CLINICAL MANAGEMENT OF SALIVARY GLAND HYPOFUNCTION AND XEROSTOMIA IN HEAD-AND-NECK CANCER PATIENTS: SUCCESSES AND BARRIERS

The most significant long-term complication of radiotherapy in the head-and-neck region is hyposalivation and its related complaints, particularily xerostomia. This review addresses the pathophysiology underlying irradiation damage to salivary gland tissue, the consequences of radiation injury, and issues contributing to the clinical management of salivary gland hypofunction and xerostomia. These include ways to (1) prevent or minimize radiation injury of salivary gland tissue, (2) manage radiation-induced hyposalivation and xerostomia, and (3) restore the function of salivary gland tissue damaged by radiotherapy. (C) 2010 Elsevier Inc

Distinct Patterns of Cytokine and Angiogenic Factor Modulation and Markers of Benefit for Vandetanib and/or Chemotherapy in Patients With Non–Small-Cell Lung Cancer

PURPOSE: There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit. METHODS: Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non-small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk. RESULTS: VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk. CONCLUSION: Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit

Comparison of MRI-assessed body fat content between lean women with polycystic ovary syndrome (PCOS) and matched controls: less visceral fat with PCOS

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous disorder. However, PCOS has a strong resemblance to the metabolic syndrome, including preponderance of visceral fat deposition. The aim of this study is to compare fat distribution between lean women with PCOS and controls matched for body composition but with regular menstrual cycles and proven fertility. METHODS: In this prospective cross-sectional study in a fertility outpatient clinic, 10 Caucasian women with PCOS and 10 controls, all with a BMI between 19 and 25 kg/m(2), were included. Fasting glucose, insulin and C-peptide concentrations, homeostasis model assessment (HOMA), hormonal levels and bioelectrical impedance analysis (BIA) variables were assessed and fat content and ovarian volume determinations were obtained with magnetic resonance imaging (MRI). Multiple axial cross-sections were calculated. RESULTS: The age of the PCOS and control groups were [mean (SD)] 28.2 years (2.6) versus 33.7 years (2.3) P <0.0001, respectively, and both groups were matched for BMI: 21.6 kg/m(2) (1.1) versus 21.8 kg/m(2) (2.1) (ns), fasting glucose, insulin, C-peptide, HOMA-insulin resistance (IR) levels and BIA parameters. PCOS cases had higher ovarian volumes and less visceral fat compared with controls. CONCLUSIONS: Lean women with PCOS have higher MRI-determined ovarian volumes and less visceral fat content when compared with control women

Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies

KAT6A Syndrome:genotype-phenotype correlation in 76 patients with pathogenic KAT6A variants

Purpose Pathogenic variants in KAT6A have recently been identified as a cause of syndromic developmental delay. Within 2 years, the number of patients identified with pathogenic KAT6A variants has rapidly expanded and the full extent and variability of the clinical phenotype has not been reported. Methods We obtained data for patients with KAT6A pathogenic variants through three sources: treating clinicians, an online family survey distributed through social media, and a literature review. Results We identified 52 unreported cases, bringing the total number of published cases to 76. Our results expand the genotypic spectrum of pathogenic variants to include missense and splicing mutations. We functionally validated a pathogenic splice-site variant and identified a likely hotspot location for de novo missense variants. The majority of clinical features in KAT6A syndrome have highly variable penetrance. For core features such as intellectual disability, speech delay, microcephaly, cardiac anomalies, and gastrointestinal complications, genotype– phenotype correlations show that late-truncating pathogenic variants (exons 16–17) are significantly more prevalent. We highlight novel associations, including an increased risk of gastrointestinal obstruction. Conclusion Our data expand the genotypic and phenotypic spectrum for individuals with genetic pathogenic variants in KAT6A and we outline appropriate clinical management