University of Grenoble
  • Grenoble, France
Recent publications
Background The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. Methods Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; ≥20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. Results The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22–0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS ≥ 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. Conclusion OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC.
Background: Whether the COVID-19 pandemic impacts Positive Airway Pressure (PAP) adherence over the long-term is unknown and only preliminary short-term data have been reported. Methods: With the aim of describing the impact of the first and second waves of COVID-19 on PAP adherence during 2020 in France, we designed a cross-sectional study of Sleep-Apnea (SA)-patients under PAP telemonitoring. To examine PAP adherence in adult SA patients, we assessed de-identified data from a non-profit healthcare provider database during the period January 1, 2019 to December 31, 2020. Included patients met the following criteria: (i) PAP-treated for at least 4 months before January 1, 2019 and with continuous PAP during both 2019 and 2020; (ii) ≥ 360 daily PAP telemonitored data per year. For PAP adherence, data were collected using the PAP-software. Results: 8477/10482 patients were finally included in the analysis [72.4% male, median age 70 years (IQ25-75: 61-77], 25.6% < 62 years old, initial Apnea-Hypopnea Index (AHI) of 41 (31-59)/h. Median PAP adherence was 7.21 (6.12-8.10) h/day in 2020 versus 7.12 (6.05-8.02) h/day in 2019, p < 0.001. The median difference in PAP adherence between the first 2020 lockdown and the corresponding 2019 weeks was 9.75 (CI95% 8.75-10.75) min/day, p < 0.001. The median difference in PAP adherence between the second 2020 lockdown and the corresponding 2019 weeks was 5.00 (CI95% 4.00-6.00) min/day, p < 0.001. If we consider the minimal clinically important difference of 30 min for PAP adherence, 30.4% and 26% of the patients increased their PAP adherence by at least 30 min during the first and second lockdowns respectively; 17.6% and 19.3% of the patients lowered their PAP adherence by at least 30 min in the first and second lockdowns, respectively. Conclusion: During the first and second lockdowns, the COVID-19 pandemic had a clinically irrelevant effect on PAP adherence for the study population. Future studies are needed to describe COVID-19 pandemic impact on PAP adherence not only for long-term PAP-treated SA patients but also for incident cases. Trial registration The COVADENE study was registered on March 1st, 2021 on ClinicalTrials.gov (Identifier: NCT04775966).
Background PEEP selection in severe COVID-19 patients under extracorporeal membrane oxygenation (ECMO) is challenging as no study has assessed the alveolar recruitability in this setting. The aim of the study was to compare lung recruitability and the impact of PEEP on lung aeration in moderate and severe ARDS patients with or without ECMO, using computed tomography (CT). Methods We conducted a two-center prospective observational case–control study in adult COVID-19-related patients who had an indication for CT within 72 h of ARDS onset in non-ECMO patients or within 72 h after ECMO onset. Ninety-nine patients were included, of whom 24 had severe ARDS under ECMO, 59 severe ARDS without ECMO and 16 moderate ARDS. Results Non-inflated lung at PEEP 5 cmH 2 O was significantly greater in ECMO than in non-ECMO patients. Recruitment induced by increasing PEEP from 5 to 15 cmH 2 O was not significantly different between ECMO and non-ECMO patients, while PEEP-induced hyperinflation was significantly lower in the ECMO group and virtually nonexistent. The median [IQR] fraction of recruitable lung mass between PEEP 5 and 15 cmH 2 O was 6 [4–10]%. Total superimposed pressure at PEEP 5 cmH 2 O was significantly higher in ECMO patients and amounted to 12 [11–13] cmH 2 O. The hyperinflation-to-recruitment ratio (i.e., a trade-off index of the adverse effects and benefits of PEEP) was significantly lower in ECMO patients and was lower than one in 23 (96%) ECMO patients, 41 (69%) severe non-ECMO patients and 8 (50%) moderate ARDS patients. Compliance of the aerated lung at PEEP 5 cmH 2 O corrected for PEEP-induced recruitment (C BABY LUNG ) was significantly lower in ECMO patients than in non-ECMO patients and was linearly related to the logarithm of the hyperinflation-to-recruitment ratio. Conclusions Lung recruitability of COVID-19 pneumonia is not significantly different between ECMO and non-ECMO patients, with substantial interindividual variations. The balance between hyperinflation and recruitment induced by PEEP increase from 5 to 15 cmH 2 O appears favorable in virtually all ECMO patients, while this PEEP level is required to counteract compressive forces leading to lung collapse. C BABY LUNG is significantly lower in ECMO patients, independently of lung recruitability.
Background: The objective of this study was to assess the preliminary efficacy and safety of conservative management compared with systematic suture in isolated vaginal or first-degree perineal tears after birth. Methods: We conducted a preliminary efficacy, open-label, randomized, controlled, and prospective trial. This study implemented Simon's 2-step plan (interim analysis and final analysis) to test the success rate of the digital compression strategy group. Primiparous women aged ≥18 years with isolated vaginal or first-degree perineal tears after spontaneous vaginal birth of a cephalic presenting term (≥37 weeks) neonate were randomly allocated to the conservative management (CM) group (digital compression if bleeding followed by suture if persistent bleeding) or a systematic suture (SS) group. The primary outcome was the success of the intervention 10 days after delivery, defined by pain as evaluated using a visual analog scale < 3, satisfactory healing defined by a REEDA score ≤ 2, and no bleeding or infection. Sexual well-being was assessed at 2 and 6 months postpartum. Results: Among 861/2209 eligible women, 143 consenting women with a superficial perineal tear were randomized: 72 in the systematic suture group and 71 in the conservative management group. Success rate was 87.8% (90% CI [70.5-93.54]) (42/55) in the systematic suture group vs 90% (90% CI [78.3-93.8]) (53/61) in the conservative management group. The REEDA score was significantly higher in the systematic suture group (1.4 vs 0.9; P = 0.036). Perineal pain was significantly higher at day 1 in the systematic suture group (2.38 vs 1.69; P = 0.034). For the Female Sexual Functional Index score, no significant difference was found between the two groups at inclusion or at 2 and 6 months postpartum. Conclusions: Conservative management of superficial perineal tears shows an efficacy rate ≥90%. Women in the conservative management group had less pain at the 1st day follow-up and lower REEDA scores at the 10th day follow-up.
Access to kidney transplantation is limited by HLA-specific sensitization. Desensitization strategies enable crossmatch-positive kidney transplantation. In this review, we describe clinical experience gained over the last 20 y using desensitization strategies before kidney transplantation and describe the different tools used (both drugs and apheresis options), including IVIg, rituximab, apheresis techniques, interleukin-6 interference, proteasome inhibition, enzymatic degradation of HLA antibodies, complement inhibition, and B cytokine interference. Although access to transplantation for highly sensitized kidney transplantation candidates has been vastly improved by desensitization strategies, it remains, however, limited by the recurrence of HLA antibodies after transplantation and the occurrence of antibody-mediated rejection.
Angioedema (AE) is a reason for emergency care when it is severe. Care is difficult when the diagnostic is not known before the attack: mast cell (MC) or bradykinin (BK) mediated. One is very common but often benign, the other rare but potentially fatal. The French national reference center of angioedema (CREAK) provides emergency physicians with a hotline and a guideline to help them manage their patients. This study aimed to describe the clinical features of AE episodes prompting a call on the CREAK hotline and classify patients depending on the suspected cause of the AE. This is a retrospective study between March and August 2019. Each physician calling on the CREAK hotline was asked to fill a clinical description form for the AE emergency. Known patients of CREAK was excluded. Eighty four patients were included. Forty one (48.8%) in the angiotensin converting enzyme inhibitors induced acquired angioedema (ACEi-AAE), 39 (46.4%) in the mast cell induced angioedema, and 4 (4.8%) in the Bradykinin mediated angioedema. The mast cell induced angioedema patients have more history of hives (29.3%) than ACEi-AAE (2.4%, P = .0004). ACEi-AAE mainly affected the tongue (58.5% vs 25.6%, P = .003) and larynx (29.3% vs 13%, P = .001). In 65.5% of cases, the etiological diagnosis was not mentioned by the appellant, but made by the hotline. In 31% of cases, the hotline suggested the administration of a specific treatment not previously provided by the caller. All the doctors who called the hotline appreciate this tele-expertise especially in case of ACEi-AAE presumptions. In addition to providing rapid AE expertise, this service also allows to educate physicians in the management of AE irrespective of its origin.
Purpose To compare the treatment response and progression-free survival (PFS) in advanced hepatocellular carcinoma (HCC) patients who received sorafenib treatment either alone or combined with radioembolization (RE). Methods Follow-up images of the patients treated within a multicenter phase II trial (SORAMIC) were assessed by mRECIST. A total of 177 patients (73 combination arm [RE + sorafenib] and 104 sorafenib arm) were included in this post-hoc analysis. Response and progression characteristics were compared between treatment arms. Survival analyses were done to compare PFS and post-progression survival between treatment arms. Multivariate Cox regression analysis was used to compare survival with factors known to influence PFS in patients with HCC. Results The combination arm had significantly higher objective response rate (61.6% vs. 29.8%, p < 0.001), complete response rate (13.7% vs. 3.8%, p = 0.022), and a trend for higher disease control rate (79.2% vs. 72.1%, p = 0.075). Progression was encountered in 116 (65.5%) patients and was more common in the sorafenib arm (75% vs. 52.0%, p = 0.001). PFS (median 8.9 vs. 5.4 months, p = 0.022) and hepatic PFS were significantly better in the combination arm (9.0 vs. 5.7 months, p = 0.014). Multivariate analysis confirmed the treatment arm as an independent predictor of PFS. Conclusion In advanced HCC patients receiving sorafenib, combination with RE has an additive anticancer effect on sorafenib treatment resulting in a higher and longer tumor response. However, the enhanced response did not translate into prolonged survival. Better patient selection and superselective treatment could improve outcomes after combination therapy.
Summary Background Data EA is the most frequent congenital esophageal malformation. Long gap EA remains a therapeutic challenge for pediatric surgeons. A case case-control prospective study from a multi-institutional national French data base was performed to assess the outcome, at age of 1 and 6 years, of long gap esophageal atresia (EA) compared with non-long gap EA/tracheo-esophageal fistula (TEF). The secondary aim was to assess whether initial treatment (delayed primary anastomosis of native esophagus vs. esophageal replacement) influenced mortality and morbidity at ages 1 and 6 years. Methods A multicentric population-based prospective study was performed and included all patients who underwent EA surgery in France from January 1, 2008 to December 31, 2010. A comparative study was performed with non-long gap EA/TEF patients. Morbidity at birth, 1 year, and 6 years was assessed. Results Thirty-one patients with long gap EA were compared with 62 non-long gap EA/TEF patients. At age 1 year, the long gap EA group had longer parenteral nutrition support and longer hospital stay and were significantly more likely to have complications both early post-operatively and before age 1 year compared with the non-long gap EA/TEF group. At 6 years, digestive complications were more frequent in long gap compared to non-long gap EA/TEF patients. Tracheomalacia was the only respiratory complication that differed between the groups. Spine deformation was less frequent in the long gap group. There were no differences between conservative and replacement groups at ages 1 and 6 years except feeding difficulties that were more common in the native esophagus group. Conclusions Long gap strongly influenced digestive morbidity at age 6 years.
Background Survival after out-of-hospital cardiac arrest (OHCA) remains poor. A physiologically distinct cardiopulmonary resuscitation (CPR) strategy consisting of 1) active compression-decompression CPR and/or automated CPR, 2) an impedance threshold device, and 3) automated controlled elevation of the head and thorax (ACE) has been shown to improve neurological survival significantly versus conventional (C) CPR in animal models. This resuscitation device combination, termed ACE-CPR, is now used clinically. Objectives To assess the probability of OHCA survival to hospital discharge after ACE-CPR versus C-CPR. Methods As part of a prospective registry study, 227 ACE-CPR OHCA patients were enrolled 04/2019 to 07/2020 from 6 pre-hospital systems in the United States. Individual C-CPR patient data (n=5,196) were obtained from three large published OHCA randomized controlled trials from high-performing pre-hospital systems. The primary study outcome was survival to hospital discharge. Secondary endpoints included return of spontaneous circulation (ROSC) and favorable neurological survival. Propensity-score matching with a 1:4 ratio was performed to account for imbalances in baseline characteristics. Results Irrespective of initial rhythm, ACE-CPR (n=222) was associated with higher adjusted odds ratios (OR) of survival to hospital discharge relative to C-CPR (n=860), when initiated in <11 minutes (3.28, 95% confidence interval [CI], 1.55 to 6.92) and <18 minutes (1.88, 95% CI, 1.03 to 3.44) after the emergency call, respectively. Rapid use of ACE-CPR was also associated with higher probabilities of ROSC and favorable neurological survival. Conclusions Compared with C-CPR controls, rapid initiation of ACE-CPR was associated with a higher likelihood of survival to hospital discharge after OHCA.
Background Clinical trials are the cornerstone of drug evaluation but are difficult to perform in children since obtaining written informed consent from both parents is very challenging. We aimed to identify determinants of parents’ decision whether or not to enrol their child in a clinical trial. Methods A Grounded Theory qualitative approach was used, based on semi-structured interviews with parents who had to give their consent to enrol their child some years before in the TOSCANE study, evaluating the occurrence of chorioretinitis. An interview guide based on bibliographic references, expert consultations and work meetings with the TOSCANE investigators was used during video interviews, conducted until saturation was reached. Interviews were audio-recorded, transcribed anonymously into text format, and double coded before analysis. Results Between April 2020 and April 2021, 18 interviews (nine consenting and nine non-consenting parents) were conducted. Saturation was reached after 16 interviews. The important determinants of parents’ decision, already described in the literature and which could result either in consent or refusal, were: investigator perceived to be human and competent, parents’ personality, parents’ working in healthcare, strong preference for one of the treatment groups, good health of the child, opinions regarding research. New determinants, such as mothers’ guilt about toxoplasmosis transmission, were identified and mostly associated with non-consent. Conclusion Parents' decisions depend on a set of determinants related to family history, personality, and perception of the disease and research, none of them predominating. These determinants suggest that a patient-centred approach could be adopted along with the adequate training of investigators, which requires future assessment.
Objectives To identify clinical and imaging parameters associated with progression of non-hypervascular hepatobiliary phase hypointense lesions during follow-up in patients who received treatment for hepatocellular carcinoma. Methods A total of 67 patients with 106 lesions were identified after screening 538 patients who underwent gadoxetic acid–enhanced MRI within the SORAMIC trial. All patients were allocated to the trial treatment according to the trial scheme, and 61 of 67 patients received systemic treatment with sorafenib (either alone or combined with locoregional therapies) during the trial period. Follow-up images after treatment according to trial scheme were reviewed for subsequent hypervascularization or > 1 cm size increase. The correlation between progression and several imaging and clinical parameters was assessed using univariable and multivariable analyses. Results On a median 178 (range, 48–1072) days follow-up period, progression was encountered in 18 (16.9%) lesions in 12 (17.9%) patients. In univariable analysis size > 12.6 mm ( p = 0.070), ECOG-PS ( p = 0.025), hypointensity at T1-weighted imaging ( p = 0.028), hyperintensity at T2-weighted imaging ( p < 0.001), hyperintensity at DWI images ( p = 0.007), and cirrhosis ( p = 0.065) were correlated with progression during follow-up. Hyperintensity at T2 images ( p = 0.011) was an independent risk factor for progression in multivariable analysis, as well as cirrhosis ( p = 0.033) and ECOG-PS ( p = 0.030). Conclusions Non-hypervascular hepatobiliary phase hypointense lesions are associated with subsequent progression after treatment in patients with HCC. T2 hyperintensity, diffusion restriction, cirrhosis, and higher ECOG-PS could identify lesions with increased risk. These factors should be considered for further diagnostic evaluation or treatment of such lesions. Key Points • Non-hypervascular hepatobiliary phase hypointense lesions have considerable risk of progression in patients with hepatocellular carcinoma receiving treatment. • T2 hyperintensity, cirrhosis, ECOG-PS, and hyperintensity at DWI are associated with increased risk of progression. • Non-hypervascular hepatobiliary phase hypointense lesions should be considered in the decision-making process of locoregional therapies, especially in the presence of these risk factors.
Home mechanical ventilation (HMV) improves quality of life and survival in patients with neuromuscular disorders (NMD). Developing countries may benefit from published evidence regarding the prevalence, cost of equipment, technical issues and organisation of HMV in NMD, facilitating the development of local turn-key HMV programmes. Unfortunately, such evidence is scattered in the existing literature. We searched Medline for publications in English and French from 2005 to 2020. This narrative review analyses 24 international programmes of HMV. The estimated prevalence (min–max) of HMV is ±7.3/100 000 population (1.2–47), all disorders combined. The prevalence of HMV is associated with the gross domestic product per capita in these 24 countries. The prevalence of NMD is about 30/100 000 population, of which ±10% would use HMV. Nocturnal (8/24 hour), discontinuous (8–16/24 hours) and continuous (>16/24 hours) ventilation is likely to concern about 60%, 20% and 20% of NMD patients using HMV. A minimal budget of about 168€/patient/year (504€/100 000 population), including the cost of equipment solely, should address the cost of HMV equipment in low-income countries. When services and maintenance are included, the budget can drastically increase up to between 3232 and 5760€/patient/year. Emerging programmes of HMV in developing countries reveal the positive impact of international cooperation. Today, at least 12 new middle, and low-income countries are developing HMV programmes. This review with updated data on prevalence, technical issues, cost of equipment and services for HMV should trigger objective dialogues between the stakeholders (patient associations, healthcare professionals and politicians); potentially leading to the production of workable strategies for the development of HMV in patients with NMD living in developing countries.
SuccFerr (N-[4-ferrocenyl,5-5-bis (4-hydroxyphenyl)-pent-4-enyl]-succinimide) has remarkable antiproliferative effects in vitro, attributed to the formation of a stabilized quinone methide. The present article reports in vivo results for a possible preclinical study. SuccFerr is lipophilic and insoluble in water, so the development of a formulation to obviate this inconvenience was necessary. This was achieved by complexation with randomly methylated cyclodextrins (RAMEßCDs). This supramolecular water-soluble system allowed the in vivo experiments below to proceed. Application of SuccFerr on the glioblastoma cancer cell line U87 indicates that it affects the cellular cycle by inducing a blockade at G0/G1 phase, linked to apoptosis, and another one at the S phase, associated with senescence. Using healthy Fischer rats, we show that both intravenous and subcutaneous SuccFerr: RAMEßCD administration at 5 mg/kg lacks toxic effects on several organs. To reach lethality, doses higher than 200 mg/kg need to be administered. These results prompted us to perform an ectopic in vivo study at 1 mg/kg i.v. ferrocidiphenol SuccFerr using F98 cells xenografted in rats. Halting of cancer progression was observed after six days of injection, associated with an immunological defense response linked to the active principle. These results demonstrate that the properties of the selected ferrocidiphenol SuccFerr transfer successfully to in vivo conditions, leading to interesting therapeutic perspectives based on this chemistry.
Objective: To compare cochlear duct length (CDL) between male and female patients by evaluating the diameter of the basal turn (distance A) on CT scans.Method: All temporal bone CT scans performed between 2014 and 2020 were reviewed in our medical center. Using multiplanar reconstructions, the length A, which is the greatest distance of the basal turn was measured on both sides. We performed an analysis of variance considering two factors: sex and side. Two different physicians carried out the measurements, an otolaryngologist and a neuroradiologist. The patients who had several CT scans allowed us to evaluate the reliability of our procedure.Results: Among the 888 CT scans reviewed, 8 were excluded because of cochlear malformations. The inter-sex difference of length A was found to be 0.29 millimeters(mm) 95% IC [0.26-0.34] and was longer in the male group (p < 0.0001). Using Alexiades' equation, we found that CDL was 34.5mm [34.37-34.61] in the male group and 33.3mm [33.13-33.38] in the female group. When one side was compared to the other, there was no significant difference (p = 0.226). An intra-class correlation found a good absolute agreement between the two screeners of 0.79.Conclusion: Males have a statistically significant longer CDL than females.
Identifying factors whose fluctuations are associated with choice inconsistency is a major issue for rational decision theory. Here, we investigated the neuro-computational mechanisms through which mood fluctuations may bias human choice behavior. Intracerebral EEG data were collected in a large group of subjects (n = 30), while they were performing interleaved quiz and choice tasks that were designed to examine how a series of unrelated feedbacks affects decisions between safe and risky options. Neural baseline activity preceding choice onset was confronted first to mood level, estimated by a computational model integrating the feedbacks received in the quiz task, and then to the weighting of option attributes, in a computational model predicting risk attitude in the choice task. Results showed that 1) elevated broadband gamma activity (BGA) in the ventromedial prefrontal cortex (vmPFC) and dorsal anterior insula (daIns) was respectively signaling periods of high and low mood, 2) increased vmPFC and daIns BGA respectively promoted and tempered risk taking by overweighting gain versus loss prospects. Thus, incidental feedbacks induce brain states that correspond to different moods and bias the evaluation of risky options. More generally, these findings might explain why people experiencing positive (or negative) outcome in some part of their life tend to expect success (or failure) in any other.
Background: A successful innovative medical device is not only technically challenging to develop but must also be readily usable to be integrated into health care professionals' daily practice. Through a user-centered design (UCD) approach, usability can be improved. However, this type of approach is not widely implemented from the early stages of medical device development. Objective: The case study presented here shows how UCD may be applied at the very early stage of the design of a disruptive medical device used in a complex hospital environment, while no functional device is available yet. The device under study is a connected sensor system to detect colorectal anastomotic leakage, the most detrimental complication following colorectal surgery, which has a high medical cost. We also aimed to provide usability guidelines for the initial design of other innovative medical devices. Methods: UCD was implemented by actively involving health care professionals and all the industrial partners of the project. The methodology was conducted in 2 European hospitals: Grenoble-Alpes University Hospital (France) and Erasmus Medical Center Rotterdam (the Netherlands). A total of 6 elective colorectal procedures and 5 ward shifts were observed. In total, 4 workshops were conducted with project partners and clinicians. A formative evaluation was performed based on 5 usability tests using nonfunctional prototype systems. The case study was completed within 12 months. Results: Functional specifications were defined for the various components of the medical device: device weight, size, design, device attachment, and display module. These specifications consider the future integration of the medical device into current clinical practice (for use in an operating room and patient follow-up inside the hospital) and interactions between surgeons, nurses, nurse assistants, and patients. By avoiding irrelevant technical development, this approach helps to promote cost-effective design. Conclusions: This paper presents the successful deployment over 12 months of a UCD methodology for the design of an innovative medical device during its early development phase. To help in reusing this methodology to design other innovative medical devices, we suggested best practices based on this case.
The prognostic impact of renal cell carcinoma (RCC) morphotype remains unclear in patients who undergo partial nephrectomy (PN). Our objective was to determine the risk factors for recurrence after PN, including RCC morphotype. Patients with RCC who had undergone PN were extracted from the prospective, national French database, UroCCR. Patients with genetic predisposition, bilateral or multiple tumours, and those who had undergone secondary totalization were excluded. Primary endpoint was 5-year, recurrence-free survival (RFS), and secondary endpoint was overall survival (OS). Risk factors for recurrence were assessed by multivariable Cox regression analysis. Overall, 2,767 patients were included (70% male; median age: 61 years [interquartile range (IQR) 51-69]). Most (71.5%) of the PN procedures were robot-assisted. Overall, 2,573 (93.0%) patients were recurrence free, and 74 died (2.7%). Five-year RFS was 84.9% (IQR 82.4-87.4). A significant difference in RFS was observed between RCC morphotypes (p < 0.001). Surgical margins (hazard ratio [HR] = 2.0 [95% confidence interval (CI): 1.3-3.2], p < 0.01), pT stage >1 (HR = 2.6 [95% CI: 1.8-3.7], p < 0.01]) and Fuhrmann grade >2 (HR = 1.9 [95% CI: 1.4-2.6], p < 0.001) were risk factors for recurrence, whereas chromophobe subtype was a protective factor (HR = 0.08 [95% CI: 0.01-0.6], p = 0.02). Five-year OS was 94.0% [92.4-95.7], and there were no significant differences between RCC subgroups (p = 0.06). The main study limitation was its design (multicentre national database), which may be responsible for declarative bias. Chromophobe morphotype was significantly associated with better RFS in RCC patients who underwent PN. Conversely, pT stage, Fuhrman group and positive surgical margins were risk factors for recurrence.
Purpose Better understanding of pharmacokinetics of oral vinorelbine (VNR) in children would help predicting drug exposure and, beyond, clinical outcome. Here, we have characterized the population pharmacokinetics of oral VNR and studied the factors likely to explain the variability observed in VNR exposure among young patients. Design/methods We collected blood samples from 36 patients (mean age 11.6 years) of the OVIMA multicentric phase II study in children with recurrent/progressive low-grade glioma. Patients received 60 mg/m² of oral VNR on days 1, 8, and 15 during the first 28-day treatment cycle and 80 mg/m², unless contraindicated, from cycle 2–12. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling within the Monolix® software. Fifty SNPs of pharmacokinetic-related genes were genotyped. The influence of demographic, biological, and pharmacogenetic covariates on pharmacokinetic parameters was investigated using a stepwise multivariate procedure. Results A three-compartment model, with a delayed double zero-order absorption and a first-order elimination, best described VNR pharmacokinetics in children. Typical population estimates for the apparent central volume of distribution (Vc/F) and elimination rate constant were 803 L and 0.60 h⁻¹, respectively. Following covariate analysis, BSA, leukocytes count, and drug transport ABCB1-rs2032582 SNP showed a dramatic impact on Vc/F. Conversely, age and sex had no significant effect on VNR pharmacokinetics. Conclusion Beyond canonical BSA and leukocytes, ABCB1-rs2032582 polymorphism showed a meaningful impact on VNR systemic exposure. Simulations showed that the identified covariates could have an impact on both efficacy and toxicity outcomes. Thus, a personalized dosing strategy, using those covariates, could help to optimize the efficacy/toxicity balance of VNR in children.
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Yoann Gaboreau
  • General Practice Department
Grégory Mounié
  • Ensimag - Grenoble-INP
Carole Peyrin
  • UMR CNRS 5105 Laboratoire de Psychologie et Neurocognition
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