Citations

Background and Purpose— Clinical equipoise of carotid revascularization therapies remains controversial. We sought to determine whether adverse outcomes after carotid endarterectomy (CEA) or carotid angioplasty and stenting (CAS) were similar using propensity score–matched analysis of retrospective data from a large hospital discharge database. Methods— All CEA and CAS cases were identified from the 2006 to 2011 Premier Perspective Database and subjected to 1:1 propensity score matching using 33 clinical covariates associated with carotid revascularization. A primary composite end point of peri- or postoperative mortality, stroke, or acute myocardial infarction and a modified composite end point excluding acute myocardial infarction were used to compare our findings with recent prospective controlled trials. Multivariate regression and Cox-proportional hazard ratio survival analysis were performed to compare revascularization therapy outcomes. Results— After 1:1 propensity score matching, 24 004 (12 002 CEA and CAS) asymptomatic and 3506 (1753 CEA and CAS) symptomatic procedures were included. The risk of the primary composite end point was significantly higher after CAS than CEA in both asymptomatic (odds ratio, 1.40 [1.19–1.65]; P <0.0001) and symptomatic (odds ratio=2.31 [1.78–3.00]; P <0.0001) presentations, irrespective of age ( P =0.28) or sex ( P =0.35). Similar findings were observed using the modified composite end point for both asymptomatic (odds ratio, 1.49 [1.25–1.78]; P <0.0001) and symptomatic (odds ratio, 3.02 [2.25–4.07]; P <0.0001) presentations. Acute myocardial infarction risk was not significantly different between revascularization therapies, regardless of clinical presentation ( P =0.71 and 0.24). Conclusions— Among individuals undergoing carotid artery revascularization from a large sample of US hospitals, CAS was associated with higher risk of perioperative mortality, stroke, and unfavorable discharges compared with CEA for all ages and clinical presentations.

ObjectiveMutations in Charcot–Marie–Tooth disease (CMT) genes are the cause of rare familial forms of polyneuropathy. Whether allelic variability in CMT genes is also associated with common forms of polyneuropathy—considered “acquired” in medical parlance—is unknown. Chemotherapy‐induced peripheral neuropathy (CIPN) occurs commonly in cancer patients and is individually unpredictable. We used CIPN as a clinical model to investigate the association of non‐CMT polyneuropathy with CMT genes.MethodsA total of 269 neurologically asymptomatic cancer patients were enrolled in the clinical trial Alliance N08C1 to receive the neurotoxic drug paclitaxel, while undergoing prospective assessments for polyneuropathy. Forty‐nine CMT genes were analyzed by targeted massively parallel sequencing of genomic DNA from patient blood.ResultsA total of 119 (of 269) patients were identified from the 2 ends of the polyneuropathy phenotype distribution: patients that were most and least susceptible to paclitaxel polyneuropathy. The CMT gene PRX was found to be deleteriously mutated in patients who were susceptible to CIPN but not in controls (p = 8 × 10−3). Genetic variation in another CMT gene, ARHGEF10, was highly significantly associated with CIPN (p = 5 × 10−4). Three nonsynonymous recurrent single nucleotide variants contributed to the ARHGEF10 signal: rs9657362, rs2294039, and rs17683288. Of these, rs9657362 had the strongest effect (odds ratio = 4.8, p = 4 × 10−4).InterpretationThe results reveal an association of CMT gene allelic variability with susceptibility to CIPN. The findings raise the possibility that other acquired polyneuropathies may also be codetermined by genetic etiological factors, of which some may be related to genes already known to cause the phenotypically related Mendelian disorders of CMT. Ann Neurol 2014;76:727–737

Abstract Introduction: Symptom control is an important objective in the care of patients with cancer and a critical goal for long-term survivors of antineoplastic treatments. Commonly used chemotherapies, including paclitaxel, are associated with a toxic effect on the peripheral nervous system in a substantial fraction of patients, termed chemotherapy induced peripheral neuropathy (CIPN), that is often debilitating. CIPN cannot be predicted from clinical parameters in neurologically normal subjects, suggesting a genetic basis as the root cause. Patients with hereditary neuropathy (HN) due to one of ~50 recognized genes are prone to developing severe CIPN even if the hereditary predisposition is clinically silent. Assessment of CIPN has usually been an afterthought of cancer treatment studies using crude symptom measurement instruments. N08C1 and N08CA are recent clinical trials_the latter analyzed only in early 2013_focusing on extensive phenotyping by patient reported outcomes (PRO) to support genetic investigations of paclitaxel-related CIPN. Massively parallel (“nextgen”) DNA sequencing is the genetic technology of choice and represents an as-yet unrealized potential to study cancer symptom control. Methods: Exome sequencing_analysis of 20,794 genes at nucleotide resolution_was performed on blood of CIPN cases (n=73) and controls (n=46) from N08C1. The primary endpoint was the association of HN genes with CIPN. Bioinformatic analysis determined SNV and other genetic variations across 6.2x107 nucleotides. The association of genes with CIPN was statistically examined by the over-dispersion test C-alpha. The role of singleton SNV was assessed by a burden test. N08CA served as validation. Results: 386,644 SNV were detected with an estimated sensitivity of 90% and specificity of 99.9%; the orthogonal validation rate (PCR of &gt;1000 genotypes) was 99.7%. The association of the minor allele (C&gt;T) at rs7349683 in the gene EPHA5, previously reported by Baldwin et al. (2012) for CALGB40101, was confirmed in N08C1. Two hereditary neuropathy genes were identified as new CIPN candidate genes: Firstly, ARHGEF10 was highly significant with p=5x10-4 based on single gene testing and p&lt;0.02 after Bonferroni correction for multiple testing of 41 hereditary neuropathy genes with non-synonymous SNV. Three SNV were predictive, rs17683288, rs2294039 and rs9657362, the latter with an odds ratio (OR)=3.62. Validation in an independent patient group (n=75) from another paclitaxel CIPN trial, N08CA, confirmed the impact of ARHGEF10 on CIPN (p&lt;0.025; rs9657362 OR=2.51). Secondly, peraxin (PRX) was disrupted by non-synonymous singleton SNV in n=8 cases and n=0 controls (OR=6.4; unadjusted p=0.04). 7 of the 8 mutations were also scored as deleterious by both Polyphen 2 and SIFT. Because PRX SNV were non-recurrent validation was performed in N08C1 by Sanger sequencing. Several neuro-genes across the exome were noted as additional CIPN gene candidates. Conclusions: ARHGEF10 and PRX associations with CIPN suggest that CIPN and HN might share genetic roots in a subset of patients. Construct validity of N08C1 is supported by confirmation of a published result from CALGB40101 relating EPHA5 to CIPN. Germline exome sequencing in cancer patients is highly informative for understanding complex pharmacogenomic traits including outcomes in symptom control research. Citation Format: Andreas S. Beutler, Amit Kulkarni, Rahul Kanwar, Rui Qin, Julie M. Cunningham, Terry M. Therneau, Charles L. Loprinzi. Sequencing symptom control: Results from the Alliance N08C1 and N08CA genetics of chemotherapy neuropathy trials. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-196. doi:10.1158/1538-7445.AM2013-LB-196

Abstract The plasma cell malignancy Multiple Myeloma (MM) is a rare but deadly form of cancer with 5 year survival rates of ∼30%. Epidemiological studies have suggested that MM exacts an especially heavy burden on African American (AA) patients. We examined a multi-ethnic cohort of MM tumors to assess potential differences in the frequency of molecular events in tumors derived from either African American (AA) or European American (EA) patients. The frequency of 14q32 translocation breakpoints at the IgH locus was compared among a series of data from 115 AA MM patients from three studies and EA MM from the Eastern Cooperative Oncology Group (ECOG). In addition, we analyzed matching genome-wide copy number and transcriptional data among 45 AA MM tumors and 196 EA MM tumors to determine differences in the frequency of molecular events in tumors from these populations. No differences were found for specific translocation subtypes; however, we detected a statistically significant difference in the overall frequency of IgH translocations between the two groups, which occurred more frequently in EA patients (52% vs. 40%; p = 0.032). When assessing genomic copy number events previously shown to be associated with poor outcome in MM, frequencies of alterations were not significant after correcting for multiple testing. Furthermore, there was not a significant difference in the association of high-risk disease using expression profiling. Our study represents the first comprehensive assessment of the frequency and distribution of molecular alterations in MM tumors from both AA and EA patients and could help shed light on possible biological features associated with population differences in incidence and outcome in MM. Citation Format: Angela S. Baker, Esteban Braggio, Susana Jacobus, Sungwon Jung, Dirk Larson, Terry Therneau, Angela Dispenzieri, Scott A. Van Wier, Gregory Ahmann, Joan Levy, Louise Perkins, Seungchan Kim, Kim Henderson, David Vesole, S. Vincent Rajkumar, Dianne F. Jelinek, John Carpten, Rafael Fonseca. Characterization of myeloma tumors from a multi-ethnic cohort using cytogenetics and genomic analysis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2021. doi:10.1158/1538-7445.AM2013-2021

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 Background and aims Affect balance reflects relative levels of negative affect (NA) and positive affect (PA) and includes four styles: Healthy (low NA/high PA), Depressive (high NA/low PA), Reactive (high NA/high PA) and Low (low NA/low PA). These affect balance styles may have important associations with clinical outcomes in patients with fibromyalgia. Herein, we evaluated the severity of core fibromyalgia symptom domains as described by the Outcomes Research in Rheumatology-Fibromyalgia working group in the context of the four affect balance styles. Methods Data from 735 patients with fibromyalgia who completed the Brief Pain Inventory, Multidimensional Fatigue Inventory, Profile of Mood States, Medical Outcomes Sleep Scale, Multiple Ability Self-Report Questionnaire, Fibromyalgia Impact Questionnaire-Revised, Medical Outcomes Study Short Form-36, and Positive and Negative Affect Schedule were included in this analysis. Results The majority (51.8%) of patients in our sample had a Depressive affect balance style; compared to patients with a Healthy affect balance style, they scored significantly worse in all fibromyalgia symptom domains including pain, fatigue, sleep disturbance, dyscognition, depression, anxiety, stiffness, and functional status ( P = <.001 to .004). Overall, patients with a Healthy affect balance style had the lowest level of symptoms, while symptom levels of those with Reactive and Low affect balance styles were distributed in between those of the Depressive and Healthy groups. Conclusions and implications The results of our cross-sectional study suggest that having a Healthy affect balance style is associated with better physical and psychological symptom profiles in fibromyalgia. Futures studies evaluating these associations longitudinally could provide rationale for evaluating the effect of psychological interventions on affect balance and clinical outcomes in fibromyalgia.

ObjectiveTo examine trends in glucocorticoid (GC) use and dosing among patients diagnosed with rheumatoid arthritis (RA) over time.MethodsA population‐based inception cohort of RA patients diagnosed during 1980–2007 was followed longitudinally through their medical records until death, migration, or December 31, 2008. GC start and stop dates were collected, along with doses in prednisone equivalents.ResultsThe study population comprised 349 patients (68% women) diagnosed in 1980–1994 and 464 (69% women) diagnosed in 1995–2007, with a median followup of 15.3 and 5.7 years, respectively. A higher proportion of patients started GCs in their first year of disease in 1995–2007 (68% versus 36%; P < 0.001), but the starting dose (mean 8.7 versus 10.3 mg; P = 0.08) and cumulative dose in the first year of use (mean 1.8g [mean daily dose 4.9 mg] versus 2.1 gm [mean daily dose 5.8 mg]; P = 0.48) were not different. A higher proportion also discontinued GCs in their first year of disease in the 1995–2007 cohort (P < 0.001). These differences in GC initiation and discontinuation persisted throughout followup. Prevalence of GC use was higher in the 1995–2007 cohort for the first 3 years of disease.ConclusionMore patients are starting GCs early in their disease course now compared to previously, which is consistent with established treatment guidelines. A higher proportion are also discontinuing GCs, but the proportion of patients taking GCs at any given point of disease during the first 4 years is higher now than previously. Despite early addition of a disease‐modifying antirheumatic drug, some patients may not be able to discontinue GCs over the long term.