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Background: Primary care physicians (PCPs) are often gatekeepers to specialist care. This study assessed the relationship between PCP density and total knee (TKA) and total hip arthroplasty (THA) outcomes., Methods: We obtained patient-level data from an institutional registry on patients undergoing elective primary TKA and THA for osteoarthritis, including Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function scores at baseline and 2 years. Using geocoding, we identified the number of PCPs in the patient's census tract (communities). We used Augmented Inverse Probability Weighting and Cross-validated Targeted Minimum Loss-Based Estimation to compare provider density and outcomes adjusting for potential confounders., Results: Our sample included 3606 TKA and 4295 THA cases. The median number of PCPs in each community was similar for both procedures: TKA 2 (interquartile range 1, 6) and for THA 2 (interquartile range 1, 7). Baseline and 2-year follow-up WOMAC pain, function, and stiffness scores were not statistically significantly different comparing communities with more than median number of PCPs to those with less than median number of PCPs. In sensitivity analyses, adding 1 PCP to a community with zero PCPs would not have statistically significantly improved baseline or 2-year follow-up WOMAC pain, function, and stiffness scores., Conclusions: In this sample of patients who underwent elective TKA or THA for osteoarthritis, we found no statistically significant association between PCP density and pain, function, or stiffness outcomes at baseline or 2 years. Further studies should examine what other provider factors affect access and outcomes in THA and TKA., (© 2021 The Authors.)

Background: Cardiorenal syndrome comprises a heterogeneous group of disorders characterized by acute or chronic cardiac and renal dysfunction., Objective: The purpose of this study was to determine the effect of cardiorenal status using a dual-marker strategy with amino-terminal pro-brain natriuretic peptide (NT-proBNP) and cystatin C on cardiac resynchronization therapy (CRT) outcomes., Methods: In 92 patients (age 66 ± 13 years; 80% male; left ventricular ejection fraction 26% ± 7%), NT-proBNP and cystatin C levels were measured at CRT implantation and at 1 month. NT-proBNP >1000 pg/mL and cystatin C >1 mg/L were considered high. Baseline cardiorenal patients were defined as having high NT-proBNP and cystatin C. At 1 month, CRT patients were categorized as (1) irreversible cardiorenal if cystatin C was persistently high; (2) progressive cardiorenal with transition from low to high cystatin C; (3) reversible cardiorenal with transition from high to low cystatin C; and (4) "normal" with stable low cystatin C. Outcomes were 6-month clinical and echocardiographic CRT response and 2 -year major adverse cardiovascular event (MACE)., Results: Compared to patients with low NT-proBNP and cystatin C, cardiorenal patients had >9-fold increase risk of CRT nonresponse (odds ratio uncompensated 9.0; compensated 36.4; both P ≤.004) and >6-fold risk of MACE (hazard ratio uncompensated 8.5; P = .005). Compared to "normal" and reversible patients (referent), irreversible patients had a 9-fold increase for CRT nonresponse (odds ratio 9.1; P <.001) and had >4-fold risk of MACE (adjusted hazard ratio 5.1; P <.001). Irreversible patients were most likely echocardiographic CRT nonresponders., Conclusion: Cardiorenal status by NT-proBNP and cystatin C can identify high-risk CRT patients, and those with both elevated concentrations have worse prognosis., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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., (© 2018 by The American Society of Hematology.)

Background: Dual-source computed tomography (CT) can evaluate left ventricular (LV) dyssynchrony, myocardial scar, and coronary venous anatomy in patients undergoing cardiac resynchronization therapy (CRT)., Objective: We aimed to determine whether dual-source CT predicts clinical CRT outcomes and reduces intraprocedural time., Methods: In this prospective study, 54 patients scheduled for CRT (mean age 63 ± 11 years; 74% men) underwent preprocedural CT to assess their venous anatomy as well as CT-derived dyssynchrony metrics and myocardial scar. Based on 1:1 randomization, the implanting physician had preimplant knowledge of the venous anatomy in half the patients. In blinded analyses, we measured time to maximal wall thickness and inward wall motion to determine (1) CT global and segmental dyssynchrony and (2) concordance of lead location to regional LV mechanical contraction. End points were 6-month CRT response measured using heart failure clinical composite score and 2-year major adverse cardiac events (MACE)., Results: There were 72% CRT responders and 17% with MACE. Two wall motion dyssynchrony indices-global wall motion and opposing anteroseptal-inferolateral wall motion-predicted MACE (P < .01). Lead location concordant to regions of maximal wall thickness was associated with less MACE (P < .01). No CT dyssynchrony metrics predicted 6-month CRT response (P = NS for all). Myocardial scar (43%), posterolateral wall scar (28%), and total scar burden did not predict outcomes (P = NS for all). Preknowledge of coronary venous anatomy by CT did not reduce implant or fluoroscopy time (P = NS for both)., Conclusion: Two CT dyssynchrony metrics predicted 2-year MACE, and LV lead location concordant to regions of maximal wall thickness was associated with less MACE. Other CT factors had little utility in CRT., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Objectives: The current meta-analysis aimed to evaluate the diagnostic performance of hybrid cardiac imaging techniques compared with stand-alone coronary computed tomography angiography (CTA) for assessment of obstructive coronary artery disease (CAD)., Background: The usefulness of coronary CTA for detecting obstructive CAD remains suboptimal at present. Myocardial perfusion imaging encompasses positron emission tomography, single-photon emission computed tomography, and cardiac magnetic resonance, which permit the identification of myocardial perfusion defects to detect significant CAD. A hybrid approach comprising myocardial perfusion imaging and coronary CTA may improve diagnostic performance for detecting obstructive CAD., Methods: PubMed and Web of Knowledge were searched for relevant publications between January 1, 2000 and December 31, 2015. Studies using coronary CTA and hybrid imaging for diagnosis of obstructive CAD (a luminal diameter reduction of >50% or >70% by invasive coronary angiography) were included. In total, 12 articles comprising 951 patients and 1,973 vessels were identified, and a meta-analysis was performed to determine pooled sensitivity, specificity, and summary receiver-operating characteristic curves., Results: On a per-patient basis, the pooled sensitivity of hybrid imaging was comparable to that of coronary CTA (91% vs. 90%; p = 0.28). However, specificity was higher for hybrid imaging versus coronary CTA (93% vs. 66%; p < 0.001). On a per-vessel basis, sensitivity for hybrid imaging against coronary CTA was comparable (84% vs. 89%; p = 0.29). Notably, hybrid imaging yielded a specificity of 95% versus 83% for coronary CTA (p < 0.001). Summary receiver-operating characteristic curves displayed improved discrimination for hybrid imaging beyond coronary CTA alone, on a per-vessel basis (area under the curve: 0.97 vs. 0.93; p = 0.047), although not on a per-patient level (area under the curve: 0.97 vs. 0.93; p = 0.132)., Conclusions: Hybrid cardiac imaging demonstrated improved diagnostic specificity for detection of obstructive CAD compared with stand-alone coronary CTA, yet improvement in overall diagnostic performance was relatively limited., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The purpose of this study was to develop and validate a simple-to-use nomogram for prediction of 5-, 10-, and 15-year survival among asymptomatic adults., Background: Simple-to-use prognostication tools that incorporate robust methods such as coronary artery calcium scoring (CACS) for predicting near-, intermediate- and long-term mortality are warranted., Methods: In a consecutive series of 9,715 persons (mean age: 53.4 ± 10.5 years; 59.3% male) undergoing CACS, we developed a nomogram using Cox proportional hazards regression modeling that included: age, sex, smoking, hypertension, dyslipidemia, diabetes, family history of coronary artery disease, and CACS. We developed a prognostic index (PI) summing the number of risk points corresponding to weighted covariates, which was used to configure the nomogram. Validation of the nomogram was assessed by discrimination and calibration applied to a separate cohort of 7,824 adults who also underwent CACS., Results: A total of 936 and 294 deaths occurred in the derivation and validation sets at a median follow-up of 14.6 years (interquartile range: 13.7 to 15.5 years) and 9.4 years (interquartile range: 6.8 to 11.5 years), respectively. The developed model effectively predicted 5-, 10-, and 15-year probability of survival. The PI displayed high discrimination in the derivation and validation sets (C-index 0.74 and 0.76, respectively), indicating suitable external performance of our nomogram model. The predicted and actual estimates of survival in each dataset according to PI quartiles were similar (though not identical), demonstrating improved model calibration., Conclusions: A simple-to-use nomogram effectively predicts 5-, 10- and 15-year survival for asymptomatic adults undergoing screening for cardiac risk factors. This nomogram may be considered for use in clinical care., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We aimed to develop a severity classification system of the main pulmonary artery diameter (mPA) and its ratio to the ascending aorta diameter (ratio PA) for the diagnosis and prognosis of pulmonary hypertension (PH) on computed tomography (CT) scans., Methods: In 228 patients (136 with PH) undergoing right heart catheterization (RHC) and CT for dyspnea, we measured mPA and ratio PA. In a derivation cohort (n = 114), we determined cutpoints for a four-tier severity grading system that would maximize sensitivity and specificity, and validated it in a separate cohort (n = 114). Cutpoints for mPA were defined with ≤27 mm(F) and ≤29 mm(M) as the normal reference range; mild as >27 to <31 mm(F) and >29 to <31 mm(M); moderate≥31-34 mm; and severe>34 mm. Cutpoints for ratio PA were defined as normal ≤0.9; mild>0.9 to 1.0; moderate>1.0 to 1.1; and severe>1.1., Results: Sensitivities for normal tier were 99% for mPA and 93% for ratio PA; while specificities for severe tier were 98% for mPA>34 mm and 100% for ratio PA>1.1. C-statistics for four-tier mPA and ratio PA were both 0.90 (derivation) and both 0.85 (validation). Severity of mPA and ratio PA corresponded to hemodynamics by RHC and echocardiography (both p < 0.001). Moderate-severe mPA values of ≥31 mm and ratio PA>1.1 had worse survival than normal values (all p ≤ 0.01)., Conclusion: A CT-based four-tier severity classification system of PA diameter and its ratio to the aortic diameter has high accuracy for PH diagnosis with increased mortality in patients with moderate-severe severity grades. These results may support clinical utilization on chest and cardiac CT reports., (Copyright © 2018 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cardiac resynchronization therapy (CRT) improves mitral regurgitation (MR) in a subset of patients. We hypothesized that biomarkers (amino-terminal pro-B type natriuretic peptide, high-sensitivity troponin I, galectin-3 [gal-3], and soluble ST2) might predict MR response after CRT., Methods: We measured levels of biomarkers during CRT implantation in 132 patients with a subsequent 2-year follow-up. MR was graded as no-trace, mild, moderate, or severe at baseline and at 6 months., Results: In patients with baseline at least mild MR, 56% had improvement at 6 months, with lower 2-year mortality vs patients without improvement (0% vs 18%; P = 0.002). At baseline, patients with MR improvement had lower high-sensitivity troponin I and gal-3 levels compared with those without improvement (19 vs 40 pg/L; P = 0.01; 14 vs 18 ng/mL; P = 0.007). In multivariable analyses, higher log-transformed gal-3 (odds ratio, 0.15; 95% confidence interval, 0.04-0.65; P = 0.01) remained an independent predictor for MR nonimprovement. Levels of pro-B type natriuretic peptide and soluble ST2 were lower at follow-up in patients with MR improvement (potentially reflecting reduced myocardial stretch and stress) without reaching statistical significance., Conclusions: Higher galectin levels at the time of CRT implantation are associated with MR nonresponse., (Copyright © 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

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 > 1mg/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., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: A significant minority of patients receiving cardiac resynchronization therapy (CRT) remain nonresponsive to this intervention., Objective: This study aimed to determine whether coronary sinus (CS) or baseline peripheral venous (PV) levels of established and emerging heart failure (HF) biomarkers are predictive of CRT outcomes., Methods: In 73 patients (aged 68 ± 12 years; 83% men; ejection fraction 27% ± 7%) with CS and PV blood samples drawn simultaneously at the time of CRT device implantation, we measured amino-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3 (gal-3), and soluble ST2 (sST2) levels. NT-proBNP concentrations >2000 pg/mL, gal-3 concentrations >25.9 ng/mL, and sST2 concentrations >35 ng/mL were considered positive on the basis of established PV cut points for identifying "high-risk" individuals with HF. CRT response was adjudicated by the HF Clinical Composite Score. A major adverse cardiovascular event (MACE) was defined as the composite end point of death, cardiac transplant, left ventricular assist device, and HF hospitalization at 2 years., Results: NT-proBNP concentrations were 20% higher in the CS than in the periphery, while gal-3 and sST2 concentrations were 10% higher in the periphery than in the CS (all P < .001). There were 45% CRT nonresponders at 6 months and 16 (22%) patients with MACE. Triple-positive CS values yielded the highest specificity of 95% for predicting CRT nonresponse. Consistently, CS strategies identified patients at higher risk of developing MACE, with >11-fold adjusted increase for triple-positive CS patients compared to triple-negative patients (all P ≤ .04). PV strategies were not predictive of MACE., Conclusion: Our findings suggest that CS sampling of HF biomarkers may be better than PV sampling for predicting CRT outcomes. Larger studies are needed to confirm our findings., (Copyright © 2014 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

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., (© 2014. Published by Elsevier Inc. All rights reserved.)

Objectives: This analysis aimed to perform a head-to-head comparison of 3 of the promising biomarkers of cardiovascular (CV) outcomes in heart failure (HF)-soluble ST2 (sST2), growth differentiation factor (GDF)-15, and highly-sensitive troponin T (hsTnT)-and to evaluate the role of serial measurement of these biomarkers in patients with chronic HF., Background: sST2, GDF-15, and hsTnT are strongly associated with CV outcomes in HF., Methods: This post-hoc analysis used data from a study in which 151 patients with chronic HF due to left ventricular systolic dysfunction were followed up over 10 months. At each visit, N-terminal pro-B-type natriuretic peptide (NT-proBNP), sST2, GDF-15, and hsTnT were measured and any major CV events were recorded., Results: Baseline values of all 3 novel biomarkers independently predicted total CV events even after adjusting for clinical and biochemical characteristics, including NT-proBNP, with the best model including all 3 biomarkers (p < 0.001). Adding serial measurement to the base model appeared to improve the model's predictive ability (with sST2 showing the most promise), but it is not clear whether this addition is a unique contribution. However, when time-dependent factors were included, only sST2 serial measurement independently added to the risk model (odds ratio: 3.64; 95% confidence interval: 1.37 to 9.67; p = 0.009) and predicted reverse myocardial remodeling (odds ratio: 1.22; 95% confidence interval: 1.04 to 1.43; p = 0.01)., Conclusions: In patients with chronic HF, baseline measurement of novel biomarkers added independent prognostic information to clinical variables and NT-proBNP. Only serial measurement of sST2 appeared to add prognostic information to baseline concentrations and predicted change in left ventricular function. (Use of NT-proBNP Testing to Guide Heart Failure Therapy in the Outpatient Setting (PROTECT)]; NCT00351390)., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Multi-detector cardiac computed tomography (CT) allows for simultaneous assessment of aortic distensibility (AD), coronary atherosclerosis, and thoracic aortic atherosclerosis., Objectives: We sought to determine the relationship of AD to the presence and morphological features in coronary and thoracic atherosclerosis., Methods: In 293 patients (53 ± 12 years, 63% male), retrospectively-gated MDCT were performed. We measured intraluminal aortic areas across 10 phases of the cardiac cycle (multiphase reformation 10% increments) at pre-defined locations to calculate the ascending, descending, and local AD (at locations of thoracic plaque). AD was calculated as maximum change in area/(minimum area × pulse pressure). Coronary and thoracic plaques were categorized as calcified, mixed, or non-calcified., Results: Ascending and descending AD were lower in patients with any coronary plaque, calcified or mixed plaque than those without (all p<0.0001) but not with non-calcified coronary plaque (p ≥ 0.46). Per 1mm Hg(-1) 10(-3) increase in ascending and descending AD, there was an 18-29% adjusted risk reduction for having any coronary, calcified plaque, or mixed coronary plaque (ascending AD only) (all p ≤ 0.04). AD was not associated with non-calcified coronary plaque or when age was added to the models (all p>0.39). Local AD was lower at locations of calcified and mixed thoracic plaque when compared to non-calcified thoracic atherosclerosis (p<0.04)., Conclusions: A stiffer, less distensible aorta is associated with coronary and thoracic atherosclerosis, particularly in the presence of calcified and mixed plaques, suggesting that the mechanism of atherosclerosis in small and large vessels is similar and influenced by advancing age., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults > 75 years of age enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. In this comparative effectiveness study, we note that older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens comparable to that of younger adults., Background: Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults ≥ 75 years of age who are enrolled in clinical trials, safety and effectiveness outside the trial setting are less established., Methods: We retrospectively collected cases of patients ≥ 75 years of age who were diagnosed with stage III and metastatic CRC and initiated treatment between January 2000 and January 2007 at 2 academic hospitals in Boston, MA. Cases were matched in a 1:2 ratio to controls who were < 75 years of age by hospital site, stage of disease (stage III vs. metastatic) and line of therapy (first- or second-line or beyond). The primary study endpoints were grade ≥ 3 treatment-associated toxicities and intolerance (number of dose delays/reductions and hospital/facility admissions during treatment). The secondary endpoint was overall survival., Results: We identified 84 patients ≥ 75 years of age (25% ≥ 80 years) and 168 controls. In the cohort, 77% had colon cancer, 75% had metastatic disease, and 60% were receiving oxaliplatin as first-line therapy. There was no significant difference in grade ≥ 3 treatment-associated toxicities between the patients and the controls (71.4% vs. 68.5%, respectively; P = .63). Further there was no statistically significant difference between patients and controls for combined endpoints of any grade ≥ 3 toxicity or hospital/facility admission (P = .92). With a median follow-up of 52 months, 2-year overall survival was similar between patients and controls (43% vs. 52%, respectively; P = .87)., Conclusion: Older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens that was comparable to that of younger adults., (Copyright © 2013 Elsevier Inc. All rights reserved.)

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 © 2012 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Objective: Pericoronary adipose tissue (PCAT) may create a pro-inflammatory state, contributing to the development of coronary artery disease (CAD). We sought to evaluate the feasibility of a novel volumetric PCAT quantification method using a novel threshold based computed tomography approach. In addition we determined the relation between PCAT volumes and CAD., Methods: In 51 patients (49.5±5.1 years, 64.8% male) who underwent 64-slice MDCT, we measured threshold-based PCAT volumes using distance and anatomic-based methods. Using the most reproducible method, we performed the proximal 40-mm distance measurement in three groups as stratified by coronary plaque and high-sensitivity C-reactive protein (hs-CRP) levels: Group 1 (presence of coronary plaque, hs-CRP >2.0 mg/L); an intermediate group (Group 2, no plaque, hs-CRP >2.0 mg/L); and Group 3 (no plaque, hs-CRP<1.0 mg/L). We compared PCAT volumes to the presence of coronary plaque on a patient (n=51) and vessel (n=153) basis. On a subsegment basis (n=1224), we compared PCAT volume to the presence of plaque as well as plaque morphology., Results: Distance-based PCAT volume measurements yielded excellent reproducibility with intra-observer intraclass correlation (ICC) of 0.997 and inter-observer ICC of 0.951. On a both a per-patient and per-vessel analysis, adjusted PCAT volume was greater in patients with plaque (Group 1) than without plaque (Groups 2 and 3, p<0.001). No difference in PCAT volume was seen between high and low hs-CRP groups without plaque (p=0.51). Adjusted PCAT volumes were higher in subsegments with plaque as compared without (p<0.001). Additionally, adjusted PCAT volume was greatest in subsegments with mixed plaque followed by non-calcified plaque, calcified plaque, and the lowest volume in segments with no plaque (p<0.001)., Conclusion: In this proof-of-concept study, threshold based PCAT volume assessment is feasible and highly reproducible. PCAT volume is increased in patients and vessels with coronary plaques. Surrounding vessel subsegments with coronary plaque, particularly mixed plaques, have greatest PCAT volume and highlight the effect of local PCAT in the development of coronary atherosclerosis., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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 (51)Cr-release assays (P = 0.047) and enzyme-linked immunosorbent assay (ELISA) for IFN-γ 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.

The impact of cumulative dosing and premature drug discontinuation (PMDD) of bortezomib (V), thalidomide (T), and dexamethasone (D) on overall survival (OS), event-free survival (EFS), time to next therapy, and post-relapse survival in Total Therapy 3 were examined, using time-dependent methodology, relevant to induction, peritransplantation, consolidation, and maintenance phases. Univariately, OS and EFS were longer in case higher doses were used of all agents during induction, consolidation (except T), and maintenance (except V and T). The favorable OS and EFS impact of D induction dosing provided the rationale for examining the expression of glucocorticoid receptor NR3C1, top-tertile levels of which significantly prolonged OS and EFS and rendered outcomes independent of D and T dosing, whereas T and D, but not V, dosing was critical to outcome improvement in the bottom-tertile NR3C1 setting. PMDD of V was an independent highly adverse feature for OS (hazard ratio = 6.44; P < .001), whereas PMDD of both T and D independently imparted shorter time to next therapy. The absence of adverse effects on postrelapse survival of dosing of any VTD components and indeed a benefit from V supports the use up-front of all active agents in a dose-dense and dose-intense fashion, as practiced in Total Therapy 3, toward maximizing myeloma survival.

The Total Therapy 3 trial 2003-33 enrolled 303 newly diagnosed multiple myeloma patients and was noted to provide superior clinical outcomes compared with predecessor trial Total Therapy 2, especially in gene expression profiling (GEP)-defined low-risk disease. We report here on the results of successor trial 2006-66 with 177 patients, using bortezomib, lenalidomide, and dexamethasone maintenance for 3 years versus bortezomib, thalidomide, and dexamethasone in year 1 and thalidomide/dexamethasone in years 2 and 3 in the 2003-33 protocol. Overall survival (OS) and event-free survival (EFS) plots were super-imposable for the 2 trials, as were onset of complete response and complete response duration (CRD), regardless of GEP risk. GEP-defined high-risk designation, pertinent to 17% of patients, imparted inferior OS, EFS, and CRD in both protocols and, on multivariate analysis, was the sole adverse feature affecting OS, EFS, and CRD. Mathematical modeling of CRD in low-risk myeloma predicted a 55% cure fraction (P < .001). Despite more rapid onset and higher rate of CR than in other molecular subgroups, CRD was inferior in CCND1 without CD20 myeloma, resembling outcomes in MAF/MAFB and proliferation entities. The robustness of the GEP risk model should be exploited in clinical trials aimed at improving the notoriously poor outcome in high-risk disease.

Landmark analyses are used to investigate the importance for survival of achieving complete response (CR), an important initial goal of myeloma therapy. With median times to CR in Total Therapy (TT) trials of approximately 1 year, this approach excludes a sizeable fraction of patients dying before such a landmark. To permit inclusion of all trial participants, we investigated the prognostic implications of both onset and duration of CR as time-dependent variables. Superseding the adverse effects of cytogenetic abnormalities and other standard prognostic parameters, both failure to achieve CR (non-CR) and, especially, loss of CR (los-CR) were independently associated with inferior survival in TT1, TT2, and TT3 protocols. In the context of gene array-defined risk, available in TT2 and TT3 subsets, both los-CR and non-CR terms were retained in the survival model as dominant adverse variables, stressing the prognostic importance of sustaining CR status, especially in high-risk disease.

We report on prognostic implications for post-relapse survival (PRS) of a gene expression profiling (GEP)-defined risk score at relapse available in 120 myeloma patients previously enrolled in tandem transplantation trial Total Therapy 2. Among the 71 patients with additional GEP baseline information, 3-year PRS was 71% in 40 patients with low risk present both at baseline and relapse contrasting with only 17% in 28 patients with high risk at relapse, 12 of whom with baseline low-risk status fared better than the remainder (P = .08). On multivariate analysis of relapse parameters available in 104 patients, high risk conferred short PRS (hazard ratio = 4.00, P < .001, R(2) = 33%), whereas relapse hyperdiploidy predicted long PRS (hazard ratio = 0.37, P = .022, cumulative R(2) = 41%). In case the initial partial response lasted less than 2 years, relapse low-risk identified 26 patients with superior 3-year PRS of 61% versus 9% among 32 with relapse high-risk (P < .001). Based on its PRS predictive power, GEP analysis should be an integral part of new agent trials in search of better therapy for high-risk myeloma.

The survival of patients with Waldenstrom macroglobulinemia (WM) varies enormously. The development of prognostic models in WM has been fraught by limited follow-up in current studies. Here, we update the outcome of a prospective WM trial with a median follow-up of 10 years for live patients. Of the 59 previously untreated patients who initially were observed, only 12 patients (21%) required therapy at a median follow-up of 100 months. Multivariate analysis among the 183 patients requiring therapy reaffirmed age 70 years or greater, previous nonprotocol therapy, and beta-2 microglobulin (B2M) of 3 mg/dL or greater as prognostic factors. Importantly, increased serum lactate dehydrogenase (LDH) was identified as an additional independent variable, which improved risk assessment beyond the recent WM international prognostic scoring system (ISSWM). By using age, previous therapy, B2M, and LDH, we identified 3 risk groups with 8-year survival estimates of 55%, 33%, and 5% (P < .001). These data provide novel insights into factors predicting long-term outcome in WM. This trial has been registered with www.cancer.gov under ID 4852904.

Smoldering multiple myeloma (SMM) is usually followed expectantly without therapy. We conducted a phase 2 trial in 76 eligible patients with SMM, combining thalidomide (THAL, 200 mg/d) with monthly pamidronate. In the first 2 years, THAL dose reduction was required in 86% and drug was discontinued in 50%. Within 4 years, 63% improved, including 25% qualifying for partial response (PR); by then, 34 patients had progressed and 17 required salvage therapy. Unexpectedly, attaining PR status was associated with a shorter time to salvage therapy for disease progression (P < .001), perhaps reflecting greater drug sensitivity of more aggressive disease. Low beta-2-microglobulin levels less than 2 mg/L were independently associated with superior overall and event-free survival. Four-year survival and event-free survival estimates of 91% and 60%, respectively, together with a median postsalvage therapy survival of more than 5 years justify the conduct of a prospective randomized clinical trial to determine the clinical value of preemptive therapy in SMM. Trial registered at http://www.clinicaltrials.gov under identifier NCT00083382.