Mark A. Applebaum

Advances in Risk Classification and Treatment Strategies for Neuroblastoma

Risk-based treatment approaches for neuroblastoma have been ongoing for decades. However, the criteria used to define risk in various institutional and cooperative groups were disparate, limiting the ability to compare clinical trial results. To mitigate this problem and enhance collaborative research, homogenous pretreatment patient cohorts have been defined by the International Neuroblastoma Risk Group classification system. During the past 30 years, increasingly intensive, multimodality approaches have been developed to treat patients who are classified as high risk, whereas patients with low- or intermediate-risk neuroblastoma have received reduced therapy. This treatment approach has resulted in improved outcome, although survival for high-risk patients remains poor, emphasizing the need for more effective treatments. Increased knowledge regarding the biology and genetic basis of neuroblastoma has led to the discovery of druggable targets and promising, new therapeutic approaches. Collaborative efforts of institutions and international cooperative groups have led to advances in our understanding of neuroblastoma biology, refinements in risk classification, and stratified treatment strategies, resulting in improved outcome. International collaboration will be even more critical when evaluating therapies designed to treat small cohorts of patients with rare actionable mutations.

Clinical features and outcomes in patients with extraskeletal Ewing sarcoma.

Ewing sarcoma can arise in either bone or soft tissue. The purpose of this study was to investigate whether patient characteristics, treatment strategies, and outcomes differ between skeletal Ewing sarcoma and extraskeletal Ewing sarcoma (EES).

Self-management skills in adolescents with chronic rheumatic disease: A cross-sectional survey

BackgroundFor adolescents with a diagnosis of lifelong chronic illness, mastery of self-management skills is a critical component of the transition to adult care. This study aims to examine self-reported medication adherence and self-care skills among adolescents with chronic rheumatic disease.MethodsCross-sectional survey of 52 adolescent patients in the Pediatric Rheumatology Clinic at UCSF. Outcome measures were self-reported medication adherence, medication regimen knowledge and independence in health care tasks. Predictors of self-management included age, disease perception, self-care agency, demographics and self-reported health status. Bivariate associations were assessed using the Students t-test, Wilcoxon rank sum test and Fisher exact test as appropriate. Independence in self-management tasks were compared between subjects age 13-16 and 17-20 using the chi-squared test.ResultsSubjects were age 13-20 years (mean 15.9); 79% were female. Diagnoses included juvenile idiopathic arthritis (44%), lupus (35%), and other rheumatic conditions (21%). Mean disease duration was 5.3 years (SD 4.0). Fifty four percent reported perfect adherence to medications, 40% reported 1-2 missed doses per week, and 6% reported missing 3 or more doses. The most common reason for missing medications was forgetfulness. Among health care tasks, there was an age-related increase in ability to fill prescriptions, schedule appointments, arrange transportation, ask questions of doctors, manage insurance, and recognize symptoms of illness. Ability to take medications as directed, keep a calendar of appointments, and maintain a personal medical file did not improve with age.ConclusionsThis study suggests that adolescents with chronic rheumatic disease may need additional support to achieve independence in self-management.

Perception of transition readiness and preferences for use of technology in transition programs: teens' ideas for the future.

Abstract Background: Efforts to facilitate transition of care to adult providers for adolescents with chronic disease are not uniformly successful and many patients encounter challenges. The goal of this study was to assess transition readiness and preferences for tools to aid in the transition process with an emphasis on technology and social media. Methods: We surveyed and performed focus groups on patients aged 13–21 years from a pediatric university-based rheumatology and general pediatric practice. Demographics and transition readiness were assessed using a questionnaire. Transition readiness was assessed by examining patient knowledge and independence with care. Focus groups were conducted to elicit perspectives about desirable features of a transition program and useful tools. Results: Thirty-five patients completed surveys; and 20 patients and 13 of their parents participated in a focus group. The median patient age was 17 years and 74.3% were female. A Likert scale (0–10, 10=most) was used to evaluate concern over changing to an adult medical provider, (mean=6.4, SD=2.6), preparedness for disease self-management (mean=6.0, SD=2.8), and perceived importance of self-managing their condition (mean=7.1, SD=3.1). Themes that emerged from focus groups included a desire for support groups with other teens, a preference for using text messaging for communication and a desire for an online health management program. Conclusions: Teens with chronic disease are able to identify health maintenance tasks and strategies that will aid in developing independence with healthcare management. These findings support the idea that developing engaging applications and support groups will assist teens in the transitioning.

Second malignancies in patients with neuroblastoma: the effects of risk-based therapy.

To investigate the incidence of second malignant neoplasms (SMN) for patients with neuroblastoma, we analyzed patients from the SEER database according to three treatment eras (Era 1: 1973–1989, Era 2: 1990–1996, and Era 3: 1997–2006) corresponding to the introduction of multi‐agent chemotherapy, risk‐based treatment, and stem cell transplant.

Clinical features and outcomes in patients with Ewing sarcoma and regional lymph node involvement

A minority of patients with Ewing sarcoma present with regional lymph node involvement. We investigated if patient characteristics and outcomes differ between patients with Ewing sarcoma with and without regional node involvement.

Clinical features and outcomes in patients with secondary Ewing sarcoma

Ewing sarcoma (EWS) is rarely diagnosed as a second malignancy. We sought to describe a cohort of patients with secondary EWS and investigate if patient characteristics and survival differ between patients with secondary and primary EWS.

Emerging and investigational therapies for neuroblastoma

ABSTRACT Introduction: Treatment for children with clinically aggressive, high-risk neuroblastoma remains challenging. Less than 50% of patients with high-risk neuroblastoma will survive long-term with current therapies, and survivors are at risk for serious treatment-related late toxicities. Here, we review new and evolving treatments that may ultimately improve outcome for children with high-risk neuroblastoma with decreased potential for late adverse events. Areas covered: New strategies for treating high-risk neuroblastoma are reviewed including: radiotherapy, targeted cytotoxics, biologics, immunotherapy, and molecularly targeted agents. Recently completed and ongoing neuroblastoma clinical trials testing these novel treatments are highlighted. In addition, we discuss ongoing clinical trials designed to evaluate precision medicine approaches that target actionable somatic mutations and oncogenic cellular pathways. Expert opinion: Advances in genomic medicine and molecular biology have led to the development of early phase studies testing biologically rational therapies targeting aberrantly activated cellular pathways. Because many of these drugs have a wider therapeutic index than standard chemotherapeutic agents, these treatments may be more effective and less toxic than current strategies. However, to effectively integrate these targeted strategies, robust predictive biomarkers must be developed that will identify patients who will benefit from these approaches and rapidly match treatments to patients at diagnosis.

Integrative genomics reveals hypoxia inducible genes that are associated with a poor prognosis in neuroblastoma patients

Neuroblastoma is notable for its broad spectrum of clinical behavior ranging from spontaneous regression to rapidly progressive disease. Hypoxia is well known to confer a more aggressive phenotype in neuroblastoma. We analyzed transcriptome data from diagnostic neuroblastoma tumors and hypoxic neuroblastoma cell lines to identify genes whose expression levels correlate with poor patient outcome and are involved in the hypoxia response. By integrating a diverse set of transcriptome datasets, including those from neuroblastoma patients and neuroblastoma derived cell lines, we identified nine genes (SLCO4A1, ENO1, HK2, PGK1, MTFP1, HILPDA, VKORC1, TPI1, and HIST1H1C) that are up-regulated in hypoxia and whose expression levels are correlated with poor patient outcome in three independent neuroblastoma cohorts. Analysis of 5-hydroxymethylcytosine and ENCODE data indicate that at least five of these nine genes have an increase in 5-hydroxymethylcytosine and a more open chromatin structure in hypoxia versus normoxia and are putative targets of hypoxia inducible factor (HIF) as they contain HIF binding sites in their regulatory regions. Four of these genes are key components of the glycolytic pathway and another three are directly involved in cellular metabolism. We experimentally validated our computational findings demonstrating that seven of the nine genes are significantly up-regulated in response to hypoxia in the four neuroblastoma cell lines tested. This compact and robustly validated group of genes, is associated with the hypoxia response in aggressive neuroblastoma and may represent a novel target for biomarker and therapeutic development.

Surveillance of Childhood Cancer Survivors: A Lifelong Affair

Treatment advances in the past several decades have greatly improved the prognosis for children diagnosed with cancer, and 5-year overall survival is now greater than 80% across all cancers. For many children with cancer, the improvement in survival has been achieved through the use of increasingly intensive, multimodal therapeutic approaches that include combinations of high-dose chemotherapeutic agents with or without radiation therapy. Survivors are known to be at risk for developing a spectrum of adverse outcomes, including early death, impaired growth and development, decreased fertility, and impaired cognitive function. However, one of the most serious treatment-related adverse events is the development of subsequent malignant neoplasms (SMNs). These subsequent cancers are a major cause of premature death, and recent studies indicate that patients surviving their first SMN remain at risk for additional neoplasms. The Childhood Cancer Survivor Study (CCSS) has led to significant advances in our understanding of the health outcomes of childhood cancer survivors. This ongoing multi-institutional research initiative has established a large and extensively characterized cohort of 5-year survivors of childhood and adolescent cancer. Importantly, follow-up of the aging CCSS cohort has provided new information about the long-term effects of treatment. Previous analysis of the CCSS cohort has demonstrated that the cumulative incidence of SMNs in patients 20 and 30 years from diagnosis was 3.2% and 7.9%, respectively, with standardized incidences higher than population controls. Additional studies have demonstrated that specific treatment exposures influence the risk of particular histologic types of subsequent malignancies. Notably, there is a 43-fold (95% CI, 27.2to 70.3-fold) increased risk of breast cancer in women after whole-lung radiation and increased odds of 3.5 (95% CI, 1.6 to 7.7) for developing a secondary sarcoma after exposure to anthracycline. The Children’s Oncology Group and others have developed riskbased guidelines for long-term follow-up of childhood and adolescent cancer survivors for SMNs and other adverse health outcomes based on the primary disease, treatment exposure, and established therapyrelated morbidities and mortality observed in the survivorship population. However, little is known about the health outcomes and/or risk of developing an SMN in the aging survivor population. Although small studies using the Surveillance, Epidemiology, and End Results (SEER) database have described the continuously increased incidence of SMNs decades after the diagnosis in osteosarcoma and neuroblastoma, the small numbers of patients and lack of detail regarding treatment exposures limit the ability to determine specific SMN risk. In the accompanying article, Turcotte et al have analyzed subsequent neoplasms (SNs) in patients included in the CCSS cohort who have reached their fifth or sixth decade of life. Of the 14,364 patients in the CCSS cohort diagnosed between 1970 and 1986, 3,171 met inclusion criteria of being at least 40 years old at the time of last survey, totaling 15,985 person-years after age 40. A total of 679 SNs were reported, and SMNs (n 196) were diagnosed in 180 unique individuals. The cumulative incidence of SNs and SMNs between the ages of 40 and 55 years was 34.6% (95% CI, 28.7% to 40.6%) and 16.3% (95% CI, 11.7% to 20.9%), respectively. There was no difference in the cumulative incidence of SMNs between those who did or did not develop an SN before age 40 years (20.8% [95% CI, 12.5% to 29.1%] and 15.4% [95% CI, 10.2% to 20.5%]; P .35). However, exposure to radiation and a history of SNs put patients at higher risk of developing an SN than those without either risk factor with cumulative incidences of 62.3% (95% CI, 51.2% to 73.5%) and 13.3% (95% CI, 4.8% to 21.8%), respectively. The correlation between therapeutic exposures and development of SMNs is well established in survivors observed for two to three decades. In the CCSS cohort of survivors older than age 40 years, all classes of chemotherapeutics were associated with a higher incidence of SMNs, although only platinum-based agents remained significant in a multivariable analysis. Therapeutic radiation exposure also increased the risk for SMNs in this cohort well into their fifth and sixth decades. Interestingly, male survivors age 40 years or older who were not exposed to therapeutic radiation were not at increased risk for SMNs, regardless of their SN history before age 40 years. Childhood cancers that generally occur at older ages such as Hodgkin lymphoma (HL) were overrepresented in the aging CCSS cohort that was analyzed, whereas malignancies that are commonly diagnosed in younger children, such as neuroblastoma and Wilms tumor, were relatively underrepresented. The makeup of the aging CCSS cohort clearly influenced the histologic types of SMNs observed. For example, 30% of the patients were HL survivors, and this group experienced a high number of new SNs (57%) after age 40 compared with other primary diagnoses, largely as a result of the high incidence of breast cancer. Females and HL survivors had increased risk of breast cancer compared with the general population regardless of prior SN status. Furthermore, female sex (relative risk, 1.9; 95% CI, 1.3 to 2.6) and radiation exposure (relative risk, 2.2; 95% CI, 1.4 to 3.3) were determined to be significant risk factors in a multivariable Poisson regression model for SMNs. Thus, it seems clear that female survivors JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 31 NOVEMBER 1 2015