Identification of a Novel Pathogenic Germline KDR Variant in Melanoma.

PURPOSE: The application of pan-cancer next-generation sequencing panels in the clinical setting has facilitated the identification of low frequency somatic mutations and the testing of new therapies in solid tumors using the "basket trial" scheme. However, little consideration has been given to the relevance of nonsynonymous germline variants, which are likely to be uncovered in tumors and germline and which may be relevant to prognostication and prediction of treatment response. EXPERIMENTAL DESIGN: We analyzed matched tumor and normal DNA from 34 melanoma patients using an Ion Torrent cancer-associated gene panel. We elected to study the germline variant Q472H in the kinase insert domain receptor (KDR), which was identified in 35% of melanoma patients in both a pilot and an independent 1,223 patient cohort. Using patient-derived melanoma cell lines and human samples, we assessed proliferation, invasion, VEGF levels, and angiogenesis by analyzing tumor microvessel density (MVD) using anti-CD34 antibody. RESULTS: Serum VEGF levels and tumor MVD were significantly higher in Q472H versus KDR wild-type (WD) patients. Primary cultures derived from melanomas harboring the KDR variant were more proliferative and invasive than KDR wild type. Finally, using a VEGFR2 antibody, we showed that KDR Q472H cells were sensitive to targeted inhibition of VEGFR2, an effect that was not observed in KDR WT cells. CONCLUSIONS: Our data support the integration of germline analysis into personalized treatment decision-making and suggest that patients with germline KDR variant might benefit from antiangiogenesis treatment. Clin Cancer Res; 22(10); 2377-85. ©2015 AACR.

Fluoxetine treatment in poststroke depression, emotional incontinence, and anger proneness: a double-blind, placebo-controlled study.

BACKGROUND AND PURPOSE: The efficacy and safety of the selective serotonin reuptake inhibitor fluoxetine have rarely been studied in the treatment of poststroke emotional disturbances. METHODS: Stroke patients (152) who had poststroke depression (PSD), emotional incontinence (PSEI), or anger proneness (PSAP) were studied. PSD was evaluated by Beck Depression Inventory and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, PSEI by Kim's criteria, and PSAP was assessed by Spielberger Trait Anger Scale. Subjects were randomly given either fluoxetine 20 mg/day (n=76) or placebo (n=76) for 3 months. Follow-up evaluations were done 1, 3, and 6 months after the beginning of the treatment. The primary outcome measurement was the scores of emotional disturbances at each follow-up assessment. The secondary outcome measurements were the percentage changes of the scores and the subjective responses of the patients. RESULTS: Although patients in the fluoxetine group more often dropped out because of adverse effects, fluoxetine administration was generally safe. Fluoxetine significantly improved PSEI and PSAP, whereas no definitive improvement of PSD was found. Improvement of PSAP was noted even at 3 months after the discontinuation of the treatment. CONCLUSIONS: Fluoxetine is efficacious in the treatment of PSEI and PSAP. Its effect on PSD is not solidly confirmed.

Poststroke fatigue: characteristics and related factors.

BACKGROUND AND PURPOSE: Poststroke fatigue (PoSF) is a common, but poorly studied problem. The purpose of the present study was to elucidate the characteristics of and the factors associated with PoSF. METHODS: We studied 220 consecutive outpatients at an average of 15 months after the onset of stroke. The presence of poststroke depression (PSD) and poststroke emotional incontinence were identified with the use of a standardized questionnaire. The presence of PoSF was assessed using the visual analogue scale and Fatigue Severity Scale. The presence of prestroke fatigue (PrSF) was also assessed. The impact of PoSF on patients' daily activities was also assessed using the Fatigue Impact Scale. RESULTS: One hundred and twenty-five patients (57%) had PoSF, 83 (38%) had PrSF and 53 (24%) had PSD. Thirty-six percent of the patients without PrSF and 50% of the patients without PSD had PoSF. The impact of PoSF on patients' daily activities was more severe in the physical domain as compared with the psychological or cognitive domains (p < 0.01). Multivariate analyses showed that the presence of PrSF (p < 0.01, OR 33.5), high modified Rankin scale (MRS; p < 0.05, OR 3.3), PSD (p < 0.05, OR 2.7) were independently associated with PoSF. Cessation of cigarette smoking (p < 0.05) and the presence of PrSF (p < 0.01) were independently related to PoSF in patients without PSD while decrease in sexual activities (p < 0.05) and the presence of dysarthria (p < 0.05) were related to PoSF in patients without PrSF. CONCLUSIONS: Fatigue is a fairly common sequela of stroke patients, exerting an impact on their daily activities, especially physical ones. PrSF is the most important factor related to PoSF, followed by high MRS and PSD. Nevertheless, the causes of PoSF appear multifactorial. Strategies to improve the PoSF should be individualized according to the causative factors.