors have been assessed: gender, mode and date of birth, dental trauma, visual disorders, ENT problems and parafunctions. An inter-group comparison had been performed by using statistical tests (Chisquare test, Fisher test and odds ratios calculation). The associated factors with mandibular asymmetry are male gender, oral ventilation, short-term vaginal nasalization, dental trauma and visual disorders. Asthma (symmetrical character of the anomaly ?), prematurity and caesarean section (by absence of trauma at delivery ?) would not be considered as associated factors. This case-control study is a first-line study that allows the identification of factors that may be associated with mandibular asymmetry. Ideally, a larger-scale prospective cohort study to increase the pertinence would clarify the risk factors for the development of mandibular asymmetry.
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http://dx.doi.org/10.1684/orthodfr.2020.19DOI Listing
October 2020

[Predictors of re-consultation and impact of the retainer on relapse and debonding rate ten years after removal of orthodontic appliances].

Orthod Fr 2020 10;91(3):179-190

Département d'Orthopédie Dento-Faciale, Faculté d'Odontologie, rue Guillaume Paradin, 69372 Lyon cedex 08, France, 56 rue de la République, 69150 Décines, France, Unité Fonctionnelle d'ODF, Centre de Traitements Dentaires, Hospices Civils de Lyon, 6-8 place Depéret, 69365 Lyon cedex 03, France.

Once the orthodontic retention phase is complete, a number of patients return to the office following retainer detachment or complaining about the stability of the result. The aim of this study was to search for predictors of re-consultation and to evaluate how the choice of retainer impacts re-consultation for misalignment or debonding. A systematic retrospective cohort study was conducted ten years after removal of orthodontic appliances. Of the 380 patients included, 23% re-consulted on average 4.5 years after appliance removal. The patients most likely to re-consult were those with a severe initial aesthetic deficit. Mandibular retainers bonded on six teeth resulted in three-fold more re-consultations than wires bonded exclusively on the canines, but the difference was non-significant. Mandibular retainers bonded on the canines certainly generated significantly more maintenance appointments than the six-teeth retainers, but fewer malposition problems (non-significant result). These results raise questions regarding indications for bonded maxillary retainers as opposed to removable devices and also regarding the management of long-term post-retention follow-up.
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http://dx.doi.org/10.1684/orthodfr.2020.17DOI Listing
October 2020

Adherence to cysteamine in nephropathic cystinosis: A unique electronic monitoring experience for a better understanding. A prospective cohort study: CrYSTobs.

Pediatr Nephrol 2021 Mar 9;36(3):581-589. Epub 2020 Sep 9.

Hospices Civils de Lyon, Service de Néphrologie Pédiatrique, et centre de référence maladies rénales et phosphocalciques rares- Néphrogones- Filière ORKiD -69500, Bron, France.

Introduction: In nephropathic cystinosis (NC), adherence to cysteamine remains challenging; poor adherence is worsening the disease progression with a decline of kidney function and increase of extrarenal morbidities. Our objective was to describe adherence to cysteamine in NC patients, using electronic monitoring systems.

Methods: Patients with confirmed NC, aged > 4 years and receiving oral cysteamine (short acting or delayed release formulation as standard of care) from 3 French reference centers, were included. Adherence to treatment was primarily assessed as the percentage of days with a good adherence score, adherence score rating from 0 (poor) to 2 (good). A descriptive analysis was performed after 1-year follow-up.

Results: Seventeen patients (10 girls, median age: 13.9 (5.4-33.0) years) were included. Median age at diagnosis was 17.0 (3.0-76.9) months and age at start of cysteamine was 21.0 (15.5-116.3) months. Median daily dose of cysteamine was 1.05 (0.55-1.63) g/m/day. Over the year, the median percentage of days with a good adherence score was 80 (1-99)% decreasing to 68 (1-99)% in patients > 11 years old. The median of average number of hours covered by treatment in a day was 22.5 (6.1-23.9) versus 14.9 (9.2-20.5) hours for delayed release versus short acting cysteamine.

Conclusion: Our data are the first describing a rather good adherence to cysteamine, decreasing in adolescents and adults. We described a potential interest of the delayed release formulation. Our data highlight the need for a multidisciplinary approach including therapeutic education and individualized approaches in NC patients transitioning to adulthood. Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04722-0DOI Listing
March 2021

Hemodynamic Response to Treatment and Outcomes in Pulmonary Hypertension Associated With Interstitial Lung Disease Versus Pulmonary Arterial Hypertension in Systemic Sclerosis: Data From a Study Identifying Prognostic Factors in Pulmonary Hypertension Associated With Interstitial Lung Disease.

Arthritis Rheumatol 2021 02 29;73(2):295-304. Epub 2020 Dec 29.

Hospices Civils de Lyon, Centre de Référence National des Maladies Pulmonaires Rares, Centre de Compétence de l'Hypertension Pulmonaire, Hôpital Louis Pradel, UMR 754, Université Claude Bernard Lyon 1, OrphaLung, RespiFil, and ERN-LUNG, Lyon, France.

Objective: Patients with systemic sclerosis and both pulmonary hypertension and interstitial lung disease (SSc-PH-ILD) generally carry a worse prognosis than patients with SSc and pulmonary arterial hypertension (SSc-PAH) without ILD. There is no evidence of the efficacy of PAH therapies in SSc-PH-ILD. We undertook this study to compare survival of and response to treatment in patients with SSc-PH-ILD and those with SSc-PAH.

Methods: We analyzed 128 patients (66 with SSc-PH-ILD and 62 with SSc-PAH) from 15 centers, in whom PH was diagnosed by right-sided heart catheterization; they were prospectively included in the PH registry. All patients received PAH-specific therapy. Computed tomography of the chest was used to confirm or exclude ILD.

Results: At baseline, patients with SSc-PH-ILD had less severe hemodynamic impairment than those with SSc-PAH (pulmonary vascular resistance 5.7 Wood units versus 8.7 Wood units; P = 0.0005) and lower diffusing capacity for carbon monoxide (median 25% [interquartile range (IQR) 18%, 35%] versus 40% [IQR 31%, 51%]; P = 0.0005). Additionally, patients with SSc-PH-ILD had increased mortality (8.1% at 1 year, 21.2% at 2 years, and 41.5% at 3 years) compared to those with SSc-PAH (4.1%, 8.7%, and 21.4%, respectively; P = 0.04). Upon treatment with PAH-targeted therapy, no improvement in the 6-minute walk distance was observed in either group. Improvement in the World Health Organization functional class was observed less frequently in patients with SSc-ILD-PH compared to those with SSc-PAH (13.6% versus 33.3%; P = 0.02). Hemodynamics improved similarly in both groups.

Conclusion: ILD confers a worse prognosis to SSc-PH. Response to PAH-specific therapy is clinically poor in SSc-PH-ILD but was not found to be hemodynamically different from the response observed in SSc-PAH.
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http://dx.doi.org/10.1002/art.41512DOI Listing
February 2021

Early Detection of Patients at Risk of Developing a Post-Traumatic Stress Disorder After an ICU Stay.

Crit Care Med 2020 Nov;48(11):1572-1579

Hospices Civils de Lyon, Hôpital Edouard Herriot, Service des Urgences Psychiatriques, Lyon, France.

Objectives: To evaluate the diagnostic accuracy of the Impact Event Scale-Revisited assessed following ICU discharge to predict the emergence of post-traumatic stress disorder symptoms at 3 months.

Design: Prospective cohort study.

Setting: Three medical or surgical ICU of a French university hospital (Lyon, France).

Patients: Patients greater than or equal to 18 years old, leaving ICU after greater than or equal to 2 nights of stay, between September 2017 and April 2018.

Interventions: Patients completed the Impact Event Scale-Revisited and the Peritraumatic Dissociative Experiences Questionnaire within 8 days after ICU discharge and the Impact Event Scale-Revisited again at 3 months by phone. Patients having an Impact Event Scale-Revisited greater than or equal to 35 at 3 months were considered as having post-traumatic stress disorder symptoms.

Measurements And Main Results: Among the 208 patients screened, 174 were included and 145 reassessed by phone at 3 months. Among the patients included at baseline, 43% presented symptoms of acute stress. At 3 months, 13% had an Impact Event Scale-Revisited greater than or equal to 35 and 17% had a score between 12 and 34. Regarding the performance of the Impact Event Scale-Revisited performed within 8 days after the ICU discharge to predict post-traumatic stress disorder symptoms at 3 months, the area under the curve was 0.90 (95% CI, 0.80-0.99), and an Impact Event Scale-Revisited greater than or equal to 12 had a sensitivity of 90%, a specificity of 71%, a positive predictive value of 32%, and a negative predictive value of 98%. History of anxiety disorder odds ratio = 3.7 (95% CI, 1.24-11.05; p = 0.02) and Impact Event Scale-Revisited greater than or equal to 12 odds ratio = 16.57 (95% CI, 3.59-76.46; p < 0.001) were identified as risk factors for post-traumatic stress disorder symptoms.

Conclusions: Impact Event Scale-Revisited assessed at ICU discharge has a good ability for the detection of patients at risk of developing post-traumatic stress disorder symptoms. Patients with history of anxiety disorder and those presenting acute stress symptoms at ICU discharge are more at risk to develop post-traumatic stress disorder symptoms.
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http://dx.doi.org/10.1097/CCM.0000000000004551DOI Listing
November 2020

Results of in vitro fertilization versus intrauterine insemination in patients with low anti-Müllerian hormone levels. A single-center retrospective study of 639 + 119 cycles.

J Gynecol Obstet Hum Reprod 2021 Mar 17;50(3):101874. Epub 2020 Jul 17.

Hospices Civils de Lyon, Service de médecine de la reproduction, Hopital Femme Mère Enfant, 59 Boulevard Pinel, 69500 Bron, France; Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69100 Villeurbanne, France.

Objectives: The aim of this study was to evaluate the results of in vitro fertilization (IVF) and intrauterine insemination (IUI) in a population of infertile women with low AMH levels, in whom both techniques were possible.

Methods: This was a retrospective analysis of 462 patients treated over 24 months in a single center comparing the live birth rates after 176 IUI and 639 IVF attempts in infertile couples. The women had AMH levels ≤ 1.2 ng/mL and at least one patent tube and their partner's sperm was of sufficient quality for IUI.

Results: The live birth rate after IVF was not sufficiently higher than after IUI, or than after IVF attempts converted to IUI for low response (odds ratios in multivariate analysis with respect to IVF: 0.61, p = 0.15 for IUI and 0.73, p = 0.6 for conversions). The pregnancy rates after IVF (13.0 %) and IUI (13.3 %) were similar (p = 0.4), and were non-significantly higher than the pregnancy rate in the IUI conversion group (8.8 %, p = 0.9). Nearly half (43.8 %) of all IVF cycles did not lead to embryo transfer.

Conclusion: In this group of women with AMH levels ≤ 1.2 ng/mL, IVF did not lead to a higher live birth rate than IUI, and more than 40 % of all IVF attempts did not lead to embryo transfer, suggesting that diminished ovarian reserve is not an indication for IVF over IUI.
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http://dx.doi.org/10.1016/j.jogoh.2020.101874DOI Listing
March 2021

Scope of health problems managed by general practitioners in Mali and France: awaiting practice transition in sub-Saharan Africa?

Fam Pract 2020 Oct;37(5):668-674

HESPER EA 7425, Université Claude Bernard Lyon 1, Univ. Lyon, Lyon, France.

Background: Minimal data are available on the clinical activity of general practitioners (GPs) in Africa.

Objective: To describe the health problems managed by GPs in Mali as compared with France where epidemiological transition is already advanced.

Methods: A retrospective, multicenter study, conducted in five Malian Community Health Centers. We compared their consultation data to those of the ECOGEN (Eléments de la COnsultation en médecine GENérale) study conducted in 128 French general practices, after data standardization for age and sex.

Results: Malian and French databases included 19 068 and 19 341 consultations, respectively. Patients had an average of 1.2 health problems managed per consultation in Mali, versus 2.2 in France. They were dominated by infections (51.3%) in Mali, including malaria (24.9%), pneumonia (9.0%) and gastrointestinal infections (5.0%). In comparison with French GPs, Malian GPs more frequently managed cardiovascular (20.2% versus 13.5%), respiratory (15.0% versus 12.4%) and digestive (13.3% versus 7.8%) problems, and less frequently musculoskeletal (3.1% versus 12.6%), endocrine/metabolic (1.5% versus 10.7%) and psychological (0.2% versus 8.2%) problems. The main activity performed by French GPs was prevention (11.0%), which was nominal in Mali. Apart from hypertension, which accounted for 18.9% of the health problems managed in Mali, chronic conditions were less often managed by Malian GPs than by French GPs (12.3% versus 39.6%).

Conclusions: Africa is currently at the crossroads where chronic conditions carried with the epidemiological transition are progressing, while the burden of communicable diseases is still overwhelming. Along with the enhancing medicalization of primary care in Mali, the transition of practices is just emerging.
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http://dx.doi.org/10.1093/fampra/cmaa035DOI Listing
October 2020

The Effects of Foot Reflexology on Chemotherapy-Induced Nausea and Vomiting in Patients with Digestive System or Lung Cancer: Protocol for a Randomized Controlled Trial.

JMIR Res Protoc 2020 Jul 14;9(7):e17232. Epub 2020 Jul 14.

HESPER EA7425, Université Lyon 1, Lyon, France.

Background: The side effects of chemotherapy, specifically chemotherapy-induced nausea and vomiting, are a concern for patients. To relieve these side effects, antiemetic drugs are recommended. However, some patients report that these drugs are not sufficiently effective. Moreover, patients with chronic disease, including cancer, are increasingly interested in complementary and alternative medicines, and express the desire for nonpharmacological treatments to be used in hospitals. Foot reflexology is a holistic approach that is reported to significantly reduce the severity of chemotherapy-induced nausea and vomiting in patients with breast cancer. Some of the chemotherapy treatments for patients with lung and digestive system cancer are moderately or highly emetic.

Objective: The primary objective of this study is to assess the benefits of foot reflexology, together with conventional treatments, on the severity and frequency of chemotherapy-induced nausea and vomiting in patients with lung or digestive system cancer. The secondary objectives to be assessed are quality of life, anxiety, and self-esteem.

Methods: This study is an open-label randomized controlled trial conducted over 22 months (18 months intervention and 4 months follow-up). Eligible participants are patients with a lung or digestive system cancer with an indication for platinum-based chemotherapy. Participants are randomized into two groups: conventional care with foot reflexology and conventional care without foot reflexology. Foot reflexology sessions (30 minutes) are performed on an outpatient or inpatient basis. It was estimated that 40 participants per group will be required. The benefits of foot reflexology will be assessed by comparing the relative change in the severity of nausea and vomiting, as assessed by a visual analogue scale, and the frequency of these side effects between the two groups. The secondary objectives will be assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; Hospital and Anxiety Depression Scale; and Body Image Questionnaire.

Results: This study was approved by the regional ethics committee (Île de France X CPP) on April 3, 2018 (No. ID RCB 2018-A00571-54). Enrollment started in June 2018. Data analysis will be performed during the second quarter of 2020 and results will be published in the last quarter of 2020.

Conclusions: The lack of knowledge regarding the efficacy and safety of foot reflexology limits oncologists to recommend it for this use. This study will provide evidence of the benefits of foot reflexology. If efficacy is confirmed, foot reflexology may be a promising complement to conventional antiemetic drugs.

Trial Registration: Clinicaltrials.gov NCT03508180; https://www.clinicaltrials.gov/ct2/show/NCT03508180.

International Registered Report Identifier (irrid): DERR1-10.2196/17232.
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http://dx.doi.org/10.2196/17232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388046PMC
July 2020

Prevalence of obesity among adult inpatients with COVID-19 in France.

Lancet Diabetes Endocrinol 2020 07 18;8(7):562-564. Epub 2020 May 18.

CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, Hôpital Lyon Sud, Pierre-Bénite 69495, France; Hospices Civils de Lyon, Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Pierre-Bénite 69495, France; COVID-O-HCL Consortium, Hospices Civils de Lyon, Lyon, France.

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http://dx.doi.org/10.1016/S2213-8587(20)30160-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234780PMC
July 2020

Observation and Interview-based Diurnal Sleepiness Inventory for measurement of sleepiness in patients referred for narcolepsy or idiopathic hypersomnia.

J Clin Sleep Med 2020 09;16(9):1507-1515

Center for Sleep Medicine and Respiratory Diseases, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France.

Study Objectives: First, to determine whether the 3-item Observation and Interview-based Diurnal Sleepiness Inventory (ODSI) measures the degree of excessive daytime sleepiness in patients with suspected narcolepsy or idiopathic hypersomnia (IH). Second, to assess the correlation between the ODSI and the Epworth Sleepiness Scale (ESS) as well as objective polysomnographic measurements. Third, to test the accuracy of the ODSI to detect narcolepsy or IH (narcolepsy/IH) compared with the ESS.

Methods: A total of 181 patients complaining of excessive daytime sleepiness filled in the ESS and the ODSI and underwent measurements including actigraphy, full-night polysomnography, Multiple Sleep Latency Test, and 24-hour bedrest sleep recording.

Results: Narcolepsy or IH was diagnosed in 76 patients. The ODSI found excessive daytime sleepiness in 92.3% of all patients and in 98.7% of those diagnosed with narcolepsy/IH. In the whole population, the ODSI was significantly positively correlated with the ESS (R = .547; 95% confidence interval: .436, .642; P < .001) and weakly with 24-hour total sleep time on bedrest recording (R = .208; 95% confidence interval: .056, .350; P = .047) but not with the Multiple Sleep Latency Test. The ODSI offered a higher negative (92.9%) and positive (44.9%) predictive value to detect narcolepsy/IH than did the ESS (66.7% and 43.3%, respectively). In the IH group, the ODSI's third-item score (daily sleepiness duration) was significantly higher in patients with than without increased 24-hour total sleep time (P = .023).

Conclusions: The ODSI is a brief, simple first-line questionnaire that explores both intensity and duration of daytime sleepiness and offers a high sensitivity to detect narcolepsy and IH.
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http://dx.doi.org/10.5664/jcsm.8574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970601PMC
September 2020

The area between ROC curves, a non-parametric method to evaluate a biomarker for patient treatment selection.

Biom J 2020 10 28;62(6):1476-1493. Epub 2020 Apr 28.

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

Treatment selection markers are generally sought for when the benefit of an innovative treatment in comparison with a reference treatment is considered, and this benefit is suspected to vary according to the characteristics of the patients. Classically, such quantitative markers are detected through testing a marker-by-treatment interaction in a parametric regression model. Most alternative methods rely on modeling the risk of event occurrence in each treatment arm or the benefit of the innovative treatment over the marker values, but with assumptions that may be difficult to verify. Herein, a simple non-parametric approach is proposed to detect and assess the general capacity of a quantitative marker for treatment selection when no overall difference in efficacy could be demonstrated between two treatments in a clinical trial. This graphical method relies on the area between treatment-arm-specific receiver operating characteristic curves (ABC), which reflects the treatment selection capacity of the marker. A simulation study assessed the inference properties of the ABC estimator and compared them with other parametric and non-parametric indicators. The simulations showed that the estimate of the ABC had low bias, power comparable to parametric indicators, and that its confidence interval had a good coverage probability (better than the other non-parametric indicator in some cases). Thus, the ABC is a good alternative to parametric indicators. The ABC method was applied to data of the PETACC-8 trial that investigated FOLFOX4 versus FOLFOX4 + cetuximab in stage III colon adenocarcinoma. It enabled the detection of a treatment selection marker: the DDR2 gene.
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http://dx.doi.org/10.1002/bimj.201900171DOI Listing
October 2020

Management and prognosis of localized duodenal neuroendocrine neoplasms.

Neuroendocrinology 2020 Apr 24. Epub 2020 Apr 24.

Introduction: The characteristics, prognostic factors, and management of duodenal neuroendocrine neoplasms (dNEN) are ill-defined given their rarity. Whether non-surgical management could be appropriate in good-prognosis non-metastatic dNEN, as for pancreatic NEN (pNEN), is unknown. We aimed to describe the management and prognosis of non-metastatic dNEN patients.

Methods: All consecutive patients with non-metastatic dNEN managed between 1981 and 2018 in two expert centers were included. Recurrence-free survival (RFS) and factors associated with recurrence were estimated.

Results: A total of 145 patients with dNEN were included. Twenty-eight sporadic, non-functioning, small (median size: 7mm), dNEN underwent endoscopic resection, with a 5-year recurrence-free survival rate of 89.4%. Local recurrence occurred in two patients, who underwent surgery without new event. The 5-year recurrence-free rate was 87.9% in patients who underwent surgery. In univariate analysis, age, size, Ki67, and lymph-node involvement were significantly associated with worse RFS for all treated (endoscopy/surgery) dNEN; multivariate analysis found age, size, and lymph-node involvement were associated with worse RFS.

Conclusion: Selected non-metastatic dNEN had a favorable outcome and appear suitable for a less invasive therapeutic strategy than oncological surgery.
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http://dx.doi.org/10.1159/000508102DOI Listing
April 2020

Collaboration between academics, small pharmaceutical company and patient organizations in the development of a new formulation of cysteamine in nephropathic cystinosis: A successful story.

Therapie 2020 Apr 13;75(2):169-173. Epub 2020 Feb 13.

Hospices civils de Lyon, EPICIME-CIC 1407 de Lyon, Inserm, department of clinical epidemiology, CHU-Lyon, 69677 Bron, France; Université de Lyon 1, 69000 Lyon, France.

Rare diseases usually concern small and disseminated population. Implementing clinical research with the right design, outcomes measures and the recruitment of patients are challenges. Collaborations, training and multidisciplinary approach are often required. In this article, we provide an overview of a successful collaboration in nephropathic cystinosis (NC), focusing on what was the key of success, the interactions between academics, the pharmaceutical company and patients organizations. NC is considered as a very rare disease. In 2010, a new formulation of cysteamine, the only available treatment to improve renal outcome of the disease, was proposed by a small American company. Studies were implemented in France under the coordination of an expert of the disease and the clinical investigation center of Lyon. The collaboration resulted in a good recruitment and retention of the patients in the study and most of all in the availability of the new formulation in France. Patients could have facilitated the research by being involved in the early stages of the studies. Involving patients and public early in the process is particularly important in rare diseases as the patient is a great source of knowledge and has his own expectations. Priorities of research, design, conduct and reporting of clinical trials can be defined in collaboration with adults but also with young patients or public, the first concerned in rare diseases. This concept is still to be developed and improved especially with paediatric patients.
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http://dx.doi.org/10.1016/j.therap.2020.02.008DOI Listing
April 2020

Age- and Sex-Specific TSH Upper-Limit Reference Intervals in the General French Population: There Is a Need to Adjust Our Actual Practices.

J Clin Med 2020 Mar 14;9(3). Epub 2020 Mar 14.

Hospices Civils de Lyon, Fédération d'Endocrinologie, Groupement Hospitalier Est, F-69677 Bron cedex, France.

It is well known that thyroid dysfunction increases with age. This study is aimed to determine reference intervals, in males and females, suitable for thyroid disease exploration during adult life using routinely collected serum thyrotropin (TSH) data in a tertiary center from 2007 to 2018. Over 11 years, 295,775 TSH levels were measured in a single lab. Among the 156,025 TSH results available for analysis, 90,538 values were from female subjects, 82,019 were from patients aged >60 years and 26,825 were from patients aged >80 years. By using an indirect approach, we determined reference values of TSH adapted to age and sex, and we then evaluated the proportion of patients who would have been reclassified with these reference values. The median TSH ranged from 1.2-1.4 mUI/L during the study period. The upper limit of reference range of TSH increased with age; in females the median to 97.5th percentile values increased continuously from the age of 30 years to the oldest age group. Using new calculated reference values in patients with TSH above the conventional upper-limit reference value (4 mUI/L), the proportion of results reclassified as within the reference interval among patients aged >60 years ranged, according to age group, from 50.5% to 65.1% of females and from 33.0% to 37.7% of males. The use of TSH age-specific and sex-specific upper-limit reference values led to the reclassification of a great number of samples, notably among women. This suggests that age-specific TSH upper-limit reference intervals in daily practice should be used in order to avoid misclassification.
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http://dx.doi.org/10.3390/jcm9030792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141356PMC
March 2020

A 40-Month Follow-Up of Ebola Virus Disease Survivors in Guinea (PostEbogui) Reveals Long-Term Detection of Ebola Viral Ribonucleic Acid in Semen and Breast Milk.

Open Forum Infect Dis 2019 Dec 8;6(12):ofz482. Epub 2019 Nov 8.

TransVIHMI, IRD/INSERM/Monpellier University, Montpellier, France.

Background: With the increasing frequency and impact of Ebola virus disease (EVD) outbreaks illustrated by recent epidemics, a good understanding of the extent of viral persistance or ribonucleic acid (RNA) detection in body fluids from survivors is urgently needed.

Methods: Ebola viral RNA shedding was studied with molecular assays in semen (n = 1368), urine (n = 1875), cervicovaginal fluid (n = 549), saliva (n = 900), breast milk (n = 168), and feces (n = 558) from EVD survivors in Guinea (PostEbogui cohort, n = 802) at a regular base period until 40 months after inclusion.

Results: Twenty-seven of 277 (9.8%) male survivors tested positive for Ebola RNA in at least 1 semen sample. The probability of remaining positive for Ebola RNA in semen was estimated at 93.02% and 60.12% after 3 and 6 months. Viral RNA in semen was more frequent in patients with eye pain ( = .036), joint pain ( = .047), and higher antibody levels to Ebola virus antigens (nucleoprotein [ = .001], glycoprotein [ = .05], and viral protein-40 [ = .05]). Ebola RNA was only rarely detected in the following body fluids from EVD survivors: saliva (1 of 454), urine (2 of 593), breast milk (2 of 168), cervicovaginal secretions (0 of 273), and feces (0 of 330). Ribonucleic acid was detected in breast milk 1 month after delivery but 500 days after discharge of Ebola treatment unit (ETU) in 1 woman who became pregnant 7 months after discharge from the ETU.

Conclusions: The frequency and potential long-term presence of viral RNA in semen confirmed that systematic prevention measures in male survivors are required. Our observation in breast milk suggests that our knowledge on viral reservoir in immune-privileged sites and its impact are still incomplete.
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http://dx.doi.org/10.1093/ofid/ofz482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047953PMC
December 2019

Risk of neoplastic change in large gastric hyperplastic polyps and recurrence after endoscopic resection.

Endoscopy 2020 06 2;52(6):444-453. Epub 2020 Mar 2.

Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'Hépato-Gastro-Entérologie et d'Endoscopie Digestive, Lyon, France.

Background: Gastric hyperplastic polyps (GHPs) have a risk of neoplastic transformation reaching 5 %. Current endoscopic resection techniques appear suboptimal with a high risk of local recurrence. This study assessed the outcomes of endoscopic resection for GHPs and identified risk factors for recurrence and neoplastic transformation.

Methods: This retrospective, multicenter, European study included adult patients with at least one GHP ≥ 10 mm who underwent endoscopic resection and at least one follow-up endoscopy. Patients with recurrent GHPs or hereditary gastric polyposis were excluded. All data were retrieved from the endoscopy, pathology, and hospitalization reports.

Results: From June 2007 to August 2018, 145 GHPs in 108 patients were included. Recurrence after endoscopic resection was 51.0 % (74 /145) in 55 patients. R0 resection or en bloc resection did not impact the risk of polyp recurrence. In multivariate analysis, cirrhosis was the only risk factor for recurrence (odds ratio [OR] 4.82, 95 % confidence interval [CI] 1.33 - 17.46;  = 0.02). Overall, 15 GHPs (10.4 %) showed neoplastic transformation, with size > 25 mm (OR 10.24, 95 %CI 2.71 - 38.69;  < 0.001) and presence of intestinal metaplasia (OR 5.93, 95 %CI 1.56 - 22.47;  = 0.01) being associated with an increased risk of neoplastic transformation in multivariate analysis.

Conclusions: Results confirmed the risk of recurrence and neoplastic transformation of large GHPs. The risk of neoplastic change was significantly increased for lesions > 25 mm, with a risk of high grade dysplasia appearing in polyps ≥ 50 mm. The risk of recurrence was high, particularly in cirrhosis patients, and long-term follow-up is recommended in such patients.
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http://dx.doi.org/10.1055/a-1117-3166DOI Listing
June 2020

Endoscopic submucosal dissection with double clip and rubber band traction for residual or locally recurrent colonic lesions after previous endoscopic mucosal resection.

Endoscopy 2020 05 7;52(5):383-388. Epub 2020 Feb 7.

Endoscopy and Gastroenterology Unit, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.

Background: Endoscopic submucosal dissection (ESD) of residual or locally recurrent (RLR) colonic lesions after previous endoscopic mucosal resection (EMR) is an attractive but challenging technique. The present study aimed to evaluate the effectiveness and safety of ESD with double clip and rubber band traction (DCT-ESD) of RLR colonic lesions.

Methods: We retrospectively analyzed all consecutive DCT-ESD procedures for RLR colonic lesions (rectum excluded) performed in two French centers. The frequency of en bloc and R0 resections, procedure speed, additional surgery, and complications were evaluated. R0 resection was also used to investigate the learning curve.

Results: Among the 53 resections, 49 (92.5 %) were performed en bloc and 42 (79.2 %) achieved R0. The median procedure speed was 21 mm/min. There were four (7.5 %) intraoperative perforations and one delayed bleeding; these were successfully treated endoscopically. There was no salvage surgery for complications. The R0 rate increased from 16/26 (61.5 %) for the first 26 procedures to 26/27 (96.3 %,  = 0.002) for the last 27 procedures.

Conclusions: DCT-ESD appears to be a safe and effective treatment for RLR colonic lesions after EMR.
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http://dx.doi.org/10.1055/a-1104-5210DOI Listing
May 2020

Compositional and mechanical properties of growing cortical bone tissue: a study of the human fibula.

Sci Rep 2019 11 26;9(1):17629. Epub 2019 Nov 26.

Univ Lyon, Université Claude Bernard Lyon 1, INSERM, Lyos UMR1033, F69622, Lyon, France.

Human cortical bone contains two types of tissue: osteonal and interstitial tissue. Growing bone is not well-known in terms of its intrinsic material properties. To date, distinctions between the mechanical properties of osteonal and interstitial regions have not been investigated in juvenile bone and compared to adult bone in a combined dataset. In this work, cortical bone samples obtained from fibulae of 13 juveniles patients (4 to 18 years old) during corrective surgery and from 17 adult donors (50 to 95 years old) were analyzed. Microindentation was used to assess the mechanical properties of the extracellular matrix, quantitative microradiography was used to measure the degree of bone mineralization (DMB), and Fourier transform infrared microspectroscopy was used to evaluate the physicochemical modifications of bone composition (organic versus mineral matrix). Juvenile and adult osteonal and interstitial regions were analyzed for DMB, crystallinity, mineral to organic matrix ratio, mineral maturity, collagen maturity, carbonation, indentation modulus, indicators of yield strain and tissue ductility using a mixed model. We found that the intrinsic properties of the juvenile bone were not all inferior to those of the adult bone. Mechanical properties were also differently explained in juvenile and adult groups. The study shows that different intrinsic properties should be used in case of juvenile bone investigation.
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http://dx.doi.org/10.1038/s41598-019-54016-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879611PMC
November 2019

Endoscopic mucosal resection with anchoring of the snare tip: multicenter retrospective evaluation of effectiveness and safety.

Endosc Int Open 2019 Nov 23;7(11):E1496-E1502. Epub 2019 Oct 23.

Gastroenterology and Endoscopy Unit, Dupuytren University Hospital, Limoges, France.

 Endoscopic mucosal resection (EMR) with snare is the recommended technique to resect non-invasive colorectal neoplastic lesions between 10 and 30 mm in diameter. The objective of EMR is to resect completely the neoplastic tissue en bloc and preferably with free margins (R0), avoiding recurrences. Anchoring the tip of the snare in the submucosa is a technical trick that allows snare sliding to be reduced and larger pieces to be caught. The aim of the present study was to evaluate the effectiveness and safety of anchoring-EMR (A-EMR).  This was a retrospective analysis of A-EMR procedures for lesions of diameter between 10 and 30 mm (endoscopic evaluation) performed consecutively in four French centers between May 2017 and January 2018. A-EMR was routinely performed for all EMR using Olympus conventional snares (10 or 25 mm). The primary outcome was evaluation of the proportion of R0 resections.  A total of 141 A-EMR procedures were performed by 10 operators. Mean lesion size was 19.8 mm. Anchoring was feasible in 96.5 % of cases. There were 81.6 % en bloc resections and 70.2 % R0 resections, with the percentage of procedures decreasing with increasing lesion size (82.8 % < 20 mm, 55.3 % 21 - 30 mm, and 50.0 % > 30 mm,  = 0.002). Complete perforations closed endoscopically occurred in 3/141 cases (2.1 %); none occurred in lesions < 20 mm in size (0 /87).  The A-EMR technique appears to be promising with a high proportion of R0 for lesions of 10 - 20 mm in size without any perforations. It could also offer an alternative to endoscopic submucosal dissection (ESD), or to hybrid techniques to reach R0 for lesions between 20 and 30 mm in size.
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http://dx.doi.org/10.1055/a-0990-9068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811348PMC
November 2019

A simplified table using validated diagnostic criteria is effective to improve characterization of colorectal polyps: the CONECCT teaching program.

Endosc Int Open 2019 Oct 1;7(10):E1197-E1206. Epub 2019 Oct 1.

Department of Endoscopy and Gastroenterology, Pavillon L, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France.

Accurate real-time endoscopic characterization of colorectal polyps is key to choosing the most appropriate treatment. Mastering the currently available classifications is challenging. We used validated criteria for these classifications to create a single table, named CONECCT, and evaluated the impact of a teaching program based on this tool.  A prospective multicenter study involving GI fellows and attending physicians was conducted. During the first session, each trainee completed a pretest consisting in histological prediction and choice of treatment of 20 colorectal polyps still frames. This was followed by a 30-minute course on the CONECCT table, before taking a post-test using the same still frames reshuffled. During a second session at 3 - 6 months, a last test (T3 M) was performed, including these same still frames and 20 new ones.  A total 419 participants followed the teaching program between April 2017 and April 2018. The mean proportion of correctly predicted/treated lesions improved significantly from pretest to post-test and to T3 M, from 51.0 % to 74.0 % and to 66.6 % respectively (  < 0.001). Between pretest and post-test, 343 (86.6 %) trainees improved, and 153 (75.4 %) at T3 M. Significant improvement occurred for each subtype of polyp for fellows and attending physicians. Between the two sessions, trainees continued to progress in the histology prediction and treatment choice of polyps CONECCT IIA. Over-treatment decreased significantly from 30.1 % to 15.5 % at post-test and to 18.5 % at T3 M (  < 0.001).  The CONECCT teaching program is effective to improve the histology prediction and the treatment choice by gastroenterologists, for each subtype of colorectal polyp.
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http://dx.doi.org/10.1055/a-0962-9737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773571PMC
October 2019

Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease-driven strategy in patients with chronic lymphocytic leukaemia (ICLL07 FILO): a single-arm, multicentre, phase 2 trial.

Lancet Haematol 2019 Sep 16;6(9):e470-e479. Epub 2019 Jul 16.

Department of Hematology, CHRU Nancy, Nancy, France.

Background: In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients.

Methods: We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up.

Findings: Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred.

Interpretation: Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed.

Funding: Roche, Janssen.
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http://dx.doi.org/10.1016/S2352-3026(19)30113-9DOI Listing
September 2019

Multicenter Evaluation of Clinical Efficacy and Safety of Per-oral Endoscopic Myotomy in Children.

J Pediatr Gastroenterol Nutr 2019 11;69(5):523-527

Gastroenterology, Edouard Herriot Hospital, Hospices Civils de Lyon and Lyon University, Lyon, France.

Objectives: Per-oral endoscopic myotomy (POEM) is a recommended treatment modality for achalasia, but there is little published data for its use in children. The objective of the present study was to evaluate whether POEM is clinically effective and safe for children.

Methods: International multicenter retrospective study conducted in 14 tertiary centers that included consecutive children who underwent POEM between January 2012 and August 2018. Outcomes, such as clinical response were assessed whenever available. Adverse events and factors associated with clinical failure were also investigated.

Results: A total of 117 patients (mean ± SD age: 14.2 ± 3.7 years) underwent POEM for achalasia (type I, n = 36; type II n=66; type III, n=8). Among these, 30 (26%) were pretreated (botulinum injection and/or pneumatic dilatation). Mean ± SD baseline Eckardt score was 7.5 ± 2.0. Clinical success was achieved in 90.6% of cases (95%CI [83.8%;95.2%]) in the intention-to-treat analysis. The mean ± SD Eckardt score post-POEM was 0.9 ± 1.2 (P < 0.001). The mean duration of follow-up time 545 days (range: 100-1612). A total of 7 adverse events occurred (4 mucosotomies, 2 subcutaneous emphysema, 1 esopleural fistula). Gastroesophageal reflux symptoms were seen in 17 patients (15%); missing data for 10 patients (9%). There was a trend towards more frequent clinical failure in achalasia associated with genetic disorders (40% vs 8%, P = 0.069).

Conclusions: POEM in pediatric patients appears to be effective and safe, although there was a trend towards more frequent clinical failure achalasia associated with genetic disorders. Further studies are needed to assess the long-term outcomes, especially the consequences of GERD.
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http://dx.doi.org/10.1097/MPG.0000000000002432DOI Listing
November 2019

Botulinum toxin for the treatment of hypercontractile esophagus: Results of a double-blind randomized sham-controlled study.

Neurogastroenterol Motil 2019 05 11;31(5):e13587. Epub 2019 Apr 11.

CHU Bordeaux, Gastroenterology, Université de Bordeaux, Bordeaux, France.

Introduction: Botulinum toxin injection is known to be efficient to treat achalasia. We conducted a randomized trial in order to evaluate its efficacy to treat symptomatic hypercontractile esophageal disorders as characterized by esophageal high-resolution manometry.

Methods: Patients with significant dysphagia and/or thoracic pain related to an hypercontractile esophageal motility disorder as defined by the Chicago Classification were randomized to receive an injection of botulinum toxin (100 U in 10 points in the distal part of the esophageal wall) or a sham procedure. Symptoms were assessed at 3 months with the Eckardt score. Patients could receive a first or second botulinum toxin injection 1 month later if symptoms persisted.

Results: Twenty-three patients (13 women, mean age 60 years) were included: 13 received botulinum toxin injection, and 10 a sham procedure. The improvement of symptoms at 3 months was significant compared to baseline, but similar in the active treatment and sham procedure arms. However, there was no change in quality of life scores. Seventeen patients received a second injection at 4 months. There was a significant trend toward improvement of symptoms up to the end of follow-up at 12 months, without a significant relationship with the administration of botulinum toxin.

Discussion: Botulinum toxin injection is not superior to a sham procedure to improve symptoms related to hypercontractile esophageal disorders, suggesting an important placebo effect in for this type of disease. This observation must be taken into account when evaluating more aggressive therapies such as endoscopic myotomy (clinicaltrials.gov: NCT01955174).
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http://dx.doi.org/10.1111/nmo.13587DOI Listing
May 2019

Bench Assessment of the Effect of a Collapsible Tube on the Efficiency of a Mechanical Insufflation-Exsufflation Device.

Respir Care 2019 Jul 12;64(7):752-759. Epub 2019 Mar 12.

Réanimation médicale, Hospices Civils de Lyon, Lyon, France.

Background: Collapsibility of upper airways may impair the efficacy of mechanical insufflation-exsufflation (MI-E) devices. The aim of this study was to determine the effect of a collapsible tube on peak expiratory flow (PEF) when using an MI-E device.

Methods: An MI-E device was attached to a lung simulator. Resistance was set at 5 and 20 cm HO/L/s (R5, R20) for compliance settings of 20, 40, and 60 mL/cm HO (C20, C40, C60). A series of 5 cycles were delivered at 3 pressures in the following order: +30/-30, +40/-40, and +50/-50 cm HO for each compliance/resistance combination with and without the collapsible tube. Each respiratory mechanics profile was tested in random order. Pressure and flow were measured upstream of the MI-E device, and the primary outcome measure was PEF. The relationships of PEF to maximum expiratory pressure were compared with and without the collapsible tube using a linear regression model.

Results: For the C20-R5 condition, the effect of the collapsible tube on the intercept (-0.35 cm HO) was not significant, but this was offset by a significant (and the largest) increase in slope (+0.12 L/s/cm HO). For the C60-R20 condition, the effect of the collapsible tube on the slope (-0.003 L/s/cm HO) was not significant, but this was offset by a significant (and the largest) increase of the intercept (+3.16 cm HO) at 30 cm HO expiratory pressure. For the other conditions, the collapsible tube significantly increased PEF at 30 cm HO expiratory pressure, and the gap further increased above this pressure as the slope increased with the collapsible tube.

Conclusions: The collapsible tube resulted in a higher PEF for all respiratory mechanics profiles tested.
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http://dx.doi.org/10.4187/respcare.06478DOI Listing
July 2019

A Bayesian method to estimate the optimal threshold of a marker used to select patients' treatment.

Stat Methods Med Res 2020 01 2;29(1):29-43. Epub 2019 Jan 2.

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

The use of a quantitative treatment selection marker to choose between two treatment options requires the estimate of an optimal threshold above which one of these two treatments is preferred. Herein, the optimal threshold expression is based on the definition of a utility function which aims to quantify the expected utility of the population (e.g. life expectancy, quality of life) by taking into account both efficacy (success or failure) and toxicity of each treatment option. Therefore, the optimal threshold is the marker value that maximizes the expected utility of the population. A method modelling the marker distribution in patient subgroups defined by the received treatment and the outcome is proposed to calculate the parameters of the utility function so as to estimate the optimal threshold and its 95% credible interval using the Bayesian inference. The simulation study found that the method had low bias and coverage probability close to 95% in multiple settings, but also the need of large sample size to estimate the optimal threshold in some settings. The method is then applied to the PETACC-8 trial that compares the efficacy of chemotherapy with a combined chemotherapy + anti-epidermal growth factor receptor in stage III colorectal cancer.
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http://dx.doi.org/10.1177/0962280218821394DOI Listing
January 2020