Identification of Driver and Passenger Mutations of FLT3 by High-Throughput DNA Sequence Analysis and Functional Assessment of Candidate Alleles

SummaryMutations in the juxtamembrane and kinase domains of FLT3 are common in AML, but it is not known whether alterations outside these regions contribute to leukemogenesis. We used a high-throughput platform to interrogate the entire FLT3 coding sequence in AML patients without known FLT3 mutations and experimentally tested the consequences of each candidate leukemogenic allele. This approach identified gain-of-function mutations that activated downstream signaling and conferred sensitivity to FLT3 inhibition and alleles that were not associated with kinase activation, including mutations in the catalytic domain. These findings support the concept that acquired mutations in cancer may not contribute to malignant transformation and underscore the importance of functional studies to distinguish “driver” mutations underlying tumorigenesis from biologically neutral “passenger” alterations

Value: A Framework for Radiation Oncology

In the current health care system, high costs without proportional improvements in quality or outcome have prompted widespread calls for change in how we deliver and pay for care. Value-based health care delivery models have been proposed. Multiple impediments exist to achieving value, including misaligned patient and provider incentives, information asymmetries, convoluted and opaque cost structures, and cultural attitudes toward cancer treatment. Radiation oncology as a specialty has recently become a focus of the value discussion. Escalating costs secondary to rapidly evolving technologies, safety breaches, and variable, nonstandardized structures and processes of delivering care have garnered attention. In response, we present a framework for the value discussion in radiation oncology and identify approaches for attaining value, including economic and structural models, process improvements, outcome measurement, and cost assessment

Value: A Framework for Radiation Oncology

In the current health care system, high costs without proportional improvements in quality or outcome have prompted widespread calls for change in how we deliver and pay for care. Value-based health care delivery models have been proposed. Multiple impediments exist to achieving value, including misaligned patient and provider incentives, information asymmetries, convoluted and opaque cost structures, and cultural attitudes toward cancer treatment. Radiation oncology as a specialty has recently become a focus of the value discussion. Escalating costs secondary to rapidly evolving technologies, safety breaches, and variable, nonstandardized structures and processes of delivering care have garnered attention. In response, we present a framework for the value discussion in radiation oncology and identify approaches for attaining value, including economic and structural models, process improvements, outcome measurement, and cost assessment

High-dose hypofractionated radiotherapy is effective and safe for tumors in the head-and-neck

ObjectivesHigh-dose, hypofractionated radiotherapy (HFRT) is sometimes used to treat malignancy in the head-and-neck (HN), both in the curative and palliative setting. Its safety and efficacy have been reported in small studies and are still controversial.Materials and methodsWe retrospectively evaluated the outcomes and toxicities of HFRT, including ultra-high-dose fractionation schemes (⩾8Gray per fraction), for HN malignancies.ResultsA total of 62 sites of measurable gross disease in 48 patients were analyzed. The median follow-up was 54.3months among five survivors and 6.0months in the remaining patients. Median RT dose was 30Gray in 5 fractions; 20/62 lesions (32%) received dose-per-fraction of ⩾8Gray. Overall response rate at first follow-up was 79%. One-year local-progression free rate was 50%. On multivariate analysis for locoregional control, dose-per-fraction ⩾6Gray was associated with control (p=0.04) and previous radiation was associated with inferior control (p=0.04). Patients who achieved complete response to RT had longer survival than those who did not (p=0.01). Increased toxicity rates were not observed among patients treated with dose-per-fraction ⩾8Gray; only re-irradiation increased toxicity rates.ConclusionDespite the poor prognostic features noted in this cohort of patients with HN malignancies, HFRT was associated with high response rates, good local control, and acceptable toxicity. Sites that were treated with 6Gray per fraction or higher and had not been previously irradiated had the best disease control. A prospective trial is warranted to further refine the use and indications of HFRT in this setting