Clinical outcomes in patients with piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae bloodstream infection.

BACKGROUND: A small proportion of Escherichia coli and Klebsiella pneumoniae demonstrate in vitro non-susceptibility to piperacillin/tazobactam but retain susceptibility to ceftriaxone. Uncertainty remains regarding how best to treat these isolates. OBJECTIVES: We sought to compare clinical outcomes between patients with piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae bloodstream infection receiving definitive therapy with ceftriaxone versus an alternative effective antibiotic. METHODS: We retrospectively identified patients with a positive blood culture for piperacillin/tazobactam-non-susceptible but ceftriaxone-susceptible E. coli or K. pneumoniae between 1 January 2013 and 31 December 2022. Patients were divided into one of two definitive treatment groups: ceftriaxone or alternative effective antibiotic. Our primary outcome was a composite of 90 day all-cause mortality, hospital readmission, or recurrence of infection. We used Cox proportional hazards models to compare time with the composite outcome between groups. RESULTS: Sixty-two patients were included in our analysis. Overall, median age was 63 years (IQR 49.5-71.0), the most common source of infection was intra-abdominal (25/62; 40.3%) and the median total duration of therapy was 12.0 days (IQR 9.0-16.8). A total of 9/22 (40.9%) patients in the ceftriaxone treatment group and 18/40 (45.0%) patients in the alternative effective antibiotic group met the composite endpoint. In an adjusted time-to-event analysis, there was no difference in the composite endpoint between groups (HR 0.67, 95% CI 0.30-1.50). The adjusted Bayesian posterior probability that the HR was less than or equal to 1 (i.e. ceftriaxone is as good or better than alternative therapy) was 85%. CONCLUSIONS: These findings suggest that ceftriaxone can be used to effectively treat bloodstream infections with E. coli or K. pneumoniae that are non-susceptible to piperacillin/tazobactam but susceptible to ceftriaxone.

Gram-negative bacteremia in solid organ transplant recipients: Clinical characteristics and outcomes as compared to immunocompetent non-transplant recipients.

BACKGROUND: Outcomes from Gram-negative bacteremia (GNB) in solid organ transplant (SOT) recipients are poorly understood. METHODS: This is a single center prospective cohort study comparing the clinical characteristics and outcomes of SOT recipients with GNB to immunocompetent non-SOT patients with GNB between 1/1/2002 through 12/31/2018. Outcomes of interest included incidence of septic shock, respiratory failure, and time to death. A multivariable logistic regression model was used to determine factors associated with incidence of septic shock and respiratory failure. Time to death was evaluated using Cox proportional hazard models. RESULTS: A total of 297 SOT and 1245 immunocompetent non-SOT patients were included. Incidence of septic shock did not significantly differ between the groups (SOT 25.3% vs. non-SOT 24.6%, p = .8225). Overall survival did not significantly differ by transplant status (30-day survival: SOT 76%, 95% confidence interval [CI] 70, 92, non-SOT 74%, 95% CI 71, 77: log rank: p = .76). SOT recipients taking three immunosuppressive medications had significantly lower odds of developing septic shock or respiratory failure requiring intubation and mechanical ventilation than those taking ≤1 agent (shock: adjusted odds ratio [aOR] 0.29, 95% CI 0.09, 0.90, p = .0316; respiratory failure: aOR 0.14, 95% CI: 0.04, 0.49, p = .0020). CONCLUSIONS: SOT recipients with GNB do not experience higher rates of septic shock, respiratory failure, or mortality than immnon-SOT recipients with GNB. Among SOT recipients, a greater number of immunosuppressive medications may be associated with improved outcomes during GNB. Future studies are needed to understand the potential relationship between levels of immunosuppression and clinical outcome in SOT recipients with GNB.

The relationship between emotional well-being and understanding of prognosis in patients with acute myeloid leukemia (AML).

PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Motor function and safety after allogeneic cord blood and cord tissue-derived mesenchymal stromal cells in cerebral palsy: An open-label, randomized trial.

AIM: To evaluate safety and motor function after treatment with allogeneic umbilical cord blood (AlloCB) or umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC) in children with cerebral palsy (CP). METHOD: Ninety-one children (52 males, 39 females; median age 3 years 7 months [range 2-5 years]) with CP due to hypoxic-ischemic encephalopathy, stroke, or periventricular leukomalacia were randomized to three arms: (1) the AlloCB group received 10 × 107 AlloCB total nucleated cells (TNC) per kilogram at baseline (n = 31); (2) the hCT-MSC group received 2 × 106 hCT-MSC at baseline, 3 months, and 6 months (n = 28); (3) the natural history control group received 10 × 107 AlloCB TNC per kilogram at 12 months (n = 31). Motor function was assessed with the Gross Motor Function Measure-66 (GMFM-66) and Peabody Developmental Motor Scale, Second Edition. RESULTS: Infusions (n = 143) were well tolerated, with eight infusion reactions (three in the AlloCB group, five in hCT-MSC) and no other safety concerns. At 12 months, the mean differences (95% confidence intervals [CI]) between actual and expected changes in GMFM-66 score were AlloCB 5.8 points (3.4-8.2), hCT-MSC 4.3 (2.2-6.4), and natural history 3.1 (1.4-5.0). In exploratory, post hoc analysis, the mean GMFM-66 score (95% CI) of the hCT-MSC group was 1.4 points higher than natural history (-1.1 to 4.0; p = 0.27), and the AlloCB group was 3.3 points higher than natural history (0.59-5.93; p = 0.02) after adjustment for baseline Gross Motor Function Classification System level, GMFM-66 score, and etiology. INTERPRETATION: High-dose AlloCB is a potential cell therapy for CP and should be further tested in a randomized, blinded, placebo-controlled trial. WHAT THIS PAPER ADDS: Unrelated donor allogeneic umbilical cord blood (AlloCB) and human umbilical cord tissue-derived mesenchymal stromal cell infusion is safe in young children with cerebral palsy. Significant changes in motor function were not observed 6 months after treatment. One year later, treatment with AlloCB was associated with greater increases in Gross Motor Function Measure-66 scores.

Patient-reported distress as an early warning sign of unmet palliative care needs and increased healthcare utilization in patients with advanced cancer.

INTRODUCTION: 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. METHODS AND MATERIALS: 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). RESULTS: 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). CONCLUSION: 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.

A single-site pilot feasibility randomized trial of a supportive care mobile application intervention for patients with advanced cancer and caregivers.

PURPOSE: Mobile health interventions can improve patient care. We developed the Digital Supportive Care Awareness and Navigation (D-SCAN) application (app) to facilitate symptom monitoring and use/awareness of cancer supportive care resources. This study tested feasibility, usability/satisfaction, and preliminary efficacy of D-SCAN. METHODS: We randomized 50 patients with advanced cancer to receive the D-SCAN intervention or usual care; 10 caregivers also received D-SCAN. The primary feasibility outcome was determined by weekly symptom survey completion and end of study procedures. We assessed secondary outcomes including usability/satisfaction, awareness/use of supportive care resources, patient activation, and quality of life via various questionnaires including the Net Promoter Score (NPS), Patient Activation Measure (PAM-13), Functional Assessment of Cancer Therapy-General (FACT-G), and Caregiver Oncology Quality of Life (CarGOQOL) questionnaire. RESULTS: Seventy-six percent of intervention patients met feasibility criteria, exceeding our pre-determined threshold of 75%. Usability/satisfaction by NPS was high, at 14.3% and 12.5% for patients and caregivers, respectively. Intervention patient and caregiver resource awareness increased by a mean of 3.7 (p = 0.27) and 4.1 items, respectively. Supportive care resource utilization increased by a mean of 0.8 items for intervention patients (p = 0.70) and 0.6 for caregivers. PAM-13 increased by a mean of 1.6 for intervention patients (p = 0.65). FACT-G increased by a mean of 1.1 for intervention patients (p = 0.91), and CarGOQoL increased by a mean of 2.2 (p = 0.41). CONCLUSION: D-SCAN is a feasible, usable, and satisfactory intervention for augmenting patient and caregiver supportive care. Further testing is necessary to formally assess D-SCAN's efficacy and impact on patients and caregivers. CLINICAL TRIAL REGISTRATION NUMBER: NCT03628794. Registered on August 14th, 2018.

CN-105 in Participants with Acute Supratentorial Intracerebral Hemorrhage (CATCH) Trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

An Exploratory Analysis of Biomarkers of Perihematomal Edema in the CN-105 in Participants with Acute Supratentorial Intracerebral Hemorrhage (CATCH) Trial.

OBJECTIVE: To identify biomarkers with potential to indicate severity of perihematomal edema and secondary tissue injury after intracerebral hemorrhage (ICH), and which could be used as surrogate markers in future clinical trials for novel ICH therapeutics. MATERIALS AND METHODS: This exploratory cohort study compared trends in neuroinflammatory biomarker levels in 18 consecutively enrolled patients with acute supratentorial ICH and 16 patients treated with the investigational neuroprotective therapy CN-105 to identify a panel of 10 biomarkers. Biomarker levels over five days post-hemorrhage were then compared with edema volumes in a larger sample of patients treated with CN-105. RESULTS: Mean normalized edema volumes increased over time; higher CRP levels were associated with increased edema volumes (p = 0.006, r = 0.56). Higher IL8, IL10, MCP, and MMP-9 levels were associated with decreased edema volumes (p = 0.005, r =-0.57; p = 0.02, r =-0.51; p = 0.02, r =-0.52; p = .002, r =-0.63, respectively). IL1-RA, IL1-B, IL23, vWF, and IL17 levels were not significantly associated with edema volumes (p > 0.05). CONCLUSIONS: This exploratory study provides some of the first insights into the longitudinal associations between markers of neuroinflammation and development of perihematomal edema and secondary tissue injury in human ICH. We hypothesize that these biomarkers could be used as surrogates for treatment effect in novel therapies intended to limit neuroinflammation after ICH.

Differences between patients with cardiovascular disease and cancer referred for palliative care.

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.

Parental limited English proficiency in pediatric stem cell transplantation: Clinical impact and health care utilization.

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 < .001). LEP patients were hospitalized on average 13 days longer than EP patients, and LEP patients were more likely to have pretransplant cytomegalovirus (CMV) reactivity (67.3%) than EP patients (p = .001). Overall survival was lower in LEP than EP, but was not statistically significant (p = .193). Multivariable Cox modeling suggested a potentially higher risk of death in LEP versus EP (hazard ratio = 1.56, 95% CI: 0.38, 6.23). CONCLUSIONS: Parental LEP in HSCT is associated with prolonged hospitalization and pretransplant CMV reactivity. These factors are associated with posttransplant complications and death. Our results suggest parental LEP is a risk factor for poor HSCT outcomes. Further study is warranted in a larger cohort.

The patient experience of ABVD treatment in Hodgkin lymphoma: a retrospective cohort study of patient-reported distress.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

A novel decision aid for acute myeloid leukemia: a feasibility and preliminary efficacy trial.

PURPOSE: 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). METHODS: 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. RESULTS: 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). CONCLUSION: 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.

A Phase II Randomized Clinical Trial of the Safety and Efficacy of Intravenous Umbilical Cord Blood Infusion for Treatment of Children with Autism Spectrum Disorder.

OBJECTIVE: To evaluate whether umbilical cord blood (CB) infusion is safe and associated with improved social and communication abilities in children with autism spectrum disorder (ASD). STUDY DESIGN: This prospective, randomized, placebo-controlled, double-blind study included 180 children with ASD, aged 2-7 years, who received a single intravenous autologous (n = 56) or allogeneic (n = 63) CB infusion vs placebo (n = 61) and were evaluated at 6 months postinfusion. RESULTS: CB infusion was safe and well tolerated. Analysis of the entire sample showed no evidence that CB was associated with improvements in the primary outcome, social communication (Vineland Adaptive Behavior Scales-3 [VABS-3] Socialization Domain), or the secondary outcomes, autism symptoms (Pervasive Developmental Disorder Behavior Inventory) and vocabulary (Expressive One-Word Picture Vocabulary Test). There was also no overall evidence of differential effects by type of CB infused. In a subanalysis of children without intellectual disability (ID), allogeneic, but not autologous, CB was associated with improvement in a larger percentage of children on the clinician-rated Clinical Global Impression-Improvement scale, but the OR for improvement was not significant. Children without ID treated with CB showed significant improvements in communication skills (VABS-3 Communication Domain), and exploratory measures including attention to toys and sustained attention (eye-tracking) and increased alpha and beta electroencephalographic power. CONCLUSIONS: Overall, a single infusion of CB was not associated with improved socialization skills or reduced autism symptoms. More research is warranted to determine whether CB infusion is an effective treatment for some children with ASD.

An analysis of missing items in real-world electronic patient reported outcomes data: implications for clinical care.

PURPOSE: Utilization of electronic patient-reported outcomes (ePROs) in the clinic can improve quality of life and prolong survival in cancer care. However, there remain unanswered questions regarding trends in missing data and the potential effect on real-time patient care. METHODS: This study utilized a prospectively collected dataset of ePROs from oncology clinics that administered the Patient Care Monitor 2.0 (PCM), a validated symptoms survey assessing 78 items for men, and 86 for women. We tabulated the frequency of missing items, by item and domain (emotional, functional and physical symptom-related), and examined these by age, gender, education, race and marital status. RESULTS: Within 20,986 encounters, there were responses to at least 1 PCM item from 6933 unique patients. The highest frequency of missing answers occurred for: "attend a paid job" (10.7%), "reduced sexual enjoyment" (3.8%), and "run" (3.7%). By domain, 12.3% of functional, 8.4% of physical symptom-related, and 1.6% of emotional constructs contained at least one missing item. For functional and physical symptom-related items, missingness was most common in patients >60 years old. CONCLUSION: The frequency of missingness was highest for functional items, like attending a paid job, suggesting that some respondents (e.g., retirees without a paid job) skipped questions that were less applicable to them. More universal issues for cancer patients, such as emotional well-being, had much lower frequencies of missingness. This suggests differential item completion that warrants further study to understand the inherent drivers. Identifying causes of missingness could improve the clinical utility of ePROs and highlight opportunities to personalize care.

Patient-reported distress in Hodgkin lymphoma across the survivorship continuum.

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 < 5 years, and surviving ≥ 5 years since diagnosis. RESULTS: A total of 1524 DT were abstracted for 304 patients (106 on treatment, 77 surviving < 5 years, and 121 surviving ≥ 5 years). Distress was low overall (median DT = 1, inter-quartile range 0-4) and was similar across survivor groups. However, actionable distress (score ≥ 4) was reported at 29.5% of clinical encounters. Patients on treatment more frequently reported actionable distress (32.5% of visits) compared with patients surviving < 5 years (20.4%) and ≥ 5 years (28.7%) (P = 0.065). Distress was associated primarily with physical and emotional problems, especially fatigue, worry, and sleep. We did not observe any associations between distress and clinical prognostic factors. CONCLUSIONS: Distress burden is low in HL, but survivorship is marked by periods of actionable distress, largely related to physical symptoms and emotional issues. This burden may be higher when on treatment and is unrelated to disease-related prognostic factors. Survivorship research typically focuses on the post-therapy period, but our results support testing the efficacy of interventions to address distress in HL during active treatment as well.

Long-Term Functional Outcomes after Hematopoietic Stem Cell Transplant for Early Infantile Krabbe Disease.

Allogeneic hematopoietic stem cell transplantation (HSCT) can retard the progression of early infantile Krabbe disease (EIKD). Superior outcomes are achieved if HSCT is performed before the onset of symptoms; however, little information is available about the long-term outcomes in surviving patients. We now describe functional outcomes in presymptomatic infants who underwent HSCT for EIKD at ≤ 2 months of age. Records of the 19 patients who underwent HSCT for EIKD at ≤ 2 months of age from 1996 to 2010 were reviewed. Long-term functional outcomes were compared between those transplanted at < 30 days and ≥ 30 days of life. Median age at transplant was 27 days (range, 19 to 61). Median follow-up of the cohort was 12.6 years. Overall survival at 5 and 10 years post-transplant was 84.2% (95% confidence interval, 58.7% to 94.6%) and 78.6% (95% confidence interval, 52.5% to 91.4%), respectively. More favorable outcomes were seen in patients who underwent HSCT at < 30 days of age, particularly in domains of mobility (P = .01), communication (P = .02), and feeding (P = .008). Improved functional outcomes were observed when HSCT was performed in the first month of life, defining a critical period for intervention. These results support the implementation of newborn screening to enable rapid diagnosis and early treatment of infants with EIKD.

Associations between expression levels of nucleotide excision repair proteins in lymphoblastoid cells and risk of squamous cell carcinoma of the head and neck.

Squamous cell carcinoma of head and neck (SCCHN) is one of the most common malignancies worldwide, and nucleotide excision repair (NER) is involved in SCCHN susceptibility. In this analysis of 349 newly diagnosed SCCHN patients and 295 cancer-free controls, we investigated whether expression levels of eight core NER proteins were associated with risk of SCCHN. We quantified NER protein expression levels in cultured peripheral lymphocytes using a reverse-phase protein microarray. Compared with the controls, SCCHN patients had statistically significantly lower expression levels of ERCC3 and XPA (P = 0.001 and 0.001, respectively). After dividing the subjects by controls' median values of expression levels, we found a dose-dependent association between an increased risk of SCCHN and low expression levels of ERCC3 (adjusted OR, 1.75, and 95% CI: 1.26-2.42; Ptrend = 0.008) and XPA (adjusted OR, 1.88; 95% CI, 1.35-2.60; Ptrend = 0.001). We also identified a significant multiplicative interaction between smoking status and ERCC3 expression levels (P = 0.014). Finally, after integrating demographic and clinical variables, we found that the addition of ERCC3 and XPA expression levels to the model significantly improved the sensitivity of the expanded model on SCCHN risk. In conclusion, reduced protein expression levels of ERCC3 and XPA were associated with an increased risk of SCCHN. However, these results need to be confirmed in additional large studies.

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.

Automated thawing increases recovery of colony-forming units from banked cord blood unit grafts.

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.

Patient-Reported Distress in Myelodysplastic Syndromes and Its Association With Clinical Outcomes: A Retrospective Cohort 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.