Nutritional status and weakness following pediatric hematopoietic cell transplantation

Survivorship after pediatric HCT has increased over the past decade. Focus on long‐term care and well‐being remains critical due to risk of poor dietary habits and exaggerated sedentary behavior, which can lead to muscle weakness, increased risk for obesity, and cardiometabolic disorders. Nutrition and physical activity are key factors in survivorship; however, data are limited. Comprehensive nutritional assessments, including nutrition‐focused physical examination, grip strength, and food/activity surveys, were completed in 36 pediatric HCT survivors (aged 2‐25 years). Patients were divided into undernutrition, normal‐nutrition, and overnutrition categories. Fifty percent of participants were classified as normal nutrition, 22% undernutrition, and 28% overnutrition. Few patients met the U.S. Dietary Guidelines recommended intake for vegetables, fiber, saturated fat, and So FAS. Patients in the undernutrition group demonstrated significantly lower grip strength than those in the normal‐ and overnutrition groups. When grip strength was normalized to body mass, patients in the overnutrition group had the highest prevalence of weakness. Using NHANES reference data, maximum grip strength and NGS cutoffs were identified that could significantly distinguish the nutrition groups. Comprehensive nutritional assessments and grip strength measurements are feasible, non‐invasive, easy to perform, and inform both under‐ and overnutrition in pediatric HCT survivors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134922/1/petr12821.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/134922/2/petr12821_am.pd

Adjuvant IL-15 does not enhance the efficacy of tumor cell lysate-pulsed dendritic cell vaccines for active immunotherapy of T cell lymphoma

There has been a recent interest in using IL-15 to enhance antitumor activity in several models because of its ability to stimulate CD8 + T cell expansion, inhibit apoptosis and promote memory T cell survival and maintenance. Previously, we reported that C6VL tumor lysate-pulsed dendritic cell vaccines significantly enhanced the survival of tumor-bearing mice by stimulating a potent tumor-specific CD8 + T cell response. In this study, we determined whether IL-15 used as immunologic adjuvant would augment vaccine-primed CD8 + T cell immunity against C6VL and further improve the survival of tumor-bearing mice. We report that IL-15 given after C6VL lysate-pulsed dendritic cell vaccines stimulated local and systemic expansion of NK, NKT and CD8 + CD44 hi T cells. IL-15 did not, however, augment innate or cellular responses against the tumor. T cells from mice infused with IL-15 following vaccination did not secrete increased levels of tumor-specific TNF-α or IFN-γ or have enhanced C6VL-specific CTL activity compared to T cells from recipients of the vaccine alone. Lastly, IL-15 did not enhance the survival of tumor-bearing vaccinated mice. Thus, while activated- and memory-phenotype CD8 + T cells were dramatically expanded by IL-15 infusion, vaccine-primed CD8 + T cell specific for C6VL were not significantly expanded. This is the first account of using IL-15 as an adjuvant in a therapeutic model of active immunotherapy where there was not a preexisting pool of tumor-specific CD8 + T cells. Our results contrast the recent studies where IL-15 was successfully used to augment tumor-reactivity of adoptively transferred transgenic CD8 + T cells. This suggests that the adjuvant potential of IL-15 may be greatest in settings where it can augment the number and activity of preexisting tumor-specific CD8 + T cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46865/1/262_2005_Article_6.pd

Differential susceptibility of C57BL/6NCr and B6.Cg-Ptprca mice to commensal bacteria after whole body irradiation in translational bone marrow transplant studies

Abstract Background The mouse is an important and widely utilized animal model for bone marrow transplant (BMT) translational studies. Here, we document the course of an unexpected increase in mortality of congenic mice that underwent BMT. Methods Thirty five BMTs were analyzed for survival differences utilizing the Log Rank test. Affected animals were evaluated by physical examination, necropsy, histopathology, serology for antibodies to infectious disease, and bacterial cultures. Results Severe bacteremia was identified as the main cause of death. Gastrointestinal (GI) damage was observed in histopathology. The bacteremia was most likely caused by the translocation of bacteria from the GI tract and immunosuppression caused by the myeloablative irradiation. Variability in groups of animals affected was caused by increased levels of gamma and X-ray radiation and the differing sensitivity of the two nearly genetically identical mouse strains used in the studies. Conclusion Our retrospective analysis of thirty five murine BMTs performed in three different laboratories, identified C57BL/6NCr (Ly5.1) as being more radiation sensitive than B6.Cg-Ptprca/NCr (Ly5.2). This is the first report documenting a measurable difference in radiation sensitivity and its effects between an inbred strain of mice and its congenic counterpart eventually succumbing to sepsis after BMT.http://deepblue.lib.umich.edu/bitstream/2027.42/112743/1/12967_2007_Article_240.pd

Etanercept plus Topical Corticosteroids as Initial Therapy for Grade One Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

AbstractClinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375

Dendritic cell-based vaccines for active immunotherapy of T -cell malignancies.

T-cell receptor idiotype protein (TCR Id) conjugated to KLH and injected with a chemical adjuvant (TCR:KLH+QS-21) induces protective, but not therapeutic, immunity against the murine T cell lymphoma, C6VL. We hypothesized that dendritic cell (DC)-based vaccines would be more effective than TCR:KLH+QS-21 vaccines in treating preexisting C6VL in vivo. DC were generated from bone marrow precursors ex vivo, loaded with either TCR:KLH or C6VL cell lysate and used to vaccinate C57B1/6 mice prior to, or following, lethal challenge with C6VL. The survival of challenged mice was monitored, and vaccine-induced immune responses were measured using standard immunologic techniques. We found that C6VL lysate-pulsed DC (C6VL-DC) vaccines display enhanced efficacy in both preventing and treating T-cell lymphoma compared to TCR:KLH+QS-21 vaccines. Tumor clearance stimulated by C6VL-DC vaccines was lysate-specific and was CD8+ T-cell-dependent. Thus, lysate-pulsed DC vaccines are an effective approach to generate potent T-cell mediated immunity against T-cell malignancies without requiring identification of tumor-specific antigens or patient-specific Id protein expression. Next, we show that while Interleukin (IL)-15 administered following C6VL-DC vaccines stimulated the expansion of NK, NKT and CD8+CD44 hi T-cells, it did not augment innate or adaptive immune clearance of C6VL or enhance the survival of tumor bearing mice. Therefore, IL-15 is not an effective adjuvant for augmenting immunity induced by C6VL-DC vaccines. We suggest that adjuvant IL-15 would be more effective in expanding a pre-existing population of tumor-specific CD8+ T-cells, rather than using it to augment primary CD8+ T-cell responses. Lastly, we show that, unlike C6VL-DC and TCR:KLH+QS-21 vaccines, DC loaded with TCR:KLH (TCR:KLH-DC) do not protect mice from C6VL challenge. While TCR:KLH-DC vaccines stimulate greater C6VL-specific cellular immunity than TCR:KLH+QS-21 vaccines, they do not stimulate Id-specific antibody production. We show that the induction of Id-specific antibodies is essential for C6VL clearance when the C6VL TCR Id is used as a tumor-specific immunogen. Investigators traditionally focus on the development of vaccines that stimulate potent cell-mediated immunity against tumors. Our studies show that antibodies can be an integral component of protective anti-tumor responses. By generating only cellular immunity against C6VL, the efficacy of Id-based vaccines for C6VL was lost.Ph.D.Health and Environmental SciencesImmunologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/124439/2/3138183.pd

Cognitive complaints by hematopoietic cell transplantation recipients and change in neuropsychological performance over time

PURPOSE. Hematopoietic stem cell transplant (HSCT) recipients are at risk for cognitive decline. Cross-sectional studies show patients’ complaints of cognitive decline do not correlate well with concurrently measured objective neuropsychological performance, but rather with emotional variables and health-related quality of life. This longitudinal study investigated whether patient self-report of cognitive status would be concordant with objectively measured neuropsychological performance after accounting for change from their own pre-transplant objective baseline. METHODS. Pre-HSCT and at 30- and 100-days post-HSCT, 46 patients underwent computerized neuropsychological testing (CogState) and completed surveys assessing patient-reported cognitive complaints, emotional symptoms (depression, anxiety), sleep quality, daytime sleepiness, physical and functional well-being. Correlations were calculated between cognitive complaints and neuropsychological performance (at each time-point and across time-points), as well as all other patient-reported variables. RESULTS. Patient-reported cognitive complaints were largely independent of concurrently assessed objective neuropsychological performance. Uniquely, our longitudinal data demonstrated significant medium to large effect size associations between subjective cognitive complaints post-HSCT with objectively measured change from pre-HSCT in attention, visual learning and working memory (p <.05 - .01). Subjective cognitive complaints post-HSCT were also associated with depression, anxiety, daytime sleepiness and physical well-being (p < .05 - .001). CONCLUSIONS. Patients appear better able to assess their cognitive functioning relative to their own baseline and changes across time rather than relative to community norms. Thus, patient complaints of cognitive compromise justify further in-depth neuropsychological, emotional, and functional assessment. Future research into relationships between cognitive complaints and neuropsychological performance should account for changes in performance over time

Cognitive function and quality of life in vorinostat-treated patients after matched unrelated donor myeloablative conditioning hematopoietic cell transplantation

Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft-versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy–General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate,.64; standard error,.23; P ≤.01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis