Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, -related schwannomatosis and non--related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments.

Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF.

Exposure-response modeling for extrapolation from adult to pediatric patients who differ with respect to prognostic factors: Application to everolimus.

Pediatric extrapolation is essential for bringing treatments to the pediatric population, especially for indications where the recruitment of pediatric patients into clinical trials is difficult and where fully powered trials are impossible. Often a similar exposure-response relationship between adult and pediatric patients can be assumed, but just matching exposures can be misleading when some prognostic factors for efficacy differ between those two patient populations. We present an example in liver transplantation where different study designs led to different (time-dependent) hazards between populations.

Identifying challenges in neurofibromatosis: a modified Delphi procedure.

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and schwannomatosis (SWN) are rare conditions with pronounced variability of clinical expression. We aimed to reach consensus on the most important manifestations meriting the development of drug trials. The five-staged modified Delphi procedure consisted of two questionnaires and a consensus meeting for 40 NF experts, a survey for 63 patient representatives, and a final workshop.

Cardiac risk assessment based on early Phase I data and PK-QTc analysis is concordant with the outcome of thorough QTc trials: an assessment based on eleven drug candidates.

Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.

Investigating Age-Related Changes in Proliferation and the Cell Division Repertoire of Parenchymal Reactive Astrocytes.

Reactive gliosis is a complicated process involving all types of glial cells and is the therapeutic target of efforts to treat several types of neuropathologies. Parenchymal astrocytes continuously survey their microenvironment to identify even tiny abnormalities in the central nervous system (CNS) homeostasis and react rapidly to brain damage, such as following ischemia, trauma, or neurodegenerative diseases, to prevent propagation of tissue damage. Aging can play causal roles in certain astroglial dysfunctions, however, still little is known to what extent the heterogeneous reaction of astrocytes at the injury site might be impaired over the course of aging.

A nonparametric method to detect increased frequencies of adverse drug reactions over time.

Signal detection is routinely applied to spontaneous report safety databases in the pharmaceutical industry and by regulators. As an example, methods that search for increases in the frequencies of known adverse drug reactions for a given drug are routinely applied, and the results are reported to the health authorities on a regular basis. Such methods need to be sensitive to detect true signals even when some of the adverse drug reactions are rare.

Model averaging for robust assessment of QT prolongation by concentration-response analysis.

Assessing the QT prolongation potential of a drug is typically done based on pivotal safety studies called thorough QT studies. Model-based estimation of the drug-induced QT prolongation at the estimated mean maximum drug concentration could increase efficiency over the currently used intersection-union test. However, robustness against model misspecification needs to be guaranteed in pivotal settings.

Changes in the Proliferative Program Limit Astrocyte Homeostasis in the Aged Post-Traumatic Murine Cerebral Cortex.

Aging leads to adverse outcomes after traumatic brain injury. The mechanisms underlying these defects, however, are not yet clear. In this study, we found that astrocytes in the aged post-traumatic cerebral cortex develop a significantly reduced proliferative response, resulting in reduced astrocyte numbers in the penumbra.

Exact and asymptotic inference in clinical trials with small event rates under inverse sampling.

In this paper, we discuss statistical inference for a 2 × 2 table under inverse sampling, where the total number of cases is fixed by design. We demonstrate that the exact unconditional distributions of some relevant statistics differ from the distributions under conventional sampling, where the sample size is fixed by design. This permits us to define a simple unconditional alternative to Fisher's exact test.

Estimating the contribution of everolimus to immunosuppressive efficacy when combined with tacrolimus in liver transplantation: a model-based approach.

Determining the efficacy contribution of an investigational drug as part of a novel combination regimen that also includes a previously untested dose of a standard treatment is challenging, particularly when "placebo control" data (combination regimen minus the investigational drug) is not available for comparison. This situation was encountered in a phase III trial that tested the combination of the investigational drug everolimus with a dose of tacrolimus lower than used in standard liver transplantation therapy. The challenge was addressed by predicting the efficacy of the placebo control from the study data using a pharmacometric-based exposure-response analysis, selected to account for features specific to the transplant setting: systematic change in drug exposure over time and sparse pharmacokinetic sampling.

Higher Risk of Hypoglycemia with Glimepiride Versus Vildagliptin in Patients with Type 2 Diabetes is not Driven by High Doses of Glimepiride: Divergent Patient Susceptibilities?

Introduction: In a previously published study, vildagliptin showed a reduced risk of hypoglycemia versus glimepiride as add-on therapy to metformin at similar efficacy. Glimepiride was titrated from a starting dose of 2 mg/day to a maximum dose of 6 mg/day. It is usually assumed that the increased hypoglycemia with glimepiride was driven by the 6 mg/day dose; it was therefore of interest to assess whether the risk of hypoglycemia is also different between vildagliptin and a low (2 mg/day) dose of glimepiride.

Analysis of 5-methyltetrahydrofolate in serum of healthy children.

5-Methyltetrahydrofolate (5MTHF) is the active one-carbon donor and the principal circulating form of plasma folates. It is involved in a number of metabolic and neurodevelopmental processes and analysis of cerebrospinal fluid (CSF) 5MTHF is of great importance in the diagnosis of cerebral folate deficiency (CFD). Serum 5MTHF levels and the 5MTHF serum/CSF ratio may be important additional parameters for the understanding of CFD.

Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH).

Background: Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN-beta) in children and adolescents with nasopharyngeal carcinoma, especially in high-risk patients, have been promising.

Methods: From 1992 to 2003, 59 patients (58 high-risk patients and 1 low-risk patient, median age 13 yrs; range, 8-25 yrs) were treated in the GPOH-NPC-91 study. The Stage II patient received irradiation as initial therapy.

Prevalence of thrombophilia and catheter-related thrombosis in cystic fibrosis.

Venous thrombosis in children and young adults is frequently associated with predisposing conditions and with an indwelling catheter or totally implantable venous access device (TIVAD). These systems are commonly used for the delivery of antibiotic therapy in patients with cystic fibrosis (CF). We reviewed our CF center's history of catheter-related events over 13 years and prospectively investigated the presence of risk factors for thrombosis in 66 children and adults with CF (age, 3-38 years; 32 females).

[Identification of geophilic and zoophilic dermatophytes in siblings with tinea capitis. A pathogenic factor or contamination?].

Two siblings of African origin presented with multiple scaling patches and alopecia on the scalp four weeks after returning from a vacation in Eritrea. Direct KOH examination revealed fungal elements; Trichophyton mentagrophytes and Trichophyton terrestre were identified in the fungal culture. We discuss the putative pathogenic role of both microorganisms in causing disease.

Effect of DNase on exercise capacity in cystic fibrosis.

DNase can reduce viscosity and facilitate expectoration of airway secretions in cystic fibrosis (CF) lung disease. We evaluated its effect on exercise performance in relation to resting pulmonary function. Fifteen sputum-producing CF patients (aged 9-28 years; FEV1 22-83% predicted) performed spirometry, body plethysmography, nitrogen washout, and incremental cardiopulmonary exercise testing before and after 8 weeks of first-time treatment with daily inhaled rhDNase.

Reduced folate transport to the CNS in female Rett patients.

Background: Previous CSF studies in Rett syndrome suggest reduced turnover of the biogenic monoamines serotonin and dopamine. Because diminished turnover may result from CNS folate depletion, the authors studied transport of folate across the blood-brain barrier.

Methods: In four patients with Rett syndrome, the authors measured CSF values of 5-methyltetrahydrofolate (5MTHF), biogenic monoamine end-metabolites, and pterins together with serum and red blood cell folate.

Inflammatory pseudotumors of the central nervous system: report of 3 cases and a literature review.

Inflammatory pseudotumors (IPs), mostly benign lesions characterized by fibrotic ground tissue and polyclonal mononuclear infiltrate, may affect all organ systems. IPs originating in the central nervous system (IP-CNS) are very rare, and their distinct histopathologic features are poorly characterized. Three otherwise healthy patients (age 8, 15, and 17 years) presented with focal neurologic symptoms (seizures, n = 2; headaches, n = 1), corresponding to a left temporal, left occipital, and left frontal IP, respectively, extending from meningeal structures into brain tissue.

Effects of thickened feeding on gastroesophageal reflux in infants: a placebo-controlled crossover study using intraluminal impedance.

Objective: Thickening of formula feedings is part of the therapeutic approach for gastroesophageal reflux (GER) in infants. However, its mechanism of action, especially regarding the occurrence of nonacid (pH >4) GER, has not yet been clearly described. The aim of this randomized, placebo-controlled crossover study was to examine the influence of formula thickened with carob (St.

Non-parametric estimators of a monotonic dose-response curve and bootstrap confidence intervals.

In this paper we consider study designs which include a placebo and an active control group as well as several dose groups of a new drug. A monotonically increasing dose-response function is assumed, and the objective is to estimate a dose with equivalent response to the active control group, including a confidence interval for this dose. We present different non-parametric methods to estimate the monotonic dose-response curve.

Psychomotor retardation, spastic paraplegia, cerebellar ataxia and dyskinesia associated with low 5-methyltetrahydrofolate in cerebrospinal fluid: a novel neurometabolic condition responding to folinic acid substitution.

Introduction: Normal brain development and function depend on the active transport of folates across the blood-brain barrier. The folate receptor-1 (FR 1) protein is localized at the basolateral surface of the choroid plexus, which is characterized by a high binding affinity for circulating 5-methyltetrahydrofolate (5-MTHF).

Patients And Methods: We report on the clinical and metabolic findings among five children with normal neurodevelopmental progress during the first four to six months followed by the acquisition of a neurological condition which includes marked irritability, decelerating head growth, psychomotor retardation, cerebellar ataxia, dyskinesias (choreoathetosis, ballism), pyramidal signs in the lower limbs and occasional seizures.

Esophageal pH monitoring and impedance measurement: a comparison of two diagnostic tests for gastroesophageal reflux.

Background: pH monitoring is the standard diagnostic tool for gastroesophageal reflux in infants. However, this method does not document the reflux of all kinds of fluid from the stomach into the esophagus, but only documents acid material. The parameters that define reflux episodes by pH monitoring have been derived empirically from observations of many infants considered healthy and ill.

Peripheral decrease and pulmonary homing of CD4+CD45RO+ helper memory T cells in cystic fibrosis.

Interstitial lung disease, although of prognostic impact for patients with cystic fibrosis (CF), remains difficult to assess without histopathologic investigations. As changes of peripheral blood lymphocyte subsets (LS) may accompany severe systemic lymphocyte immune responses, we compared peripheral LS of 44 patients with CF, 23 non-CF patients with recurrent pulmonary infections and 83 healthy controls (flow cytometry; CD3, CD19, CD16, CD56, CD4, CD8, CD11b, CD45RA, CD45RO, HLA-DR and CD25 antigens). Additional immunohistochemistry was performed on lung tissue of four CF patients aged 0.