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Purpose: The 21st Century Cures Act Final Rule mandates increased transparency and accessibility of the Electronic Health Record (EHR). This mandate has exacerbated tensions in adolescent healthcare between transparency and confidentiality. This study evaluates clinicians' perspectives on how well the EHR maintains confidentiality for adolescents in the post-Cures Act era., Methods: A web-based survey was distributed via the national listserv of the Society for Adolescent Health and Medicine in March-April 2022. English-speaking members practicing in the Unites States who used an EHR to document clinical visits with minors were eligible. The survey included questions about EHR training, features, and approach to information sharing with adolescent patients and proxies., Results: Participants included 97 respondents from 32 states. Most participants were physicians (98%) and identified themselves as attending (89%). Several EHR vendors were represented, although the majority used Epic (76%). As has been seen in prior studies, there remains significant variability in approaches to patient portal access for adolescent patients and their adult proxies. Respondents report that training around adolescent-specific privacy issues remains infrequent and is perceived as inadequate. Adolescent providers, despite feeling confident in navigating the EHR generally, continue to report low rates of confidence in how well their EHR may protect adolescent privacy., Discussion: Clinicians have persistent concerns about adolescent confidentiality postimplementation of the 21st Century Cures Act. Sharing sufficient information while protecting adolescent confidentiality might require standardization by EHR vendors to improve granularity of proxy information sharing. Healthcare institutions must also commit to training providers on management of adolescent confidentiality., (Copyright © 2023 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Schwannomas are common peripheral nerve sheath tumors. Imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) can help to distinguish schwannomas from other types of lesions. However, there have been several reported cases describing the misdiagnosis of aneurysms as schwannomas., Observations: A 70-year-old male with ongoing pain despite spinal fusion surgery underwent MRI. A lesion was noted along the left sciatic nerve, which was believed to be a sciatic nerve schwannoma. During the surgery for planned neurolysis and tumor resection, the lesion was noted to be pulsatile. Electromyography mapping and intraoperative ultrasound confirmed vascular pulsations and turbulent flow within the aneurysm, so the surgery was aborted. A formal CT angiogram revealed the lesion to be an internal iliac artery (IIA) branch aneurysm. The patient underwent coil embolization with complete obliteration of the aneurysm., Lessons: The authors report the first case of an IIA aneurysm misdiagnosed as a sciatic nerve schwannoma. Surgeons should be aware of this potential misdiagnosis and potentially use other imaging modalities to confirm the lesion before proceeding with surgery.

Background: The 21st Century Cures Act mandates the immediate, electronic release of health information to patients. However, in the case of adolescents, special consideration is required to ensure that confidentiality is maintained. The detection of confidential content in clinical notes may support operational efforts to preserve adolescent confidentiality while implementing information sharing., Objectives: This study aimed to determine if a natural language processing (NLP) algorithm can identify confidential content in adolescent clinical progress notes., Methods: A total of 1,200 outpatient adolescent progress notes written between 2016 and 2019 were manually annotated to identify confidential content. Labeled sentences from this corpus were featurized and used to train a two-part logistic regression model, which provides both sentence-level and note-level probability estimates that a given text contains confidential content. This model was prospectively validated on a set of 240 progress notes written in May 2022. It was subsequently deployed in a pilot intervention to augment an ongoing operational effort to identify confidential content in progress notes. Note-level probability estimates were used to triage notes for review and sentence-level probability estimates were used to highlight high-risk portions of those notes to aid the manual reviewer., Results: The prevalence of notes containing confidential content was 21% (255/1,200) and 22% (53/240) in the train/test and validation cohorts, respectively. The ensemble logistic regression model achieved an area under the receiver operating characteristic of 90 and 88% in the test and validation cohorts, respectively. Its use in a pilot intervention identified outlier documentation practices and demonstrated efficiency gains over completely manual note review., Conclusion: An NLP algorithm can identify confidential content in progress notes with high accuracy. Its human-in-the-loop deployment in clinical operations augmented an ongoing operational effort to identify confidential content in adolescent progress notes. These findings suggest NLP may be used to support efforts to preserve adolescent confidentiality in the wake of the information blocking mandate., Competing Interests: None declared., (Thieme. All rights reserved.)

Rationale: Differences in body composition may contribute to variability in exercise capacity (EC) and physical activity (PA) in individuals with chronic obstructive pulmonary disease (COPD). Most studies have used bioimpedance-based surrogates of muscle (lean) mass; relatively few studies have included consideration of fat mass, and limited studies have been performed using dual X-ray absorptiometry (DXA) to assess body composition. Objectives: To determine whether DXA-assessed muscle (lean) and fat mass exhibit differential correlations with EC and PA in subjects with COPD. Methods: U.S. veterans with COPD (defined as forced expiratory volume in 1 second/forced vital capacity < 0.7 or emphysema on clinical chest computed tomography) had DXA-assessed body composition, EC (6-minute-walk distance), objective PA (average daily step counts), and self-reported PA measured at enrollment. Associations among EC, PA, and body composition were examined using Spearman correlations and multivariable models adjusted a priori for age, sex, race, and lung function. Results: Subjects ( n  = 98) were predominantly White (90%), obese (mean body mass index, 30.2 ± 6.2 kg/m 2 ), and male (96%), with a mean age of 69.8 ± 7.9 years and moderate airflow obstruction (mean forced expiratory volume in 1 second percentage predicted, 68 ± 20%). Modest inverse correlations of EC and PA with fat mass were observed (Spearman's rho range, -0.20 to -0.34), whereas measures of muscle (lean) mass were not significantly associated with EC or PA. The ratio of appendicular skeletal muscle mass (ASM) to weight, which considers both muscle (lean) and fat mass, was consistently associated with EC (8.4 [95% confidence interval, 2.9-13.8] meter increase in 6-minute walk distance per 1% increase in ASM-to-weight ratio), objective PA (194.8 [95% confidence interval, 15.2-374.4] steps per day per 1% increase in ASM-to-weight ratio), and self-reported PA in multivariable-adjusted models. Conclusions: DXA-assessed body composition measures that include consideration of both lean and fat mass are associated with cross-sectional EC and PA in COPD populations. Clinical trial registered with www.clinicaltrials.gov (NCT02099799).

Treating Veterans with chronic obstructive pulmonary disease complicated by pulmonary hypertension (COPD-PH) using phosphodiesterase type-5 inhibitor pharmacotherapy is common, but efficacy data are lacking. To address this further, patients with COPD-PH from five Department of Veterans Affairs hospitals were randomized (1∶1) to receive placebo or oral tadalafil (40 mg/day) for 12 months. The primary endpoint was changed from baseline in 6-min walk distance at 12 months. Secondary endpoints included change from baseline in pulmonary vascular resistance, mean pulmonary artery pressure, and symptom burden by the University of California San Diego shortness of breath questionnaire scale at 6 months. A total of 42 subjects (all male; 68 ± 7.6 years old) were randomized to placebo ( N  = 14) or tadalafil ( N  = 28). The group imbalance was related to under-enrollment. Compared to placebo, no significant difference was observed in the tadalafil group for change from the primary endpoint or change in mean pulmonary artery pressure or pulmonary vascular resistance from baseline at 6 months. A clinically meaningful improvement was observed in the secondary endpoint of shortness of breath questionnaire score in the tadalafil versus placebo group at 6 months. There was no significant difference in major adverse events between treatment groups, and tadalafil was well tolerated overall. For Veterans with COPD-PH enrolled in this study, once-daily treatment with tadalafil did not improve 6-min walk distance or cardiopulmonary hemodynamics although a decrease in shortness of breath was observed. Under-enrollment and imbalanced randomization confound interpreting conclusions from this clinical trial and limit the generalization of our findings., Competing Interests: B.A.M. serves as a consultant for Actelion; is the PI on a research project study pulmonary hypertension sponsored by Deerfield; and is coinventor of patents or patent applications that are related to pulmonary hypertension (U.S. Patent #9,605,047; PCT/US2015/029672; Provisional ID: #62475955; Provisional ID: #24624; Provisional ID: #24622)., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Objectives: Reproductive health is an important issue in the care of adolescents and young adults (AYA). Unfortunately, many AYAs, particularly those with chronic medical conditions, may not regularly access primary care to address these issues. This study evaluates the impact of an inpatient reproductive health consult service on reproductive health care., Methods: A reproductive health-focused screening consult service was initiated in June 2017 at an academic teaching hospital. Patients aged 15 to 26 admitted to pediatric ward teams were eligible for screening. A retrospective chart review was conducted from December 2016 to June 2019 to determine the effect of the consult service on the primary outcome, documentation of a psychosocial assessment, and reproductive health concerns., Results: Nine hundred twenty-nine encounters were analyzed (345 preintervention and 584 during intervention), representing 675 patients. The proportion of encounters with a documented psychosocial assessment increased from 14.8% to 41.3% during the intervention (P < .001); a reproductive health screening consult was responsible for 37.3% (109 of 292) of the documented assessments. There were high self-reported rates of sexual activity (38%), substance use (47%), and mood concerns (48%) among hospitalized AYA; all behaviors were documented at statistically significant increased frequencies (P < .001) during the intervention compared with preintervention., Conclusions: Initiation of an inpatient reproductive health screening consult service led to increased documentation of psychosocial assessments, including increased documentation of sexual health history and other risk factors. With improved screening of reproductive and psychosocial needs, targeted interventions can meet underrecognized needs among hospitalized AYA., (Copyright © 2022 by the American Academy of Pediatrics.)

We examined the performance of a commercially-available handheld bioimpedance (BIA) device relative to dual X-ray absorptiometry (DXA) to assess body composition differences among Veterans with chronic obstructive pulmonary disease (COPD). Body composition was measured using DXA and BIA (Omron HBF-306C) at a single time point. Correlations between BIA- and DXA-assessed percent fat, fat mass, and fat-free mass were analyzed using Spearman (ρ) and Lin Concordance Correlation Coefficients (ρ c ). Mean differences in fat mass were visualized using Bland-Altman plots. Subgroup analyses by obesity status (BMI < 30 versus ≥ 30) were performed. Among 50 participants (96% male; mean age: 69.5 ± 6.0 years), BIA-assessed fat mass was strongly correlated (ρ = 0.94) and demonstrate excellent concordance (ρ c  = 0.95, [95%CI: 0.93-0.98]) with DXA, with a mean difference of 2.7 ± 3.2 kg between BIA and DXA. Although Spearman correlations between BIA- and DXA-assessed percent fat and fat-free mass were strong (ρ = 0.8 and 0.91, respectively), concordance values were only moderate (ρ c  = 0.67 and 0.74, respectively). Significantly stronger correlations were observed for obese relative to non-obese subjects for total percent fat (ρ obese  = 0.85 versus ρ non-obese  = 0.5) and fat mass (ρ obese  = 0.96 versus ρ non-obese  = 0.84). A handheld BIA device demonstrated high concordance with DXA for fat mass and moderate concordance for total percent fat and fat-free mass.ClinicalTrials.gov: NCT02099799., (© 2022. The Author(s).)

Background: Novel strategies to complement current methods of education delivery by healthcare providers in clinic encounters or in pulmonary rehabilitation are needed to promote COPD self-management., Methods: We developed a COPD web-based platform that delivers education as part of a physical activity intervention. We examined COPD knowledge in persons with COPD who used a web-mediated, pedometer-based physical activity intervention. Knowledge was assessed with the Bristol COPD Knowledge Questionnaire (BCKQ) at baseline, 3, 6, 9, and 12 months. Scores range from 0 to 100, with higher scores indicating greater knowledge. Repeated measures ANOVA (PROC MIXED, SAS 9.4) examined trends across the 12 months and identified changes from baseline at 3, 6, 9, and 12 months., Results: We enrolled 72 participants with COPD, 93% males with mean ± sd age of 69 ± 7 years and FEV1% predicted of 60 ± 23%. There was a significant increase from baseline to 9 months (p = 0.012), although this increase did not persist at 12 months. Among the 13 topics, participants scored the highest at baseline on smoking knowledge (65.3 ± 17.4) and the lowest on inhaled steroids (9.7 ± 15.4). Across the 12 months, there were significant increases in knowledge about inhaled bronchodilators (p = 0.011) and inhaled steroids (p = 0.035). At 12 months, there were significant improvements in knowledge about exercise (p = 0.004), vaccination (p = 0.027), inhaled bronchodilators (p = 0.002), and inhaled steroids (p = 0.002)., Conclusion: An internet-mediated intervention may provide another option for COPD education delivery and support for disease self-management., (Published by Elsevier Ltd.)

Background: Exercise capacity (EC) and physical activity (PA) are independent, potentially modifiable predictors of clinical outcomes in COPD. Molecular measures of biological age may help characterize variability in EC and PA observed among COPD patients., Methods: Veterans with COPD (FEV 1 /FVC<0.7 or emphysema on chest computed tomography) enrolled in 2 cohorts at VA Boston completed questionnaires, a 6-min walk distance (6MWD) for EC, and blood collection at enrollment. PA data (average daily step count) was collected using an HJ-720 ITC pedometer over ≥5 days. A subset of subjects returned for repeat assessment after 12 weeks. DNA methylation data was generated using the HumanMethylationEPIC platform; epigenetic estimates of biological age and age acceleration were generated using established algorithms. Multivariable models examined the associations between biological age, 6MWD, PA and future acute exacerbations (AEs), adjusting for chronological age, sex, race, smoking status, pack-years, body mass index, cohort, and estimated cell counts., Results: Subjects (n = 269) were predominantly male (98.5%), white (92.9%), and elderly (70.6 ± 8.5 years) with average FEV 1 % of 57.7 ± 21.1, 6MWD of 374.3 ± 93.5 m, and daily steps of 3043.4 ± 2374 at baseline. In adjusted models, multiple measures of baseline epigenetic age and age acceleration were inversely associated with 6MWD; only GrimAge was inversely associated with PA. Longitudinal change in Hannum-Age was inversely associated with change in EC at 12 weeks (n = 94). No measures of biological age were significantly associated with prospective AEs over 1.3 ± 0.3 years., Conclusions: Epigenetic measures of biological age are independent predictors of EC and PA, but not AEs, among individuals with COPD., (Published by Elsevier Ltd.)

Improving exercise capacity is a primary objective in COPD. Declines in exercise capacity result in reduced physical activity and health-related quality of life (HRQoL). Self-management interventions can teach patients skills and behaviours to manage their disease. Technology-mediated interventions have the potential to provide easily accessible support for disease self-management. We evaluated the effectiveness of a web-based self-management intervention, focused on physical activity promotion, on exercise capacity in COPD. This 6-month randomised controlled trial (NCT02099799) enrolled 153 persons with COPD at two US sites (VABoston, n=108; VABirmingham, n=45). Participants were allocated (1:1) to the web-based self-management intervention (physical activity promotion through personalised, progressive step-count goals, feedback, online COPD-related education and social support via an online community) or usual care. The primary outcome was exercise capacity (6-min walk distance (6 MWD)). Secondary outcomes included physical activity (daily steps per day), HRQoL (St. George's Respiratory Questionnaire Total Score), dyspnoea, COPD-related knowledge and social support. Change in step-count goals reflected intervention engagement. Participants' mean age was 69 (sd=7), and mean forced expiratory volume in 1 s % predicted was 61% (sd=21%). Change in 6MWD did not differ between groups. Intervention participants improved their mean daily step counts by 1312 more than those in the usual care group (p<0.001). Groups did not differ on other secondary outcomes. VABirmingham participants were significantly more engaged with the intervention, although site did not modify the effect of the intervention on 6MWD or secondary outcomes. The intervention did not improve exercise capacity but improved physical activity at 6 months. Additional intervention modifications are needed to optimise its COPD self-management capabilities., Competing Interests: Conflict of interest: J.A. Cooper Jr has nothing to disclose. Conflict of interest: R.L. Goldstein has nothing to disclose. Conflict of interest: M. Polak has nothing to disclose. Conflict of interest: P.N. Cruz Rivera has nothing to disclose. Conflict of interest: D.R. Gagnon has nothing to disclose. Conflict of interest: A. Samuelson has nothing to disclose. Conflict of interest: S. Moore has nothing to disclose. Conflict of interest: R. Kadri has nothing to disclose. Conflict of interest: C.R. Richardson has nothing to disclose. Conflict of interest: M.L. Moy has nothing to disclose., (Copyright ©The authors 2021.)

Background: Pain is a common but underappreciated symptom experienced by people with Chronic Obstructive Pulmonary Disease (COPD). The relationships between pain and physical activity (PA) and exercise capacity are poorly understood., Methods: This retrospective secondary analysis includes three cohorts of Veterans with COPD who participated in longitudinal studies evaluating PA and exercise capacity with objective measures of daily step counts and 6-min walk test (6MWT) distance, respectively. Pain was assessed using the bodily pain domain of the Veterans RAND-36. In two cohorts, participants were randomly assigned to a web-based, pedometer-mediated PA intervention which has previously been demonstrated to improve PA., Results: Three-hundred and seventy-three (373) unique study participants were included in this analysis. Eighty-three percent (n = 311) of the population reported at least mild pain and/or at least a little bit of interference due to pain at baseline. Cross-sectionally, greater bodily pain was associated with lower 6MWT distance (β = 0.51; 95% CI 0.20, 0.82; p = 0.0013). Longitudinally, worsening bodily pain was associated with a decline in 6MWT distance (β = 0.30; 95% CI 0.03, 0.58; p = 0.0312). There was no association between baseline bodily pain and baseline daily step counts, baseline bodily pain and change in PA, or change in bodily pain and change in PA. Compared to usual care, our PA intervention improved bodily pain scores (β = 6.17; 95% CI 1.84, 10.45; p = 0.0054). Bodily pain scores did not affect the impact of the intervention on daily step counts., Conclusion: Pain is highly prevalent and significantly associated with lower exercise capacity among Veterans with COPD. Worsening pain co-occurred with decline in exercise capacity but not PA. Our intervention reduced pain, although pain did not affect the impact of the intervention on PA., (© 2021. The Author(s).)

Persons with COPD experience co-occurring dyspnea and pain. Little is known about the relationship between symptom co-occurrence with physical activity (PA) and exercise. Novel diagnostic tools are needed for accurate symptom discrimination. In this secondary analysis, we examined relationships between baseline assessments of pain, dyspnea, objectively measured PA, and exercise capacity in persons with COPD who previously enrolled in three PA studies. Pain was assessed with the bodily pain domain of the Veterans RAND-36 (VR-36), and dyspnea with the modified Medical Research Council (mMRC) scale. Average daily step count was assessed with the Omron HJ-720ITC or FitBit Zip pedometer, and exercise capacity with 6-minute walk test (6MWT). We also conducted a pilot neuroimaging study. Neuroimaging data were acquired on a Siemens 3-Tesla Magnetom Prismafit whole-body scanner. Analysis of variance assessed trends in daily step count and 6MWT distance across categories of co-occurring pain and dyspnea. General linear models examined relationships between cortical thickness and resting state functional connectivity (fc) with symptoms and functional status. In 373 Veterans, 98% were male with mean age 70.5± 8.3 years and FEV1% predicted 59 ± 21%. Compared to those with no co-occurrence of pain and dyspnea, those with co-occurrence walked 1,291-1,444 fewer steps per day and had an 80-85 m lower 6MWT distance. Ten males participated in the pilot neuroimaging study. Predominant findings were that lower cortical thickness and greater fc were associated with higher pain and dyspnea, p<0.05. Greater cortical thickness and lower fc were associated with higher daily step count and 6MWT distance, p<0.05. Regional patterns of associations differed for pain and dyspnea, suggesting that cortical thickness and fc may discriminate symptoms. Co-occurring dyspnea and pain in COPD are associated with significant reductions in PA and exercise capacity. It may be feasible for neuroimaging markers to discriminate between pain and dyspnea., Competing Interests: The authors have declared that no competing interests exist.

Multiple myeloma (MM) is a hematologic malignancy that is characterized by the accumulation of abnormal plasma cells (PCs) in the bone marrow (BM). Patient outcome may be improved with BiTE (bispecific T-cell engager) molecules, which redirect T cells to lyse tumor cells. B-cell maturation antigen (BCMA) supports PC survival and is highly expressed on MM cells. A half-life extended anti-BCMA BiTE molecule (AMG 701) induced selective cytotoxicity against BCMA-expressing MM cells (average half-maximal effective concentration, 18.8 ± 14.8 pM), T-cell activation, and cytokine release in vitro. In a subcutaneous mouse xenograft model, at all doses tested, AMG 701 completely inhibited tumor formation (P < .001), as well as inhibited growth of established tumors (P ≤ .001) and extended survival in an orthotopic MM model (P ≤ .01). To evaluate AMG 701 bioactivity in cynomolgus monkeys, a PC surface phenotype and specific genes were defined to enable a quantitative digital droplet polymerase chain reaction assay (sensitivity, 0.1%). Dose-dependent pharmacokinetic and pharmacodynamic behavior was observed, with depletion of PC-specific genes reaching 93% in blood and 85% in BM. Combination with a programmed cell death protein 1 (PD-1)-blocking antibody significantly increased AMG 701 potency in vitro. A model of AMG 701 binding to BCMA and CD3 indicates that the distance between the T-cell and target cell membranes (ie, the immunological synapse) is similar to that of the major histocompatibility complex class I molecule binding to a T-cell receptor and suggests that the synapse would not be disrupted by the half-life extending Fc domain. These data support the clinical development of AMG 701., (© 2020 by The American Society of Hematology.)

Background: The autologous vein remains the standard conduit for lower extremity and coronary artery bypass grafting despite a 30%-50% 5-y failure rate, primarily attributable to intimal hyperplasia (IH) that develops in the midterm period (3-24 mo) of graft maturation. Our group discovered that externally strengthening vein grafts by cross-linking the adventitial collagen with photochemical tissue passivation (PTP) mitigates IH in an arteriovenous model at 4 wk. We now investigate whether this effect is retained in the midterm period follow-up., Methods: Six Hanford miniature pigs received bilateral carotid artery interposition vein grafts. In each animal, the external surface of one graft was treated with PTP before grafting, whereas the opposite side served as the untreated control. The grafts were harvested after 3 mo. Ultrasound evaluation of all vein grafts was performed at the time of grafting and harvest. The grafts were also evaluated histomorphometrically and immunohistologically for markers of IH., Results: All vein grafts were patent at 3 mo except one graft in the PTP-treated group because of early technical failure. The control vein grafts had significantly greater IH than PTP-treated grafts at 3 mo, as evidenced by the intimal area (2.6 ± 1.0 mm 2 versus 1.4 ± 1.5 mm 2 , respectively, P = 0.045) and medial area (5.1 ± 1.9 mm 2 versus 2.7 ± 2.4 mm 2 , respectively, P = 0.048). The control grafts had an increased presence and proliferation of mural myofibroblasts with greater smooth muscle actin and proliferating cell nuclear antigen staining., Conclusions: PTP treatment to the external surface of the vein grafts decreases IH at 3 mo after arteriovenous grafting and may prevent future graft failure., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite advances in the treatment of acute myeloid leukemia (AML), novel therapies are needed to induce deeper and more durable clinical response. Bispecific T-cell Engager (BiTE) molecules, which redirect patient T cells to lyse tumor cells, are a clinically validated modality for hematologic malignancies. Due to broad AML expression and limited normal tissue expression, fms-related tyrosine kinase 3 (FLT3) is proposed to be an optimal BiTE molecule target. Expression profiling of FLT3 was performed in primary AML patient samples and normal hematopoietic cells and nonhematopoietic tissues. Two novel FLT3 BiTE molecules, one with a half-life extending (HLE) Fc moiety and one without, were assessed for T-cell-dependent cellular cytotoxicity (TDCC) of FLT3-positive cell lines in vitro, in vivo , and ex vivo FLT3 protein was detected on the surface of most primary AML bulk and leukemic stem cells but only a fraction of normal hematopoietic stem and progenitor cells. FLT3 protein detected in nonhematopoietic cells was cytoplasmic. FLT3 BiTE molecules induced TDCC of FLT3-positive cells in vitro , reduced tumor growth and increased survival in AML mouse models in vivo Both molecules exhibited reproducible pharmacokinetic and pharmacodynamic profiles in cynomolgus monkeys in vivo , including elimination of FLT3-positive cells in blood and bone marrow. In ex vivo cultures of primary AML samples, patient T cells induced TDCC of FLT3-positive target cells. Combination with PD-1 blockade increased BiTE activity. These data support the clinical development of an FLT3 targeting BiTE molecule for the treatment of AML., (©2020 American Association for Cancer Research.)

Cystinuria comprises less than 1% of kidney stones and is associated with impaired health-related quality of life (HRQOL). Limited evidence is available regarding HRQOL of patients with cystinuria treated with tiopronin (Thiola ® ). The objective of this study was to assess the HRQOL of patients with or without tiopronin treatment. For this cross-sectional survey, patients on tiopronin treatment were recruited through the "Thiola ® Total Care Hub," a specialty pharmacy used to dispense tiopronin, and compared with patients not taking tiopronin (non-tiopronin group) who were identified from the Cystinuria Contact Registry at New York University School of Medicine. Consented patients responded to a survey that included questions about their experiences with kidney stones, the Wisconsin stone quality of life (WISQOL) (disease-specific) questionnaire, and the short form-36 version 2 (SF-36v2) (generic) HRQOL questionnaire. Statistical analyses included independent-sample t tests, one-way analysis of variance (ANOVA), and correlations. The survey was completed by 312 patients: 267 in the tiopronin group (144 male, 123 female; mean 49 years) and 45 in the non-tiopronin group (10 male, 35 female; mean 48 years). Both groups utilized pain medications similarly (24% overall). Patients on tiopronin had a significantly better HRQOL than patients not on tiopronin for all WISQOL domains (p < 0.001) and all but the physical functioning SF-36v2 domain (p < 0.001), where both groups approached the US normative mean, when controlling for the last stone event. Compared with patients in the non-tiopronin group, patients taking tiopronin reported better HRQOL on both the WISQOL and SF-36v2.

Study Design: Observational study., Objective: Assess associations between vitamin D levels and other risk factors on future chest illness in a chronic spinal cord injury (SCI) cohort., Setting: Veterans Affairs Boston and the Boston, MA community., Methods: Between August 2009 and August 2017, 253 participants with chronic SCI were followed over a median of 3.2 years (up to 7.4 years) with two to four visits a median of 1.7 years apart. At each visit, plasma 25-hydroxyvitamin D level was obtained, spirometry performed, and a respiratory questionnaire assessing chest illnesses since last visit was completed. Repeated measures negative binomial regression was used to assess chest illness risk longitudinally., Results: At entry, 25% had deficient vitamin D levels (<20 nanograms/milliliter (ng/ml)), 52% were insufficient (20 to <30 ng/ml), and 23% were sufficient (≥30 ng/ml). Over 545 study visits, chest illnesses (n = 106) were reported by 60 participants. In multivariable models (including previous chest illness history), deficient vitamin D levels (compared with those with sufficient levels) were associated with future chest illness though with wide confidence limits (relative risk (RR) = 1.36, 95% confidence intervals (CI) = 0.74, 2.47). The strongest association with chest illness during the follow-up period was in persons who reported pneumonia/bronchitis after injury and a chest illness in the three years before study entry (RR = 7.62; 95% CI = 3.70, 15.71)., Conclusion: Assessed prospectively in chronic SCI, there was a suggestive association between deficient vitamin D levels and future chest illness. Past chest illness history was also strongly associated with future chest illness.

Purpose: Electronic health records (EHRs) have led to more transparency and improvements in patient safety, yet electronic access to personal health information can pose significant threats to maintaining confidentiality for adolescents. To date, no studies have explored clinicians' perspectives on EHR functionality and institutional policies related to confidentiality and health information sharing for adolescents aged <18 years., Methods: A Web-based survey was sent out via the national listserv of the Society for Adolescent Health and Medicine. All English-speaking members practicing in the U.S. were eligible to participate. The survey included questions about demographics, EHR functionality, information sharing, and attitudes about confidentiality within the EHR., Results: Participants included 212 clinicians who consented to the survey and used an EHR to document clinical visits with minors. Most participants were physicians and nurse practitioners (96.5%), and 60.0% had been on their institution's EHR for >5 years. Positive findings included high levels of experience and comfort using the EHR and awareness of confidential features within their EHR. However, providers reported lack of training related to confidentiality within the EHR, low confidence in their EHR's ability to maintain confidentiality, and variation in approaches to portal access for adolescents and their adult proxies., Conclusions: Despite high comfort levels and robust EHR functionality at many institutions, significant concerns about adolescent confidentiality remain. Varying institutional approaches to protecting confidentiality underscores the need for a standardized and comprehensive framework to enable providers and institutions to take better care of adolescents in the age of EHRs., (Copyright © 2019 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Study Design: Cross-sectional study OBJECTIVES: To determine clinical factors associated with telomere length in persons with chronic spinal cord injury (SCI)., Setting: Veterans Affairs Medical Center, Boston, MA., Methods: Two hundred seventy-eight participants with chronic SCI provided blood samples for measurement of C-reactive protein (CRP), interleukin-6 (IL-6), and telomere length, completed respiratory health questionnaires, underwent dual X-ray absorptiometry (DXA) to assess body fat, and completed spirometry. High-throughput real-time PCR assays were used to assess telomere length in leukocyte genomic DNA. Linear regression models were used to assess cross-sectional associations with telomere length., Results: Telomere length was inversely related to age (p < 0.0001). In age-adjusted models, gender, race, injury duration, %-total and %-trunk fat, body mass index (BMI), %-predicted forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV 1 ), chronic cough or phlegm, CRP, IL-6, wheeze, smoking, diabetes, heart disease, chronic obstructive pulmonary disease (COPD), skin ulcer, urinary tract infection (UTI), or chest illness history were not significantly associated with telomere length. There was a suggestive age-adjusted association between persons with the most severe SCI (cervical motor complete and AIS C) and shorter telomere length (p = 0.055), an effect equivalent to ~8.4 years of premature aging. There were similar age-adjusted associations with telomere length between persons using a wheelchair (p = 0.059) and persons with chronic urinary catheter use (p = 0.082) compared to persons without these characteristics., Conclusions: Our results suggest that clinical characteristics such as decreased mobility and bladder dysfunction that are common in individuals with more severe SCI are associated with shorter telomere length.

Background and Objectives: Wound contracture formation from excessive myofibroblast activity can result in debilitating morbidities. There are currently no treatments to prevent contracture. Photochemical tissue passivation (PTP), an established, safe, and user-friendly treatment modality, crosslinks collagen by a light-activated process, thus modulating the wound healing response and scarring. We hypothesised that PTP treatment would reinforce wounds by blunting the fibrotic response thus limiting contracture., Study Design/materials and Methods: Full-thickness, 1 cm × 1 cm excisional wounds were created on the dorsum of 32 C57BL/6 mice. Treated wounds were painted with photosensitizing dye and exposed to visible light. Wounds were serially photographed over 6 weeks to measure wound contracture. At 7, 14, 21, and 42 days after wound creation, mice were euthanized and wounds were harvested for histologic review by a dermatopathologist., Results: By Day 7, control wounds had significantly more contracture than those treated with PTP (33.0 ± 17.1% and 19.3 ± 9.0%, respectively; P = 0.011). PTP-treated wounds maintained approximately 20% less contracture than controls from Day 14 and on (P < 0.05). By Day 42, wounds had contracted by 86.9 ± 5.5% in controls and 64.2 ± 3.2% in PTP-treated wounds (P < 0.03). Histologically, PTP wounds had earlier growth and development of dermal collagen, neovascularization, and development of skin appendages, compared with control wounds., Conclusions: PTP significantly limits contracture of full-thickness wounds and improves wound healing. PTP-treated wounds histologically demonstrate more mature structural organization than untreated wounds and closely resemble native skin. PTP treatment may be applicable not only for excisional wounds, but also for wounds with a high incidence of contracture and associated morbidity. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc., (© 2019 Wiley Periodicals, Inc.)

Rationale: Shorter leukocyte telomere length (LTL) is associated with reduced health-related quality of life and increased risk for acute exacerbations (AEs) and mortality in chronic obstructive pulmonary disease (COPD). Increased physical activity and exercise capacity are associated with reduced risk for AEs and death. However, the relationships between LTL and physical activity, exercise capacity, and AEs in COPD are unknown., Methods: Data from 3 COPD cohorts were examined: Cohort 1 (n = 112, physical activity intervention trial), Cohorts 2 and 3 (n = 182 and 294, respectively, separate observational studies). Subjects completed a 6-minute walk test (6MWT) and provided blood for LTL assessment using real-time PCR. Physical activity was measured as average daily step count using an accelerometer or pedometer. Number of self-reported AEs was available for 1) the year prior to enrollment (Cohorts 1 and 3) and 2) prospectively after enrollment (all cohorts). Multivariate models examined associations between LTL and average daily step count, 6MWT distance, and AEs., Results: A significant association between longer LTL and increased 6MWT distance was observed in the three combined cohorts (β = 3x10-5, p = 0.045). No association between LTL and average daily step count was observed. Shorter LTL was associated with an increased number of AEs in the year prior to enrollment (Cohorts 1 and 3 combined, β = -1.93, p = 0.04) and with prospective AEs (Cohort 3, β = -1.3388, p = 0.0003)., Conclusions: Among COPD patients, increased LTL is associated with higher exercise capacity, but not physical activity. Shorter LTL was associated with AEs in a subgroup of cohorts., Competing Interests: Dr. Moy reports receiving an honorarium for consulting from AstraZeneca, outside the submitted work. This does not impact our compliance with PLOS ONE policies on sharing data and materials.

Study Objectives: Low physical activity (PA) is associated with poor health outcomes in chronic obstructive pulmonary disease (COPD). Overlap syndrome (OVS), the co-occurrence of COPD and obstructive sleep apnea (OSA), is highly prevalent. Little is known about PA in OVS, and its relationship with markers of systemic inflammation., Methods: We studied 256 persons with stable COPD, 61 (24%) of whom had OVS, who were well characterized in two previous PA studies. PA was directly assessed with the Omron HJ-720ITC pedometer. C-reactive protein (CRP) and interleukin-6 (IL-6) were assayed from peripheral blood. Linear regression models, adjusting for age and forced expiratory volume in 1 second (FEV1) % predicted, assessed daily step counts and CRP and IL-6 levels in OVS, compared to COPD alone. Linear regression models, adjusting for age, FEV1 % predicted, and coronary artery disease, assessed the relationships between PA and CRP and IL-6 in those with OVS versus those with COPD alone., Results: Compared to COPD alone, persons with OVS walked 672 fewer steps per day (95% CI -1,317 to -28, P = .041). Those with OVS had significantly higher levels of CRP and IL-6 compared to COPD alone. In OVS, each 1,000 fewer steps walked was associated with a 0.875 ng/mL (95% CI 0.767 to 0.997) increase in IL-6, independent of lung function., Conclusions: Persons with OVS have significantly lower levels of PA and higher levels of inflammatory biomarkers, compared to COPD alone. Lower PA is significantly associated with higher IL-6 levels in OVS., (Copyright © 2019 American Academy of Sleep Medicine. All rights reserved.)

Context/objective: Individuals with chronic spinal cord injury (SCI) have an increased risk of morbidity and mortality attributable to respiratory diseases. Previous studies in non-SCI populations suggest that vitamin D may be a determinant of respiratory health. Therefore, we sought to assess if lower vitamin D levels were associated with decreased pulmonary function in persons with chronic SCI., Design: Cross-sectional study., Setting: Veterans Affairs Medical Center., Participants: 312 participants (260 men and 52 women) with chronic SCI recruited from VA Boston and the community participating in an epidemiologic study to assess factors influencing respiratory health., Methods: Participants provided a blood sample, completed a respiratory health questionnaire, and underwent spirometry. Linear regression methods were used to assess cross-sectional associations between plasma 25-hydroxyviatmin D and spirometric measures of pulmonary function., Outcome Measures: Forced expiratory volume in one second (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC., Results: Adjusted and unadjusted for a number of confounders, there was no significant association between plasma vitamin D levels and FEV 1 , FVC, or FEV 1 /FVC. For example, in fully adjusted models, each 10 ng/ml increase in vitamin D was associated with a 4.4 ml (95%CI -64.4, 73.2, P = 0.90) ml change in FEV 1. Conclusion: There was no significant cross-sectional association between plasma vitamin D and FEV 1 , FVC, or FEV 1 /FVC in this cohort of individuals with chronic SCI.

Extracellular matrix materials mechanically dissociated into submillimeter particles have a larger surface area than sheet materials and enhanced cellular attachment. Decellularized porcine mesothelial extracellular matrix microparticles were seeded with bone marrow-derived mesenchymal stromal cells and cultured in a rotating bioreactor. The mesenchymal stromal cells attached and grew to confluency on the microparticles. The cell-seeded microparticles were then encapsulated in varying concentrations of fibrin glue, and the cells migrated rapidly off the microparticles. The combination of microparticles and mesenchymal stromal cells was then applied to a splinted full-thickness cutaneous in vivo wound model. There was evidence of increased cell infiltration and collagen deposition in mesenchymal stromal cells-treated wounds. Cell-seeded microparticles have potential as a cell delivery and paracrine therapy in impaired healing environments.

Study Design: Cross-sectional study., Objectives: Determine dietary, lifestyle, and clinical factors associated with plasma 25-hydroxyvitamin D [25(OH)D] levels in persons with chronic spinal cord injury (SCI)., Setting: Veterans Affairs Medical Center in Boston, MA., Methods: 174 participants completed food frequency and health questionnaires, provided a blood sample, and underwent dual x-ray absorptiometry (DXA) to assess %total body fat. Linear regression models were used to assess cross-sectional associations of personal, lifestyle, and nutritional factors with plasma 25(OH)D., Results: Independent factors positively associated with higher plasma 25(OH)D included vitamin D intake, age, hours of planned exercise, female sex, white race, wine consumption, and if a never or former smoker. The most important predictor of 25(OH)D was supplement intake. The majority of subjects (98.9% for vitamin D and 74.1% for calcium) did not meet the recommended daily allowance for adults from their diet alone. Level and completeness of SCI, injury duration, mobility, %total body fat, time outside, and comorbid diseases were not associated with plasma 25(OH)D., Conclusions: Plasma 25(OH)D level in chronic SCI is not associated with clinical factors specific to SCI such as injury level and completeness, injury duration, and mobility mode, but related to supplement intake and other lifestyle factors.

Context/Objective Persons with chronic spinal cord injury (SCI) have an increased risk of respiratory-related morbidity and mortality and chronic respiratory symptoms are clinical markers of future respiratory disease. Therefore, we sought to assess potentially modifiable factors associated with respiratory symptoms, with a focus on circulating vitamin D and measures of body fat. Design Cross-sectional study. Setting Veterans Affairs Medical Center. Participants Three hundred forty-three participants (282 men and 61 women) with chronic SCI participating in an epidemiologic study to assess factors influencing respiratory health recruited from VA Boston and the community. Methods Participants provided a blood sample, completed a respiratory health questionnaire, and underwent dual x-ray absorptiometry (DXA) to assess % body fat. Logistic regression was used to assess cross-sectional associations between respiratory symptoms and plasma vitamin D and measures of body fat with adjustment for a number of potential confounders. Outcome Measures Chronic cough, chronic phlegm, any wheeze, persistent wheeze. Results After adjustment for a number of confounders (including smoking), participants with greater %-android, gynoid, trunk, or total body fat had increased odds ratios for any wheeze and suggestive associations with persistent wheeze, but not with chronic cough or phlegm. Vitamin D levels were not associated with any of the respiratory symptoms. Conclusion Increased body fat, but not vitamin D, was associated with wheeze in chronic SCI independent of a number of covariates.

Objectives: To assess pediatric providers' attitudes and barriers to initiating a contraceptive method in the inpatient setting., Methods: Pediatric attending physicians and trainees from 5 academic institutions were surveyed about contraceptive prescribing practices, attitudes, and potential barriers to initiating contraception in the inpatient setting., Results: In 2016, 271 pediatric providers (34.0% were attending physicians, 18.1% fellows, and 47.9% residents) completed the survey; the response rate was 19.2%. Most participants practiced in both inpatient and outpatient settings (95.7% and 85.0%, respectively). More providers felt confident screening for sexual activity among young adults as compared with adolescents (71.9% vs 65.6%). The same was true for discussing contraceptive options (44.0% vs 38.8%, respectively). Inpatient providers reported seeing adolescents and young adults privately, discussing confidentiality, and asking about sex less than half of the time. More than 80% of providers agreed that it would be appropriate to initiate a contraceptive method for inpatients; 35.8% had done so, and 85.2% indicated that having additional consultation would increase initiation of a contraceptive method in the hospital (88.1% felt similarly for long-active reversible contraception methods). General barriers to initiating contraception included insufficient training, insufficient exposure to adolescents and young adults to maintain skills, and lack of time. Barriers specific to the inpatient setting included concerns about follow-up, confidentiality, and interference with the treatment plan., Conclusions: Initiation of a contraceptive method in the inpatient setting is acceptable to providers. In our findings, it is suggested that strategies are needed to enhance provision of these services by addressing confidentiality concerns and educating providers., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Background: Adipose tissue produces leptin, which is pro-inflammatory, and adiponectin, which has anti-inflammatory properties. Participants with chronic spinal cord injury (SCI) have increased body fat and are at increased risk for respiratory illness., Objective: To assess the associations between leptin and adiponectin with pulmonary function in a chronic SCI cohort., Design: Cross-sectional study., Setting: Veterans Affairs Medical Center., Participants: A total of 285 participants (237 men and 48 women) with chronic SCI with mean (standard deviation) injury duration 17.8 (13.2) years from the VA Boston and the community participating in an epidemiologic study assessing factors associated with respiratory health., Methods: Participants (24.6% cervical American Spinal Injury Association Impairment Scale (AIS) level A, B, and C; 33.6% other AIS A, B, and C; 41.8% AIS D) provided a blood sample, completed a respiratory health questionnaire, and underwent spirometry. Linear regression methods were used to assess cross-sectional associations between plasma leptin and adiponectin with spirometric measures of pulmonary function adjusted for age, race, gender, and height. Level and severity of SCI, mobility mode, body mass index, smoking, chronic obstructive pulmonary disease, asthma, chest injury history, laboratory batch, and other potential confounders were also considered., Main Outcome Measurements: forced expiratory volume in 1 second (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC., Results: There was a statistically significant inverse relationship between plasma leptin assessed in quartiles or as a continuous covariate with FEV 1 and FVC. In fully adjusted models, each interquartile range (16,214 pg/mL) increase in leptin was associated with a significant decrease in FEV 1 (-93.1 mL; 95% confidence interval = -166.2, -20.0) and decrease in FVC (-130.7 mL; 95% confidence interval = -219.4, -42.0). There were no significant associations between leptin and FEV 1 /FVC or between plasma adiponectin with FEV 1 , FVC, or FEV 1 /FVC., Conclusion: Plasma leptin in individuals with chronic SCI is inversely associated with FEV 1 and FVC, independently of SCI level and severity and other covariates. This finding suggests that plasma leptin may contribute to reduced pulmonary function in chronic SCI., Level of Evidence: II., (Copyright © 2018 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

Objective: We hypothesized that decreasing vein compliance would protect the vein against stretch injury and reduce intimal hyperplasia (IH)., Background: Although arteriovenous fistulas (AVFs) are the criterion standard for vascular access, their effectiveness is limited by poor patency with 40% to 60% failing due to IH. Venous stretch injury from exposure to arterial pressure induces IH. Photochemical tissue passivation (PTP) crosslinks adventitial collagen, decreasing vein compliance to resemble that of an artery., Methods: AVFs were created between the femoral artery and epigastric vein in rats (n = 29). PTP was performed on the vein immediately before vessel anastomosis. AVFs were harvested after four weeks. Venous diameter was measured at the initial procedure and harvest. Intimal area was measured for each segment. Ultrasound was performed at harvest to measure AVF flow., Results: Following AVF construction, venous diameter increased by 10% ± 18% for PTP-treated vessels and 78% ± 27% for controls (P ≤ 0.0001). At one month, PTP reduced AVF dilation by 71% compared to control (69% ± 29% vs 241% ± 78%; P ≤ 0.0001). Both juxta-anastomotic intimal area and total intimal area were reduced in PTP-treated vessels compared to control vessels. Specifically, intimal area was 0.024 ± 0.018 and 0.095 ± 0.089 mm for PTP-treated juxta-anastomotic segments of AVF and control, respectively (P < 0.05). Mean total intimal area for PTP-treated and control AVF were 0.080 ± 0.042 and 0.190 ± 0.110 mm, respectively (P < 0.03). AVF flow was 46.9 ± 35.3 and 19.1 ± 10.1 mL/min for PTP-treated and control AVF, respectively (P < 0.109)., Conclusions: These data demonstrate that PTP represents a promising therapy for the prevention of AVF IH, a process that might improve surgical outcomes for patients receiving hemodialysis.

Study Design: Cross-sectional study., Objectives: Determine clinical factors associated with plasma C-reactive protein (CRP) in persons with chronic spinal cord injury (SCI)., Setting: Veterans Affairs Medical Center in Boston, MA, USA., Methods: Participants provided a blood sample, completed a respiratory health questionnaire and underwent dual X-ray absorptiometry (DXA) to assess total and regional body fat. Linear regression models were used to assess cross-sectional associations with plasma CRP., Results: In multivariable models, factors associated with a higher CRP included a greater BMI, urinary catheter use, a respiratory illness in the past week and non-white race. Mean CRP also increased with decreasing mobility (motorized wheelchair >hand-propelled wheelchair >walk with an assistive device >walk independently). Results were similar when adjusting for percentage android, gynoid, trunk or total fat mass in place of BMI. Level and completeness of SCI was not associated with CRP in multivariable models., Conclusions: Clinical characteristics common in chronic SCI are associated with plasma CRP. These factors are more important than the level and completeness of SCI and some are potentially modifiable.

Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.

The EZH2 histone methyltransferase mediates the humoral immune response and drives lymphomagenesis through formation of bivalent chromatin domains at critical germinal center (GC) B cell promoters. Herein we show that the actions of EZH2 in driving GC formation and lymphoma precursor lesions require site-specific binding by the BCL6 transcriptional repressor and the presence of a non-canonical PRC1-BCOR-CBX8 complex. The chromodomain protein CBX8 is induced in GC B cells, binds to H3K27me3 at bivalent promoters, and is required for stable association of the complex and the resulting histone modifications. Moreover, oncogenic BCL6 and EZH2 cooperate to accelerate diffuse large B cell lymphoma (DLBCL) development and combinatorial targeting of these repressors results in enhanced anti-lymphoma activity in DLBCLs., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Aggressive double- and triple-hit (DH/TH) diffuse large B-cell lymphomas (DLBCLs) feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls posttranscriptional dynamics of key messenger RNA (mRNA) species including those encoding BCL6, MYC, and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E. eIF4E drives nuclear export and translation of BCL6, MYC, and BCL2 mRNA. eIF4E RNA-immunoprecipitation sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes B-cell receptor signaling, cellular metabolism, and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes, DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counterregulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative antilymphoma activity in DH/TH DLBCL in vitro and in vivo., (© 2016 by The American Society of Hematology.)

Rationally designed combinations of targeted therapies for refractory cancers, such as activated B cell-like diffuse large B cell lymphoma (ABC DLBCL), are likely required to achieve potent, durable responses. Here, we used a pharmacoproteomics approach to map the interactome of a tumor-enriched isoform of HSP90 (teHSP90). Specifically, we chemically precipitated teHSP90-client complexes from DLBCL cell lines with the small molecule PU-H71 and found that components of the proximal B cell receptor (BCR) signalosome were enriched within teHSP90 complexes. Functional assays revealed that teHSP90 facilitates BCR signaling dynamics by enabling phosphorylation of key BCR signalosome components, including the kinases SYK and BTK. Consequently, treatment of BCR-dependent ABC DLBCL cells with PU-H71 attenuated BCR signaling, calcium flux, and NF-κB signaling, ultimately leading to growth arrest. Combined exposure of ABC DLBCL cell lines to PU-H71 and ibrutinib, a BCR pathway inhibitor, more potently suppressed BCR signaling than either drug alone. Correspondingly, PU-H71 combined with ibrutinib induced synergistic killing of lymphoma cell lines, primary human lymphoma specimens ex vivo, and lymphoma xenografts in vivo, without notable toxicity. Together, our results demonstrate that a pharmacoproteome-driven rational combination therapy has potential to provide more potent BCR-directed therapy for ABC DLCBL patients.