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Object The object of this study was to assess outcomes after surgery for recurrent intracranial glioma. Methods The authors retrospectively reviewed cases involving adult patients with intracranial glioma patients undergoing initial surgery (biopsy or resection) and one or more additional surgeries at their institution. Results A total of 323 operations were performed in 131 patients. The median survival was 76 months after first surgery, 36 months after second, 24 months after third, and 26.5 months after 4 or more surgeries. The overall complication rate was 12.8% after first surgery, 27.0% after second (OR 2.52, p = 0.0068), 22.0% after third (OR 1.92, not statistically significant [NS]), and 22.2% after 4 or more (OR 1.95, NS). Neurological complications occurred in 4.8% of patients at first surgery, 12.1% at second (OR 2.7, p = 0.0437), 8.2% at third (OR 1.75, NS), and 11.1% at 4 or more surgeries (OR 2.4583, NS). Regional complications occurred in 6.2% after first surgery, 9.9% after second surgery (OR 2.30, p = 0.095), 13.7% after third surgery (OR 3.31, p = 0.015), and 22.2% after 4 or more surgeries (OR 5.95, p = 0.056). Systemic complications occurred in 3.2% after first surgery, in 7.3% after second surgery (OR 2.3, p = 0.NS), in 4.1% after third surgery (OR 1.3, NS), and 0% after 4 or more surgeries. Reduction in Karnofsky Performance Status score occurred in 0% after first surgery, 8.1% after second surgery (OR 3.13, p = 0.0018), 10.2% after third surgery (OR 5.52, p < 0.0001), and 11.1% after 4 or more surgeries (OR 1.037, NS). Conclusions Postoperative survival is relatively prolonged but complication risk increases in patients with glioma who undergo multiple cranial surgeries. The largest increase in neurological risk occurs between the first and second surgery. In contrast, regional complication risk increases consistently with each surgery. The risk of systemic complications is not significantly altered with increasing surgeries. However, these complications only result in a modestly increased risk of functional decline after 2 or more surgeries. These findings may help counsel patients considering multiple glioma surgeries.

SummaryMyelofibrosis (MF) patients can present with a wide spectrum of disease characteristics. We analysed the consistency of ruxolitinib efficacy across patient subgroups in the COntrolled MyeloFibrosis Study With ORal JAK Inhibitor Treatment (COMFORT‐I,) a double‐blind trial, where patients with intermediate‐2 or high‐risk MF were randomized to twice‐daily oral ruxolitinib (n = 155) or placebo (n = 154). Subgroups analysed included MF subtype (primary, post‐polycythaemia vera, post‐essential thrombocythaemia), age (≤65, > 65 years), International Prognostic Scoring System risk group, baseline Eastern Cooperative Oncology Group performance status (0, 1, ≥2), JAK2 V617F mutation (positive, negative), baseline haemoglobin level (≥100, <100 g/l), baseline platelet count (100–200 × 109/l, >200 × 109/l), baseline palpable spleen size (≤10, >10 cm), and baseline quartile of spleen volume and Total Symptom Score (TSS; Q1 = lowest, Q4 = highest). Mean percentage change from baseline to week 24 in spleen volume and TSS were calculated for ruxolitinib and placebo in each subgroup. Overall survival was estimated by Kaplan–Meier method according to original randomization group. In ruxolitinib‐treated patients, reductions in spleen volume and TSS and evidence of improved survival relative to placebo across subgroups were consistent with those seen in the COMFORT‐I population, confirming that ruxolitinib is an effective therapy for the spectrum of MF patients studied in COMFORT‐I.

Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer’s disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain’s connectivity pattern, allowing us to discover genetic variants that affect the human brain’s wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer’s disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism ( MACROD2 ), development ( NEDD4 ), and mental retardation ( UBE2A ) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.

Purpose To assess the effects of ruxolitinib on symptom burden and quality of life (QoL) and to evaluate the ability of the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 to measure meaningful changes in myelofibrosis-related symptoms in patients with myelofibrosis. Patients and Methods COMFORT-I (Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment–I) is a double-blind, placebo-controlled phase III study evaluating ruxolitinib in patients with intermediate-2 or high-risk myelofibrosis. Exploratory analyses were conducted on the following patient-reported outcomes (PROs) assessments: modified MFSAF v2.0 (individual symptoms and Total Symptom Score [TSS]), European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Scale, and Patient Global Impression of Change (PGIC). Results Patients receiving ruxolitinib experienced improvements in individual myelofibrosis-related symptoms, although patients receiving placebo experienced worsening (P < .001). The majority (91%) of ruxolitinib-treated patients designated as ≥ 50% TSS responders (≥ 50% TSS improvement) self-reported their condition as either “Much improved” or “Very much improved” on the PGIC. These patients achieved significant improvements in the EORTC QLQ-C30 functional domains and Global Health Status/QoL versus patients receiving placebo, who experienced worsening on these measures (P ≤ .0135). Ruxolitinib-treated patients with a lesser degree of symptom improvement (< 50% TSS responders) also achieved improvements over placebo on these measures. The degree of spleen volume reduction with ruxolitinib correlated with improvements in TSS, PGIC, PROMIS Fatigue Scale, and EORTC Global Health Status/QoL. Ruxolitinib-treated patients who achieved a ≥ 35% reduction in spleen volume experienced the greatest improvements in these PROs. Conclusion Ruxolitinib-treated patients achieved clinically meaningful improvements in myelofibrosis-related symptoms and QoL, but patients receiving placebo reported worsening of symptoms and other PROs.

Omega-3 fatty acids found in fish oil have been suggested to protect against cardiovascular disease, yet underlying mechanisms remain unclear. Despite the well-documented link between mental stress and cardiovascular risk, no study has examined neural cardiovascular reactivity to mental stress after fish oil supplementation. We hypothesized that fish oil would blunt the blood pressure, heart rate (HR), and muscle sympathetic nerve activity (MSNA) responsiveness to mental stress and/or augment limb vasodilation associated with mental stress. Blood pressure, HR, MSNA, forearm vascular conductance (FVC), and calf vascular conductance (CVC) responses were recorded during a 5-min mental stress protocol in 67 nonhypertensive subjects before and after 8 wk of fish oil ( n = 34) or placebo supplementation ( n = 33). Fish oil blunted HR reactivity to mental stress (group × condition × time interactions, P = 0.012) but did not alter blood pressure reactivity to mental stress (interactions, P > 0.05). Fish oil blunted total MSNA reactivity to mental stress (interaction, P = 0.039) but did not alter MSNA burst frequency and burst incidence reactivity (interactions, P > 0.05). Finally, fish oil significantly blunted CVC reactivity to mental stress (interaction, P = 0.013) but did not alter FVC reactivity (interaction, P > 0.05). In conclusion, 8 wk of fish oil supplementation significantly attenuated both HR and total MSNA reactivity to mental stress and elicited a paradoxical blunting of calf vascular conductance. These findings support and extend the growing evidence that fish oil may have positive health benefits regarding neural cardiovascular control in humans.

The aim of this study was to determine the effect of prolonged 11β-hydroxysteroid dehydrogenase-1 (11β-HSD1) inhibition on basal and hormone-stimulated glucose metabolism in fasted conscious dogs. For 7 days prior to study, either an 11β-HSD1 inhibitor (HSD1-I; n = 6) or placebo (PBO; n = 6) was administered. After the basal period, a 4-h metabolic challenge followed, where glucagon (3×-basal), epinephrine (5×-basal), and insulin (2×-basal) concentrations were increased. Hepatic glucose fluxes did not differ between groups during the basal period. In response to the metabolic challenge, hepatic glucose production was stimulated in PBO, resulting in hyperglycemia such that exogenous glucose was required in HSD-I ( P < 0.05) to match the glycemia between groups. Net hepatic glucose output and endogenous glucose production were decreased by 11β-HSD1 inhibition ( P < 0.05) due to a reduction in net hepatic glycogenolysis ( P < 0.05), with no effect on gluconeogenic flux compared with PBO. In addition, glucose utilization ( P < 0.05) and the suppression of lipolysis were increased ( P < 0.05) in HSD-I compared with PBO. These data suggest that inhibition of 11β-HSD1 may be of therapeutic value in the treatment of diseases characterized by insulin resistance and excessive hepatic glucose production.

The objective of this study is to characterize the outcomes of primary antifungal prophylaxis with voriconazole in patients receiving intensive chemotherapy for acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS). We conducted a single center, retrospective, cohort study of consecutive adult patients with AML or MDS at Mayo Clinic between January 1, 2006 and July 1, 2010. The study included patients undergoing induction or first relapse combination chemotherapy who received voriconazole 200 mg orally twice daily as prophylaxis during the neutropenic phase. Patient records were evaluated until 30 days after neutrophil recovery for development of invasive fungal infection (IFI) as defined per EORTC/MSG 2008 criteria with computed tomography scans independently reviewed by a radiologist. Therapeutic drug monitoring and reasons for voriconazole discontinuation were documented. Twenty four episodes of IFI were detected among 165 consecutive patients for an overall incidence of 145 per 1000 patients. The incidence of IFI was 24, 42, and 78 per 1000 patients for proven, probable, and possible infection, respectively. Four patients developed proven IFI (n = 2 Aspergillus spp., n = 2 Rhizopus spp.). Serum voriconazole trough concentrations were available in 39 patients, and no statistically significant difference in voriconazole trough level was observed between those with versus without an IFI. Voriconazole prophylaxis was discontinued in 81 patients due to suspected IFI (n = 24), fever of unknown origin (n = 19), adverse events (n = 23), and other causes (n = 17). Voriconazole as primary IFI prophylaxis is safe and may be beneficial in AML/MDS patients receiving intensive chemotherapy. Am. J. Hematol. 88:283–288, 2013. © 2013 Wiley Periodicals, Inc.

Background The contribution of copy-number variation (CNV) to disease has been highlighted with the widespread adoption of array-based comparative genomic hybridisation (aCGH) and microarray technology. Contiguous gene deletions involving ANKRD11 in 16q24.3 are associated with autism spectrum disorder (ASD) and intellectual disability (ID), while 16q24.1 deletions affecting FOXF1 are associated with congenital renal malformations, alveolar capillary dysplasia, and various other abnormalities. The disease associations of deletions in the intervening region, 16q24.2, have only been defined to a limited extent. Aim To determine whether deletions affecting 16q24.2 are correlated with congenital anomalies. Methods 35 individuals, each having a deletion in 16q24.2, were characterised clinically and by aCGH and/or SNP-genotyping microarray. Results Several of the 35 16q24.2 deletions identified here closely abut or overlap the coding regions of FOXF1 and ANKRD11, two genes that have been previously associated with the disease. 25 patients were reported to have ASD/ID, and three were found to have bilateral hydronephrosis. 14 of the deletions associated with ASD/ID overlap the coding regions of FBXO31 and MAP1LC3B. These same genes and two others, C16orf95 and ZCCHC14, are also included in the area of minimal overlap of the three deletions associated with hydronephrosis. Conclusions Our data highlight 16q24.2 as a region of interest for ASD, ID and congenital renal malformations. These conditions are associated, albeit without complete penetrance, with deletions affecting C16orf95, ZCCHC14, MAP1LC3B and FBXO31. The function of each gene in development and disease warrants further investigation.

Abstract Systemic mastocytosis (SM) is characterized by accumulation of neoplastic mast cells and is classified into indolent and aggressive forms. The latter include aggressive SM (ASM), mast cell leukemia (MCL), and SM associated with a myeloid neoplasm wherein 1 or both disease compartments exhibit advanced features. These variants, henceforth collectively referred to as advanced SM for the purposes of this report, are typically characterized by organ damage and shortened survival duration. In contrast to indolent SM, in which symptoms are usually managed by noncytotoxic antimediator therapy, cytoreduction is usually necessary for disease control in advanced SM. Unfortunately, current drug treatment of these patients rarely results in complete clinical and histopathologic remissions or improved survival time. Previously defined response criteria were adapted to the heterogeneous presentations of advanced SM and the limited effects of available drugs. However, recent advances in understanding the molecular pathogenesis of SM and the corresponding prospect in targeted therapy make it a priority to modify these criteria. Our current study is the product of an international group of experts and summarizes the challenges in accomplishing this task and forwards a new proposal for response criteria, which builds on prior proposals and should facilitate response evaluation in clinical trials.

Improving professional attitudes and behaviors requires critical self reflection. Research on reflection is necessary to understand professionalism among medical students. The aims of this prospective validation study at the Mayo Medical School and Cleveland Clinic Lerner College of Medicine were: (1) to develop and validate a new instrument for measuring reflection on professionalism, and (2) determine whether learner variables are associated with reflection on the gross anatomy experience. An instrument for assessing reflections on gross anatomy, which was comprised of 12 items structured on five‐point scales, was developed. Factor analysis revealed a three‐dimensional model including low reflection (four items), moderate reflection (five items), and high reflection (three items). Item mean scores ranged from 3.05 to 4.50. The overall mean for all 12 items was 3.91 (SD = 0.52). Internal consistency reliability (Cronbach's α) was satisfactory for individual factors and overall (Factor 1 α = 0.78; Factor 2 α = 0.69; Factor 3 α = 0.70; Overall α = 0.75). Simple linear regression analysis indicated that reflection scores were negatively associated with teamwork peer scores ( P = 0.018). The authors report the first validated measurement of medical student reflection on professionalism in gross anatomy. Critical reflection is a recognized component of professionalism and may be important for behavior change. This instrument may be used in future research on professionalism among medical students. Anat Sci Educ 6: 232–238. © 2012 American Association of Anatomists.