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Abstract: Background and purpose: To evaluate the risk factors for radiation-induced lung toxicity (RILT) from post-operative radiation therapy (PORT) in patients with non-small cell lung cancer (NSCLC). Material and methods: Ninety NSCLC patients who received PORT with or without chemotherapy from November 2002 to March 2006 were retrospectively analyzed. Each individual''s radiotherapy plans were reviewed to determine the percentage of the whole lung volume that received more than a specific dose of irradiation (Vdose). The endpoint was RILT of grade 2 or higher. Data of potential risk factors for RILT were extracted from the medical records and evaluated by logistic regression modeling, the t-test, and the Chi-square test. Results: A total of 20 patients received pneumonectomy, while the remaining 70 received lobectomy. In the lobectomy group, 9 patients (10%) developed ≥grade 2 RILT. Among the clinical factors, only adjuvant chemotherapy was significantly correlated with RILT (p =0.039). For lung dosimetric factors, V20 through V40 were all significantly higher in the RILT group than in the non-RILT group. In the lobectomy group, the incidence of RILT was 27.3% in patients who received adjuvant chemotherapy and whose V20 was greater than 20%. It was 9.7% in lobectomy patients with one of the risk factors, and 0.0% in those with no risk factors (p =0.032). Conclusions: The lung toxicity of PORT was found to be acceptably low. Adjuvant chemotherapy and lung dosimetric factors of V20–V40 were significantly correlated with RILT risk in NSCLC patients. [Copyright &y& Elsevier]

Purpose: To test whether radiation-induced elevations of transforming growth factor-β1 (TGF-β1) during radiation therapy (RT) correlate with radiation-induced lung toxicity (RILT) in patients with non-small-cell lung cancer (NSCLC) and to evaluate the ability of mean lung dose (MLD) to improve the predictive power. Methods and Materials: Eligible patients included those with Stage I–III NSCLC treated with RT with or without chemotherapy. Platelet-poor plasma was obtained pre-RT and at 4–5 weeks (40–50 Gy) during RT. TGF-β1 was measured using an enzyme-linked immunosorbent assay. The primary endpoint was ≥ Grade 2 RILT. Mann-Whitney U test, logistic regression, and chi-square were used for statistical analysis. Results: A total of 165 patients were enrolled in this study. The median radiation dose was 60 Gy, and the median MLD was 15.3 Gy. Twenty-nine patients (17.6%) experienced RILT. The incidence of RILT was 46.2% in patients with a TGF-β1 ratio > 1 vs. 7.9% in patients with a TGF-β1 ratio ≤ 1 (p < 0.001), and it was 42.9% if MLD > 20 Gy vs. 17.4% if MLD ≤ 20 Gy (p = 0.024). The incidence was 4.3% in patients with a TGF-β1 ratio ≤ 1 and MLD ≤ 20 Gy, 47.4% in those with a TGF-β1 ratio >1 or MLD > 20 Gy, and 66.7% in those with a TGF-β1 ratio >1 and MLD > 20 Gy (p < 0.001). Conclusions: Radiation-induced elevation of plasma TGF-β1 level during RT is predictive of RILT. The combination of TGF- β1 and MLD may help stratify the patients for their risk of RILT. [Copyright &y& Elsevier]

[Display omitted] • Studies about prognostic factors of NSCLC patients with BOM are lacking. • Five significant independent prognostic factors for them were found. • We developed a GPA model to estimate life expectancy and to guide interventions. • The more distal metastases to the spine, the worse the prognosis. This retrospective study investigated prognostic factors in advanced non-small cell lung cancer (NSCLC) with bone-only metastasis, and developed a graded prognostic assessment (GPA) model to estimate patient survival. The primary endpoint was overall survival. We investigated the patients with advanced NSCLC with bone-only metastasis at the initial diagnosis and diagnosed between 2013 and 2019 in our hospital. A log-rank test and Cox proportional hazards model were used to examine factors. A GPA model was developed in the training set based on the factors that were determined significant according to their hazard ratios and verified by the validation set. We finally included 220 patients for analysis. These patients were divided into two groups, 147 cases for the training cohort and 73 for the validation cohort. The following were significant independent prognostic factors, and were included in the GPA model: smoking; EGFR (epidermal growth factor receptor) sensitive/ALK (anaplastic lymphoma kinase) mutations; loss of weight; hypoalbuminemia; and primary site treated by surgery or radiotherapy. GPA score of nil was assigned to smoking, without sensitive mutations, loss of weight, hypoalbuminemia, and without local treatment of primary site; the corresponding superior alternatives were scored 1.5, 2.0, 1.5, 1.5, and 1.5, respectively. The median survival times of patients with GPA scores of nil to 3.0, 3.5 to 6.0, and 6.5 to 8.0 were 14.2, 29.5, and 56.6 months in the training set (P < 0.001) and 15.2, 31.2, and 54.0 months in the validation set (P < 0.001). The survival time of patients with NSCLC with bone-only metastasis was dramatically influenced by the presence of the determined prognostic factors. The GPA model developed in this study may be a useful clinical tool to estimate the life expectancy of these patients, and guide treatment. [ABSTRACT FROM AUTHOR]

Summary: Background: This study aimed to further investigate the role of circulating TGF-β1 during radiation therapy (RT) in predicting radiation-induced lung toxicity (RILT). Methods and materials: Patients with stages I–III non-small cell lung cancer treated with RT based therapy were included in this study. Platelet poor plasma was obtained pre-RT, at 2 and 4 weeks during-RT, and at the end of RT. TGF-β1 was measured using an enzyme-linked immunosorbent assay. The primary endpoint for RILT was ≥grade 2 radiation pneumonitis or fibrosis. Results: Twenty-six patients with a minimum follow-up of 12 months were included. Six patients (23.1%) experienced ≥grade 2 RILT. There was no significant difference in absolute TGF-β1 levels pre-RT, at 2 and 4 weeks during-RT, or at the end of RT between patients with and without RILT. The TGF-β1 ratios (over the pre-RT levels) for patients with and without RILT at 2, 4 weeks during-, and the end of RT were 2.8±2.2 and 1.0±0.6 (P =0.123), 2.3±1.3 and 0.8±0.5 (P =0.001), 1.5±0.9 and 0.8±0.5 (P =0.098), respectively. Using 2.0 as a cut-off, the TGF-β1 ratio at 4 weeks during-RT predicted RILT with a sensitivity and specificity of 66.7% and 95.0%, respectively. Conclusion: Elevation of plasma TGF-β1 level 4 weeks during-RT is significantly predictive of RILT. The role of plasma TGF-β1 in predicting RILT deserves further study. [Copyright &y& Elsevier]

Purpose: To determine whether the effect of radiation dose varies with gross tumor volume (GTV) in patients with stage I/II non–small cell lung cancer (NSCLC). Methods and Materials: Included in the study were 114 consecutive patients with medically inoperable stage I/II NSCLC treated with three-dimensional conformal radiotherapy between 1992 and 2004. The median biologic equivalent dose (BED) was 79.2 Gy (range, 58.2–124.5 Gy). The median GTV was 51.8 cm3 (range, 2.1–727.8 cm3). The primary endpoint was overall survival (OS). Kaplan-Meier estimation and Cox regression models were used for survival analyses. Results: Multivariate analysis showed that there was a significant interaction between radiation dose and GTV (p < 0.001). In patients with BED ≤79.2 Gy (n = 68), the OS medians for patients with GTV >51.8 cm3 and ≤51.8 cm3 were 18.2 and 23.9 months, respectively (p = 0.015). If BED was >79.2 Gy (n = 46), no significant difference was found between GTV groups (p = 0.681). For patients with GTV >51.8 cm3 (n = 45), the OS medians in those with BED >79.2 Gy and ≤79.2 Gy were 30.4 and 18.2 months, respectively (p < 0.001). If GTV was ≤51.8 cm3 (n = 45), the difference was no longer significant (p = 0.577). Conclusion: High-dose radiation is more important for patients with larger tumors and may be effective in reducing the adverse outcome associated with large GTV. Further prospective studies are needed to confirm this finding. [Copyright &y& Elsevier]

Abstract: Background and purpose: To determine the dose to regional nodal stations in patients with T1–3N0M0 non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3DCRT) without intentional elective nodal irradiation (ENI). Materials and methods: Twenty-three patients with medically inoperable T1–3N0M0 NSCLC were treated with 3DCRT without ENI. Hilar and mediastinal nodal regions were contoured on planning CT. The prescription dose was normalized to 70Gy. Equivalent uniform dose (EUD) and other dosimetric parameters (e.g., V 40) were calculated for each nodal station. Results: The median EUD for the whole group ranged from 0.4 to 4.4Gy for all elective nodal regions. Gross tumor volume (GTV) and the relationship between GTV and hilum were significantly correlated with irradiation dose to ipsilateral hilar nodal regions (P <.05). For patients with GTV⩾30.2cm3 (diameter≈4cm) and or having any overlap with hilum, the median EUDs were 9.6, 22.6, and 62.9Gy for ipsilateral lower paratracheal, subcarinal, and ipsilateral hilar regions, respectively. The corresponding median V40 were 32.5%, 39.3%, and 97.6%, respectively. Conclusions: Although incidental nodal irradiation dose is low in the whole group, the dose to high-risk nodal regions is considerable in patients with T1–3N0 NSCLC when the primary is large and/or centrally located. [Copyright &y& Elsevier]

The characteristics and prognostic factors of small-cell lung cancer (SCLC) patients with bone metastases at first diagnosis have scarcely been reported. This study aimed to analyze the prognostic factors of these patients and to develop a scoring system for survival to provide evidence for clinical treatment decisions. The records of 102 SCLC patients with bone metastasis at the time of diagnosis who were seen in our hospital between May 2010 and May 2015 were retrospectively reviewed. The log-rank test and multivariate Cox regression analysis were used to evaluate potential clinical predictors of survival. A scoring system was developed based on the hazard ratios of significant independent prognostic factors. The most common site of bone metastases was the spine (64.7%), and 26 patients (25.6%) had a single bone metastasis. The median survival was 10.4 months, and the 2-year survival rate was 10.3%. Age, number of bone metastases, and occurrence of extraosseous distant metastases were significant independent prognostic factors for overall survival. Based on their scores, patients were divided into three groups. The median survival times of the three groups were 6.4 months, 8.5 months and 12.4 months, and the 2-year survival rates were 0%, 2.9%, and 19.3% (p=0.000). Twenty-six patients (25.5%) developed skeletal-related events (SREs), and the most common SREs were radiation to the bone (22.5%) and spinal cord compression (11.8%). This study includes preliminary clinical data of SCLC patients with bone metastases at the time of diagnosis, and more studies are needed. [ABSTRACT FROM AUTHOR]

Radiation pneumonitis (RP) is one of the common side effects of radiation therapy in the thoracic region. Radiomics and dosiomics quantify information implicit within medical images and radiation therapy dose distributions. In this study we demonstrate the prognostic potential of radiomics, dosiomics, and clinical features for RP prediction. Radiomics, dosiomics, dose-volume histogram (DVH) metrics, and clinical parameters were obtained on 314 retrospectively collected and 35 prospectively enrolled patients diagnosed with lung cancer between 2013 to 2019. A radiomics risk score (R score) and dosiomics risk score (D score), as well as a DVH-score, were calculated based on logistic regression after feature selection. Six models were built using different combinations of R score, D score, DVH score, and clinical parameters to evaluate their added prognostic power. Overoptimism was evaluated by bootstrap resampling from the training set, and the prospectively collected cohort was used as the external test set. Model calibration and decision-curve characteristics of the best-performing models were evaluated. For ease of further evaluation, nomograms were constructed for selected models. A model built by integrating all of the R score, D score, and clinical parameters had the best discriminative ability with areas under the curve of 0.793 (95% confidence interval [CI], 0.735-0.851), 0.774 (95% CI, 0.762-0.786), and 0.855 (95% CI, 0.719-0.990) in the training, bootstrapping, and external test sets, respectively. The calibration curve image showed good agreement between the predicted and actual values, with a slope of 1.21 and intercept of –0.04. The decision curve image showed a positive net benefit for the final model based on the nomogram. Radiomic and dosiomic features have the potential to assist with the prediction of RP, and the combination of radiomics, dosiomics, and clinical parameters led to the best prognostic model in the present study. [ABSTRACT FROM AUTHOR]

The hydrodynamic performance of an integrated oscillating water column (OWC) combined with a cylindrical caisson type breakwater was investigated. A three-dimensional numerical wave tank was established to simulate the overall energy conversion performance and hydrodynamics of the integrated system with the software Star-CCM+. The developed Computational Fluid Dynamics (CFD) model was initially verified with the published physical results and numerical results derived from an analytical solution. The effects of the structural geometry and the pneumatic damping of the PTO system on the wave absorption and power conversion efficiency of the proposed device were investigated using this developed model. Based on this proposed numerical model, the velocity of the air flow, the corresponding air pressure characteristics in the air turbine nozzle and chamber zone were discussed. The results indicate that this proposed half-open land based OWC is adapted to absorb shorter nearshore waves, characterized by dimensionless wave number kd approaching 1.49. Furthermore, a larger opening inlet zone for this proposed OWC would shift the resonant corresponding kd to higher wave frequencies, while lowering the opening inlet could help to increase the power extraction efficiency for long waves. The peak hydrodynamic efficiency is observed at a ratio of OWC inlet width to diameter B / D of 0.97, which is approximately six times larger than that at B / D = 0.5. The inclusion of an impulse turbine yields a more uniform pressure distribution within the central chamber and effectively mitigates wave reflection for smaller incident waves, with maximum efficiency achieved using 37 blades. The property of the efficiency mitigation with insufficient certain intake depth of the wave chamber should be avoided for system design. • A novel dual cylindrical OWC incorporated into a fixed caisson type breakwater was numerically investigated. • The effects of the chamber geometry and the PTO damping on the primary-stage power conversion efficiency are studied. • The flow field of the hybrid system in and around the OWC chamber is investigated. • The effect of impulse turbine on the secondary-stage performance as well as efficiency is considered. [ABSTRACT FROM AUTHOR]

Purpose: The use of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) with surgical resection has not been fully identified. This study undertook to assess the factors affecting the risk of brain metastases in patients with stage I-III SCLC after surgical resection. The implications of PCI treatment for these patients are discussed. Methods and Materials: One hundred twenty-six patients treated with surgical resection for stage I-III SCLC from January 1998-December 2009 were retrospectively analyzed to elucidate the risk factors of brain metastases. Log-rank test and Cox regression model were used to determine the risk factors of brain metastases. Results: The median survival time for this patient population was 34 months, and the 5-year overall survival rate was 34.9%. For the whole group, 23.0% (29/126) of the patients had evidence of metastases to brain. Pathologic stage not only correlated with overall survival but also significantly affected the risk of brain metastases. The 5-year survival rates for patients with pathologic stages I, II, and III were 54.8%, 35.6%, and 14.1%, respectively (P=.001). The frequency of brain metastases in patients with pathologic stages I, II, and III were 6.25% (2/32), 28.2% (11/39), and 29.1% (16/55) (P=.026), respectively. A significant difference in brain metastases between patients with complete resection and incomplete resection was also observed (20.5% vs 42.9%, P=.028). The frequency of brain metastases was not found to be correlated with age, sex, pathologic type, induction chemotherapy, adjuvant chemotherapy, or adjuvant radiation therapy. Conclusions: Stage I SCLC patients with complete resection had a low incidence of brain metastases and a favorable survival rate. Stage II-III disease had a higher incidence of brain metastases. Thus, PCI might have a role for stage II-III disease but not for stage I disease. [ABSTRACT FROM AUTHOR]

Purpose: To study the effects of radiation dose, chemotherapy, and their interaction in patients with unresectable or medically inoperable Stage III non–small–cell lung cancer (NSCLC). Methods and Materials: A total of 237 consecutive Stage III NSCLC patients were evaluated. Median follow-up was 69.0 months. Patients were treated with radiation therapy (RT) alone (n = 106), sequential chemoradiation (n = 69), or concurrent chemoradiation (n = 62). The primary endpoint was overall survival (OS). Radiation dose ranged from 30 to 102.9 Gy (median 60 Gy), corresponding to a bioequivalent dose (BED) of 39 to 124.5 Gy (median 72 Gy). Results: The median OS of the entire cohort was 12.6 months, and 2- and 5-year survival rates were 22.4% and 10.0%, respectively. Multivariable Cox regression model demonstrated that Karnofsky performance status (p = 0.020), weight loss < 5% (p = 0.017), chemotherapy (yes vs. no), sequence of chemoradiation (sequential vs. concurrent; p < 0.001), and BED (p < 0.001) were significant predictors of OS. For patients treated with RT alone, sequential chemoradiation, and concurrent chemoradiation, median survival was 7.4, 14.9, and 15.8 months, and 5-year OS was 3.3%, 7.5%, and 19.4%, respectively (p < 0.001). The effect of higher radiation doses on survival was independent of whether chemotherapy was given. Conclusion: Radiation dose and use of chemotherapy are independent predictors of OS in Stage III NSCLC, and concurrent chemoradiation is associated with the best survival. There is no interaction between RT dose and chemotherapy. [Copyright &y& Elsevier]

• EDRIC was an independent prognostic factor for metastasis of patients with LA-NSCLC who received thoracic radiotherapy. • EDRIC was affected by gross tumor volume (GTV) and lymph node (N) stage. • The association between EDRIC and overall survival (OS) was influenced by GTV. • EDRIC showed a trend of negative correlation with OS in patients with smaller GTV. In previous studies, the estimated dose of radiation to immune cells (EDRIC) showed a correlation with overall survival (OS) of patients with locally advanced non-small cell lung cancer (LA-NSCLC) who received thoracic radiotherapy. However, several factors such as gross tumor volume (GTV) and lymph node (N) stage may impact EDRIC. The purpose of this study was to identify the factors influencing EDRIC and to further assess the prognostic relevance of EDRIC. We retrospectively analyzed 201 patients with LA-NSCLC who received radiotherapy between 2012 and 2017. EDRIC was calculated based on the model developed by Jin et al. Kaplan–Meier method and Cox proportional hazards regression were used to analyze the correlation of potential factors with OS, local progression-free survival (LPFS), and distant metastasis-free survival (DMFS). Spearman's rank correlation was used to assess the correlation between variables. Both GTV and N stage showed a positive correlation with EDRIC (r = 0.347, P < 0.001 and r = 0.249, P < 0.001, respectively). EDRIC was independently associated with DMFS (HR 1.185, P < 0.001). GTV was associated with OS (HR 1.006, P < 0.001), LPFS (HR 1.003, P = 0.017), and DMFS (HR 1.003, P = 0.032). While using GTV as a stratification factor in Kaplan–Meier analysis, EDRIC showed a trend of negative correlation with OS in GTV ≤ 66.6 cm3 group (P = 0.061). EDRIC was an independent prognostic factor for metastasis and it was affected by GTV and N stage. However, the effect of EDRIC on OS was influenced by GTV. [ABSTRACT FROM AUTHOR]

The present paper investigates a hybrid breakwater-oscillating water column (OWC) system by integrating a heaving floater wave energy converter (WEC). Both the water oscillating of the OWC and the wave-induced relative motion of the floater hinged in front of the OWC device are employed to extract wave energy. A three-dimensional wave tank is numerically modelled by Star-CCM + Computational Fluid Dynamics (CFD) software to investigate the hydrodynamic performance of the hybrid system. The hydrodynamic characteristics of symmetric and asymmetric floaters in terms of wave attenuation and energy extraction performance are examined. Four floaters with different bottom shapes are considered. The results indicate that the asymmetric floaters lead to a higher capture width ratio (CWR) and better wave attenuation performance, such that CWR of the hybrid system integrated with the Berkley Wedge bottom shape can reach up to 81.2%. The effects of the radius ratio, the submerged opening height, and the distance between the oscillating buoy (OB) and OWC device are further analyzed. The findings of this paper reveal that the geometrical parameters of the hybrid system have significant effects on wave energy absorption efficiency and hydrodynamic performance. The results provide advice on the design of wave energy devices. • A hybrid WEC combined with a dual-cylindrical OWC and OB is put forward. • The effects of four different floater shapes are compared. • The effect of the radius ratio of the system is studied. • The submergence of the opening should be considered large enough to prevent air escape through it. [ABSTRACT FROM AUTHOR]

In this paper, a hybrid Oscillating Water Column (OWC)system combining with a heaving floater Wave Energy Converters (WEC) was investigated. The traditional cylindrical-type breakwater consists of dual cylinders with an opening inlet located at the outer wavefront wall, allowing a ring-type wave chamber formed between two cylinders. The oscillating buoy OB is hinged at the front of the OWC device. The WAVE Chamber formed between the two breakwater cylinders is to be used as OWC. Based on the Computational Fluid Dynamics (CFD) software Star CCM+, A three-dimensional numerical wave tank is developed to investigate the hydrodynamic performance of the hybrid system, and the numerical model is validated with published experimental results. The power take-off (PTO) damping performance and the hydrodynamic efficiency affected by water conditions and geometrical dimensions of the device are discussed. Results show that the after combining the floater to the breakwater-type WEC, a great improvement on frequency bandwidth was achieved and the efficiency increase to 83.28% compared to the case of a single device, which was of 57%. Furthermore, the effects of the opening inlet height and the volume ratio of the OWC chamber were studied to optimize the certain geometrical parameters. Lower height ratio of the opening inlet of the OWC chamber should be avoid for larger water depth condition while designing such a hybrid system. • An OWC-type breakwater with a heaving floater is put forward. • The new hybrid system has good improvement on power extraction performance. • The dual-cylindrical OWC can more effectively extract shorter waves and protect coast. • Effect of geometrical properties and PTO damping on hydrodynamic efficiency are shown. • Cost-sharing of integrated system can make WEC device economically competitive. [ABSTRACT FROM AUTHOR]

Purpose: Radiation-induced pneumonitis (RP) is the most common dose-limiting complication in lung cancer patients treated with radiotherapy. Accumulating evidence indicates that P53 and the ataxia telangiectasia-mutated protein (ATM)—dependent signaling response cascade play a crucial role in radiation-induced diseases. Consistent with this, our previous study showed that a functional genetic ATM polymorphism was associated with increased RP risk. Methods and Materials: To evaluate the role of genetic P53 polymorphism in RP, we analyzed the P53 Arg72Pro polymorphism in a cohort including 253 lung cancer patients receiving thoracic irradiation. Results: We found that the P53 72Arg/Arg genotype was associated with increased RP risk compared with the 72Pro/Pro genotype. Furthermore, the P53 Arg72Pro and ATM –111G>A polymorphisms display an additive combination effect in intensifying the risk of developing RP. The cross-validation test showed that 63.2% of RP cases can be identified by P53 and ATM genotypes. Conclusions: These results indicate that genetic polymorphisms in the ATM-P53 pathway influence susceptibility to RP and genotyping P53 and ATM polymorphisms might help to identify patients susceptible to developing RP when receiving radiotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Radiation-induced esophageal toxicity (RIET) is a dose-limiting toxicity in lung cancer patients receiving radiotherapy. Accumulating evidence indicates that DNA repair and the cytokine pathways play essential roles in radiation-induced diseases. Genetic polymorphisms of genes in these pathways may affect gene function and/or gene expression and lead to different treatment-related esophageal toxicity. Materials and methods: This study investigated the association of 21 polymorphisms in 14 genes, with the occurrence of ⩾grade 2 acute RIET. Genotypes were analyzed among 213 stage III lung cancer patients receiving radiotherapy. Results: We used Cox proportional hazard model to examine the effects of genotypes on ⩾grade 2 acute RIET risk and Kaplan–Meier estimator to compare effects of different genotypes on such risk. Multivariate analysis showed that CT or TT genotype of TGF-β1-509C/T polymorphism was associated with a significantly higher RIET risk (adjusted hazard ratio [HR]=2.47; 95% confidence interval (CI)=1.17–5.24; P =0.018, or HR=3.86; 95% CI=1.50–9.92; P =0.005), respectively, compared with the CC genotype. Moreover, Lys/Gln+Gln/Gln genotypes of XPD Lys751Gln polymorphism were also associated with a significantly decreased RIET risk (adjusted HR=0.55; 95% CI=0.32–0.96; P =0.030). Conclusions: This report, for the first time, examined the influence of inherited variation in the DNA repair and the cytokine pathways on RIET. [ABSTRACT FROM AUTHOR]

Purpose: Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity, we hypothesized that variations in this gene might be associated with radiation-induced pneumonitis (RP). Methods and Materials: A total of 253 lung cancer patients receiving thoracic irradiation between 2004 and 2006 were included in this study. Common Terminology Criteria for Adverse Events version 3.0 was used to grade RP. Five haplotype-tagging single nucleotide polymorphisms (SNPs) in the ATM gene were genotyped using DNA from blood lymphocytes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of RP for genotypes were computed by the Cox model, adjusted for clinical factors. The function of the ATM SNP associated with RP was examined by biochemical assays. Results: During the median 22-month follow-up, 44 (17.4%) patients developed grade ≥ 2 RP. In multivariate Cox regression models adjusted for other clinical predictors, we found two ATM variants were independently associated with increased RP risk. They were an 111G > A) polymorphism (HR, 2.49; 95% CI, 1.07–5.80) and an ATM 126713G > A polymorphism (HR, 2.47; 95% CI, 1.16–5.28). Furthermore, genotype-dependent differences in ATM expression were demonstrated both in cell lines (p < 0.001) and in individual lung tissue samples (p = 0.003), which supported the results of the association study. Conclusions: Genetic polymorphisms of ATM are significantly associated with RP risk. These variants might exert their effect through regulation of ATM expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy. [Copyright &y& Elsevier]

Purpose: To determine whether time to treatment (TTT) has an effect on overall survival (OS) in patients with unresectable or medically inoperable Stage III non-small cell lung cancer (NSCLC) and whether patient or treatment factors are associated with TTT.Methods and Materials: Included in the study were 237 consecutive patients with Stage III NSCLC treated at University of Michigan Hospital (UM) or the Veterans Affairs Ann Arbor Healthcare System (VA). Patients were treated with either palliative or definitive radiotherapy and radiotherapy alone (n = 106) or either sequential (n = 69) or concurrent chemoradiation (n = 62). The primary endpoint was OS.Results: Median follow-up was 69 months, and median TTT was 57 days. On univariate analysis, the risk of death did not increase significantly with longer TTT (p = 0.093). However, subset analysis showed that there was a higher risk of death with longer TTT in patients who survived >or= 5 years (p = 0.029). Younger age (p = 0.027), male sex (p = 0.013), lower Karnofsky Performance Score (KPS) (p = 0.002), and treatment at the VA (p = 0.001) were significantly associated with longer TTT. However, on multivariate analysis, only lower KPS remained significantly associated with longer TTT (p = 0.003).Conclusion: Time to treatment is significantly associated with OS in patients with Stage III NSCLC who lived longer than 5 years, although it is not a significant factor in Stage III patients as a whole. Lower KPS is associated with longer TTT. [ABSTRACT FROM AUTHOR]

Background Concurrent chemoradiotherapy is the standard treatment for unresectable stage III non-small lung cancer, with frequently unsatisfactory results. We aimed to evaluate the efficacy and safety of the addition of continuous intravenous infusion of recombinant human endostatin (Endostar) to concurrent chemoradiotherapy. Methods We did this prospective, phase 2 study (HELPER) in patients with inoperable stage III non-small-cell lung cancer (defined by the American Joint Committee on Cancer 7th edn staging system) with an E performance score of 0–2; diagnoses were made on the basis of pathology or cytology results. All enrolled patients received thoracic radiation at doses of 60–66 Gy and continuous intravenous infusions of Endostar (7·5 mg/m 2 per 24h, 120 h continuously, 120 h per cycle; from day −5 to day −1, days 10–13, days 24–28, and days 38–42). Additionally, patients received two cycles of etoposide (50 mg/m 2 ; days 1–5 and days 29–33) plus cisplatin (50 mg/m 2 ; day 1, 8, 29, and 36). The primary endpoint was progression-free survival and the secondary endpoints were objective response, overall survival, local recurrence-free survival, and toxicities. Findings From November, 2012, to June, 2015, 73 patients were enrolled and 67 patients were evaluable. 56 patients were male and 11 patients were female. The median age was 59 years (range 31–69). Most patients (44, 66%) had squamous cell carcinoma. 27 patients (40%) had stage IIIa disease, and 40 (60%) had stage IIIb disease. Severe adverse events were observed in two patients (one had massive haemoptysis and one had pneumonia). The most common adverse event was leucopenia (96%; 45% were grade 3–4). The complete response was 12% and partial response was 64%. The median follow-up time was 37·1 months (range 20·1–52·1). The median overall survival was 34·7 months (21·9–47·4), progression-free survival was 13·3 months (5·5–21·0), and local recurrence-free survival was 27·1 months. Progression-free survival was 51% at 1 year, 35% at 2 years, and 28% at 3 years, overall survival was 82% at 1 year, 60% at 2 years, and 48% at 3 years, and local recurrence-free survival was 73% at 1 year, 55% at 2 years, and 50% at 3 years. Interpretation For patients with unresectable stage III non-small-cell lung cancer, continuous intravenous human recombinant endostatin in combination with concurrent chemoradiotherapy is an effective treatment with tolerable toxicities. A phase 3 study is warranted. Funding None. [ABSTRACT FROM AUTHOR]