Keegan Herndon (proseslip8)

BACKGROUND AND PURPOSE Radiation-induced lung damage (RILD) is a common consequence of lung cancer radiotherapy (RT) with unclear evolution over time. We quantify radiological RILD longitudinally and correlate it with dosimetry and respiratory morbidity. MATERIALS AND METHODS CTs were available pre-RT and at 3, 6, 12 and 24-months post-RT for forty-five subjects enrolled in a phase 1/2 clinical trial of isotoxic, dose-escalated chemoradiotherapy for locally advanced non-small cell lung cancer. Fifteen CT-based measures of parenchymal, pleural and lung volume change, and anatomical distortions, were calculated. Respiratory morbidity was assessed with the Medical Research Council (MRC) dyspnoea score and spirometric pulmonary function tests (PFTs) FVC, FEV1, FEV1/FVC and DLCO. RESULTS FEV1, FEV1/FVC and MRC scores progressively declined post-RT; FVC decreased by 6-months before partially recovering. Radiologically, an early phase (3-6 months) of acute inflammation was characterised by reversible parenchymal change and non-progressive anatomical distortion. A phase of chronic scarring followed (6-24 months) with irreversible parenchymal change, progressive volume loss and anatomical distortion. Post-RT increase in contralateral lung volume was common. Normal lung volume shrinkage correlated longitudinally with mean lung dose (r = 0.30-0.40, p = 0.01-0.04). Radiological findings allowed separation of patients with predominant acute versus chronic RILD; subjects with predominantly chronic RILD had poorer pre-RT lung function. CONCLUSIONS CT-based measures enable detailed quantification of the longitudinal evolution of RILD. The majority of patients developed progressive lung damage, even when the early phase was absent or mild. Pre-RT lung function and RT dosimetry may allow to identify subjects at increased risk of RILD. BACKGROUND AND PURPOSE Effective combination treatments with fractionated radiotherapy rely on a proper understanding of the dynamic responses that occur during treatment. We explored the effect of clinical fractionated radiotherapy on the development and timing of radioresistance in tumor cells. METHODS AND MATERIALS Different colon (HT29/HCT116/COLO320/SW480/RKO) and high-grade astrocytoma (D384/U-251MG) cancer cell lines were treated for 6 weeks with daily fractions of 2 Gy, 5 days per week. Clonogenic survival was determined throughout the treatment period. In addition, the radiosensitivity of irradiated and non-irradiated was compared. Finally, the effect of different dose fractions on the development of radioresistance was determined. RESULTS All cell lines developed radioresistance within 2-3 weeks during fractionated radiotherapy. This was characterized by the occurrence of a steady state phase of clonogenic survival. SGC 0946 supplier In U-251MG cells this was accompanied by increased cell senescence and stemness. After recovering from six weeks of treatment, the radiosensitivity of fractionally irradiated and non-irradiated cells was similar. Including transient radioresistance, described as (α/β)-(d+1), as a factor in the classic LQ model resulted in a perfect fit with the experimental data observed during fractionated radiotherapy. This was confirmed when different dose fractions were applied. CONCLUSIONS Fractionated irradiation of cancer cells in vitro following clinical radiation schedules induces a reversible radioresistance response. This adaptive response can be included in the LQ model as a function of the dose fraction and the alpha/beta-ratio of a given cell line. These findings warrant further investigation of the mechanisms and clinical relevance of adaptive radioresistance. Although the associations between endosulfan and adverse cardiovascular health have been reported, the toxic effects and underlying mechanism of endosulfan on the heart are not well understood. In this study, we examined the cardiotoxicity induced by endosulfan using