New dosing nomogram and population pharmacokinetic model for young and very young children receiving busulfan for hematopoietic stem cell transplantation conditioning.

BACKGROUND: Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants. PROCEDURE: To ensure both efficacy and safety, we set up in 2005 an observational study designed for children not fully assessed during the drug registration procedure. From a large cohort of 540 patients, we developed a Bu population pharmacokinetic model based on body weight (BW) and maturation concepts to reduce IIV and optimize exposure. A new dosing nomogram was evaluated to better fit the population pharmacokinetic model. RESULTS: Bu clearance IIV was significantly decreased from 61.3% (covariate-free model) to 28.6% when combining BW and maturation function. Median Bu area under the curve (AUC) was 1179 µmol/L × min compared to 1025 with the EMA dosing nomogram for children <9 kg. The target AUC was reached for each BW strata, significantly increasing the percentages of patients achieving reaching the targeted AUC as compared to FDA schedule. CONCLUSION: This new model made it possible to propose a novel dosing nomogram that better considered children below 16 kg of BW and allowed better initial exposure as compared to existing dosing schedules. This nomogram, which would be easy to use to determine an optimal dosing schedule in daily practice, will need to be validated in clinical routine. Therapeutic drug monitoring remains strongly advisable for small children and those with specific diseases.

Plasma 7-Hydroxymethotrexate Levels Versus Methotrexate to Predict Delayed Elimination in Children Receiving High-Dose Methotrexate.

BACKGROUND: The aim of this study was to investigate the correlation between 7-hydroxymethotrexate (7-OHMTX) and creatinine and to evaluate the predictive value of 7-OHMTX levels on delayed elimination at 24 and 48 hours. In addition, differences in methotrexate (MTX), 7-OHMTX levels, and MTX metabolism using the ratio MTX/7-OHMTX were determined according to age. METHODS: The authors included a total of 106 cycles, corresponding to 33 patients (mean age: 9.8 years, range: 2-18 years) suffering from acute lymphoblastic leukemia, non-Hodgkin lymphoma and osteosarcoma and receiving high-dose MTX (HD-MTX). Plasma MTX, 7-OHMTX, and creatinine at T24 and T48 hours were measured. RESULTS: Children older than 14 years had significantly higher MTX levels at T48 hours (1.25 versus 0.5 µmol/L, P < 0.05) and a higher MTX/7-OHMTX ratio (0.63 versus 0.20, P < 0.05) than children younger than 6 years. Plasma 7-OHMTX at T24 and T48 hours was positively correlated with serum creatinine and creatinine ratio at T24 and T48 hours. MTX levels provided a better specificity and sensitivity at both 24 and 48 hours than 7-OHMTX to predict delayed MTX elimination. A MTX threshold close to 0.83 µmol/L at T48 hours improved specificity from 58% to 82% and keeps sensitivity at 100%. The authors identified a cut-off at 65 µmol/L for MTX at T24 hours with a good sensitivity (75%) and specificity above 50%. CONCLUSIONS: These results confirm the concentration-dependent nephrotoxicity of 7-OHMTX. Children older than 14 years old had a higher MTX levels at 48 hours and a higher MTX/7-OHMTX ratio, suggesting a faster metabolism in younger children. This study identified a higher and more specific MTX threshold at T48 hours compared to those currently used, and a new threshold at T24 hours.

End-stage renal disease treated in Provence-Alpes Côte d'Azur: 12-years follow-up and forecast to the year 2030.

BACKGROUND: This study describes the time trend of renal replacement therapy for end-stage renal disease (ESRD) in the Provence-Alpes Côte d'Azur region (PACA) between 2004 and 2015, and forecasts up to 2030. METHODS: A longitudinal study was conducted on all ESRD patients treated in PACA and recorded in the French Renal Epidemiology and Information Network (REIN) during this period. Time trends and forecasts to 2030 were analyzed using Poisson regression models. RESULTS: Since 2004, the number of new patients has steadily increased by 3.4% per year (95% CI, 2.8-3.9, p < 0.001) and the number of patients receiving RRT has increased by 3.7% per year (RR 1.037, 95% CI: 1.034-1.039, p < 0.001). If these trends continue, the PACA region will be face with 7371 patients on dialysis and 3891 with a functional renal transplant who will need to be managed in 2030. The two most significant growth rates were the percentage of obese people (RR 1.140, 95% CI: 1.131-1.149, p < 0.001) and those with diabetes (RR 1.070, 95% CI; 1.064-1.075, p < 0.001). CONCLUSION: This study highlights the increase in the number of ESRD patients over 12 years, with no prospect of stabilization. These findings allow us to anticipate the quality and quantity of care offered and to propose more preventive measures to combat obesity and diabetes.

Geographical access to hemodialysis: an analysis of patient choices / Accès géographique à l'hémodialyse : une analyse sur les choix des patients

Introduction: Patients do not always go to the facility closest to their home. Description: A study was carried out in Provence-Alpes Côtes d'Azur (PACA) on patients' preferences to mobilize the hemodialysis offer. Methods: The data were extracted from the REIN Registry. Potential access was compared with actual access. A survey was carried out among a sample of patients travelling an additional distance of more than 25 km. Results: About a quarter of the patients did not travel to the nearest facility. Of these, 16.3% travelled an additional distance of over 25 km. Patients' choices were determined by the relationship of trust with the team that first set up dialysis, followed by their desire to be followed in a multi-purpose facility. Discussion: While distance remained the decisive factor, human factors were cited in the majority of cases to explain the bypass. Conclusion: The links between the first team and the next one should be strengthened.

Introduction: Les patients ne se rendent pas toujours dans l'établissement le plus proche de leur domicile. Description: Une étude a été réalisée en Provence-Alpes Côtes d'Azur (PACA) sur les préférences des patients à mobiliser l'offre d'hémodialyse. Méthodes: Les données ont été extraites du Registre REIN. L'accès potentiel a été comparé à l'accès réalisé. Une enquête a été effectuée auprès d'un échantillon de patients parcourant une distance supplémentaire supérieure à 25 km. Résultats: Environ un quart des patients ne se rendait pas dans la structure la plus proche. Parmi eux, 16,3 % parcouraient un trajet supplémentaire supérieur à 25 km. Les choix des patients étaient déterminés par la relation de confiance avec l'équipe de la première mise en place de dialyse, puis par le souhait d'être suivis dans une structure polyvalente. Discussion: Si la distance restait le facteur décisif, les facteurs humains étaient majoritairement cités. Conclusion: Il faudrait renforcer les liens entre la première équipe et celle qui prend la suite.

[Evaluation of ambulance transport relevance of dialysis patients in the PACA region (France), and estimation of savings by the Health Insurance]. / Évaluation de la pertinence des transports par ambulance des patients dialysés en région PACA, et estimation des économies réalisables par l'Assurance maladie.

INTRODUCTION: Patient transport represents the second largest item of cost of dialysis after hospitalization. A significant proportion of patients transported by ambulance are self-sufficient for walking. DESCRIPTION: A study was carried out in the PACA region (France) to analyse the profile of patients transported by ambulance and self-sufficient for walking and then to evaluate the savings for the Health Insurance. METHODS: A triangulation of data was carried out using data from haemodialysis patients recorded in the French REIN Registry in 2017 and data from two surveys: one of a sample of patients transported by ambulance and autonomous in walking, and the other of 62 nephrologists. RESULTS: The data from the REIN register allowed us to estimate that 44 % of patients transported by ambulance are self-sufficient for walking. Our study allowed us to estimate that 2/3 of patients transported by ambulance, self-sufficient for walking, have a reason for being transported by ambulance; for the third without a reason, the health insurance savings would amount to €2 million per year with a reclassification of their transport as seated transport. The survey of prescribers showed that there are exemptions justified by a temporary deterioration in health and/or housing conditions, but also by the lack of seated transport. CONCLUSION: One third of the patients, transported by ambulance and self-sufficient for walking, would have an inappropriate transport. This would be explained by the fluctuating state of health of the patients and would also linked to the lack of seated transportation. Savings are possible and depend in part on improved management of the supply.

ED patients: how nonurgent are they? Systematic review of the emergency medicine literature.

Nonurgent visits to emergency departments (ED) are a controversial issue; they have been negatively associated with crowding and costs. We have conducted a critical review of the literature regarding methods for categorizing ED visits into urgent or nonurgent and analyzed the proportions of nonurgent ED visits. We found 51 methods of categorization. Seventeen categorizations conducted prospectively in triage areas were based on somatic complaint and/or vital sign collection. Categorizations conducted retrospectively (n = 34) were based on the diagnosis, the results of tests obtained during the ED visit, and hospital admission. The proportions of nonurgent ED visits varied considerably: 4.8% to 90%, with a median of 32%. Comparisons of methods of categorization in the same population showed variability in levels of agreement. Our review has highlighted the lack of reliability and reproducibility.

[Description of trajectories of patients with end-stage renal disease from the REIN registry]. / Description synthétique des trajectoires des patients insuffisants rénaux chroniques terminaux à partir du registre REIN.

CONTEXT AND OBJECTIVES: Since 2001, the aim of the REIN registry has been to identify patients suffering from end-stage renal disease and benefiting from replacement therapy in France. The analysis of trajectories aims to evaluate the flow of patients between the different types of treatment in order to better understand and predict patient pathways. The objective of this study was to analyse the incoming and outgoing flows at 1 year of patients prevalent in the REIN registry on 12/31/2017. METHODS: Flow analysis was carried out on patients prevalent on 12/31/2017 in the REIN registry by studying the before and after treatment modalities on 12/31/2016 and 12/31/2018. This analysis was initially carried out on all patients, then in sub-groups for each of the 5 treatment modalities. RESULTS: The analyses covered 85,472 patients prevalent on 12/31/2017. The overall analysis showed that more than 20% of patients had been diagnosed with end-stage renal disease the year before. Regarding inflow, there was a relative stability for patients treated with self-care hemodialysis, in-center haemodialysis, peritoneal dialysis, and graft, in contrast to patients treated with hemodialysis in a medical unit. Regarding outgoing flows, proportion of deaths at one year was 9%. Peritoneal dialysis was the modality with the highest outflow proportion at one year. CONCLUSION: Analysis of patients' trajectories shows variable evolution profiles according to treatment modality and thus could be a valuable tool in the evaluation and improvement of management and care in the field of end-stage renal disease.

Clinical-Based vs. Model-Based Adaptive Dosing Strategy: Retrospective Comparison in Real-World mRCC Patients Treated with Sunitinib.

Different target exposures with sunitinib have been proposed in metastatic renal cell carcinoma (mRCC) patients, such as trough concentrations or AUCs. However, most of the time, rather than therapeutic drug monitoring (TDM), clinical evidence is preferred to tailor dosing, i.e., by reducing the dose when treatment-related toxicities show, or increasing dosing if no signs of efficacy are observed. Here, we compared such empirical dose adjustment of sunitinib in mRCC patients, with the parallel dosing proposals of a PK/PD model with TDM support. In 31 evaluable patients treated with sunitinib, 53.8% had an empirical change in dosing after treatment started (i.e., 46.2% decrease in dosing, 7.6% increase in dosing). Clinical benefit was observed in 54.1% patients, including 8.3% with complete response. Overall, 58.1% of patients experienced treatment discontinuation eventually, either because of toxicities or progressive disease. When choosing 50-100 ng/mL trough concentrations as a target exposure (i.e., sunitinib + active metabolite N-desethyl sunitinib), 45% patients were adequately exposed. When considering 1200-2150 ng/mL.h as a target AUC (i.e., sunitinib + active metabolite N-desethyl sunitinib), only 26% patients were in the desired therapeutic window. TDM with retrospective PK/PD modeling would have suggested decreasing sunitinib dosing in a much larger number of patients as compared with empirical dose adjustment. Indeed, when using target trough concentrations, the model proposed reducing dosing for 61% patients, and up to 84% patients based upon target AUC. Conversely, the model proposed increasing dosing in 9.7% of patients when using target trough concentrations and in 6.5% patients when using target AUC. Overall, TDM with adaptive dosing would have led to tailoring sunitinib dosing in a larger number of patients (i.e., 53.8% vs. 71-91%, depending on the chosen metrics for target exposure) than a clinical-based decision. Interestingly, sunitinib dosing was empirically reduced in 41% patients who displayed early-onset severe toxicities, whereas model-based recommendations would have immediately proposed to reduce dosing in more than 80% of those patients. This observation suggests that early treatment-related toxicities could have been partly avoided using prospective PK/PD modeling with adaptive dosing. Conversely, the possible impact of model-based adapted dosing on efficacy could not be fully evaluated because no clear relationship was found between baseline exposure levels and sunitinib efficacy measured at 3 months.

Teleradiology as a relevant indicator of the impact of COVID-19 pandemic management on emergency room activities: a nationwide worrisome survey.

OBJECTIVES: To evaluate the impact of COVID-19's lockdown on radiological examinations in emergency services. METHODS: Retrospective, multicentre analysis of radiological examinations requested, via our teleradiology network, from 2017 to 2020 during two timeframes (calendar weeks 5-8 and then 12-15). We included CT scans or MRIs performed for strokes, multiple traumas (Body-CT), cranial traumas (CTr) and acute non-traumatic abdominal pain (ANTAP). We evaluated the number and percentages of examinations performed, of those with a pathological conclusion, and of examinations involving the chest. RESULTS: Our study included 25 centres in 2017, 29 in 2018, 43 in 2019 and 59 in 2020. From 2017 to 2019, the percentages of examinations were constant, which was also true for chest CTs. Each centre's number of examinations, gender distribution and patient ages were unchanged. In 2020, examinations significantly decreased: suspected strokes decreased by 36% (1052 vs 675, p < 0.001), Body-CT by 62% (349 vs 134, p < 0.001), CTr by 52% (1853 vs 895, p < 0.001) and for ANTAP, appendicitis decreased by 38% (45 vs 90, not statistically significant (NS)) sigmoiditis by 44% (98 vs 55, NS), and renal colic by 23% (376 vs 288, NS). The number of examinations per centre decreased by 13% (185.5 vs 162.5, p < 0.001), whereas the number of examinations of the "chest" region increased by 170% (1205 vs 3766, p < 0.001). CONCLUSION: Teleradiology enabled us to monitor the impact of the COVID-19 pandemic management on emergency activities, showing a global decrease in the population's use of care.

[Comparison of peritoneal dialysis and hemodialysis survival in Provence-Alpes-Côte d'Azur]. / Étude comparative de survie entre les techniques de dialyse : dialyse péritonéale versus hémodialyse en région Provence-Alpes-Côte d'Azur.

PURPOSE: To analyze and compare survival of patients initially treated with peritoneal dialysis (PD) or hemodialysis (HD). METHODS: We used data from the French REIN registry. We included all patients aged 18 years or more who started dialysis between 1st January 2004 and 12 December 2012 in Provence-Alpes-Côte d'Azur Region (PACA). These patients were followed up until 30 June 2014. Survival curves were generated using the Kaplan-Meier technique and tested using the log-rank test. Variables predictive of all-cause mortality were determined using Cox regression models. The propensity score was used. MAIN RESULTS: Survival was similar between initial dialysis modalities: PD and HD, even after adjusting for the propensity score. But, when we exclude the patients who had switched from one technique of dialysis to another, survival was better in HD patients. According to the multivariate analysis, advanced age and the lack of walking autonomy appear to be associated with an increase in mortality in dialysis patients. But, the presence of hypertension improve the survival in this cohort. CONCLUSION: The survival is similar between hemodialysis and peritoneal dialysis.

Phase I study of non-pegylated liposomal doxorubicin in children with recurrent/refractory high-grade glioma.

PURPOSE: To determine the maximum recommended dose (RD) and pharmacokinetics of Myocet®, a non-pegylated liposomal doxorubicin, in children. METHODS: Eligible patients were children with refractory high-grade glioma who had received prior chemotherapy and radiotherapy but no anthracyclines. Cohorts of at least three patients each received escalating doses of Myocet® starting at 60 mg/m(2) at 3-week intervals, administered intravenously over 1 h, and then doses were escalated to 75 mg/m(2) corresponding to the adult RD. Periodic blood samples were collected, and plasma doxorubicin and doxorubicinol concentrations were quantified to characterise the pharmacokinetics of Myocet®. RESULTS: Between October 2010 and January 2013, 13 children aged 6-17 years were treated. In total, 27 courses were administered, at the 60 mg/m(2) dose level in seven patients without dose-limiting toxicity (DLT), and at 75 mg/m(2) in six patients of whom two experienced DLT (grade 4 neutropenia). The most common grade 3-4 toxicities reported for all courses were neutropenia (35 and 38 %, respectively), thrombocytopenia (12 and 4 %, respectively); and grade 3 vomiting, nausea, mucositis, and fever (4 % each). Mean estimates of central volume of distribution at steady state, clearance, and elimination half-life of doxorubicin were 24.8 L, 15 L/h/m(2), and 34.8 h, respectively, with a large interpatient variability. CONCLUSION: The RD of Myocet® administered every 3 weeks to paediatric patients was 60 mg/m(2). The efficacy of Myocet® in paediatric patients with high-grade glioma remains to be determined and should be studied in Phase II trials.

[Epidemiological characteristics of elderly dialysed patients aged 75 and more. Study conducted in the Provence-Alpes-Côte d'Azur region of France]. / Caractéristiques épidémiologiques des personnes dialysées âgées de 75 ans et plus. Etude dans la région Provence-Alpes-Côte d'Azur.

INTRODUCTION: One of the consequences of an ageing French population is the large number of elderly patients with end stage renal failure (ESRF). Nephrologists will be increasingly confronted with the growing number of elderly patients and the sometimes-precarious health of the extremely elderly. OBJECTIVE: To describe the epidemiological characteristics of the populations of patients over 75 years in ESRF, treated by dialysis in the Provence Alpes Côte d'Azur region (Paca) in 1999. METHOD: Cross-sectional survey. RESULT: Of the 2347 patients treated by dialysis and resident in the Paca region, 25,1% are aged 75 or more. The prevalence for this age group is of 1428 patients per million persons (pmp) versus 429 pmp for those aged under 75 years. Elderly patients are more frequently treated by dialysis in centres, with shorter dialysis duration. They have more complications related to treatment (perdialytic hypotension, irregular cardiac rhythm), more dependence and more frequently exhibit comorbidity, with the exception of hepatitis C which is less frequent in this population (p<0.0001). The number of patients aged 75 and over treated with dialysis increased 53% between 1995 and 1999 in the Paca region compared with an overall increase of 17% during the same period. The recourse to hemodialysis in a centre for these patients increased by 39.4% whereas it has decreased by 2.4% in younger populations (p<0.0001). In fact, the use of autodialysis has risen enormously: +309% for those aged 75 years and more and +88.1% for others. CONCLUSION: The increase in the prevalence of elderly people undergoing dialysis will present problems due to a saturation point which is now being reached in dialysis centres. It is clear that those who forecast health care provisions will need to adapt the supply and demand better to the requirements of the population.

[Trend of travelling times for haemodialysis patients in the Provence-Alpes-Côte-d'Azur region between 1995 and 2008]. / Évolution du temps de transport des patients hémodialysés en région Provence-Alpes-Côte-d'Azur entre 1995 et 2008.

OBJECTIVE: We analysed the trend of travel-times for haemodialysis patients in the Provence-Alpes-Côte-d'Azur region between 1995 and 2008 in relation with the reforms concerning the health care provision of haemodialysis. METHODS: We conducted this study using data from three cross sectional surveys for 1995, 1999 and 2002, including all dialysis patients, and from the Renal Epidemiology and Information Network register for 2008. The data focuses on sociodemographic, medical characteristics and travel-times for haemodialysis patients. RESULTS: The number of haemodialysis patients increased from 1807 patients in 1995 to 3141 in 2008. The travel-time has decreased steadily between 1995 and 2008 (18.2 min versus 15, P<0.0001). The number of patients with a travel-time more than 45 min decreased from 7.2 to 3.5% between 1995 and 2008. The number of dialysis facilities has increased steadily between 1995 and 2008. CONCLUSION: The favorable trend in the health care provision has resulted in an improvement of accessibility by reducing travel-times.