Barriers to Receiving Follow-up Care Among Childhood Cancer Survivors.

Little is known on why adherence to follow-up care in childhood cancer survivors (CCS) is lacking. This study characterized barriers to adherence to follow-up care among CCS, identified sociodemographic correlates of barriers, and examined whether barriers to follow-up care relate to health-related quality of life. Adult CCS (N=84) were anonymously surveyed via REDCap using the Barriers to Care Questionnaire (BCQ) and the Quality of Life Scale-Cancer Survivor (QOL-CS). Both descriptive and correlation analyses were conducted. The median BCQ total score was 88.5 (interquartile ranges:78.4 to 95.7), with the greatest barriers reported in the Skills (eg, ease of navigating the healthcare system) and Pragmatism subscales (eg, cost). There was a statistically significant correlation between the BCQ total score and the QOL-CS total score (rs=0.47, P <0.0001) and the physical, psychological, and social QOL-CS subscales (all P 's<0.05). The results found that barriers to follow-up care for CCS are mostly related to cost and appointment logistics, and that more barriers to care is associated with lower health-related quality of life among CCS. Identifying barriers to follow-up care is the first step in improving adherence, which would allow for earlier detection of late effects of cancer therapy and thereby result in reductions in morbidity and mortality.

Cost of survivorship care and adherence to screening-aligning the priorities of health care systems and survivors.

Childhood cancer survivors (CCS) experience significant morbidity due to treatment- related late effects and benefit from late-effects surveillance. Adherence to screening recommendations is suboptimal. Survivorship care programs often struggle with resource limitations and may benefit from understanding institution-level financial outcomes associated with patient adherence to justify programmatic development and growth. The purpose of this study is to examine how CCS adherence to screening recommendations relates to the cost of care, insurance status, and institution-level financial outcomes. A retrospective chart review of 286 patients, followed in a structured survivorship program, assessed adherence to the Children's Oncology Group follow-up guidelines by comparing recommended versus performed screening procedures for each patient. Procedure cost estimates were based on insurance status. Institutional profit margins and profit opportunity loss were calculated. Bivariate statistics tested adherent versus nonadherent subgroup differences on cost variables. A generalized linear model predicted the likelihood of adherence based on cost of recommended procedures, controlling for age, gender, race, and insurance. Adherence to recommended surveillance procedures was 50.2%. Nonadherence was associated with higher costs of recommended screening procedures compared to the adherent group estimates ($2,469.84 vs. $1,211.44). Failure to perform the recommended tests resulted in no difference in reimbursement to the health system between groups ($1,249.63 vs. $1,211.08). For the nonadherent group, this represented $1,055.13 in "lost profit opportunity" per visit for patients, which totaled $311,850 in lost profit opportunity due to nonadherence in this subgroup. In the final model, nonadherence was related to higher cost of recommended procedures (p < .0001), older age at visit (p = .04), Black race (p = .02), and government-sponsored insurance (p = .03). Understanding institutional financial outcomes related to patient adherence may help inform survivorship care programs and resource allocation. Potential financial burden to patients associated with complex care recommendations is also warranted.

Severe Coronavirus Disease 2019 Infection in an Adolescent Patient After Hematopoietic Stem Cell Transplantation.

Infection with the severe acute respiratory syndrome coronavirus 2 causes severe acute lung injury in approximately 5% of infected adults, but few reports have been made of severe pediatric disease. We present an adolescent patient who contracted severe acute respiratory syndrome coronavirus 2 one week after a paternal haplo-identical hematopoietic stem cell transplant, with development of severe hyperferritinemic acute lung injury and macrophage activation-like syndrome. We present her case and a comparison of her laboratory data with those of a cohort of pediatric patients with coronavirus disease 2019 without severe disease.

How I approach peer support in pediatric hematology/oncology.

Peer support has begun to gain traction as a mechanism for improving well-being in medicine. In this paper, we share our experience building, training, and piloting a peer support team based on a "critical incident stress management" model. The HOPES team (Helping Our Peers Endure Stress) is dedicated to, and composed entirely of, members of our division of pediatric hematology/oncology. Peer support will not solve all the well-being problems afflicting medicine. It is, however, a very good place to start.

Congenital Hepatoblastoma and Beckwith-Wiedemann Syndrome.

Following the discovery of a fetal hepatic tumor, labor was induced at 38 weeks, and a phenotypically normal female was delivered vaginally. A serum alpha-fetoprotein level at birth was 373,170 ng/mL. Postnatal magnetic resonance imaging confirmed a mass in the right lobe of the liver, and a percutaneous core biopsy revealed an epithelial type hepatoblastoma with predominantly embryonal histology. Methylation testing revealed hypomethylation at imprinting center 2, consistent with a diagnosis of Beckwith-Wiedemann syndrome. This case suggests that Beckwith-Wiedemann syndrome testing should be considered in all patients with hepatoblastoma, even in the absence of other phenotypic stigmata.

Caring for survivors of childhood cancer: it takes a village.

PURPOSE OF REVIEW: Over 80% of children diagnosed with cancer are now cured. The burgeoning population of survivors of childhood cancer experiences high rates of morbidity and mortality due to 'late-effects' of treatment. These can be defined as any consequence of treatment that persists beyond or develops after the completion of cancer therapy. Awareness of late-effects is critically important for pediatricians and adult providers alike, as late-effects impact children in proximity to cancer treatment, as well as adults many decades removed. This review presents the importance of lifelong follow-up care for survivors, highlights existing screening guidelines, and reviews various models of survivor care. RECENT FINDINGS: National and international guidelines have been developed to standardize screening for survivors, and multiple models of survivorship care exist. The optimal model likely depends on individual factors, including the survivor's needs and preferences, as well as local resources. Key strategies for the successful care of survivors include accurate risk-stratification for specific late-effects, individualized screening plans, education of survivors and professionals, clear communication between providers, and well coordinated transition of care across services. SUMMARY: Early identification and management of late-effects are important for survivors of childhood cancer. Providers should be familiar with the risks for specific late-effects and have access to screening guidelines. The strengths and weaknesses of care models, along with individual circumstances, should be considered in designing the optimal approach to care for each survivor.

Burnout in pediatric hematology/oncology-time to address the elephant by name.

The last decade has brought increasing recognition that the wellness of health care providers has an impact on the quality of care, patient satisfaction, and health care economics. This review will describe models of burnout, discuss the impact of burnout on medicine with a focus on pediatric hematologists/oncologists, and present interventions that may help ameliorate physician burnout.

Therapeutic plasma exchange for a case of refractory opsoclonus myoclonus ataxia syndrome.

Opsoclonus myoclonus ataxia syndrome (OMAS) can be refractory to standard therapies and devastating. Alternative treatments are imperative. A 14-month-old male diagnosed with neuroblastoma and paraneoplastic OMAS achieved complete cancer remission with chemotherapy. The OMAS, however, persisted over the subsequent 4 years despite numerous immune-modulatory and immunosuppressive therapies. The patient ultimately achieved complete remission following therapeutic plasma exchange (TPE) combined with rituximab and intravenous immunoglobulin. After three asymptomatic years, he relapsed. Upon reintroducing TPE and rituximab plus oral prednisolone, the patient rapidly achieved a second complete remission. This case offers proof-of-principle for the potential efficacy of TPE for neuroblastoma-associated OMAS.

Racial and ethnic disparities in treatment and survival of pediatric sarcoma.

BACKGROUND: Childhood sarcomas are rare and require complex interdisciplinary care including surgery, chemotherapy, and radiation. The goal of this study was to determine if racial or ethnic disparities exist for pediatric sarcoma patients in the United States. METHODS: The United States' National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify patients aged 0-21 diagnosed with primary sarcomas from 1973 to 2012. Patients were considered by race and ethnicity. Survival curves were computed using the Kaplan-Meier method and the log-rank test. RESULTS: A total of 11,502 patients were included in this study. When stratified by race, non-Hispanic black and Hispanic patients were significantly more likely to present with advanced stage disease than white patients. White patients were more likely to receive radiation therapy than black and Hispanic patients (P = 0.01). There was no significant difference between patients who underwent surgery (P = 0.21). Overall survival was better for white patients than black or Hispanic ones. Despite the overall 5-year survival improvement during the study period (56.2%-70.3%), survival disparities between race and ethnicity have grown. CONCLUSIONS: Racial and ethnic disparities do exist with respect to stage, treatment, and survival of these rare tumors. Black and Hispanic patients are presenting at more advanced stage and have overall worse survival. This survival disparity has widened over the past 4 decades.

Looking for trouble: Adherence to late-effects surveillance among childhood cancer survivors.

BACKGROUND: Childhood cancer survivors (CCSs) are at high risk of morbidity and mortality from long-term complications of their cancer treatment. The Children's Oncology Group developed screening guidelines to enable the early identification of and intervention for late effects of cancer treatment. There is a paucity of data on the adherence of CCSs to screening recommendations. PROCEDURE: A retrospective analysis of medical records to evaluate the rate of adherence of CCSs to the personalized, risk-based recommendations provided to them in the context of a structured long-term follow-up program over a 3-year period. RESULTS: Two hundred eighty-six CCSs visited the survivorship clinic 542 times during the 3-year study period. The overall rate of adherence to recommended screening was 74.2%. Using a univariate model and greater age at diagnosis and at screening recommendation were associated with decreased screening adherence. Gender, cancer diagnosis, radiation therapy, anthracycline exposure, and hematopoietic stem cell transplant were not significantly associated with adherence. In a multivariate model, age over 18 years at the time of the visit was significantly associated with decreased adherence (P < 0.0329) (odds ratio: 1.53, 95% confidence interval: 1.04-2.25). CONCLUSIONS: Adherence to recommended screening tests is suboptimal among CCSs, with lower rates of adherence in CCSs older than 18 years of age compared with those younger than 18 years of age. Given the morbidity and mortality from the late effects of therapy among young adult CCSs, it is critically important to identify and remove barriers to late-effects screening among CCSs.

Arterial stiffness in childhood cancer survivors.

BACKGROUND: Cardiovascular disease is prevalent among childhood cancer survivors (CCS). Arterial stiffness measured by pulse wave velocity (PWV) may be predictive of cardiovascular morbidity. Increased PWV has been seen in adults following chemotherapy. PURPOSE: To evaluate PWV in a cohort of CCS and healthy controls. PATIENTS AND METHODS: All participants were >6 years old. CCS were >12 months off-therapy and free of cardiac disease, diabetes, and kidney dysfunction. Height, weight, blood pressure (BP), medications, cancer diagnosis, age at diagnosis, time off therapy, chemotherapy, and radiation exposures were recorded. PWV was measured on all participants. RESULTS: Sixty-eight CCS (mean 17.3 ± 6 years, 52.9% male), and 51 controls (mean 18.4 ± 5.5 years, 37.3% male) were evaluated. Among CCS, 34% had lymphoma, 44% leukemia, and 22% solid tumors, and 49% were exposed to radiation. CCS were off therapy 7 ± 4.2 years. Both groups were statistically similar in age, BMI, and BP. CCS ≥ 18 years old had significantly higher PWV compared to controls ≥ 18 years old (6.37 ± 0.89 vs. 5.76 ± 0.88 m/sec, P = 0.012). The relationship persisted in a regression model adjusted for age, sex, and BMI z-score (ß = 0.52, 95%CI 0.051-0.979, P = 0.03). Seventy percent of CCS ≥ 18 had elevated PWV compared to established norms. Radiation therapy, anthracycline dose, and chemotherapy exposures were not predictive of increased PWV in CCS. CONCLUSIONS: CCS ≥ 18 demonstrated prematurely elevated PVW. Further studies are needed to determine the predictive value of PWV in this population and its utility as a screening modality.

Fertility preservation for adolescent women with cancer.

As the cure rate for adolescents with cancer has improved, the focus on future reproductive potential has increased. Despite a concerted effort to reduce the impact of cancer treatment on fertility through the alteration of therapy and the implementation of protective measures, many adolescent women with cancer remain at risk for impaired reproductive potential. Although the only standard-of-care approach to fertility preservation in this population remains embryo cryopreservation, there has been intense development of oocyte and ovarian cryopreservation as viable alternatives. This article focuses on the developing modalities of fertility preservation for adolescent women diagnosed with cancer.

Noninvasive bioluminescent imaging of primary patient acute lymphoblastic leukemia: a strategy for preclinical modeling.

The efficient engraftment in immune-deficient mice achieved with both acute lymphoblastic leukemia (ALL) cell lines and primary samples has facilitated identification of the antileukemia activity of a wide variety of agents. Despite widespread usage, however, little is known about the early ALL localization and engraftment kinetics in this model, limiting experimental read-outs primarily to survival and endpoint analysis at high disease burden. In this study, we report that bioluminescent imaging can be reproducibly achieved with primary human ALL samples. This approach provides a noninvasive, longitudinal measure of leukemia burden and localization that enhances the sensitivity of treatment response detection and provides greater insight into the mechanism of action of antileukemia agents. In addition, this study reveals significant cell line- and species-related differences in leukemia migration, especially early in expansion, which may confound observations between various leukemia models. Overall, this study demonstrates that the use of bioluminescent primary ALL allows the detection and quantitation of treatment effects at earlier, previously unquantifiable disease burdens and thus provides the means to standardize and expedite the evaluation of anti-ALL activity in preclinical xenograft studies.

Part 1: Hormone replacement for survivors of childhood cancer with ovarian failure--when is it worth the risk?

Survivors of childhood cancer represent a rapidly growing population of patients, some of whom experience temporary or permanent premature ovarian failure (POF) as a consequence of their disease or treatment. Although the risks and benefits of exogenous hormones have been extensively explored in menopausal women 50 years of age and older, there is scant data on the long-term safety of exogenous hormones in childhood cancer survivors. Although there are certainly benefits that can be achieved through hormone replacement for this unique population, many of these patients also have very long hormone exposure times and a markedly increased baseline risk for second malignancies, including breast cancer. Given the significant potential risks, hormone replacement should not be reflexively instituted in childhood cancer survivors with POF. It should only be considered following a thorough, balanced discussion of the risks and benefits of hormone replacement with each patient.

Insidious iron burden in pediatric patients with acute lymphoblastic leukemia.

BACKGROUND: A significant iron burden may occur after only 10 blood transfusions in patients with hematologic disorders. Children with acute lymphoblastic leukemia (ALL) routinely receive blood transfusions during therapy, although few studies to date have quantified transfusion-related iron burden in these patients. This study quantifies the transfused blood volume and resultant iron load in a large cohort of pediatric patients with ALL, and evaluates risk factors that may impact transfusion volume. METHODS: This single institution retrospective study evaluated 107 patients who completed therapy for ALL between July 1995 and March 2007. Age, weight, and hemoglobin at presentation, ALL risk category, leukemia cell type, and volume of blood transfusions were collected from medical records. RESULTS: Patients received an average of 115 ml/kg of blood (77 mg/kg iron) during treatment. There was a significant association between the volume of packed red blood cells and ALL risk category. Patients with standard-risk disease received 90 ml/kg (60 mg/kg iron), patients with high-risk disease 196 ml/kg (131 mg/kg iron) and patients with T-cell disease 114 ml/kg (76 mg/kg iron). There was no correlation between age or hemoglobin at presentation with amount of blood received. CONCLUSIONS: Patients with ALL often receive a substantial amount of iron during therapy, with patients with high-risk disease receiving the greatest load. As iron overload has an overlapping toxicity profile with chemotherapy and is treatable, screening for increased iron burden and iron-related morbidities should be considered during long-term follow-up of patients with ALL, particularly in those with high-risk ALL.

Autologous and allogeneic cellular therapies for high-risk pediatric solid tumors.

Since the 1950s, the overall survival of children with cancer has gone from almost zero to approaching 80%. Although there have been notable successes in treating solid tumors such as Wilms tumor, some childhood solid tumors have continued to elude effective therapy. With the use of megatherapy techniques such as tandem transplantation, dose escalation has been pushed to the edge of dose-limiting toxicities, and any further improvements in event-free survival will have to be achieved through novel therapeutic approaches. This article reviews the status of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for many pediatric solid tumor types. Most of the clinical experience in transplant for pediatric solid tumors is in the autologous setting, so some general principles of autologous HSCT are reviewed. The article then examines HSCT for diseases such as Hodgkin disease, Ewing sarcoma, and neuroblastoma, and the future of cell-based therapies by considering some experimental approaches to cell therapies.

Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo.

Persistence of T cells engineered with chimeric antigen receptors (CARs) has been a major barrier to use of these cells for molecularly targeted adoptive immunotherapy. To address this issue, we created a series of CARs that contain the T cell receptor-zeta (TCR-zeta) signal transduction domain with the CD28 and/or CD137 (4-1BB) intracellular domains in tandem. After short-term expansion, primary human T cells were subjected to lentiviral gene transfer, resulting in large numbers of cells with >85% CAR expression. In an immunodeficient mouse xenograft model of primary human pre-B-cell acute lymphoblastic leukemia, human T cells expressing anti-CD19 CARs containing CD137 exhibited the greatest antileukemic efficacy and prolonged (>6 months) survival in vivo, and were significantly more effective than cells expressing CARs containing TCR-zeta alone or CD28-zeta signaling receptors. We uncovered a previously unrecognized, antigen-independent effect of CARs expressing the CD137 cytoplasmic domain that likely contributes to the enhanced antileukemic efficacy and survival in tumor bearing mice. Furthermore, our studies revealed significant discrepancies between in vitro and in vivo surrogate measures of CAR efficacy. Together these results suggest that incorporation of the CD137 signaling domain in CARs should improve the persistence of CARs in the hematologic malignancies and hence maximize their antitumor activity.