Citations

AbstractBackground: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk.Impact: Further replication in independent samples is warranted. Cancer Epidemiol Biomarkers Prev; 22(11); 2094–101. ©2013 AACR.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.

Background and Purpose— Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. Methods— The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research–generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. Conclusions— The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

ObjectivesTo 1) describe and validate an ultrasound‐guided ischial bursa injection technique in an unembalmed cadaveric model and 2) to compare the distance between the ischial tuberosity and the sciatic nerve in a hip neutral versus 90° flexed hip position in asymptomatic volunteers.DesignThe first part was a single‐blind prospective study. The second part was a prospective cohort study.SettingAn academic institution procedural skills laboratory and outpatient clinic.ParticipantsThe first part of the study involved 1 cadaveric specimen. The second part of the study involved 20 asymptomatic subjects. The mean age of the subjects was 28 years, and the mean (standard deviation) body mass index was 23.2 ± 2.8 kg/m2 (minimum, 18.3 kg/m2; maximum, 29.5 kg/m2).MethodsIn the first part of the study, a single operator completed bilateral ultrasound‐guided ischial bursa injections in an unembalmed cadaveric specimen by using diluted colored latex. In the second part of the study, ultrasound was used in 20 asymptomatic volunteer subjects (10 men and 10 women) to measure the distance from the lateral edge of the ischial tuberosity to the sciatic nerve.Main Outcome MeasurementsThe injections were graded for accuracy as follows: accurate (all injectate contained within the ischial bursa), accurate with overflow (injectate within the ischial bursa but also located in adjacent structures other than the needle track), or inaccurate (injectate not within the ischial bursa). The second part of the study measured the distance from the ischial tuberosity to the sciatic nerve with subjects in 2 different positions (prone and side lying with the tested hip flexed to 90°).ResultsPostinjection cadaveric dissections revealed that both ultrasound‐guided injections accurately placed liquid latex within the ischial bursae. There was no evidence of injury to surrounding neurovascular structures. Among asymptomatic volunteers, the average distance between the ischial tuberosity and the sciatic nerve increased from 28.4 mm (range, 20.5‐38.9 mm) in the neutral position to 41.9 mm (range, 30.9‐66.0 mm) with the hip flexed to 90° (average change, 13.5 mm away from the ischial tuberosity; P = .0001).ConclusionsUltrasound‐guided ischial bursa injections are technically feasible. Flexing the hip to 90° increases the distance between the ischial tuberosity and the sciatic nerve in asymptomatic volunteers, thus potentially resulting in a safer needle trajectory when ischial bursa injections are clinically indicated. Further investigation in clinical settings is warranted to validate these findings.

We searched MEDLINE, CINAHL, and Cochrane Library database for articles published between January 1990 and December 2012. The update of this clinical practice guideline is based on 237 clinical trials, 54 reviews, and 23 meta-analyses on blood gas analysis (BGA) and hemoximetry. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation scoring system. BGA and hemoximetry are recommended for evaluating a patient's ventilatory, acid-base, and/or oxygenation status. BGA and hemoximetry are suggested for evaluating a patient's response to therapeutic interventions. BGA and hemoximetry are recommended for monitoring severity and progression of documented cardiopulmonary disease processes. Hemoximetry is recommended to determine the impact of dyshemoglobins on oxygenation. Capillary BGA is not recommended to determine oxygenation status. Central venous BGA and hemoximetry are suggested to determine oxygen consumption in the setting of early goal-directed therapies. For the assessment of oxygenation, a peripheral venous P O 2 is not recommended as a substitute for an arterial blood measurement (P aO 2 ). It is not recommended to use venous P CO 2 and pH as a substitute for arterial blood measurement of P aCO 2 and pH. It is suggested that hemoximetry is used in the detection and evaluation of shunts during diagnostic cardiac catheterization.

Abstract Background: Ovarian carcinoma is composed of five major histologic types, which associate with outcome and predict therapeutic response. Our aim was to evaluate histologic type assessments across the centers participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model. Methods: Tissue microarrays (TMA) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was conducted for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histologic type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review. Results: The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases subdivided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of endometrioid carcinoma compared with HGSC became significant [RR 0.60; 95% confidence interval (CI), 0.37–0.93; P = 0.021], consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2. Conclusions: Research cohorts, particularly those across different centers within consortia, show significant variability in original histologic type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type. Impact: Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology. Cancer Epidemiol Biomarkers Prev; 22(10); 1677–86. ©2013 AACR.

ABSTRACT Several recent studies suggest that obesity may be a risk factor for fracture. The aim of this study was to investigate the association between body mass index (BMI) and future fracture risk at different skeletal sites. In prospective cohorts from more than 25 countries, baseline data on BMI were available in 398,610 women with an average age of 63 (range, 20–105) years and follow up of 2.2 million person-years during which 30,280 osteoporotic fractures (6457 hip fractures) occurred. Femoral neck BMD was measured in 108,267 of these women. Obesity (BMI ≥ 30 kg/m2) was present in 22%. A majority of osteoporotic fractures (81%) and hip fractures (87%) arose in non-obese women. Compared to a BMI of 25 kg/m2, the hazard ratio (HR) for osteoporotic fracture at a BMI of 35 kg/m2 was 0.87 (95% confidence interval [CI], 0.85–0.90). When adjusted for bone mineral density (BMD), however, the same comparison showed that the HR for osteoporotic fracture was increased (HR, 1.16; 95% CI, 1.09–1.23). Low BMI is a risk factor for hip and all osteoporotic fracture, but is a protective factor for lower leg fracture, whereas high BMI is a risk factor for upper arm (humerus and elbow) fracture. When adjusted for BMD, low BMI remained a risk factor for hip fracture but was protective for osteoporotic fracture, tibia and fibula fracture, distal forearm fracture, and upper arm fracture. When adjusted for BMD, high BMI remained a risk factor for upper arm fracture but was also a risk factor for all osteoporotic fractures. The association between BMI and fracture risk is complex, differs across skeletal sites, and is modified by the interaction between BMI and BMD. At a population level, high BMI remains a protective factor for most sites of fragility fracture. The contribution of increasing population rates of obesity to apparent decreases in fracture rates should be explored. © 2014 American Society for Bone and Mineral Research.

Abstract Interleukin-2 (IL-2), a product of activated T-cells, is now being used in a number of protocols for cancer immunotherapy. In one stem cell transplantation protocol for breast cancer, IL-2 is used together with interferon- γ (IFN- γ ) and cyclosporine to stimulate a graft-versus-tumor response and improve the likelihood of a prolonged remission. We present the case of a patient who developed peripheral eosinophilia, perihilar infiltrates, and hypoxemia after autologous stem cell transplantation and the use of recombinant IL-2 and IFN- γ. Histologic analysis of transbronchial lung biopsies demonstrated a few eosinophils within the bronchial submucosa. Immunostaining using antibodies directed against eosinophil major basic protein (MBP), however, revealed massive extracellular deposition of this toxic granule protein throughout the lung parenchyma. IL-2 therapy is well known to induce a peripheral eosinophilia and to be associated with the capillary leak syndrome characterized by weight gain, edema, and oliguria. The findings noted in this case report suggest that the eosinophil activation that accompanies immunologic therapy with IL-2 can result in direct toxicity to the lung and a localized vascular leak syndrome. This syndrome should be considered in the differential diagnosis of pulmonary infiltrates that occur acutely after bone marrow transplantation with cytokine augmentation.