Respiratory emergency department use from diagnosis through survivorship in children, adolescents, and young adults with cancer.

BACKGROUND: Children and adolescents and young adults (AYAs) with cancer often experience severe respiratory morbidity and mortality from the therapies used to treat their cancers. Few studies have examined respiratory outcomes among this population using emergency department (ED) visits as an objective measure of respiratory health. METHODS: ED visits for respiratory conditions were identified for children and AYAs diagnosed with cancer, 0-25 years of age, from 1997 through 2012 (2535 cases) and compared with a birthdate-matched and sex-matched cohort without cancer drawn from the general population (7605 controls). Negative binomial regression with robust standard errors was used to estimate incidence rates, rate ratios (RRs), and 95% confidence intervals for primary respiratory ED visits, combined and by diagnosis (asthma, respiratory disease, and respiratory infection) from 1997 through 2015. Analyses were performed for new cases (0 to <5 years from diagnosis) and survivors (5-18 years from diagnosis). RESULTS: Subjects were followed for an average of 8 years (range, 0-18 years). Relative to the comparison cohort, cancer cases had higher incidence rates for all types of respiratory ED visits over both follow-up times. New cases had significantly higher RRs for any respiratory condition (RR, 4.14), respiratory disease (RR, 4.62), and respiratory infection (RR, 4.74). Among survivors, the RRs for any respiratory condition (RR, 2.00) and respiratory infection (RR, 2.10) were significantly elevated, although the magnitude tended to decline in survivorship. Demographic and clinical risk factors found to be associated with respiratory ED visits included Hispanic/other race/ethnicity, male sex, exposure to chemotherapy, diagnosis at a younger age, and a diagnosis of leukemia. CONCLUSIONS: The results of the current study demonstrated that children and AYAs with cancer face an increased burden of respiratory complications compared with a comparison cohort without cancer from diagnosis through survivorship.

Infection-related mortality in Hispanic and non-Hispanic children with cancer.

BACKGROUND: Hispanic children with cancer experience poorer survival than their White counterparts. Infection is a known cause of cancer-related mortality; however, little is known about the risk of infection-related death among Hispanic children with cancer. We examine the association of Hispanic ethnicity with infection-related mortality and life-threatening events among children with cancer. PROCEDURE: For a cohort of all pediatric cancer patients diagnosed from 1986 to 2012 and treated at a single tertiary care center, we obtained national death records to determine all-cause mortality and infection-related mortality, as well as intensive care unit (ICU) admissions as a surrogate for life-threatening events. Cox proportional hazard models assessed all-cause mortality and infection-related mortality using ethnicity as the main independent variable. ICU admission rates were modeled using a zero-inflated Poisson regression model. Models were adjusted for gender, diagnosis year, age, residential location, and diagnosis. RESULTS: Of 6,198 patients, 741 (12%) were Hispanic. Mean follow-up was 11 years (SD = 8.04). There were 1,205 deaths, with 193 attributable to infection. Differences in all-cause mortality between Hispanic and non-Hispanic patients did not reach significance (hazard ratio [HR] = 1.14, 95% confidence interval [CI]: 0.96-1.36). However, Hispanic patients were 68% (HR = 1.68, 95% CI: 1.16-2.43) more likely to have an infection-related cause of death. Hispanic ethnicity was statistically associated with a higher rate of ICU admissions (rate ratio = 1.32, 95% CI: 1.12-1.56). CONCLUSION: Hispanic pediatric cancer patients were more likely to have an infection-related death and higher rates of ICU admissions than non-Hispanic patients. Infection may be an overlooked contributor to poorer outcomes among Hispanic patients.

The impact of language barriers and immigration status on the care experience for Spanish-speaking caregivers of patients with pediatric cancer.

BACKGROUND: An increasing proportion of pediatric cancer patients in the United States are Latino and many have Spanish-speaking immigrant parents with limited English proficiency (LEP). Little is known about how language or undocumented immigration status impacts their care experience. PROCEDURE: A cross-sectional survey was administered to English (N = 310) and Spanish-speaking LEP (N = 56) caregivers of pediatric cancer patients. To assess differences in healthcare experiences between the language groups, t-tests and chi-square statistics were used. Multivariable logistic regression evaluated associations between primary language and knowledge of clinical trial status. RESULTS: Spanish-speaking caregivers were more likely to report higher rates of quitting or changing jobs as a direct result of their child's cancer, and their children were more likely to experience a delay in education. Although Spanish-speaking caregivers reported higher satisfaction with care, 32% reported feeling that their child would have received better care if English was their primary language. Spanish-speaking caregivers were more likely to incorrectly identify whether their child was on a clinical trial compared with English-speaking caregivers. The majority of Spanish-speaking caregivers reported at least one undocumented caregiver in the household and 11% of them avoided or delayed medical care for their child due to concerns over their undocumented immigration status. CONCLUSIONS: Language barriers and undocumented immigration status may negatively impact the quality of informed decision-making and the care experience for Spanish-speaking LEP caregivers of pediatric cancer patients. These families may benefit from culturally appropriate Spanish language resources to improve communication and open a dialogue regarding undocumented immigration status.

Geography and the burden of care in pediatric cancers.

BACKGROUND: Childhood cancers typically require rigorous treatment at specialized centers in urban areas, which can create substantial challenges for families residing in remote communities. We evaluated the impact of residence and travel time on the burden of care for families of childhood cancer patients. PROCEDURE: We conducted a cross-sectional, self-administered survey of 354 caregivers of pediatric cancer patients at a children's hospital serving a seven state area. Measures included the impact of cancer treatment on relocation, employment, schooling, and finances. We evaluated these domains by rural/urban residence and travel time (>1 hour and >2 hours) to the hospital in multivariable regression models. RESULTS: Of the 29% of caregivers who reported moving residences as their child was diagnosed, 33% reported that the move was due to their child's cancer. Rural and remote (e.g., >1 hour travel time) caregivers missed more days of work during the first month after diagnosis than did urban and local caregivers, however, these differences did not persist over the first 6 months of therapy. One-third of caregivers reported quitting or changing jobs as a direct result of their child being diagnosed with cancer. Rural respondents had greater out-of-pocket travel expenses and reported a significantly greater perceived financial burden. Rural patients missed more school days and were at an increased risk of having to repeat a grade. CONCLUSIONS: Childhood cancer has an appreciable impact on the lives of patients and caregivers. The burden is greater for those living far from a treatment center.

Geographic Access to Pediatric Cancer Care in the US.

Importance: Although access to pediatric cancer care has implications for use of such care and patient outcomes, little is known about the geographic accessibility of pediatric cancer care and how it may vary by population characteristics across the continental US. Objective: To estimate the travel time to pediatric cancer care settings in the continental US, identify potential disparities among subgroups of children and adolescents and young adults (AYAs), and identify areas needing improved access to pediatric cancer care. Design, Setting, and Participants: This cross-sectional study collected data from August 1 to December 1, 2021. Pediatric oncologists' service locations in 2021 served as the pediatric cancer care settings, data for which were scraped from 2 websites containing information about health professionals. Demographic characteristics for younger children and AYAs aged 0 to 21 years were obtained from the 2015 to 2019 American Community Survey 5-year estimates. Data were analyzed from January 1 to April 31, 2022. Main Outcomes and Measures: The main outcome was the travel time from geographic centroids of zip code tabulation areas to the nearest pediatric oncologist. The median (IQR) travel times for each demographic subgroup were estimated. Per capita pediatric oncologist supply was calculated by dividing the total number of pediatric oncologists for each state or US Census division by its population. Results: Of the 90 498 890 children and AYAs included in the study, 63.6% were estimated to travel less than 30 minutes and 19.7% to travel between 30 and 60 minutes (for a total of 83.3%) to the nearest pediatric oncologist. Median (IQR) travel times were longest for the American Indian or Alaska Native pediatric population (46 [16-104] minutes) and residents of rural areas (95 [68-135] minutes), areas with high deprivation levels (36 [13-72] minutes), and the South (24 [13-47] minutes) and Midwest (22 [11-51] minutes) compared with the general population of children and AYAs. The pediatric oncologist supply was lowest in Wyoming (0 oncologists per 100 000 pediatric population) and highest in Washington, DC (53.3 oncologists per 100 000 pediatric population). Pediatric oncologist supply across Census divisions was lowest in the Mountain division (3.3 oncologists per 100 000 pediatric population) and highest in the New England division (8.1 oncologists per 100 000 pediatric population). Conclusions and Relevance: Results of this study showed that most children and AYAs in the continental US had adequate access to pediatric cancer care, although disparities existed among racial and ethnic groups and residents in rural areas, areas with high deprivation levels, and some Southern and Midwestern states. Reducing these disparities may require innovative approaches, such as expanding the capabilities of local facilities and creating partnerships with adult oncology centers and primary care physicians.

Adherence to Oral Medications During Maintenance Therapy Among Children and Adolescents With Acute Lymphoblastic Leukemia: A Medication Refill Analysis.

Adherence to oral medications during maintenance therapy is essential for pediatric patients with acute lymphoblastic leukemia. Self-reported or electronic monitoring of adherence indicate suboptimal adherence, particularly among particular sociodemographic groups. This study used medication refill records to examine adherence among a national sample of pediatric patients with acute lymphoblastic leukemia. Patients in a national claims database, aged 0 to 21 years with a diagnosis of acute lymphoblastic leukemia and in the maintenance phase of treatment, were included. Medication possession ratios were used as measures of adherence. Overall adherence and adherence by sociodemographic groups were examined. Adherence rates were 85% for 6-mercaptopurine and 81% for methotrexate. Adherence was poorer among patients 12 years and older. Oral medication adherence rates were suboptimal and similar to or lower than previously documented rates using other methods of assessing adherence. Refill records offer a promising avenue for monitoring adherence. Additional work to identify groups most at-risk for poor adherence is needed. Nurses are well positioned to routinely monitor for medication adherence and to collaborate with the multidisciplinary team to address barriers to adherence.

Social Media Use Among Parents and Caregivers of Children With Cancer.

Social media as an effective source of information and support among parents and other caregivers of children with cancer has not been explored. The purpose of this cross-sectional study was to describe caregivers' reasons for using social media, social media sites used, and predictors of social media usage. This study sample included 215 caregivers (96% parents) of children with cancer receiving cancer-related care at a tertiary children's hospital in the Intermountain West. Most of caregivers (74%) reported using social media in relation to their child's cancer and reported using social media to provide and receive support and information about their child's diagnosis or treatment. Our findings suggest that social media could be a delivery platform for future interventions seeking to meet the informational and emotional needs of caregivers of children with cancer. An awareness of how parents and caregivers of children receiving cancer-related treatment use social media can help nurses understand their ongoing informational and emotional needs. Nurses can also support parents and caregivers in selecting reputable sources of support that are accessible via social media.

Risk of hospitalization among survivors of childhood and adolescent acute lymphoblastic leukemia compared to siblings and a general population sample.

BACKGROUND: Acute Lymphoblastic Leukemia (ALL) has a high survival rate, but cancer-related late effects in the early post-treatment years need documentation. Hospitalizations are an indicator of the burden of late effects. We identify rates and risk factors for hospitalization from five to ten years after diagnosis for childhood and adolescent ALL survivors compared to siblings and a matched population sample. METHODS: 176 ALL survivors were diagnosed at ≤22 years between 1998 and 2008 and treated at an Intermountain Healthcare facility. The Utah Population Database identified siblings, an age- and sex-matched sample of the Utah population, and statewide inpatient hospital discharges. Sex- and birth year-adjusted Poisson models with Generalized Estimating Equations and robust standard errors calculated rates and rate ratios. Cox proportional hazards models identified demographic and clinical risk factors for hospitalizations among survivors. RESULTS: Hospitalization rates for survivors (Rate:3.76, 95% CI=2.22-6.36) were higher than siblings (Rate:2.69, 95% CI=1.01-7.18) and the population sample (Rate:1.87, 95% CI=1.13-3.09). Compared to siblings and population comparisons, rate ratios (RR) were significantly higher for survivors diagnosed between age 6 and 22 years (RR:2.87, 95% CI=1.03-7.97 vs siblings; RR:2.66, 95% CI=1.17-6.04 vs population comparisons). Rate ratios for diagnosis between 2004 and 2008 were significantly higher compared to the population sample (RR:4.29, 95% CI=1.49, 12.32), but not siblings (RR:2.73, 95% CI=0.54, 13.68). Survivors originally diagnosed with high-risk ALL did not have a significantly higher risk than siblings or population comparators. However, high-risk ALL survivors (Hazard ratio [HR]:3.36, 95% CI=1.33-8.45) and survivors diagnosed from 2004 to 2008 (HR:9.48, 95% CI=1.93-46.59) had the highest risk compared to their survivor counterparts. CONCLUSIONS: Five to ten years after diagnosis is a sensitive time period for hospitalizations in the ALL population. Survivors of childhood ALL require better long-term surveillance.

ReCAP: Gaps in Insurance Coverage for Pediatric Patients With Acute Lymphoblastic Leukemia.

PURPOSE: Continuous insurance coverage is an important component of effective health care. Evaluation of insurance gaps in pediatric cancer care is an understudied area. METHODS: We conducted a retrospective analysis of payer data from outpatient oncology encounters at Primary Children's Hospital (Salt Lake City, UT) over the first 2 years of therapy for pediatric patients with acute lymphoblastic leukemia diagnosed from 1998 to 2010 (N = 380). Using logistic regression, we evaluated demographic and clinical predictors (age at diagnosis, sex, ethnicity, high/standard acute lymphoblastic leukemia risk, and rural/urban county of residence at diagnosis) of a gap in health insurance. RESULTS: The median age at diagnosis was 4 years (interquartile range, 3 to 8 years), and 172 patients (45%) were girls. In the first 2 years of treatment, 45 patients (12%) experienced a gap in health insurance. The odds of having a gap in insurance coverage decreased by 16% each year from 1998 to 2010 (odds ratio, 0.84; 95% CI, 0.76 to 0.93; test for trend, P = .001). Public insurance at diagnosis was associated with a four-fold increased likelihood of experiencing an insurance gap (odds ratio, 4.09; 95% CI, 1.98 to 8.44; P < .001) compared with patients with private insurance at diagnosis. CONCLUSION: Gaps in insurance coverage during pediatric cancer treatment are not uncommon, which highlights the importance of discussing insurance status at diagnosis and throughout a patient's treatment course to help patients and their families prepare for any changes and avoid unnecessary financial burden. Future research should focus on examining the effect of insurance gaps on patient outcomes and evaluating likelihood of gaps in insurance after health care reform.

Pegasparaginase treatment alters thrombin generation by modulating the protein C and S system in acute lymphoblastic leukaemia/lymphoma.

Paediatric patients with acute lymphoblastic leukaemia/lymphoma treated with pegasparaginase are at an increased risk of thrombosis. We evaluated changes in thrombin generation in the presence and absence of thrombomodulin using paired plasma samples collected from paediatric patients treated with pegasparaginase. Postpegasparaginase samples were significantly less sensitive to reductions in thrombin generation in the presence of thrombomodulin compared with prepegasparaginase, suggesting reduced protein C and S activity. This corresponded to a significant decrease in protein C and protein S antigen. Alterations in the protein C and S pathway may contribute to the increased risk of thrombosis in patients treated with pegasparaginase.

A meta-analysis of body mass index of adolescent and adult survivors of pediatric acute lymphoblastic leukemia.

PURPOSE: We conducted a meta-analysis of existing studies to examine body mass index (BMI) of adolescent and adult survivors of pediatric acute lymphoblastic leukemia (ALL) compared to individuals without cancer. METHODS: Studies were identified and reviewed using specific inclusion criteria. The effect size was odds ratio (OR) of the prevalence of overweight/obese BMI (≥ 25 kg/m(2)) in ALL survivors versus comparison groups. Study data were coded and validated. Fixed-effects (FE) and random-effects (RE) estimates of the effect size were estimated. RESULTS: A total of 9 studies met our inclusion criteria. Survivors were more likely to be overweight/obese compared to comparison groups (FE OR = 1.12, 95% CI 1.06-1.18 and RE OR = 1.28, 95% CI 1.07-1.53). When limited to studies from North American samples, female survivors were overweight/obese more often than the comparison groups (FE OR = 1.30, 95% CI 1.19-1.43). CONCLUSIONS: Adolescent and adult survivors of pediatric ALL, especially female survivors, may be at a higher risk of being overweight/obese compared to individuals without cancer. However, few studies provided detailed information on patient and treatment factors (e.g., cranial radiation) that can impact BMI. Standardized reporting of study content is vital for providing robust information on the risk of developing late effects among cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: Adolescent and adult survivors of pediatric ALL require additional weight management resources such as targeted counseling for physical activity and dietician support both early in treatment and after the end of their therapy. Female survivors may need additional guidance to develop healthy eating practices and to participate in exercise programs.

The genomic landscape of juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a myeloproliferative neoplasm (MPN) of childhood with a poor prognosis. Mutations in NF1, NRAS, KRAS, PTPN11 or CBL occur in 85% of patients, yet there are currently no risk stratification algorithms capable of predicting which patients will be refractory to conventional treatment and could therefore be candidates for experimental therapies. In addition, few molecular pathways aside from the RAS-MAPK pathway have been identified that could serve as the basis for such novel therapeutic strategies. We therefore sought to genomically characterize serial samples from patients at diagnosis through relapse and transformation to acute myeloid leukemia to expand knowledge of the mutational spectrum in JMML. We identified recurrent mutations in genes involved in signal transduction, splicing, Polycomb repressive complex 2 (PRC2) and transcription. Notably, the number of somatic alterations present at diagnosis appears to be the major determinant of outcome.

Risk of hospitalization for survivors of childhood and adolescent cancer.

BACKGROUND: Childhood cancer survivors may be at increased risk of hospitalization because of cancer-related late effects. METHODS: Using data from population-based research resources in Utah, we identified childhood and adolescent cancer survivors who were diagnosed from 1973 to 2005 (N = 2,571). We selected a comparison cohort based on birth year and sex (N = 7,713). Hospitalizations from 1996 to 2010, excluding pregnancy and delivery, were determined from discharge records. Multivariable regressions were used to evaluate hospitalization admissions, length of stay, and diagnosis for survivors starting five years from diagnosis versus the comparison cohort. RESULTS: When follow-up began in 1996, there were N = 1,499 survivors and N = 7,219 comparisons who were alive and eligible for follow-up. Average follow-up for survivors was 13.5 years (SD = 8.5) and for the comparison 14.0 years (SD = 8.7; P = 0.05). Survivors were hospitalized, on average, 1.62 (SD = 3.37) times contrasted to 0.79 (SD = 1.73) for the comparison cohort. In multivariable analyses, the hazard ratio (HR) of any hospitalization since 1996 was higher for survivors than the comparison cohort [HR, 1.52, 95% confidence interval (CI), 1.31-1.66]. Survivors experienced a higher hospital admission rate [rate ratio (RR) = 1.67; 95% CI, 1.58-1.77] than the comparison cohort. The number of hospitalizations was highest for neuroblastoma (RR = 2.21; 95% CI, 1.84-2.66) and bone tumors (RR = 2.55; 95% CI, 2.14-3.02) in reference to the comparison cohort. Survivors were hospitalized because of blood disorders more often (HR, 14.2; 95% CI, 6.3-32.0). CONCLUSIONS: The risk of hospitalization and lengths of stay are elevated among childhood cancer survivors. IMPACT: Research to identify strategies to prevent and manage survivors' health problems in outpatient settings is needed.

Cancer risk in children and adolescents with birth defects: a population-based cohort study.

OBJECTIVE: Birth defects are an increasing health priority worldwide, and the subject of a major 2010 World Health Assembly Resolution. Excess cancer risk may be an added burden in this vulnerable group of children, but studies to date have provided inconsistent findings. This study assessed the risk for cancer in children and young adolescents with major birth defects. METHODS AND FINDINGS: This retrospective, statewide, population-based, cohort study was conducted in three US states (Utah, Arizona, Iowa). A cohort of 44,151 children and young adolescents (0 through 14 years of age) with selected major, non-chromosomal birth defects or chromosomal anomalies was compared to a reference cohort of 147,940 children without birth defects randomly sampled from each state's births and frequency matched by year of birth. The primary outcome was rate of cancer prior to age 15 years, by type of cancer and type of birth defect. The incidence of cancer was increased 2.9-fold (95% CI, 2.3 to 3.7) in children with birth defects (123 cases of cancer) compared to the reference cohort; the incidence rates were 33.8 and 11.7 per 100,000 person-years, respectively. However, the excess risk varied markedly by type of birth defect. Increased risks were seen in children with microcephaly, cleft palate, and selected eye, cardiac, and renal defects. Cancer risk was not increased with many common birth defects, including hypospadias, cleft lip with or without cleft palate, or hydrocephalus. CONCLUSION: Children with some structural, non-chromosomal birth defects, but not others, have a moderately increased risk for childhood cancer. Information on such selective risk can promote more effective clinical evaluation, counseling, and research.

Mcl1 downregulation sensitizes neuroblastoma to cytotoxic chemotherapy and small molecule Bcl2-family antagonists.

Neuroblastoma (NB) is a common, highly lethal pediatric cancer, with treatment failures largely attributable to the emergence of chemoresistance. The pro-survival Bcl2 homology (BH) proteins critically regulate apoptosis, and may represent important therapeutic targets for restoring drug sensitivity in NB. We used a human NB tumor tissue microarray to survey the expression of pro-survival BH proteins Mcl1 and Bcl2, and correlated expression to clinical prognostic factors and survival. Primary NB tumors heterogeneously expressed Mcl1 or Bcl2, with high expression correlating to high-risk phenotype. Co-expression is infrequent (11%), but correlates to reduced survival. Using RNA interference, we investigated the functional relevance of Mcl1 and Bcl2 in high-risk NB cell lines (SK-N-AS, IMR-5, NLF). Mcl1 knockdown induced apoptosis in all NB cell lines, while Bcl2 knockdown inhibited only NLF, suggesting functional heterogeneity. Finally, we determined the relevance of Mcl1 in resistance to conventional chemotherapy (etoposide, doxorubicin) and small molecule Bcl2-family antagonists (ABT-737 and AT-101). Mcl1 silencing augmented sensitivity to chemotherapeutics 2- to 300-fold, while Bcl2 silencing did not, even in Bcl2-sensitive NLF cells. Resistance to ABT-737, which targets Bcl2/-w/-x, was overcome by Mcl1 knockdown. AT-101, which also neutralizes Mcl1, had single-agent cytotoxicity, further augmented by Mcl1 knockdown. In conclusion, Mcl1 appears a predominant pro-survival protein contributing to chemoresistance in NB, and Mcl1 inactivation may represent a novel therapeutic strategy. Optimization of compounds with higher Mcl1 affinity, or combination with additional Mcl1 antagonists, may enhance the clinical utility of this approach.