Sharon M. Castellino

Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study

The contribution of specific cancer therapies, comorbid medical conditions, and host factors to mortality risk after pediatric Hodgkin lymphoma (HL) is unclear. We assessed leading morbidities, overall and cause-specific mortality, and mortality risks among 2742 survivors of HL in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study of survivors diagnosed from 1970 to 1986. Excess absolute risk for leading causes of death and cumulative incidence and standardized incidence ratios of key medical morbidities were calculated. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of risks for overall and cause-specific mortality. Substantial excess absolute risk of mortality per 10,000 person-years was identified: overall 95.5; death due to HL 38.3, second malignant neoplasms 23.9, and cardiovascular disease 13.1. Risks for overall mortality included radiation dose ≥ 3000 rad ( ≥ 30 Gy; supra-diaphragm: HR, 3.8; 95% CI, 1.1-12.6; infradiaphragm + supradiaphragm: HR, 7.8; 95% CI, 2.4-25.1), exposure to anthracycline (HR, 2.6; 95% CI, 1.6-4.3) or alkylating agents (HR, 1.7; 95% CI, 1.2-2.5), non-breast second malignant neoplasm (HR, 2.6; 95% CI 1.4-5.1), or a serious cardiovascular condition (HR, 4.4; 95% CI 2.7-7.3). Excess mortality from second neoplasms and cardiovascular disease vary by sex and persist > 20 years of follow-up in childhood HL survivors.

Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years of age. We sequenced the exomes of six individuals from three families with SCCOHT. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth affected family, which also carried a segregating SMARCA4 germline mutation. All the familial tumors sequenced harbored either a somatic mutation or loss of the wild-type allele. Immunohistochemical analysis of these cases and additional familial and non-familial cases showed loss of SMARCA4 (BRG1) protein in 38 of 40 tumors overall. Sequencing of cases with available DNA identified at least one germline or somatic deleterious SMARCA4 mutation in 30 of 32 cases. Additionally, the SCCOHT cell line BIN-67 had biallelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to improvements in genetic counseling and new treatment approaches.

Minority Adult Survivors of Childhood Cancer: A Comparison of Long-Term Outcomes, Health Care Utilization, and Health-Related Behaviors From the Childhood Cancer Survivor Study

PURPOSE To determine the influence of race/ethnicity on outcomes in the Childhood Cancer Survivor Study (CCSS). PATIENTS AND METHODS Of CCSS adult survivors in the United States, 443 (4.9%) were black, 503 (5.6%) were Hispanic and 7,821 (86.6%) were white. Mean age at interview, 26.9 years (range, 18 to 48 years); mean follow-up, 17.2 years (range, 8.7 to 28.4 years). Late mortality, second malignancy (SMN) rates, health care utilization, and health status and behaviors were assessed for blacks and Hispanics and compared with white survivors. RESULTS Late mortality rate (6.5%) and 15-year cumulative incidence of SMN (3.5%) were similar across racial/ethnic groups. Minority survivors were more likely to have lower socioeconomic status (SES); final models were adjusted for income, education, and health insurance. Although overall health status was similar, black survivors were less likely to report adverse mental health (females: odds ratio [OR], 0.6; 95% CI, 0.4 to 0.9; males: OR, 0.5; 95% CI, 0.3 to 0.8). Differences in health care utilization and behaviors noted: Hispanic survivors were more likely to report a cancer center visit (females: OR, 1.5; 95% CI, 1.1 to 2.0; males: OR, 1.7; 95% CI, 1.2 to 2.3); black females were more likely (OR, 1.6; 95% CI, 1.1 to 2.4), and Hispanic females less likely to have a recent Pap smear (OR, 0.7; 95% CI, 0.5 to 1.0); black and Hispanic survivors were less likely to report smoking; black survivors were less likely to report problem drinking. CONCLUSION Adjusted for SES, adverse outcomes in CCSS were not associated with minority status. Importantly, black survivors reported less risky behaviors and better preventive practices. Hispanic survivors had equitable access to cancer related care.

Hyaluronan Synthase 3 Variant and Anthracycline-Related Cardiomyopathy: A Report From the Children's Oncology Group

PURPOSE The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. PATIENTS AND METHODS By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. RESULTS By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). CONCLUSION Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.

Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children's Oncology Group Report.

Hematopoietic cell transplantation (HCT) is an important curative treatment for children with high-risk hematologic malignancies, solid tumors, and, increasingly, nonmalignant diseases. Given improvements in care, there are a growing number of long-term survivors of pediatric HCT. Compared with childhood cancer survivors who did not undergo transplantation, HCT survivors have a substantially increased burden of serious chronic conditions and impairments involving virtually every organ system and overall quality of life. This likely reflects the joint contributions of pretransplantation treatment exposures and organ dysfunction, the transplantation conditioning regimen, and any post-transplantation graft-versus-host disease (GVHD). In response, the Childrens Oncology Group (COG) has created long-term follow-up guidelines (www.survivorshipguidelines.org) for survivors of childhood, adolescent, and young adult cancer, including those who were treated with HCT. Guideline task forces, consisting of HCT specialists, other pediatric oncologists, radiation oncologists, organ-specific subspecialists, nurses, social workers, other health care professionals, and patient advocates systematically reviewed the literature with regards to late effects after childhood cancer and HCT since 2002, with the most recent review completed in 2013. For the most recent review cycle, over 800 articles from the medical literature relevant to childhood cancer and HCT survivorship were reviewed, including 586 original research articles. Provided herein is an organ system-based overview that emphasizes the most relevant COG recommendations (with accompanying evidence grade) for the long-term follow-up care of childhood HCT survivors (regardless of current age) based on a rigorous review of the available evidence. These recommendations cover both autologous and allogeneic HCT survivors, those who underwent transplantation for nonmalignant diseases, and those with a history of chronic GVHD.

Pediatric genitourinary tumors.

Purpose of review We will review the 2007/2008 literature on pediatric genitourinary tumors. Recent findings Newly identified constitutional epigenetic defects in Wilms tumor genes extend the understanding of Wilms tumor risk in children lacking syndromic features, and add to the complexity of the pathogenesis of these tumor suppressor genes. Pediatric renal cell carcinoma has distinct molecular characteristics and clinical associations from the adult counterpart. The pathway from PAX3-FKHR translocation to the development of rhabdomyosarcoma tumors has been further elucidated. Summary Therapeutic strategies continue to be driven by developments in molecular diagnostics in pediatric genitourinary tumors.

Delineating the Age Ranges Used to Define Adolescents and Young Adults

TO THE EDITOR: We were extremely pleased to see Journal of Clinical Oncology promoting awareness of the unique treatment issues that involve adolescents and young adults diagnosed with cancer by publishing an issue devoted to this topic on November 10, 2010. As noted in the overview by Thomas et al, this is an emerging field with implications for a broad array of health care providers and the health care system itself. Challenges particular to cancer outcomes in this group include biologic variation in tumors, treatment effectiveness and tolerance, adherence, fertility preservation, and early death. Because these challenges vary by age among adolescents and young adults, we were interested to note the substantial variability in the age ranges used by authors to define this group. A majority of authors adopted the strategy of describing ages in cited studies or reports without explicitly stating the age range they intended to address. Perhaps the best example of this was in the article by Veal et al, who described epidemiologic data consistently beginning at age 15 years but with varying cutoffs at ages 24, 29, and 39 years of age. These authors also presented a summary table of clinical pharmacology studies in adolescents and young adults in which participants’ ages ranged from 0.04 to 54 years. The authors of the overview described adolescents and young adults as “between the ages of 15 and 40.” Several authors explicitly stated age ranges. Butow et al adopted the World Health Organization definition of ages 12 to 24 years, whereas Wein et al and Ferrari et al described the age range as 15 to 29 years, with the possibility of including up to age 39 years. The challenge of defining age ranges for adolescents and young adults in the oncology context is not exclusive to the November 10, 2010, issue of JCO. The National Cancer Institute’s Adolescent and Young Adult Oncology Progress Review Group considered the issue carefully and focused their work on individuals diagnosed with cancer from ages 15 to 39 years. Yet a Surveillance, Epidemiology and End Results monograph about cancer epidemiology in adolescents and young adults published in the same year used a range of age 15 to 29 years. Other journals have feature issues that are similar to the November 10, 2010, issue of JCO, and have used a number of age ranges to describe the adolescent and young adult group. For example, in the May-June 2005 issue of Current Problems in Pediatric and Adolescent Health Care, the group was defined as “15 to approximately 30” years of age, although the only available survival statistics were from a group of patients who were 20 to 39 years of age. Professional organizations also differ; the Children’s Oncology Group’s Adolescents and Young Adults Committee defines the group as including age 15 to 29 years, whereasneedsofpatientsage15to39yearsareaddressed in the recently launched Focus Under Forty educational efforts of the American Society of Clinical Oncology and LIVESTRONG. Public data sources, clinics, and research studies vary widely in the age characterization of adolescents and young adults. Inconsistencies in defining an age range for adolescents and young adults are understandable given the realities of the complex biologic and psychosocial developmental processes experienced in the lengthy transition from childhood to adulthood in Western cultures. Treadgold and Kuperberg addressed this issue in the November 10, 2010, issue of JCO and noted that adolescents and young adults are not a “homogeneous entity.” They went on to point out the important differences in “lived experience” across the age span, which they define on the basis of emerging consensus as the “early teen years to the end of the thirties.” We sympathize with the challenges faced in defining appropriate age ranges for adolescents and young adults in the oncology context. Yet we also fear that failing to clearly delineate age ranges could be a substantial barrier to advancing clinical care and research for a population known to be at risk for poorer cancer outcomes than those diagnosed with cancer at younger or older ages. Thus, we urge that all communications from this emerging field explicitly define the age range being addressed and the rationale for that range. In addition to facilitating comparisons of clinical experiences and research findings from groups of adolescents and young adults, presenting a rationale for each age range selection will help identify situations in which the entire group can reasonably be considered together versus those in which narrower age ranges may be more appropriate. Without explicit age range definitions that are grounded in careful thought, progress in oncology care and research for adolescents and young adults may be slowed.

Age-Dependent Changes in Health Status in the Childhood Cancer Survivor Cohort

PURPOSE To compare age-dependent changes in health status among childhood cancer survivors and a sibling cohort. METHODS Adult survivors of childhood cancer and siblings, all participants of the Childhood Cancer Survivor Study, completed three surveys assessing health status. At each of three time points, participants were classified as having poor outcomes in general health, mental health, function, or daily activities if they indicated moderate to extreme impairment. Generalized linear mixed models were used to compare survivors with siblings for each outcome as a function of age and to identify host- and treatment-related factors associated with age-dependent worsening health status. RESULTS Adverse health status outcomes were more frequent among survivors than siblings, with evidence of a steeper trajectory of age-dependent change among female survivors with impairment in at least one health status domain (P = .01). In adjusted models, survivors were more likely than siblings to report poor general health (prevalence ratio [PR], 2.37; 95% CI, 2.09 to 2.68), adverse mental health (PR, 1.66; 95% CI, 1.52 to 1.80), functional impairment (PR, 4.53; 95% CI, 3.91 to 5.24), activity limitations (PR, 2.38; 95% CI, 2.12 to 2.67), and an adverse health status outcome in any domain (PR, 2.10; 95% CI, 1.97 to 2.23). Cancer treatment and health behaviors influence the magnitude of differences by age groups. Chronic conditions were associated with adverse health status outcomes across organ systems. CONCLUSION The prevalence of poor health status is higher among survivors than siblings, increases rapidly with age, particularly among female participants, and is related to an increasing burden of chronic health conditions.

Developing Interventions for Cancer-Related Cognitive Dysfunction in Childhood Cancer Survivors

Survivors of childhood cancer frequently experience cancer-related cognitive dysfunction, commonly months to years after treatment for pediatric brain tumors, acute lymphoblastic leukemia (ALL), or tumors involving the head and neck. Risk factors for cancer-related cognitive dysfunction include young age at diagnosis, treatment with cranial irradiation, use of parenteral or intrathecal methotrexate, female sex, and pre-existing comorbidities. Limiting use and reducing doses and volume of cranial irradiation while intensifying chemotherapy have improved survival and reduced the severity of cognitive dysfunction, especially in leukemia. Nonetheless, problems in core functional domains of attention, processing speed, working memory and visual-motor integration continue to compromise quality of life and performance. We review the epidemiology, pathophysiology and assessment of cancer-related cognitive dysfunction, the impact of treatment changes for prevention, and the broad strategies for educational and pharmacological interventions to remediate established cognitive dysfunction following childhood cancer. The increased years of life saved after childhood cancer warrants continued study toward the prevention and remediation of cancer-related cognitive dysfunction, using uniform assessments anchored in functional outcomes.

Effect of Race on the Outcome of Pediatric Patients With Hodgkin's Lymphoma

PURPOSE Some cooperative groups have found a survival disadvantage in black children with various childhood cancers. We examine the effects of race on clinical outcomes among children with Hodgkins lymphoma (HL) treated with contemporary therapy at a tertiary care childrens hospital. PATIENTS AND METHODS Retrospective analysis of 327 children and adolescents diagnosed with HL between 1990 and 2005. Patients were treated with risk-directed multimodal therapy regardless of race, ethnicity, or ability to pay. Event-free and overall survival rates were compared for black and white children. Clinical characteristics, socioeconomic factors, and biologic features were analyzed for prognosis of treatment failure. RESULTS The 262 white and 65 black patients did not differ significantly in presenting features, clinical characteristics, or enrollment in a clinical trial. More black patients (71% v 45%) resided in poor counties (P < .001). While black and white children were equally likely to have progressive disease or early relapse, black children were 3.7 times (95% CI, 1.7 to 8.0) more likely to relapse 12 months or more after diagnosis. The 5-year event-free survival was 71% +/- 6.1% (SE) for black and 84% +/- 2.4% for white children (P = .01). However, the 5-year survival rate did not differ between white and black children (94.4% v 94.7%). While black race and low hemoglobin concentration were independent predictors of treatment failure, only low hemoglobin concentration independently predicted poor survival. CONCLUSION Black children with Hodgkins lymphoma have lower event-free survival than white children, but both populations have the same 5-year overall survival.