Citations

Key Points High WBC is an independent predictor of early HD in APL.

Genome-wide association studies have identified >50 common variants associated with kidney function, but these variants do not fully explain the variation in eGFR. We performed a two-stage meta-analysis of associations between genotypes from the Illumina exome array and eGFR on the basis of serum creatinine (eGFRcrea) among participants of European ancestry from the CKDGen Consortium ( n Stage1 : 111,666; n Stage2 : 48,343). In single-variant analyses, we identified single nucleotide polymorphisms at seven new loci associated with eGFRcrea ( PPM1J , EDEM3, ACP1, SPEG, EYA4, CYP1A1 , and ATXN2L ; P Stage1 <3.7×10 −7 ), of which most were common and annotated as nonsynonymous variants. Gene-based analysis identified associations of functional rare variants in three genes with eGFRcrea, including a novel association with the SOS Ras/Rho guanine nucleotide exchange factor 2 gene, SOS2 ( P =5.4×10 −8 by sequence kernel association test). Experimental follow-up in zebrafish embryos revealed changes in glomerular gene expression and renal tubule morphology in the embryonic kidney of acp1- and sos2 -knockdowns. These developmental abnormalities associated with altered blood clearance rate and heightened prevalence of edema. This study expands the number of loci associated with kidney function and identifies novel genes with potential roles in kidney formation.

Background: Mitral valve (MV) repair is preferred over replacement in clinical guidelines and is an important determinant of the indication for surgery in degenerative mitral regurgitation. However, the level of evidence supporting current recommendations is low, and recent data cast doubts on its validity in the current era. Accordingly, the aim of the present study was to analyze very long-term outcome after MV repair and replacement for degenerative mitral regurgitation with a flail leaflet. Methods: MIDA (Mitral Regurgitation International Database) is a multicenter registry enrolling patients with degenerative mitral regurgitation with a flail leaflet in 6 tertiary European and US centers. We analyzed the outcome after MV repair (n=1709) and replacement (n=213) overall, by propensity score matching, and by inverse probability-of-treatment weighting. Results: At baseline, patients undergoing MV repair were younger, had more comorbidities, and were more likely to present with a posterior leaflet prolapse than those undergoing MV replacement. After propensity score matching and inverse probability-of-treatment weighting, the 2 treatments groups were balanced, and absolute standardized differences were usually <10%, indicating adequate match. Operative mortality (defined as a death occurring within 30 days from surgery or during the same hospitalization) was lower after MV repair than after replacement in both the entire population (1.3% versus 4.7%; P <0.001) and the propensity-matched population (0.2% versus 4.4%; P <0.001). During a mean follow-up of 9.2 years, 552 deaths were observed, of which 207 were of cardiovascular origin. Twenty-year survival was better after MV repair than after MV replacement in both the entire population (46% versus 23%; P <0.001) and the matched population (41% versus 24%; P <0.001). Similar superiority of MV repair was obtained in patient subsets on the basis of age, sex, or any stratification criteria (all P <0.001). MV repair was also associated with reduced incidence of reoperations and valve-related complications. Conclusions: Among patients with degenerative mitral regurgitation with a flail leaflet referred to mitral surgery, MV repair was associated with lower operative mortality, better long-term survival, and fewer valve-related complications compared with MV replacement.

Objectives: Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. Patients and Methods: Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m 2 of gemcitabine (on days 1, 8), 650 mg/m 2 of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. Results: In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P =0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P =0.39). Conclusions: Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.

Key Points Under current treatment approaches, patients with LA GVHD have poor overall and failure-free survival. Levels of AREG are elevated in LA GVHD, and the AREG/EGF ratio is predictive of overall survival and nonrelapse mortality in LA GVHD.

Purpose Extramedullary disease (EMD) at diagnosis in patients with acute myeloid leukemia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in consecutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD. Methods Patients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results. Results Of the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites. The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD ( P = .005), skin involvement ( P = .002), spleen ( P < .001), and liver ( P < .001), but not CNS ( P = .34), nodal involvement ( P = .94), and gingival hypertrophy ( P = .24), was associated with a shorter overall survival. In contrast, in multivariable analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. Conclusion This large study demonstrates that EMD at any site is common but is not an independent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, irrespective of the presence of EMD.