Citations

ScopeWe reevaluated previously reported associations between variants in pathways of one‐carbon (1‐C) (folate) transfer genes and ovarian carcinoma (OC) risk, and in related pathways of purine and pyrimidine metabolism, and assessed interactions with folate intake.Methods and resultsOdds ratios (OR) for 446 genetic variants were estimated among 13 410 OC cases and 22 635 controls, and among 2281 cases and 3444 controls with folate information. Following multiple testing correction, the most significant main effect associations were for dihydropyrimidine dehydrogenase (DPYD) variants rs11587873 (OR = 0.92; p = 6 × 10−5) and rs828054 (OR = 1.06; p = 1 × 10−4). Thirteen variants in the pyrimidine metabolism genes, DPYD, DPYS, PPAT, and TYMS, also interacted significantly with folate in a multivariant analysis (corrected p = 9.9 × 10−6) but collectively explained only 0.2% of OC risk. Although no other associations were significant after multiple testing correction, variants in SHMT1 in 1‐C transfer, previously reported with OC, suggested lower risk at higher folate (pinteraction = 0.03–0.006).ConclusionVariation in pyrimidine metabolism genes, particularly DPYD, which was previously reported to be associated with OC, may influence risk; however, stratification by folate intake is unlikely to modify disease risk appreciably in these women. SHMT1 SNP‐by‐folate interactions are plausible but require further validation. Polymorphisms in selected genes in purine metabolism were not associated with OC.

Abstract Purpose: This phase I, multicenter, open-label, single-arm, dose-escalation, and dose-expansion study evaluated the safety, tolerability, and antitumor activity of MEDI-573 in adults with advanced solid tumors refractory to standard therapy or for which no standard therapy exists. Experimental Design: Patients received MEDI-573 in 1 of 5 cohorts (0.5, 1.5, 5, 10, or 15 mg/kg) dosed weekly or 1 of 2 cohorts (30 or 45 mg/kg) dosed every 3 weeks. Primary end points included the MEDI-573 safety profile, maximum tolerated dose (MTD), and optimal biologic dose (OBD). Secondary end points included MEDI-573 pharmacokinetics (PK), pharmacodynamics, immunogenicity, and antitumor activity. Results: In total, 43 patients (20 with urothelial cancer) received MEDI-573. No dose-limiting toxicities were identified, and only 1 patient experienced hyperglycemia related to treatment. Elevations in levels of insulin and/or growth hormone were not observed. Adverse events observed in >10% of patients included fatigue, anorexia, nausea, diarrhea, and anemia. PK evaluation demonstrated that levels of MEDI-573 increased with dose at all dose levels tested. At doses >5 mg/kg, circulating levels of insulin-like growth factor (IGF)-I and IGFII were fully suppressed. Of 39 patients evaluable for response, none experienced partial or complete response and 13 had stable disease as best response. Conclusions: The MTD of MEDI-573 was not reached. The OBD was 5 mg/kg weekly or 30 or 45 mg/kg every 3 weeks. MEDI-573 showed preliminary antitumor activity in a heavily pretreated population and had a favorable tolerability profile, with no notable perturbations in metabolic homeostasis. Clin Cancer Res; 20(18); 4747–57. ©2014 AACR.

To study the relationship between glycosylated hemoglobin (HgbA1c) and myocardial perfusion in type 2 diabetes mellitus (T2DM) patients, we prospectively enrolled 24 patients with known or suspected coronary artery disease (CAD) who underwent adenosine stress by real-time myocardial perfusion echocardiography (RTMPE). HgbA1c was measured at time of RTMPE. Microbubble velocity (β min−1), myocardial blood flow (MBF, mL/min/g), and myocardial blood flow reserve (MBFR) were quantified. Quantitative MCE analysis was feasible in all patients (272/384 segments, 71%). Those with HgbA1c > 7.1% had significantly lowerβreserveand MBFR than those with HgbA1c ≤ 7.1%(P<0.05). In patients with suspected CAD, there was a significant inverse correlation between MBFR and HgbA1c (r=-0.279,P=0.01); however, in those with known CAD, this relationship was not significant (r=-0.117,P=0.129). Using a MBFR cutoff value > 2 as normal, HgbA1c > 7.1% significantly increased the risk for abnormal MBFR, (adjusted odds ratio: 1.92, 95% CI: 1.12–3.35,P=0.02). Optimal glycemic control is associated with preservation of MBFR as determined by RTMPE, in T2DM patients at risk for CAD.

Abstract Pretreatment evaluation is performed to determine the number, location, and size of the brain metastases and magnetic resonance imaging (MRI) is the recommended imaging technique, particularly in patients being considered for surgery or stereotactic radiosurgery. A contiguous thin-cut volumetric MRI with gadolinium with newer gadolinium-based agents can improve detection of small brain metastases. A systemic workup and medical evaluation are important, given that subsequent treatment for the brain metastases will also depend on the extent of the extracranial disease and on the age and performance status of the patient. Patients with hydrocephalus or impending brain herniation should be started on high doses of corticosteroids and evaluated for possible neurosurgical intervention. Patients with moderate symptoms should receive approximately 4–8 mg/d of dexamethasone in divided doses. The routine use of corticosteroids in patients without neurologic symptoms is not necessary. There is no proven benefit of anticonvulsants in patient without seizures. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

SummaryThe role of eosinophils in the progression and resolution of allergic respiratory inflammation is poorly defined despite the commonality of their presence and in some cases their use as a biomarker for disease severity and/or symptom control. However, this ambiguity belies the wealth of insights that have recently been gained through the use of eosinophil‐deficient/attenuated strains of mice that have demonstrated novel immunoregulatory and remodelling/repair functions for these cells in the lung following allergen provocation. Specifically, studies of eosinophil‐deficient mice suggest that eosinophils contribute to events occurring in the lungs following allergen provocation at several key moments: (i) the initiating phase of events leading to Th2‐polarized pulmonary inflammation, (ii) the suppression Th1/Th17 pathways in lung‐draining lymph nodes, (iii) the recruitment of effector Th2 T cells to the lung, and finally, (iv) mechanisms of inflammatory resolution that re‐establish pulmonary homoeostasis. These suggested functions have recently been confirmed and expanded upon using allergen provocation of an inducible eosinophil‐deficient strain of mice (iPHIL) that demonstrated an eosinophil‐dependent mechanism(s) leading to Th2 dominated immune responses in the presence of eosinophils in contrast to neutrophilic as well as mixed Th1/Th17/Th2 variant phenotypes in the absence of eosinophils. These findings highlighted that eosinophils are not exclusively downstream mediators controlled by T cells, dendritic cells (DC) and/or innate lymphocytic cells (ILC2). Instead, eosinophils appear to be more aptly described as significant contributors in complex interrelated pathways that lead to pulmonary inflammation and subsequently promote resolution and the re‐establishment of homoeostatic baseline. In this review, we summarize and put into the context the evolving hypotheses that are now expanding our understanding of the roles eosinophils likely have in the lung following allergen provocation.

Objective:To evaluate the cost–effectiveness of the following three treatments of uterine fibroids in a population of premenopausal women who wish to preserve their uteri: myomectomy, magnetic resonance-guided focused ultrasound (MRgFUS) and uterine artery embolization (UAE).Materials & methods:A decision analytic Markov model was constructed. Cost–effectiveness was calculated in terms of US$ per quality-adjusted life year (QALY) over 5 years. Two types of costs were calculated: direct costs only, and the sum of direct and indirect (productivity) costs. Women in the hypothetical cohort were assessed for treatment type eligibility, were treated based on eligibility, and experienced adequate or inadequate symptom relief. Additional treatment (myomectomy) occurred for inadequate symptom relief or recurrence. Sensitivity analysis was conducted to evaluate uncertainty in the model parameters.Results: In the base case, myomectomy, MRgFUS and UAE had the following combinations of mean cost and mean QALYs, respectively: US$15,459, 3.957; US$15,274, 3.953; and US$18,653, 3.943. When incorporating productivity costs, MRgFUS incurred a mean cost of US$21,232; myomectomy US$22,599; and UAE US$22,819. Using probabilistic sensitivity analysis (PSA) and excluding productivity costs, myomectomy was cost effective at almost every decision threshold. Using PSA and incorporating productivity costs, myomectomy was cost effective at decision thresholds above US$105,000/QALY; MRgFUS was cost effective between US$30,000 and US$105,000/QALY; and UAE was cost effective below US$30,000/QALY.Conclusion:Myomectomy, MRgFUS, and UAE were similarly effective in terms of QALYs gained. Depending on assumptions about costs and willingness to pay for additional QALYs, all three treatments can be deemed cost effective in a 5-year time frame.

Background There is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used first line. Methods A peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) was carried out to identify randomized and quasi-randomized controlled trials of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses. Results Two independent reviewers screened 831 titles and abstracts for eligibility. Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included. Individual studies were then assigned a US Preventive Services Task Force quality rating. The GRADE scheme was used to assign a level of evidence and recommendation strength for each intervention. Interpretation We strongly recommend the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence. We weakly recommend the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence. We found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence. Based on moderate-quality evidence, we recommend weakly against the use of acetaminophen and magnesium sulfate. Based on low-quality evidence, we recommend weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol.

Transthoracic fine needle aspiration (TFNA)/core needle biopsy (CNB) under computed tomography (CT) guidance has proved useful in the assessment of pulmonary nodules. We sought to determine the TFNA false‐negative (FN) rate at our institution and identify potential causes of FN diagnoses. Medical records were reviewed from 1,043 consecutive patients who underwent CT‐guided TFNA with or without CNB of lung nodules over a 5‐year time period (2003–2007). Thirty‐seven FN cases of “negative” TFNA/CNB with malignant outcome were identified with 36 cases available for review, of which 35 had a corresponding CNB. Cases were reviewed independently (blinded to original diagnosis) by three pathologists with 15 age‐ and sex‐matched positive and negative controls. Diagnosis (i.e., nondiagnostic, negative or positive for malignancy, atypical or suspicious) and qualitative assessments were recorded. Consensus diagnosis was suspicious or positive in 10 (28%) of 36 TFNA cases and suspicious in 1 (3%) of 35 CNB cases, indicating potential interpretive errors. Of the 11 interpretive errors (including both suspicious and positive cases), 8 were adenocarcinomas, 1 squamous cell carcinoma, 1 metastatic renal cell carcinoma, and 1 lymphoma. The remaining 25 FN cases (69.4%) were considered sampling errors and consisted of 7 adenocarcinomas, 3 nonsmall cell carcinomas, 3 lymphomas, 2 squamous cell carcinomas, and 2 renal cell carcinomas. Interpretive and sampling error cases were more likely to abut the pleura, while histopathologically, they tended to be necrotic and air‐dried. The overall FN rate in this patient cohort is 3.5% (1.1% interpretive and 2.4% sampling errors). Diagn. Cytopathol. 2014;42:1063–1068;. © 2014 Wiley Periodicals, Inc.

BACKGROUND:Youth ice hockey is an exciting sport with growing participation in the United States. Updated assessment of injury patterns is needed to determine risk factors for severe injury and develop preventive efforts. The purpose of this study was to evaluate our experience as a level 1 pediatric trauma center in Minnesota treating injured youth ice hockey players.METHODS:Children ≤18 years old who presented to our institution from July 1997 to July 2013 with an injury sustained while participating in ice hockey were identified. Patient demographic information, injury characteristics, and outcomes including use of computed tomography, hospital admission, and procedures were obtained. Age- and gender-specific patterns were determined for injuries and outcomes.RESULTS:Over 16 years, 168 injuries in 155 children occurred, including 26 (15.5%) injuries in girls. Extremity injuries were most common, followed by traumatic brain injury. Injuries to the spine, face, and trunk were less common. Traumatic brain injury and injuries to the spine were most common in younger children (≤14 years old) and girls, whereas injuries to the face were most common in older players (≥15 years old). Most injuries resulted from intentional contact. Admission to the hospital was needed in 65 patients, including 14 (8.3%) who needed intensive care. A major procedure was needed by 23.2% of patients because of their injuries.CONCLUSIONS:Youth ice hockey trauma can be severe, necessitating a thorough evaluation of injured children. Injury patterns are influenced by age and gender, providing an opportunity for targeted preventive efforts.