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Chinese Americans are a fast‐growing immigrant group with worse rheumatic disease outcomes compared to white populations and frequently use traditional Chinese medicine (TCM). Whether TCM use is associated with lower adherence to Western rheumatic medications is unknown. The present study was undertaken to examine adherence to Western medications for systemic rheumatic diseases in the Chinese American immigrant population and its association with TCM use. Chinese Americans actively treated for a systemic rheumatic disease were recruited from 2 Chinatown clinics. Sociodemographic, TCM use, and clinical data were gathered. Self‐reported health status was assessed using Patient‐Reported Outcome Measurement Information System short forms. Adherence was stratified using the 8‐item Morisky Medication Adherence Scale. Factors independently associated with high adherence were identified using multivariable logistic regression. Of 230 subjects, the median age was 55 years (range 20–97 years), 65% were female, 71% had a high school education or less, 70% were enrolled in Medicaid, and 22% reported fluency in English. The most common rheumatic diagnoses were rheumatoid arthritis (41%), systemic lupus erythematosus (17%), and seronegative spondyloarthropathies (15%). One‐half reported TCM use in the past year, and 28% reported high adherence to Western rheumatic medications. In multivariable analysis, high adherence was associated with TCM use (odds ratio [OR] 3.96, P< 0.001), being married (OR 3.69, P= 0.004), medication regimen complexity (OR 1.13, P= 0.004), and older age (OR 1.06, P< 0.001), and was negatively associated with anxiety (OR 0.94, P= 0.001). While adherence to Western rheumatic medications was low in this cohort, interestingly, it was higher among TCM users compared to nonusers. TCM use appears to represent a complementary rather than an alternate approach to disease management for these patients. Future studies should evaluate whether TCM use is associated with better disease outcomes.

To evaluate the longitudinal responsiveness (sensitivity to change) of the Patient‐Reported Outcomes Measurement Information System (PROMIS) Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE). Outpatients with SLE who were receiving care at an academic medical center completed the PROMIS10 at 2 visits that were a minimum of 1 month apart. Responsiveness of the PROMIS10 global physical and mental health domains to Patient‐Reported improvement or deterioration of health status was evaluated, as measured by standard validated instruments. Effect sizes of changes in PROMIS10 scores between visits were evaluated using Kruskal‐Wallis testing. A total of 223 SLE patients enrolled and completed baseline surveys, with 186 (83.4%) completing a second set of questionnaires. The PROMIS10 demonstrated mild‐to‐moderate responsiveness to Patient‐Reported improvement (effect size 0.29) and worsening (effect sizes –0.27 and –0.54) of health status for both global physical health and global mental health. Changes in the PROMIS10 correlated poorly with changes in physician‐reported measures of disease activity. The PROMIS10 showed responsiveness over time to Patient‐Reported changes in SLE health status, but not physician‐assessed changes. These data suggest that the PROMIS10 can be used to efficiently measure and monitor important aspects of the SLE patient experience that are not captured by standard physician‐derived metrics. Further studies are needed to evaluate the role of the PROMIS10 in optimizing longitudinal disease management in SLE and to determine its responsiveness in other chronic health conditions.

To determine whether racial disparities in total knee replacement (TKR) failure are explained by poverty. Black and white New York state residents, enrolled in a prospective single‐institution TKRregistry January 1, 2008 to February 6, 2012, who underwent primary unilateral TKR(n = 4,062) were linked to the New York Statewide Planning and Research Cooperative System database (January 1, 2008 to December 31, 2014) to capture revisions performed at outside institutions. Patients were linked by geocoded addresses to residential census tracts. Multivariable Cox regression was used to assess predictors of TKRrevision. Multivariable logistic regression was used to analyze predictors of TKRfailure, defined as TKRrevision in New York state ≤2 years after surgery, or as Hospital for Special Surgery (HSS) TKRquality of life score “not improved” or “worsened” 2 years after surgery. The mean ± SDage was 68.4 ± 10 years, 64% of patients were female, 8% lived in census tracts with >20% of the population under the poverty line, and 9% were black. Median follow‐up time was 5.3 years. A total of 3% of patients (122 of 4,062) required revision a median 454 days (interquartile range 215–829) after surgery. TKRrevision risk was higher in blacks than whites, with a hazard ratio of 1.69 (95% confidence interval 1.01–2.81), but in multivariable analysis, only younger age, male sex, and constrained prosthesis were predictors of TKRrevision. TKRfailure occurred in 200 of 2,832 cases (7%) with 2‐year surveys. Risk factors for TKRfailure were non‐osteoarthritis TKRindication, low surgeon volume, and low HSSExpectations Survey score, but not black race. Community poverty was not associated with TKRrevision or failure. There was a trend toward higher TKRrevision risk in blacks, but poverty did not modify the relationship between race and TKRrevision or failure.

Objective.Chinese Americans are a fast-growing immigrant group with more severe rheumatic disease manifestations than whites and often a strong cultural preference for traditional Chinese medicine (TCM). We aimed to examine TCM use patterns and association with patient-reported outcomes (PRO) among Chinese American rheumatology patients.Methods.Chinese Americans actively treated for systemic rheumatic diseases were recruited from urban Chinatown rheumatology clinics. Data on sociodemographics, acculturation, clinical factors, and TCM use (11 modalities) were gathered. Self-reported health status was assessed using Patient Reported Outcomes Measurement Information System (PROMIS) short forms. TCM users and nonusers were compared. Factors independently associated with TCM use were identified using multivariable logistic regression.Results.Among 230 participants, median age was 57 years (range 20–97), 65% were women, 71% had ≤ high school education, 70% were on Medicaid insurance, 47% lived in the United States for ≥ 20 years, and 22% spoke English fluently. Half used TCM in the past year; these participants had worse self-reported anxiety, depression, fatigue, and ability to participate in social roles and activities compared with nonusers. In multivariable analysis, TCM use was associated with belief in TCM, female sex, ≥ 20 years of US residency, reporting Western medicine as ineffective, and shorter rheumatic disease duration.Conclusion.Among these Chinese American rheumatology patients, TCM users had worse PRO in many physical and mental health domains. TCM use may be a proxy for unmet therapeutic needs. Asking about TCM use could help providers identify patients with suboptimal health-related quality of life who may benefit from targeted interventions.

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.

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.

Total knee arthroplasty (TKA) outcomes are worse for patients from poor neighborhoods, but whether education mitigates the effect of poverty is not known. We assessed the interaction between education and poverty on 2‐year Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function. Patient‐level variables from an institutional registry were linked to USCensus Bureau data (census tract [CT] level). Statistical models including patient and CT‐level variables were constructed within multilevel frameworks. Linear mixed‐effects models with separate random intercepts for each CTwere used to assess the interaction between education and poverty at the individual and community level on WOMACscores. Of 3,970 TKApatients, 2,438 (61%) had some college or more. Having no college was associated with worse pain and function at baseline and 2 years (P= 0.0001). Living in a poor neighborhood (>20% below poverty line) was associated with worse 2‐year pain (P= 0.02) and function (P= 0.006). There was a strong interaction between individual education and community poverty with WOMACscores at 2 years. Patients without college living in poor communities had pain scores that were ~10 points worse than those with some college (83.4% versus 75.7%; P< 0.0001); in wealthy communities, college was associated with a 1‐point difference in pain. Function was similar. In poor communities, those without college attain 2‐year WOMACscores that are 10 points worse than those with some college; education has no impact on TKAoutcomes in wealthy communities. How education protects those in impoverished communities warrants further study.

Objective.Rates of total knee arthroplasty (TKA) and total hip arthroplasty (THA) remain high for patients with rheumatoid arthritis (RA), who are at risk of flaring after surgery. We aimed to describe rates, characteristics, and risk factors of RA flare within 6 weeks of THA and TKA.Methods.Patients with RA were recruited prior to elective THA and TKA surgery and prospectively followed. Clinicians evaluated RA clinical characteristics 0–2 weeks before and 6 weeks after surgery. Patients answered questions regarding disease activity including self-reported joint counts and flare status weekly for 6 weeks. Per standard of care, biologics were stopped before surgery, while glucocorticoids and methotrexate (MTX) were typically continued. Multivariable logistic regression was used to identify baseline characteristics associated with postsurgical RA flares.Results.Of 120 patients, the mean age was 62 years and the median RA duration 14.8 years. Ninety-eight (82%) met 2010/1987 American College of Rheumatology/European League Against Rheumatism criteria, 53 (44%) underwent THA (and the rest TKA), and 61 (51%) were taking biologics. By 6 weeks, 75 (63%) had flared. At baseline, flarers had significantly higher disease activity (as measured by the 28-joint Disease Activity Score), erythrocyte sedimentation rate, C-reactive protein, and pain. Numerically more flarers used biologics, but stopping biologics did not predict flares, and continuing MTX was not protective. A higher baseline disease activity predicted flaring by 6 weeks (OR 2.12, p = 0.02).Conclusion.Flares are frequent in patients with RA undergoing arthroplasty. Higher baseline disease activity significantly increases the risk. Although more patients stopping biologics flared, this did not independently predict flaring. The effect of early postsurgery flares requires further study.

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Objective.To assess the feasibility, validity, and reliability of the Patient Reported Outcomes Measurement Information System Global Health Short Form (PROMIS10) in outpatients with systemic lupus erythematosus (SLE).Methods.SLE outpatients completed PROMIS10, Medical Outcomes Study Short Form-36 (SF-36), LupusQoL-US, and selected PROMIS computerized adaptive tests (CAT) at routine visits at an SLE Center of Excellence. Construct validity was evaluated by correlating PROMIS10 physical and mental health scores with PROMIS CAT, legacy instruments, and physician-derived measures of disease activity and damage. Test-retest reliability was determined among subjects reporting stable SLE activity at 2 assessments 1 week apart using intraclass correlation coefficients (ICC).Results.A diverse cohort of 204 out of 238 patients with SLE (86%) completed survey instruments. PROMIS10 physical health scores strongly correlated with physical function, pain, and social health domains in PROMIS CAT, SF-36, and LupusQoL, while mental health scores strongly correlated with PROMIS depression CAT, SF-36, and LupusQoL mental health domains (Spearman correlations ≥ 0.70). Active arthritis, comorbid fibromyalgia (FM), and anxiety were associated with worse PROMIS10 scores, but sociodemographic factors and physician-assessed flare status were not. Test-retest reliability for PROMIS10 physical and mental health scores was high (ICC ≥ 0.85). PROMIS10 required < 2 minutes to complete.Conclusion.PROMIS10 is valid and reliable, and can efficiently screen for impaired physical function, pain, and emotional distress in outpatients with SLE. With strong correlations to LupusQoL and SF-36 but significantly reduced responder burden, PROMIS10 is a promising tool for measuring patient-reported outcomes in routine SLE clinical care and value-based healthcare initiatives.

Objective.The aims of this study were to assess the construct validity and the test-retest reliability of Patient Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests (CAT) in patients with systemic lupus erythematosus (SLE).Methods.Adults with SLE completed the Medical Outcomes Study Short Form-36, LupusQoL-US version (“legacy instruments”), and 14 selected PROMIS CAT. Using Spearman correlations, PROMIS CAT were compared with similar domains measured with legacy instruments. CAT were also correlated with the Safety of Estrogens in Lupus Erythematosus National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) disease activity and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) scores. Test-retest reliability was evaluated using ICC.Results.There were 204 outpatients with SLE enrolled in the study and 162 completed a retest. PROMIS CAT showed good performance characteristics and moderate to strong correlations with similar domains in the 2 legacy instruments (r = −0.49 to 0.86, p < 0.001). However, correlations between PROMIS CAT and the SELENA-SLEDAI disease activity and SDI were generally weak and statistically insignificant. PROMIS CAT test-retest ICC were good to excellent, ranging from 0.72 to 0.88.Conclusion.To our knowledge, these data are the first to show that PROMIS CAT are valid and reliable for many SLE-relevant domains. Importantly, PROMIS scores did not correlate well with physician-derived measures. This disconnect between objective signs and symptoms and the subjective patient disease experience underscores the crucial need to integrate patient-reported outcomes into clinical care to ensure optimal disease management.

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.

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.

To investigate predictors of trial start-up times, high attrition, and poor protocol adherence in amyotrophic lateral sclerosis (ALS) trials.

OBJECTIVES To describe the characteristics and outcomes after resection of incidentally discovered, nonfunctioning pancreatic endocrine tumors (PETs). DESIGN Case series. SETTING Academic hospital. PATIENTS Consecutive patients with an incidentally identified, nonfunctioning PET resected from May 1, 1977, through July 31, 2009. MAIN OUTCOME MEASURES Operative morbidity and survival after resection. RESULTS A total of 139 patients with median age of 56 years (range, 21-85 years) underwent resection; tumor size ranged from 0.4 to 17.0 cm, with median size of 3.0 cm. No perioperative deaths were reported. Sixty-one patients (43.9%) experienced a perioperative complication. Twenty-six tumors (18.7%) were classified as benign, 39 (28.1%) as malignant, and 72 (51.8%) as uncertain. We were unable to confidently classify 2 tumors due to lack of information regarding mitotic rate in the pathology report. Complete follow-up was available for 112 patients (80.6%) (median, 34.2 months). Five-year actuarial survival rates were 88.8% for patients with benign disease, 92.5% for patients with tumors of uncertain biology, and 49.8% for those with malignant tumors (P = .01). Late metastasis, tumor recurrence, or disease progression were seen in 1 patient (3.8%) with tumors initially classified as benign, 8 patients (11.1%) with uncertain tumors, and 15 patients (38.5%) with tumors classified as malignant (P &lt; .001). Of the 39 patients with tumors 2 cm or smaller, 3 (7.7%) had late metastases or recurrence. When compared with patients with symptomatic, nonfunctioning PETs, no large difference was observed in tumor size, patient age, disease, or survival. CONCLUSIONS Incidentally detected, nonfunctioning PETs can display aggressive behavior, even when small. Although patients with malignant disease had diminished survival and increased rates of recurrence, benign histologic findings did not eliminate the possibility of progression. Patients with incidentally discovered, nonfunctioning PETs should undergo tumor resection and careful postoperative surveillance, even if surgical pathologic findings suggest benign disease.Arch Surg. 2011;146(5):534-538--

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.

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.

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 postrelapse 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, R2 = 33%), whereas relapse hyperdiploidy predicted long PRS (hazard ratio = 0.37, P = .022, cumulative R2 = 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.

We report on prognostic implications for postrelapse 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, R2= 33%), whereas relapse hyperdiploidy predicted long PRS (hazard ratio = 0.37, P= .022, cumulative R2= 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 β-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.

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 β-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.govunder 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.

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.govunder identifier NCT00083382.

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Introduction:Spatial risk factors are increasingly recognized to predict cardiovascular events independently of traditional risk factors. However, these spatial risk factors have been studied only individually and primarily in high-income countries.Hypothesis:We hypothesize that spatial risk factors independently predict all-cause and cardiovascular mortality.Methods:We developed exposure models for the following spatial risk factors in Golestan Provence, Iran: outdoor air pollution, proximity to traffic, proximity to health facilities, population density, land cover, socioeconomic environment, and light-at-night. Spatial exposures were assigned to 50,045 individuals in the Golestan Cohort Study, who have been followed-up for up to 12 years. Using a multivariable Cox proportional hazards spatial frailty model, we determined the impact of these exposures, as well as household fuel use and traditional risk factors, on cardiovascular mortality.Results:Spatial surfaces demonstrated spatial variability of the spatial risk factors (Figure), and outdoor air pollution also displayed temporal variability. Exposure to outdoor air pollution 5 years prior to enrollment, household kerosene and biomass fuel use, and proximity to advanced health facilities independently increased total and cardiovascular mortality (Table).Conclusions:Both outdoor air pollution and household fuel use independently predicted cardiovascular mortality in a middle-income country. Following this approach, future studies can better estimate the total impact of the environment on cardiovascular events.