Citations

Background— The objective was to evaluate the effects of aortic annulus size on valve hemodynamics and clinical outcomes in those patients included in the Placement of Aortic Transcatheter Valves (PARTNER) randomized controlled trial cohort A and the nonrandomized continued access cohort. Methods and Results— Patients included the randomized controlled trial (n=574) and nonrandomized continued access (n=1358) cohorts were divided in tertiles according to aortic annulus diameter (small aortic annulus tertile, medium aortic annulus tertile, and large aortic annulus tertile [LAA], respectively) as measured by transthoracic echocardiography. Severe prosthesis–patient mismatch was defined as an effective aortic orifice area of <0.65 cm 2 /m 2 . In the randomized controlled trial cohort, patients in the small aortic annulus tertile who underwent transcatheter aortic valve replacement had a lower incidence of severe prosthesis–patient mismatch (19.7% versus 37.5%; P =0.03) and only a trend toward a higher incidence of moderate-to-severe paravalvular leaks compared with surgical aortic valve replacement (5.7% versus 0%; P =0.06). In the LAA tertile, there were no differences in the rate of prosthesis–patient mismatch between groups, and a significant increase in moderate-to-severe paravalvular leaks was associated with transcatheter aortic valve replacement (9% versus 0%; P =0.01). There were no differences in mortality between transcatheter aortic valve replacement and surgical aortic valve replacement. In the nonrandomized continued access cohort, there were no differences in prosthesis–patient mismatch between the small aortic annulus and LAA tertiles, but a higher rate of moderate-to-severe paravalvular leaks was observed in the LAA tertile (5.9% versus 11.5%; P =0.009). Patients in the LAA tertile had a higher mortality rate at 1-year follow-up ( P =0.02), and differences persisted in multivariable analysis ( P =0.048 for LAA versus medium aortic annulus tertile, P =0.035 for LAA versus small aortic annulus tertile). Conclusions— Aortic annulus size had a major impact on valve hemodynamics and clinical outcomes after transcatheter aortic valve replacement and surgical aortic valve replacement. This study highlights the importance of considering aortic annulus size in the evaluation of high-risk patients who are candidates for aortic valve replacement. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.

Background— Cardiac resynchronization therapy with defibrillator (CRT-D) reduces morbidity and mortality among selected patients with heart failure in clinical trials. The effectiveness of this therapy in clinical practice has not been well studied. Methods and Results— We compared a cohort of 4471 patients from the National Cardiovascular Data Registry’s Implantable Cardioverter-Defibrillator (ICD) Registry hospitalized primarily for heart failure and who received CRT-D between April 1, 2006, and December 31, 2009, to a historical control cohort of 4888 patients with heart failure without CRT-D from the Acute Decompensated Heart Failure National Registry (ADHERE) hospitalized between January 1, 2002, and March 31, 2006. Both registries were linked with Medicare claims to evaluate longitudinal outcomes. We included patients from the ICD Registry with left ventricular ejection fraction ≤35% and QRS duration ≥120 ms who were admitted for heart failure. We used Cox proportional hazards models to compare outcomes with and without CRT-D after adjustment for important covariates. After multivariable adjustment, CRT-D was associated with lower 3-year risks of death (hazard ratio, 0.52; 95% confidence interval, 0.48–0.56; P <0.001), all-cause readmission (hazard ratio, 0.69; 95% confidence interval, 0.65–0.73; P <0.001), and cardiovascular readmission (hazard ratio, 0.60; 95% confidence interval, 0.56–0.64; P <0.001). The association of CRT-D with mortality did not vary significantly among subgroups defined by age, sex, race, QRS duration, and optimal medical therapy. Conclusions— CRT-D was associated with lower risks of mortality, all-cause readmission, and cardiovascular readmission than medical therapy alone among patients with heart failure in community practice.

Abstract Background: Fluoro-deoxyglucose positron emission tomography (FDG-PET) scans are used for diagnosis and staging of known or suspected non-small cell lung cancer (NSCLC). Single institution studies examining the impact of avidity on survival have reported mixed results. The purpose of this study is to evaluate the association between FDG-PET avidity and survival in the national prospective ACOSOG Z4031 trial in patients with pathological Stage I NSCLC. Methods: Between 2004 and 2006, 1074 patients with known or suspected clinical stage I (cT1-2N0M0) NSCLC were enrolled in the ACOSOG Z4031 trial and underwent surgical resection. FDG-PET results were abstracted from radiology interpretations included in the case report forms. FDG-PET avidity was categorized based on either radiologist description or reported maximum standard uptake value (SUV). The four categories were: 1) not avid and not cancerous (SUV=0), 2) low avidity and likely not cancerous (SUV&gt;0 and &lt;2.5), 3) avid and probably cancerous (SUV≥2.5 and &lt;5) and 4) highly avid and likely cancerous (SUV≥5). The lesion was classified as avid if in categories 3 or 4. The final diagnosis was determined by pathological examination and all cause mortality was reported. Cox proportional hazard regression was used to assess the impact of FDG-PET avidity on survival. The covariates used in the model included pStage, gender, age, race, and preoperative lesion size. Kaplan-Meier survival curves were calculated and the log-rank test was used to determine differences in survival based on FDG-PET avidity. Results: There were 51 enrolling sites in 39 cities with 969 eligible participants. Preoperative FDG-PET results were available for 540 participants with NSCLC and 81% had FDG-PET avid or highly avid lesions. 400 patients had pStage I NSCLC and the 5 year survival was 70% with 95%CI (65%, 75%). FDG-PET avidity, male gender, age, and lesion size negatively impacted survival. FDG-PET avidity in pStage I disease still negatively impacted survival (p=0.03) when controlling for lesion size. The 5 year survival for Stage I disease was 80% with 95%CI (68%, 88%) in FDG-PET negative patients and 67% with 95% CI (61%, 72%) in FDG-PET positive patients (p=0.02). Conclusions: In a national surgical population with pathological stage I NSCLC, FDG-PET avidity negatively impacted five year survival, independently of lesion size. Further work should be done to determine if chemotherapy would be beneficial in patients with PET avid lesions and pStage I NSCLC. Citation Format: Eric L. Grogan, Stephen A. Deppen, Heidi Chen, Karla V. Ballman, Francys C. Verdial, Melinda C. Aldrich, Paul A. Decker, David H. Harpole, Robert J. Cerfolio, Robert J. Keenan, David R. Jones, Thomas A. D'Amico, Joseph B. Shrager, Bryan F. Meyers, Joe B. Putnam. FDG-PET avidity negatively impacts survival in pStage I NSCLC in the ACOSOG Z4031 trial. [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-296. doi:10.1158/1538-7445.AM2013-LB-296

Abstract Janus kinase-2 (JAK2)/STAT pathway activation is commonly observed in myeloproliferative neoplasms and plays an important role in disease development and progression. The V617F activating mutation in the JAK2 pseudokinase domain is found in 95% of patients with polycythemia vera (PV) and in 50-70% of patients with primary myelofibrosis (MF) or essential thrombocythemia (ET). Studies have shown the clinical efficacy of JAK2 inhibitors in treating MF in terms of a reduction in splenomegaly and relief of constitutional symptoms. A reduction in the JAK2V617F allele burden after treatment with a JAK2-targeted agent could be a surrogate for a disease-modifying effect of this therapy. To demonstrate this, a robust method that can accurately measure the JAK2V617F allele burden is required. Here, we report the development of a sensitive quantitative PCR (qPCR) assay to determine the JAK2V617F allele burden in patients treated with SAR302503, the validation of the assay in a Phase 0 clinical study and implementation in a phase II study using samples from patients with MF. The assay demonstrated robust performance, with high sensitivity (LLOD=0.05% and LLOQ=0.5%) and accuracy. A phase 0 study in MF, PV, and ET patients showed that (1) there was minimal intra-subject sampling variability in JAK2V617F allele burden, and (2) whole-blood samples are stable for at least 48 hours at ambient conditions for DNA preparation without a significant impact on JAK2V617F allele burden measurement.Of the 31 patients with intermediate-2 or high-risk MF enrolled in a phase II clinical study (NCT01420770), baseline samples were available for 29 patients and of these, 26 were JAK2V617F-positive using this assay. Of the 19/26 patients for whom samples were available at all 3 time points, the median allele burden was 93% at baseline, 87% at the end of Cycle 3, and 78% at the end of Cycle 6. Among the 24 patients who were JAK2V617F-positive and for whom spleen measurements were available at the end of Cycle 6, a total of 15 (63%) had a spleen response (≥ 35% reduction in spleen volume by MRI versus baseline). In contrast, two JAK2V617F-negative patients did not have a spleen response. Patients with baseline allele burden levels of 0 to &lt;25%, 25% to 75%, and ≥75% showed spleen response rates of 50%, 44%, and 69%, respectively, at the end of Cycle 6. JAK2V617F allele burden will continue to be assessed every 3 cycles. Longer follow up is needed to determine the clinical effect of allele burden reduction. Citation Format: Feng Liu, Moshe Talpaz, Animesh Pardanani, Catriona Jamieson, Nashat Gabrail, Ayalew Tefferi, Tianlei Lei, Rita Greco, Francisco Adrian, Nikki Daskalakis, Claudia Lebedinsky, Pamela Cohen, Donald Bergstrom. Determination of JAK2V617F allele burden in a phase II study of patients with myelofibrosis treated with SAR302503 using a sensitive and robust allele-specific qPCR assay. [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-294. doi:10.1158/1538-7445.AM2013-LB-294

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.

Deletion of 15q11.2‐q13 results in either Prader–Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region (PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent‐of‐origin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain. © 2014 Wiley Periodicals, Inc.

Background and purposeSome recent studies in older, largely white populations suggest that vitamin D, measured by 25‐hydroxyvitamin D [25(OH)D], is important for cognition, but such results may be affected by reverse causation. Measuring 25(OH)D in late middle age before poor cognition affects behavior may provide clearer results.MethodsThis was a prospective cohort analysis of 1652 participants (52% white, 48% black) in the Atherosclerosis Risk in Communities (ARIC) Brain MRI Study. 25(OH)D was measured from serum collected in 1993–1995. Cognition was measured by the delayed word recall test (DWRT), the digit symbol substitution test (DSST) and the word fluency test (WFT). Dementia hospitalization was defined by ICD‐9 codes. Adjusted linear, logistic and Cox proportional hazards models were used.ResultsMean age of participants was 62 years and 60% were female. Mean 25(OH)D was higher in whites than blacks (25.5 vs. 17.3 ng/ml, P < 0.001). Lower 25(OH)D was not associated with lower baseline scores or with greater DWRT, DSST or WFT decline over a median of 3 or 10 years of follow‐up (P > 0.05). Over a median of 16.6 years, there were 145 incident hospitalized dementia cases. Although not statistically significant, lower levels of 25(OH)D were suggestive of an association with increased dementia risk [hazard ratio for lowest versus highest race‐specific tertile: whites 1.32 (95% confidence interval 0.69, 2.55); blacks 1.53 (95% confidence interval 0.84, 2.79)].ConclusionsIn contrast to prior studies performed in older white populations, our study of late middle age white and black participants did not find significant associations between lower levels of 25(OH)D with lower cognitive test scores at baseline, change in scores over time or dementia risk.