Citations

Hepatic ischemia/reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSCs) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from mesenchymal stem cells (MSC‐EV) on tissue injury. The effects of systemically administered mouse bone marrow–derived MSC‐EV were evaluated in an experimental murine model of hepatic IRI induced by cross‐clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of up to 6 hours. Compared with controls, intravenous administration of MSC‐EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase 3–positive and apoptotic cells, and reduced serum aminotransferase levels. MSC‐EV increased hepatic messenger RNA (mRNA) expression of NACHT, LRR, and PYD domains‐containing protein 12, and the chemokine (C‐X‐C motif) ligand 1, and reduced mRNA expression of several inflammatory cytokines such as interleukin 6 during IRI. MSC‐EV increased cell viability and suppressed both oxidative injury and nuclear factor kappa B activity in murine hepatocytes in vitro. In conclusion, the administration of extracellular vesicles derived from bone marrow–derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.Liver Transplantation 23 791–803 2017 AASLD.

ObjectiveTo develop response criteria for adult dermatomyositis (DM) and polymyositis (PM).MethodsExpert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus.ResultsConsensus was reached for a conjoint analysis–based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0–100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001).ConclusionThe response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

184 Background: While evidence of the challenges of cancer caregiving has been growing, scant research addresses the experience of partners of young adults with cancer. These individuals and their relationships may be particularly vulnerable to stress, especially when managing the complexity of cancer care and survivorship with their partner. We sought to evaluate psychosocial concerns and mental health in the partners of young survivors of early stage breast cancer (BC). Methods: We invited partners of young women w/BC diagnosed at age ≤ 40 yrs enrolled in a prospective cohort study to participate in a one-time survey evaluating psychosocial concerns including quality of life, coping, social support, financial insecurity, partnership concerns, parenting concerns, anxiety and depression. Logistic regression was used to explore predictors of anxiety (score > 8 on Hospital Anxiety and Depression Scale (HADS)). Results: Most respondents (284/289) were male, with median age 43 yrs (range 27-65). The median time of survey completion was 62 months (range 16 -114) after their partner’s dx. Respondents were mostly white (93%), working full time (94%), and college educated (78%); 29% reported some financial stress, 74% were parenting children < 18 yrs, and 32% reported at least a fair amount of relationship concern. 42% (106/250) had anxiety (39/289 respondents (13%) had incomplete/missing HADS). In univariable analyses, lower education, working full time, parenting concerns, insufficient social support and maladaptive coping were associated (p < .05) with anxiety. In the multivariable model, only maladaptive coping remained significantly associated with anxiety (p < .01, OR = 2.32 (95% CI: 1.22, 4.39)). Conclusions: Partners of young BC survivors who used less constructive/more maladaptive coping strategies experience negative mental health outcomes after tx has ended. Caregivers’ anxiety may have implications for both their own and survivors’ health and QOL. Future interventions might focus on the development of constructive coping strategies to enhance adjustment and role effectiveness in dealing with the impact of cancer.

Background— Data on the clinical use of left atrial (LA) hemodynamic monitoring during MitraClip procedure are limited. This study evaluated the association between intraprocedural changes in LA pressure after MitraClip and improvement in exercise capacity as documented by 6-minute walk test (6MWT). Methods and Results— Study population included 50 patients who underwent MitraClip at the Mayo Clinic (Rochester, MN), between June 2014 and July 2016 and completed both baseline and 30-day follow-up 6MWT. Primary outcome for the current analysis was defined as 6MWT improvement above the median. Mean age of the study population was 79±10 years, and 34 (68%) were men. Baseline preprocedural 6MWT distance was 308 m (interquartile range [IQR], 234–394 m). Acute, intraprocedural change in LA pressure after MitraClip was 3 mm Hg (IQR, 1–6 mm Hg), and change in V wave was 11 mm Hg (IQR, 6–19 mm Hg). Median 6MWT improvement was 25 m (IQR, 19–47 m). Univariate analysis showed that patients with ≤ mild postprocedural mitral regurgitation were 4-fold more likely to experience an improvement in 6MWT ( P =0.02). Multivariate model demonstrated that each 5 mm Hg decrease in V wave was associated with 49% increased likelihood for improvement in 6-minute walk ( P =0.04). Similar model with V-wave change as a dichotomous variable showed that patients with a V-wave decrease of ≥11 mm Hg were 3.8× more likely to improve their 6MWT ( P =0.05). Conclusions— Acute changes in LA pressure after MitraClip procedure are associated with clinical improvement as measured by 6MWT. Continuous LA pressure monitoring may be a useful tool for procedural guidance during transcatheter mitral repair.

Abstract Background: Despite the well-established survival benefit associated with adjuvant hormonal treatment, younger women with hormone receptor positive (HR+) breast cancer (BC) are less adherent to endocrine therapy (ET) as prescribed, compared to their older counterparts, and may have unique issues that contribute to ET non-adherence. In an effort to identify factors that can be targeted to improve ET uptake and adherence, we sought to evaluate ET initiation in young women with BC. Methods: As part of a multi-center, prospective cohort enrolling women with newly diagnosed BC at age ≤40 years between 2006-2016, we identified 657 women with HR+, Stage 0-III BC. Participants complete serial surveys that included questions about socio-demographics, fertility concerns, and treatment. Women who did not report taking tamoxifen or an aromatase inhibitor (AI) at least once in the 18 months after diagnosis (dx) were classified as non-initiators. Variables significant at p&lt;0.20 in univariable models were entered into a multivariable logistic regression model to identify independent (p&lt;0.05) predictors of non-initiation. Results: By 18 months post-dx, 15% (99/657) had not initiated ET; among women with Stage 0 BC, 77% (51/66) had not initiated vs 8% (48/591) with invasive BC (p&lt;0.0001). Among initiators (N=558), 93% were on tamoxifen, with 7% reporting AI alone or in addition to tamoxifen; 97% started ET within 12 months of dx. Among women with invasive BC (Table), non-initiation was associated with having less than a college degree (OR: 2.49 95% CI: 1.25-4.94), non-Caucasian race (OR: 2.58 95% CI: 1.18-5.64) and non-receipt of radiation (OR: 0.40 95% CI: 0.21-0.75).Age at dx, marital status, having children, employment, perceived financial comfort, fertility concern, stage, surgery, and chemotherapy were not significantly associated with non-initiation. Conclusion: Most young women with HR+ DCIS do not take adjuvant ET despite the potential benefits (substantially reduced risk of local recurrence and contralateral BC) and very low risk of serious toxicity. Among young women with invasive HR+ BC, a significant minority fails to start ET within 18 months of dx. Adjuvant ET non-initiation may contribute in part to the racial and SES outcomes disparities that have been observed. Further study is needed to elucidate barriers to initiation with the goal of developing targeted interventions that will enhance ET initiation and adherence in general. Table. Predictors of ET non-initiation in women with invasive BC (N=577*) Univariable Multivariable Median (range)OR (95% CI)pOR (95% CI)ppAge at dx (years)36 (17-40)1.08 (0.99-1.18)0.07 N (%) Financial comfort300 (51)0.88 (0.49-1.60)0.68 Non-white59 (10)2.68 (1.25-5.71)0.012.58 (1.18-5.64)0.02Full employment282 (48)0.76 (0.42-1.39)0.38 Less than college graduate95 (16)2.61 (1.36-5.02)0.0042.49 (1.25-4.94)0.009Married/living as married452 (77)0.79 (0.41-1.55)0.50 Children pre-diagnosis369 (62)1.11 (0.60-2.05)0.75 Fertility concern234 (40)0.92 (0.50-1.70)0.80 Stage (ref=3) 1244 (41)1.22 (0.47-3.15)0.68 2259 (44)1.27 (0.50-3.24)0.62 Mastectomy vs lumpectomy335 (57)1.16 (0.64-2.12)0.63 Radiation therapy331 (56)0.40 (0.21-0.73)0.0030.40 (0.21-0.75)0.004Chemotherapy411 (70)0.66 (0.36-1.22)0.18 *multivariable analytic cohort Citation Format: Rosenberg SM, Gelber S, Ruddy KJ, Tamimi RM, Schapira L, Borges VF, Come S, Meyer ME, Partridge AH. Drugs don't work if people don't take them: Non-initiation of endocrine therapy in young women [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-09-07.

Objectives: Effective pharmacologic treatments directly targeting lung injury in patients with the acute respiratory distress syndrome are lacking. Early treatment with inhaled corticosteroids and beta agonists may reduce progression to acute respiratory distress syndrome by reducing lung inflammation and enhancing alveolar fluid clearance. Design: Double-blind, randomized clinical trial (ClinicalTrials.gov: NCT01783821). The primary outcome was longitudinal change in oxygen saturation divided by the F io 2 (S/F) through day 5. We also analyzed categorical change in S/F by greater than 20%. Other outcomes included need for mechanical ventilation and development of acute respiratory distress syndrome. Setting: Five academic centers in the United States. Patients: Adult patients admitted through the emergency department at risk for acute respiratory distress syndrome. Interventions: Aerosolized budesonide/formoterol versus placebo bid for up to 5 days. Measurements and Main Results: Sixty-one patients were enrolled from September 3, 2013, to June 9, 2015. Median time from presentation to first study drug was less than 9 hours. More patients in the control group had shock at enrollment (14 vs 3 patients). The longitudinal increase in S/F was greater in the treatment group ( p = 0.02) and independent of shock ( p = 0.04). Categorical change in S/F improved ( p = 0.01) but not after adjustment for shock ( p = 0.15). More patients in the placebo group developed acute respiratory distress syndrome (7 vs 0) and required mechanical ventilation (53% vs 21%). Conclusions: Early treatment with inhaled budesonide/formoterol in patients at risk for acute respiratory distress syndrome is feasible and improved oxygenation as assessed by S/F. These results support further study to test the efficacy of inhaled corticosteroids and beta agonists for prevention of acute respiratory distress syndrome.

94 Background: Technetium (Tc99m) trofolastat (USANC) is a novel urea-based small molecule SPECT radiotracer with utility in imaging overexpression of PSMA in prostate cancer (PCa). Unlike earlier agents targeting PSMA, this ligand is rapidly internalized and retained in tumors. We conducted an open-label, multicenter phase 2 study in the US and Europe (NCT01667536). An interim analysis was performed at approximately 50% accrual. Methods: Patients (pts) with confirmed adenocarcinoma of the prostate scheduled for RP with EPLND at high risk for disease outside of the prostate gland were eligible. High risk pts were ≥cT3 or Kattan nomogram score ≥130. Within 30 days of screening, pts required a bone scan and pelvic MRI. After enrollment, pts received trofolastat followed by whole-body planar and SPECT/CT imaging 3 to 6 hrs later. Pts then underwent RP with EPLND within 21 days. SPECT/CT images were evaluated centrally by 3 readers blinded to clinical information and compared to on-site pathology assessments using a common scoring template. The primary endpoint was the ability of trofolastat to detect PCa within the gland. Secondary endpoints included detection of extent and location within the gland, pelvic lymph nodes and comparative performance against MRI. Results: 84 pts were enrolled to date from 16 centers. Interim data is available for 54 pts. A majority (≥2/3) of SPECT/CT readers correctly identified the presence or absence of primary PCa in 51/54 (94%, 85-98 95% CI) patients including 2 true-negative cases treated with neoadjuvant enzalutamide. Sensitivity and specificity were 94% (84-98 95% CI) and 100% (34-100 95% CI) respectively. Conclusions: Based on the interim data available, trofolastat has accurately detected primary prostate carcinoma within the gland with high sensitivity and specificity in high-risk pts prior to surgery. Updated results, analyses of secondary endpoints, pelvic lymph nodes, and comparative performance vs. MRI from this ongoing study will be presented. Clinical trial information: NCT01667536. [Table: see text]