Assessment of proxy-reported responses as predictors of motor and sensory peripheral neuropathy in children with B-lymphoblastic leukemia.

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN.

Patient-reported neurocognitive function in adult survivors of childhood and adolescent osteosarcoma and Ewing sarcoma.

PURPOSE: Little is known regarding long-term neurocognitive outcomes in osteosarcoma and Ewing sarcoma (EWS) survivors despite potential risk factors. We evaluated associations among treatment exposures, chronic health conditions, and patient-reported neurocognitive outcomes in adult survivors of childhood osteosarcoma and EWS. METHODS: Five-year survivors of osteosarcoma (N = 604; median age 37.0 years) and EWS (N = 356; median age 35.0 years) diagnosed at < 21 years from 1970 to 1999, and 697 siblings completed the Childhood Cancer Survivor Study Neurocognitive Questionnaire and reported chronic health conditions, education, and employment. Prevalence of reported neurocognitive difficulties were compared between diagnostic groups and siblings. Modified Poisson regression identified factors associated with neurocognitive difficulties. RESULTS: Osteosarcoma and EWS survivors, vs. siblings, reported higher prevalences of difficulties with task efficiency (15.4% [P = 0.03] and 14.0% [P = 0.04] vs. 9.6%, respectively) and emotional regulation (18.0% [P < 0.0001] and 15.2% [P = 0.03] vs. 11.3%, respectively), adjusted for age, sex, and ethnicity/race. Osteosarcoma survivors reported greater memory difficulties vs. siblings (23.5% vs. 16.4% [P = 0.01]). Comorbid impairment (i.e., ≥ 2 neurocognitive domains) was more prevalent in osteosarcoma (20.0% [P < 0.001]) and EWS survivors (16.3% [P = 0.02]) vs. siblings (10.9%). Neurological conditions were associated with worse task efficiency (RR = 2.17; 95% CI = 1.21-3.88) and emotional regulation (RR = 1.88; 95% CI = 1.01-3.52), and respiratory conditions were associated with worse organization (RR = 2.60; 95% CI = 1.05-6.39) for EWS. Hearing impairment was associated with emotional regulation difficulties for osteosarcoma (RR = 1.98; 95% CI = 1.22-3.20). Patient report of cognitive difficulties was associated with employment but not educational attainment. CONCLUSIONS: Survivors of childhood osteosarcoma and EWS are at increased risk for reporting neurocognitive difficulties, which are associated with employment status and appear related to chronic health conditions that develop over time. IMPLICATIONS FOR CANCER SURVIVORS: Early screening, prevention, and treatment of chronic health conditions may improve/prevent long-term neurocognitive outcomes.

A preliminary, prospective study of peripheral neuropathy and cognitive function in patients with breast cancer during taxane therapy.

Dramatic improvements in cancer survival have occurred in the last decade, but the quality of life for many survivors is compromised due to severe, long-lasting, and often irreversible side effects of chemotherapy. The neurological side effects, chemotherapy induced peripheral neuropathy (CIPN) and cancer related/induced cognitive impairment (CRCI/CICI), are under-recognized and can occur after chemotherapy, immunotherapy, or radiation. The cellular mechanisms underlying these neurological side effects are poorly understood and there are no effective treatments or preventions, other than reduction or termination of cancer therapy. In our preliminary prospective, non-interventional study to examine the side effects of chemotherapy in patients with breast cancer (NCT03872141), patients with breast cancer who received standard of care single agent weekly taxane-based chemotherapy were assessed at baseline, midpoint, and end of treatment for neurological and cognitive changes and for blood levels of potential protein biomarkers (n = 13). CIPN and CRCI both showed an increase in severity with accumulating taxane and these changes were compared to protein alternations over the course of treatment. Using peripheral blood collected from patients (n = 10) during chemotherapy and tested with an antibody array curated by the MD Anderson RPPA Core), we found that 19 proteins were increased, and 12 proteins decreased over 12 weeks of treatment. Among those downregulate were proteins known to be critical for neuronal viability and function including GRB2 (growth factor receptor-bound protein 2) and NCS1 (neuronal calcium sensor 1). Concurrently, proteins associated with apoptosis, including BAK1 (Bcl-1 homologous antagonist/killer), were upregulated. These results support the proposal that CIPN and CRCI increase with increasing taxane exposure, and identified several proteins that are altered with taxane exposure that could be implicated in their pathogenesis. In conclusion, our study provides evidence for progressive neurological changes and the rationale to investigate the molecular basis for these changes with the goal of target identification for mitigation of these neurological side effects.

Hispanic Ethnicity Differences in Birth Characteristics, Maternal Birthplace, and Risk of Early-Onset Hodgkin Lymphoma: A Population-Based Case-Control Study.

BACKGROUND: Hispanic ethnicity differences in the risk of early-onset Hodgkin lymphoma diagnosed at <40 years are understudied. We conducted a population-based case-control study to evaluate associations between birth characteristics and early-onset Hodgkin lymphoma with a focus on potential ethnic differences. METHODS: This study included 1,651 non-Hispanic White and 1,168 Hispanic cases with Hodgkin lymphoma endorsing a range of races diagnosed at the age of 0 to 37 years during 1988-2015 and 140,950 controls without cancer matched on race/ethnicity and year of birth from the California Linkage Study of Early-Onset Cancers. OR and 95% confidence intervals (CI) were estimated from multivariable logistic regression models. RESULTS: Having a foreign-born mother versus a United States-born mother (i.e., the reference group) was associated with an increased risk of early-onset Hodgkin lymphoma among non-Hispanic Whites (OR = 1.52; 95% CI, 1.31-1.76; P < 0.01) and a decreased risk among Hispanics (OR = 0.78; 95% CI, 0.69-0.88; P < 0.01). Among both race groups, risk of early-onset Hodgkin lymphoma increased with birthweight and maternal age (all Ptrends < 0.01). Among non-Hispanic Whites, each 5-year increase in maternal age (OR = 1.11; 95% CI, 1.04-1.18; Ptrend < 0.01) and paternal age (OR = 1.07; 95% CI, 1.02-1.13; Ptrend < 0.01) was associated with increased risk of early-onset Hodgkin lymphoma. Compared with female Hispanics, male Hispanics had an increased risk of early-onset Hodgkin lymphoma (OR = 1.26; 95% CI, 1.12-1.42; P < 0.01). CONCLUSIONS: Maternal birthplace may play a role in risk of early-onset Hodgkin lymphoma that differs by ethnicity. IMPACT: The ethnic differences observed between certain birth characteristics, maternal birthplace, and early-onset Hodgkin lymphoma raise questions about the underlying biological, generational, lifestyle, residential, and genetic contributions to the disease.

Persistence of Chemotherapy-Induced Peripheral Neuropathy Despite Vincristine Reduction in Childhood B-Acute Lymphoblastic Leukemia.

BACKGROUND: Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children's Oncology Group AALL0932 randomized reduction in vincristine and dexamethasone (every 4 weeks vs 12 weeks during maintenance in the average-risk subset of National Cancer Institute standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall and by treatment group. METHODS: AALL0932 standard-B-ALL patients aged 3 years and older were evaluated at T1-T4 (end consolidation, maintenance month 1, maintenance month 18, 12 months posttherapy). Physical and occupational therapists (PT/OT) measured motor CIPN (hand and ankle strength, dorsiflexion and plantarflexion range of motion), sensory CIPN (finger and toe vibration and touch), function (dexterity [Purdue Pegboard], and walking efficiency [Six-Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age- and sex-matched z scores and proportion impaired were measured longitudinally and compared between groups. RESULTS: Consent and data were obtained from 150 participants (mean age = 5.1 years [SD = 1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (P < .001) and walking efficiency (P = .02) improved from T1-T4, and only dorsiflexion range of motion (46.7% vs 14.7%; P = .008) and handgrip strength (22.2% vs 37.1%; P = .03) differed in vincristine and dexamethasone every 4 weeks vs vincristine and dexamethasone 12 weeks at T4. Proxy-reported outcomes improved from T1 to T4 (P < .001), and most did not differ between groups. CONCLUSIONS: CIPN is prevalent early in B-ALL therapy and persists at least 12 months posttherapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency.

Biomarkers of Chemotherapy-Induced Peripheral Neuropathy: Current Status and Future Directions.

Chemotherapy induced peripheral neuropathy (CIPN) is an often severe and debilitating complication of multiple chemotherapeutic agents that can affect patients of all ages, across cancer diagnoses. CIPN can persist post-therapy, and significantly impact the health and quality of life of cancer survivors. Identifying patients at risk for CIPN is challenging due to the lack of standardized objective measures to assess for CIPN. Furthermore, there are no approved preventative treatments for CIPN, and therapeutic options for CIPN remain limited once it develops. Biomarkers of CIPN have been studied but are not widely used in clinical practice. They can serve as an important clinical tool to identify individuals at risk for CIPN and to better understand the pathogenesis and avenues for treatment of CIPN. Here we review promising biomarkers of CIPN in humans and their clinical implications.

Physical Therapy Utilization Among Hospitalized Patients With Pediatric Acute Lymphoblastic Leukemia.

PURPOSE: Patients with pediatric acute lymphoblastic leukemia (ALL) are at risk for impaired physical function from treatment. Early physical therapy (PT) may improve physical function and health in children with ALL, yet little is known about PT utilization in this population. METHODS: Leveraging the Premier Healthcare Database, we conducted a cohort study including participants hospitalized with ALL at age 0-21 years from January 1, 2010, through March 31, 2017. A generalized mixed linear model assessed sociodemographic and clinical variables associated with receiving PT within 1 year of first hospitalization. RESULTS: Among 5,488 pediatric ALL patients from 330 hospitals (median age 7 years, interquartile range = 4-14 years), only 27.2% overall and 58.9% with neuromuscular conditions received PT within a year of first ALL admission. In multivariable analysis, patients more likely to receive PT were age 10-14 years (odds ratio [OR] = 1.46; 95% CI, 1.20 to 1.76) or 15-21 years (OR = 1.66; 95% CI, 1.36 to 2.02) versus 0-4 years and Hispanic (OR = 1.27; 95% CI, 1.04 to 1.56) versus White. Patients less likely to receive PT were treated by a nonhematology/oncology pediatric (OR = 0.56; 95% CI, 0.46 to 0.70) or adult (OR = 0.50; 95% CI, 0.38 to 0.65) specialist versus a pediatric hematologist/oncologist and treated at a nonteaching hospital (OR = 0.53; 95% CI, 0.36 to 0.79) versus a teaching hospital. CONCLUSION: Only 27.2% of pediatric ALL patients overall and 58.9% with neuromuscular conditions receive inpatient PT within a year of first ALL admission. Interventions to increase inpatient PT services to pediatric ALL patients and address disparities in PT utilization may improve the physical function and long-term health of survivors.

A Case of Pheochromocytoma as a Subsequent Neoplasm in a Survivor of Childhood Embryonal Rhabdomyosarcoma.

Childhood cancer survivors are at risk for subsequent neoplasms. We describe the clinical presentation and genetic testing of a 29-year-old woman diagnosed with a pheochromocytoma 22 years post-treatment for childhood embryonal rhabdomyosarcoma of the bladder. Genetic testing for cancer predisposition revealed a pathogenic variant in BRCA2 and a variant of uncertain significance in MSH2. Pathogenic variants associated with deafness were also identified in GJB2. This article reports a novel subsequent neoplasm following childhood embryonal rhabdomyosarcoma, and discusses the potential contribution of genetic cancer predisposition to this case as well as the clinical implications of genetic testing.

Clinical decision rule for obtaining peripheral blood cultures in febrile oncology patients.

BACKGROUND: The utility of peripheral blood cultures in pediatric oncology patients presenting with fever is controversial. A recent systematic review showed that about one in 40 bloodstream infections (BSIs) would be missed if only central venous line (CVL) cultures are obtained. OBJECTIVE: To derive a clinical decision rule for obtaining peripheral blood cultures in pediatric oncology patients presenting to a pediatric emergency department (PED) with fever and a CVL. DESIGN/METHOD: A retrospective chart review was performed on pediatric oncology patients referred to the PED for fever while on therapy. Logistic regression with a random intercept was used to determine independent predictors of BSI and generate a prediction model for obtaining peripheral blood cultures. The decision rule was generated from the best performance as measured by a receiver operator curve. Bootstrapping analysis was performed for internal validation. RESULTS: Predictors that were significant and independently associated with positive peripheral blood cultures included vasopressor support (odds ratio [OR] 16.5, 95% confidence interval [CI]: 2.80-97.71), acute myeloid leukemia (AML) diagnosis (OR 6.9, 95% CI: 1.81-25.98), hypotension (OR 4.0, 95% CI: 1.05-15.17), mucositis (OR 8.2, 95% CI: 2.48-27.01), and maximum temperature in PED ≥39°C (OR 6.6, 95% CI: 2.36-18.20). The area under the curve (AUC) for this model was 0.90 (95% CI: 0.82-0.97) in the derivation cohort and 0.90 (95% CI: 0.81-0.98) after the internal validation. CONCLUSIONS: We derived a clinical prediction model for deciding when to obtain peripheral blood cultures in febrile oncology patients with CVLs on active therapy. Future studies should focus on prospective and external validation of this diagnostic prediction tool.

Newly identified chemotherapy-induced peripheral neuropathy in a childhood cancer survivorship clinic.

Chemotherapy-induced peripheral neuropathy (CIPN), a debilitating side effect of pediatric cancer therapy, can be challenging to diagnose. We estimated the prevalence of newly identified and previously diagnosed CIPN in the regional HEROS Childhood Cancer Survivorship Clinic. From 2016 to 2018, 148 survivors (45.3% female, age 17.1 [SD 7.7] years, 81.8% in ongoing routine oncology follow-up) had their initial survivorship evaluation at an average of 7.4 (SD 6.6) years from diagnosis. Fifty-six survivors (37.8%) had CIPN, of these 46 (82.1%) were newly identified. Our findings demonstrate CIPN may be missed in routine oncology care, and new methods are needed to screen for CIPN.

Longitudinal Evaluation of Neuromuscular Dysfunction in Long-term Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

BACKGROUND: Children treated for cancer are at risk for neuromuscular dysfunction, but data are limited regarding prevalence, longitudinal patterns, and long-term impact. METHODS: Longitudinal surveys from 25,583 childhood cancer survivors ≥5 years from diagnosis and 5,044 siblings from the Childhood Cancer Survivor Study were used to estimate the prevalence and cumulative incidence of neuromuscular dysfunction. Multivariable models adjusted for age, sex, race, and ethnicity estimated prevalence ratios (PR) of neuromuscular dysfunction in survivors compared with siblings, and associations with treatments and late health/socioeconomic outcomes. RESULTS: Prevalence of neuromuscular dysfunction was 14.7% in survivors 5 years postdiagnosis versus 1.5% in siblings [PR, 9.9; 95% confidence interval (CI), 7.9-12.4], and highest in survivors of central nervous system (CNS) tumors (PR, 27.6; 95% CI, 22.1-34.6) and sarcomas (PR, 11.5; 95% CI, 9.1-14.5). Cumulative incidence rose to 24.3% in survivors 20 years postdiagnosis (95% CI, 23.8-24.8). Spinal radiotherapy and increasing cranial radiotherapy dose were associated with increased prevalence of neuromuscular dysfunction. Platinum exposure (vs. none) was associated with neuromuscular dysfunction (PR, 1.8; 95% CI, 1.5-2.1), even after excluding survivors with CNS tumors, cranial/spinal radiotherapy, or amputation. Neuromuscular dysfunction was associated with concurrent or later obesity (PR, 1.1; 95% CI, 1.1-1.2), anxiety (PR, 2.5; 95% CI, 2.2-2.9), depression (PR, 2.1; 95% CI, 1.9-2.3), and lower likelihood of graduating college (PR, 0.92; 95% CI, 0.90-0.94) and employment (PR, 0.8; 95% CI, 0.8-0.9). CONCLUSIONS: Neuromuscular dysfunction is prevalent in childhood cancer survivors, continues to increase posttherapy, and is associated with adverse health and socioeconomic outcomes. IMPACT: Interventions are needed to prevent and treat neuromuscular dysfunction, especially in survivors with platinum and radiation exposure.

Pulmonary Metastasis of Low-risk Perinatal Neuroblastoma After Resection: Implications for Surveillance.

In the wake of the Children's Oncology Group (COG) ANBL00P2 trial and the ongoing ANBL1232 trial, an increasing number of children with neonatal neuroblastoma are being managed nonoperatively. We report the case of a patient with low-risk, non-MYCN amplified, neuroblastoma that was diagnosed and resected in the neonatal period but subsequently developed pulmonary metastases by the age of 7 months. Though rare, the possibility of low-risk disease metastasizing during surveillance should be recognized and may not be identified by current protocols.