Disparities in pediatric cancer survivorship care: A systematic review.

BACKGROUND: Childhood cancer survivors (CCS) experience many long-term health problems that can be mitigated with recommended survivorship care. However, many CCS do not have access to survivorship care nor receive recommended survivorship care. We reviewed the empirical evidence of disparities in survivorship care for CCS. METHODS: This systematic review searched PubMed, CINAHL, and PsycINFO for studies on survivorship care for CCS (PROSPERO: CRD42021227965) and abstracted the reported presence or absence of disparities in care. We screened 7945 citations, and of those, we reviewed 2760 publications at full text. RESULTS: A total of 22 studies reported in 61 publications met inclusion criteria. Potential disparities by cancer treatment (N = 14), diagnosis (N = 13), sex (N = 13), and current age (N = 13) were frequently studied. There was high quality of evidence (QOE) of survivorship care disparities associated with non-White race, Hispanic ethnicity, and being uninsured. Moderate QOE demonstrated disparities among CCS who were unemployed and older. Lower QOE was found for disparities based on cancer diagnosis, cancer treatment, age at diagnosis, time since diagnosis, sex, insurance type, income, educational attainment, and geographic area. CONCLUSIONS: We found strong empirical evidence of disparities in survivorship care for CCS associated with race, ethnicity, and insurance status. Multiple other disparate groups, such as those by employment, income, insurance type, education, cancer diagnosis, age at diagnosis, time since diagnosis, cancer treatment, geographic area, sex, and self-identified gender warrant further investigation. Prospective, multilevel research is needed to examine the role of other patient characteristics as potential disparities hindering adequate survivorship care in CCS.

Pediatric Metastatic Hepatoblastoma With an ARID1A Mutation and Rhabdoid Cells.

The small cell undifferentiated component of hepatoblastoma is an uncommon histologic component and is distinguished from small cell undifferentiated like pattern (originally called hepatoblastoma and now recognized to be malignant rhabdoid tumor) by the bi-allelic SMARCB1 mutations or copy number alterations in the latter. AT-rich interactive domain-containing protein 1A (ARID1A) is a part of the ATP-dependent switch/sucrose non-fermentable complex assembly, but mutations have not been reported as drivers of malignant rhabdoid tumor. ARID1A mutations in hepatocellular carcinoma are associated with poor prognosis but its significance in hepatoblastoma is unknown. We report a unique case of hepatoblastoma in a 19-month-old female with an unusual/atypical small cell undifferentiated component with ARID1A and beta-catenin mutations. It had an aggressive clinical course despite treatment, with metastases to the left psoas muscle, perihepatic and paratracheal lymph nodes, spinal cord, and leptomeninges. Leptomeningeal metastases resulted in diffuse cerebral edema and death. The initial diagnostic biopsy did not reveal rhabdoid cells while all metastatic foci showed cells with rhabdoid morphology in the autopsy specimens. Although this rhabdoid component resembled malignant rhabdoid tumor morphologically, molecular analyses failed to show mutations or deletions of SMARCB1.

Interventions to address disparities and barriers to pediatric cancer survivorship care: a scoping review.

PURPOSE: Many childhood cancer survivors experience disparities due to barriers to recommended survivorship care. With an aim to demonstrate evidence-based approaches to alleviate barriers and decrease disparities, we conducted a scoping review of (1) proposed strategies and (2) evaluated interventions for improving pediatric cancer survivorship care. METHODS: We searched research databases (PubMed, CINAHL, and PsycINFO), research registries, and grey literature (websites of professional organizations and guideline clearing houses) for guidelines and published studies available through October 2020 (scoping review registration: https://doi.org/10.17605/OSF.IO/D8Q7Y ). RESULTS: We identified 16 proposed strategies to address disparities and barriers endorsed by professional organizations including clinical practice guidelines (N=9), policy statements (N=4), and recommendations (N=3). Twenty-seven published studies evaluated an intervention to alleviate disparities or barriers to survivorship care; however, these evaluated interventions were not well aligned with the proposed strategies endorsed by professional organizations. Most commonly, interventions evaluated survivorship care plans (N=11) or models of care (N=11) followed by individual survivorship care services (N=9). Interventions predominantly targeted patients rather than providers or systems and used technology, education, shared care, collaboration, and location-based interventions. CONCLUSIONS: Published studies aimed at overcoming disparities and barriers to survivorship care for childhood cancer survivors revealed that gaps remain between published recommendations and empirical evaluations of interventions aiming to reduce barriers and disparities. IMPLICATIONS FOR CANCER SURVIVORS: Additional research is needed to identify evidence-based interventions to improve survivorship care for childhood cancer survivors.

Catastrophic congenital hemangioma with severe coagulopathy leading to fatal cardiac failure: Case report and review.

We present a complex case of a neonate, delivered urgently for hydrops fetalis, with a large vascular mass of the extremity, diagnosed postnatally as a congenital hemangioma. The patient suffered immediate cardiac compromise and severe coagulopathy atypical for the diagnosis and subsequently died from these complications. Treatment was imperative but challenging due to a lack of a standardized treatment approach and few historical reports of equally critically ill patients. In this report, we review potential medical and surgical interventions and discuss treatment considerations in similar, life-threatening cases of congenital hemangiomas.

A Population-Based Analysis of 30-Year Mortality among Five-Year Survivors of Adolescent and Young Adult Cancer: The Roles of Primary Cancer, Subsequent Malignancy, and Other Health Conditions.

Despite an aggregate 5-year survival of 85%, many adolescents and young adults (AYAs, 15-39 years old) treated for cancer die prematurely decades later. To develop a more complete understanding of this problem, particularly the role of specific subsequent malignant neoplasms (SMNs), we used the SEER-9 registry to analyze causes of death (COD: Primary cancer, SMN, non-malignant conditions) among 162,317 AYAs diagnosed with first cancer between 1975-2012 and surviving 5 or more years. Cumulative mortality, attributable mortality, standardized mortality ratios (SMRs), and adjusted hazard ratios were determined for each cancer site and COD. At 30 years, cumulative mortality due to primary cancer was matched by that due to all other causes (12.8% 95% CI [12.5%, 13.0%] for primary cancer versus 12.8% [12.5%, 13.1%] for all other causes combined) in the combined cohort, and was overtaken by non-malignant conditions in Hodgkin lymphoma, testicular, cervical/uterine, and thyroid cancers. Overall, SMNs accounted for 20% of malignant deaths, the most common being lung/bronchus (25.6%), colorectal/liver/biliary/pancreas (19.1%), and breast (10.2%). For non-malignant conditions, excess risk was noted overall (SMR 1.37, 95% CI [1.34, 1.40]) and for infectious (1.97 [1.85, 2.10]), renal (1.85 [1.60, 2.13]), cardio/cerebrovascular (1.38 [1.33, 1.43]), and suicide (1.15 [1.04, 1.27]). Racial minorities were at significantly higher risk across all COD. Safer therapy, longitudinal monitoring, and primary/secondary preventive strategies are needed to reduce late mortality in this vulnerable population.

Prevalence and risk factors for cisplatin-induced hearing loss in children, adolescents, and young adults: a multi-institutional North American cohort study.

BACKGROUND: Cisplatin is used to treat a wide range of childhood cancers and cisplatin-induced hearing loss (CIHL) is a common and debilitating toxicity. We aimed to address persistent knowledge gaps in CIHL by establishing benchmarks for the prevalence of and risk factors for CIHL. METHODS: In this multi-institutional cohort study, children (age 0-14 years), adolescents, and young adults (age 15-39 years) diagnosed with a cisplatin-treated tumour from paediatric cancer centres, who had available cisplatin dosing information, and primary audiology data for central review from consortia located in Canada and the USA were eligible for inclusion. Audiology was centrally reviewed and CIHL graded using the consensus International Society of Pediatric Oncology (SIOP) Boston Ototoxicity Scale. We assessed the prevalence of moderate or severe CIHL (SIOP grade ≥2) at latest follow-up and end of therapy, in each demographic, diagnosis, and treatment group and their relative contributions to risk for CIHL. Secondary endpoints explored associations of cisplatin dose reductions and CIHL with survival. We also examined whether cisplatin dose reductions and CIHL were associated with survival outcomes. FINDINGS: We included 1481 patients who received cisplatin. Of the 1414 (95·5%) participants who had audiometry at latest follow-up (mean 3·9 years [SD 4·2] since diagnosis), 620 (43·8%) patients developed moderate or severe CIHL. The highest prevalence of CIHL was seen in the youngest patients (aged <5 years; 360 [59·4%] of 606 patients) and those with a CNS tumour (221 [50·9%] of 434 patients), hepatoblastoma (110 [65·9%] of 167 patients), or neuroblastoma (154 [62·1%] of 248 patients). After accounting for cumulative cisplatin dose, higher fractionated doses were associated with risk for CIHL (for each 10mg/m2 increase per day, adjusted odds ratio [aOR] 1·15 [95% CI 1·07-1·25]; for each 50 mg/m2 increase per cycle aOR 2·16 [1·37-3·51]). Vincristine exposure was newly identified as a risk factor for CIHL (aOR 3·55 [2·19-5·84]). Dose reductions and moderate or severe CIHL were not significantly associated with survival differences. INTERPRETATION: Using this large, multicentre cohort, benchmarks were established for the prevalence of CIHL in patients treated with cisplatin. Variations in cisplatin dosing confer additive risk for developing CIHL and warrant investigation as a potential approach to decrease the burden of therapy. FUNDING: US National Institutes of Health and National Institute on Deafness and Other Communication Disorders, US National Institutes of Health and National Cancer institute, St Baldrick's Foundation, Genome Canada, Genome British Columbia, Canadian Institutes of Health Research, the Canada Foundation for Innovation, University of British Columbia, British Columbia Children's Hospital Research Institute, British Columbia Provincial Health Services Authority, Health Canada, and C17 Research Network.

Custom Pediatric Oncology Next-Generation Sequencing Panel Identifies Somatic Mosaicism in Archival Tissue and Enhances Targeted Clinical Care.

BACKGROUND: Disorders in the PIK3CA-related overgrowth spectrum because of somatic mosaicism are associated with segmental overgrowth of the body in conjunction with vascular, skeletal, and brain malformations such as hemimegalencephaly. A pathogenic variant may only be detectable in affected tissue and not in peripheral blood or saliva samples; therefore archival tissue may be the only relevant available specimen for testing. Although this is a common approach for cancer testing, it is not typically used for constitutional genetic disorders. METHODS: PIK3CA mosaicism was assessed with a custom pediatric oncology next-generation sequencing panel (OncoKids) designed to capture somatic mutations in pediatric malignancies. The panel covers a wide range of targets including PIK3CA and AKT1 hotspots. We used OncoKids on archival formalin-fixed, paraffin-embedded or frozen samples from seven patients with facial hemihypertrophy and lipomas, hemimegalencephaly, or hemihypertrophy with a lymphovascular malformation. The age of the archival tissue examined by next-generation sequencing ranged from two to 13 years (median 5 years). Every patient had clinical manifestations within the PIK3CA-related overgrowth spectrum and had a sample of an affected tissue available for testing from a prior surgical intervention. RESULTS: PIK3CA mosaicism was detected in all seven patients and the mutant allele fraction was lower in the lymphovascular malformation tissues (8% to 11%) than in brain (20% to 32%) and lipomatous (16% to 23%) tissues. CONCLUSIONS: Our study highlights the clinical utility of using a robust, oncology-focused next-generation sequencing assay to identify PIK3CA mosaicism in noncancer cases. It is feasible to use archival samples that are more than a decade old to obtain a molecular diagnosis, which can then be used to improve health care management.

Emerging Cancer Survival Trends, Disparities, and Priorities in Adolescents and Young Adults: A California Cancer Registry-Based Study.

BACKGROUND: Although landmark studies in the 1990s demonstrated that adolescents and young adults (AYAs, ages 15-39 years) with cancer had lower survival improvement compared to other ages, therapeutic advances warrant reappraisal of those observations. We utilized more recent data to study site-specific AYA survival trends and disparities and gain a more contemporary understanding of this problem. METHODS: Using California Cancer Registry data from 1988 to 2014, we calculated 1) 5-year overall survival improvement for AYAs compared to other age groups; 2) hazard ratios (HRs) of death for AYAs comparing 2001-2014 with 1988-2000 stratified by site, stage, sex, age group, race and ethnicity, and socioeconomic status (SES); and 3) site-specific adjusted HRs (aHRs) for AYA risk groups and interaction analyses by time period. RESULTS: For all cancers combined, AYAs demonstrated survival improvement that exceeded all other age groups, largely due to reduced mortality in human immunodeficiency virus and acquired immunodeficiency syndrome-related cancers. The strongest predictor of death was cancer stage (aHR = 6.32 for distant vs localized, 95% confidence interval [CI] = 6.20 to 6.45). The aHR of death was statistically significantly higher for blacks (1.46, 95% CI = 1.42 to 1.50), Asian and Pacific Islanders (1.12, 95% CI = 1.09 to 1.15), and Latino whites (1.06, 95% CI = 1.04 to 1.08) compared to non-Latino whites, and was statistically significantly higher for low SES compared to high (1.31, 95% CI = 1.29 to 1.34). Survival disparities by stage, race and ethnicity, and SES worsened over time. CONCLUSIONS: For AYAs in aggregate, the historical cancer survival improvement gap has been closed. However, the growing survival disparities in AYA subsets reported here, including advanced stage disease, racial and ethnic minorities, and low SES, highlight new priorities in need of increased attention, including inequities in cancer care and delivery within this vulnerable population.

Obesity and Risk for Second Malignant Neoplasms in Childhood Cancer Survivors: A Case-Control Study Utilizing the California Cancer Registry.

BACKGROUND: Obesity is a known modifiable risk factor associated with adverse outcomes in children with cancer. We sought to determine whether obesity during childhood cancer treatment increases risk for second malignant neoplasms (SMN). METHODS: In this case-control study, cases (with SMN) and controls (with a single-primary cancer) were selected from the California Cancer Registry who had primary cancer diagnosed <21 years treated at Children's Hospital Los Angeles between 1988 and 2014. Controls were matched 3:1 to cases at the registry level by clinical factors. Medical records were abstracted for cancer treatment exposures, cancer predisposition syndrome, body mass index (BMI), BMI Z-score, and BMI category at diagnosis and end of therapy (EOT). RESULTS: A total of 59 cases and 130 controls were included. Median age at primary cancer diagnosis was 6 years, 64.5% were male, median time from primary cancer to SMN was 7.5 years, and 31.7% were obese or overweight. In matched multivariable analyses, there were elevated but nonsignificant associations between SMN and higher BMI Z-score at diagnosis [OR 1.27 (0.99-1.63)] and higher BMI categories at diagnosis [adjusted OR (aOR) overweight, 1.25 (0.55-2.52); aOR obese, 2.51 (1.00-6.29)]. There was a significantly increased risk for SMN among patients who were obese at both diagnosis and EOT [aOR, 4.44 (1.37-14.34)]. CONCLUSIONS: This study suggests that obesity during childhood cancer treatment may be associated with increased risk for SMNs, particularly among those obese throughout therapy. IMPACT: Additional studies to confirm these findings and to develop interventions have the potential to impact SMN development in children with cancer.

A Reappraisal of Sex-Specific Cancer Survival Trends Among Adolescents and Young Adults in the United States.

BACKGROUND: Cancer survival among adolescents and young adults (AYAs) was previously reported as showing little or no improvement compared to younger or older counterparts. The role of the HIV/AIDS epidemic in the AYA survival deficit has not been evaluated. METHODS: Using cancer registry data from the Surveillance, Epidemiology, and End Results program (SEER 9), we examined sex-specific 5-year relative survival trends for children (0-14 years old), AYAs (15-39 years old), and older adults (40 years and older) diagnosed with cancer during 1973-2009 and followed through the end of 2014. The analysis was conducted with and without Kaposi sarcoma (KS) and lymphomas, and by two time periods: 1973-1977 (before the human immunodeficiency virus/acquired immunodeficiency syndrome [HIV/AIDS] epidemic) and 2005-2009 (after the HIV/AIDS epidemic waned). RESULTS: A total of 3 209 721 invasive cancer cases were included in the study (27 646 children, 213 930 AYAs, and 2 968 145 older adults; 24 803 children, 178 741 AYAs, and 2 844 062 older adults when KS and lymphoma cases were excluded). We found that 5-year relative survival for AYAs exceeded that of children and older adults before the onset of the HIV/AIDS epidemic (eg, during 1973-1979, 0.58-0.67 among male AYAs as compared with 0.47-0.61 for male children and 0.36-0.42 for male older adults; among female AYAs, the numbers were 0.73-0.77 as compared with 0.51-0.65 for female children and 0.52-0.55 for female older adults); substantially declined during 1983-1997 when HIV/AIDS lacked effective treatment among male AYAs; and returned to be higher than most age groups by the late 1990s after HIV/AIDS was controlled. Nonetheless, comparison of survival improvement between 1973-1977 and 2005-2009 demonstrated less progress in AYAs than other age groups, which was due to AYAs' better baseline survival and larger survival gains among children and older adults in recent years. CONCLUSIONS: Apart from the temporary impact of HIV/AIDS, survival among AYA cancer patients has shown sustained improvement and superiority relative to other age groups. However, these encouraging findings do not negate the distinctive challenges in cancer diagnosis, treatment, and survivorship faced by AYAs.

Utility of Echocardiography as Screening for Late-onset Anthracycline-induced Cardiotoxicity in Pediatric Cancer Survivors: Observations from the First Decade After End of Therapy.

Current screening guidelines are available for anthracycline-induced cardiotoxicity. However, the utility of echocardiogram screening for late-onset anthracycline cardiotoxicity especially in the decade immediately after end of therapy is debatable. A retrospective chart review of patients seen in the Thriving after Cancer Clinic at Rady Children's Hospital January 2006 to December 2013 was performed. Treatment data, echocardiogram results, cardiology referral notes and cardiac medication data were abstracted from anthracycline-exposed survivors. Descriptive and univariate comparative statistics were performed. Of 368 patients (45% female, median 5.3 y old at diagnosis [range 0 to 18.3], median 5.0 y from end of therapy [EOT] [range 0 to 18.2]), a total of 4 patients (10-year cumulative incidence after EOT 1.3%; 95% confidence interval, 0.1%-19.7%) required cardiac medication for late-onset cardiotoxicity (>1 y after EOT). Those requiring medication for late-onset cardiotoxicity were exposed to more anthracyclines than survivors without cardiotoxicity (median, 360 mg/m [range, 300 to 375 mg/m] vs. 182 mg/m [range, 26 to 515 mg/m], P=0.009). None had neck or chest radiation. In this population, medication initiation for late-onset anthracycline cardiotoxicity was limited predominantly to the first 3 years after EOT, with the next >13 years after EOT. These findings add to the growing body of literature assessing current guidelines to inform improvements in screening practices of survivorship providers.

Association of clinical trial enrollment and survival using contemporary therapy for pediatric acute lymphoblastic leukemia.

While early studies reported superior survival for cancer patients enrolled on clinical trials, recent findings are inconclusive. We investigated the association between enrollment on contemporary trials and event-free survival (EFS) in pediatric B-cell acute lymphoblastic leukemia (B-ALL). In a retrospective cohort of 274 children (1-21 years) treated for B-ALL from 2008 to 2015, 55.5% enrolled with no disparity in enrollment by age, sex, or ethnicity. Three-year EFS was similar for enrolled and not enrolled patients (90.1% [95% CI, 82.5-94.5] versus 86.5% [95% CI, 77.7-92.0]). Clinical trial enrollment did not affect pediatric B-ALL survival, albeit in a limited-size cohort treated at a single academic institution.

Liver Transplantation for Hepatocellular Carcinoma in Young Adults: A United Network for Organ Sharing Study.

PURPOSE: Orthotopic liver transplantation (OLT) is curative for hepatocellular carcinoma (HCC). HCC is typically a disease of older adults (OAs); therefore, characteristics and outcomes of OLT for young adults (YAs) (ages 18-40) are not described. The objective of this study was to assess the characteristics and outcomes of YAs with HCC receiving OLT and compare these to OAs (ages >40 years). METHODS: YAs with HCC who had OLT from the United Network for Organ Sharing (UNOS) database were included in this study. As a comparison group, OAs with HCC were matched 4:1 to the YA group. Descriptive statistics of demographics, comorbidities, and outcomes were generated. Kaplan-Meier product limit estimates were used to assess patient and graft survival. Conditional logistic regression and Cox proportional hazards frailty models were used to compare the groups. RESULTS: A total of 464 YAs received OLT for HCC. The most common underlying liver diseases were hepatitis C virus (21.3%), hepatitis B virus (HBV, 15.5%), and autoimmune/cholestatic disease (12.3%). An increased number of YAs received OLT for HCC after implementation of model for end-stage liver disease scoring. One thousand two hundred eighty OAs served as the comparison group. Post-transplant 5-year survival was 73.1% in YAs with a retransplantation rate of 7.8%. In OAs, survival and retransplantation rates were lower (68.6% p = 0.093; 4.3% p = 0.001). CONCLUSION: Four hundred sixty-four YAs with HCC received OLT in the UNOS database. Compared to the older population, survival and retransplantation rates were higher. HBV, which is vaccine preventable, is a frequent contributor to HCC in YAs.