Simplifying intensity-modulated radiotherapy plans with fewer beam angles for the treatment of oropharyngeal carcinoma.

The first aim of the present study was to investigate the feasibility of using fewer beam angles to improve delivery efficiency for the treatment of oropharyngeal cancer (OPC) with inverse-planned intensity-modulated radiation therapy (IP-IMRT). A secondary aim was to evaluate whether the simplified IP-IMRT plans could reduce the indirect radiation dose. The treatment plans for 5 consecutive OPC patients previously treated with a forward-planned IMRT (FP-IMRT) technique were selected as benchmarks for this study. The initial treatment goal for these patients was to deliver 70 Gy to > or = 95% of the planning gross tumor volume (PTV-70) and 59.4 Gy to > or = 95% of the planning clinical tumor volume (PTV-59.4) simultaneously. Each case was re-planned using IP-IMRT with multiple beam-angle arrangements, including four complex IP-IMRT plans using 7 or more beam angles, and one simple IMRT plan using 5 beam angles. The complex IP-IMRT plans and simple IP-IMRT plans were compared to each other and to the FPIMRT plans by analyzing the dose coverage of the target volumes, the plan homogeneity, the dose-volume histograms of critical structures, and the treatment delivery parameters including delivery time and the total number of monitor units (MUs). When comparing the plans, we found no significant difference between the complex IP-IMRT, simple IP-IMRT, and FP-IMRT plans for tumor target coverage (PTV-70: p = 0.56; PTV-59.4: p = 0.20). The plan homogeneity, measured by the mean percentage isodose, did not significantly differ between the IP-IMRT and FP-IMRT plans (p = 0.08), although we observed a trend toward greater inhomogeneity of dose in the simple IP-IMRT plans. All IP-IMRT plans either met or exceeded the quality of the FP-IMRT plans in terms of dose to adjacent critical structures, including the parotids, spinal cord, and brainstem. As compared with the complex IP-IMRT plans, the simple IP-IMRT plans significantly reduced the mean treatment time (maximum probability for four pairwise comparisons: p = 0.0003). In conclusion, our study demonstrates that, as compared with complex IP-IMRT, simple IP-IMRT can significantly improve treatment delivery efficiency while maintaining similar target coverage and sparing of critical structures. However, the improved efficiency does not significantly reduce the total number of MUs nor the indirect radiation dose

Clinical, Biochemical and Genetic Analyses in Two Korean Patients with Medium-chain Acyl-CoA Dehydrogenase Deficiency

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive hereditary metabolic disorder of mitochondrial fatty acid β-oxidation. It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness. The most frequently isolated mutation in the acyl-CoA dehydrogenase, medium-chain (ACADM) gene of Caucasian patients with MCADD is c.985A>G, but ethnic variations exist in the frequency of this mutation. Here, we describe 2 Korean pediatric cases of MCADD, which was detected during newborn screening by tandem mass spectrometry and confirmed by molecular analysis. The levels of medium-chain acylcarnitines, including octanoylcarnitine (C8), hexanoylcarnitine (C6), and decanoylcarnitine (C10), were typically elevated. Molecular studies revealed that Patient 1 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.461T>G (p.L154W) mutations, and Patient 2 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.1189T>A (p.Y397N) mutations. We detected asymptomatic patients with MCADD by using a newborn screening test and confirmed it by ACADM mutation analysis. This report presents evidence of the biochemical and molecular features of MCADD in Korean patients and, to the best of our knowledge, this is the first report of the c.461T>G mutation in the ACADM gene

Long-term Correction of Very Long-chain Acyl-CoA Dehydrogenase Deficiency in Mice Using AAV9 Gene Therapy

Very long-chain acyl-coA dehydrogenase (VLCAD) is the rate-limiting step in mitochondrial fatty acid oxidation. VLCAD-deficient mice and patients clinical symptoms stem from not only an energy deficiency but also long-chain metabolite accumulations. VLCAD-deficient mice were treated systemically with 1 × 1012 vector genomes of recombinant adeno-associated virus 9 (rAAV9)-VLCAD. Biochemical correction was observed in vector-treated mice beginning 2 weeks postinjection, as characterized by a significant drop in long-chain fatty acyl accumulates in whole blood after an overnight fast. Changes persisted through the termination point around 20 weeks postinjection. Magnetic resonance spectroscopy (MRS) and tandem mass spectrometry (MS/MS) revealed normalization of intramuscular lipids in treated animals. Correction was not observed in liver tissue extracts, but cardiac muscle extracts showed significant reduction of long-chain metabolites. Disease-specific phenotypes were characterized, including thermoregulation and maintenance of euglycemia after a fasting cold challenge. Internal body temperatures of untreated VLCAD−/− mice dropped below 20 °C and the mice became lethargic, requiring euthanasia. In contrast, all rAAV9-treated VLCAD−/− mice and the wild-type controls maintained body temperatures. rAAV9-treated VLCAD−/− mice maintained euglycemia, whereas untreated VLCAD−/− mice suffered hypoglycemia following a fasting cold challenge. These promising results suggest rAAV9 gene therapy as a potential treatment for VLCAD deficiency in humans