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BACKGROUND To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes posttransplantation. METHODS We analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre-HCT depression requiring treatment versus those without pre-HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post-HCT using Poisson models. We also compared the incidence of grade 2-4 acute and chronic graft-versus-host disease (GVHD) in allogeneic HCT. RESULTS The study included 1116 (15%) patients with pre-transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre-transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04-1.23; P = 0.004) and a higher incidence of grade 2-4 acute GVHD (HR, 1.25; 95% CI, 1.14-1.37; P

Introduction Chimeric antigen receptor (CAR) T cell immunotherapy represents a novel and increasingly used treatment modality for patients with relapsed and/or refractory B cell malignancies. Acute neurological toxicities of CAR-T cell therapy (e.g. immune effector cell-associated neurotoxicity syndrome) are well described, though delayed cognitive and emotional functioning and quality of life (QOL) are less well studied, with mechanisms of all incompletely understood. Given the known bidirectional relationship between neuroinflammation and depression, and the role of kynurenine (Kyn) metabolism in both, we studied QOL through patient-reported outcomes (PROs) and neurotoxicity and their relationship to Kyn metabolites. Methods Patients with relapsed refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia treated with CAR-20/19-T cells on our Phase I/Ib clinical trial (NCT03019055) (N=16) were included. Patients were excluded if they had a history of previous allogeneic hematopoietic stem cell transplantation. Study subjects provided serum and PROs through self-report surveys at the following time points: baseline/ apheresis, Day-14 (D14), D28, and D90 post-intervention. The following scales were used to assess QOL: Inventory of Depression and Anxiety Symptoms (IDAS), Brief Pain Inventory (BPI), Fatigue Severity Index (FSI), and Pittsburgh Sleep Quality Index (PSQI). Tryptophan and its metabolites (kynurenine (Kyn), 3-Hydroxy-anthranilic Acid (3-HAA), 3-Hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA)) and neurotoxicity grades were measured for all 16 subjects. Patients were evaluated for neurotoxicity with the CTCAE 5.0. The measurements were log-transformed to stabilize the variances and allow modeling of the expected multiplicative effects. A mixed effects longitudinal model was used for all eligible patients to evaluate the impact of time on all PRO variables over the 4 timepoints through 90 days post CAR-T infusion. Neurotoxicity was evaluated two ways: as a categorical variable with 5 levels (0 to -4) and as a continuous variable. Results Depression symptoms improved over time with the lowest value at Day 90, though the changes were not statistically significant (P = .072). Remaining QOL PRO variables did not show statistically significant changes, tending to improve or remain stable over time (Table 1 & Figure 1). Mean Kyn levels significantly changed over time (P = .028; Table 2). This effect is most pronounced in patients with Grade 3/4 neurotoxicity where Kyn levels rise at Day 14 and Day 28 followed by a decrease by Day 90 (Figure 2). Among patients who exhibited neurotoxicities, baseline levels of 3-HAA and 3-HK before CAR-T therapy were elevated; though nonsignificant, similar trends were not observed in the other metabolites (Figure 2). These observations however were significant when neurotoxicity was evaluated as a continuous variable (Table 2) with 3-HAA and 3-HK higher in patients with higher grade neurotoxicities (P = .015 and .070). Conclusions Our findings suggest that CAR-T therapy does not impair QOL and may in fact result in improved mood in the early months following cell infusion, adding to recent literature about long-term QOL in CAR-T survivors. Here, we also identify elevated baseline 3-HAA and 3-HK levels as well as increased Kyn levels following CAR-T therapy, with the first two associated with worse neurotoxicity. Most interestingly, we find higher levels of 3-HAA and 3-HK in patients who experience neurotoxicities. Correlational studies will be needed to confirm potential relationships between PROs and metabolites. Disclosures Hari: Incyte Corporation: Consultancy; Takeda: Consultancy; BMS: Consultancy; Amgen: Consultancy; GSK: Consultancy; Janssen: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Kite Pharma: Consultancy, Honoraria; Lily: Consultancy, Honoraria.

This secondary analysis of a large, multicenter Blood and Marrow Transplant Clinical Trials Network randomized trial assessed whether patient-reported outcomes (PROs) and socioeconomic status (SES) before hematopoietic stem cell transplantation (HCT) are associated with each other and predictive of clinical outcomes, including time to hematopoietic recovery, acute graft-versus-host disease, hospitalization days, and overall survival (OS) among 646 allogeneic and autologous HCT recipients. Pretransplantation Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores of the Short-Form 36 were correlated with each other and with SES variables. PROs and SES variables were further evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors (P

BackgroundClinical outcomes among allogeneic hematopoietic cell transplant (HCT) recipients are negatively affected by low socioeconomic status (SES), yet the biological mechanisms accounting for this health disparity remain to be elucidated. Among unrelated donor HCT recipients with acute myelogenous leukemia, one recent pilot study linked low SES to increased expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA) in peripheral blood mononuclear cells, which involves up-regulation of pro-inflammatory genes and down-regulation of genes involved in type I interferon response and antibody synthesis.MethodsThis study examined these relationships using additional measures in a larger archival sample of 261 adults who received an unrelated donor HCT for acute myelogenous leukemia to 1) identify cellular and molecular mechanisms involved in SES-related differences in pre-transplant leukocyte transcriptome profiles, and 2) evaluate pre-transplant CTRA biology associations with clinical outcomes through multivariable analysis controlling for demographic-, disease-, and transplant-related covariates.ResultsLow SES individuals showed increases in classic monocyte activation and pro-inflammatory transcription control pathways as well as decreases in activation of nonclassic monocytes, all consistent with the CTRA biological pattern. Transplant recipients in the highest or lowest quartiles of the CTRA pro-inflammatory gene component had a more than 2-fold elevated hazard of relapse (hazard ratio [HR] = 2.47, 95% confidence interval [CI] = 1.44 to 4.24), P = .001; HR = 2.52, 95% CI = 1.46 to 4.34, P = .001) and more than 20% reduction in leukemia-free survival (HR = 1.57, 95% CI = 1.08 to 2.28, P = .012; HR = 1.49, 95% CI = 1.04 to 2.15, P = .03) compared with the middle quartiles.ConclusionsThese findings identify SES- and CTRA-associated myeloid- and inflammation-related transcriptome signatures in recipient pre-transplant blood samples as a potential novel predictive biomarker of HCT-related clinical outcomes.

BACKGROUND Routine monitoring of cancer-related distress is recognized as essential to quality care and mandated by a major accrediting organization. However, to the authors' knowledge, few cancer-specific measures have been developed to date to assess the multiple cancer-related factors contributing to this distress. In the current study, the authors examined the psychometric properties of the Cancer and Treatment Distress (CTXD) measure over time in hematopoietic cell transplantation (HCT) recipients. METHODS As a secondary analysis of a multicenter randomized controlled clinical trial, adult patients undergoing autologous or allogeneic HCT completed patient-reported outcomes including the CTXD and the Medical Outcomes Study Short Form-36 (SF-36) before transplantation and 100 days and 180 days after HCT. RESULTS Across 21 transplantation centers, a total of 701 patients consented, underwent transplantation, and were included in the current analyses, 645 of whom were alive at 100 days and 618 of whom were alive at 180 days. Internal consistency reliability was found to be strong for the overall CTXD at the 3 time points: Cronbach alphas (α) were .94, .95, and .95, respectively. Subscale reliability met hypothesized levels of an α>.70 across time, with the lowest reliability noted for the Identity subscale at 180 days (α = .77). Correlations with the SF-36 Mental Health subscale were higher than with the Physical Functioning subscale at each time point, thereby supporting convergent and discriminant validity. Strong correlations of the pretransplantation CTXD with the posttransplantation CTXD and SF-36 Mental Health subscale supported predictive validity. CONCLUSIONS The CTXD is reliable and valid as a measure of cancer distress both before and after HCT. It may be a useful tool for measuring dimensions of distress and for defining those patients requiring treatment for distress during and after transplantation. Cancer 2016. © 2016 American Cancer Society.

Quality of life is increasingly recognized as an important secondary endpoint of hematopoietic cell transplantation (HCT). The current study examined the extent to which attrition results in biased estimates of patient quality of life. The study also examined whether patients differ in terms of trajectories of quality of life in the first 6 months after transplantation. A secondary data analysis was conducted of 701 participants who enrolled in the Blood and Marrow Transplantation Clinical Trials Network 0902 trial. Participants completed the Medical Outcomes Study Short Form 36, a measure of quality of life, before undergoing transplantation and again 100 days and 180 days after transplantation. Results indicated that attrition resulted in slightly biased overestimates of quality of life but the amount of overestimation remained stable over time. Patients could be grouped into 3 distinct classes based on physical quality of life: (1) low and stable; (2) average and declining, then stable; and (3) average and stable. Four classes of patients emerged for mental quality of life: (1) low and stable; (2) average, improving, then stable; (3) higher than average (by almost 1 SD) and stable; and (4) average and stable. Taken together, these data provide a more comprehensive understanding of quality of life that can be used to educate HCT recipients and their caregivers.

OBJECTIVE: This meta-analysis examines the efficacy of interventions to reduce alcohol consumption and related problems among college student members of Greek letter organizations. METHOD: Studies were identified through electronic bibliographic database searches and reviews of reference sections of relevant articles, and studies were included if the study evaluated (a) an individual-level alcohol intervention, (b) sampled fraternity or sorority members, and (c) measured alcohol consumption or problems. Included were 15 studies with 21 separate interventions (n = 6,026; 18% women). Independent raters coded sample, design, methodological features, and intervention content. Between- and within-group weighted mean effect sizes were calculated using random-effects models. Potential moderators, determined a priori, examined variability in effect sizes. RESULTS: Interventions targeting fraternity or sorority members were not successful in reducing alcohol consumption and related problems relative to controls; however, participants in these interventions did reduce the quantity consumed on specific occasions and the frequency of drinking days from pre- to post-test. Interventions that addressed alcohol expectancies were associated with less alcohol consumption on specific occasions. Interventions that provided moderation strategies and skills-training, identified high-risk situations, or encouraged setting goals were associated with less reduction in the frequency of heavy drinking. CONCLUSIONS: Extant alcohol interventions show limited efficacy in reducing consumption and problems among fraternity and sorority members. More robust interventions are needed for use with student members of Greek letter organizations. (PsycINFO Database Record(c) 2016 APA, all rights reserved). Language: en

Purpose: Low socioeconomic status (SES) is associated with adverse outcomes among unrelated donor hematopoietic stem cell transplant (HCT) recipients, but the biologic mechanisms contributing to this health disparity are poorly understood. Therefore, we examined whether social environment affects expression of a stress-related gene expression profile known as the conserved transcriptional response to adversity (CTRA), which involves upregulation of proinflammatory genes and downregulation of genes involved in type I IFN response and antibody synthesis. Experimental Design: We compared pretransplant leukocyte CTRA gene expression between a group of 78 high versus low SES recipients of unrelated donor HCT for acute myelogenous leukemia in first remission. Post hoc exploratory analyses also evaluated whether CTRA gene expression was associated with poor clinical outcomes. Results: Peripheral blood mononuclear cells collected pre-HCT from low SES individuals demonstrated significant CTRA upregulation compared with matched HCT recipients of high SES. Promoter-based bioinformatics implicated distinct patterns of transcription factor activity, including increased CREB signaling and decreased IRF and GR signaling. High expression of the CTRA gene profile was also associated with increased relapse risk and decreased leukemia-free survival. Conclusions: Low SES is associated with increased expression of the CTRA gene profile, and CTRA gene expression is associated with adverse HCT clinical outcomes. These findings provide a biologic framework within which to understand how social environmental conditions may influence immune function and clinical outcomes in allogeneic HCT. Clin Cancer Res; 22(1); 69–78. ©2015 AACR. See related commentary by Turcotte and Verneris, p. 6

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has become the standard treatment for many diseases, but it is an intense and distinctive experience for patients. HSCT-related mortality is present throughout the whole process of transplantation, from pretransplantation to recovery. Long-term rehabilitation and the uncertain risk of death evoke feelings of vulnerability, helplessness, and intense fear. Zimmermann et al. proposed that spiritual well-being is an important dimension of quality of life and that patients at the end stage of life require spiritual support in addition to physical care, psychological care, and social support. Therefore, the purpose of this review is to examine the role of spirituality in the process of HSCT. METHOD: A systematic mixed studies review (SMSR) was based on Pluye and Hong’s framework to understand the role of spirituality in patients’ experiences while undergoing HSCT. We use the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement to report the results of integration. RESULTS: Fifteen original qualitative studies, 19 quantitative studies, and one mixed method study were included in the systematic mixed studies review. The evidence from the review revealed the following three themes: the spiritual experiences of HSCT patients, the spiritual coping styles of HSCT patients, and the spiritual need changes brought about by HSCT. DISCUSSION: Few medical institutions currently offer spiritual healing, although HSCT patients with different cultural backgrounds may have different spiritual experiences and spiritual coping styles. Psychotherapists or nurses should be considered to provide spiritual care for patients undergoing HSCT, to help patients cope with disease pressures, promote HSCT patients’ comfort, and improve their quality of life.

Fatigue is a commonly reported quality of life concern after hematopoietic stem cell transplant (HSCT). Fatigue severity, duration, and interference with daily activities were evaluated at post-transplant milestones during acute recovery and through 6 years post-HSCT. We also investigated whether disease and treatment factors (allogeneic or autologous graft, diagnosis, treatment regimen), inflammation, and psychological symptoms during the peri-transplant period predicted early and long-term fatigue. Participants were 433 (191 allogeneic, 242 autologous) HSCT recipients who completed measures of fatigue (FSI), depression and anxiety (IDAS) pre-HSCT, and 1, 3, and 6 months, and 1, 3, and 6 years post-HSCT. A subset (n = 210) provided blood samples during the first 6 months post-HSCT for determination of circulating cytokine levels (IL-6, TNFα, IL-10). The majority of participants reported clinically significant fatigue at 1 (83.9%), 3 (68.4%), and 6 months (64.7%) post-HSCT. Mixed effects regression models evaluated predictors of fatigue during early recovery. Allogeneic HSCT recipients showed a slower recovery, reporting more fatigue than autologous HSCT recipients at 3 and 6 months post-HSCT, but comparable fatigue at other points (interaction z=2.99, p=0.003). No other disease or treatment factors predicted fatigue. After covarying for transplant type and patient age, higher IL-6, TNFα and IL-10 levels (all p

Introduction Chimeric antigen receptor (CAR) T-cell therapy is a promising novel T-cell immunotherapy in cancer treatment that has shown clinical efficacy in treating refractory CD19+ B-cell malignancies. However, its use is associated with severe immune-mediated toxicities, including cytokine release syndrome (CRS) and CAR T-cell-related encephalopathy syndrome (CRES). CRS is a systemic inflammatory immune response resulting in symptoms ranging from constitutional to profound organ dysfunction; CRES is a neurotoxicity that can occur concurrently or separately from CRS. Objective This case report and discussion provide an overview of CRES and CRS and highlight special considerations for consultation-liaison (CL) psychiatrists. Method We describe a case of a woman treated with CAR T-cell therapy who developed CRES and CRS, including neuropsychiatric manifestations. We reviewed the literature using “Pubmed” search terms of “CAR T-cell therapy” and “CRS” or “CRES”. Discussion We provide an overview of CRS and CRES. We also highlight special considerations for the CL psychiatrist including completing a delirium workup, weighing risks/benefits of psychotropic agents to treat neuropsychiatric manifestations of CRES, and recognizing the potential for long-term behavioral health symptoms related to CRES, CRS, or their treatments. Conclusion CAR T-cell immunotherapy is becoming more prevalent. It is imperative that CL psychiatrists become familiar with this immunotherapy's toxicities including pathophysiology, neuropsychiatric manifestations, and evaluation and management to ensure optimal patient care. Finally, since immune activation, inflammation, and cytokine activation - as occurs with CRES - are known to affect cognitive and/or emotional functioning, CL psychiatrists must remain vigilant for these potential long-term psychiatric complications.

OBJECTIVE: The purpose of the current study was to (1) assess healthcare providers’ beliefs about and referral patterns to yoga and meditation services, and (2) evaluate the effectiveness of a brief yoga/meditation educational presentation to increase providers’ intent to recommend these programs. METHOD: A brief 5-min presentation regarding the benefits of yoga and meditation for cancer patients and instruction about referring and enrolling patients was delivered in four different oncology settings: breast, gynecologic, radiation, and surgical. Healthcare provider participants filled out pre- and post-surveys assessing knowledge and attitudes surrounding yoga and meditation classes. RESULTS: A total of 40 healthcare providers were surveyed, consisting of 18 physicians, 12 nurses, six nurse practitioners, two physician assistants, one pharmacist, and one clinical researcher. Of these 40 healthcare providers, 43% were unaware at baseline that yoga and meditation classes were offered through the cancer center and 55% responded that they rarely or never recommend yoga or meditation for patients. Following a brief presentation about the benefits of yoga and meditation for cancer patients, 90% of providers stated they would be more likely to recommend these services to patients in the future. There was a significant (p < 0.01) increase in providers from pre- to post-presentation (65 to 85%) stating they strongly believe yoga and meditation can provide physical or emotional benefits for their patients. SIGNIFICANCE OF RESULTS: These data demonstrate that a brief educational intervention about yoga and meditation for cancer patients is effective at significantly increasing provider knowledge about the benefits of these therapeutic modalities, with a majority indicating they are more likely to recommend these services in the future. Increasing provider awareness regarding the health-promoting benefits of such supportive services for cancer patients could result in greater service utilization as well as physical and emotional benefits for patients.

For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n = 697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P, SCOPUS: ar.j, info:eu-repo/semantics/published

Historically, sickness symptomatology in cancer patients has been studied as aggregated phenomena arising from a similar inflammatory etiology. A parent clinical trial analyzed depression, anxiety, fatigue, sleep, and pain as separate variables in hematopoietic cell transplant (HCT) recipients experiencing cytokine blockade with an interleukin-6 receptor antagonist, tocilizumab. Contrary to initial hypotheses, tocilizumab recipients had worse post-HCT levels of depression, anxiety, pain, and sleep. Interestingly, we found that fatigue, as assessed by the Fatigue Symptom Inventory (FSI) administered at baseline and post-transplant days + 28 (D + 28), D + 100, and D + 180, was not similarly affected. Fatigue levels did not differ between the 25 patients who received one prophylactic dose of tocilizumab prior to allogeneic HCT and a historical control group of 63 HCT patients who did not receive tocilizumab. In addition, whereas fatigue scores pre- and post-HCT were correlated in control patients (0.54 at D + 28, p

BACKGROUND In hematopoietic cell transplantation (HCT), current risk adjustment strategies are based on clinical and disease-related variables. Although patient-reported outcomes (PROs) predict mortality in multiple cancers, they have been less well studied within HCT. Improvements in risk adjustment strategies in HCT would inform patient selection, patient counseling, and quality reporting. The objective of the current study was to determine whether pre-HCT PROs, in particular physical health, predict survival among patients undergoing autologous or allogeneic transplantation. METHODS In this secondary analysis, the authors studied pre-HCT PROs that were reported by 336 allogeneic and 310 autologous HCT recipients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902 protocol, a study with broad representation of patients who underwent transplantation in the United States. RESULTS Among allogeneic HCT recipients, the pre-HCT Medical Outcomes Study Short Form-36 Health Survey (SF-36) physical component summary (PCS) scale independently predicted overall mortality (hazards ratio, 1.40 per 10-point decrease; P

Objective: Hematopoietic stem cell transplantation (HCT) is a stressful and rigorous medical procedure involving significant emotional and immune challenges. The endocannabinoid (eCB) signaling system is involved in regulation of both the immune system and emotional reactivity, yet little is known about its function during HCT. We investigated the role of the eCB signaling system in a group of HCT recipients. Methods: A total of 19 HCT recipients were enrolled and provided psychosocial data and blood samples at three peri-transplant time points: prior to transplant, hospital discharge, and approximately 100 days post-transplant. Psychosocial factors, inflammatory molecules, and the eCBs were determined and assessed for changes over this period and association with each other. Results: HCT recipients demonstrated significant changes over the peri-transplant period in inflammatory molecules and psychosocial functioning, but not in circulating concentrations of the eCBs. Associations among these variables were most likely to be present pre-transplant and least likely to be present immediately post-transplant, with depressive symptoms and inflammation most significantly associated. The eCB 2-arachidonoylglycerol (2-AG) was significantly, positively associated with both interleukin (IL)-6 and C-reactive protein (CRP) and negatively associated with depressive symptoms. Conclusions: The eCB signaling system may have alternative sources and regulatory mechanisms in addition to the immune system. Given the significant associations with inflammatory molecules and depressive symptoms in the peri-transplant period, it is important to better understand this system and its potential implications in the setting of complex and stressful medical procedures such as HCT.

Background Repurposing existing medications for antineoplastic purposes can provide a safe, cost-effective, and efficacious means to further augment available cancer care. Clinical and preclinical studies suggest a role for the ß-adrenergic antagonist (ß-blocker) propranolol in reducing rates of tumor progression in both solid and hematologic malignancies. In patients undergoing hematopoietic cell transplantation (HCT), the peri-transplant period is a time of increased activity of the ß-adrenergically-mediated stress response. Methods We conducted a proof-of-concept randomized controlled pilot study assessing the feasibility of propranolol administration to patients between ages 18–75 who received an autologous HCT for multiple myeloma. Feasibility was assessed by enrollment rate, tolerability, adherence, and retention. Results One hundred fifty-four patients underwent screening; 31 (20%) enrolled in other oncology trials that precluded dual trial enrollment and 9 (6%) declined to enroll in the current trial. Eighty-nine (58%) did not meet eligibility requirements and 25 (16%) were eligible; of the remaining eligible patients, all were successfully enrolled and randomized. The most common reasons for ineligibility were current ß-blocker use, age, logistics, and medical contraindications. 92% of treatment arm patients tolerated and remained on propranolol for the study duration; 1 patient discontinued due to hypotension. Adherence rate in assessable patients (n = 10) was 94%. Study retention was 100%. Conclusions Findings show that it is feasible to recruit and treat multiple myeloma patients with propranolol during HCT, with the greatest obstacle being other competing oncology trials. These data support further studies examining propranolol and other potentially repurposed drugs in oncology populations. Trial registration This randomized controlled trial was registered at clinicaltrials.gov with the identifier NCT02420223 on April 17, 2015.

Sleep disruption has received little attention in hematopoietic cell transplantation (HCT). The goal of this study was to describe severity, course, and predictors of sleep disruption following HCT. A secondary data analysis was conducted of the Blood and Marrow Transplantation Clinical Trials Network (BMT CTN) 0902 study. Participants completed a modified version of the Pittsburgh Sleep Quality Index prior to transplant and 100 and 180 days posttransplant. Growth mixture models were used to characterize subgroups of patients based on baseline sleep disruption and change over time. A total of 570 patients (mean age 55 years, 42% female) were included in the current analyses. Patients could be grouped into four distinct classes based on sleep disruption: (1) clinically significant sleep disruption at baseline that did not improve over time (20%); (2) clinically significant sleep disruption at baseline that improved over time (22%); (3) sleep disruption that did not reach clinical significance at baseline and did not improve over time (45%); and (4) no sleep disruption at baseline or over time (13%). These data provide a more comprehensive understanding of sleep disruption that can be used to develop interventions to improve sleep in HCT recipients.

There is much variability in the expression of sickle cell disease (SCD) and recent works suggest that environmental and social factors may also influence this variability. This paper aims to use geographic information systems technology to examine the association between socio-environmental exposures and health outcomes in all persons who have attended or currently attend the Sickle Cell Unit in Jamaica. Rural patients presented for clinical care at older ages and had less annual visits to clinic. Persons travelled relatively long distances to seek SCD care and those travelling longer had less health maintenance visits. Urban patients had a higher prevalence of significant pain crises (69.4% vs. 55.8%, p value

Introduction Hematopoietic stem cell transplantation (HCT) produces pro-inflammatory cytokines including IL-6 which can activate central nervous system (CNS) pathways to cause depressed mood, anxiety, fatigue, and sleep disturbance. Tocilizumab (toci), an IL-6 receptor antagonist, is an FDA approved treatment for cytokine release syndrome (CRS), a serious complication of CAR-T cell therapy. However, toci results in transient elevations of IL-6 in the CNS and there is concern that this may worsen neurotoxicity. Objective We hypothesized that increased circulating IL-6 levels would be associated with more severe symptoms among a cohort of alloHCT recipients receiving toci. Methods Data were obtained from a parent clinical trial evaluating the effectiveness of toci to prevent aGVHD in a cohort of 35 patients undergoing alloHCT. A subset of 25 patients from this cohort completed quality of life (QOL) measures pre-HCT and at day +28 post-transplant (D+28). IL-6 levels were measured pre-HCT and at D+28. The relationships between IL-6 and depression, anxiety, fatigue, and sleep were correlated in four ways using Spearman correlation: 1) cross-sectionally at baseline and at D+28; 2) change in both QOL and IL-6 from baseline to D+28; 3) baseline IL-6 level with D+28 QOL; and 4) baseline IL-6 level with change in QOL from baseline to D+28. Results Contrary to the hypothesis, IL-6 was not significantly associated with any of the QOL measures at baseline or D+28. There was a trend toward a relationship between depression and IL-6 at baseline (Fig 1; r=-0.40; p=0.06), although the association was not in the hypothesized direction; i.e., higher IL-6 was associated with less depression. Similarly, the correlations between baseline to D+28 change in IL-6 and change in QOL, baseline IL-6 and D+28 QOL, and baseline IL-6 and change in QOL were not significant. Conclusions IL-6 was not significantly associated with depression, anxiety, pain, or sleep in this cohort of alloHCT recipients receiving toci, although there was a trend toward an association between higher IL-6 and lower depression at baseline. This finding suggests that the symptoms and neurotoxicity experienced by individuals who receive toci for CRS may not be IL-6 mediated. Blockade of peripheral IL-6 receptors may lead to increased release of other cytokines, increased CNS IL-6 levels, or actions of other physiological systems and warrants further investigation.

Beta-adrenergic signaling regulates multiple molecular pathways that contribute to cancer progression; beta-adrenergic antagonists efficiently block many of these effects in animals. We previously demonstrated that hematopoietic cell transplant (HCT) patients exposed to socioeconomic stress show activation of a conserved transcriptional response to adversity (CTRA) transcriptome profile, which in turn is associated with increased relapse and decreased disease-free survival. We conducted a randomized controlled trial to evaluate whether the beta-antagonist propranolol is effective in decreasing gene expression of CTRA-related genes of 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for one week prior to transplant and 4 weeks following transplant. Blood was collected at baseline, Day −2, and Day +28. Intention-to-treat analyses assessed effects on the 53-gene CTRA indicator profile and measures of CTRA-related cellular processes. Twelve participants were randomized to the intervention group and 13 to the control arm. Relative to the control group, propranolol-treated patients showed greater decreases from baseline to Day −2 and Day +28 for both CTRA gene expression (p = .017) and bioinformatic measures of CD16- classical monocyte activation (p = .005). Propranolol-treated patients also showed up-regulation of CD34+ hematopoietic progenitor cells (p = .011). Peri-transplant administration of propranolol can down-regulate CTRA gene expression, inhibit myeloid-based cellular dynamics, and up-regulate the CD34+ cells. Ongoing follow-up and future replication studies will be required to assess impacts on clinical outcomes.

Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0902 evaluated whether exercise and stress management training before hematopoietic cell transplantation (HCT) improved physical and mental functioning after HCT. Neither overall survival nor other patient-reported transplantation outcomes were improved by the training intervention. In some animal studies of HCT, moderate-intensity exercise for 8 weeks before HCT has been associated with positive effects on hematopoietic progenitors, resulting in improved donor engraftment and improved survival. Accordingly, we performed a secondary analysis of data from BMT CTN 0902 to determine whether exercise engagement before HCT was associated with engraftment and survival. We found no significant associations between self-reported pre-HCT exercise levels and engraftment or survival. There was also no effect of pretransplantation exercise on either neutrophil or platelet engraftment. These findings do not support the observations in animal models but are limited by several shortcomings that do not refute the hypothesis that exercise before HCT may be beneficial.

The development of PTLD is a rare severe adverse event following ASCT. We report on a child with DS who developed PTLD following autologous transplant for relapsed Hodgkins disease. He was successfully treated with cyclophosphamide, prednisone and rituximab. We also present a comprehensive review of the literature of PTLD in pediatric patients following ASCT.

In hematopoietic cell transplantation (HCT), current risk adjustment strategies are based on clinical and disease-related variables. Although patient-reported outcomes (PROs) predict mortality in multiple cancers, they have been less well studied within HCT. Improvements in risk adjustment strategies in HCT would inform patient selection, patient counseling, and quality reporting. The objective of the current study was to determine whether pre-HCT PROs, in particular physical health, predict survival among patients undergoing autologous or allogeneic transplantation.In this secondary analysis, the authors studied pre-HCT PROs that were reported by 336 allogeneic and 310 autologous HCT recipients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0902 protocol, a study with broad representation of patients who underwent transplantation in the United States.Among allogeneic HCT recipients, the pre-HCT Medical Outcomes Study Short Form-36 Health Survey (SF-36) physical component summary (PCS) scale independently predicted overall mortality (hazards ratio, 1.40 per 10-point decrease; P.001) and performed at least as well as currently used, non-PRO risk indices. Survival probability estimates at 1 year for the first, second, third, and fourth quartiles of the baseline PCS were 50%, 65%, 75%, and 83%, respectively. Early post-HCT decreases in PCS were associated with higher overall and treatment-related mortality. When adjusted for patient variables included in the US Stem Cell Therapeutic Outcomes Database model for transplant center-specific reporting, the SF-36 PCS retained independent prognostic value.PROs have the potential to improve prognostication in HCT. The authors recommend the routine collection of PROs before HCT, and consideration of the incorporation of PROs into risk adjustment for quality reporting.

s / Biol Blood Marrow Transplant 22 (2016) S19eS481 S23 Cox regression analyses controlling for significant confounders. Results: We included 1116 (15%) patients with pre-HCT depression and 6317 (85%) patients without pre-HCT depression transplanted between 2008 and 2012. Patients with pre-HCT depression were similar to those without pre-HCT depressionwith regards to age, disease distribution, disease risk index, time from diagnosis to transplant, conditioning regimen, receipt of total body irradiation, graft type, donor type, and stem cell source, but they were more likely to be female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. In multivariable analyses, pre-HCT depression was associated with higher overall mortality (HR 1.13, 95% CI 1.04-1.23, p 1⁄4 0.004) and higher risk of grade II-IV acute GVHD (HR 1.25, 95%CI 1.141.37, p < 0.0001), but similar risk of chronic GVHD (HR 1.06, 95% CI 0.96-1.16, p 1⁄4 0.26). Pre-HCT depression was associated with fewer days alive and out-of-the hospital during the first 100 days (Means Ratio (MR)1⁄4 0.97, 95% CI 0.95-0.99, P1⁄4 0.004). Conclusion: Pre-HCT depression was associated with higher mortality, fewer days out of the hospital in the first 100 days, and higher risk of acute GVHD among allogeneic HCT recipients. Therefore patients with pre-HCT depression represent a highly vulnerable population at risk for posttransplant mortality and complications, and they may benefit from more intensive medical and psychological interventions.

Research investigating the undesirable outcomes of residency training mostly focuses on the effects of stress and long work-hours on patient outcomes (1), as well as physician satisfaction (2), mental health (3–5), and recruitment and retention (6, 7). There is little research, however, examining the physiological and physical health implications of the stress of such training on physicians themselves. Although current research falls short of fully understanding the health effects of medical training, there are some data, mostly from other populations, that our own “health practices” are ruining our health. With the newer and more restrictive set of the Accreditation Council for Graduate Medical Education (ACGME) residency requirements recently implemented in July 2011, it is an especially salient time to consider further research into the health effects of residency training that might knowledgeably inform policy organizations. Although there may be historical reasons and advantages for the current residency paradigm, such as healthcare demand and training experience, it is nevertheless important that we understand the physiological and neurobiological, or psychoneuroimmunological (PNI), implications of residency training on our young doctors. The stresses on today’s residents seem perhaps greater than they were several decades ago (8), although there are no direct comparison studies. Indeed, many residents report experiencing much stress and anxiety, with undesirable repercussions extending beyond their work life, although such feelings are rarely discussed (9, 10). For purposes of this article, we will consider “stress” to include sleep deprivation, perceived psychological stress, mood alterations, and social isolation. The Importance of Resident Well-Being The Institute of Medicine issued a report in 2008 setting guidelines for resident duty-hours to enhance sleep, supervision, and safety (11), spurred, in large part, by the findings that adverse events, including death, were the result of sleepdeprived and over-extended interns and residents (12). These recommended changes are undeniably important to curtail such events; however, they fail to recognize the mental and physical health-related effects of such conditions on its trainees. Whereas 45% of outpatients visiting primary care physicians report being excessively bothered by stress (13), we physicians may be less adept at practicing what we preach to our patients. By comparison, residents report a greater number of health complaints than the average worker (14). It is imperative to the integrity of the functioning of our healthcare system that we as physicians care for each other and ourselves as we would our patients. Further knowledge regarding the health effects of residency training could greatly inform healthcare policy creation. The stress-promoting effects of the practice of medicine as an attending physician are also of great importance. Because of its unique conditions, however, residency exemplifies

Passive smoking has been shown to adversely affect the health of infants and children. Black children and adults appear to be more susceptible to a variety of tobacco smoke health hazards for unknown reason. The objectives of this study were as follows: (1) to correlate the number of cigarettes reported to have been smoked by parents with urine and hair concentrations of cotinine in children; and (2) to identify race differences in systemic exposure to cotinine in children. This was an observational study in a consulting pediatric office on 169 nonsmoking children between 2 and 18 years of age, not actively smoking. The outcome measures of interest were urinary cotinine concentrations corrected for milligram of creatinine and hair concentration of cotinine (per milligram of hair). There were significant correlations between the number of cigarettes the child was exposed to and urinary cotinine (r=0.68, p=0.0001) or hair cotinine concentrations (r=0.19, p=0.02), and between urinary and hair cotinine (r=0.3, p=0.0005). In this cohort, parents of black children (n=21) tended to smoke less (6.6 ± 3/d, mean±SEM) than white parents (n=97) (12 ± 1.8, mean ± SEM) (p=0.2). Despite being exposed to less cigarettes, black children had higher hair concentrations of cotinine than white children (0.89 ± 0.25 ng/mg vs 0.48 ± 0.05 ng/mg; p=0.05). The ratio hair/urine concentrations of cotinine was twofold higher in black children (0.035±0.01 vs 0.019 ± 0.002; p=0.004). White children with dark hair did not differ significantly from white children with fair hair in any of these indexes. The amount of urinary cotinine per milligram of creatinine caused by 1 cigarette per day was twofold higher in black children (14.7 ± 5.2 ng/mg of creatinine) than in white children (6.3 ± 1.2 ng/mg of creatinine) (p=0.02). These data suggest that black children handle cigarette smoke differently from white children and that black children have higher systemic exposure to this constituent of cigarette smoke.

Psychosocial and socioeconomic factors have predicted morbidity and mortality following hematopoietic cell transplantation (HCT). However, previous studies suffer from methodological limitations, and few investigate biobehavioral pathways. This multi-center study assessed whether pre-HCT psychosocial and socioeconomic measures are associated with each other and predictive of clinical outcomes including hematopoietic recovery, acute graft versus host disease, hospitalization days, and overall survival (OS) in the 711 participants in the BMT CTN 0902, an RCT of pre-transplant exercise and stress management for autologous and allogeneic HCT recipients. Pre-transplant Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores (MCS and PCS) of the SF-36 were tested in baseline correlations with socioeconomic assessments; all were evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors ( p p = .002); lower pre-transplant income was related to worse physical functioning ( p = .005) and increased distress ( p = .008); lack of employment at the time of transplant was associated with worse physical functioning ( p p = .003). In this large heterogeneous cohort of HCT recipients, while socioeconomic and psychosocial factors were correlated at baseline, they were not associated with any clinical outcomes as has been previously reported, highlighting the complexity of biobehavioral relationships in HCT.

Introduction: Depression is associated with increased mortality among healthy individuals and patients with various medical conditions including cardiovascular disease and cancer. The impact of an existing diagnosis of depression prior to autologous and allogeneic hematopoietic stem cell transplantation (HCT) on clinical outcomes including overall survival has not been studied. Methods: We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry to compare overall survival and hospital-length-of-stay during the first 100 days after autologous (n= 3786) or allogeneic (n = 7433) HCT for adult (≥ 18 years) patients with hematologic malignancies with an existing diagnosis of pre-transplant depression requiring treatment vs. those without pre-transplant depression. Data regarding an existing diagnosis of pre-transplant depression requiring treatment were collected from medical chart reviews and reported to the CIBMTR. Data for autologous and allogeneic HCT were analyzed separately. Using Cox proportional hazards regression models adjusting for patient-, disease-(including the disease risk index for allogeneic HCT), donor-(for allogeneic HCT), and transplant-related variables, we compared overall survival between patients with or without pre-transplant depression. To account for early deaths, we compared the number of days alive and out of the hospital in the first 100 days post-transplantation using Poisson models adjusting for patient-, disease-, and transplant-related variables. Among patients undergoing allogeneic HCT, we also compared the risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD among patients with or without pre-transplant depression using Cox proportional hazard regression analyses controlling for significant confounders. Results: We included 1116 (15%) patients with pre-transplant depression and 6317 (85%) patients without pre-transplant depression who underwent allogeneic HCT between 2008 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to age, disease distribution, disease risk index, time from diagnosis to transplant, conditioning regimen, receipt of total body irradiation, graft type, donor type, and donor source, but they were more likely to be female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. In multivariable analyses, pre-transplant depression was associated with higher overall mortality (HR 1.13, 95% CI 1.04-1.23, p = 0.004) and higher risk of grade II-IV acute GVHD (HR 1.25, 95%CI 1.14-1.37, p < 0.0001), but similar risk of chronic GVHD (HR 1.06, 95% CI 0.96-1.16, p = 0.26). Pre-transplant depression was associated with fewer days alive and out-of-the hospital (Means Ratio (MR) = 0.97, 95% CI 0.95-0.99, P = 0.004). Among patients undergoing autologous HCT, we included 512 (13.5%) patients with pre-transplant depression and 3274 (86.5%) patients without pre-transplant depression between 2007 and 2012. Patients with pre-transplant depression were similar to those without pre-transplant depression with regards to disease distribution, disease status prior to HCT, time from diagnosis to transplant, conditioning regimen, and year of transplant, but they were slightly younger, more likely be to female, white, divorced, less educated, not working full-time, and had lower performance status and higher number of comorbid conditions. Pre-transplant depression in autologous HCT recipients was not associated with overall survival in multivariable analyses (HR 1.15, 95% CI 0.98-1.34, p = 0.096), but was significantly associated with fewer days alive and out of the hospital (MR = 0.98, 95% CI 0.97-0.99, p = 0.002). Conclusion: Pre-transplant depression was associated with higher mortality and higher risk of acute GVHD among patients undergoing allogeneic HCT. Moreover, pre-transplant depression is associated with a longer hospital-length-of stay during the first 100 days after autologous and allogeneic HCT. Therefore patients with pre-transplant depression represent a highly vulnerable population at risk for post-transplant mortality and complications, and they may benefit from more intensive interventions to mitigate the risk of depression on their post-transplant outcomes. Disclosures Chen: Bayer: Consultancy, Research Funding. Lee:Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Hahn:Novartis: Equity Ownership; NIH/NHLBI: Research Funding.

OBJECTIVE To determine whether there is a relationship between depressive symptoms and cortisol assessed at first morning awakening, 6 PM, and 9 PM in a population-based sample of midlife women. If this relationship is not linear, we aim to test whether this relationship is nonlinear, only present in those with more severe depressive symptoms, better accounted for by diurnal slope, or only apparent under uncontaminated conditions. METHODS We investigated the cross-sectional association between cortisol and depressive symptoms, assessed by the Center for Epidemiological Studies Depression scale (CES-D) in 408 midlife women (45.7% African Americans, 54.3% white; mean age, 50.4 years) participating in the Chicago site of the Study of Women's Health Across the Nation. RESULTS Diurnal cortisol slope is significantly flatter for women with higher CES-D scores than for less depressed women (p < .05 for the interaction). This relationship remains significant even after adjusting for age, smoking status, race, education, income, menopausal status, hormone replacement therapy, body mass index, medications, and wake time, as well as possibly contaminating factors, including physical activity, smoking, eating, or caffeine or alcohol consumption before saliva collection. Results using depression assessed categorically (CES-D cutoff ≥16) were similar to those using continuous depression in both unadjusted and adjusted analyses (p = .005 for the interaction of CES-D by time). CONCLUSIONS In this population-based sample of midlife women, greater depressive symptoms were associated with a significantly flatter diurnal cortisol slope than those with fewer symptoms, even after adjusting for covariates and possibly contaminating behaviors.

Objective Multiple psychosocial factors appear to affect cancer progression in various populations; however, research investigating the relationship between psychosocial factors and outcomes following hematopoietic stem cell transplantation (HCT) is scarce. Subject to adverse immunological and psychological conditions, HCT patients may be especially vulnerable to psychosomatic health sequelae; therefore, we studied whether optimism and anxiety influence the pertinent clinical outcome of days to neutrophil engraftment (DTE). Method 54 adults undergoing either autologous or allogeneic HCT completed self-report questionnaires measuring optimism and anxiety. We assessed the association between these psychosocial variables and DTE. Results Greater optimism and less anxiety were associated with the favorable outcome of fewer DTE in autologous HCT recipients, though this relationship was no longer significant when reducing the sample size to only subjects who filled out their baseline survey by the time of engraftment. Conclusion Our findings are suggestive that optimism and anxiety may be associated with time to neutrophil recovery in autologous, but not allogeneic, adult HCT recipients. Further investigation in larger, more homogeneous subjects with consistent baseline sampling is warranted.

During the last decade several studies have shown that children whose parents smoke have higher rates of asthma. Recently, hair concentrations of cotinine have been shown to reflect systemic exposure to this constituent of smoke in both children and adults. At the present time it is not known, however, why some children exposed to passive smoking have asthma while others, similarly exposed, do not. The present study aimed at verifying whether asthmatic children are different from nonasthmatic children exposed to similar degrees of passive smoking in the way their bodies handle nicotine, a constituent of cigarette smoke. Seventy-eight asthmatic children were compared to 86 control children, all attending a consulting pediatric clinic in Toronto. A questionnaire completed by the parents and children detailed the daily number of cigarettes the child was exposed to and the identity of the smokers. Clinical data were extracted from the patients' charts. Urinary (corrected for creatinine) and hair concentrations of cotinine were measured by radioimmunoassays. The asthmatic and control children were of similar age, gender, and ethnic distribution, parental education, and socioeconomic status. Parents of asthmatic children tended to report a lower daily number of cigarettes (7.4 +/- 1.3/day vs. 11.2 +/- 2.3/day, p = 0.14), and this report agreed with the trend of urinary cotinine (47.1 +/- 9.1 ng/mg vs. 62.6 +/- 11.5 ng/mg, respectively). Conversely, children with asthma had on average twofold higher concentrations of cotinine in their hair (0.696 +/- 0.742 ng/mg) than control children (0.386 +/- 0.383) (p = 0.0001). In a similar manner, the hair:urine concentration ratio was significantly higher in children with asthma (0.028 +/- 0.002) than in their controls (0.18 +/- 0.003) (p = 0.0001). These results suggest that under exposure to similar amounts of nicotine, children with asthma have on average twofold higher systemic exposure to this constituent of cigarette smoke. These data suggest that out of all children passively exposed to environmental tobacco smoke, those who exhibit asthma have a higher systemic exposure to nicotine, possibly due to lower clearance rate. This is the first evidence of pharmacokinetic predisposition to environmental tobacco smoke as an etiological factor in pediatric asthma.

The endocannabinoid system modulates neural processes and down-regulates pro-inflammatory, stress-related signals. Inflammatory-mediated processes significantly contribute to increased morbidity and mortality in hematopoietic stem cell transplantation (HCT). The relationship between inflammatory molecules and the endocannabinoid system is poorly understood, and its activity has never been examined in HCT recipients. We conducted a pilot study evaluating 19 individuals undergoing HCT for any reason and collected psychosocial data and blood samples at 3 timepoints: (1) prior to transplant, (2) hospital discharge (within days of neutrophil engraftment), and (3) Day + 100. Serum was analyzed for inflammatory (TNF-a, IL-6, IL-10, IL-8, VEGF, CRP) and endocannabinoid molecules. Psychosocial measures included depressive symptoms, anxiety, and social support. Canonical correlation analysis indicated a significant association between change in inflammatory molecules and change in psychosocial scores between the first and second time points ( r = 1.0, p p = .02; CRP, p p = .01; CRP, p = .03). These data suggest that circulating 2-AG concentrations are related to critical immune modulators, IL-6 and CRP. Future research should address whether the endocannabinoid system may buffer the adverse physiological effects of negative psychosocial factors post-transplant.