Primary Diffuse Leptomeningeal Melanomatosis in a Child with Extracranial Metastasis: Case Report.

Primary meningeal melanomatosis is an extremely rare tumor with very few documented responses to treatment. A 3-year-old male with a complex past medical history, including prematurity and shunted hydrocephalus, was diagnosed with primary meningeal melanomatosis with peritoneal implants. Molecular testing revealed an NRAS Q61R mutation. The patient received proton craniospinal radiation followed by immunotherapy with nivolumab (1 mg/kg) and ipilimumab (3 mg/kg) IV every 3 weeks and, upon progression, he was switched to a higher dose of nivolumab (3 mg/kg IV every 2 weeks) and binimetinib (24 mg/m2/dose, twice a day). The patient had significant improvement of CNS disease with radiation therapy and initial immunotherapy but progression of extracranial metastatic peritoneal and abdominal disease. Radiation was not administered to the whole abdomen. After two cycles of nivolumab and treatment with the MEK inhibitor binimetinib, he had radiographic and clinical improvement in abdominal metastasis and ascitis. He ultimately died from RSV infection, Klebsiella sepsis, and subdural hemorrhage without evidence of tumor progression. This is the first report of a child with primary meningeal melanomatosis with extracranial metastatic disease with response to a combination of radiation, immunotherapy and MEK inhibitor therapy.

Clinical outcomes in a large pediatric cohort of patients with ependymoma treated with proton radiotherapy.

BACKGROUND: Treatment for pediatric ependymoma includes surgical resection followed by local radiotherapy (RT). Proton RT (PRT) enables superior sparing of critical structures compared with photons, with potential to reduce late effects. We report mature outcomes, patterns of failure, and predictors of outcomes in patients treated with PRT. METHODS: One hundred fifty patients (<22 y) with World Health Organization grades II/III ependymoma were treated with PRT between January 2001 and January 2019 at Massachusetts General Hospital. Demographic, tumor, and treatment-related characteristics were analyzed. Event-free survival (EFS), overall survival (OS), and local control (LC) were assessed. RESULTS: Median follow-up was 6.5 years. EFS, OS, and LC for the intracranial cohort (n = 145) at 7 years were 63.4%, 82.6%, and 76.1%. Fifty-one patients recurred: 26 (51.0%) local failures, 19 (37.3%) distant failures, and 6 (11.8%) synchronous failures. One hundred sixteen patients (77.3%) underwent gross total resection (GTR), 5 (3.3%) underwent near total resection (NTR), and 29 (19.3%) underwent subtotal resection (STR). EFS for the intracranial cohort at 7 years for GTR/NTR and STR was 70.3% and 35.2%. With multivariate analysis, the effect of tumor excision persisted after controlling for tumor location. There was no adverse effect on disease control if surgery to RT interval was within 9 weeks of GTR/NTR. CONCLUSION: PRT is effective and safe in pediatric ependymoma. Similar to previous studies, GTR/NTR was the most important prognostic factor. Intervals up to 9 weeks from surgery to PRT did not compromise disease outcomes. There was no LC benefit between patients treated with >54 Gray relative biological effectiveness (GyRBE) versus ≤54 GyRBE.

Prolongation of radiotherapy duration is associated with inferior overall survival in patients with pediatric medulloblastoma and central nervous system primitive neuroectodermal tumors.

BACKGROUND: The importance of radiotherapy (RT) duration in medulloblastoma in the modern era of chemotherapy has not been well elucidated. The aim of this study was to determine the impact of RT treatment duration on overall survival (OS) in pediatric medulloblastoma and cenral nervous system neuroectodermal tumors (PNETs). METHODS: The National Cancer Database (NCDB) was queried to identify patients with newly diagnosed medulloblastoma and CNS PNETs diagnosed between 2004 and 2014. Patients were excluded if they had extraneural metastasis, did not receive standard craniospinal irradiation dose, had a nonstandard total dose outside of 54 or 55.8 Gy, did not receive adjuvant chemotherapy, or if the RT duration was outside of the expected range of 37 to 80 days. The Kaplan-Meier estimator was used to estimate the association between RT duration (≤45 days or >45 days) and OS. Multivariate Cox regression was used to assess other confounders of OS. RESULTS: Six-hundred twenty-five patients met inclusion criteria, of which 181 were assigned to the "RT long" (>45 days) cohort (29.0%) and 444 (71.0%) to the "RT short" group (≤45 days). The five-year OS for the "RT short" compared with "RT long" cohort was 82.2% versus 70.9%, respectively (log-rank, P < 0.0037). For average risk patients, the five-year OS was 84.6% versus 86.4% for "RT short" and "RT long," respectively (log-rank, P = 0.40). However, for high-risk patients, five-year OS was 77.7% versus 51.0% (log-rank, P < 0.0001) in the "RT short" and "RT long" cohorts. CONCLUSION: For patients with high-risk medulloblastoma and CNS PNETs, RT duration >45 days was associated with inferior OS.

Increased distance from a treating proton center is associated with diminished ability to follow patients enrolled on a multicenter radiation oncology registry.

PURPOSE: Consistent follow-up and data collection are necessary to identify long-term benefits/detriments of proton radiotherapy. Obtaining comprehensive clinical follow-up can be difficult and time-intensive for proton centers. Here we evaluate what factors affect maximum follow-up time among MGH Pediatric Proton Consortium Registry (PPCR) participants. PATIENTS AND METHODS: Enrollment in the PPCR was offered to any patient <22 years receiving protons. Patients were excluded from analysis if they were taken off study due to death or withdrawal. Distance from MGH was calculated by the great-circle formula. We utilized both univariate and multivariate analyses to determine risk factors associated with follow-up time. RESULTS: 333 PPCR patients enrolled between 10/2012 and 03/2017 were included. Median follow-up was 2.4 years (<1-5.5), and median distance away from the proton center was 256.4 km (<1.6-16,949.6). Distance from MGH significantly predicted follow-up time: patients living outside the Boston Metropolitan Statistical Area, >121 km from the proton center, had average follow-up that was 0.53 years less compared to those living within 121 km (p = 0.0002). Loss in average follow-up was also associated with Medicaid insurance, treatment delay due to insurance, and non-White race. Those co-enrolled on a proton trial or seen at a facility had significantly increased follow-up by almost one year (p < 0.0001). CONCLUSION: Patients living further from treating proton center have shorter follow-up durations. Increased distance from treating centers may adversely affect clinical outcomes research. Enhanced sharing of medical information among care providers and improved collection methods are needed to effectively evaluate the benefits of proton therapy.