Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial.

BACKGROUND: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real­time treatment decisions for children with relapsed/refractory solid tumors. METHODS: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real­time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. RESULTS: A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy. CONCLUSIONS: This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.

A pilot study of genomic-guided induction therapy followed by immunotherapy with difluoromethylornithine maintenance for high-risk neuroblastoma.

BACKGROUND: Survival for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapies. AIMS: To study the feasibility and safety of incorporating a genomic-based targeted agent to induction therapy for HRNB as well as the feasibility and safety of adding difluoromethylornithine (DFMO) to anti-GD2 immunotherapy. METHODS: Twenty newly diagnosed HRNB patients were treated on this multicenter pilot trial. Molecular tumor boards selected one of six targeted agents based on tumor-normal whole exome sequencing and tumor RNA-sequencing results. Treatment followed standard upfront HRNB chemotherapy with the addition of the selected targeted agent to cycles 3-6 of induction. Following consolidation, DFMO (750 mg/m2 twice daily) was added to maintenance with dinutuximab and isotretinoin, followed by continuation of DFMO alone for 2 years. DNA methylation analysis was performed retrospectively and compared to RNA expression. RESULTS: Of the 20 subjects enrolled, 19 started targeted therapy during cycle 3 and 1 started during cycle 5. Eighty-five percent of subjects met feasibility criteria (receiving 75% of targeted agent doses). Addition of targeted agents did not result in toxicities requiring dose reduction of chemotherapy or permanent discontinuation of targeted agent. Following standard consolidation, 15 subjects continued onto immunotherapy with DFMO. This combination was well-tolerated and resulted in no unexpected adverse events related to DFMO. CONCLUSION: This study demonstrates the safety and feasibility of adding targeted agents to standard induction therapy and adding DFMO to immunotherapy for HRNB. This treatment regimen has been expanded to a Phase II trial to evaluate efficacy.

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.

Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2- and 5-year EFS were 86.4% [95% confidence interval (CI) 79.3%-94.2%] and 85.2% [77.8%-93.3%] for the NMTRC003/003b subset vs 78.3% [69.5%-88.3%] and 65.6% [55.5%-77.5%] for the historical control group. The 2- and 5-year OS were 98.8% [96.4-100%] and 95.1% [90.5%-99.9%] vs 94.4% [89.3%-99.9%] and 81.6% [73.0%-91.2%], respectively. DFMO maintenance for HRNB after completion of standard of care therapy was associated with improved EFS and OS relative to historical controls treated at the same institutions. These results support additional investigations into the potential role of DFMO in preventing relapse in HRNB.

Postal workers' occupational and leisure-time sun safety behaviors (United States).

OBJECTIVES: United States Postal Service letter carriers are exposed to long bouts of UVR and thus are vulnerable to skin cancer. While previous studies have shown that occupational sun protection is often deficient, few studies have examined outdoor workers' behavior during leisure time. METHODS: Subjects (n = 2,660) self-reported widebrim hat and sunscreen use over the past five workdays and past two non-working days using Likert-type scales. Generalized linear mixed models and generalized estimating equations were used to compare hat and sunscreen rates and predictors during occupational and leisure time. RESULTS: On average, carriers spent 3.9 h outside during workdays and 3.3 h during non-working days. Sunscreen and widebrim hat use during the workday is low and rates of use are significantly lower during non-working days. CONCLUSIONS: Sun safety interventions for carriers should encourage sun protection at all times when outdoors.

Ethnoracial differences among outdoor workers in key sun-safety behaviors.

BACKGROUND: Few sun-safety studies have included ethnoracially diverse groups. Comparison across such groups of sun-safety behaviors was the main objective of this analysis. METHODS: Postal workers (n =2543) self-reported frequency of sunscreen, wide-brim hat, and sunglasses use during the last 5 workdays on 5-point Likert-type scales ranging from "never" to "always." Responses were dichotomized by "always" versus all other responses. Generalized estimating equations were used to assess the association between ethnicity/race and frequency of each sun safety behavior. The baseline data reported in this paper were collected in the summer of 2001, and the randomized trial was completed in the summer of 2004. RESULTS: Ethnicity/race was significantly related to sunscreen and sunglasses use. For both sunscreen and sunglasses, the white group had significantly higher "always" rates than the other four groups (30% vs 14% to 23% and 63% vs 44% to 52%, respectively). CONCLUSIONS: The results of this study indicated that although non-Latino white employees tended to have higher rates of sun-safety behaviors, the rates of adequate protection of all groups were low.

Validating outdoor workers' self-report of sun protection.

BACKGROUND: Few studies assessing sun safety behaviors have used validated survey instruments. Using an observational strategy, this study measured the validity of self-report of occupational sun protection behaviors. METHODS: Postal workers (N = 1,036) self-reported their frequency of protective clothing and sunglasses use during the past 5 workdays on Likert scales ranging from "Never" to "Always". Responses were dichotomized by Always vs. all other responses. Data collectors observed these same behaviors during mail delivery several days before survey administration. Agreement between the two measures was computed. RESULTS: Self-report for all items was significantly related to observed behaviors, with Kappa values in the good to excellent range (Kappas = 0.51-0.83). CONCLUSIONS: For outdoor postal workers, survey items assessing recent occupational use of sun-protective items had high levels of validity.

Promotion of frequent tanning sessions by indoor tanning facilities: two studies.

BACKGROUND: Indoor tanning may increase the risk of melanoma and other health problems. Frequent users of indoor tanning facilities may be at particularly high risk. OBJECTIVE: In study 1 our purpose was to assess the prevalence and nature of indoor tanning advertisements; in study 2 we aimed to assess tanning facility compliance to recommended exposure schedules. METHODS: In study 1, tanning facility advertisements over a 4-month period from 24 San Diego County newspapers were monitored. In study 2, we assessed compliance with recommended exposure schedules via a telephone interview of 60 San Diego County tanning facilities. RESULTS: Approximately 75% of the indoor tanning advertisements promoted unlimited tanning. Only 5% of facilities were in compliance with recommended tanning schedules, and 100% offered "unlimited" tanning packages. CONCLUSIONS: These findings suggest that the indoor tanning industry, through pricing incentives that allow frequent sessions, may be promoting overexposure to UVR. Stronger legislation is needed to address this issue.