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 Regorafenib is an oral multikinase inhibitor that inhibits several kinases relevant to tumor biology in several cancers, including colorectal carcinoma (CRC) and gastrointestinal stromal tumor (GIST). In phase III trials, regorafenib significantly improved overall survival versus placebo in patients with metastatic CRC progressing after all available standard therapies, and significantly prolonged progression-free survival in patients with advanced GIST in whom at least imatinib and sunitinib had failed. Thus, this agent holds promise as a new standard of care for CRC and GIST patients after disease progression following all other approved therapies. The clinical trials reported to date show that this new treatment has a consistent adverse event profile that is quite different from that of traditional cytotoxic chemotherapies. The most common adverse events of regorafenib include dermatologic and mucosal toxicities (especially hand-foot skin reaction, rash, and oral mucositis), constitutional symptoms (e.g., fatigue, nausea, and weight loss), vascular effects (especially hypertension), and gastrointestinal symptoms (e.g., diarrhea). To help health care professionals anticipate and manage the adverse events associated with regorafenib, we describe our experiences in clinical trials and show that such toxicities can be effectively managed with close observation of patients from initiation of dosing, along with prompt appropriate interventions, including dose modifications, if necessary.

Abstract There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD‐I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre‐mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus .

Purpose Studies of diffuse large B-cell lymphoma (DLBCL) are typically evaluated by using a time-to-event approach with relapse, re-treatment, and death commonly used as the events. We evaluated the timing and type of events in newly diagnosed DLBCL and compared patient outcome with reference population data. Patients and Methods Patients with newly diagnosed DLBCL treated with immunochemotherapy were prospectively enrolled onto the University of Iowa/Mayo Clinic Specialized Program of Research Excellence Molecular Epidemiology Resource (MER) and the North Central Cancer Treatment Group NCCTG-N0489 clinical trial from 2002 to 2009. Patient outcomes were evaluated at diagnosis and in the subsets of patients achieving event-free status at 12 months (EFS12) and 24 months (EFS24) from diagnosis. Overall survival was compared with age- and sex-matched population data. Results were replicated in an external validation cohort from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Lymphome Non Hodgkinien 2003 (LNH2003) program and a registry based in Lyon, France. Results In all, 767 patients with newly diagnosed DLBCL who had a median age of 63 years were enrolled onto the MER and NCCTG studies. At a median follow-up of 60 months (range, 8 to 116 months), 299 patients had an event and 210 patients had died. Patients achieving EFS24 had an overall survival equivalent to that of the age- and sex-matched general population (standardized mortality ratio [SMR], 1.18; P = .25). This result was confirmed in 820 patients from the GELA study and registry in Lyon (SMR, 1.09; P = .71). Simulation studies showed that EFS24 has comparable power to continuous EFS when evaluating clinical trials in DLBCL. Conclusion Patients with DLBCL who achieve EFS24 have a subsequent overall survival equivalent to that of the age- and sex-matched general population. EFS24 will be useful in patient counseling and should be considered as an end point for future studies of newly diagnosed DLBCL.

ABSTRACT A 65-year-old male with known hypertension and hypercholesterolemia sought medical attention because of a 3-month history of skin swelling on his upper back. Histopathology and molecular techniques were employed and identified an organism in the Onchocerca genus. This represents a very uncommon example of cutaneous infection by a zoonotic Onchocerca species.

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.

SummaryBackgroundCurrent diagnostic guidelines recommend that eosinophilic oesophagitis (EoE) should be diagnosed only after GERD is excluded by a lack of response to a trial of acid suppression. There is limited information available providing outcome data about the effectiveness of this approach.AimTo examine the impact of double‐dose proton pump inhibitor (PPI) therapy on symptoms, endoscopic and histological features in patients with documented oesophageal eosinophilia consistent with EoE (≥15 eosinophils/high‐power field).MethodsSixty consecutive symptomatic patients with documented oesophageal eosinophilia received open‐label omeprazole 20 mg orally twice daily before meals for 8 weeks. Clinical, endoscopic and histological (resolution: 0–5 eosinophils/HPF, partial improvement: 5–14 eosinophils/HPF), or no improvement: (≥15 eosinophils/HPF) evaluation was repeated at the end of this period. An expert GI pathologist, unaware of the study aims, reviewed all slides.ResultsClinical improvement occurred in 43 (71.6%), endoscopic signs were reduced in 34 (61.8%) and normalised in 12 (21.8%), and histologically, 34 (56.6%) improved, while 15 (25%) obtained complete resolution. Overall, 22 patients (36.7%) obtained both complete clinical and histological remission.ConclusionsMore than 50% of patients with documented oesophageal eosinophilic infiltration in the EoE range improved when treated with a double‐dose PPI trial for 8 weeks. These findings support the published guidelines recommending a PPI trial prior to diagnosing EoE, and confirm the existence of an eosinophilic oesophageal infiltrationPPI‐responsive population.

AbstractBackgroundHippocampal volumetry on magnetic resonance imaging is recognized as an Alzheimer's disease (AD) biomarker, and manual segmentation is the gold standard for measurement. However, a standard procedure is lacking. We operationalize and quantitate landmark differences to help a Delphi panel converge on a set of landmarks.MethodsOne hundred percent of anatomic landmark variability across 12 different protocols for manual segmentation was reduced into four segmentation units (the minimum hippocampus, the alveus/fimbria, the tail, and the subiculum), which were segmented on magnetic resonance images by expert raters to estimate reliability and AD‐related atrophy.ResultsIntra‐ and interrater reliability were more than 0.96 and 0.92, respectively, except for the alveus/fimbria, which were 0.86 and 0.77, respectively. Of all AD‐related atrophy, the minimum hippocampus contributed to 67%; tail, 24%; alveus/fimbria, 4%; and the subiculum, 5%.ConclusionsAnatomic landmark variability in available protocols can be reduced to four discrete and measurable segmentation units. Their quantitative assessment will help a Delphi panel to define a set of landmarks for a harmonized protocol.

ScopeAndrogen receptor (AR) signaling is critical for all aspects of prostate growth and tumorigenesis. The glucosinolate‐derived phenethyl isothiocyanate (PEITC) has recently been demonstrated to reduce the risk of prostate cancer (PCa) and inhibit PCa cell growth. We previously reported that p300/CBP‐associated factor (PCAF), a co‐regulator for AR, is upregulated in PCa cells through suppression of the mir‐17 gene. Here, we assessed the effects of PEITC on PCAF expression and AR‐regulated transcriptional activity in PCa cells.Methods and resultsUsing AR‐responsive LNCaP cells, we observed the inhibitory effects of PEITC on the dihydrotestosterone‐stimulated AR transcriptional activity and cell growth of PCa cells. Interestingly, overexpression of PCAF attenuated the inhibitory effects of PEITC on dihydrotestosterone‐stimulated AR transcriptional activity. Expression of PCAF was upregulated in PCa cells through suppression of miR‐17. PEITC treatment significantly decreased PCAF expression and promoted transcription of miR‐17 in LNCaP cells. Functional inhibition of miR‐17 attenuated the suppression of PCAF in cells treated by PEITC.ConclusionOur results indicate that PEITC inhibits AR‐regulated transcriptional activity and cell growth of PCa cells through miR‐17‐mediated suppression of PCAF, suggesting a new mechanism by which PEITC modulates PCa cell growth.