Citations

AbstractIntroductionThe genetics underlying posterior cortical atrophy (PCA), typically a rare variant of Alzheimer's disease (AD), remain uncertain.MethodsWe genotyped 302 PCA patients from 11 centers, calculated risk at 24 loci for AD/DLB and performed an exploratory genome‐wide association study.ResultsWe confirm that variation in/near APOE/TOMM40 (P = 6 × 10−14) alters PCA risk, but with smaller effect than for typical AD (PCA: odds ratio [OR] = 2.03, typical AD: OR = 2.83, P = .0007). We found evidence for risk in/near CR1 (P = 7 × 10−4), ABCA7 (P = .02) and BIN1 (P = .04). ORs at variants near INPP5D and NME8 did not overlap between PCA and typical AD. Exploratory genome‐wide association studies confirmed APOE and identified three novel loci: rs76854344 near CNTNAP5 (P = 8 × 10−10 OR = 1.9 [1.5–2.3]); rs72907046 near FAM46A (P = 1 × 10−9 OR = 3.2 [2.1–4.9]); and rs2525776 near SEMA3C (P = 1 × 10−8, OR = 3.3 [2.1–5.1]).DiscussionWe provide evidence for genetic risk factors specifically related to PCA. We identify three candidate loci that, if replicated, may provide insights into selective vulnerability and phenotypic diversity in AD.

Abstract Background: Many epithelial ovarian cancer (EOC) risk factors relate to hormone exposure and elevated estrogen levels are associated with obesity in postmenopausal women. Therefore, we hypothesized that gene–environment interactions related to hormone-related risk factors could differ between obese and non-obese women. Methods: We considered interactions between 11,441 SNPs within 80 candidate genes related to hormone biosynthesis and metabolism and insulin-like growth factors with six hormone-related factors (oral contraceptive use, parity, endometriosis, tubal ligation, hormone replacement therapy, and estrogen use) and assessed whether these interactions differed between obese and non-obese women. Interactions were assessed using logistic regression models and data from 14 case–control studies (6,247 cases; 10,379 controls). Histotype-specific analyses were also completed. Results: SNPs in the following candidate genes showed notable interaction: IGF1R (rs41497346, estrogen plus progesterone hormone therapy, histology = all, P = 4.9 × 10−6) and ESR1 (rs12661437, endometriosis, histology = all, P = 1.5 × 10−5). The most notable obesity–gene–hormone risk factor interaction was within INSR (rs113759408, parity, histology = endometrioid, P = 8.8 × 10−6). Conclusions: We have demonstrated the feasibility of assessing multifactor interactions in large genetic epidemiology studies. Follow-up studies are necessary to assess the robustness of our findings for ESR1, CYP11A1, IGF1R, CYP11B1, INSR, and IGFBP2. Future work is needed to develop powerful statistical methods able to detect these complex interactions. Impact: Assessment of multifactor interaction is feasible, and, here, suggests that the relationship between genetic variants within candidate genes and hormone-related risk factors may vary EOC susceptibility. Cancer Epidemiol Biomarkers Prev; 25(5); 780–90. ©2016 AACR.

In April 2012, the Organ Procurement and Transplantation Network (OPTN) implemented an online explant pathology form for recipients of liver transplantation who received additional wait‐list priority for their diagnosis of hepatocellular carcinoma (HCC). The purpose of the form was to standardize the data being reported to the OPTN, which had been required since 2002 but were submitted to the OPTN in a variety of formats via facsimile. From April 2012 to December 2014, over 4500 explant forms were submitted, allowing for detailed analysis of the characteristics of the explanted livers. Data from the explant pathology forms were used to assess agreement with pretransplant imaging. Explant data were also used to assess the risk of recurrence. Of those with T2 priority, 55.7% were found to be stage T2 on explant. Extrahepatic spread (odds ratio [OR] = 6.8; P < 0.01), poor tumor differentiation (OR = 2.8; P < 0.01), microvascular invasion (OR = 2.6; P < 0.01), macrovascular invasion (OR = 3.2; P < 0.01), and whether the Milan stage based on the number and size of tumors on the explant form was T4 (OR = 2.4; P < 0.01) were the strongest predictors of recurrence. In conclusion, this analysis confirms earlier findings that showed an incomplete agreement between pretransplant imaging and posttransplant pathology in terms of HCC staging, though the number of patients with both no pretransplant treatment and no tumor in the explant was reduced from 20% to <1%. In addition, several factors were identified (eg, tumor burden, age, sex, region, ablative therapy, alpha‐fetoprotein, Milan stage, vascular invasion, satellite lesions, etc.) that were predictive of HCC recurrence, allowing for more targeted surveillance of high‐risk recipients. Continued evaluation of these data will help shape future guidelines or policy recommendations. Liver Transplantation 22 757–764 2016 AASLD.

Lower melatonin level, melatonin receptor gene variations, and atenolol treatment are associated with glucose dysregulation. We investigated whether atenolol‐related glucose and melatonin changes are correlated, and whether single nucleotide polymorphisms (SNPs) in melatonin candidate genes contribute to interindividual variation in glucose change. Hypertensive Caucasians (n = 232) from the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study treated with atenolol for 9 weeks were studied. Urinary 6‐sulfatoxymelatonin (aMT6s) was measured pre‐ and posttreatment and normalized to urinary creatinine. Pharmacogenetic effects on glucose change of 160 SNPs in 16 melatonin candidate genes were assessed with multiple linear regression. Atenolol was associated with increased glucose (1.8 ± 10.1mg/dl, P = 0.02) and decreased aMT6s (–4.5 ± 10.1 ng/mg, P < 0.0001). However, the aMT6s change was not correlated with post‐atenolol glucose change. SNP rs11649514 in PRKCB was associated with glucose change (P = 1.0×10−4). PRKCB is involved in the melatonin‐insulin regulatory pathway, and may be important in mediating clinically meaningful atenolol‐related hyperglycemia.

ObjectivesBipolar disorder (BD) is a complex disease associated with various hereditary traits, including a higher body mass index (BMI). In a prior genome‐wide association study, we found that BMI modified the association of rs12772424 – a common variant in the gene encoding transcription factor 7‐like 2 (TCF7L2) – with risk for BD. TCF7L2 is a transcription factor in the canonical Wnt pathway, involved in multiple disorders, including diabetes, cancer and psychiatric conditions. Here, using an independent sample, we evaluated 26 TCF7L2 single nucleotide polymorphisms (SNPs) to explore further the association of BD with the TCF7L2–BMI interaction.MethodsUsing a sample of 662 BD cases and 616 controls, we conducted SNP‐level and gene‐level tests to assess the evidence for an association between BD and the interaction of BMI and genetic variation in TCF7L2. We also explored the potential mechanism behind the detected associations using human brain expression quantitative trait loci (eQTL) analysis.ResultsThe analysis provided independent evidence of an rs12772424–BMI interaction (p = 0.011). Furthermore, while overall there was no evidence for SNP marginal effects on BD, the TCF7L2–BMI interaction was significant at the gene level (p = 0.042), with seven of the 26 SNPs showing SNP–BMI interaction effects with p < 0.05. The strongest evidence of interaction was observed for rs7895307 (p = 0.006). TCF7L2 expression showed a significant enrichment of association with the expression of other genes in the Wnt canonical pathway.ConclusionsThe current study provides further evidence suggesting that TCF7L2 involvement in BD risk may be regulated by BMI. Detailed, prospective assessment of BMI, comorbidity, and other possible contributing factors is necessary to explain fully the mechanisms underlying this association.

Background: Delivering specialty care remotely directly into people's homes can enhance access for and improve the healthcare of individuals with chronic conditions. However, evidence supporting this approach is limited. Materials and Methods: Connect.Parkinson is a randomized comparative effectiveness study that compares usual care of individuals with Parkinson's disease in the community with usual care augmented by virtual house calls with a Parkinson's disease specialist from 1 of 18 centers nationally. Individuals in the intervention arm receive four virtual visits from a Parkinson's disease specialist over 1 year via secure, Web-based videoconferencing directly into their homes. All study activities, including recruitment, enrollment, and assessments, are conducted remotely. Here we report on interest, feasibility, and barriers to enrollment in this ongoing study. Results: During recruitment, 11,734 individuals visited the study's Web site, and 927 unique individuals submitted electronic interest forms. Two hundred ten individuals from 18 states enrolled in the study from March 2014 to June 2015, and 195 were randomized. Most participants were white (96%) and college educated (73%). Of the randomized participants, 73% had seen a Parkinson's disease specialist within the previous year. Conclusions: Among individuals with Parkinson's disease, national interest in receiving remote specialty care directly into the home is high. Remote enrollment in this care model is feasible but is likely affected by differential access to the Internet.

BACKGROUNDThe objective of the current study was to establish a process for validating immunohistochemistry (IHC) protocols for use on the Cellient cell block (CCB) system.METHODSThirty antibodies were initially tested on CCBs using IHC protocols previously validated on formalin‐fixed, paraffin‐embedded tissue (FFPE). Cytology samples were split to generate thrombin cell blocks (TCB) and CCBs. IHC was performed in parallel. Antibody immunoreactivity was scored, and concordance or discordance in immunoreactivity between the TCBs and CCBs for each sample was determined. Criteria for validation of an antibody were defined as concordant staining in expected positive and negative cells, in at least 5 samples each, and concordance in at least 90% of the samples total. Antibodies that failed initial validation were retested after alterations in IHC conditions.RESULTSThirteen of the 30 antibodies (43%) did not meet initial validation criteria. Of those, 8 antibodies (calretinin, clusters of differentiation [CD] 3, CD20, CDX2, cytokeratin 20, estrogen receptor, MOC‐31, and p16) were optimized for CCBs and subsequently validated. Despite several alterations in conditions, 3 antibodies (Ber‐EP4, D2‐40, and paired box gene 8 [PAX8]) were not successfully validated.CONCLUSIONSNearly one‐half of the antibodies tested in the current study failed initial validation using IHC conditions that were established in the study laboratory for FFPE material. Although some antibodies subsequently met validation criteria after optimization of conditions, a few continued to demonstrate inadequate immunoreactivity. These findings emphasize the importance of validating IHC protocols for methanol‐fixed tissue before clinical use and suggest that optimization for alcohol fixation may be needed to obtain adequate immunoreactivity on CCBs. Cancer (Cancer Cytopathol) 2016;124:89‐99. © 2016 American Cancer Society.

Purpose CALGB 49907 showed the superiority of standard therapy, which included either cyclophosphamide/doxorubicin (AC) or cyclophosphamide/methotrexate/fluorouracil over single-agent capecitabine in the treatment of patients age ≥ 65 with early-stage breast cancer. The treatment allowed dosing adjustments of methotrexate and capecitabine for pretreatment renal function. The purpose of the current analysis was to assess the relationship between pretreatment renal function and five end points: toxicity, dose modification, therapy completion, relapse-free survival, and overall survival. Methods Pretreatment renal function was defined as creatinine clearance (CrCl) using the Cockcroft-Gault equation. Multivariable logistic and proportional hazards regression were used to model separately for each regimen the relationship between CrCl and the first three binary end points and the last two time-to-event end points, respectively, after adjusting for variables of prognostic importance. Results Six hundred nineteen assessable patients were analyzed. The incidence of stage III (moderate) or stage IV (severe) renal dysfunction was 72%, 64%, and 75% for treatment with cyclophosphamide/methotrexate/fluorouracil, AC, and capecitabine, respectively. There was no relationship for any regimen between pretreatment renal function and the five end points. For AC, as CrCl increased, the odds of nonhematologic toxicity decreased (P = .008), whereas for capecitabine, as CrCl increased, the odds of experiencing toxicity of any type also increased (P = .035). Patients with renal insufficiency who received dose modifications were not at increased risk for complications compared with those who did not have renal insufficiency and received a full dose. Conclusion Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients.