Citations

Key Points Agents that inhibit both complexes containing the mammalian target of rapamycin are particularly toxic to acute lymphocytic leukemia cells. This killing reflects engagement of a 4EBP1/c-MYC/PUMA axis downstream of mTORC1 and an NF-κB/EGR1/BIM axis downstream of mTORC2.

Background.Noninvasive prenatal screening (NIPS) is revolutionizing prenatal screening as a result of its increased sensitivity, specificity. NIPS analyzes cell-free fetal DNA (cffDNA) circulating in maternal plasma to detect fetal chromosome abnormalities. However, cffDNA originates from apoptotic placental trophoblast; therefore cffDNA is not always representative of the fetus. Although the published data for NIPS testing states that the current technique ensures high sensitivity and specificity for aneuploidy detection, false positives are possible due to isolated placental mosaicism, vanishing twin or cotwin demise, and maternal chromosome abnormalities or malignancy.Results.We report a case of false negative cell-free DNA (cfDNA) screening due to fetoplacental mosaicism. An infant male with negative cfDNA screening result was born with multiple congenital abnormalities. Postnatal chromosome and FISH studies on a blood specimen revealed trisomy 13 in 20/20 metaphases and 100% interphase nuclei, respectively. FISH analysis on tissues collected after delivery revealed extraembryonic mosaicism.Conclusions.Extraembryonic tissue mosaicism is likely responsible for the false negative cfDNA screening result. This case illustrates that a negative result does not rule out the possibility of a fetus affected with a trisomy, as cffDNA is derived from the placenta and therefore may not accurately represent the fetal genetic information.

Background and Purpose— Emerging evidence demonstrating the high sensitivity of early brain computed tomography (CT) brings into question the necessity of always performing lumbar puncture after a negative CT in the diagnosis of spontaneous subarachnoid hemorrhage (SAH). Our objective was to determine the sensitivity of brain CT using modern scanners (16-slice technology or greater) when performed within 6 hours of headache onset to exclude SAH in neurologically intact patients. Methods— After conducting a comprehensive literature search using Ovid MEDLINE, Ovid EMBASE, Web of Science, and Scopus, we conducted a meta-analysis. We included original research studies of adults presenting with a history concerning for spontaneous SAH and who had noncontrast brain CT scan using a modern generation multidetector CT scanner within 6 hours of symptom onset. Our study adheres to the preferred reporting items for systematic reviews and meta-analyses (PRISMA). Results— A total of 882 titles were reviewed and 5 articles met inclusion criteria, including an estimated 8907 patients. Thirteen had a missed SAH (incidence 1.46 per 1000) on brain CTs within 6 hours. Overall sensitivity of the CT was 0.987 (95% confidence intervals, 0.971–0.994) and specificity was 0.999 (95% confidence intervals, 0.993–1.0). The pooled likelihood ratio of a negative CT was 0.010 (95% confidence intervals, 0.003–0.034). Conclusions— In patients presenting with thunderclap headache and normal neurological examination, normal brain CT within 6 hours of headache is extremely sensitive in ruling out aneurysmal SAH.

ObjectiveInfantile spasms are seizures associated with a severe epileptic encephalopathy presenting in the first 2 years of life, and optimal treatment continues to be debated. This study evaluates early and sustained response to initial treatments and addresses both clinical remission and electrographic resolution of hypsarrhythmia. Secondarily, it assesses whether response to treatment differs by etiology or developmental status.MethodsThe National Infantile Spasms Consortium established a multicenter, prospective database enrolling infants with new diagnosis of infantile spasms. Children were considered responders if there was clinical remission and resolution of hypsarrhythmia that was sustained at 3 months after first treatment initiation. Standard treatments of adrenocorticotropic hormone (ACTH), oral corticosteroids, and vigabatrin were considered individually, and all other nonstandard therapies were analyzed collectively. Developmental status and etiology were assessed. We compared response rates by treatment group using chi‐square tests and multivariate logistic regression models.ResultsTwo hundred thirty infants were enrolled from 22 centers. Overall, 46% of children receiving standard therapy responded, compared to only 9% who responded to nonstandard therapy (p < 0.001). Fifty‐five percent of infants receiving ACTH as initial treatment responded, compared to 39% for oral corticosteroids, 36% for vigabatrin, and 9% for other (p < 0.001). Neither etiology nor development significantly modified the response pattern by treatment group.InterpretationResponse rate varies by treatment choice. Standard therapies should be considered as initial treatment for infantile spasms, including those with impaired development or known structural or genetic/metabolic etiology. ACTH appeared to be more effective than other standard therapies. ANN NEUROL 2016;79:475–484

ObjectiveTo describe surgical outcomes and perioperative complications in patients taking antiplatelet and anticoagulation medications while undergoing cochlear implantation.Study DesignCase series with chart review.SettingTwo tertiary otologic referral center.Subjects and MethodsForty‐six adult patients (2005‐2014) who underwent cochlear implantation while on perioperative antiplatelet and/or anticoagulation therapy without interruption. Outcomes included estimated intraoperative blood loss, perception of increased difficulty secondary to bleeding, and postoperative complications attributable to continuing anticoagulation or antiplatelet therapy.ResultsThe cases of 46 patients (mean age, 69.5 years; 30.2% female) were analyzed. Of these, 39 patients were taking aspirin, 10 warfarin, and 7 clopidogrel. Aside from 3 (6.5%) patients with postoperative bruising without hematoma and 1 patient (2.2%) who reported self‐resolving oral cavity blood, no intraoperative or postoperative complications occurred in any patient that could be ascribed to antiplatelet or anticoagulant use.ConclusionThese data demonstrate that the risk of perioperative complications from continued antiplatelet or anticoagulation therapy is low. For subjects who are at risk of major complications (eg, deep venous thrombosis, pulmonary embolism, myocardial infarction, cerebrovascular accident) from temporary medication cessation, continuing antiplatelet or anticoagulation therapy through the perioperative period is an appropriate strategy.

The sphenopalatine ganglion (SPG) has attracted the interest of practitioners treating head and face pain for over a century because of its anatomical connections and role in the trigemino‐autonomic reflex. In this review, we discuss the anatomy of the SPG, as well as what is known about its role in the pathophysiology of headache disorders, including cluster headache and migraine. We then address various therapies that target the SPG, including intranasal medication delivery, new SPG blocking catheter devices, neurostimulation, chemical neurolysis, and ablation procedures.

ObjectiveTo prospectively analyze quality‐of‐life outcomes following transoral diverticulotomy with cricopharyngeal myotomy (DCPM) for Zenker’s diverticulum (ZD).Study DesignProspective single‐group study.SettingsTertiary academic institution.Subjects and MethodsA prospective multicenter study performed from January 1, 2012, to July 1, 2014, included 18 patients presenting with ZD undergoing DCPM. Standardized questionnaires—including the 10‐item Eating Assessment Tool (EAT‐10), Functional Outcome of Swallowing Scale (FOSS), and the Reflux Symptom Index (RSI)—were completed preoperatively and at 3 and 6 months postoperatively. Videofluoroscopic studies were obtained and analyzed by our senior speech‐language pathologist, who was blinded to the clinical outcomes.ResultsEighteen patients were included (11 women; mean age, 72.6 years; range, 53‐86 years). All patients had ZD on preoperative videofluoroscopic swallowing studies. The most common comorbidities included hypertension (10 of 18, 55.6%), dyslipidemia (8 of 18, 44.4%), hiatal hernia (6 of 18, 33.3%), and gastroesophageal reflux disease (5 of 18, 27.8%). Median preoperative RSI was 27 (interquartile range [IQR], 22.5‐31.5); FOSS, 2 (IQR, 2‐3); and EAT‐10, 21.5 (IQR, 13.5‐27.5). The 3‐month questionnaire (88.9% completion) demonstrated an improved median RSI of 5 (IQR, 1‐7.5; P <. 001), FOSS of 0 (IQR, 0; P <. 001), and EAT‐10 of 0 (IQR, 0‐3; P <. 001). Fourteen patients (77.8%) completed the 6‐month questionnaire, demonstrating a median RSI of 4 (IQR, 0‐8), FOSS of 0 (IQR, 0‐0.5), and EAT‐10 of 1 (IQR, 0‐3). While regurgitation decreased following surgery (P =. 007), nighttime cough did not (P =. 25).ConclusionThis study supports an improvement in functional outcome and quality of life in patients with ZD undergoing DCPM.

ABSTRACT Background Anthracyclines are commonly used chemotherapeutic agents with proven efficacy in such malignancies as breast cancer, Hodgkin and non-Hodgkin lymphomas. These agents are associated with irreversible accumulative dose-related cardiomyopathy. Many agents have been examined to reduce cardiotoxicity risk. Aims We performed a systematic review and meta-analysis to determine the efficacy of β-blockers and angiotensin antagonists to prevent early-onset anthracyclines-induced left ventricular dysfunction and cardiac events. Methods Relevant articles were searched in PubMed, EMBASE and Cochrane database of systematic reviews up to July 2015. Eligible studies were limited to randomised controlled trials comparing the efficacy of cardioprotective agents (β-blocker and angiotensin antagonist) with control (either no treatment or placebo) in adult patients (age &gt;18 years) treated with anthracyclines-based regimens. Results Pooled analysis showed an association of β-blockers and/or angiotensin antagonists treatment with higher post-chemotherapy left ventricular ejection fraction (LVEF) of 64.03% compared with 57.48% for control treatment. The mean difference estimate (95% CI) was 6.06% (0.54 to 11.58), p=0.03, with significant heterogeneity, I2 (95% CI)=96% (82.7 to 109.3). Though the point estimate for the relative rate of cardiac events was lower in the experimental arm, the difference was not statistically significant. In an exploratory subgroup analysis, the benefit of experimental agents on LVEF preservation was prominent in patients treated with higher accumulative dose of anthracyclines, but not in the lower dose group. Conclusions β-Blockers and angiotensin antagonists treatments were associated with better LVEF preservation, and the benefit was prominent in patients treated with higher anthracyclines accumulative dose. Unexplained heterogeneity remains, indicating the need for more controlled studies. This analysis provides some support for the routine use of β-blockers or angiotensin antagonists in patients undergoing anthracyclines treatment, especially when higher accumulative dose is expected.

Background and Purpose— Prior meta-analysis showed that carotid endarterectomy benefits decline with increasing surgical delay following symptoms. For symptomatic patients in the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST), we assessed if differences in time between symptoms and carotid endarterectomy or carotid artery stenting are associated with differences in risk of periprocedural stroke or death. Methods— We analyzed the 1180 symptomatic patients in CREST who received their assigned procedure and had clearly defined timing of symptoms. Patients were classified into 3 groups based on time from symptoms to procedure: <15, 15 to 60, and >60 days. Results— For carotid endarterectomy, risk of periprocedural stroke or death was not significantly different for the 2 later time periods relative to the earliest time period (hazard ratio, 0.74; 95% confidence interval, 0.22–2.49 for 15–60 days and hazard ratio, 0.91; 95% confidence interval, 0.25–3.33 for >60 days; P =0.89). For carotid artery stenting, risk of periprocedural stroke or death was also not significantly different for later time periods relative to the earliest time period (hazard ratio, 1.12; 95% confidence interval, 0.53–2.40 for 15–60 days and hazard ratio, 1.15; 95% confidence interval, 0.48–2.75 for >60 days; P =0.93). Conclusions— Time from symptoms to carotid endarterectomy or carotid artery stenting did not alter periprocedural safety, supporting early revascularization regardless of modality. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00004732.