Access to Chimeric Antigen Receptor T Cell Clinical Trials in Underrepresented Populations: A Multicenter Cohort Study of Pediatric and Young Adult Acute Lymphobastic Leukemia Patients.

Chimeric antigen receptor T cell (CAR-T) therapy is a promising approach to improve survival for children and adults with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL), but these clinical trials might not be equally accessible to patients of low socioeconomic status (SES) or to patients from racial or ethnic minority groups. We sought to describe the sociodemographic characteristics of pediatric and adolescent and young adult (AYA) patients enrolled in CAR-T clinical trials and to compare these characteristics to those of other patients with r/r B-ALL. We conducted a multicenter retrospective cohort study at 5 pediatric consortium sites to compare the sociodemographic characteristics of patients treated and enrolled in CAR-T trials at their home institution, other patients with r/r B-ALL treated at these sites, and patients referred from an external hospital for CAR-T trials. The patients were age 0 to 27 years with r/r B-ALL treated at 1 of the consortium sites between 2012 and 2018. Clinical and demographic data were collected from the electronic health record. We calculated distance from home to treating institution and assigned SES scores based on census tract. Among the 337 patients treated for r/r B-ALL, 112 were referred from an external hospital to a consortium site and enrolled in a CAR-T trial and 225 were treated primarily at a consortium site, with 34% enrolled in a CAR-T trial. Patients treated primarily at a consortium site had similar characteristics regardless of trial enrollment. Lower proportions of Hispanic patients (37% versus 56%; P = .03), patients whose preferred language was Spanish (8% versus 22%; P = .006), and publicly insured patients (38% versus 65%; P = .001) were referred from an external hospital than were treated primarily at a consortium site and enrolled in a CAR-T trial. Patients who are Hispanic, Spanish-speaking, or publicly insured are underrepresented in referrals from external hospitals to CAR-T centers. External provider implicit bias also may influence referral of these patients. Establishing partnerships between CAR-T centers and external hospital sites may improve provider familiarity, patient referral, and patient access to CAR-T clinical trials.

Perceptions of patient disease burden and management approaches in systemic mastocytosis: Results of the TouchStone Healthcare Provider Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by the KIT D816V mutation and has a broad range of debilitating symptoms. In this study, the authors evaluated SM disease perceptions and management strategies among US health care providers (HCPs). METHODS: Hematologist/oncologist (H/O) HCPs and allergist/immunologist (A/I) HCPs who were treating four or more patients with SM completed an online, 51-item TouchStone HCP Survey, which queried provider characteristics, perceptions of disease burden, and current management. Descriptive analyses by specialty and SM subtype were performed. RESULTS: Of 304 HCPs contacted, 111 (37%) met eligibility criteria, including 51% A/I specialists and 49% H/O specialists. On average, the HCPs had 14 years of practice experience and cared for 20 patients with SM. A/I HCPs saw more patients with nonadvanced SM (78%) compared with H/O HCPs, who saw similar proportions of patients with nonadvanced SM (54%) and advanced SM (46%). HCPs reported testing 75% of patients for the KIT D816V mutation and found an estimated prevalence of 47%. On average, HCPs estimated 8 months between symptom onset and SM diagnosis. HCPs reported that 62% of patients with indolent SM felt depressed or discouraged because of symptoms. In terms of treatment goals for SM, both types of specialists prioritized symptom improvement for nonadvanced SM and improved survival for advanced SM while also prioritizing improving patient quality of life. CONCLUSIONS: Both A/I and H/O specialists highlighted unmet needs for patients with SM. The HCPs surveyed reported a lower rate of KIT D816V mutations and a perceived shorter time between symptom onset and SM diagnosis compared with published estimates. LAY SUMMARY: Specialists treating systemic mastocytosis (SM) completed a 51-item questionnaire about their clinical practices and perceptions of disease impact. The study included 111 hematology, oncology, allergy, and immunology physicians. Physicians reported that most patients had nonadvanced disease, yet SM symptoms significantly disrupted their patients' lives. Physicians estimated that SM is diagnosed within months of symptom onset, in contrast with published reports of years' long delays reported by patients with SM. This study identified unmet needs that can inform educational and patient management priorities in this rare disease.

Patient-reported outcomes among patients with systemic mastocytosis in routine clinical practice: Results of the TouchStone SM Patient Survey.

BACKGROUND: Systemic mastocytosis (SM) is a rare clonal neoplasm driven by KIT D816V and other mutations. Data were collected from the patient perspective on disease burden and included an SM-specific symptom assessment tool. METHODS: US adults aged 18 years and older with a self-reported SM diagnosis completed an online TouchStone SM Patient Survey of 100 items, including the 12-item Short-Form Health Survey, the Indolent Systemic Mastocytosis Symptom Assessment Form, and the Work Productivity and Activity Impairment Questionnaire, as well as questions about SM diagnosis, the impact of SM on daily activities, work impairment, and health care use. The results were analyzed using descriptive statistics. RESULTS: Fifty-six individuals completed the survey (89% women; median age, 48 years; mean time since diagnosis, 6.7 years), reporting indolent SM (66%), aggressive SM (9%), smoldering SM (5%), and unknown SM subtype (18%). Over a 1-year recall, respondents reported seeking emergency care for anaphylaxis (30%) and taking three or more prescription medications (52%) for SM. Over one half of patients (54%) reduced their work hours because of SM, and 64% avoided leaving home because of symptoms. A majority of respondents (93%) had experienced ≥10 SM-related symptoms, noting that the most bothersome were anaphylactic episodes (18%), abdominal/stomach pain (16%), diarrhea/loose stools (13%), and fatigue (11%). Whereas an Indolent Systemic Mastocytosis Symptom Assessment Form-derived total symptom score of 28 is used to indicate moderate-to-severe symptoms, the mean total symptom score was 52.7. Mental and physical component summary scores from the 12-item Short-Form Health Survey were below population norms. CONCLUSIONS: Patients who were surveyed reported substantial symptom burden and unmet needs because of SM, as evidenced by seeking emergency care and reporting bothersome symptoms, poor quality of life, and reduced work hours and productivity. LAY SUMMARY: The objective of this research was to understand the burden and unmet needs in the rare disease of systemic mastocytosis (SM) to guide future care. Fifty-six patients completed an online survey containing questions about their diagnosis, medications, health care use, quality of life, and SM symptoms. The results demonstrated that SM is associated with severe and burdensome symptoms, anaphylactic events, emergency department visits, use of multiple medications, reduced ability to work, and poor physical and psychological quality of life. These findings suggest the need for future advances to address unmet needs in patients affected by SM.

Moral Distress in Pediatric Residents and Pediatric Hospitalists: Sources and Association With Burnout.

OBJECTIVE: Moral distress is increasingly identified as a major problem affecting healthcare professionals, but it is poorly characterized among pediatricians. Our objective was to assess the sources of moral distress in residents and pediatric hospitalist attendings and to examine the association of moral distress with reported burnout. METHODS: Cross-sectional survey from January through March 2019 of pediatric residents and hospital medicine attending physicians affiliated with 4 free-standing children's hospitals. Moral distress was measured using the Measure of Moral Distress for Healthcare Professionals (MMD-HP). Burnout was measured using 2 items adapted from the Maslach Burnout Inventory. RESULTS: Respondents included 288 of 541 eligible pediatric residents (response rate: 53%) and 118 of 168 pediatric hospitalists (response rate: 70%; total response rate: 57%). The mean MMD-HP composite score was 93.4 (SD = 42.5). Residents reported significantly higher frequency scores (residents: M = 38.5 vs. hospitalists: M = 33.3; difference: 5.2, 95% confidence interval [CI], 2.9-7.5) and composite scores (residents: M = 97.6 vs hospitalists: M = 83.0; difference:14.6, 95% CI, 5.7-23.5) than hospitalists. The most frequent source of moral distress was "having excessive documentation requirements that compromise patient care," and the most intense source of moral distress was "be[ing] required to work with abusive patients/family members who are compromising quality of care." Significantly higher mean MMD-HP composite scores were observed among participants reporting that they felt burned out at least once per week (M= 114.6 vs M= 82.3; difference: 32.3, 95% CI, 23.5-41.2). CONCLUSIONS: Pediatric residents and hospitalists report experiencing moral distress from a variety of patient-, team-, and system-level sources, and this distress is associated with burnout.

Utilization of fetal fibronectin testing and pregnancy outcomes among women with symptoms of preterm labor.

OBJECTIVES: To identify pregnant health plan members triaged through the emergency department (ED), including labor and delivery (ELD) units, with symptoms of preterm labor (PTL), and evaluate the use of fetal fibronectin (fFN) testing; and to calculate the rate of hospitalization and timing of delivery in relation to the ED visit. METHODS: Retrospective cohort study using Medical Outcomes Research for Effectiveness and Economics Registry®, a national multipayer claims database. A cohort of pregnant women evaluated in an ELD with a diagnosis of PTL from June 2012 through November 2015 was identified. The proportion of women with PTL who received fFN testing was calculated. RESULTS: A total of 23,062 patients met the criteria for inclusion in the study. The rate of fFN testing prior to delivery was 12.0%. Of the 23,062 patients included in the analysis, 75.9% were discharged home. Of those who were discharged from the emergency room, one in five went on to deliver within 3 days and almost 96% of this group was not screened for the presence of fFN. Of the remaining 24.1% of patients admitted to the hospital, 91.3% delivered during their stay. In a sensitivity analysis, the percentage of women who delivered within 3 days of the ELD encounter was lower for women who received fFN testing only (6.6%) versus those who had a history of transvaginal ultrasound (TVUS) only (21.6%). Furthermore, the rate of delivery within 3 days was lowest among patients who had both fFN testing and TVUS (4.7%). CONCLUSION: The utilization of fFN testing is 12%. The majority of pregnant patients triaged through the ELD with symptomatic PTL do not receive an fFN test. As part of PTL evaluation, fFN testing may identify women at increased risk for preterm delivery and help determine appropriate patient management.

Fetal fibronectin testing and pregnancy outcomes among Texas Medicaid patients at risk for preterm birth.

OBJECTIVES: Fetal fibronectin (fFN) testing between the 24th and 34th weeks of pregnancy in patients with symptomatic preterm labor (PTL) helps assess the risk of spontaneous preterm birth (sPTB), yet the extent of its use is unknown. We assessed use of fFN testing among Texas Medicaid enrollees with symptomatic PTL and evaluated time to infant delivery and healthcare utilization/costs. STUDY DESIGN: Retrospective cohort study using medical and pharmacy claims for Texas Medicaid enrollees. METHODS: We identified pregnant women triaged through the emergency department (ED) and hospital labor-and-delivery units with symptomatic PTL between January 1, 2012, and May 31, 2015. Patients with fFN testing prior to delivery were propensity score matched 1:1 to patients without fFN testing. Primary outcomes included time to delivery from initial PTL encounter and all-cause maternal healthcare utilization and costs. RESULTS: A total of 29,553 women met the criteria for analysis, of whom 14% had a record of receiving fFN testing. Each matched cohort included 4098 patients. Compared with those who did not, patients who underwent fFN testing had significantly more clinical risk factors (mean [SD]: 1.7 [1.1] vs 1.1 [1.0]; P <.0001) and were less likely to deliver during the initial hospital stay (odds ratio [OR], 0.539; 95% CI, 0.489-0.594), deliver ≤3 days following the hospital/ED encounter (OR, 0.499; 95% CI, 0.452-0.551); and receive their first PTL diagnosis during the initial hospital/ED encounter (OR, 0.598; 95% CI, 0.539-0.665). Patients who had an fFN test, compared with those who did not, had 17.5% higher total costs (P <.0001) during the 5 months prior to delivery, but had gestation lengths 9.4 days longer (24.6 vs 15.2 days) than those without testing. CONCLUSIONS: Frequency of fFN testing was low in Texas Medicaid enrollees with symptomatic PTL. Patients with fFN testing had longer gestation periods and were less likely to deliver within ≤3 days of a hospital/ED encounter for PTL. These results support the role of fFN in screening for risk for sPTB among women with symptomatic PTL.

Suicide trends among persons aged 10-24 years--United States, 1994-2012.

Suicide is the second leading cause of death among persons aged 10-24 years in the United States and accounted for 5,178 deaths in this age group in 2012. Firearm, suffocation (including hanging), and poisoning (including drug overdose) are the three most common mechanisms of suicide in the United States. Previous reports have noted that trends in suicide rates vary by mechanism and by age group in the United States, with increasing rates of suffocation suicides among young persons. To test whether this increase is continuing and to determine whether it varies by demographic subgroups among persons aged 10-24 years, CDC analyzed National Vital Statistics System mortality data for the period 1994-2012. Trends in suicide rates were examined by sex, age group, race/ethnicity, region of residence, and mechanism of suicide. Results of the analysis indicated that, during 1994-2012, suicide rates by suffocation increased, on average, by 6.7% and 2.2% annually for females and males, respectively. Increases in suffocation suicide rates occurred across demographic and geographic subgroups during this period. Clinicians, hotline staff and others who work with young persons need to be aware of current trends in suffocation suicides in this group so that they can accurately assess risk and educate families. Media coverage of suicide incidents and clusters should follow established guidelines to avoid exacerbating risk for "suicide contagion" among vulnerable young persons.* Suicide contagion is a process by which exposure to the suicide or suicidal behavior of one or more persons influences others who are already vulnerable and thinking about suicide to attempt or die by suicide. Early prevention strategies are needed to reduce the likelihood of young persons developing suicidal thoughts and behavior.

Processing and Characterization of Cellulose Nanocrystals/Polylactic Acid Nanocomposite Films.

The focus of this study is to examine the effect of cellulose nanocrystals (CNC) on the properties of polylactic acid (PLA) films. The films are fabricated via melt compounding and melt fiber spinning followed by compression molding. Film fracture morphology, thermal properties, crystallization behavior, thermo-mechanical behavior, and mechanical behavior were determined as a function of CNC content using scanning electron microscopy, differential scanning calorimetry, X-ray diffraction, dynamic mechanical analysis, and tensile testing. Film crystallinity increases with increasing CNC content indicating CNC act as nucleating agents, promoting crystallization. Furthermore, the addition of CNC increased the film storage modulus and slightly broadened the glass transition region.

NK cell genotype and phenotype at diagnosis of acute lymphoblastic leukemia correlate with postinduction residual disease.

PURPOSE: Not all natural killer (NK) cells are equally cytotoxic against leukemia because of differences in receptor gene content and surface expression. We correlated NK cell genotype and phenotype at diagnosis of childhood acute lymphoblastic leukemia (ALL) with minimal residual disease (MRD) after induction chemotherapy. EXPERIMENTAL DESIGN: The NK cells and leukemia blasts of 244 patients were analyzed at diagnosis by killer-cell immunoglobulin-like receptor (KIR) typing and immunophenotyping. The results were correlated statistically with postinduction MRD status. RESULTS: The odds of being MRD positive in patients with KIR telomeric (Tel)-A/B genotype were 2.85 times the odds in those with Tel-A/A genotype (P = 0.035). MRD-positive patients were more likely to have KIR2DL5A (P = 0.006) and expressed less activating receptor NKp46 and FASL on their NK cells (P = 0.0074 and P = 0.029, respectively). The odds of being MRD positive increased by 2.01-fold for every percentage increase in NK cells expressing KIR2DL1 in the presence of HLA-C2 ligand (P = 0.034). The quantity of granzyme B inhibitor PI-9 in the leukemia blasts was greater in patients who were MRD positive (P = 0.038). Collectively, five NK cell-related factors (Tel-B-associated KIR2DL5A, NKp46, FASL, granzyme B, and PI-9) are strongly associated with MRD positivity at the end of induction with 100% sensitivity and 80% specificity. CONCLUSIONS: Our data support the hypothesis that NK cells with a strong effector phenotype in the setting of decreased leukemia resistance are associated with better leukemia control.

Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation.

BACKGROUND: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma. MATERIALS AND METHODS: Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated. RESULTS: Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y). CONCLUSIONS: Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.

Ovarian torsion in a patient with müllerian agenesis: increased risk?

BACKGROUND: Patients with müllerian agenesis may be at an increased risk of ovarian torsion due to the absence of the utero-ovarian ligament and the fact that the ovary is not tethered to a fixed and relatively non-mobile structure, the uterus. CASE: We report a case of a 14-year-old female with abdominal pain who had a physical examination suggestive of müllerian agenesis. Imaging was non-diagnostic and demonstrated an abdominal mass. Emergent surgery revealed ovarian torsion. SUMMARY AND CONCLUSION: We present this case of ovarian torsion and müllerian agenesis, in order to highlight the association and to review potential risk factors.

Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen.

The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest after UVR, as well as reduced levels of the DNA damage recognition protein, XPC. When ectopically expressed in uninfected UISO cells, mutant but not wild-type T antigen resulted in loss of repair of UVR-induced cyclobutane pyrimidine dimers and reductions in XPC, p53 and p21 levels, whereas both wild-type and mutant T antigen inhibited cell cycle arrest after UVR. Similarly, only mutant T antigen in normal fibroblasts inhibited DNA repair and XPC expression, while both mutant and wild-type T antigens produced cell cycle dysregulation. Wild-type T antigen expression produced large T, 57 kT and small T antigens while mutant T antigen was only detectable as a truncated large T antigen protein. Expression of wild-type large T antigen but not small T antigen inhibited the G1 checkpoint in UISO cells, but neither wild-type large T nor small T antigens affected DNA repair, suggesting that large T antigen generates cell cycle defects, and when mutated may also impair DNA repair. These results indicate that T antigen expression by MCV can inhibit key responses to UVR-induced DNA damage and suggest that progressive MCV-mediated abrogation of genomic stability may be involved in Merkel cell carcinogenesis.

Natural variation in Drosophila stressed locomotion meets or exceeds variation caused by hsp70 mutation: analysis of behavior and performance.

Thermotolerance involves more than life or death. Investigating the complexity of this trait will aid identification of its genetic contributors. We examined variation in thermally stressed walking behavior and performance in natural Drosophila melanogaster strains and strains mutant for the heat shock protein Hsp70, to determine which aspects of locomotion are affected by heat shock and genotype. We developed software for the large-scale capture, analysis, and visualization of locomotion, and determined: (1) Heat shock and thermal pretreatment significantly and differentially impact fly locomotor behavior and performance. (2) Stressed locomotion traits vary extensively among natural strains. (3) Interactions among treatments, strains, and traits are substantial and often counterintuitive. (4) Hsp70 overexpressing flies are faster and more basally thermoprotected in performance than Hsp70 null flies, but null flies are more unidirectional. (5) Natural variation in most stressed locomotion traits exceeds that caused by Hsp70 mutation, reveals uncoupling between thermoprotection of behavior and performance, and suggests significant genetic variation for trait-specific modifiers of thermotolerance.

Influenza vaccination by race among disabled community dwelling older women.

Disabled older adults have been shown to be at risk for underutilization of some preventive services relative to able-bodied individuals. The Women's Health and Aging Study surveyed female Medicare enrollees in Baltimore, Maryland, who were among the most disabled community-dwelling women at the start of the study. Longitudinal survey data from the study were used to test for the existence or emergence of racial variation in influenza vaccination rates, for which racial variation has been shown in the general population. The primary analysis, using data on the same women before and after Medicare flu shot coverage began, suggested that influenza vaccination rates increased after Medicare coverage began and that there was no difference by race. A secondary analysis using data on women who were interviewed only after Medicare flu shot coverage began showed some racial variation, although the difference may have been larger prior to coverage. The utilization rate did not approach the Healthy People 2010 target.

Cost effectiveness of treatment for benign prostatic hyperplasia: an economic model for comparison of medical, minimally invasive, and surgical therapy.

PURPOSE: To evaluate the cost effectiveness of minimally invasive therapy relative to medical (alpha-blocker) therapy and transurethral resection (TURP) for patients with moderate to severe symptoms of benign prostatic hyperplasia (BPH). METHODS: We constructed a decision-analytic Markov model for a hypothetical cohort of 65-year-old men with moderate to severe BPH symptoms. Microwave thermotherapy was selected to represent minimally invasive treatment. Cost-effectiveness analysis was performed with 25 health states using the 3 treatments, 5 short-term clinical events, and 17 possible long-term outcomes. Each health state had an associated cost and utility. Quality of life (QoL) and utility estimates were obtained by interviewing 13 men with BPH symptoms using the standard gamble reference methods. Patients were classified as risk averse (RA) or non-risk averse (NRA) on the basis of their attitudes to risk. We calculated the incremental cost effectiveness of microwave thermotherapy relative to medical therapy and TURP over 5 years after treatment initiation. Event probabilities were obtained from the literature, a consensus panel, and published randomized clinical trials. RESULTS AND CONCLUSIONS: The utility values generated were internally consistent and externally valid for a hypothetical cohort of 10,000 RA patients. Microwave thermotherapy was preferred by the NRA group, while medical therapy was preferred by the RA group. Surgery was least preferred by both groups. Microwave thermotherapy had a small incremental cost but improved QoL in comparison with medical therapy. Microwave thermotherapy had a higher utility and lower cost than TURP and thus was dominant over TURP. This analytical method can be applied to evaluate the cost effectiveness of any BPH therapy.