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Aims Galectin-3 is a prognostic heart failure (HF) biomarker that may mediate cardiac fibrosis. We examined the value of serial galectin-3 measurement for prognosis and response to therapy in chronic HF. Methods and results A total of 151 subjects with LV systolic dysfunction (LVSD) were followed through 908 visits over 10 ± 3 months. The amount of time spent with a galectin-3 level ≤ 20.0 ng/mL and changes between baseline and subsequent values were considered across visits, and used to assess risk for adverse cardiovascular (CV) events and associations with LV remodelling. Medication effects on galectin-3 were examined. Median galectin-3 values at baseline, 3 months, and 6 months were higher in patients with CV events (21.7 vs. 18.4 ng/mL, P = 0.03; 21.7 vs. 16.5 ng/mL, P = 0.03; 23.2 vs. 16.0 ng/mL, P = 0.007). Galectin-3 concentration changed in 35.2% of subjects during study procedures; time spent at ≤ 20.0 ng/mL was significantly associated with a lower rate of CV events, independently predicted fewer CV events even adjusted for relevant variables including study allocation, NT-proBNP, and renal function [odds ratio (OR) = 0.90; P = 0.05], and predicted increase in LV ejection fraction (OR = 1.20; P = 0.04). Serial galectin-3 measurement at 6 months added prognostic value beyond the baseline level (P = 0.02). There were no significant effects of medications on galectin-3 levels. Conclusion In chronic HF due to LVSD, serial galectin-3 measurement adds incremental prognostic information and predicts LV remodelling. In this study, HF therapies had no clear effects on galectin-3 levels. [ABSTRACT FROM AUTHOR]

Background Biomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)–positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node–negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole. Methods A prospective–retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided. Results High H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03). Conclusions In the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence. [ABSTRACT FROM PUBLISHER]

Abstract: Purpose: To present outcome and toxicity results of the first real-time intraoperative MRI-guided interstitial approach to gynecologic cancer. Methods and Materials: From February 2004 to December 2006, 25 patients with gynecologic malignancies were enrolled and treated in a prospective clinical trial of real-time MRI-guided interstitial brachytherapy. This was followed by a confirmatory CT imaging scan. Statistical analyses included Kaplan–Meier estimates for overall and relapse-free survival. Results: MRI visualization of needles during placement permitted accurate placement with no inadvertent insertions. This prevented unnecessary normal-tissue perforation as confirmed by CT simulation. With a mean followup of 3.8 years (range, 2–6.8), 1-, 2-, and 3-year overall survival rates were 80%, 60% and 43%, respectively; corresponding relapse-free survival rates were 79%, 65%, and 59%, respectively. Actuarial acute toxicity rates for any grade were 0% at 0–14 days and 80% (all grade 1) at 14–90 days. Long-term (>180 days) actuarial toxicity rates were 8% gastrointestinal, 4% bladder and 4% vaginal. Conclusions: Real-time MRI guidance during insertion of interstitial needles followed by 3D-planning maximized opportunities for tumor targeting and sparing of normal tissues. Although image guidance requires additional anesthesia time, clinical outcomes indicate potential for a successful reduction in toxicity using 3D image-guided in addition to 3D image-planned brachytherapy. [Copyright &y& Elsevier]

Background: Myxofibrosarcomas (MFS) are a historically heterogeneous group of tumors that exhibit a propensity for local recurrence. The objectives of this study were to analyze the prognostic factors and outcomes of patients with MFS treated at a single institution. Methods: We retrospectively reviewed the records of 69 consecutive patients with pathologically confirmed MFS of the extremities or superficial trunk who underwent surgery from August 1995 to November 2010. Clinicopathologic features, treatments, and patient outcomes were reviewed. Results: Sixty-nine patients were identified, of whom 38 were men (55 %). The median age was 62 years. Sixty-four patients (93 %) presented with primary tumors, and 5 patients (7 %) presented with locally recurrent tumors. Median tumor size was 6.0 cm, and 44 patients (64 %) had grade 3 tumors (FNCLCC [Fédération Nationale des Centres de Lutte Contre le Cancer] classification). Margins were microscopically positive in 14 patients (20 %) and negative in 55 patients (80 %), including close margins (<1 mm) in 14 patients (20 %). Fifty-three patients (77 %) received radiotherapy. At a median follow-up of 41 months, there were 11 local (16 %) and 11 distant (16 %) recurrences. The local and distant 5-year recurrence-free survival rates were 72 % and 82 %, and the 5-year overall survival was 61 %. Increased age (scaled by 0.1; hazard ratio [HR] 1.80, P = 0.002) and tumor size (HR 1.12, P = 0.004) were negatively correlated with overall survival. Positive/close (<1 mm) margin status (HR 4.34, P = 0.030) predicted worsened local recurrence-free survival. Conclusions: MFS exhibit a propensity for local recurrence, which is predicted by resection with positive or close margins. Aggressive surgery combined with radiotherapy may contribute to more effective local control. [ABSTRACT FROM AUTHOR]

Background: Desmoid tumors are rare and exhibit a highly unpredictable natural history. We sought to analyze prognostic factors associated with recurrence in a large single-institution study of patients with desmoid tumors. Methods: We performed a retrospective review of 177 patients with desmoid tumor who underwent macroscopically complete surgical resection, with or without the addition of radiotherapy (RT) or systemic therapy, from 1970 to 2009. We examined patterns of presentation, all known risk factors for recurrence, and their association with recurrence-free survival (RFS). Results: Twenty-two patients (12 %) had intra-abdominal desmoid tumors, and 155 (88 %) had extra-abdominal tumors. Patterns of presentation included primary ( n = 133, 75 %) and locally recurrent ( n = 44, 25 %) disease. Treatment was surgery alone in 125 patients (71 %), surgery and RT in 36 (20 %), and surgery and systemic therapy with or without RT in 20 (11 %). Median follow-up was 40 months. Overall, the local relapse rate was 29 %, and 10-year RFS was 60 %. R0 resection status was the only predictor of freedom from local recurrence on multivariate analysis (odds ratio 0.32; 95 % confidence interval 0.15-0.66; P = 0.002). The selective use of adjuvant RT appeared to improve local control in patients with positive margins. Conclusions: For patients with desmoid tumors undergoing surgery, wide excision with negative margins should be the goal, but not at the expense of function, as fewer than half of patients with positive margins will experience recurrence. [ABSTRACT FROM AUTHOR]

Introduction: Strength measures with reduced variability and higher sensitivity could improve efficiency in clinical trials of amyotrophic lateral sclerosis (ALS). The Accurate Test of Limb Isometric Strength (ATLIS) was developed to precisely and conveniently measure force in 12 muscle groups. In this study we evaluate the reliability and validity of the ATLIS testing protocol. Methods: Twenty healthy adults and 10 patients with ALS were tested twice by the same or by different evaluators to determine test-retest and interrater reliability. Twenty healthy adults were examined using ATLIS and a well-validated strength testing protocol (TQNE) to assess criterion-based validity. Results: Mean absolute variation between tests was 8.6%, and intraclass correlation coefficients for each muscle group were high (range 0.82-0.99). The Pearson correlation coefficient of mean ATLIS and TQNE scores was 0.90. A subject survey demonstrated high user acceptance of ATLIS. Conclusions: ATLIS is convenient for patients and evaluators, produces precise strength measurements, and is easily moved between examining rooms. Muscle Nerve 45: 81-85, 2012 [ABSTRACT FROM AUTHOR]

Background aims. Immunotherapy targeting MAGE-A3 in multiple myeloma (MM) could eradicate highly aggressive and proliferative clonal cell populations responsible for relapse. However, expression of many cancer-testis antigens, including MAGE-A3, can be heterogeneous, leading to the potential for tumor escape despite MAGE-A3-induced immunity. We hypothesized that a combination of the hypomethylating agent 5-azacitidine (5AC) and the histone deacetylase inhibitor (HDACi) MGCD0103 (MGC) could induce MAGE-A3 expression in MAGE-A3-negative MM, resulting in recognition and killing of MM cells by MAGE-A3-specific cytotoxic T lymphocytes (CTL). Methods. Gene expression analyses of MAGE-A3 expression in primary MM patient samples at diagnosis and relapse were completed to identify populations that would benefit from MAGE-A3 immunotherapy. MM cell lines were treated with 5AC and MGC. Real-time polymerase chain reaction (PCR) and Western blotting were performed to assess MAGE-A3 RNA and protein levels, respectively. Chromium-release assays and interferon (IFN) secretion assays were employed to ascertain MAGE-A3 CTL specificity against treated targets. Results. Gene expression analysis revealed that MAGE-A3 is expressed in MM patients at diagnosis (25%) and at relapse (49%). We observed de novo expression of MAGE-A3 RNA and protein in MAGE-A3-negative cell lines treated with 5AC. MGC treatment alone did not induce expression but sequential 5AC/MGC treatment led to enhanced expression and augmented recognition by MAGE-A3-specific CTL, as assessed by 51Cr-release assays ( P == 0.047) and enzyme-linked immunosorbent assay (ELISA) for IFN-γγ secretion ( P == 0.004). Conclusions. MAGE-A3 is an attractive target for immunotherapy of MM and epigenetic modulation by 5AC, and MGC can induce MAGE-A3 expression and facilitate killing by MAGE-A3-specific CTL. [ABSTRACT FROM AUTHOR]

BACKGROUND: Myeloma survival varies markedly with International Staging System classification, presence of cytogenetic abnormalities, and, especially, gene expression profiling-based risk and delTP53 status, whose collective impact has not been examined in the context of specific therapies. METHODS: The authors examined overall survival (OS), event-free survival (EFS), and complete response duration (CRD) in Total Therapy 2 with randomization to a control or thalidomide arm and in Total Therapy 3 with added bortezomib. Among 612 patients with complete data sets, multivariate analyses were used to investigate the relative contributions to OS, EFS, and CRD of International Staging System stage, cytogenetic abnormalities, and gene expression profiling-derived risk and delTP53 status, in the context of the 3 Total Therapy regimens. RESULTS: Whereas gene expression profiling risk segregated outcomes within all 3 International Staging System stages, International Staging System 3 conferred inferior prognosis only in low-risk myeloma, whereas the grave prognosis of high-risk disease was International Staging System-independent. After adjusting for gene expression profiling-defined high risk and delTP53 in multivariate analysis, International Staging System 3 and cytogenetic abnormalities both retained independent adverse implications for OS, EFS, and CRD. Among the 86% with low-risk disease, cytogenetic abnormalities and delTP53 both affected all 3 endpoints negatively, whereas the International Staging System 3 effect was limited to OS. Total Therapy 3 improved survival outcomes beyond results obtained with Total Therapy 2. CONCLUSIONS: In the genomic era, standard laboratory variables, such as International Staging System stage and presence of cytogenetic abnormalities, continue to impact survival after adjusting for gene expression profiling risk and delTP53 status, providing a basis for stratification in our current practice of gene expression profiling risk-based treatment assignment. [ABSTRACT FROM AUTHOR]

Background: Total hip replacement (THR)/total knee replacement (TKR) studies do not uniformly measure patient centered domains, pain, and function. We aim to validate existing measures of pain and function within subscales of standard instruments to facilitate measurement.Methods: We evaluated baseline and 2-year pain and function for THR and TKR using Hip disability and Osteoarthritis Outcome Score (HOOS)/Knee Injury and Osteoarthritis Outcome Score (KOOS), with primary unilateral TKR (4796) and THR (4801). Construct validity was assessed by correlating HOOS/KOOS pain and activities of daily living (ADL), function quality of life (QOL), and satisfaction using Spearman correlation coefficients. Patient relevant thresholds for change in pain and function were anchored to improvement in QOL; minimally clinically important difference (MCID) corresponded to "a little improvement" and a really important difference (RID) to a "moderate improvement." Pain and ADL function scores were compared by quartiles using Kruskal-Wallis.Results: Two-year HOOS/KOOS pain and ADL function correlated with health-related QOL (KOOS pain and Short Form 12 Physical Component Scale ρ = 0.54; function ρ = 0.63). Comparing QOL by pain and function quartiles, the highest levels of pain relief and function were associated with the most improved QOL. MCID for pain was estimated at ≥20, and the RID ≥29; MCID for function ≥14, and the RID ≥23. The measures were responsive to change with large effect sizes (≥1.8).Conclusion: We confirm that HOOS/KOOS pain and ADL function subscales are valid measures of critical patient centered domains after THR/TKR, and achievable thresholds anchored to improved QOL. Cost-free availability and brevity makes them feasible, to be used in a core measurement set in total joint replacement trials. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: By virtue of its proximity to structures vital to cardiac conduction, aortomitral continuity calcification (AMCC) may help identify patients at highest risk for developing atrioventricular conduction disease requiring permanent pacemaker implantation (PPMI). We aim to determine the association of AMCC and need for PPMI after transcatheter aortic valve replacement. Methods: Of 614 patients who underwent transcatheter aortic valve replacement (11.8% PPMI rate), we included 136 patients (age 85±8 years, 47% male) without a preexisting intracardiac device or prior valve surgery who underwent preprocedural computed tomography. We analyzed for the presence of AMCC, aortic valve calcification, and mitral annular calcification as well as quantified AMCC and aortic valve calcification score using the Agatston method. We further stratified AMCC score into 3 categories: 0, 1 to 300, and >300. End point was PPMI at 1 month after transcatheter aortic valve replacement. Results: There were 51 (38%) new PPMIs (median time to PPMI, 5 days). Patients who underwent PPMI had a higher prevalence of AMCC than patients without PPMI (69% versus 32%; P <0.0001), as well as higher median AMCC score (263 versus 0; P <0.0001). There was no difference in aortic valve calcification and mitral annular calcification between patients with and without PPMI (all P ≥0.09). Patients with AMCC had a 4-fold increase in odds for PPMI compared with those without (adjusted odds ratio, 4.0; P =0.0026). Compared with patients with an AMCC score of 0, patients with an AMCC score >300 had greater than a 5-fold increased odds for PPMI (adjusted odds ratio, 5.7; P =0.0016). Conclusions: Presence of AMCC, particularly with AMCC score >300, is associated with the need for PPMI after transcatheter aortic valve replacement. [ABSTRACT FROM AUTHOR]

Background: Patients with inflammatory arthritis (IA) are at increased risk of prosthetic joint infections (PJI), yet differentiating between septic and aseptic failure is a challenge. The aim of our systematic review is to evaluate synovial biomarkers and their efficacy at diagnosing PJI in patients with IA.Methods: A comprehensive literature search was performed in the following databases from inception to January 2018: Ovid MEDLINE, Ovid EMBASE, and the Cochrane Library. Searches across the databases retrieved 367 results. Two of 5 reviewers independently screened a total of 298 citations. Discrepancies were resolved by a third reviewer. Twenty articles fit our criteria, but due to methodological differences findings could not be pooled for meta-analysis. For 5 studies, raw data were provided, pooled, and used to derive optimal diagnostic cut points.Results: Our final analysis included 1861 non-IA patients, including 426 patients with PJI, and 90 IA patients of whom 26 had PJI. There was a significant difference among the 4 groups for serum C-reactive protein (CRP), erythrocyte sedimentation rate, and synovial CRP, polymorphonuclear neutrophil percent, white blood cells, interleukin (IL)-6, IL-8, and IL-1b. Polymorphonuclear neutrophil percent had the highest sensitivity (95.2%) and specificity (85.0%) to detect infections with an optimum threshold of 78%.Conclusion: While levels of synovial white blood cells, IL-6, IL-8, and serum CRP appear higher in patients with IA, there is overlap with those who are not infected. Further studies are needed to explore diagnostic tests that will better detect PJI in patients with IA. [ABSTRACT FROM AUTHOR]

Background: Community characteristics such as poverty affect total knee arthroplasty (TKA) outcomes. However, it is unknown whether other community factors such as immigrant proportion (IP) also affect outcomes. Our objective was to determine the association of neighborhood IP on preoperative (pre-op) and 2-year postoperative (post-op) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function after elective TKA.Methods: Patients in a high volume institutional TKA registry between May 2007 and February 2011 were retrospectively analyzed. Demographics, pre-op and 2-year post-op WOMAC pain and function scores, and geocodable addresses were obtained. Patient-level variables were linked to US Census Bureau census tract data. The effect of patient and neighborhood-level factors on WOMAC scores were analyzed using linear mixed effects models.Results: 3898 TKA patients were analyzed. Pre-op and 2-year post-op WOMAC pain and function scores were between 2.75-4.88 WOMAC points worse in neighborhoods with a high IP (≥ 40%) compared to low IP (< 10%). In multivariable analyses, these differences were not statistically significant. Women had worse pre-op and 2-year post-op WOMAC scores (all p ≤ 0.04), but this difference was not influenced by neighborhood IP (all pinteraction NS).Conclusions: Patients living in high (≥40%) IP neighborhoods do not have worse pre-op or 2-year post-op pain and function outcomes after TKA compared to those living in low (< 10%) IP neighborhoods. Although sex differences favoring males are notable, these differences are not associated with IP. High neighborhood IP do not appear to affect outcomes after TKA. [ABSTRACT FROM AUTHOR]

Introduction: Regression of ECG left ventricular hypertrophy (LVH) with blood pressure (BP) lowering therapy is associated with reduced cardiovascular (CV) events. It is unknown whether this association applies in patients with diabetes. Hypothesis: To evaluate the association between ECG Cornell voltage and CV outcomes in patients with diabetes undergoing BP lowering therapy. Methods: This is a post hoc analysis of 4,006 participants with baseline ECGs from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial BP study. Participants were randomized to intensive BP control (goal systolic BP <120 mmHg) or standard BP control (goal <140 mmHg). LVH was calculated using Cornell voltage (R amplitude aVL+ S amplitude lead V3). On-treatment Cornell voltage was examined as both a continuous and dichotomized time-varying covariate in univariate and multivariable Cox models. Hazard ratios (HR) were calculated for a primary composite outcome (first occurrence of CV death, nonfatal MI, or stroke) and for individual CV outcomes. Results: Mean age for the cohort was 62.4±6.5 years, 49.4% were female, 58.5% White, 23.8% Black, and 7.0% Hispanic. Mean BMI was 32.2±5.5 kg/m2 and mean Cornell voltage was 1453.3±548.6 μV. During a mean 5.6 years follow-up, multivariable Cox regression analysis (adjusted for common CV risk factors and randomized arm) demonstrated that higher time-varying Cornell voltage was significantly associated with an increased risk of the primary outcome, whether treated as a continuous (HR 1.24, 95% CI 1.12-1.37, p<0.001) or dichotomous variable (HR 1.60, 95%CI 1.28-1.99, p<0.001 for quartile 4 versus the bottom 3 quartiles), with similar results for individual CV outcomes and all-cause mortality (Table). Conclusions: In patients with diabetes on BP lowering therapy, higher on-treatment ECG Cornell voltage was a strong predictor of CV morbidity and mortality even after adjusting for randomized BP arm and other predictors of CV outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Background: Timing of administration of adjuvant chemoradiation (CRT) for pancreatic cancer has varied across studies. To date, the impact of timing of adjuvant CRT on long-term outcomes has not been evaluated. This study evaluates the effect of timing of adjuvant CRT on locoregional control (LRC) and overall survival (OS). Methods and Materials: We performed a review of 159 patients with resected pancreatic adenocarcinoma who received adjuvant CRT between 1998 and 2010. Median dose of CRT was 50.4 Gy. The primary study variable was timing of CRT, dichotomized as immediate CRT versus delayed CRT. Consistent with Radiation Therapy Oncology Group (RTOG) 9704, immediate chemoradiation was defined as after ≤1 cycle of chemotherapy, whereas delayed CRT was defined as after >1 cycle. Cox multivariate analysis (MVA) was performed. Results: Median follow-up was 55 months. Seventy-four percent of patients received immediate CRT, and 26% patients received delayed CRT. Patients treated with delayed CRT were more likely to receive adjuvant gemcitabine (100% vs 53%; P < .001). Timing of adjuvant CRT was not associated with LRC or OS on univariate or MVA. Preoperative carcinoembryonic antigen ≥1.3 ng/mL (hazard ratio, 3.18; P = .017) and positive margins (hazard ratio, 5.35; P < .001) were associated with lower rates LRC on MVA. Higher lymph node positivity ratio and not receiving adjuvant gemcitabine were independently associated with worse OS. Conclusions: Timing of adjuvant CRT for resectable pancreatic cancer may not significantly affect LRC or OS. These findings support the ongoing RTOG 0848 trial design, and provide reassurance that delaying CRT until completion of chemotherapy should not significantly impact LRC. [Copyright &y& Elsevier]

Abstract: Purpose: To determine the prevalence and significance of incidental, subcentimeter hepatic lesions in patients with a new diagnosis of pancreatic cancer. Materials and Methods: This Institutional Review Board-approved retrospective study included 101 patients [45% men, median age 63 years (34-85)] treated for localized pancreatic adenocarcinoma at Brigham and Women''s Hospital and Dana Farber Cancer Institute from January 1999 to December 2007. Initial staging and follow-up computed tomographic scans were reviewed to determine the frequency of liver lesions that were initially too small to characterize and later proved to be metastases. Clinical variables known to be prognostic for patients with pancreatic cancer were also recorded. Using Cox regression, we calculated adjusted hazard ratios to determine the association between presence of liver lesions and overall survival. Results: A total of 31 patients (30.7%) had subcentimeter hepatic lesions on staging scans. Of these patients, 21 (20.7% of total, 67.7% of patients with lesions) had eventual metastases to the liver. Finally, of this group, 5 patients (5.0% of total, 16.1% of patients with lesions) eventually had a metastatic focus at the specific site of the original lesion. Liver lesions predicted the occurrence of metastatic disease to the liver compared with patients without lesions (67.7% with lesions vs 44.4% without, P = .034). The presence of subcentimeter liver lesions at diagnosis was significantly associated with reduced overall survival (hazard ratio 1.65; 95% confidence interval 1.03-2.64, P = .036). Conclusions: Subcentimeter lesions in the liver are common in patients with a new diagnosis of pancreatic cancer. Approximately 16% of these lesions represent metastases. The presence of indeterminate liver lesions may be associated with reduced overall survival. [Copyright &y& Elsevier]

Background Despite the benefit of CRT in select patients with heart failure (HF), there remains significant need for predicting those at risk for adverse outcomes for this effective but costly therapy. CysC, an emerging marker of renal function, is predictive of worsening symptoms and mortality in patients with HF. This study assessed the utility of baseline and serial measures of cystatin C (CysC), compared to conventional creatinine-based measures of renal function (estimated glomerular filtration rate, eGFR), in predicting clinical outcomes following cardiac resynchronization therapy (CRT). Methods In 133 patients, we measured peripheral venous (PV) and coronary sinus (CS) CysC concentrations and peripheral creatinine levels at the time of CRT implant. Study endpoints included clinical response to CRT at 6 months and major adverse cardiac events (MACE) at 2 years. Results While all 3 renal metrics were predictive of MACE (all adjusted p ≤ 0.02), only CysC was associated with CRT non-response at 6 months (adjusted odds ratio 3.6, p = 0.02). CysC improved prediction of CRT non-response (p ≤ 0.003) in net reclassification index analysis compared to models utilizing standard renal metrics. Serial CysC > 1 mg/L was associated with 6-month CRT non-response and reduced 6-minute walk distance as well as 2-year MACE (all p ≤ 0.04). Conclusion In patients undergoing CRT, CysC demonstrated incremental benefit in the prediction of CRT non-response when compared to standard metrics of renal function. Baseline and serial measures of elevated CysC were predictive of CRT non-response and functional status at 6 months as well as long-term clinical outcomes. [ABSTRACT FROM AUTHOR]

Background Radiotherapy can impair Health Related Quality of Life (HRQoL) in survivors of childhood brain tumors, but proton radiotherapy (PRT) may mitigate this effect. This study compares HRQoL in PRT and photon (XRT) pediatric brain tumor survivors. Methods HRQoL data were prospectively collected on PRT-treated patients aged 2–18 treated at Massachusetts General Hospital (MGH). Cross-sectional PedsQL data from XRT treated Lucile Packard Children’s Hospital (LPCH) patients provided the comparison data. Results Parent proxy HRQoL scores were reported at 3 years for the PRT cohort (PRT-C) and 2.9 years (median) for the XRT cohort (XRT-C). The total core HRQoL score for the PRT-C, XRT-C, and normative population differed from one another and was 75.9, 65.4 and 80.9 respectively ( p = 0.002; p = 0.024; p < 0.001). The PRT-C scored 10.3 and 10.5 points higher than the XRT-C in the physical (PhSD) and psychosocial (PsSD) summary domains of the total core score (TCS, p = 0.015; p = 0.001). The PRT-C showed no difference in PhSD compared with the normative population, but scored 6.1 points less in the PsSD ( p = 0.003). Compared to healthy controls, the XRT-C scored lower in all domains ( p < 0.001). Conclusions The HRQoL of pediatric brain tumor survivors treated with PRT compare favorably to those treated with XRT and similar to healthy controls in the PhSD. [ABSTRACT FROM AUTHOR]

Background: Environmental exposures account for a growing proportion of global mortality. Large cohort studies are needed to characterize the independent impact of environmental exposures on mortality in low-income settings. Methods: We collected data on individual and environmental risk factors for a multiethnic cohort of 50,045 individuals in a low-income region in Iran. Environmental risk factors included: ambient fine particular matter air pollution; household fuel use and ventilation; proximity to traffic; distance to percutaneous coronary intervention (PCI) center; socioeconomic environment; population density; local land use; and nighttime light exposure. We developed a spatial survival model to estimate the independent associations between these environmental exposures and all-cause and cardiovascular mortality. Findings: Several environmental factors demonstrated associations with mortality after adjusting for individual risk factors. Ambient fine particulate matter air pollution predicted all-cause mortality (per μg/m3, HR 1.20, 95% CI 1.07, 1.36) and cardiovascular mortality (HR 1.17, 95% CI 0.98, 1.39). Biomass fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.23, 95% CI 0.99, 1.53) and cardiovascular mortality (HR 1.36, 95% CI 0.99, 1.87). Kerosene fuel use without chimney predicted all-cause mortality (reference = gas, HR 1.09, 95% CI 0.97, 1.23) and cardiovascular mortality (HR 1.19, 95% CI 1.01, 1.41). Distance to PCI center predicted all-cause mortality (per 10km, HR 1.01, 95% CI 1.004, 1.022) and cardiovascular mortality (HR 1.02, 95% CI 1.004, 1.031). Additionally, proximity to traffic predicted all-cause mortality (HR 1.13, 95% CI 1.01, 1.27). In a separate validation cohort, the multivariable model effectively predicted both all-cause mortality (AUC 0.76) and cardiovascular mortality (AUC 0.81). Population attributable fractions demonstrated a high mortality burden attributable to environmental exposures. Interpretation: Several environmental factors predicted cardiovascular and all-cause mortality, independent of each other and of individual risk factors. Mortality attributable to environmental factors represents a critical opportunity for targeted policies and programs. [ABSTRACT FROM AUTHOR]

Objective To identify individual-level factors associated with hospital readmission among individuals with SSc-associated pulmonary hypertension (SSc-PH). Methods Individuals enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) registry contributed clinical data related to SSc-PH disease severity and hospital admissions. Readmission was defined as a subsequent hospitalization within 12 months of any hospital discharge. Characteristics were compared between individuals with and without readmissions using Fisher's exact test, Wilcoxon rank-sum test, or Kruskal–Wallis test. Logistic regression was used to estimate associations between clinical predictors and likelihood of readmission. Results Of 572 individuals with SSc-PH enrolled in PHAROS, 54% had ≥1 hospitalizations between 2005 and 2016. Among individuals ever-hospitalized, 34% had ≥1 readmission. Individuals with vs without readmissions had shorter median (IQR) time between index hospitalization date and next PHAROS visit [37 (3, 80) vs 81 (42, 136) days, P <0.001]. Index admissions related to PH or SSc (vs non-PH/SSc related) were associated with an increased odds of 12-month readmission [aOR 6.6 (95% CI 3.2, 13.6) and aOR 2.2 (95% CI 1.1, 4.5), respectively]. Readmission was less likely among home oxygen users (vs non-users) (aOR 0.44; 95% CI 0.22, 0.89). Race, age, sex, disease duration and disease subtype were not associated with readmission. Conclusion The strongest predictor for 12-month readmission was an index hospitalization reason related to PH. Home oxygen use was associated with lower odds of readmission. Future studies should determine whether testing for the need for home oxygen mediates the risk of readmission in SSc-PH. [ABSTRACT FROM AUTHOR]

BACKGROUND Early identification of mutations may guide patients with metastatic colorectal cancer toward targeted therapies that may be life prolonging. The authors assessed tumor genotype correlations with clinical characteristics to determine whether mutational profiling can account for clinical similarities, differences, and outcomes. METHODS Under Institutional Review Board approval, 222 patients with metastatic colon adenocarcinoma (n = 158) and rectal adenocarcinoma (n = 64) who underwent clinical tumor genotyping were reviewed. Multiplexed tumor genotyping screened for >150 mutations across 15 commonly mutated cancer genes. The chi-square test was used to assess genotype frequency by tumor site and additional clinical characteristics. Cox multivariate analysis was used to assess the impact of genotype on overall survival. RESULTS Broad-based tumor genotyping revealed clinical and anatomic differences that could be linked to gene mutations. NRAS mutations were associated with rectal cancer versus colon cancer (12.5% vs 0.6%; P < .001) and with age ≥56 years (7% vs 0.9%; P = .02). Conversely, v-raf murine sarcoma viral oncogene homolog B ( BRAF) mutations were associated with colon cancer (13% vs 3%; P = .024) and older age (15.8% vs 4.6%; P = .006). TP53 mutations were associated with rectal cancer (30% vs 18%; P = .048), younger age (14% vs 28.7%; P = .007), and men (26.4% vs 14%; P = .03). Lung metastases were associated with PIK3CA mutations (23% vs 8.7%; P = .004). Only mutations in BRAF were independently associated with decreased overall survival (hazard ratio, 2.4; 95% confidence interval, 1.09-5.27; P = .029). CONCLUSIONS The current study suggests that underlying molecular profiles can differ between colon and rectal cancers. Further investigation is warranted to assess whether the differences identified are important in determining the optimal treatment course for these patients. Cancer 2014;120:1482-1490. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: With sacubitril/valsartan treatment, B-type natriuretic peptide (BNP) concentrations increase; it remains unclear whether change in BNP concentrations is similar across all assays for its measurement. Effects of sacubitril/valsartan on atrial natriuretic peptide (ANP) concentrations in patients are unknown. Lastly, the impact of neprilysin inhibition on mid-regional pro-ANP (MR-proANP), N-terminal pro-BNP (NT-proBNP), proBNP1-108, or C-type natriuretic peptide (CNP) is not well understood.Objectives: This study sought to examine the effects of sacubitril/valsartan on results from different natriuretic peptide assays.Methods: Twenty-three consecutive stable patients with heart failure and reduced ejection fraction were initiated and titrated on sacubitril/valsartan. Change in ANP, MR-proANP, BNP (using 5 assays), NT-proBNP (3 assays), proBNP1-108, and CNP were measured over 3 visits.Results: Average time to 3 follow-up visits was 22, 46, and 84 days. ANP rapidly and substantially increased with initiation and titration of sacubitril/valsartan, more than doubling by the first follow-up visit (+105.8%). Magnitude of ANP increase was greatest in those with concentrations above the median at baseline (+188%) compared with those with lower baseline concentrations (+44%); ANP increases were sustained. Treatment with sacubitril/valsartan led to inconsistent changes in BNP, which varied across methods assessed. Concentrations of MR-proANP, NT-proBNP, and proBNP1-108 variably declined after treatment; whereas CNP concentrations showed no consistent change.Conclusions: Initiation and titration of sacubitril/valsartan led to variable changes in concentrations of multiple natriuretic peptides. These results provide important insights into the effects of sacubitril/valsartan treatment on individual patient results, and further suggest the benefit of neprilysin inhibition may be partially mediated by increased ANP concentrations. [ABSTRACT FROM AUTHOR]

Hemophilic arthropathy (HA) is a debilitating degenerative joint disease that is a major manifestation of the bleeding disorder hemophilia A. HA typically begins with hemophilic synovitis that resembles inflammatory arthritides, such as rheumatoid arthritis, and frequently results in bone loss in patients. A major cause of rheumatoid arthritis is inappropriate release of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) by the TNF-α convertase (TACE; also referred to as ADAM17) and its regulator, iRhom2. Therefore, we hypothesized that iRhom2/ADAM17-dependent shedding of TNF-α also has a pivotal role in mediating HA. Here, we show that addition of blood or its components to macrophages activates iRhom2/ADAM17-dependent TNF-α shedding, providing the premise to study the activation of this pathway by blood in the joint in vivo. For this, we turned to hemophilic FVIII-deficient mice (F8-/- mice), which develop a hemarthrosis following needle puncture injury with synovial inflammation and significant osteopenia adjacent to the affected joint. We found that needle puncture-induced bleeding leads to increased TNF-α levels in the affected joint of F8-/- mice. Moreover, inactivation of TNF-α or iRhom2 in F8-/- mice reduced the osteopenia and synovial inflammation that develops in this mouse model for HA. Taken together, our results suggest that blood entering the joint activates the iRhom2/ADAM17/TNF-α pathway, thereby contributing to osteopenia and synovitis in mice. Therefore, this proinflammatory signaling pathway could emerge as an attractive new target to prevent osteoporosis and joint damage in HA patients. [ABSTRACT FROM AUTHOR]

Objective: To assess the safety and efficacy of treatment with belimumab in patients with early diffuse cutaneous systemic sclerosis (dcSSc) treated with background mycophenolate mofetil (MMF). Methods: In this 52‐week, investigator‐initiated, single‐center, double‐blind, placebo‐controlled, pilot study, 20 patients with dcSSc recently started on MMF were randomized 1:1 to additionally receive belimumab at 10 mg/kg intravenously or placebo. We assessed safety, efficacy, and differential gene expression. Results: In the belimumab group, the median modified Rodnan skin thickness score (MRSS) decreased from 27 (interquartile range [IQR] 26.5, 31) to 18 (IQR 11, 23) (P = 0.039). In the placebo group, the median MRSS decreased from 28 (IQR 22, 28) to 21 (IQR 14, 25) (P = 0.023). The median change in MRSS was –10 (IQR –13, –9) in the belimumab group and –3.0 (IQR –15, –1) in the placebo group (P = 0.411). There were no significant differences between the groups in the number of adverse events (AEs). A significant decrease in expression of B cell signaling and profibrotic genes and pathways was observed in patients with improved MRSS in the belimumab group but not in the placebo group. Conclusion: Patients in both treatment groups experienced significant improvements in MRSS. The median difference was greater in the belimumab group but did not achieve statistical significance in this small pilot study. AEs were similar between the groups. Changes in gene expression were consistent with mechanism of action and showed that clinical response to treatment with belimumab is associated with a significant decrease in profibrotic genes and pathways. Additional studies are needed to determine the role of belimumab in the treatment of dcSSc. [ABSTRACT FROM AUTHOR]

Background and aims Coronary computed tomography angiography (CCTA) permits effective identification of diffuse CAD and atherosclerotic plaque characteristics (APCs). We sought to examine the usefulness of diffuse CAD beyond luminal narrowing and APCs by CCTA to detect vessel-specific ischemia. Methods 407 vessels (n = 252 patients) from the DeFACTO diagnostic accuracy study were retrospectively analyzed for percent plaque diffuseness (PD). Percent plaque diffuseness (PD) was obtained on per-vessel level by summation of all contiguous lesion lengths and divided by total vessel length, and was logarithmically transformed (log percent PD). Additional CCTA measures of stenosis severity including minimal lumen diameter (MLD), and APCs, such as positive remodeling (PR) and low attenuation plaque (LAP), were also included. Vessel-specific ischemia was defined as fractional flow reserve (FFR) ≤0.80. Multivariable regression, discrimination by area under the receiver operating characteristic curve (AUC), and category-free net reclassification improvement (cNRI) were assessed. Results Backward stepwise logistic regression revealed that for every unit increase in log percent PD, there was a 58% (95% CI: 1.01–2.48, p = 0.048) rise in the odds of having an abnormal FFR, independent of stenosis severity and APCs. The AUC indicated no further improvement in discriminatory ability after adding log percent PD to the final parsimonious model of MLD, PR, and LAP (AUC difference: 0.003, 95% CI: −0.003–0.010, p = 0.33). Conversely, adding log percent PD to the base model of MLD, PR, and LAP improved cNRI by 0.21 (95% CI: 0.01–0.41, p < 0.001). Conclusions Accounting for diffuse CAD may help improve the accuracy of CCTA for detecting vessel-specific ischemia. [ABSTRACT FROM AUTHOR]

BACKGROUND Histologic response to chemotherapy has been shown to be an independent prognostic factor in patients with osteosarcoma and Ewing sarcoma. However, in patients with soft tissue sarcoma (STS), the prognostic impact of histologic response to chemotherapy is less clear. In the current study, the authors sought to determine the prognostic significance of treatment-induced pathologic necrosis in patients receiving neoadjuvant chemoradiotherapy for STS. METHODS Between 1989 and 2011, a total of 113 patients with grade 2 or 3 (graded according to the National Cancer Institute grading system using 3 tiers) extremity or truncal STS were identified who received neoadjuvant interdigitated chemoradiotherapy according to protocol followed by surgery. The extent of tumor necrosis in the resected specimens was quantified and correlated with outcome. RESULTS The median tumor necrosis rate was 90%, and 103 patients (91%) received all 3 cycles of planned neoadjuvant chemotherapy. The likelihood of achieving ≥95% necrosis was not related to the number of preoperative cycles of chemotherapy received but was found to be related to tumor histology (62% for malignant fibrous histiocytoma vs 0% for synovial sarcoma [ P<.001]; 56% for myxoid liposarcoma vs 0% for synovial sarcoma [ P = .002]). At a median follow-up of 6 years, there were no statistically significant differences noted in the 5-year local control, disease-specific survival, and overall survival rates for patients with ≥95% necrosis (50 patients; 44%) and <95% necrosis (63 patients; 56%), even when stratifying by histology. CONCLUSIONS In a homogeneous population of patients with high-grade extremity and truncal STS who were treated with neoadjuvant chemoradiotherapy, the extent of pathologic tumor necrosis did not correlate with outcome. Cancer 2014;120:3676-3682. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]