Citations

The development of insulin resistance has been associated with impaired mitochondrial fatty acid oxidation (FAO), but the exact relationship between FAO capacity and glucose metabolism continues to be debated. To address this controversy, patients with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) deficiency underwent an oral glucose tolerance test (OGTT) and measurement of energy expenditure, body composition, and plasma metabolites. Compared with controls, patients with LCHAD deficiency had a trend toward higher total body fat and extramyocellular lipid deposition but similar levels of intramyocelluar and intrahepatic lipids. Resting energy expenditure was similar between the groups, but respiratory quotient was higher and total energy expenditure was lower in LCHAD-deficient patients compared with controls. High-molecular-weight (HMW) adiponectin levels were lower and plasma long-chain acylcarnitines were higher among LCHAD-deficient patients. Fasting and post-OGTT levels of glucose, insulin, and ghrelin, along with estimates of insulin sensitivity, were the same between the groups. Despite decreased capacity for FAO, lower total energy expenditure and plasma HMW adiponectin, and increased plasma acylcarnitines, LCHAD-deficient patients exhibited normal glucose tolerance. These data suggest that inhibition of the FAO pathway in humans is not sufficient to induce insulin resistance.

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.

BACKGROUNDThe management of pediatric melanoma (PM) has largely been extrapolated from adult data. However, the behavior of PM appears to differ from its adult counterparts. Therefore, an international PM registry was created and analyzed.METHODSTwelve institutions contributed deidentified clinicopathologic and outcome data for patients diagnosed with PM from 1953 through 2008.RESULTSOverall survival (OS) data were reported for 365 patients with invasive PM who had adequate follow‐up data. The mean age of the patients was 16 years (range 1 year‐21 years). The 10‐year OS rate, 80.6%, tended to vary by patient age: 100% for those aged birth to 10 years, 69.7% for those aged > 10 years to 15 years, and 79.5% for those aged > 15 years to 20 years (P = .147). Patients with melanomas measuring ≤ 1 mm had a favorable prognosis (10‐year OS rate of 97%), whereas survival was lower but similar for patients with melanomas measuring > 1 mm to 2 mm, > 2 mm to 4 mm, and > 4 mm (70%, 78%, and 80%, respectively; P = .0077). Ulceration and lymph node metastasis were found to be correlated with worse survival (P = .022 and P = .017, respectively). The 10‐year OS rate was 94.1% for patients with American Joint Committee on Cancer stage I disease, 79.6% for those with stage II disease, and 77.1% for patients with stage III disease (P < .001).CONCLUSIONSTumor thickness, ulceration, lymph node status, and stage were found to be significant predictors of survival in patients with PM, similar to adult melanoma. There is a trend toward increased survival in children aged ≤ 10 years versus adolescents aged > 10 years. Further analyses are needed to probe for potential biological and behavioral differences in pediatric versus adult melanoma. Cancer 2013;119:4012–4019. © 2013 American Cancer Society.

BACKGROUNDDrug choice and delivered dose of treatment potentially influence outcome in patients treated for follicular lymphoma (FL). Historically, observational studies have evaluated drug choice. The National LymphoCare Study (NLCS) is a prospective, observational study of patients with FL who were enrolled at academic and community practice sites in the United States between 2004 and 2007. In the current study, the authors report on measures of delivered dose and its impact on outcomes for the most common first‐line regimens.METHODSAll evaluable patients with FL who were treated with initial rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP); rituximab plus cyclophosphamide, vincristine, and prednisone (R‐CVP); or rituximab plus a fludarabine‐containing regimen (R‐Flu) were included. Associations between baseline factors, choice of treatment, number of cycles received, completion of therapy, and patient outcomes were assessed.RESULTSA total of 646 patients received R‐CHOP, 297 received R‐CVP, and 222 received R‐Flu. Characteristics were similar between the 3 groups with the following exceptions. Patients receiving R‐CHOP were more often found to have grade 3 FL and patients receiving R‐CVP were older and had higher Follicular Lymphoma International Prognostic Index scores. The majority of patients (80%) received ≥ 5 cycles of treatment. Toxicity, but not disease progression, was commonly cited as the reason for the early discontinuation of treatment (51% vs 6%). Time to retreatment was shorter for patients receiving ≤ 4 cycles, regardless of the treatment regimen used. The number of cycles was associated with overall survival, progression‐free survival, and lymphoma‐related mortality for patients receiving R‐CVP.CONCLUSIONSThe majority of patients with FL receiving chemoimmunotherapy in the NLCS completed ≥ 5 cycles of treatment. Strategies to improve dose delivery appear unlikely to impact outcomes, except possibly in patients receiving R‐CVP. Although early treatment discontinuation appears to be associated with survival, this analysis does not implicate causality. Cancer 2013;119:4129–4136. © 2013 American Cancer Society.

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.

Objective Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer. Design We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10 −4 was used to determine statistical significance of the associations. Results Two correlated SNPs—rs10090154 and rs4242382—in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10 −5 ), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites. Conclusions This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.