Jesse D. Troy

Associations Between Anthropometry, Cigarette Smoking, Alcohol Consumption, and Non-Hodgkin Lymphoma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Prospective studies of lifestyle and non-Hodgkin lymphoma (NHL) are conflicting, and some are inconsistent with case-control studies. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial was used to evaluate risk of NHL and its subtypes in association with anthropometric factors, smoking, and alcohol consumption in a prospective cohort study. Lifestyle was assessed via questionnaire among 142,982 male and female participants aged 55-74 years enrolled in the PLCO Trial during 1993-2001. Hazard ratios and 95% confidence intervals were calculated using Cox proportional hazards regression. During 1,201,074 person-years of follow-up through 2006, 1,264 histologically confirmed NHL cases were identified. Higher body mass index (BMI; weight (kg)/height (m)(2)) at ages 20 and 50 years and at baseline was associated with increased NHL risk (P(trend) < 0.01 for all; e.g., for baseline BMI > or =30 vs. 18.5-24.9, hazard ratio = 1.32, 95% confidence interval: 1.13, 1.54). Smoking was not associated with NHL overall but was inversely associated with follicular lymphoma (ever smoking vs. never: hazard ratio = 0.62, 95% confidence interval: 0.45, 0.85). Alcohol consumption was unrelated to NHL (drinks/week: P(trend) = 0.187). These data support previous studies suggesting that BMI is positively associated with NHL, show an inverse association between smoking and follicular lymphoma (perhaps due to residual confounding), and do not support a causal association between alcohol and NHL.

Autologous Cord Blood Infusions Are Safe and Feasible in Young Children with Autism Spectrum Disorder: Results of a Single-Center Phase I Open-Label Trial

Despite advances in early diagnosis and behavioral therapies, more effective treatments for children with autism spectrum disorder (ASD) are needed. We hypothesized that umbilical cord blood‐derived cell therapies may have potential in alleviating ASD symptoms by modulating inflammatory processes in the brain. Accordingly, we conducted a phase I, open‐label trial to assess the safety and feasibility of a single intravenous infusion of autologous umbilical cord blood, as well as sensitivity to change in several ASD assessment tools, to determine suitable endpoints for future trials. Twenty‐five children, median age 4.6 years (range 2.26–5.97), with a confirmed diagnosis of ASD and a qualified banked autologous umbilical cord blood unit, were enrolled. Children were evaluated with a battery of behavioral and functional tests immediately prior to cord blood infusion (baseline) and 6 and 12 months later. Assessment of adverse events across the 12‐month period indicated that the treatment was safe and well tolerated. Significant improvements in childrens behavior were observed on parent‐report measures of social communication skills and autism symptoms, clinician ratings of overall autism symptom severity and degree of improvement, standardized measures of expressive vocabulary, and objective eye‐tracking measures of childrens attention to social stimuli, indicating that these measures may be useful endpoints in future studies. Behavioral improvements were observed during the first 6 months after infusion and were greater in children with higher baseline nonverbal intelligence quotients. These data will serve as the basis for future studies to determine the efficacy of umbilical cord blood infusions in children with ASD. Stem Cells Translational Medicine 2017;6:1332–1339

Development and validation of a rapid, aldehyde dehydrogenase bright–based cord blood potency assay

Banked, unrelated umbilical cord blood provides access to hematopoietic stem cell transplantation for patients lacking matched bone marrow donors, yet 10% to 15% of patients experience graft failure or delayed engraftment. This may be due, at least in part, to inadequate potency of the selected cord blood unit (CBU). CBU potency is typically assessed before cryopreservation, neglecting changes in potency occurring during freezing and thawing. Colony-forming units (CFUs) have been previously shown to predict CBU potency, defined as the ability to engraft in patients by day 42 posttransplant. However, the CFU assay is difficult to standardize and requires 2 weeks to perform. Consequently, we developed a rapid multiparameter flow cytometric CBU potency assay that enumerates cells expressing high levels of the enzyme aldehyde dehydrogenase (ALDH bright [ALDH(br)]), along with viable CD45(+) or CD34(+) cell content. These measurements are made on a segment that was attached to a cryopreserved CBU. We validated the assay with prespecified criteria testing accuracy, specificity, repeatability, intermediate precision, and linearity. We then prospectively examined the correlations among ALDH(br), CD34(+), and CFU content of 3908 segments over a 5-year period. ALDH(br) (r = 0.78; 95% confidence interval [CI], 0.76-0.79), but not CD34(+) (r = 0.25; 95% CI, 0.22-0.28), was strongly correlated with CFU content as well as ALDH(br) content of the CBU. These results suggest that the ALDH(br) segment assay (based on unit characteristics measured before release) is a reliable assessment of potency that allows rapid selection and release of CBUs from the cord blood bank to the transplant center for transplantation.

Myelodysplastic syndromes in the United States: an update for clinicians

Abstract Myelodysplastic syndromes (MDS) are heterogeneous malignant bone marrow disorders diagnosed most often in elderly white persons. MDS have significant clinical consequences, including cytopenias leading to infection, bleeding, and death; and approximately one-third of cases progress to acute myeloid leukemia (AML). Only one potentially curative therapy exists—allogeneic hematopoietic stem cell transplant (HSCT)—but this therapy is not widely used due to associated morbidity and mortality in elderly patients. Recent research suggests MDS occurs more frequently than previously thought and may be responsible for a substantial proportion of unexplained anemias in elderly persons. Incidence of MDS is expected to increase with increases in life expectancy. Therefore, we offer this comprehensive narrative update of MDS to inform the medical community treating the population at risk for MDS, with a focus on MDS epidemiology and clinical management in the United States. This review includes a brief historical background of MDS, provides an overview of the population burden of disease, discusses the molecular pathology of MDS, describes the clinical features and management of MDS, and discusses future directions in MDS research. Our objective is to inform general medicine practitioners and call attention to the need for translational research in MDS.

Sex difference in immune response to vaccination: A participant-level meta-analysis of randomized trials of IMVAMUNE smallpox vaccine.

INTRODUCTION Previous research shows immune response to vaccination differs by sex but this has not been explored for IMVAMUNE, a replication-deficient smallpox vaccine developed in response to the potential for bioterrorism using smallpox. METHODS We conducted a participant-level meta-analysis (N=275, 136 men, 139 women) of 3 randomized trials of IMVAMUNE conducted at 13 centers in the US through a federally-funded extramural research program. Studies were eligible for inclusion if they tested the standard dose (1×10(8)TCID₅₀/mL on Days 0 and 28) of liquid formulation IMVAMUNE, were completed at the time of our search, and enrolled healthy vaccinia-naïve participants. Models of the peak log₂ ELISA and PRNT titers post-second vaccination were constructed for each study with sex as a covariate. Results from these models were combined into random effects meta-analyses of the sex difference in response to IMVAMUNE. We then compared this approach with fixed effects models using the combined participant level data. RESULTS In each study the mean peak log₂ ELISA titer was higher in men than women but no single study demonstrated a statistically significant difference. Combination of the adjusted study-specific estimates into the random effects model showed a higher mean peak log₂-titer in men compared with women (absolute difference [men-women]: 0.32, 95% CI: 0.02-0.60). Fixed effects models controlling for study showed a similar result (log₂ ELISA titer, men-women: 0.34, 95% CI: 0.04-0.63). This equates to a geometric mean peak titer that is approximately 27% higher in men than women (95% CI: 3-55%). Peak log₂ PRNT titers were also higher (although not significantly) in men (men-women: 0.14, 95% CI: -0.30 to 0.58). CONCLUSION Our results show statistically significant differences in response to IMVAMUNE comparing healthy, vaccinia-naïve men with women and suggest that sex should be considered in further development and deployment of IMVAMUNE and other MVA-based vaccines.

Effect of Autologous Cord Blood Infusion on Motor Function and Brain Connectivity in Young Children with Cerebral Palsy: A Randomized, Placebo‐Controlled Trial

Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double‐blind, placebo‐controlled, crossover study of a single intravenous infusion of 1–5 × 107 total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post‐treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty‐three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure‐66 (GMFM‐66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post‐ACB treatment, those who received doses ≥2 × 107/kg demonstrated significantly greater increases in GMFM‐66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales‐2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071–2078

Childhood passive smoke exposure is associated with adult head and neck cancer

INTRODUCTION Passive smoke is carcinogenic but its association with head and neck squamous cell carcinoma (HNSCC) is uncertain. METHODS We conducted a case-control study of childhood passive smoke exposure (CPSE) and HNSCC in 858 cases and 806 frequency-matched controls using an interviewer-administered questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with logistic regression controlling for adult smoking in the total study population, and in never-smokers only (184 cases and 415 controls). CPSE was also studied in oropharyngeal separately from other HNSCC using polytomous logistic regression. RESULTS CPSE was associated with HNSCC (OR, 1.28; 95% CI, 1.01-1.63) after controlling for adult smoking and other factors. This association was similar in magnitude, although not statistically significant, among subjects who never smoked as adults (OR, 1.19, 95% CI, 0.80-1.76). CPSE was associated more strongly with oropharyngeal cancer (a HNSCC subtype commonly associated with human papillomavirus (HPV) infection) than with HNSCC at non-oropharyngeal sites (OR, 2.02; 95% CI, 1.01-4.06, N=52 cases vs. OR, 1.04; 95% CI, 0.68-1.60, N=132 cases; P-for-heterogeneity=0.08). CONCLUSIONS Data from this large US-based case control study suggest a role for CPSE in HNSCC etiology.

A cord blood monocyte–derived cell therapy product accelerates brain remyelination

Microglia and monocytes play important roles in regulating brain remyelination. We developed DUOC-01, a cell therapy product intended for treatment of demyelinating diseases, from banked human umbilical cord blood (CB) mononuclear cells. Immunodepletion and selection studies demonstrated that DUOC-01 cells are derived from CB CD14+ monocytes. We compared the ability of freshly isolated CB CD14+ monocytes and DUOC-01 cells to accelerate remyelination of the brains of NOD/SCID/IL2Rγnull mice following cuprizone feeding-mediated demyelination. The corpus callosum of mice intracranially injected with DUOC-01 showed enhanced myelination, a higher proportion of fully myelinated axons, decreased gliosis and cellular infiltration, and more proliferating oligodendrocyte lineage cells than those of mice receiving excipient. Uncultured CB CD14+ monocytes also accelerated remyelination, but to a significantly lesser extent than DUOC-01 cells. Microarray analysis, quantitative PCR studies, Western blotting, and flow cytometry demonstrated that expression of factors that promote remyelination including PDGF-AA, stem cell factor, IGF1, MMP9, MMP12, and triggering receptor expressed on myeloid cells 2 were upregulated in DUOC-01 compared to CB CD14+ monocytes. Collectively, our results show that DUOC-01 accelerates brain remyelination by multiple mechanisms and could be beneficial in treating demyelinating conditions.

Durable Chimerism and Long-Term Survival after Unrelated Umbilical Cord Blood Transplantation for Pediatric Hemophagocytic Lymphohistiocytosis: A Single-Center Experience

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune dysregulation characterized by fever, hepatosplenomegaly, cytopenias, central nervous system disease, increased inflammatory markers, and hemophagocytosis. Currently, allogeneic hematopoietic stem cell transplantation is the only curative approach for patients with HLH, with reported survival ranging from 50% to 70% with myeloablative conditioning (MAC) regimens. However, donor availability and transplantation-related mortality associated with conventional MAC are major barriers to success. Unrelated umbilical cord blood transplantation (UCBT) provides a readily available alternative donor source for patients lacking matched related donors. Accordingly, we report the results of UCBT in 14 children treated between 1998 and 2016. All children received standard HLH chemotherapy before UCBT. The median age at diagnosis was 2.7 months (range, .8 to 10.4) and at transplantation was 7.5 months (range, 3.8 to 17). Ten patients received MAC with busulfan/cyclophosphamide/etoposide /antithymocyte globulin (ATG) (n = 5), busulfan/cyclophosphamide /ATG (n = 4), or busulfan /melphalan/ATG (n = 1). Four patients received reduced-toxicity conditioning (RTC) with alemtuzumab/fludarabine/melphalan/hydroxyurea ± thiotepa. Cord blood units were mismatched at either 1 (n = 9) or 2 (n = 5) loci and delivered a median total nucleated cell dose of 11.9 × 107/kg (range, 4.6 to 27.9) and CD34+ dose of 3.1 × 105/kg (range, 1.1 to 6.8). The cumulative incidence of neutrophil engraftment by day 42 was 78.6% (95% confidence interval [CI], 42.9% to 93.4%) with a median of 19 days (range, 13 to 27), and that for platelet (50,000) engraftment by day 100 was 64.3% (95% CI, 28.2% to 85.7%) with a median of 51 days (range, 31 to 94). Six patients developed either grade II (n = 5) or grade IV (n = 1) acute graft-versus-host disease (GVHD); no extensive chronic GVHD was seen. Ten patients (71.4%) are alive and well at a median of 11.2 years after transplantation (range, .85 to 18.25), 9 of whom maintain sustained full donor chimerism after a single UCBT, whereas 1 patient with autologous recovery after first UCBT with RTC has achieved full donor chimerism after a second UCBT with MAC. This series demonstrates that, in combination with standard HLH therapy, UCBT after MAC or RTC conditioning can provide long-term survival with durable complete donor chimerism comparable to that of conventional donors. UCBT should be considered for patients with HLH lacking a fully matched related or unrelated adult donor.

Polymorphisms in NAT2 and GSTP1 are associated with survival in oral and oropharyngeal cancer

INTRODUCTION Functional polymorphisms in drug metabolizing enzymes (DMEs) may be determinants of survival in oral and oropharyngeal squamous cell carcinoma (OOSCC). METHODS OOSCC cases (N=159) with a history of either tobacco or alcohol use were genotyped for polymorphisms in eight DMEs. Overall and disease-specific survival were analyzed using Kaplan-Meier plots and the log-rank test. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) in exploratory analyses of patient subgroups. RESULTS Kaplan-Meier analyses showed N-acteyltransferase-2 (NAT2) fast acetylators experienced a 19.7% higher 5-year survival rate than slow acetylators (P=0.03) and this association was similar in oropharyngeal and oral cancer. After multiple adjustment, including tumor site and stage, the NAT2 fast acetylator phenotype was associated with improved overall survival (vs. slow acetylators) provided chemotherapy or radiation were not used (HR, 0.26; 95% CI, 0.10-0.66). However, NAT2 phenotype was unrelated to survival in patients treated with chemoradiotherapy (HR, 1.21; 95% CI, 0.54-2.73) or radiotherapy (HR, 0.67; 95% CI, 0.31-1.59) (P-for-NAT2/treatment-interaction=0.04). Normal activity GSTP1 was associated with a 19.2% reduction in 5-year disease-specific survival relative to reduced activity GSTP1 (P=0.04) but this association was not modified by treatment. CONCLUSIONS Our results suggest that functional polymorphisms in NAT2 and GSTP1 are associated with OOSCC survival. Confirmation of these results in larger studies is required.