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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 Massively parallel sequencing allows simultaneous testing of multiple genes associated with cancer susceptibility. Guidelines are available for variant classification; however, interpretation of these guidelines by laboratories and providers may differ and lead to conflicting reporting and, potentially, to inappropriate medical management. We describe conflicting variant interpretations between Clinical Laboratory Improvement Amendments–approved commercial clinical laboratories, as reported to the Prospective Registry of Multiplex Testing (PROMPT), an online genetic registry. Methods Clinical data and genetic testing results were gathered from 1,191 individuals tested for inherited cancer susceptibility and self-enrolled in PROMPT between September 2014 and October 2015. Overall, 518 participants (603 genetic variants) had a result interpreted by more than one laboratory, including at least one submitted to ClinVar, and these were used as the final cohort for the current analysis. Results Of the 603 variants, 221 (37%) were classified as a variant of uncertain significance (VUS), 191 (32%) as pathogenic, and 34 (6%) as benign. The interpretation differed among reporting laboratories for 155 (26%). Conflicting interpretations were most frequently reported for CHEK2 and ATM, followed by RAD51C, PALB2, BARD1, NBN, and BRIP1. Among all participants, 56 of 518 (11%) had a variant with conflicting interpretations ranging from pathogenic/likely pathogenic to VUS, a discrepancy that may alter medical management. Conclusions Conflicting interpretation of genetic findings from multiplex panel testing used in clinical practice is frequent and may have implications for medical management decisions.

Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left‐sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30–50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome‐wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein‐coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non‐syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. © 2016 Wiley Periodicals, Inc.

BACKGROUNDHydroxyethyl starch (HES) is reportedly associated with an increased risk of renal failure and death when used for fluid resuscitation in critically ill patients. HES can be used during therapeutic leukocytapheresis (TL) procedures to enhance cell separation. The purpose of this study was to evaluate the occurrence of adverse events associated with HES during TL procedures.STUDY DESIGN AND METHODSWe performed a retrospective review of patients who underwent TL with and without HES in the period 2009 to 2013 at six academic medical institutions.RESULTSA difference‐in‐difference regression analysis was used to estimate the mean change before and after TL in selected outcomes in the HES group relative to the average change in the non‐HES group. Selected outcomes included serum creatinine, estimated glomerular filtration rate (eGFR), and white blood cell (WBC) count. A total of 195 patients who underwent 278 TL procedures were studied. We found no significant differences in serum creatinine levels and eGFR on Days 1 and 7 after TL procedure between patients who received and those who did not receive HES. The rate of adverse events and overall and early mortality were similar in both groups. Patients with acute myeloid leukemia who received HES had greater WBC reduction when HES was used. Additionally, patients who received HES had improvement in pulmonary leukostasis symptoms.CONCLUSIONHES, used at low doses during TL procedures, was not associated with adverse events previously ascribed to its use as a volume expander.

Purpose To determine the effects of carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) on health-related quality of life (HR-QoL) in the Carfilzomib, Lenalidomide, and Dexamethasone Versus Lenalidomide and Dexamethasone for the Treatment of Patients With Relapsed Multiple Myeloma (ASPIRE) trial. Methods Patients with relapsed multiple myeloma were randomly assigned to receive KRd or Rd. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and myeloma-specific module were administered at baseline; day 1 of cycles 3, 6, 12, and 18; and after treatment. The Global Health Status/Quality of Life (GHS/QoL) scale and seven subscales (fatigue, nausea and vomiting, pain, physical functioning, role functioning, disease symptoms, and adverse effects of treatment) were compared between groups using a mixed model for repeated measures. The percentages of responders with ≥ 5- or 15-point GHS/QoL improvement at each cycle were compared between groups. Results Baseline questionnaire compliance was excellent (94.1% of randomly assigned patients). KRd patients had higher GHS/QoL scores versus Rd patients over 18 treatment cycles (two-sided P < .001). The minimal important difference was met at cycle 12 (5.6 points) and approached at cycle 18 (4.8 points). There was no difference between groups for the other prespecified subscales from ASPIRE. A higher proportion of KRd patients met the GHS/QoL responder definition (≥ 5-point improvement) with statistical differences at cycle 12 (KRd v Rd patients, 25.5% v 17.4%, respectively) and 18 (KRd v Rd patients, 24.2% v 12.9%, respectively). Conclusion KRd improves GHS/QoL without negatively affecting patient-reported symptoms when compared with Rd. These data further support the benefit of KRd in patients with relapsed multiple myeloma.

Background: Anterior cruciate ligament reconstruction (ACLR) using a hamstring tendon autograft often results in hamstring muscle strength asymmetry. However, the effect of hamstring muscle strength asymmetry on knee mechanics has not been reported. Hypothesis: Participants with hamstring strength asymmetry would demonstrate altered involved limb knee mechanics during walking and jogging compared with those with more symmetric hamstring strength at least 2 years after ACLR with a hamstring tendon autograft. Study Design: Controlled laboratory study. Methods: There were a total of 45 participants at least 2 years after ACLR (22 male, 23 female; mean time after ACLR, 34.6 months). A limb symmetry index (LSI) was calculated for isometric hamstring strength to subdivide the sample into symmetric hamstring (SH) (LSI ≥90%; n = 18) and asymmetric hamstring (AH) (LSI <85%; n = 18) groups. Involved knee kinematic and kinetic data were collected using 3-dimensional motion analysis during gait and jogging. Peak sagittal-, frontal-, and transverse-plane knee angles and sagittal-plane knee moments and knee powers were calculated. Independent-samples t tests and analyses of covariance were used to compare involved knee kinematic and kinetic variables between the groups. Results: There were no differences in sagittal- and frontal-plane knee angles between the groups ( P > .05 for all). The AH group demonstrated decreased tibial internal rotation during weight acceptance during gait ( P = .01) and increased tibial external rotation during jogging at initial contact ( P = .03) and during weight acceptance ( P = .02) compared with the SH group. In addition, the AH group demonstrated decreased peak negative knee power during midstance ( P = .01) during gait compared with the SH group, after controlling for gait speed, which differed between groups. Conclusion: Participants with hamstring strength asymmetry showed altered involved knee mechanics in the sagittal plane during gait and in the transverse plane during gait and jogging compared with those with more symmetric hamstring strength. Clinical Relevance: Hamstring strength asymmetry is common at 3 years after ACLR with a hamstring tendon autograft and affects involved knee mechanics during gait and jogging. Additional research is warranted to further investigate the longitudinal effect of these alterations on knee function and joint health after ACLR.