ABSTRACT
Purpose: The aim of this study was to comprehensively review all studies examining clinical outcomes of craniospinal irradiation with proton radiotherapy for medulloblastoma (MB) to determine whether theoretical dosimetric advantages have translated into superior clinical outcomes (including survival and toxicities) compared with traditional photon-based techniques. Methods and Materials: We performed a systematic review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles reporting on clinical outcomes of pediatric and/or adult patients with MB treated with proton radiotherapy were included. Evidence quality was assessed using a modified Newcastle Ottawa scale and GRADE score. Results: Thirty-five studies were included, with a total of 2059 patients reported (representing an estimated 630-654 unique patients). None of the studies were randomized, 12 were comparative, 9 were prospective, 3 were mixed, and 22 were retrospective. Average mean/median follow-up was 5.0 years (range, 4 weeks to 12.6 years). The majority of studies (n = 19) reported on treatment with passive scatter proton beams exclusively. Average study quality was 6.0 out of 9 (median, 6; standard deviation, 1.6). Nine studies scored ≥8 out of 9 on the modified Newcastle Ottawa Scale; an overall "moderate" GRADE score was assigned. Well-designed comparative cohort studies with adequate follow-up demonstrate superior neurocognitive outcomes, lower incidence of hypothyroidism (23% vs 69%), sex hormone deficiency (3% vs 19%), greater heights, and reduced acute toxicities in patients treated with protons compared to photons. Overall survival (up to 10 years), progression-free survival (up to 10 years), brain stem injury, and other endocrine outcomes were similar to those reported for photon radiation. There was insufficient evidence to make conclusions on endpoints of quality of life, ototoxicity, secondary malignancy, alopecia, scoliosis, cavernomas, and cerebral vasculopathy. Conclusions: Moderate-grade evidence supports proton radiotherapy as a preferred treatment for craniospinal irradiation of MB based on equivalent disease control and comparable-to-improved toxicity versus photon beam radiation therapy.
ABSTRACT
AIMS: Recent evidence has demonstrated that ketone bodies, particularly ß-hydroxybutyrate (BHB), are beneficial to the failing heart due to their potential as an alternative energy substrate as well as their anti-inflammatory and anti-oxidative properties. Exogenous supplementation of ketones also helps prevent heart failure (HF) development in rodent models, but whether ketones can be used to treat HF remains unexplored. Herein, we investigated whether chronic supplementation of ketones is beneficial for the heart in a mouse model of established HF. METHODS AND RESULTS: To elevate circulating ketone levels, we utilized (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate [ketone ester (KE)]. C57Bl/6N male mice were subjected to transverse aortic constriction (TAC) surgery. After developing HF, mice were treated with either 20% KE or vehicle via drinking water for 2 weeks. In another cohort, mice 3-4 weeks post-TAC received acute intravenous infusions of BHB or saline for 1 h and their cardiac function was measured. 20% KE significantly elevated blood BHB in mice (P < 0.01) without inducing ketoacidosis or altering other metabolic parameters. Mice with overt HF (30-45% ejection fraction) treated with 20% KE displayed significantly elevated circulating ketone levels compared with vehicle-treated mice (P < 0.05). The significant cardiac dysfunction in mice with HF continued to worsen after 2 weeks of vehicle treatment, whereas this decline was absent in KE-treated mice (mean difference 4.7% ejection fraction; P < 0.01). KE treatment also alleviated TAC-induced cardiomyocyte hypertrophy (P < 0.05) and reduced the TAC-induced elevated cardiac periostin (P < 0.05), a marker of activated fibroblasts. Cardiac fibrosis was also significantly reduced with KE treatment in TAC mice (P < 0.01). In another cohort, acute BHB infusion significantly increased the cardiac output of mice with HF (P < 0.05), providing further support that ketone therapy can be used to treat HF. CONCLUSIONS: We show that chronic treatment of exogenous ketones is of benefit to the failing heart and that chronic ketone elevation may be a therapeutic option for HF. Further investigations to elucidate the underlying mechanism(s) are warranted.
