BRAFV600E immunopositive Melanomas Show Low Frequency of Heterogeneity and Association With Epithelioid Tumor Cells: A STROBE-Compliant article

Treatment of BRAF^V600E-mutant melanoma by small molecule inhibitors that target BRAF or MEK kinases is increasingly used in clinical practice and significantly improve patient outcome. However, patients eventually become resistant and therapeutic improvement is required. Molecular diversity within individual tumors (intratumor heterogeneity) and between tumors within a single patient (intrapatient heterogeneity) poses a significant challenge to precision medicine.Using immunohistochemistry, we determined the extent of BRAF^V600E intratumor and intrapatient heterogeneity and the influence of morphological heterogeneity in a large series of 171 melanomas of 81 patients.The BRAF^V600E mutation rate found in our melanoma series is 44%, with none of 22 (0%) melanoma in situ, 23 of 56 (41%) primary tumors, 28 of 59 (48%) regional metastases, and 24 of 34 (71%) distant metastases harboring the mutation. In general, a diffuse homogeneous immunostaining was seen, even in tumors consisting of more than one cell type, that is, epithelioid, spindle, and/or small cell types. Nevertheless, BRAF^V600E-mutant melanomas more often had a purely epithelioid cell population (P = 0.063), that is more evident among distant metastases (P = 0.014). Only two of 75 (3%) mutated specimens (one primary and one metastasis) displayed heterogeneous BRAF^V600E expression. The primary tumor was also morphologically heterogeneous and exclusively displayed BRAF^V600E in the epithelioid component, confirming an association between BRAF^V600E and epithelioid cells. Twenty-eight of 30 patients (93%) had concordant BRAF mutation status between their tumors.Taken together, BRAF^V600E intratumor and intrapatient heterogeneity in melanoma is diminutive, nevertheless, the identified exceptions will have important implications for the clinical management of this disease.     

Paternal influences on treatment outcome of behavioral parent training in children with attention-deficit/hyperactivity disorder

This study aims to explore the influence of paternal variables on outcome of behavioral parent training (BPT) in children with attention-deficit/hyperactivity disorder (ADHD). 83 referred, school-aged children with ADHD were randomly assigned to BPT plus ongoing routine clinical care (RCC) or RCC alone. Treatment outcome was based on parent-reported ADHD symptoms and behavioral problems. Moderator variables included paternal ADHD symptoms, depressive symptoms, and parenting self-efficacy. We conducted repeated measures analyses of variance (ANOVA) for all variables, and then analyzed the direction of interaction effects by repeated measures ANOVA in high and low scoring subgroups. Paternal ADHD symptoms and parenting self-efficacy played a moderating role in decreasing behavioral problems, but not in decreasing ADHD symptoms. Paternal depressive symptoms did not moderate either treatment outcome. BPT is most beneficial in reducing children’s behavioral problems when their fathers have high levels of ADHD symptoms or high-parenting self-efficacy.     

The interplay between drugs and the kidney in premature neonates

The kidney plays a central role in the clearance of drugs. However, renal drug handling entails more than glomerular filtration and includes tubular excretion and reabsorption, and intracellular metabolization by cellular enzyme systems, such as the Cytochrome P450 isoenzymes. All these processes show maturation from birth onwards, which is one of the reasons why drug dosing in children is not simply similar to dosing in small adults. As kidney development normally finishes around the 36th week of gestation, being born prematurely will result in even more immature renal drug handling. Environmental effects, such as extra-uterine growth restriction, sepsis, asphyxia, or drug treatments like caffeine, aminoglycosides, or non-steroidal anti-inflammatory drugs, may further hamper drug handling in the kidney. Dosing in preterm neonates is therefore dependent on many factors that need to be taken into account. Drug treatment may significantly hamper postnatal kidney development in preterm neonates, just like renal immaturity has an impact on drug handling. The restricted kidney development results in a lower number of nephrons that may have several long-term sequelae, such as hypertension, albuminuria, and renal failure. This review focuses on the interplay between drugs and the kidney in premature neonates.