BackgroundWe determined factors associated with morbidity and outcomes of a series of non-small cell lung cancer (NSCLC) patients treated with dose-escalated chemoradiotherapy at the University of Pittsburgh Lung Cancer Program.Methods and materialsThe records of 170 stage III NSCLC patients treated with definitive intent were retrospectively reviewed. All patients received four-dimensional CT simulation scan and had respiratory gating if tumor movement exceeded 5 mm. Overall survival (OS), locoregional control (LRC), and freedom from distant metastasis (FFDM) were calculated using log-rank and Cox regression analysis.ResultsFor the present series of patients, median follow-up was 36.6 months, median survival 27.4 months, and the 2- and 4-year OS was 56.0 and 30.7%, respectively. The 4-year LRC and FFDM were 43.9 and 40.7%, respectively. No benefit was associated with irradiation doses above 66 Gy in OS (p = 0.586), LRC (p = 0.440), or FFDM (p = 0.230). On univariate analysis, variables associated with worse survival included: clinical stage IIIB (p = 0.037), planning target volume (PTV) over 450 cc (p < 0.001), heart V30 over 40% (p = −0.048), and esophageal mean dose over 20% (p = 0.024), V5 (p = −0.015), and V60 (p = −0.011). On multivariable analysis, PTV above 450 cc (52.2 vs. 25.3 months, p < 0.001) and esophageal V60 >20% (43.8 vs. 21.3 months, p = −0.01) were associated with lower survival. Grade 2 or higher acute lung toxicity and esophagitis were detected in 9.5 and 59.7%, respectively of patients. Grade 2 or higher acute lung toxicity was reduced if lung V5 was ≤65 (7.4 vs. 23.8%, p = 0.03). Grade 2 or higher acute esophagitis was reduced if V60 ≤ 20% (62 vs. 81.3%, p = 0.018). The use of intensity-modulated radiation therapy was more frequent in stage IIIB compared to stage IIIA patients (56.5 vs. 39.5%, p = 0.048) and was associated with a higher lung V5 and V10.ConclusionThe outcomes of a program of dose-escalated chemoradiotherapy for unresectable stage IIIA and IIIB NSCLC patients were consistent with other studies and showed no benefit to radiation doses above 66 Gy. Furthermore, maintaining low esophageal V60 and lung V5 were associated with lower morbidity and mortality.

Nitric oxide (NO . ), an important signaling molecule and a component of inflammatory response, is involved in tumorigenesis. However, the quantity of NO. and the cellular microenvironment influences the role of NO . in tumor development. We used a genetic strategy to test the hypothesis that an inflammatory microenvironment with an enhanced level of NO . accelerates spontaneous tumor development. C. parvuminduced inflammation and increased NO . synthase-2 (NOS2) expression coincided with accelerated spontaneous tumor development, mostly lymphomas, in p53À/ÀNOS2+/+ C57BL6 mice when compared with the controls (P = 0.001). However, p53À/ÀNOS2À/À mice did not show any difference in tumor latency between C. parvum-treated and control groups. In C. parvum-treated p53À/ÀNOS2+/+ mice, tumor development was preceded by a higher expression of NOS2 and phosphorylated Akt-Ser 473

No abstract

Fanconi anemia (FA) is an inherited disorder characterized by defective DNA repair and cellular sensitivity to DNA crosslinking agents. Clinically, FA is associated with high risk for marrow failure, leukemia and head and neck squamous cell carcinoma (HNSCC). Radiosensitivity in FA patients compromises the use of total-body irradiation for hematopoietic stem cell transplantation and radiation therapy for HNSCC. A radioprotector for the surrounding tissue would therefore be very valuable during radiotherapy for HNSCC. Clonogenic radiation survival curves were determined for pre- or postirradiation treatment with the parent nitroxide Tempol or JP4-039 in cells of four FA patient-derived cell lines and two transgene-corrected subclonal lines. FancG–/– (PD326) and FancD2–/– (PD20F) patient lines were more sensitive to the DNA crosslinking agent mitomycin C (MMC) than their transgene-restored subclonal cell lines (both P < 0.0001). FancD2–/– cells were more radiosensitive than the transgene restored subclonal cell line (ñ = 2.0 ± 0.7 and 4.7 ± 2.2, respectively, P = 0.03). In contrast, FancG–/– cells were radioresistant relative to the transgene-restored subclonal cell line (ñ = 9.4 ± 1.5 and 2.2 ± 05, respectively, P = 0.001). DNA strand breaks measured by the comet assay correlated with radiosensitivity. Cell lines from a Fanc-C and Fanc-A patients showed radiosensitivity similar to that of Fanc-D2–/– cells. A fluorophore-tagged JP4-039 (BODIPY-FL) analog targeted the mitochondria of the cell lines. Preirradiation or postirradiation treatment with JP4-039 at a lower concentration than Tempol significantly increased the radioresistance and stabilized the antioxidant stores of all cell lines. Tempol increased the toxicity of MMC in FancD2–/– cells. These data provide support for the potential clinical use of JP4-039 for normal tissue radioprotection during chemoradiotherapy in FA patients.

No abstract

Deep convolutional neural network (DCNN) has shown great success in various medical image segmentation tasks, including organ-at-risk (OAR) segmentation from computed tomography (CT) images. However, most studies use the dataset from the same source(s) for training and testing so that the ability of a trained DCNN to generalize to a different dataset is not well studied, as well as the strategy to address the issue of performance drop on a different dataset. In this study we investigated the performance of a well-trained DCNN model from a public dataset for thoracic OAR segmentation on a local dataset and explored the systematic differences between the datasets. We observed that a subtle shift of organs inside patient body due to the abdominal compression technique during image acquisition caused significantly worse performance on the local dataset. Furthermore, we developed an optimal strategy via incorporating different numbers of new cases from the local institution and using transfer learning to improve the accuracy and robustness of the trained DCNN model. We found that by adding as few as 10 cases from the local institution, the performance can reach the same level as in the original dataset. With transfer learning, the training time can be significantly shortened with slightly worse performance for heart segmentation.

The aim of this study is to provide a practical approach to the planning technique and evaluation of plan quality for the multi-lesion, single-isocenter stereotactic ablative radiotherapy (SABR) of the lung. Eleven patients with two or more lung lesions underwent single-isocenter volumetric-modulated arc therapy (VMAT) radiosurgery or IMRS. All plans were normalized to the target maximum dose. For each plan, all targets were treated to the same dose. Plan conformity and dose gradient were maximized with dose-control tuning structures surrounding targets. For comparison, multi-isocenter plans were retrospectively created for four patients. Conformity index (CI), homogeneity index (HI), gradient index (GI), and gradient distance (GD) were calculated for each plan. V5, V10, and V20 of the lung and organs at risk (OARs) were collected. Treatment time and total monitor units (MUs) were also recorded. One patient had four lesions and the remainder had two lesions. Six patients received VMAT and five patients received intensity-modulated radiosurgery (IMRS). For those treated with VMAT, two patients received 3-arc VMAT and four received 2-arc VMAT. For those treated with IMRS, two patients were treated with 10 and 11 beams, respectively, and the rest received 12 beams. Prescription doses ranged from 30 to 54 Gy in three to five fractions. The median prescribed isodose line was 84% (range: 80–86%). The median maximum dose was 57.1 Gy (range: 35.7–65.1 Gy). The mean combined PTV was 49.57 cm3 (range: 14.90–87.38 cm3). For single-isocenter plans, the median CI was 1.15 (range: 0.97–1.53). The median HI was 1.19 (range: 1.16–1.28). The median GI was 4.60 (range: 4.16–7.37). The median maximum radiation dose (Dmax) to total lung was 55.6 Gy (range: 35.7–62.0 Gy). The median mean radiation dose to the lung (Dmean) was 4.2 Gy (range: 1.1–9.3 Gy). The median lung V5 was 18.7% (range: 3.8–41.3%). There was no significant difference in CI, HI, GI, GD, V5, V10, and V20 (lung, heart, trachea, esophagus, and spinal cord) between single-isocenter and multi-isocenter plans. This multi-lesion, single-isocenter lung SABR planning technique demonstrated excellent plan quality and clinical efficiency and is recommended for radiosurgical treatment of two or more lung targets for well-suited patients.

Stereotactic body radiotherapy (SBRT) of lung tumors via the ring‐mounted Halcyon Linac, a fast kilovoltage cone beam CT‐guided treatment with coplanar geometry, a single energy 6MV flattening filter free (FFF) beam and volumetric modulated arc therapy (VMAT) is a fast, safe, and feasible treatment modality for selected lung cancer patients. Four‐dimensional (4D) CT‐based treatment plans were generated using advanced AcurosXB algorithm with heterogeneity corrections using an SBRT board and Halcyon couch insert. Halcyon VMAT‐SBRT plans with stacked and staggered multileaf collimators produced highly conformal radiosurgical dose distribution to the target, lower intermediate dose spillage, and similar dose to adjacent organs at risks (OARs) compared to SBRT‐dedicated highly conformal clinical noncoplanar Truebeam VMAT plans following the RTOG‐0813 requirements. Due to low monitor units per fraction and less multileaf collimator (MLC) modulation, the Halcyon VMAT plan can deliver lung SBRT fractions with an overall treatment time of less than 15 min (for 50 Gy in five fractions), significantly improving patient comfort and clinic workflow. Higher pass rates of quality assurance results demonstrate a more accurate treatment delivery on Halcyon. We have implemented Halcyon for lung SBRT treatment in our clinic. We suggest others use Halcyon for lung SBRT treatments using abdominal compression or 4D CT‐based treatment planning, thus expanding the access of curative ultra‐hypofractionated treatments to other centers with only a Halcyon Linac. Clinical follow‐up results for patients treated on Halcyon Linac with lung SBRT is ongoing.