Can surgically assisted rapid palatal expansion (SARPE) be recommended over orthodontic rapid palatal expansion (ORPE) for girls above the age of 14? : A cone-beam CT study on midpalatal suture maturation.

BACKGROUND: For patients with a maxillary transversal deficiency (MTD), various treatment options are available, partly based on the practitioner's experience. This study aimed to determine a cut-off age for decision making between surgically assisted rapid palatal expansion (SARPE) over orthodontic rapid palatal expansion (ORPE) based on skeletal maturation in a female population. METHODS: A total of 100 cone beam computed tomography (CBCT) images of young females were analyzed on maturation of the pterygomaxillary (PMS), zygomaticomaxillary (ZMS), transpalatal (TPS), and midpalatal (MPS) sutures. Based on the maturation of these four junctions, four independent observers had to determine whether they would prefer ORPE or SARPE to widen the maxilla. RESULTS: For the PMS, the results show a closure of 83-100% from 13 to 17 years. As for the TPS, a closure of 78-85% was observed from 15 years of age. For the 15- to 17-year-old females, a closed ZMS was present in 32-47%. Regarding MPS, closed sutures presented in 61% (stages D and E) of the 15-year-old females. The cut-off age at which SARPE was recommended was 15.1 years for the orthodontist observers and 14.8 years for the maxillofacial surgeon observers. CONCLUSIONS: Significant maturation of MPS was reached at the age of 15 in a female population. The PMS, TPS, MPS, and ZMS closed sequentially. A comprehensive diagnostic approach is necessary for choosing the appropriate treatment. When in doubt, age could assist decision making in a female population, with a cut-off age of 15 years in favor of SARPE based on this study.

Exposure-Efficacy Analysis of Asciminib in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase.

Asciminib (Scemblix) is a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200 mg twice a day (b.i.d.) or 40 to 200 mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40 mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure-efficacy relationship, in which the efficacy was assessed through BCR::ABL1 transcript levels over time. Specifically, a three-compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80 mg in patients without the T315I mutation and 200 mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult-to-treat populations.

Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases.

BACKGROUND: Asciminib, a first-in-class, highly potent and specific ABL/BCR-ABL1 inhibitor, has shown superior efficacy compared to bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, treated with two or more tyrosine kinase inhibitors. This study aimed to describe pharmacokinetic (PK) properties of asciminib and to identify clinically relevant covariates impacting its exposure. METHODS: A population PK (PopPK) model was developed using a two-compartment model with delayed first-order absorption and elimination. The analysis included PK data from two clinical studies (Phases 1 and 3) involving 353 patients, with total daily dose of asciminib in the range of 20-400 mg. RESULTS: The nominal total daily dose was incorporated as a structural covariate on clearance (CL), and body weight (BW) was included as a structural covariate via allometric scaling on CL and central volume. Renal function and formulation were included as statistically significant covariates on CL and absorption (ka), respectively. The simulation results revealed a modest but clinically non-significant effect of baseline BW and renal function on ka. Correlations between covariates, such as baseline demographics and disease characteristics, heavy smoking status, hepatic function, and T315I mutation status, were not statistically significant with respect to CL, and they were not incorporated in the final model. Additionally, the final model-based simulations demonstrated comparable exposure and CL for asciminib 40 mg twice daily and 80 mg once daily (an alternative regimen not studied in the Phase 3 trial), as well as similar PK properties in patients with and without the T315I mutation. CONCLUSIONS: The final PopPK model adequately characterized the PK properties of asciminib and assessed the impact of key covariates on its exposure. The model corroborates the use of the approved asciminib dose of 80 mg total daily dose as 40 mg twice daily, and supports the use of 80 mg once daily as an alternative dose regimen to facilitate patient's compliance. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION]: First-in-human (CABL001X2101, Phase 1), ClinicalTrials.gov identifier: NCT02081378 [28 February 2014]; ASCEMBL (CABL001A2301, Phase 3), ClinicalTrials.gov identifier: NCT03106779 [10 April 2017].

Model-Informed Drug Development for Everolimus Dosing Selection in Pediatric Infant Patients.

Everolimus is currently approved in Europe as an adjunctive therapy for patients aged ≥ 2 years with tuberous sclerosis complex (TSC)-associated treatment-refractory partial-onset seizures, based on the EXIST-3 study (NCT01713946) results. As TSC-associated seizures can also affect children aged between 6 months and 2 years, a modeling and simulation (M&S) approach was undertaken to extrapolate exposure (trough plasma concentration (Cmin )) after a dose of 6 mg/m2 and reduction in seizure frequency (RSF). A physiologically based pharmacokinetic model using Simcyp was developed to predict Cmin in adult and pediatric patients, which was then used by a population pharmacodynamic model and a linear mixed effect model to predict short-term and long-term efficacy in adults (for validation) and in children, respectively. Based on the results of the M&S study, everolimus at the dose of 6 mg/m2 is anticipated to be an efficacious treatment in children 6 months to 2 years of age (up to 77.8% RSF) with concentrations within the recommended target range.

Physiologically Based Pharmacokinetic Modeling to Supplement Nilotinib Pharmacokinetics and Confirm Dose Selection in Pediatric Patients.

In adult patients, nilotinib is indicated for chronic myeloid leukemia at an approved oral dose of 300 or 400 mg BID. Physiologically based pharmacokinetic (PBPK) model was developed to describe and supplement limited PK data in the pediatric population ranging from 2 to less than 6 years of age and ultimately inform dosing regimen. An adult Simcyp PBPK model was established and verified with clinical pharmacokinetic data after a single or multiple oral doses of 400 mg nilotinib (230 mg/m2). The model was then applied to a pediatric PBPK model, taking account of ontogeny profiles of metabolizing enzymes and pediatric physiological parameters. The model was further verified using observed pediatric PK data in 12- to <18-year-old and from 6- to <12-year-old patients. The PBPK models were able to recover, describe, and supplement the limited nilotinib concentration-time data profile in 2- to <6-year-old patients after a single dose and Cmin,ss after BID dosing. The exposure (Cmax,ss, Cmin,ss, and AUCtau,ss) was predicted to be similar across age groups. PBPK model simulations confirmed that body surface area-normalized dosing regimen of 230 mg/m2 is considered appropriate for pediatric patients >2 to <18 years of age.

Population pharmacokinetics-pharmacodynamics of oral everolimus in patients with seizures associated with tuberous sclerosis complex.

Everolimus is approved in Europe and in the USA for the adjunctive treatment of patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with tuberous sclerosis complex. The objective of this analysis was to establish a population pharmacokinetic (PK)/pharmacodynamic model describing the relationship between seizure frequency and everolimus exposure to confirm the recommended target concentration range of 5-15 ng/mL. The PK model was a two-compartment model with first order absorption and clearance. CYP3A and P-gp inducers and body-surface area were shown to impact everolimus exposure, justifying dose adjustments. A Poisson distribution was found to adequately describe the random nature of daily seizure counts during the screening phase. A placebo effect on the Poisson seizure mean was implemented as an asymptotic exponential function of time leading to a new steady-state seizure mean. The everolimus effect was implemented as an inhibitory Emax function of Cmin on the seizure mean, where Emax exhibited an asymptotic exponential increase over time to a higher steady-state value. Increasing age was found to decrease the baseline seizure mean and to prolong the half-life of the increase in Emax. The dependence of seizure frequencies on Cmin was explored by simulation. The responder rate increased with increasing Cmin. As Cmin decreased below 5 ng/mL, variability in response became larger and responder rates decreased more rapidly. The results supported the recommended target concentration range for everolimus of 5-15 ng/mL to ensure treatment efficacy.

Model-Based Approach to Predict Adherence to Protocol During Antiobesity Trials.

Development of antiobesity drugs is continuously challenged by high dropout rates during clinical trials. The objective was to develop a population pharmacodynamic model that describes the temporal changes in body weight, considering disease progression, lifestyle intervention, and drug effects. Markov modeling (MM) was applied for quantification and characterization of responder and nonresponder as key drivers of dropout rates, to ultimately support the clinical trial simulations and the outcome in terms of trial adherence. Subjects (n = 4591) from 6 Contrave® trials were included in this analysis. An indirect-response model developed by van Wart et al was used as a starting point. Inclusion of drug effect was dose driven using a population dose- and time-dependent pharmacodynamic (DTPD) model. Additionally, a population-pharmacokinetic parameter- and data (PPPD)-driven model was developed using the final DTPD model structure and final parameter estimates from a previously developed population pharmacokinetic model based on available Contrave® pharmacokinetic concentrations. Last, MM was developed to predict transition rate probabilities among responder, nonresponder, and dropout states driven by the pharmacodynamic effect resulting from the DTPD or PPPD model. Covariates included in the models and parameters were diabetes mellitus and race. The linked DTPD-MM and PPPD-MM was able to predict transition rates among responder, nonresponder, and dropout states well. The analysis concluded that body-weight change is an important factor influencing dropout rates, and the MM depicted that overall a DTPD model-driven approach provides a reasonable prediction of clinical trial outcome probabilities similar to a pharmacokinetic-driven approach.

Prediction of shrinkage of individual parameters using the bayesian information matrix in non-linear mixed effect models with evaluation in pharmacokinetics.

PURPOSE: When information is sparse, individual parameters derived from a non-linear mixed effects model analysis can shrink to the mean. The objective of this work was to predict individual parameter shrinkage from the Bayesian information matrix (M BF ). We 1) Propose and evaluate an approximation of M BF by First-Order linearization (FO), 2) Explore by simulations the relationship between shrinkage and precision of estimates and 3) Evaluate prediction of shrinkage and individual parameter precision. METHODS: We approximated M BF using FO. From the shrinkage formula in linear mixed effects models, we derived the predicted shrinkage from M BF . Shrinkage values were generated for parameters of two pharmacokinetic models by varying the structure and the magnitude of the random effect and residual error models as well as the design. We then evaluated the approximation of M BF FO and compared it to Monte-Carlo (MC) simulations. We finally compared expected and observed shrinkage as well as the predicted and estimated Standard Errors (SE) of individual parameters. RESULTS: M BF FO was similar to M BF MC. Predicted and observed shrinkages were close . Predicted and estimated SE were similar. CONCLUSIONS: M BF FO enables prediction of shrinkage and SE of individual parameters. It can be used for design optimization.

[Flexible ureteroscopy and holmium-Yag laser: material and technique]. / Urétéroscopie souple et laser holmium-Yag : matériel et technique.

Flexible ureteroscopy combined with Holmium-YAG laser is an effective, reproducible and minimally traumatic diagnostic and therapeutic technique perfectly adapted to diseases of the upper urinary tract. This technology must be part of the therapeutic armamentarium of any centre involved in the management of urinary stones. The technical facilities must be complete and adapted. Flexible ureteroscopy is a technique with a rapid learning curve once the operator is familiar with all of the equipment. This article describes the material and technique of flexible ureteroscopy combined with Holmium-YAG laser.

[Reduction of the renal transplantation cold ischaemia time by the use of a timesheet]. / Reduction des durées d'ischémie froide des transplants rénaux par la mise en place d'une fiche de traçabilité horaire.

OBJECTIVE: Reduction of the cold ischaemia time is one of the major objectives designed to improve the quality and cost of renal transplantation. Based on the experience of other centres, we report the impact of using a renal transplantation timesheet on the cold ischaemia time in our centre. MATERIAL AND METHOD: Since March 2004, we have used a renal transplantation timesheet with the collaboration of all personnel involved in transplantation (coordination, nephrologists, clinical pathologists). For each kidney harvested, the name of the personnel and the start and end times of their interventions were recorded. The authors report the results for the first 7 months. Cold ischaemia times and the incidence of delayed graft function were studied. RESULTS: 47 kidneys were harvested between 01/03/2004 and 30/9/2004 in our centre and 46 transplantations were performed. The mean cold ischaemia time was 14 h 51 min, i.e. a reduction of 8 hours 58 minutes compared to that observed in 2003 (23 h 50 min) (p < 0.01). Delayed graft function (DGF) was observed in 10/46 (21.74%) recipients. This DGF rate was significantly lower than that observed in 2003 (DGF 2003 = 30%), while the mean donor serum creatinine was higher (155 +/- 177 micromol/l vs 98 +/- 71 micromol/l in 2003, p < 0.05). The longest delays were those related to availability of an operating room (n=2: 10 h and 14 h). CONCLUSION: The use of a renal transplantation timesheet allowed a significant reduction of the cold ischaemia time and DGF rate. It requires the collaboration of all renal transplantation personnel and is an indicator of motivation. This timesheet allowed the correction of certain habits that can still be improved. These results should lead to an improvement of the results and cost of renal transplantation.

[Treatment of inferior caliceal stones by flexible ureteroscopy]. / Traitement des calculs caliciels inférieurs par urétéroscopie souple.

OBJECTIVE: Evaluation of the treatment of inferior caliceal stones by flexible ureterorenoscopy and Holinium-YAG laser on a series of 69 operations. MATERIAL AND METHOD: Between April 1998 and December 2003, 69 flexible ureteroscopies were performed for 55 stones in 49 patients. The mean age of the patients was 51.6 years (range: 18-78). The mean stone diameter was 12.8 mm (range: 5-3 1). 46% of stones had been pretreated by ESWL, PCNL or surgery. Endocorporeal lithotripsy was performed by Holmium-YAG laser in 45 cases, Lithoclast in 5 cases and en bloc extraction in 3 cases. Technical features, efficacy and morbidity were studied. The results were classified into fragment-free (FS), residual fragments (RF) < or = 4 mm, RF > 4 mm and failures. The results were evaluated on D0-D1 and at 3 months on a plain abdominal x-ray and ultrasound. RESULTS: The mean operating time was 61 minutes (range: 25-120). Nine stones required several procedures. 20% of stones were cystine stones. A ureteric stent was placed in 67 cases. The mean length of stay was 2.5 days (D0-D8). At 3 months, after one or several ureteroscopies, the results were: 22% FS, 40% RF < or = 4 mm, 13% RF > 4 mm and 25% failures. One half of failures occurred during the first 14 ureteroscopy procedures. There were 13 minor complications and no major complications. CONCLUSIONS: The results of flexible ureteroscopy in the treatment of inferior caliceal stones are encouraging, especially with standardization of the technique. It appears to be a good compromise between ESWL and PCNL, particularly for stones between 10 and 20 mm, cystine stones and after failure of reference techniques.

[Tubulopapillary tumours of the kidney: prognostic value and therapeutic implications of the distinction between type 1 and type 2 based on a series of 58 cases]. / Les tumeurs tubulo-papillaires du rein: intérêt pronostique de la distinction type 1/type 2. A propos de 58 cas.

OBJECTIVE: The purpose of this study was to demonstrate the prognostic value of subdivision of tubulopapillary tumours into 2 histological subtypes and to discuss the therapeutic implications. MATERIALS AND METHODS: This was a single-centre retrospective study of 58 cases from a series of 414 patients operated for renal cancer between 1988 and 2001 based on review of histology slides (biopsies and operative specimens). The radiological assessment was based on ultrasound reports and review of CT scans. Karyotypes were described by cytogenetic analysis. RESULTS AND DISCUSSION: Tubulopapillary tumours represented 14% of all kidney tumours with a male prevalence of 77% and a mean age of 56.5 years. The overall mean follow-up was 62.6 months. Treatment consisted of 25 right radical nephrectomies, 29 left radical nephrectomies and 4 partial nephrectomies. 84% of tumours were low-grade and 80% were low stage T1 or T2. Multifocal lesions were observed in 31% of cases. Synchronous bilateral lesions were observed in 12% of cases. The 5-year survival was 95% and the 10-year survival was 87%, correlated with stage, grade, tumour diameter, presence of necrosis and low enhancement. According to the data reported by Delahunt, 2 subtypes can be distinguished: Type I tumours (75%) with low grade and low stage were correlated with a high rate of multifocal lesions (30%) with a genetic predisposition. Type 2 tumours (25%), usually unifocal, were correlated with a higher grade and stage, confirmed by their poorer prognosis. Biopsy allows a distinction of the type and grade of the tumour. CONCLUSIONS: In our series, for equivalent mean tumour diameters (55 mm), tubulopapillary tumours treated by radical nephrectomy had a good prognosis regardless of their subtype. Classification of the tumour by biopsy prior to surgery could have implications for therapeutic management. For type 1 tubulopapillary tumours identified on preoperative biopsy, we propose radical nephrectomy due to the high risk of multifocal lesions (30%). Although partial nephrectomy may be indicated for type 1 tubulopapillary tumours less than 4 cm, the patient must be informed about the risk of recurrence and the importance of long-term follow-up. Studies including a larger number of patients must be conducted to compare the survival associated with type 2 tumours compared to that of the classical histological subtype.