Citations

Abstract Background: Sugar-sweetened beverage (SSB) intake has been associated with an increased risk of obesity and type II diabetes. However, its association with endometrial cancer is unclear. Methods: We evaluated dietary intake of SSB, fruit juice, sugar-free beverages, sweets/baked goods, starch, and sugars among 23,039 postmenopausal women in the Iowa Women's Health Study. Incident estrogen-dependent type I and estrogen-independent type II endometrial cancers were identified via linkage with the Surveillance Epidemiology and End Results Registry. Risks of type I and type II endometrial cancers were separately compared by energy-adjusted dietary intake in Cox proportional hazards regression models. Results: From 1986 to 2010, 506 type I and 89 type II incident endometrial cancers were identified. An increased risk of type I endometrial cancer was observed with increasing SSB intake after adjustment for body mass index (BMI) and other cofounders (Ptrend = 0.0005). Compared with nondrinkers of SSB, the risk was 78% higher [95% confidence intervals (CI), 1.32–2.40] among women in the highest quintile of SSB intake. The observed association was not modified by BMI, physical activity, history of diabetes, or cigarette smoking. Higher risk of type I endometrial cancer was also observed with higher intake of sugars. None of the dietary items included in the analysis was associated with type II endometrial cancer risk. Conclusion: Higher intake of SSB and sugars was associated with an increased risk of type I, but not type II, endometrial cancer. Impact: SSB intake may be a risk factor for type I endometrial cancer regardless of other lifestyle factors. Cancer Epidemiol Biomarkers Prev; 22(12); 2384–94. ©2013 AACR.

Background and purposeTrochlear headaches are a recently recognized cause of headache, of which both primary and inflammatory subtypes are recognized. The clinical features, long‐term prognosis and optimal treatment strategy have not been well defined.MethodsA cohort of 25 patients with trochlear headache seen at the Mayo Clinic between 10 July 2007 and 28 June 2012 were identified.ResultsThe diagnosis of trochlear headache was not recognized by the referring neurologist or ophthalmologist in any case. Patients most often presented with a new daily from onset headache (n = 22, 88%). The most characteristic headache syndrome was reported as continuous, achy, periorbital pain associated with photophobia and aggravation by eye movement, especially reading. Individuals with a prior history of migraine were likely to have associated nausea and experience trochlear migraine. Amongst individuals with trochleitis, 5/12 (41.6%) had an identified secondary mechanism. Treatment responses were generally, but not invariably, favorable to dexamethasone/lidocaine injections near the trochlea. At a median follow‐up of 34 months (range 0–68), 10/25 (40%) of the cohort had experienced complete remission.ConclusionsTrochlear headaches are poorly recognized, have characteristic clinical features, and often require serial injections to optimize the treatment outcome. The identification of trochleitis should prompt neuroimaging to look for a secondary cause.

Abstract A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76–0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75–0.95; P = 0.006). Considering a multiple-testing–corrected significance threshold of P < 2.5 × 10−5, only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79–0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852–61. ©2013 AACR.

Abstract Glioblastoma multiforme is an aggressive, treatment-refractory type of brain tumor for which effective therapeutic targets remain important to identify. Here, we report that cyclophilin B (CypB), a prolyl isomerase residing in the endoplasmic reticulum (ER), provides an essential survival signal in glioblastoma multiforme cells. Analysis of gene expression databases revealed that CypB is upregulated in many cases of malignant glioma. We found that suppression of CypB reduced cell proliferation and survival in human glioblastoma multiforme cells in vitro and in vivo. We also found that treatment with small molecule inhibitors of cyclophilins, including the approved drug cyclosporine, greatly reduced the viability of glioblastoma multiforme cells. Mechanistically, depletion or pharmacologic inhibition of CypB caused hyperactivation of the oncogenic RAS–mitogen-activated protein kinase pathway, induction of cellular senescence signals, and death resulting from loss of MYC, mutant p53, Chk1, and Janus-activated kinase/STAT3 signaling. Elevated reactive oxygen species, ER expansion, and abnormal unfolded protein responses in CypB-depleted glioblastoma multiforme cells indicated that CypB alleviates oxidative and ER stresses and coordinates stress adaptation responses. Enhanced cell survival and sustained expression of multiple oncogenic proteins downstream of CypB may thus contribute to the poor outcome of glioblastoma multiforme tumors. Our findings link chaperone-mediated protein folding in the ER to mechanisms underlying oncogenic transformation, and they make CypB an attractive and immediately targetable molecule for glioblastoma multiforme therapy. Cancer Res; 74(2); 484–96. ©2013 AACR.

Propensity score (PS) methods have proliferated in recent years in observational studies in general and in observational comparative effectiveness research (CER) in particular. PS methods are an important set of tools for estimating treatment effects in observational studies, enabling adjustment for measured confounders in an easy-to-understand and transparent way. This article demonstrates how PS methods have been used to address specific CER questions from 2001 through to 2012 by identifying six impactful studies from this period. This article also discusses areas for improvement, including data infrastructure, and a unified set of guidelines in terms of PS implementation and reporting, which will boost confidence in evidence generated through observational CER using PS methods.

Background: Coronary heart disease (CHD) poses a major health burden in the Gulf countries. Knowledge of novel genetic and proteomic markers of CHD will provide more precise estimates of risk while defining the pathways important in individual patients, revealing new targets for intervention, and ultimately enabling an individualized approach to care. We describe design of a biorepository with linkage to medical records to facilitate discovery of biomarkers for CHD. Methods: The goal of the Qatar Cardiovascular Biorepository (QCBio) is to archive plasma and DNA of 1000 Qatari patients with CHD and 1000 age, gender, and ethnicity-matched controls who have no history of CHD. Cases will include patients needing percutaneous intervention for symptomatic CHD or admitted with an acute coronary syndrome (myocardial infarction or unstable angina). Controls will be identified from the blood bank as adults who have no history of CHD. Relevant risk factors and comorbid conditions will be ascertained by electronic medical record (EMR)-based electronic phenotyping algorithms that included diagnosis and procedure codes, medication use and laboratory data. We will include processes to promote use of the biorepository by Qatari investigators by facilitating access to the repository for biomarker research, while maintaining the highest ethical standards with emphasis on patient confidentiality and stewardship of the biospecimens. Results: Thus far, we have a) created a patient questionnaire in Arabic to obtain information on demographic factors, cardiovascular disease risk factors, and family history; b) hired the technologist for sample processing, aliquoting, and DNA extraction; c) hired and trained the study coordinators who will recruit patients; d) developed consent forms in Arabic; e) put in place a Laboratory Information Management System (LIMS) for sample tracking; and f) set up a website for the study. We have obtained approval from the Hamad Medical Center IRB and recruitment is about to begin. We will present the progress made at various seminars and conferences of the Cardiology Department to increase awareness of QCBio.

There are no systematic data regarding nonmaintained induction for those patients with multiple myeloma (MM) who do not receive consolidative autologous stem cell transplantation. Of 173 patients with newly diagnosed MM treated with lenalidomide and dexamethasone (LenDex) as primary therapy, 31 patients had their lenalidomide discontinued for reasons other than progression or alternate therapy. Median progression free survival (PFS) from the time of discontinuing lenalidomide was longer in patients who received lenalidomide ≥1 year (39 vs. 13 months, P < 0.05); there was no difference in PFS for those treated for 1–2 years as compared to ≥2 years. Among those taking lenalidomide for ≥1 year PFS was superior in patients who were in very good partial response (VGPR) or better as compared to those with partial response (48.4 versus 14.8 months, P < 0.05). All patients who progressed and were rechallenged with LenDex responded. These analyses illustrate that discontinuation of lenalidomide after 1 year among those patients achieving a ≥VGPR can result in long‐term disease control. Am. J. Hematol. 89:302–305, 2014. © 2013 Wiley Periodicals, Inc.