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Background Treatment options for patients with COVID-19-related acute respiratory distress syndrome (ARDS) are desperately needed. Allogeneic human umbilical cord derived mesenchymal stromal cells (hCT-MSCs) have potential therapeutic benefits in these critically ill patients, but feasibility and safety data are lacking. Materials and Methods In this phase I multisite study, 10 patients with COVID-19-related ARDS were treated with 3 daily intravenous infusions of hCT-MSCs (1 million cells/kg, maximum dose 100 million cells). The primary endpoint assessed safety. Results Ten patients (7 females, 3 males; median age 62 years (range 39-79)) were enrolled at 2 sites and received a total of 30 doses of study product. The average cell dose was 0.93 cells/kg (range 0.56-1.45 cells/kg and total dose range 55-117 million cells) with 5/30 (17%) of doses lower than intended dose. Average cell viability was 85% (range 63%-99%) with all but one meeting the >70% release criteria. There were no infusion-related reactions or study-related adverse events, 28 non-serious adverse events in 3 unique patients, and 2 serious adverse events in 2 unique patients, which were expected and unrelated to the study product. Five patients died: 3 by day 28 and 5 by day 90 of the study (median 27 days, range 7-76 days). All deaths were determined to be unrelated to the hCT-MSCs. Conclusion We were able to collect relevant safety outcomes for the use of hCT-MSCs in patients with COVID-19-related ARDS. Future studies to explore their safety and efficacy are warranted.

Four decades ago, Broxmeyer et al. demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al. reported the first successful matched sibling cord blood transplant (CBT) in a child with Fanconi Anemia. In 1991, Rubinstein et al. established an unrelated donor CB bank, and in 1993, the first unrelated CBT used a unit from this bank. Since that time, >40 000 CBTs have been performed worldwide. Early outcomes of CBT were mixed and demonstrated the importance of cell dose from the CB donor. We hypothesized that improvements in CB banking and transplantation favorably impacted outcomes of CBT today and performed a retrospective study combining data from Eurocord and Duke University in 4834 children transplanted with a single unrelated CB unit (CBU) from 1993 to 2019. Changes in standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic graft-versus-host disease [GvHD], treatment related mortality [TRM], and relapse) over 3 time periods (1: 2010 to 2019) were studied. Increased cell dose and degree of HLA matching were observed over time. OS, times to engraftment, and DFS improved over time. The incidence of TRM and GvHD decreased while the incidence of relapse remained unchanged. Relative contributions of cell dose and HLA matching to transplant outcomes were also assessed and showed that HLA matching was more important than cell dose in this pediatric cohort.

Questionable research practices (QRP) are actions taken by researchers that span a range of concern related to violation of research best practices, and ultimately expose institutions and research participants to risk. Numerous studies have shown that QRP are common. The continued prevalence of QRP indicates that existing approaches for dealing with QRP are falling short. In this editorial we discuss the risks associated with QRP and propose mitigation strategies at the institutional level using a common QRP as an example, questionable treatment of subgroup analyses. We argue that the need for institutional intervention in cases such as this are particularly motivating when both the investigator and the institution have a substantial financial conflict of interest related to intellectual property that requires the investigator's expertise to continue developing. To address this, we propose an expansion of the traditional conflict of interest management process.

PURPOSE: Insured patients with cancer face high treatment-related, out-of-pocket (OOP) costs and often cannot access financial assistance. We conducted a randomized, controlled trial of Bridge, a patient-facing app designed to identify eligible financial resources for patients. We hypothesized that patients using Bridge would experience greater OOP cost reduction than controls. METHODS: We enrolled patients with cancer who had OOP expenses from January 2018 to March 2019. We randomly assigned patients 1:1 to intervention (Bridge) versus control (financial assistance educational websites). Primary and secondary outcomes were self-reported OOP costs and subjective financial distress 3 months postenrollment. In post hoc analyses, we analyzed application for and receipt of financial assistance at 3 months postenrollment. We used chi-square, Mann-Whitney tests, and logistic regression to compare study arms. RESULTS: We enrolled 200 patients. The median age was 57 years (IQR, 47.0-63.0). Most patients had private insurance (71%), and the median household income was $62,000 in US dollars (USD) (IQR, $36,000-$100,000 [USD]). Substantial missing data precluded assessment of primary and secondary outcomes. In post hoc analyses, patients in the Bridge arm were more likely than controls to both apply for and receive financial assistance. CONCLUSION: We were unable to test our primary outcome because of excessive missing follow-up survey data. In exploratory post hoc analyses, patients who received a financial assistance app were more likely to apply for and receive financial assistance. Ultimately, our study highlights challenges faced in identifying measurable outcomes and retaining participants in a randomized, controlled trial of a mobile app to alleviate financial toxicity.

This manuscript describes an experiential learning program for future collaborative biostatisticians (CBs) developed within an academic medical center. The program is a collaborative effort between the Biostatistics, Epidemiology, and Research Design (BERD) Methods Core and the Master of Biostatistics (MB) program, both housed in the Department of Biostatistics and Bioinformatics at Duke University School of Medicine and supported in partnership with the Duke Clinical and Translational Science Institute. To date, the BERD Core Training and Internship Program (BCTIP) has formally trained over 80 students to work on collaborative teams that are integrated throughout the Duke School of Medicine. This manuscript focuses on the setting for the training program, the experiential learning model on which it is based, the structure of the program, and lessons learned to date.

Preclinical and early phase clinical studies suggest that an appropriately dosed umbilical cord blood (CB) infusion has the potential to help improve motor function in young children with cerebral palsy (CP). As many children with CP do not have their own CB available, use of allogeneic cells would extend access to this potentially beneficial therapy to more children. In this phase I, open-label study, 15 children, aged 1 to 6 years, with moderate to severe spastic CP were treated with a single intravenous infusion of allogeneic human leukocyte antigen (HLA) matched or partially matched sibling CB with a cell dose of ≥2.5 × 107 cells/kg based on the pre-cryopreservation count (median infused cell dose, 3.3 × 107; range, 1.8-5.2 × 107). There were a total of 49 adverse events (AEs) over a 2-year time period, but there were no AEs related to the CB infusions. Specifically, there were no acute infusion reactions and no antibody formation against platelets, red blood cells, or donor-specific HLA antigens. Donor cells were not detected in peripheral blood 6 months later. Six months after infusion, participants were assessed for response and experienced a mean ± SD increase of 4.7 ± 2.5 points on the Gross Motor Function Measure-66 and 1 ± 2.9 points on the Peabody Gross Motor Quotient. Appropriately dosed, allogeneic partially or fully HLA-matched sibling CB infusion is well tolerated and potentially beneficial in young children with CP.

Endogenous apolipoprotein (apo) E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apoE-mimetic peptides effectively penetrate the central nervous system compartment and downregulate acute inflammation. CN-105 is a novel apoE-mimetic pentapeptide with excellent evidence of functional and histological improvement in preclinical models of intracerebral hemorrhage (ICH). The CN-105 in participants with Acute supraTentorial intraCerebral Hemorrhage (CATCH) trial is a first-in-disease-state multicenter open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH. Eligible patients were aged 30–80 years, had confirmed primary supratentorial ICH, and were able to intiate CN-105 administration (1.0 mg/kg every 6 h for 72 h) within 12 h of symptom onset. A priori defined safety end points, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes, were analyzed. For clinical outcomes, CATCH participants were compared 1:1 with a closely matched contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on days 0, 1, 2, and 5 and ordinal modified Rankin Scale score at 30 days after ICH were compared. In 38 participants enrolled across six study sites in the United States, adverse events occurred at an expected rate without increase in hematoma expansion or neurological deterioration. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day modified Rankin Scale score, after adjustment for ICH score, sex, and race/ethnicity, as compared with a matched contemporary cohort. CN-105 administration represents an excellent translational candidate for treatment of acute ICH because of its safety, dosing feasibility, favorable pharmacokinetics, and possible improvement in neurological recovery.

Adults with acute myeloid leukemia (AML) face considerable distress and often have a poor prognosis. However, little is known about these patients’ perceptions of prognosis and how this relates to emotional well-being (EWB). We conducted a prospective, observational study of 50 adult patients with AML initiating chemotherapy, and surveyed them longitudinally for 6 months about their prognosis, treatment goals, quality of life, and EWB (by FACT-G). We derived a prognostic estimate for each patient based on data from published trials summarized in National Comprehensive Care Network Guidelines. We used descriptive statistics and longitudinal modeling to test the hypothesis that more accurate prognostic awareness is associated with worse EWB. Most patients (n = 43; 86%) had an objectively poor prognosis attributable to relapsed disease, complex karyotype, or FLT3 mutation. Yet, 74% of patients reported expecting a 50% or greater chance of cure. Patients with a poor prognosis more often had discordant prognostic estimates, compared to those with favorable risk AML (OR = 7.25, 95% CI 1.21, 43.37). Patient-reported prognostic estimates did not vary significantly over time. At baseline, patients who better understood their prognosis had worse EWB and overall quality-of-life scores (EWB 12 vs. 19.5; p = 0.01; FACT-G 65 vs. 75.5; p = 0.01). Patients with AML overestimate their prognosis, and awareness of a poor prognosis is associated with worse emotional well-being. Efforts are needed to improve patients’ understanding of their prognosis, and to provide more psychosocial support and attention to well-being as part of high-quality leukemia care.

There are limited real-world data about patient-reported outcomes with immunotherapies (IO) in metastatic non-small cell lung cancer (mNSCLC). We describe patient-reported distress and clinical outcomes with IO-based treatments or cytotoxic chemotherapies (Chemo).We conducted a single-institution retrospective chart review of adults with mNSCLC treated at Duke from 03/2015 to 06/2020. At each visit, patients self-reported their distress level and sources of distress using the NCCN Distress Thermometer (DT) and its 39-item Problem List. We abstracted demographic, clinical, distress, and investigator assessed-clinical response data, then analyzed these using descriptive statistics and generalized estimating equations.Data from 152 patients were analyzed in four groups: Chemo alone, IO + Chemo, single agent IO, dual agent IO. Distress was worse before treatment start in all groups, and the odds of actionable distress (DT score 4) decreased by 10 % per month. The most frequent sources of distress were physical symptoms (e.g., fatigue, pain), which remained high longitudinally. Patients receiving IO had higher clinical response rates and a lower rate of unplanned healthcare encounters compared to patients treated with Chemo alone. Only one-third of all patients were seen by palliative care.This single-center, real-world evidence study demonstrates that patients with mNSCLC experience significant distress prior to starting first-line treatment. IO treatment was associated with higher clinical benefit rates and lower healthcare utilization compared to chemotherapy. Symptom distress persists over time, highlighting potential unmet palliative and supportive care needs in mNSCLC care in the IO treatment era.

Psychological distress is prevalent in Hodgkin lymphoma (HL). Many patients, regardless of prognosis, receive ABVD chemotherapy as first-line treatment, but few studies have specifically examined the nature of distress during this shared treatment experience. We conducted a retrospective study of patient-reported distress in HL patients receiving ABVD treatment at a single tertiary care facility. Distress was measured using the National Comprehensive Cancer Network Distress Thermometer and Problem List (PL). We used descriptive statistics and generalized estimating equations to assess the prevalence of distress and specific problem items during treatment and associations with patient- and disease-related factors. We collected data from 50 patients comprising 467 unique encounters, with 369/467 (79.0%) reporting a distress thermometer score. Median distress score was 2 (IQR: 0–5), but actionable distress (distress thermometer ≥4) was noted for 118/369 (32.0%) encounters. Actionable distress was only related to having a prior cancer, which conferred lower odds of actionable distress (OR 0.23, 95% CI 0.07–0.74, p=0.01) Physical and emotional problems were reported for 287/369 (77.8%) and 125/369 (33.9%) visits, respectively. Female patients had greater odds of both physical (OR 3.17, 95% CI 1.32–7.66, p=0.01) and emotional (OR 3.31, 95% CI 1.25–8.73, p=0.02) problems. ABVD treatment is associated with a high frequency of actionable distress, with physical and emotional problems acting as primary drivers. Female patients may be particularly vulnerable, while cancer survivors may be uniquely resilient. These findings demonstrate the need to thoroughly screen for and appropriately tailor distress management strategies for HL patients during treatment with ABVD.

PURPOSE: Advance care planning (ACP) is a process in which patients share their values, goals, and preferences regarding future medical care. ACP can improve care quality, yet may be challenging to address for patients with cancer. We sought to characterize key components of ACP in patients with cancer as compared with patients with noncancer serious illness referred to palliative care (PC). METHODS: We performed a retrospective cross-sectional analysis of initial outpatient PC visits from the Quality Data Collection Tool for PC database from 2015 to 2019. Quality Data Collection Tool is a web-based point-of-care specialty PC registry to track quality metrics. RESULTS: We analyzed 1,604 patients with cancer and 1,094 patients without cancer: 44% of patients were female, 87% were White, and 98% were non-Hispanic. The average age was 72.2 years (standard deviation [SD] 15.4). Patients with cancer were on average younger than patients without cancer (66.5 [SD: 13.9] v 80.5 [SD: 13.8]) and had a higher Palliative Performance Scale (PPS) (59.5 [SD: 22.4] v 33.4 [SD: 25.1]). In our unadjusted comparison, patients with cancer were less likely to be DNR/DNI (37% v 53%; P < .0001) and less likely to have an advance directive (53% v 73%; < .0001); rates of healthcare proxy identification were similar (92.8% v 94.5%; P = .10). These differences did not persist when we accounted for age, race, sex, and PPS, with age being the primary explanatory factor. CONCLUSION: Despite having serious illness meriting PC referral, many patients with cancer in our study lacked advance directives. This highlights both the important role of oncologists in facilitating ACP and the utility of PC playing a complementary role.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by a poor prognosis but also a paradoxical possibility of cure. This renders decision-making complex and imminent. Unfortunately, many patients with AML misestimate their prognosis and treatment risk. While decision aids can improve illness understanding and reduce decisional conflict, there are no validated decision aids for AML. We developed and tested a novel AML decision aid (NCT03442452). Patients (n = 20) were recruited at Duke University from May 2018 to February 2019. Participants completed assessments of AML knowledge and decisional conflict, before and after using the electronic decision aid. The primary endpoint was feasibility (endpoint met if > 80% of study participants completed all study components). Secondary analyses of efficacy were conducted using paired t tests for dependent pre-/post-samples. The primary endpoint of feasibility was met (100% of participants completed all study components). Secondary analyses showed improved knowledge and reduced decisional conflict after using the decision aid. Knowledge scores improved from a mean of 11.8 (out of 18) correct items at baseline to 15.1 correct items after using the decision aid (mean difference 3.35; p < 0.0001). Decisional conflict scores reduced significantly from baseline to post-test as well (mean difference − 6.5; p = 0.02). These findings suggest that our AML decision aid is a useful tool to improve the patient experience and promote shared decision-making in AML. A randomized efficacy trial is planned.

This communication describes the process and results of a curriculum review of a first-year sequence of courses in statistical inference within a Master of Biostatistics program. Our primary aim was to develop an innovative course in statistical theory that meets the needs of a diverse student audience, the majority of whom are seeking a terminal master’s degree while a minority will pursue PhD training in biostatistics. The main results were (1) different course paths for job-bound and PhD-bound students; and (2) the development of an innovative first course in statistical inference, which is a computationally-aided self-discovery of a salient (albeit not comprehensive) set of key concepts and techniques pertaining to statistical inference. The redesign process addressed a key conceptual barrier: namely, the unexamined assumption that deductive proofs are a necessary condition for rigorous presentation. Consistent with the principles of constructivism, we navigated this barrier by redefining the task to which pedagogic rigor should be applied: namely, to help students to develop a sound mental map of statistical inference. We believe that the approach we used to accomplish this redefined task could be generalized to additional aspects of statistical education, among others.

In this multicenter study, we investigated the kinetics of neutrophil recovery in relation to acuity and survival among 125 children undergoing allogeneic hematopoietic cell transplantation (allo-HCT) who required invasive mechanical ventilation (IMV). Recovery of neutrophils, whether prior to or after initiation of IMV, was associated with a significantly decreased risk of death relative to never achieving neutrophil recovery. A transient increase in acuity (by oxygenation index and vasopressor requirements) occurred among a subset of the patients who achieved neutrophil recovery after initiation of IMV; 61.5% of these patients survived to discharge from the intensive care unit (ICU). Improved survival among patients who subsequently achieved neutrophil recovery on IMV was not limited to those with peri-engraftment respiratory distress syndrome. The presence of a respiratory pathogen did not affect the risk of death while on IMV but was associated with an increased length of IMV (p

Student evaluation is a key consideration for educational program administrators because program success depends on students’ ability to demonstrate successful development of core competencies. Student evaluations must therefore be aligned with learning objectives and overall program goals. Graduate level educational programs typically incorporate course-level and program-level evaluations, e.g., a final examination in a single course vs. a qualifying examination that assesses knowledge gained from several courses. While there is often considerable attention given to the structure of these evaluations at the program level, the format is typically left to the instructor’s discretion. We argue in this article that there are administrative advantages to encouraging instructors to adopt creative forms of assessment that extend beyond the typical concerns related to program structure. Specifically, we argue that advantages can be gained in terms of increasing student engagement, adding real world context to student evaluations, maintaining positive program culture, and reducing the opportunity for cheating. We present two examples of creative assessments implemented in a 2-year Master of Biostatistics program, along with a discussion of three key questions administrators should consider as they work with instructors to develop innovative assessment methods: (1) what changes to make; (2) in what order to make those changes; and (3) how to consult with instructors about making those changes.

Cancer patients' sources of distress are often unaddressed, and patient-reported distress data could be utilized to identify those with unmet and impending care needs. We explored the association between moderate/severe distress and healthcare utilization in a large sample of non-small cell lung cancer (NSCLC) and non-colorectal gastrointestinal cancer patients.Adult patients treated between July 2013 and March 2019. Data from the NCCN Distress Thermometer (DT) and the accompanying "Problem List" were extracted from the EHR. A DT score of ≥ 4 indicates "actionable distress." Statistical analysis was performed using descriptive analysis for patient characteristics, clinical outcomes, and sources of distress. Generalized linear mixed models were fit to determine the relationship between distress and healthcare utilization (hospitalization, emergency department (ED) visit, or both).The ten most frequently reported problems were from the Physical and Emotional domains of the Problem List. Distress was mostly related to physical symptoms (pain, fatigue) and emotional issues (worry, fears, sadness, nervousness). Patients with actionable distress generally reported more problems across all their visits. Actionable distress was associated with higher odds of the composite outcome measure of hospitalization or visiting the ED, within both the next 3 months (OR = 1.37; 95% CI = 1.19, 1.58; p 0.001) and 6 months (OR = 1.19; 95% CI = 1.03, 1.37; p = 0.019).Patients with significant distress had marked utilization of ED and inpatient services. DT scores are a source of untapped data in the EHR that can highlight patients in need of intervention, including palliative care and cancer support services.

BACKGROUND Limited English proficiency (LEP) is associated with adverse clinical outcomes. The clinical impact of LEP in hematopoietic stem cell transplant (HSCT) has not been studied. The objectives of this study were to compare HSCT outcomes and health care utilization of Hispanic pediatric patients with and without parental LEP. METHODS We conducted a retrospective review of Hispanic/Latino pediatric patients receiving HSCT at a single institution. Families were identified as LEP or English proficient (EP) based on clinicians' notes, social work documentation, or the signature of a Spanish interpreter on treatment consents. RESULTS A total of 83 Hispanic/Latino patients were identified with 53 (65.1%) having parental LEP. More patients in the LEP group had a documented financial burden at pretransplant psychosocial evaluation (72.2% vs. 41.4%, p = .009). LEP patients were more likely to have health insurance coverage through government-sponsored Medicaid (76.9% vs. 27.6%, p

Simple Summary The X-linked inhibitor of apoptosis protein (XIAP) is considered the most potent inhibitor of cell death, and it is well established that XIAP promotes resistance to chemotherapy, radiation, and anti-cancer immune responses. This study evaluates the correlations between XIAP expression and clinicopathological features, including disease-free survival (DFS) and pathological complete response (pCR) to chemotherapy, in more than 2300 invasive primary breast cancer samples. We found a significant association of XIAP expression with younger patients’ age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, and PAM50 luminal B subtype. Analysis of molecular subtypes revealed a stronger prognostic value in HR+/HER2− tumors. Higher XIAP expression was associated with shorter DFS and lower pCR rate to chemotherapy in both uni- and multivariate analyses. All these correlations were observed at both the RNA and protein level, indicating the potential of XIAP as a promising therapeutic target in primary invasive breast cancer. Abstract XIAP, the most potent inhibitor of cell death pathways, is linked to chemotherapy resistance and tumor aggressiveness. Currently, multiple XIAP-targeting agents are in clinical trials. However, the characterization of XIAP expression in relation to clinicopathological variables in large clinical series of breast cancer is lacking. We retrospectively analyzed non-metastatic, non-inflammatory, primary, invasive breast cancer samples for XIAP mRNA (n = 2341) and protein (n = 367) expression. XIAP expression was analyzed as a continuous value and correlated with clinicopathological variables. XIAP mRNA expression was heterogeneous across samples and significantly associated with younger patients’ age (≤50 years), pathological ductal type, lower tumor grade, node-positive status, HR+/HER2− status, and PAM50 luminal B subtype. Higher XIAP expression was associated with shorter DFS in uni- and multivariate analyses in 909 informative patients. Very similar correlations were observed at the protein level. This prognostic impact was significant in the HR+/HER2− but not in the TN subtype. Finally, XIAP mRNA expression was associated with lower pCR rate to anthracycline-based neoadjuvant chemotherapy in both uni- and multivariate analyses in 1203 informative patients. Higher XIAP expression in invasive breast cancer is independently associated with poorer prognosis and resistance to chemotherapy, suggesting the potential therapeutic benefit of targeting XIAP.

Human age-related thymus involution is characterized by loss of developing thymocytes and the thymic epithelial network that supports them, with replacement by adipose tissue. The mechanisms that drive these changes are difficult to study in vivo due to constant trafficking to and from the thymus. We hypothesized that the loss of thymocytes that occurs during human thymic organ cultures could model some aspects of thymus involution and begin to identify mechanisms that drive age-related changes in the thymic microenvironment. Potential mechanistically important candidate molecules were initially identified by screening conditioned media from human thymus organ cultures using antibody microarrays. These candidates were further validated using cultured tissue extracts and conditioned media. Results were compared with gene expression studies from a panel of well-characterized (non-cultured) human thymus tissues from human donors aged 5 days to 78 years. L-selectin released into conditioned media was identified as a biomarker for the content of viable thymocytes within the cultured thymus. Levels of the chemokines CCL21 and CXCL12, likely produced by surviving thymic epithelial cells, increased markedly in conditioned media as thymocytes were lost during culture. Native non-cultured thymus from adults older than 18 years also showed a strong trend toward increased CCL21 expression, in conjunction with significant decreases in thymocyte-related mRNAs compared with thymus from subjects younger than 18 years. Together, these findings demonstrate that use of postnatal human thymus organ cultures can model some aspects of human age-related thymic involution. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-020-00301-1.

e24138 Background: Distress has a negative impact on the patient experience of cancer. We previously demonstrated that patients with metastatic non-small cell lung cancer (mNSCLC) face significant and sustained distress during first-line treatment. However, the association between distress and unplanned healthcare utilization (HCRU) is not well understood. Here we examine this association. Methods: We conducted secondary analyses of data from 152 adult patients with mNSCLC treated at Duke Cancer Institute who were part of a retrospective chart review study (3/15-6/20). For the original investigation, demographic, clinical, and distress data were abstracted. NCCN Distress Thermometer (DT) scores were recorded at each clinic visit from start of first-line therapy to end of first year, change in therapy or death. The DT is an 11-point ordinal scale, with a 39-item Problem List, assessing overall distress. DT scores of > = 4 indicate actionable distress. Further HCRU data were analyzed, including unplanned hospitalizations, 30-day readmissions, length of stay, clinic visits, infusion center visits, emergency department (ED) visits, and death. Descriptive statistical analyses were performed for sources of distress and HCRU. To examine the association between distress and HCRU, we utilized an adjusted frailty model (for baseline demographics, metastatic site, and National Cancer Institute Index). This Cox proportional hazards model allowed for multiple HCRU events per patient and included actionable distress as a time-dependent covariate. Results: First, the proportion of actionable DT scores (423/1652, 25.6%) was strikingly high. Most DTs included report of at least one physical problem (n = 1593, 96.4%), regardless of distress level. However, emotional problems (e.g., worry, nervousness, depression) were reported much more frequently when the DT score was actionable (61.9% vs. 20.8%). At the patient level (n = 152), actionable distress was associated with increased HCRU. For example, a larger proportion of those with an average DT score > = 4 had at least one hospitalization (n = 22, 53.7%), infusion center visit (n = 11, 26.8%) or ED visit (n = 28, 68.3%) compared to patients with a non-actionable average DT score. Furthermore, HCRU was 54% more likely to occur after a patient reporting actionable distress compared to a patient reporting lower distress levels any time during treatment (adjusted HR 1.54; CI 1.20, 1.97). A one-point increase in distress was associated with an 8% increase in risk of HCRU (HR 1.08; CI 1.03, 1.13) at any point during treatment. Conclusions: Patients with mNSCLC experience high levels of distress, with actionable distress appearing to be driven significantly by emotional problems. Patient-reported distress is also associated with HCRU. Intervention development and testing is needed to address the unmet psychological needs in lung cancer care and their potential impact on unplanned HCRU.

We describe an innovative preorientation curriculum (POC) for a Master of Biostatistics (MB) program. The goal of the POC is to fill critical skills gaps for students entering the MB program from heterogeneous backgrounds so they are prepared to engage in the program’s rigorous, fast-paced training upon arrival. To achieve this goal, we introduce a structured approach to thinking that forms the foundation of a sound mental map of Biostatistics, which will assist students in their subsequent efforts to master the discipline. Based on constructivist principles, the POC covers mathematical and statistical theory, data analysis methods, programming, and statistical practice through a sequence of instruction that encourages reflection, extension, and connection between topics. The POC is modular, self-paced, and offered online via a cloud-hosted interactive learning management system (LMS). Students are required to complete the curriculum prior to the MB program orientation. We describe the rationale, design, features, and initial evaluation of the POC. Finally, to help programs interested in designing similar curricula, we provide a detailed instruction sequence description of one topic.

We describe an innovative, semester-long course in biology and communication skills for master’s degree students in biostatistics. The primary goal of the course is to make the connection between biological science and statistics more explicit. The secondary goals are to teach oral and written communication skills in an appropriate context for applied biostatisticians, and to teach a structured approach to thinking that enables students to become lifelong learners in biology, study design, and the application of statistics to biomedical research. Critical evaluation of medical literature is the method used to teach biology and communication. Exercises are constructivist in nature, designed to be hands-on and encourage reflection through writing and oral communication. A single disease area (cancer) provides a motivating example to: 1) introduce students to the most commonly used study designs in medical and public health research, 2) illustrate how study design is used to address questions about human biology and disease, 3) teach basic biological concepts necessary for a successful career in biostatistics, and 4) train students to read and critically evaluate publications in peer-reviewed journals. We describe the design and features of the course, the intended audience, and provide detailed examples for instructors interested in designing similar courses.

Background: Information routinely collected during a palliative care consultation request may help predict the level of complexity of that patient encounter. Objectives: We examined whether patient and consultation characteristics, as captured in consultation requests, are associated with the number of unmet palliative care needs that emerge during consultation, as an indicator of complexity. Design: We performed a retrospective cohort analysis of palliative care consultations. Setting: We analyzed quality-of-care data from specialty palliative care consultations contained in the Quality Data Collection Tool of the Global Palliative Care Quality Alliance from 2012 to 2017. Measurements: Using 13 point-of-care assessments of quality of life, symptoms, advance care planning, and prognosis, we created a complexity score ranging from 0 (not complex) to 13 (highest complexity). Using multivariable linear regression, we examined the relationships of consultation setting and patient characteristics with complexity score. Results: Patients in our cohort (N = 3121) had an average complexity score of 6.7 (standard deviation = 3.7). Female gender, nonwhite race, and neurological (e.g., dementia) and noncancer primary diagnosis were associated with increased complexity score. The hospital intensive care unit, compared with the general floor, was associated with higher complexity scores. In contrast, outpatient and residence, compared with the general floor, were associated with lower complexity scores. Conclusion: Patient, disease, and care setting factors known at the time of specialty palliative care consultation request are associated with level of complexity, and they may inform teams about the right service provisions, including time and expertise, required to meet patient needs.

BackgroundEndogenous apoliloprotein E mediates neuroinflammatory responses and recovery after brain injury. Exogenously administered apolipoprotein E-mimetic peptides can effectively penetrate the brain and down-regulate acute inflammation. CN-105 is a novel apolipoprotein E-mimetic pentapeptide with excellent preclinical evidence as an acute intracerebral hemorrhage (ICH) therapeutic. TheCN-105 in participants withAcute supraTentorial intraCerebralHemorrhage (CATCH) trial is a first-in-disease-state, multi-center, open-label trial evaluating safety and feasability of CN-105 administration in patients with acute primary supratentorial ICH.MethodsEligible patients were age 30-80 years, had confirmed primary supratentorial ICH, and able to intiate CN-105 administration (1.0 mg/kg every 6 hours for 72 hours) within 12 hours of symptom onset.A prioridefined safety endpoints, including hematoma volume, pharmacokinetics, and 30-day neurological outcomes were analyzed. For comparisons, CATCH participants were matched 1:1 with a contemporary ICH cohort through random selection. Hematoma volumes determined from computed tomography images on Days 0, 1, 2, and 5 and ordinal modified Rankin Score at 30 days after ICH were compared.ResultsIn 39 participants enrolled across six study sites in the United States, adverse events occurred at expected rate without increase in hematoma expansion or neurological deterioration or significant serum accumulation. CN-105 treatment had an odds ratio (95% confidence interval) of 2.69 (1.31–5.51) for lower 30-day mRS, after adjustment for ICH Score, sex, and race/ethnicity, compared to matched contemporary cohort.ConclusionCN-105 administration represents an excellent translational candidate as an actue ICH therapeutic due to its safety, dosing feasibility, favorable pharmacokinetics, and evidence of improved neurological recovery.

Statistical efficiency can be gained in clinical trials by using composites of time-to-event outcomes when the individual component outcomes have low event rates. However, the utility of continuous composite outcome measures is not as clear. Efficiency can be either gained or lost by using a continuous composite outcome measure depending on several factors, including the strength of correlation between the component outcomes and the size of the treatment effect on each component. In this article we review these concepts from the standpoint of planning a new trial. Statistical properties of composites formed from normally distributed continuous outcomes are discussed. An example dataset is used to demonstrate concepts and complete mathematical details are provided. Finally, a conceptual model for clinical trial design with continuous composites is proposed that could be used as a guide to evaluate the utility of a continuous composite outcome in a future trial based on existing knowledge in the therapeutic area.

Our analysis from a national registry shows that compared to cancer, cardiovascular disease patients referred to palliative care are a decade older, have worse functional status and clinician-estimated prognosis. Both groups have very high symptom burden, with cardiovascular disease patients experiencing more dyspnea while pain, nausea, and fatigue are more common in cancer.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by a poor prognosis but also a paradoxical possibility of cure. This renders decision-making complex and imminent. Unfortunately, many patients with AML misestimate their prognosis and treatment risk. While decision aids can improve illness understanding and reduce decisional conflict, there are no validated decision aids for AML. We developed and tested a novel AML decision aid (NCT03442452).Patients (n = 20) were recruited at Duke University from May 2018 to February 2019. Participants completed assessments of AML knowledge and decisional conflict, before and after using the electronic decision aid. The primary endpoint was feasibility (endpoint met if80% of study participants completed all study components). Secondary analyses of efficacy were conducted using paired t tests for dependent pre-/post-samples.The primary endpoint of feasibility was met (100% of participants completed all study components). Secondary analyses showed improved knowledge and reduced decisional conflict after using the decision aid. Knowledge scores improved from a mean of 11.8 (out of 18) correct items at baseline to 15.1 correct items after using the decision aid (mean difference 3.35; p0.0001). Decisional conflict scores reduced significantly from baseline to post-test as well (mean difference - 6.5; p = 0.02).These findings suggest that our AML decision aid is a useful tool to improve the patient experience and promote shared decision-making in AML. A randomized efficacy trial is planned.

Purpose Hodgkin lymphoma (HL) survivors face long-term, elevated risk of treatment-related sequelae, including psychosocial distress associated with poor health outcomes. The magnitude and sources of distress are not well described in the routine care of HL outside of clinical trials. Methods We conducted a retrospective cohort study of patients visiting a tertiary-care center for treatment or long-term follow-up of HL. Patient-reported distress was documented using the National Comprehensive Cancer Network Distress Thermometer (DT) and Problem List. Three survivor groups were compared using descriptive methods: on treatment, surviving

BACKGROUND The cell dose infused for cord blood transplantation strongly correlates with outcomes following transplantation. Post thaw recoveries can be improved by washing cord blood units (CBUs) in dextran/albumin. Early methods used a labor-intensive manual process. We have recently developed and validated an automated washing method. We now report our results of a study comparing cellular recoveries achieved after manual and automated wash, as well as the impact on engraftment following allogeneic transplantation. STUDY DESIGN AND METHODS CBUs distributed by the Carolinas Cord Blood Bank for clinical use at Duke University after manual or automated wash were included in this report. Precryopreservation total nucleated cell count, total CD34+, colony-forming units, recoveries, and sterility were analyzed by wash method. Patient age, cell dose/weight, diagnosis, conditioning regimen, immunosuppression, and time to neutrophil engraftment were also analyzed. RESULTS Manual and automated washed CBUs yielded similar total nucleated cell count and total CD34+ recoveries. Significantly higher colony-forming units recoveries were achieved after automated washing. Patients who received CBUs washed via an automated method experienced earlier neutrophil engraftment. CONCLUSION While manual and automated washing achieved similar post thaw cellular recoveries, automated washed CBUs demonstrated higher colony-forming unit recovery, which is an important predictor of potency and engraftment. Furthermore, we demonstrated that automated washing was associated with earlier neutrophil engraftment. Our findings favor the use of an automated wash method over a manual approach.

Stroke is a major cause of death and long-term disability, affecting one in six people worldwide. The only currently available approved pharmacological treatment for ischemic stroke is tissue plasminogen activator; however, relatively few patients are eligible for this therapy. We hypothesized that intravenous (IV) infusion of banked unrelated allogeneic umbilical cord blood (UCB) would improve functional outcomes in patients with ischemic stroke. To investigate this, we conducted a phase I open-label trial to assess the safety and feasibility of a single IV infusion of non-human leukocyte antigen (HLA) matched, ABO matched, unrelated allogeneic UCB into adult stroke patients. Ten participants with acute middle cerebral artery ischemic stroke were enrolled. UCB units were matched for blood group antigens and race but not HLA, and infused 3–9 days post-stroke. The adverse event (AE) profile over a 12 month postinfusion period indicated that the treatment was well-tolerated in these stroke patients, with no serious AEs directly related to the study product. Study participants were also assessed using neurological and functional evaluations, including the modified Rankin Score (mRS) and National Institute of Health Stroke Scale (NIHSS). At 3 months post-treatment, all participants had improved by at least one grade in mRS (mean 2.8 ± 0.9) and by at least 4 points in NIHSS (mean 5.9 ± 1.4), relative to baseline. Together, these data suggest that a single i.v. dose of allogeneic non-HLA matched human UCB cells is safe in adults with ischemic stroke, and support the conduct of a randomized, placebo-controlled phase 2 study.

Background: NCCN defines distress as a multifactorial, unpleasant emotional experience of a psychological nature that may interfere with patients' ability to cope with cancer symptoms and treatment. Patients with myelodysplastic syndromes (MDS) are at risk for distress due to the largely incurable nature of this hematopoietic malignancy and its symptom burden, yet associations with clinical outcomes are unknown. Methods: We retrospectively reviewed patient-reported distress data from adult ambulatory patients with MDS visiting a single, tertiary care medical center from July 2013 to September 2015. Demographic, diagnostic, treatment, and comorbidity information were abstracted from records along with NCCN Distress Thermometer (DT) and Problem List (PL) scores. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazards regression. Results: We abstracted 376 DT scores (median, 1; range, 0-10) from 606 visits and 110 patients (median, 2 DT scores/patient; range, 1-16). NCCN Guidelines suggest that patients with DT scores ≥4 should be evaluated for referral to specialty services to address unmet needs. A total of 54 patients (49%) had at least 1 DT score ≥4 and 20 (18%) had 2 or more DT scores ≥4; 98 patients (89.1%) reported 1,379 problems during 23,613 person-days of follow-up (median, 4 problems/patient/visit; range, 1-23). The 5 most frequently reported problems were fatigue (181 times; 78 patients), pain (95 times; 46 patients), worry (80 times; 45 patients), sleep (78 times; 41 patients), and tingling hands/feet (68 times; 33 patients). After adjustment for risk stratification at diagnosis, a single point increase on the DT was associated with an increased risk of death (hazard ratio, 1.18; 95% CI, 1.01-1.36). Conclusions: Patients with MDS experience a high burden of distress, and patient-reported distress is associated with clinical outcomes. Distress should be further studied as a prognostic variable and a marker of unmet needs in MDS.

Background & Aim: Umbilical cord blood (CB) and mesenchymal stromal cells (MSC) have shown safety in children with cerebral palsy (CP). While early phase clinical trials suggest potential functional benefit, small sample sizes, heterogeneous populations, and variable cell doses have impaired accurate assessment of motor gains following treatment. Aim: Describe change in gross motor function in young children with CP after treatment with high-dose allogeneic unrelated donor CB or allogeneic, third party human cord tissue-derived MSC (hCT-MSC) 12 months post treatment. Methods, Results & Conclusion: We conducted a phase 2 randomized trial of 90 children ages 2-4 years with hypertonic CP due to hypoxic ischemic encephalopathy, periventricular leukomalacia, or in utero stroke/bleed. Randomization, stratified by etiology and severity (Gross Motor Function Classification System (GMFCS) level), was to: (a) 10×107 total nucleated cells (TNC)/kg allogeneic CB at baseline, (b) three doses of 2×106 cells/kg hCT-MSC given at baseline, 3, and 6 months, or (c) Natural History in which 10×107 TNC/kg allogeneic CB was given at one year. Infusions were intravenous and premedicated with diphenhydramine and methylprednisolone without immunosuppression. Primary outcome was change in motor function one-year post enrollment, measured by the Gross Motor Function Measure-66 (GMFM-66). Ninety children (median 3.5 years) were randomized and completed baseline and 6-month evaluations. Due to the COVID pandemic, only 68 completed 12-month assessments. The only adverse events (AEs) related to the cell products were 8 transient infusion reactions (3 CB, 5 hCT-MSC). An additional 95 non-severe AEs and 33 severe AEs were unrelated to the products. At 6 months, there was no statistical difference in change in GMFM-66 scores between Natural History (n=31) and either treatment group (CB n=31, hCTMSC n=28). At 12 months, after adjustment for baseline GMFCS level, GMFM-66 score, and etiology of CP, the mean GMFM-66 score of the hCT- MSC group (n=23) was 1.4 points higher than Natural History (n=25;95% CI: -1.1, 4.0;p=0.27) and the CB group (n=20) was 3.3 points higher than Natural History (95% CI: 0.59, 5.93;p=0.02). High dose allogeneic CB, but not hCT-MSC, infusion is associated with gross motor improvement in young children with CP, consistent with the dose effect in a prior study of autologous CB. A phase 3 randomized placebo-controlled study should be performed to confirm the CB observation.

Four decades ago, Hal Broxmeyer demonstrated that umbilical cord blood (CB) contained hematopoietic stem cells (HSC) and hypothesized that CB could be used as a source of donor HSC for rescue of myeloablated bone marrow. In 1988, Gluckman et al reported the first successful cord blood transplant (CBT) of a child with Fanconi Anemia using matched sibling CB. This patient survives and 35 years later still has durable hematopoiesis from the CB donor graft. In 1991, Rubinstein et al established an unrelated donor (UD) CB bank and in 1993 the first UD CBT was using a unit from this bank. Since that time, >40,000 CBTs have been performed worldwide. We hypothesized that changes in cord blood banking (increased size, diversity, and quality of banked units enabling selection of units with higher cell doses and closer HLA matching) and in transplantation (less use of steroids, availability of newer therapies for prophylaxis and treatment of graft versus host disease [GVHD], improved antifungal and antiviral detection and therapeutics) have improved outcomes of CBT today. To address this hypothesis, we performed a retrospective study combining data from Eurocord and Duke University in a large cohort of children transplanted with a single UD CB unit (CBU) from 1993-2019. Standard transplant outcomes (overall survival [OS], disease free survival [DFS], acute and chronic GVHD, treatment related mortality [TRM], and relapse) and changes in outcomes over 3 time periods (1:2010, n=1802) were studied. Relative contributions of cell dose and HLA matching to transplant outcomes over time were assessed. A total of 4834 patients (4015 from Eurocord and 819 from Duke) were analyzed. The majority of patients, (59%, n=2839) had malignant diagnoses including 1422 with ALL, 887 with AML and 167 with MDS. Of the 1995 with non-malignant diagnoses, 761 had inborn errors of metabolism, 644 had primary immunodeficiency, 325 had a bone marrow failure syndrome and 206 had a histiocytic disorder. Half of the patients had positive serologies for CMV prior to transplant. The median age of the cohort fell from 5.2 to 3.25 years over time. In patients with malignancies, use of total body irradiation decreased over time. The median total nucleated cell (TNC) and CD34+ cell doses administered were 8.07x10e7 and 6.17x10e5 cells/kg and increased over time. HLA matching and transplantation of patients in earlier disease states also increased over time, p In conclusion, we analyzed the largest cohort of pediatric patients undergoing CBT over the past 3 decades. OS, DFS and engraftment have improved over time accompanied by decreases in TRM and acute GVHD. Relapse and chronic GVHD were stable and remain low. These improvements are explained by the increased availability of high quality banked CBUs enabling selection of closer HLA matching and units with higher cell doses. The numbers of CBTs have decreased in the past decade, but these results support the ongoing use of CBT in children lacking matched related or unrelated donors. Figure 1 Figure 1. Disclosures Kurtzberg: Neurogene: Consultancy; CryoCell: Patents & Royalties: Duke licensed IP, and data and regulatory packages for manufacturing and use of cord blood and cord tissue MSCs in the treatment of patients with hypoxic ischemic encephalopathy, cerebral palsy, autism, acute ischemic stroke, COVID-ARDS, and COVID-MIS-C. ; Sinocell: Patents & Royalties: Duke licensed IP, data, and regulatory packages for use of autologous and sibling cord blood to treat children with cerebral palsy.; Celularity: Current holder of stock options in a privately-held company. Troy: SinoCell: Patents & Royalties; CryoCell: Patents & Royalties; Bristol Myers Squibb: Research Funding; Synthetic Biologics: Honoraria; Gamida Cell: Consultancy; The EMMES Corporation: Consultancy; The Community Data Roundtable: Consultancy; AegisCN: Consultancy.

BackgroundThere are limited published real-world data about patient-reported outcomes with immunotherapies (IO) in metastatic non-small cell lung cancer (mNSCLC). We describe the patient experience with first-line IO-based treatments vs. chemotherapy in this setting.MethodsWe conducted a retrospective chart review of adult patients with mNSCLC treated at Duke University from March 2015-June 2020. At each visit, patients self-reported their distress level and sources of distress using the NCCN Distress Thermometer (DT) tool, consisting of an 11-point ordinal scale reporting overall distress and a 39-item Problem List (PL). We abstracted demographic, clinical, distress, response data (by investigator assessment), then analyzed these data using descriptive statistics and generalized estimating equations accounting for clustering of clinic visits within participants and generalized linear models accounting for study exposure time.Results152 patients were analyzed in four groups: single agent immunotherapy (IO alone, n=40), dual immunotherapy (IO+IO, n=27), chemo-immunotherapy (IO+Chemo, n=46), and chemotherapy alone (n=39). Patients were followed for up to 1 year or earliest of: death, last contact, or 2nd line therapy start. Participants' mean age was 65.7 years. In all patients, overall distress was worst before treatment start (figure 1), and the odds of actionable distress (DT score >4) decreased over time by 10% per month (OR=0.901, 95% CI:0.813, 0.998, p=0.045). There were no significant differences in actionable distress across treatment groups. Symptom distress remained high over time, while other sources of distress (practical, family, and emotional) decreased. The most frequent sources of symptom distress were fatigue (90% of patients ever reported, 40% of all DTs), pain (75% of patients, 30% of DTs), and breathing (68% of patients, 22% of DTs) (figure 2). Treatment with chemotherapy alone yielded the fewest tumor responses (50%) and lowest clinical benefit rate (74.4%) compared to any IO therapy. Unplanned healthcare utilization was significantly different across treatment groups; IO+IO resulted in the lowest utilization rate (0.57, 95% CI:0.36, 0.90), while chemotherapy yielded the highest (1.46, 95% CI:1.00,2.12). Palliative care was utilized in 40% of patients; among those with actionable distress at any time (n=113; 74%), 53% (n=60) had a palliative care visit.ConclusionsThis single-center, real-world evidence study demonstrates that patients with mNSCLC experience significant distress prior to starting first-line treatment, with persistent symptom distress over time. Furthermore, IO treatment is associated with reduced healthcare utilization compared to chemotherapy. Increased utilization of integrated palliative care services may improve the patient experience of mNSCLC treatment, especially for management of symptom distress.Ethics ApprovalThis clinical study involves retrospective analyses of data extracted from medical charts and was approved by Duke University School of Medicine Institutional Review Board (IRB#106013).ConsentAs there was no prospective enrollment of subjects, consent was obtained through a Waiver or Alteration of Consent and Authorization and Decedent Research Notification of the Health Insurance Portability and Accountability Act (HIPAA) 1996.Abstract 636 Figure 1Overall distress thermometer scores over timeAbstract 636 Figure 2Most frequently reported problems by treatment type

Introduction The CANS is the most popular measurement tool in the System of Care (SoC), with the potential to generate an estimated 1.9 million evaluations per year in the United States. This dataset has broad potential for decision support and outcomes monitoring, yet many SoC services do not yet leverage this information asset. We report here the results of a pilot project in which we applied machine learning methods to CANS data for the purpose of identifying clinical profiles associated with improvement in a public community-based behavioral health program in Pennsylvania. Methods We analyzed over 7,000 CANS from 3,385 children who participated in Pennsylvania’s Medicaid-funded behavioral health rehabilitation services (BHRS) program during 2013–2019. A gradient boosting classifier was developed to identify children most likely to experience a total score improvement on the CANS while participating in BHRS. Separate models were constructed for children with and without autism spectrum disorder (ASD). CANS-based clinical profiles associated with improvement were also identified. Analyses were run using Python Sci-Ki version 0.20.3 and Linearly Interpretable Model-agnostic Explanations (LIME) version 0.1.1.33. Results The mean age of BHRS participants was 9.85 years (standard deviation: 3.47) and the majority were white (54%) or African American (11.5%). The median length of stay was 963 days (range: 541–2,008) and 39% (N = 1,330) had a diagnosis of ASD. A total of 49.9% of children had a CANS total score improvement. Precision of the gradient boosting classifier was 70% and 79% for children with and without ASD, respectively. Fourteen profiles were associated with improvement in ASD (mean probability of improvement per profile = 0.95, range: 0.88–1.0) and 55 such profiles were identified in children without ASD (mean probability of improvement: 0.91, range: 0.86–1.0). Conclusion Machine learning can be applied to the CANS to identify children who have high probability of improvement in BHRS. These methods may have utility as an adjunct to existing decision support systems for SoC services.

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, {"type":"clinical-trial","attrs":{"text":"NCT01147653","term_id":"NCT01147653"}}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

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.

For pediatric patients with acute lymphoblastic leukemia (ALL), relapse is an important cause of treatment failure after unrelated cord blood transplant (UCBT). Compared to other donor sources, relapse is similar or even reduced after UCBT despite less graft-versus-host disease (GvHD). We performed a retrospective analysis to identify risk factors associated with the 5-year cumulative incidence (CI) of relapse after UCBT. In this retrospective, registry-based study, we examined the outcomes of 640 children (

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 children's 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 children's 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.