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Objective Although hematopoietic stem cell transplant (HSCT) patients may experience neurocognitive impairment, experiences of neurobehavioral problems (including apathy and disinhibition) are understudied. These experiences reflect behavioral signs and symptoms of neurological dysfunction that can potentially reduce health-related quality of life (HRQOL). Understanding them is important because they may be confused with other diagnoses, including depression, potentially leading to inappropriate treatments. The objectives of this preliminary cross-sectional study were to describe HSCT patients' neurobehavioral functioning pre-HSCT and post-HSCT and to examine relations with HRQOL. Methods Patients (n = 42) 9 months to 3 years post-HSCT completed measures of neurobehavioral functioning to report apathy and disinhibition pre-HSCT (retrospectively) and post-HSCT (currently). Paired t-tests and McNemar tests were used to explore differences in the incidence of patient-reported neurobehavioral problems within and across time points. Regression analyses were conducted to examine relations between neurobehavioral functioning and physical and mental HRQOL. Results Elevated levels of apathy were reported by many patients post-HSCT (36%) and increased significantly from pre-HSCT to post-HSCT (p = 0.001). Hierarchical regression analysis indicated that higher levels of apathy were associated with reduced mental HRQOL (p

Psycho-Oncology Psycho-Oncology (2014) Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/pon.3553 Clinical Correspondence Systematic light exposure in the treatment of cancer-related fatigue: a preliminary study William H. Redd 1 *, Heiddis Valdimarsdottir 1,2 , Lisa M. Wu 1 , Gary Winkel 1 , Emily E. Byrne 1 , Melba A. Beltre 1 , Elizabeth S. Liebman 1 , Tanya Erazo 1 , Judy A. Hayes 1 , Luis Isola 3 , Eileen Scigliano 3 , Yeraz Meschian 1 , Susan Lutgendorf 4 and Sonia Ancoli-Israel 5 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Psychology, Reykjavik University, Iceland Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA Department of Psychology, University of Iowa, Iowa, IA, USA Departments of Psychiatry and Medicine, University of California, San Diego, CA, USA *Correspondence to: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. E-mail: william. redd@mssm.edu Received: 1 October 2013 Revised: 13 March 2014 Accepted: 25 March 2014 Dear Editor, Introduction Cancer-related fatigue (CRF) is the most commonly reported side effect of cancer treatment [1]. It is defined by the National Comprehensive Cancer Network as ‘a distressing, persistent, subjective sense of physical, emotional, and cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity’. Patients feel tired even after resting, have reduced capacity to carry out normal activities, experience slow physical recovery from tasks, and report diminished concentration. Most patients experience CRF during their treatment, and many continue to experience CRF long after all treatment has ended. In our research with survivors of hematopoietic stem cell transplantation (HSCT) 1–3 years off treatment, 40% of those interviewed reported clinically significant CRF. Various pharmacological and nonpharmacological interventions have been studied to treat CRF with generally mild to moderate effect sizes [1]. An alternate intervention may be systematic bright white light (BWL) exposure, which is far less costly and involves less patient burden than other interventions. Reviews and meta-analyses [2] have reported that BWL is effective in reducing sleep and circadian rhythm problems associated with other disorders (e.g., depression and jet lag) but has not been previously tested for the effect on fatigue. Recent research from our group has shown that, when given during chemotherapy, BWL compared with Copyright © 2014 John Wiley & Sons, Ltd. dim red light (DRL) keeps CRF from getting worse [3]. However, to date, the impact of BWL on fatigue among survivors of cancer has not been examined. This preliminary efficacy trial sought to determine the impact of BWL on CRF among survivors of breast and gynecologic cancers who had completed all cancer treat- ment and survivors of hematological malignancy who had completed HSCT. We tested the hypothesis that the BWL condition would result in a significant reduction in CRF compared with the DRL condition. Methods Participants Thirty-six survivors of cancer from the Mount Sinai Hospital in New York, NY, participated in the study (Figure 1) across all four seasons. Inclusion criteria were the following: up to 3.5 years post-HSCT, up to 3 years postcompletion of che- motherapy or chemotherapy and radiation for breast cancer, or any time postcompletion of treatment for gynecologic cancer; 18 years of age or older; and reporting clinically significant fatigue as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale. Exclusion criteria were the following: pregnancy, confounding underlying medical illnesses such as signi- ficant preexisting anemia, history of mania (which is a contraindication for light treatment) or current clinical depression, and any other physical or psychological impairment including a sleep disorder that would limit par- ticipation. The study was approved by the Program for the Protection of Human Subjects at Mount Sinai Hospital.

Background The current FDA-approved time interval between plerixafor dosing and apheresis initiation is approximately 11 hours, but this time interval is impractical for most care providers. Few studies have examined mobilization kinetics beyond 11 hours in multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) patients. Therefore, this study's intent was to analyze an interval of 17 to 18 hours between plerixafor dosing and apheresis initiation. Study Design and Methods In 11 patients with MM or NHL, 240 μg/kg plerixafor was administered at 5 p.m. on Day 4 of granulocyte–colony-stimulating factor (G-CSF) mobilization. Peripheral blood (PB) CD34+ and CD34+CD38− concentrations were enumerated every 2 hours until 7 a.m. and immediately before apheresis on Day 5, for a total interval time of 17 to 18 hours after plerixafor. Data were analyzed using mixed-model analysis of repeated measures and paired t testing. Results Ten of the 11 subjects achieved a CD34+ product count of more than 2 × 106/kg with a single leukapheresis procedure. All 10 had a preplerixafor PB CD34+ concentration ([CD34+]) of at least 10/μL. PB [CD34+] was not different between 10 and 18 hours after plerixafor (p = 0.8). In contrast, PB CD34+CD38− concentrations significantly increased from 10 to 18 hours after plerixafor (p = 0.03). Conclusions In MM and NHL patients with adequate preplerixafor [CD34+], leukapheresis initiated 14 to 18 hours after plerixafor and G-CSF mobilization may not impair adequate CD34+ collection and may increase more primitive CD34+CD38− collection. In this subset of patients, late-afternoon dosing of plerixafor at 5 p.m. with initiation of next-day apheresis as late as 11 a.m. appears feasible without loss of efficacy.

Hematopoietic stem cell transplantation (HSCT) is a demanding treatment for hematologic malignancies. The toxic preparative regimen most patients receive (high-dose chemotherapy, sometimes with total body irradiation) suppresses or destroys their immune function, necessitating protective isolation and causing side effects including fatigue, cognitive difficulties, and sexual dysfunction [1–2]. For many survivors these difficulties are resolved within the first year after transplant; however, they can persist, and survivors continue to face increased risk of all-cause mortality [3–5]. HSCT has also been associated with depression, anxiety, fear of cancer recurrence, and symptoms of post-traumatic stress disorder before, during, and after transplant [4, 6–7]. These physical and psychological effects occur in conjunction with practical difficulties that have been conceptualized as chronic stressors in other populations. Here we focus on three that are interrelated and commonly reported after transplant: persistent financial, employment, and insurance stressors. These stressors (which we refer to collectively as economic survivorship stressors) have the potential to exacerbate negative physical and psychological effects of transplant, thereby reducing survivors' health-related quality of life (HRQOL). HRQOL encompasses the extent to which survivors experience a sense of well-being, have the ability to carry out activities of daily living, and experience disease-related symptoms. It represents a critical aspect of the transplant recovery and survivorship experience, and economic survivorship stressors may adversely affect HRQOL through biological, behavioral, and psychological pathways [8–9]. For instance, financial stress (perceived inadequacy of financial resources) is associated with worse physical and psychological health in community populations [10–12], and has been associated with decreased HRQOL and elevated distress among low-income survivors of breast and gynecologic cancers [13]. Cancer-related financial stress and strain have also been associated with adverse psychological well-being among survivors of breast, prostate, and lung cancer [14]. Furthermore, qualitative work conducted with cancer survivors and their caregivers has demonstrated that financial worries and difficulties have a negative impact on family lifestyle, activities, roles, and relationships [15]. In HSCT, the potential for financial stress is high because of the costliness of the treatment [2], and additional expenses due to treatment-related complications, medications, transportation to and from transplant facilities, and routine medical follow-up. Employment-related problems are associated with financial stress, in addition to being stressful in their own right. Cancer survivors report difficulties including non-supportive work environments, changes in work schedules and relationships with colleagues, perceived employer discrimination, and reductions in perceived work ability, all of which may be persistent areas of concern with implications for their return to work, financial standing, and overall well-being [16]. Among HSCT survivors, enduring physical effects of transplant can prevent or substantially delay return to work [6]. One study found that approximately 40% of HSCT survivors had not returned to work 1-year post-transplant, and approximately 30% had not returned 2-years post-transplant [17]. Caregivers also lose income due to missed work, and incur substantial out-of-pocket expenses in order to stay at or near the treatment center [18]. Finally, many transplant survivors struggle with health insurance claims, policy caps, and obtaining future coverage. In one study approximately 32% of survivors reported that obtaining insurance was problematic, and 31% reported concerns about changing jobs for fear of losing health insurance coverage [19]. In a study of 10-year survivors of HSCT, 24% reported a history of health insurance denial compared to 0% of age-, sex-, and race-matched controls [5]. In addition to being a source of stress and frustration, insurance problems may increase financial burden among survivors who require ongoing surveillance. The role of insurance stress in cancer survivors' HRQOL has not been explored, although health insurance status has been shown to predict HRQOL in some studies. For instance, lack of insurance coverage has been associated with poorer HRQOL among survivors of prostate cancer [20]. However, insurance status was unrelated to HRQOL in a sample of Hispanic and African-American cancer patients [21]. The present study investigated these economic survivorship stressors and their association with HRQOL among survivors of HSCT. Participants were 181 men and women who had undergone HSCT 9–36 months prior to assessment. First, we examined survivors' post-transplant perceptions of financial, employment, and insurance stressors. Second, we investigated these perceived stressors as predictors of survivors' HRQOL, hypothesizing that greater economic survivorship stress would be associated with poorer HRQOL. Because stress and coping theory posits that people's perceptions of a situation (as opposed to the situation's objective characteristics) are most important in determining health [22], we predicted that associations between economic survivorship stress and HRQOL would remain even after controlling for objective indicators of socioeconomic position including income, education, and employment status. We also examined potential confounding effects of survivors' sociodemographic and medical characteristics on the hypothesized associations. A final, exploratory aspect of this study was based on the fact that people's social environments and personal resources influence how they appraise and respond to a stressor [22]. Informed by both relative deprivation theory [23–24], which predicts that greater financial disparities are associated with poorer health in part because people experience distress when they perceive their economic standing as worse than others, and social comparison theory [25], which posits that people compare themselves to others when evaluating themselves on a particular dimension, we reasoned that survivors would appraise economic survivorship stressors differently depending on their economic standing relative to others in their social environment. We investigated the effects of the financial crisis that occurred during this study, which led to a sudden, profound shift in the economic well-being of many Americans. We hypothesized that, compared to survivors who completed the study before the crisis, those who completed it after the crisis would appraise each of these stressors as less dire because of the knowledge that many people were experiencing similar problems. Although pinpointing the exact timing of the recession is difficult, experts identify the very public failures in the financial sector in September 2008 as a pivotal turning point [26–27]. We also examined whether the portion of survivors' transplant paid by health insurance, which varies across individuals and affects how much of the treatment costs they bear, would moderate the association between economic survivorship stress and HRQOL. This situational factor may influence how people appraise their financial demands; thus, we predicted that the adverse effects of each economic survivorship stressor on HRQOL would be amplified among those participants whose insurance covered the smallest portions of their transplant expenses.

Hematopoietic stem cell transplant (HSCT; also commonly known as bone marrow transplant) is an aggressive treatment for hematological malignancies that causes numerous physical and psychological difficulties, including significant distress and poor quality of life [1, 2]. Although previously a treatment of last resort, HSCTs are now indicated early in the course of many diseases. This shift in treatment strategy has resulted in improved survival rates [3, 4], but has also led to a greater focus on lingering side effects found among survivors. Researchers have recently begun to examine the potential neurotoxic effects of HSCT as well as the deleterious neurological impact of the cancers it treats. There are two ways in which such cognitive impairments have been measured: neuropsychological assessment (objective) and self-report measures of cognitive functioning (subjective). HSCT patients have impaired cognitive function using both forms of measurement [5–7]. However, in general, objective neuropsychological test results are not correlated with subjective cognitive functioning [7, 8]. Thus, patients may demonstrate deficits on neuropsychological tests but perceive little impairment in daily functioning, or they may demonstrate relatively normal neuropsychological test results despite perceiving considerable daily impairment. Despite the fact that subjective cognitive functioning is often not correlated with objective neuropsychological impairment, it is associated with poorer psychological adjustment and quality of life. For instance, Booth-Jones and colleagues [7] investigated HSCT patients who were 6-months post-discharge and found that poorer subjective cognitive functioning was associated with greater depressive symptomatology as well as poorer physical and mental quality of life. Similar associations have also been found in women receiving adjuvant therapy for breast cancer for whom self-reports of memory and concentration difficulties were associated with psychological distress and poorer quality of life [9]. Mechanisms through which subjective cognitive impairment affects distress and quality of life are not currently well-defined, but they are worth clarifying because they may be good targets for psychosocial interventions. One possible mechanism is suggested by Bandura’s social cognitive theory and its emphasis on self-efficacy, or “belief in one’s capabilities to organize and execute the courses of action required to manage prospective situations” [10]. HSCT survivors’ self-efficacy for managing symptoms is particularly likely to have implications for their well-being because of their high physical and psychosocial symptom burden after treatment [1]. Indeed, low self-efficacy has been associated with elevated psychological distress and poorer quality of life in other cancer patients [e.g., 11–13]. Thus, experiencing difficulties such as memory problems and poor concentration may cause survivors to doubt their ability to manage symptoms, which in turn may adversely affect their psychological adjustment and quality of life. Evidence from other patient populations supports the plausibility of such a mechanism. For example, in chronic pain patients, self-efficacy has been shown to mediate the relationship between self-reported pain intensity and outcomes such as disability and depression [14]. Self-efficacy for managing cognitive symptoms has also been found to mediate the relationship between community integration and global life satisfaction in patients with traumatic brain injury [15]. If self-efficacy were similarly conceptualized as a mediator among HSCT survivors suffering from subjective cognitive impairment, it might explain the link between subjective cognitive impairment and distress and poor quality of life. Thus, the purpose of the present study was to examine whether self-efficacy for symptom management mediates relations between subjective cognitive functioning and the following outcomes: psychological adjustment (i.e., depressed mood and anxiety), and health-related quality of life. We hypothesized that among HSCT survivors, poorer subjective cognitive functioning would be associated with lower levels of self-efficacy for symptom management, which would in turn be associated with poorer adjustment and quality of life.

Objectives: The precise role of positron emission tomography (PET/CT) for predicting relapse/progression in multiple myeloma remains uncertain. We compared the predictive values of PET/CT, concurrent laboratory testing (labs), and their combination in prediction of 12-month progression, as determined by current International Myeloma Working Group (IMWG) criteria. Methods: PET/CT and labs (serum chemistry, β2-microglobulin, immunofixation, bone marrow biopsy, serum free light chains) were reviewed, and date of relapse/progression was determined by IMWG criteria. Results: The median time from therapy to PET/CT imaging was 12.0 months (1.0–110) and median time to progression (TTP) was 29.8 months (1.6–130+). Overall survival and survival-without-progression at last follow-up were 84% and 49%, respectively. Sensitivity of PET/CT for predicting relapse/progression was lower than that of labs (0.67 vs. 0.89, ns), but PET/CT was more specific (0.89 vs. 0.79, ns). When labs and PET/CT data were combined, a positive result for either test was 89% sensitive and a positive result for both tests was 100% specific for predicting 12-month progression of disease. Kaplan–Meier analysis showed significantly greater TTP for those with a negative vs. positive PET/CT (P = 0.0005), negative vs. positive labs (P

Objectives. Noninvasive evaluation of fibrosis is an on-going effort in the management of chronic hepatitis C. This study was planned to noninvasively evaluate fibrosis staging. Design. We evaluated the biochemical, functional [aminopyrine breath test (ABT)] and ultrasonographic variables of 75 chronic hepatitis C patients. Results. Clinical [body mass index (BMI)], biochemical [aspartate aminotransferase (AST), alanine aminotransferase (ALT) and platelets (PLT)] and ratio indexes, together with the ABT, showed a higher relationship with fibrosis: initial (score ≤ 2) versus evident (score > 2) fibrosis: BMI (24 ± 2 vs. 26 ± 2, P = 0.0007), AST (56 ± 36 vs. 88 ± 65, P = 0.0159), ALT (92 ± 54 vs. 139 ± 108, P = 0.0290), PLT (220 ± 64 vs. 173 ± 61, P = 0.0007), PLT/spleen diameter ratio (PLT/SPD) (2133 ± 786 vs. 1540 ± 681, P = 0.0003), AST/platelet count ratio index (APRI) (0.80 ± 0.87 vs. 1.51 ± 1.47, P = 0.0010), ABT%d/h30 min (10.8 ± 4.5 vs. 7.6 ± 3.8, P = 0.0007), ABT%d/cum120 min (8.9 ± 3.3 vs. 6.5 ± 3.1, P = 0.0007). Considering the differences between fibrosis score 2 and 3 patients, BMI, ABT and PLT/SPD ratio proved to be statistically significant. Multivariate stepwise analysis (with and without BMI) identified two models for distinguishing between initial and evident fibrosis: Model 1: −0.569 +(BMI × 0.107) + (APRI × 0.169)−(PLT/SPD × 0.304), and Model 2: 2.376 + (APRI × 0.152)−(ABTd/h30 × 0.043)−(PLT/SPD × 0.249). These models showed concordance in identifying or ruling out evident fibrosis in 76% and 78.7% of the patients respectively. The PLT/SPD ratio also showed 78.7% concordance with the histological score. Conclusion. These results suggest that noninvasive evaluation of fibrosis in chronic hepatitis C may be considered an effective tool thanks to the use of an inexpensive, reproducible ratio index.

We report a case of a 67-year-old male who underwent OLT from a deceased, sex-matched donor. Two months later he developed Evans syndrome and GVHD of the skin. Donor and recipient were matched for HLA-A and -B loci in the direction of rejection but mismatched in the direction of GVHD and fully mismatched for DRB1. These mismatches were permissible for engraftment of donor T-cells but led to GVHD. Chimerism appeared restricted to the T-cell compartment. In this case, partially matched passenger lymphocytes triggered a graft versus host reaction. In addition, alloantibodies caused cytopenias that improved after immunosuppression. HLA typing was critical in confirming this rare diagnosis and elucidating its cause. Recipients of solid organs from donors that are partially matched in the direction of rejection may need to be closely monitored for GVHD.

Cord blood (CB) progenitor/stem cells (P/SC) are ideal targets for early gene therapy in individuals prenatally diagnosed with genetic disorders. Most retroviral transduction protocols were developed using adult peripheral blood stem cells (PBSC) and bone marrow (BM). Less is known about retroviral transduction of CB P/SC. We examined how timing, multiplicity of infection (MOI), and polycations in the transduction media affect transduction efficiency. Rates of transduction were determined in recently isolated CD34+ enriched CB cells and in colonies derived after various times in liquid cultures (LC). CB mononuclear cells (MNC) were separated by ficoll-hypaque centrifugation and enriched for CD34+ cells. Purity was assessed by flow cytometry. Transduction were performed with clinical-grade retroviral stocks at MOIs of 1–20. Transduction was performed with fetal bovine serum (FBS) or autologous plasma, IL-3, GM-CSF, IL-6, and SCF. The retroviral vector contained LacZ and neomycin resistance (neo) reporter genes. Transduction was determined by X-gal stain and by PCR amplification of the reporter genes. No drug selection was used. Twenty-five experiments were done. CB volumes ranged from 35–150 ml. MNC and CD34+ cell counts ranges were: 0.14–840 × 106 and 0.1–4.2 × 106, respectively. Transduction efficiency in liquid cultures ranged from 4–63%. Higher rates were seen using MOI ≥ 10, 2 μg/ml polybrene, and 10% autologous CB plasma. In colonies, transduction rates were 63 to 72% by PCR and 32% by X-gal staining. In LTC-IC derived colonies, transduction was 7% by PCR. Short incubations of CD34+ CB cells with purified retroviral stocks, polybrene, and autologous sera result in high transduction rates of committed progenitors and moderately low efficiencies of transduction of LTC-IC in the absence of drug selection. Am. J. Hematol. 57:16–23, 1998. © 1998 Wiley-Liss, Inc.

We report a patient with spent-phase polycythaemia vera (S-PV) and massive splenomegaly who failed to engraft after a syngeneic granulocyte colony-stimulating factor-primed peripheral blood stem cell transplant (SCT), but later engrafted after splenectomy. Bone marrow (BM) showed resolution of myelofibrosis (MF) and absent endogenous erythroid colonies. This case demonstrated that (1) normal haematopoiesis can be restored after syngeneic SCT despite extensive MF, and (2) fibrosis can regress following a total body irradiation-containing regimen and syngeneic SCT. As a graft-versus-BM stroma effect is non-existent in syngeneic transplants, there may be a role for autologous SCT to obliterate MF in S-PV.

We have previously demonstrated systemic resistance to methotrexate (MTX) in transgenic mice carrying a foreign, mutant dihydrofolate reductase (DHFR, E.C. 1.5.1.3) gene. The new gene was introduced as a cDNA cloned into an expression vector driven by the simian virus 40 (SV40) early promoter. Previous physiologic studies suggested that transgenic mice tolerated drug doses invariably lethal to controls on the basis of gastrointestinal (GI) resistance to MTX. In the present study we evaluated foreign gene expression at the RNA level in the three major sites of MTX toxicity: intestine, liver, and bone marrow. The transgene was transcriptionally active in small bowel, and levels of expression were high in animals tolerating the largest doses of MTX. The gene was also expressed in the liver in some pedigrees, but was not detected in hemopoietic tissues of any of the pedigrees tested. Our studies correlate the site of expression of a drug resistant dhfr gene with an altered physiologic response to MTX, and demonstrate that transgenic mice can be used as a test system for expression of genes considered for use in somatic gene therapy.