Citations

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Abstract Objectives: To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods: The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Results: Twenty-one guideline statements were established. Conclusions: Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.

Objectives.— To develop evidence-based guideline recommendations through a systematic review of the literature to establish standard molecular biomarker testing of colorectal cancer (CRC) tissues to guide epidermal growth factor receptor (EGFR) therapies and conventional chemotherapy regimens. Methods.— The American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and American Society of Clinical Oncology convened an expert panel to develop an evidence-based guideline to establish standard molecular biomarker testing and guide therapies for patients with CRC. A comprehensive literature search that included more than 4,000 articles was conducted. Results.— Twenty-one guideline statements were established. Conclusions.— Evidence supports mutational testing for EGFR signaling pathway genes, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize CRC molecular testing are presented.

BACKGROUNDTo evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post‐transplantation.METHODSWe analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre‐HCT depression requiring treatment versus those without pre‐HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post‐HCT using Poisson models. We also compared the incidence of grade 2‐4 acute and chronic graft‐versus‐host disease (GVHD) in allogeneic HCT.RESULTSThe study included 1116 (15%) patients with pre‐transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre‐transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04‐1.23; P = 0.004) and a higher incidence of grade 2‐4 acute GVHD (HR, 1.25; 95% CI, 1.14‐1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre‐transplant depression was associated with fewer days‐alive‐and‐out‐of‐the hospital (means ratio [MR] = 0.97; 95% CI, 0.95‐0.99; P = 0.004). There were 512 (13.5%) patients with Pre‐transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre‐transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98‐1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97‐0.99; P = 0.002).CONCLUSIONPre‐transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre‐transplant depression represent a population that is at risk for post‐transplant complications. Cancer 2017;123:1828–1838. © 2017 American Cancer Society.

Objectives This study evaluated our experience after implementing a pelvic floor rehabilitation program including behavioral modification, biofeedback, and vaginal electrogalvanic stimulation (EGS). Methods This prospective cohort study evaluated outcomes of patients with pelvic floor dysfunction (urinary or defecatory dysfunction, pelvic pain/dyspareunia) who underwent pelvic floor rehabilitation. Patients received 4 to 7 sessions (1 every 2 weeks) including biofeedback and concluded with 30 minutes of vaginal EGS. Surveys assessed subjective changes in symptoms; success was evaluated using a 10-point visual analog scale (VAS) at the final session (10 = most successful). Paired comparisons of responses at baseline and final treatment were evaluated. Results Ninety-four patients were followed up through therapy completion. Treatment indications included urinary (89.4%), defecatory (33.0%), and pelvic pain or dyspareunia (30.9%); 44.7% of patients had a combination of indications. Among women with urinary symptoms, the percentage reporting leakage decreased from 92.9% to 79.3% (P = 0.001), leakage at least daily decreased from 69.0% to 39.5% (P < 0.001), daily urgency with leakage decreased from 42.7% to 19.5% (P = 0.001), daily urgency without leakage decreased from 41.5% to 18.3% (P < 0.001), and median VAS rating (0 = not at all, 10 = a great deal) of daily life interference decreased from 5 to 1.5 (P < 0.001). The median success ratings were 8, 8, and 7 for treatment of urinary symptoms, pelvic pain/dyspareunia, and bowel symptoms, respectively. Conclusions An aggressive pelvic rehabilitation program including biofeedback with vaginal EGS had a high rate of self-reported subjective success and satisfaction and should be considered a nonsurgical treatment option in patients with pelvic floor dysfunction.

Objectives Rectovaginal fistulae (RVF) often represent surgical challenges, and treatment must be individualized. We describe outcomes after primary surgical repair stratified by fistula etiology and surgical approach. Methods This retrospective cohort study included women who underwent surgical management of RVF at a tertiary care center between July 1, 2001 and December 31, 2013. Cases were stratified according to the following etiology: cancer (RVF-C), inflammatory bowel disease or infectious (RVF-I), and other (RVF-O). Patients with prior surgical treatment of RVF were excluded. Surgical approaches included local (seton, plug), transvaginal or endorectal, abdominal, diversion alone, or definitive (completion proctocolectomy with permanent colostomy or pelvic exenteration). Recurrence-free survival was estimated using the Kaplan-Meier method, and comparisons between subgroups were evaluated based on fitting Cox proportional hazards models. Censoring occurred at last relevant clinical follow-up. Factors contributing to recurrence-free survival were evaluated including age, body mass index, smoking status, fistula etiology, ileostomy, and surgical approach. Results During the study period, 107 women underwent surgical repair of RVF. The most common fistula etiology was RVF-I (54.2%), followed by RVF-O (23.4%), and RVF-C (22.4%). Ninety-four women underwent fistula repair by the local (29.9%), transvaginal/endorectal (25.2%), abdominal approach (19.6%), or diversion alone (13.1%), whereas 13 underwent definitive surgery (12.2%). Recurrence-free survival was significantly different depending on surgical approach ( P < 0.001), but not etiology ( P = 0.71). Recurrence-free survival (95% confidence interval) at 1 year after surgery was 35.2% (21.8%–56.9%) for the local approach, 55.6% (37.0%–83.3%) for the transvaginal or endorectal approach, 95% (85.9%–100%) for the abdominal approach, and 33.3% (15%–74.2%) for those with diversion only. Conclusions Recurrence rates after RVF repair are high and did not differ by fistula etiology. Abdominal repair of RVF had significantly fewer recurrences.