Cytochrome P450 2D6 and outcomes of adjuvant tamoxifen therapy: results of a meta-analysis

Pharmacological evidence shows that cytochrome P450 2D6 (CYP2D6) function is important in the conversion of tamoxifen to its active metabolites. Many retrospective analyses have assessed the role of both CYP2D6 genotype and concurrent administration of drug inhibitors of CYP2D6 on outcome of tamoxifen therapy. These studies have frequently been of small size and their data highly variable. A published data meta-analysis of trials evaluating outcomes of tamoxifen therapy in early breast cancer was undertaken. Hazard ratios (HRs) were extracted for disease-free survival (DFS) and overall survival (OS). Pooled estimates were computed using inverse-variance and random-effect modeling. Data from 10 studies assessing CYP2D6 genotype were included in a meta-analysis. There was significant heterogeneity in the definition of comparison groups between studies. When compared to reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR 2.07, 95% CI 0.96–4.49, P = 0.06) but not OS (HR 1.36, 95% CI 0.73–2.52, P = 0.34). Pooling of data from two studies evaluating CYP2D6 drug inhibitors showed that concomitant administration of these with tamoxifen was associated with a non-significant association with DFS (HR 1.37, 95% CI 0.69–2.73, P = 0.37). Analysis of the effect of CYP2D6 drug inhibitors on OS was not possible. The effect of CYP2D6 genotype on breast cancer seems to be relatively small and may not warrant testing of CYP2D6 genotype in all women with hormone receptor positive breast cancer. The effect of CYP2D6 genotype on outcome in low-risk patients may not be clinically relevant, while the upfront use of aromatase inhibitors is a reasonable alternative to tamoxifen in high-risk post-menopausal women, irrespective of CYP2D6 genotype. There are limited data supporting the association of potent inhibitors of CYP2D6 and detrimental outcome, but avoidance of such drugs seems reasonable.     

Laparoscopic splenopexy of a wandering spleen.

A laparoscopic technique for splenopexy of a wandering spleen using an absorbable mesh in an adult woman is described for the first time. This patient was referred to surgery because of recurrent biliary colic secondary to cholecystolithiasis. The wandering spleen had been diagnosed at least 4 years earlier, but a conservative approach had been adopted for a symptomless patient. Laparoscopic cholecystectomy was performed concomitantly with splenopexy. Laparoscopic splenopexy seems a feasible and safe procedure, especially when performed by experienced laparoscopic surgeons.     

Mass medical repatriation of injured civilians after terrorist attack in Mombassa, Kenya: medical needs, resources used, and lessons learned

INTRODUCTION: On 28 November 2002, three suicide bombers crashed their car into a hotel in Mombassa, Kenya; 12 people were killed, including three Israelis, and 80 were wounded (22 of whom were Israeli). The Israeli Defense Force Airborne Medical Evacuation Flight Teams participated in a repatriation mission to bring the wounded home. OBJECTIVES: The objectives of this study are to outline the distinctive aspects of this mission, as well as to share the experiences and lessons learned. METHODS: Israeli Army debriefing reports were used to study the composition of the crew, medical equipment taken, injury distribution, mode of operation, and mission schedule. RESULTS: A total of six fixed-wing aircraft were used--two Boeing 707s and four Hercules C-130s--with a total of 54 medical team members on board. A total of 260 Israelis were repatriated, 22 of whom were wounded, and three were dead. Of the casualties, 14 were conveyed sitting, and eight supine. The time from the first landing in Kenya to the evacuation of the last supine patient was 5.5 hours. Nurses, as well as social workers, played a central role in the mission. A forward team, including five doctors, was used for the initial organization and for gathering information on the medical status of the casualties. CONCLUSIONS: There was redundancy in the medical crew and medical equipment sent. The need for improved infrastructure on the medical aircraft was stressed. Based on this experience, a new mode for operation for similar missions in the future was formulated.     

Cutaneous malignant melanoma and Parkinson disease: Common pathways?

The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser‐phosphorylated α‐synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM‐targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811–820     

Cognitive state following mild stroke: A matter of hippocampal mean diffusivity

The hippocampus is known to play a vital role in learning and memory and was demonstrated as an early imaging marker for Alzheimer's disease (AD). However, its role as a predictor for mild cognitive impairment and dementia following stroke is unclear. The main purpose of this study was to examine the associations between hippocampal volume, mean diffusivity (MD) and connectivity and cognitive state following stroke. Eighty three consecutive first ever mild to moderate stroke or transient ischemic attack (TIA) survivors from our ongoing prospective TABASCO (Tel Aviv Brain Acute Stroke Cohort) study underwent magnetic resonance imaging scans within 7 days of stroke onset. Hippocampal volume was measured from T1 weighted images, hippocampal mean diffusivity was calculated from diffusion tensor imaging and connectivity was calculated from resting state fMRI. Global cognitive assessments were evaluated during hospitalization and 6 and 12 months later using a computerized neuropsychological battery. Multiple linear regression analysis was used to test which of the hippocampi measurements best predict cognitive state. All three imaging parameters were significantly correlated to each other (|r's| >0.3, P's < 0.005), and with cognitive state 6 and 12 months after the event. Multiple regression analyses demonstrated the predictive role of hippocampal mean diffusivity (β = ?0.382, P = 0.026) on cognitive state, above and beyond that of volume and connectivity of this structure. To our knowledge, the combination of hippocampal volume, mean diffusivity and connectivity in first ever post stroke or TIA patients has not yet been considered in relation to cognitive state. The results demonstrate the predictive role of hippocampal mean diffusivity, suggesting that these changes may precede and contribute to volumetric and connectivity changes in the hippocampi, potentially serving as a marker for early identification of patients at risk of developing cognitive impairment or dementia. © 2015 Wiley Periodicals, Inc.     

Increased dopamine receptor signaling and dopamine receptor-G protein coupling in denervated striatum

Chronic interruption of the nigrostriatal dopaminergic pathway leads to sensitized dopaminergic responses in striatum. We attempted to explore the mechanism(s) underlying this dopaminergic supersensitivity by assessing dopamine receptor signaling and receptor-G protein coupling in unilateral 6-hydroxydopamine-lesioned rats. Dopamine-stimulated adenylyl cyclase activity as well as dopamine-activated guanosine 5'-O-(3-[(35)S]thiotriphosphate) ([(35)S]GTPgammaS) binding and [(3)H]palmitate incorporation by Galpha proteins were enhanced in tissues obtained from denervated striata without apparent changes in Galpha protein levels. Moreover, high-affinity binding sites of the D(1) dopamine receptor increased in lesioned compared with control striata without altering the expression level of the receptor. These denervation-mediated changes appear to correlate with the increase in D(1) dopamine receptor binding sites that co-immunoprecipitated with Galphas(olf)/q(11) proteins. In contrast, the total number of D(2) receptor binding sites was increased, yielding an increase in absolute number of high-affinity sites without significant changes in the proportion of high-affinity sites. Stimulation of the D(2) dopamine receptor enhanced coupling to Galphai protein; this was increased in the striata lesioned. The results provide an important molecular mechanism by which dopamine receptor-regulated signaling is enhanced following denervation of dopaminergic input to striatum. Although D(1) dopamine receptor supersensitivity appears to be mediated by enhanced coupling of the receptor to its G proteins, sensitization in the D(2) dopamine receptor system is mediated by increased D(2) receptor density and enhanced D(2) receptor-Gi protein coupling.