Predicting Lung Cancer in Korean Never-Smokers With Polygenic Risk Scores.

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer and these loci have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs); PRSs were calculated using a pruning-thresholding-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31-2.23) using the 40%-60% percentile group as the reference, and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747-0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong's test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.

Deep learning model integrating positron emission tomography and clinical data for prognosis prediction in non-small cell lung cancer patients.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of lung cancers are non-small cell lung cancer (NSCLC), accounting for approximately 85% of all lung cancer types. The Cox proportional hazards model (CPH), which is the standard method for survival analysis, has several limitations. The purpose of our study was to improve survival prediction in patients with NSCLC by incorporating prognostic information from F-18 fluorodeoxyglucose positron emission tomography (FDG PET) images into a traditional survival prediction model using clinical data. RESULTS: The multimodal deep learning model showed the best performance, with a C-index and mean absolute error of 0.756 and 399 days under a five-fold cross-validation, respectively, followed by ResNet3D for PET (0.749 and 405 days) and CPH for clinical data (0.747 and 583 days). CONCLUSION: The proposed deep learning-based integrative model combining the two modalities improved the survival prediction in patients with NSCLC.

Prognostic significance of location index in resected T1-sized early-stage non-small cell lung cancer.

BACKGROUND: While the central location is a known adverse prognostic factor in lung cancer, a precise definition of central lung cancer has not yet emerged. PURPOSE: To determine the prognostic significance of central lung cancer (defined by location index) in resected T1-sized early-stage non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: Patients with resected T1-sized early-stage NSCLC between 2010 and 2015 at a single tertiary cancer center were retrospectively reviewed. Central lung cancer was defined by a location index of the second tertile or less. Kaplan-Meier analysis with log-rank test and multivariable Cox regression analysis were performed to analyze the relationship between central lung cancer and the prognosis of relapse-free survival (RFS) and overall survival (OS). Inter-observer agreement was assessed using Cohen's kappa value and intraclass correlation coefficient (ICC). RESULTS: Overall, 289 patients (169 men; median age 65 years; interquartile range 58-70 years) were evaluated. Central lung cancer (defined by location index) was adversely associated with RFS (P = 0.005) and OS (P = 0.01). Multivariable Cox regression analysis showed that central lung cancer was independently associated with poor RFS (adjusted hazard ratio 1.91; 95% confidence interval [CI] 1.12-3.24; P = 0.017) and OS (adjusted hazard ratio 1.69; 95% CI 1.04-2.74; P = 0.033). Location index demonstrated excellent inter-observer agreement (Cohen's kappa value 0.88; 95% CI 0.82-0.93) with a high ICC (0.98; 95% CI 0.97-0.98). CONCLUSION: Central lung cancer defined by a location index of the second tertile or lower is an independent adverse prognostic factor in resected T1-sized early-stage NSCLC.

A method for early diagnosis of lung cancer from tumor originated DNA fragments using plasma cfDNA methylome and fragmentome profiles.

Early detection is critical for minimizing mortality from cancer. Plasma cell-free DNA (cfDNA) contains the signatures of tumor DNA, allowing us to quantify the signature and diagnose early-stage tumors. Here, we report a novel tumor fragment quantification method, TOF (Tumor Originated Fragment) for the diagnosis of lung cancer by quantifying and analyzing both the plasma cfDNA methylation patterns and fragmentomic signatures. TOF utilizes the amount of ctDNA predicted from the methylation density information of each cfDNA read mapped on 6243 lung-tumor-specific CpG markers. The 6243 tumor-specific markers were derived from lung tumor tissues by comparing them with corresponding normal tissues and healthy blood from public methylation data. TOF also utilizes two cfDNA fragmentomic signatures: 1) the short fragment ratio, and 2) the 5' end-motif profile. We used 298 plasma samples to analyze cfDNA signatures using enzymatic methyl-sequencing data from 201 lung cancer patients and 97 healthy controls. The TOF score showed 0.98 of the area under the curve in correctly classifying lung cancer from normal samples. The TOF score resolution was high enough to clearly differentiate even the early-stage non-small cell lung cancer patients from the healthy controls. The same was true for small cell lung cancer patients.

Survival time prediction by integrating cox proportional hazards network and distribution function network.

BACKGROUND: The Cox proportional hazards model is commonly used to predict hazard ratio, which is the risk or probability of occurrence of an event of interest. However, the Cox proportional hazard model cannot directly generate an individual survival time. To do this, the survival analysis in the Cox model converts the hazard ratio to survival times through distributions such as the exponential, Weibull, Gompertz or log-normal distributions. In other words, to generate the survival time, the Cox model has to select a specific distribution over time. RESULTS: This study presents a method to predict the survival time by integrating hazard network and a distribution function network. The Cox proportional hazards network is adapted in DeepSurv for the prediction of the hazard ratio and a distribution function network applied to generate the survival time. To evaluate the performance of the proposed method, a new evaluation metric that calculates the intersection over union between the predicted curve and ground truth was proposed. To further understand significant prognostic factors, we use the 1D gradient-weighted class activation mapping method to highlight the network activations as a heat map visualization over an input data. The performance of the proposed method was experimentally verified and the results compared to other existing methods. CONCLUSIONS: Our results confirmed that the combination of the two networks, Cox proportional hazards network and distribution function network, can effectively generate accurate survival time.

Esophagus Segmentation in CT Images via Spatial Attention Network and STAPLE Algorithm.

One essential step in radiotherapy treatment planning is the organ at risk of segmentation in Computed Tomography (CT). Many recent studies have focused on several organs such as the lung, heart, esophagus, trachea, liver, aorta, kidney, and prostate. However, among the above organs, the esophagus is one of the most difficult organs to segment because of its small size, ambiguous boundary, and very low contrast in CT images. To address these challenges, we propose a fully automated framework for the esophagus segmentation from CT images. The proposed method is based on the processing of slice images from the original three-dimensional (3D) image so that our method does not require large computational resources. We employ the spatial attention mechanism with the atrous spatial pyramid pooling module to locate the esophagus effectively, which enhances the segmentation performance. To optimize our model, we use group normalization because the computation is independent of batch sizes, and its performance is stable. We also used the simultaneous truth and performance level estimation (STAPLE) algorithm to reach robust results for segmentation. Firstly, our model was trained by k-fold cross-validation. And then, the candidate labels generated by each fold were combined by using the STAPLE algorithm. And as a result, Dice and Hausdorff Distance scores have an improvement when applying this algorithm to our segmentation results. Our method was evaluated on SegTHOR and StructSeg 2019 datasets, and the experiment shows that our method outperforms the state-of-the-art methods in esophagus segmentation. Our approach shows a promising result in esophagus segmentation, which is still challenging in medical analyses.

Suppression of Mig-6 overcomes the acquired EGFR-TKI resistance of lung adenocarcinoma.

BACKGROUND: The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. METHODS: We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. RESULTS: Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. CONCLUSION: Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.

Delayed diagnosis of lung cancer due to misdiagnosis as worsening of sarcoidosis: a case report.

BACKGROUND: The concurrence of sarcoidosis and primary lung cancer is very rare. We report a very rare case with a delayed diagnosis of primary lung cancer due to its misdiagnosis as worsening of pulmonary sarcoidosis. CASE PRESENTATION: A 68-year-old man presented to the outpatient department for evaluation of a mass in the right hilar area with lymphadenopathies in subcarinal and both interlobar areas on chest computed tomography (CT). Sufficient core samples were obtained from subcarinal and bilateral interlobar lymph nodes using endobronchial ultrasonography (EBUS) guided transbronchial needle aspiration (TBNA). EBUS could not reach the right hilar lymph node due to its high angle. The pathologic findings were consistent with sarcoidosis. After 5 months, chest CT revealed aggravation of the right upper paratracheal lymphadenopathy. Assuming worsening of sarcoidosis, he was prescribed an oral corticosteroid for 5 months. However, follow-up chest CT showed a newly developed right lower paratracheal lymphadenopathy and worsening right hilar lymphadenopathy. Bronchoscopy and EBUS were performed once again. Transbronchial lung biopsy from the right upper lobe and EBUS-TBNA from the right lower paratracheal lymph node revealed adenocarcinoma from the lung. CONCLUSIONS: Although coexistence of sarcoidosis and lung cancer is very rare, the clinician should consider the possibility of accompanying lung cancer in sarcoidosis patients who are not responding to initial corticosteroid therapy.

Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery.

BACKGROUND: We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC. METHODS: Sixty-four single nucleotide polymorphisms (SNPs) in the Notch pathway genes were evaluated in the discovery study (n = 354) and two sequential validation studies (n = 772 and n = 746, respectively). The association of genotype with overall survival (OS) and disease-free survival (DFS) was evaluated. RESULTS: Of the 64 SNPs analyzed in the discovery study, 9 were significantly associated with OS or DFS. Among them, the association remained significant only for Deltex-1 (DTX1) rs1732786A>G in the first validation study. The second validation study confirmed again the association between DTX1 rs1732786A>G and survival outcomes. In the combined analysis, rs1732786A>G was significantly associated with better OS and DFS (adjusted HR ·aHR· for OS, 0.75; 95% CI 0.64-0.87; P = 0.0002; aHR for DFS, 0.79; 95% CI 0.71-0.89; P = 0.0001). In vitro luciferase assay showed that the rs1732786G allele was associated with higher promoter activity compared to rs1732786A allele. Consistently, relative mRNA expression level of DTX1 showed significant positive correlation with rs1732786 A-to-G change (Ptrend = 0.02) in tumor tissues. CONCLUSIONS: These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.

Altered Hypothalamus-Pituitary-Adrenal Axis Function: A Potential Underlying Biological Pathway for Multiple Concurrent Symptoms in Patients With Advanced Lung Cancer.

OBJECTIVE: Patients with advanced cancer commonly experience multiple symptoms that present as groups or clusters. The present study aimed to examine whether hypothalamus-pituitary-adrenal (HPA) axis dysfunction underlies the concurrent multiple symptoms in patients with advanced cancer. METHODS: Patients' cortisol levels were determined in saliva samples collected after awakening (0, 30, and 60 minutes after awakening) and at nighttime (21:00-22:00 PM) from 46 patients with lung cancer (15.2% women), with a mean (standard deviation) age of 64.3 (9.2) years and 47 healthy participants (53.2% women; age = 62.0 [4.6] years). Cancer-related symptoms were measured using the M.D. Anderson Symptom Inventory (MDASI). RESULTS: Compared with healthy participants, patients showed a significantly reduced cortisol awakening response (F(1,364) = 46.2, p < .001) and had flatter diurnal slope of cortisol (larger ß values) (mean [standard error of the mean] = -0.64 [0.06] versus -0.18 [0.05], p < .001). Altered HPA axis function was significantly and adversely associated with performance status and burden of symptoms (all p values < .01). However, each MDASI item varied widely in the degree of association with the HPA axis function. Hierarchical clustering analysis based on Spearman's rank correlation with complete linkage identified that nausea was clustered with vomiting, numbness, and dry mouth, whereas the other nine MDASI core symptoms associated with altered HPA axis function were clustered together. CONCLUSIONS: Altered HPA axis function may be a possible biological pathway that can explain the concurrence of core symptoms in patients with advanced lung cancer.

Caveolin-1 enhances brain metastasis of non-small cell lung cancer, potentially in association with the epithelial-mesenchymal transition marker SNAIL.

BACKGROUND: Caveolin-1 (Cav-1) plays an important role in the development of various human cancers. We investigated the relationship between Cav-1 expression and non-small cell lung cancer (NSCLC) progression in the context of brain metastasis (BM). METHODS: Cav-1 expression was investigated in a series of 102 BM samples and 49 paired primary NSCLC samples, as well as 162 unpaired primary NSCLC samples with (63 cases) or without (99 cases) metastasis to distant organs. Human lung cancer cell lines were used for in vitro functional analysis. RESULTS: High Cav-1 expression in tumor cells was observed in 52% (38/73) of squamous cell carcinomas (SQCs) and 33% (45/138) of non-SQCs. In SQC, high Cav-1 expression was increased after BM in both paired and unpaired samples of lung primary tumors and BM (53% vs. 84% in paired samples, P = 0.034; 52% vs. 78% in unpaired samples, P = 0.020). Although the difference in median overall survival in patients NSCLC was not statistically significant, high Cav-1 expression in tumor cells (P = 0.005, hazard ratio 1.715, 95% confidence index 1.175-2.502) was independent prognostic factors of overall survival on multivariate Cox regression analyses, in addition to the presence of BM and non-SQC type. In vitro assays revealed that Cav-1 knockdown inhibited the invasion and migration of lung cancer cells. Genetic modulation of Cav-1 was consistently associated with SNAIL up- and down-regulation. These findings were supported by increased SNAIL and Cav-1 expression in BM samples of SQC. CONCLUSIONS: Cav-1 plays an important role in the BM of NSCLC, especially in SQC. The mechanism may be linked to SNAIL regulation.

A Prospective Observational Study Evaluating the Correlation of c-MET Expression and EGFR Gene Mutation with Response to Erlotinib as Second-Line Treatment for Patients with Advanced/Metastatic Non-Small-Cell Lung Cancer.

OBJECTIVES: We aimed to evaluate the prevalence and predictive role of c-MET expression and EGFR mutation in the efficacy of erlotinib in non-small-cell lung cancer (NSCLC). METHODS: We prospectively recruited 196 patients with stage IV or recurrent NSCLC treated with erlotinib after failure of first-line chemotherapy. Immunohistochemistry was used to evaluate c-MET overexpression, silver in situ hybridization (SISH) to assess gene copy number, and real-time polymerase chain reaction to detect EGFR mutations, respectively, in tumor tissue. RESULTS: The major histologic type was adenocarcinoma (66.8%). c-MET was overexpressed in 55.8% (87/156) and dominant in females as well as non-squamous histology. Although c-MET gene amplification and high polysomy were observed in 2.0% (3/152) and 11.2% (17/152), they did not correlate with any characteristics. EGFR mutation was detected in 13.1% (20/153). The objective response rate of erlotinib was higher (61.1 vs. 3.7%, p < 0.001) and the median progression-free survival (PFS) was longer (10.2 vs. 1.9 months, p < 0.001) in EGFR-sensitizing mutations. However, c-MET positivity did not show a significant correlation with response to erlotinib or PFS. CONCLUSION: We reconfirmed EGFR mutation as a strong predictive marker of NSCLC. However, c-MET positivity was not associated with response or PFS, although c-MET overexpression correlated with some clinical characteristics.

Correlation of biologically effective dose and the tumor control in Stage I (<5 cm) non-small cell lung cancer with stereotactic ablative radiotherapy: a single institutional cohort study.

BACKGROUNDS: Stereotactic ablative radiotherapy (SABR) is one of the newly developed innovative radiotherapy and of which optimal dose prescription needs to be standardized. We aimed to investigate the dose-response relationship for patients with SABR. METHODS: Fifty-three patients with Stage I non-small cell lung cancer patients, who underwent SABR between November 2006 and January 2015, were evaluated retrospectively. Thirteen patients (24.5%), who refused the surgery were included and 40 patients (75.5%) were medically inoperable at diagnosis. The median age was 74 years. The median SABR dose was 50 Gy in 3-8 fractions and the median biologically effective dose (BED;α/ß = 10) was 105.6 Gy (range: 60-160.53 Gy). RESULTS: The median follow-up was 37.1 months. The 1 and 3 year local control rates were 91.7% and 85.1%. The 3 year overall and progression-free survival rate were 63.3% and 47.5%, respectively, and freedom from progression was 62.2%. Local control rate and 3-year overall survival according to tumor size was 100% and 79.4% in T1 tumors in a while 61.8% and 45% in T2a tumors. The 3-year local and regional control by BED10 was 79.4% and 69.4% in ≤100 Gy vs. 89.1% and 100% in >100 Gy (P = 0.526, 0.004). Dyspnea more than Grade 3 was reported in six (11.3%) patients and Grade 1 chest pain was shown in five (9.4%) patients. CONCLUSIONS: The excellent regional control was conferred with a prescription of more than BED10 of 100 Gy, which also might be needed to achieve better local tumor control in T2a patients with tolerable lung function.

Clinical Validation of a Protein Biomarker Panel for Non-Small Cell Lung Cancer.

We validated the diagnostic performance of a previously developed blood-based 7-protein biomarker panel, AptoDetect™-Lung (Aptamer Sciences Inc., Pohang, Korea) using modified aptamer-based proteomic technology for lung cancer detection. Non-small cell lung cancer (NSCLC), 200 patients and benign nodule controls, 200 participants were enrolled. In a high-risk population corresponding to ≥ 55 years of age and ≥ 30 pack-years, the diagnostic performance was improved, showing 73.3% sensitivity and 90.5% specificity with an area under the curve of 0.88. AptoDetect™-Lung (Aptamer Sciences Inc.) offers the best validated performance to discriminate NSCLC from benign nodule controls in a high-risk population and could play a complementary role in lung cancer screening.

Efficacy of Afatinib in a Previously-Treated Patient with Non-Small Cell Lung Cancer Harboring HER2 Mutation: Case Report.

Human epidermal growth factor receptor 2 (HER2) mutation in non-small cell lung cancer (NSCLC) is an oncogenic driver that possibly becomes a druggable target to HER2-targeted therapy. The benefit of HER2-targeted therapy is much less defined especially in eastern populations. We provide evidence of clinical benefit of afatinib in a 50-year-old Asian woman with HER2-mutant NSCLC who previously failed cytotoxic chemotherapy and gefitinib treatment. Next-generation sequencing of the tumor tissue revealed a HER2 exon 20 mutation (c.2437A>G), which has never been reported. The patient was treated with afatinib for more than four months. She showed rapid radiologic response within a month, and maintained stable state until the last dose of afatinib.

Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance.

The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cell's dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.

Belotecan/cisplatin versus etoposide/cisplatin in previously untreated patients with extensive-stage small cell lung carcinoma: a multi-center randomized phase III trial.

BACKGROUND: No novel chemotherapeutic combinations have demonstrated superior efficacy to etoposide/cisplatin (EP), a standard treatment regimen for extensive-stage small cell lung carcinoma (ES-SCLC) over the past decade. We aimed to compare the efficacy and safety of belotecan/cisplatin (BP) and EP regimens in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. METHODS: We conducted a multi-center, randomized, open-label, parallel-group, phase III clinical study. A total of 157 patients were recruited at 14 centers with 147 patients meeting the inclusion/exclusion criteria and randomized to either BP (n = 71) or EP (n = 76) treatment arms. A non-inferior response rate (RR) in the BP arm, analyzed by intent-to-treat analysis according to Response Evaluation Criteria in Solid Tumors version 1.0 criteria, was used as the primary endpoint. The secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: In the BP arm, one patient had a complete response, 41 had a partial response (PR), and 17 had stable disease (SD). In the EP arm, 35 patients had PR and 28 had SD. The RR in the BP arm was non-inferior to the EP regimen in patients with ES-SCLC (BP: 59.2 %, EP: 46.1 %, difference: 13.1 %, 90 % two-sided confidence interval: -0.3-26.5, meeting the predefined non-inferiority criterion of -15.0 %). No significant differences in OS or PFS were observed between the treatment arms. Hematologic toxicities, including grade 3/4 anemia and thrombocytopenia, were significantly more prevalent in the BP arm than the EP arm. CONCLUSIONS: The RR to the BP regimen was non-inferior to the EP regimen in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. Hematologic toxicities were significantly more prevalent in the BP group, indicating that BP should be used with care, particularly in patients with a poor performance status. Further studies assessing PFS and OS are required to validate the superiority of the BP regimen. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00826644 . Date of Registration: January 21, 2009.

Predictive factors for survival and correlation to toxicity in advanced Stage III non-small cell lung cancer patients with concurrent chemoradiation.

OBJECTIVE: Concurrent chemoradiotherapy is the standard treatment for locally advanced Stage III non-small cell lung cancer in patients with a good performance status and minimal weight loss. This study aimed to define subgroups with different survival outcomes and identify correlations with the radiation-related toxicities. METHODS: We retrospectively reviewed 381 locally advanced Stage III non-small cell lung cancer patients with a good performance status or weight loss of <10% who received concurrent chemoradiotherapy between 2004 and 2011. Three-dimensional conformal radiotherapy was administered once daily, combined with weekly chemotherapy. The Kaplan-Meier method was used for survival comparison and Cox regression for multivariate analysis. Multivariate analysis was performed using all variables with P values <0.1 from the univariate analysis. RESULTS: Median survival of all patients was 24 months. Age > 75 years, the diffusion lung capacity for carbon monoxide ≤80%, gross tumor volume ≥100 cm(3) and subcarinal nodal involvement were the statistically significant predictive factors for poor overall survival both in univariate and multivariate analyses. Patients were classified into four groups according to these four predictive factors. The median survival times were 36, 29, 18 and 14 months in Groups I, II, III and IV, respectively (P < 0.001). Rates of esophageal or lung toxicity ≥Grade 3 were 5.9, 14.1, 12.5 and 22.2%, respectively. The radiotherapy interruption rate differed significantly between the prognostic subgroups; 8.8, 15.4, 22.7 and 30.6%, respectively (P = 0.017). CONCLUSION: Severe toxicity and interruption of radiotherapy were more frequent in patients with multiple adverse predictive factors. To maintain the survival benefit in patients with concurrent chemoradiotherapy, strategies to reduce treatment-related toxicities need to be deeply considered.

Once-Daily OROS Hydromorphone for Management of Cancer Pain: an Open-Label, Multi-Center, Non-Interventional Study.

Extended-release osmotic extended-release oral delivery system (OROS) hydromorphone is a strong synthetic opioid designed to maintain a constant blood concentration by once daily dosing. The objective of this observational study was to investigate the clinical usefulness of OROS hydromorphone in patients with cancer pain of moderate to severe intensity. Patients with cancer pain who required strong opioids were administered with OROS hydromorphone for 4 weeks. We assessed changes in pain intensity using a numerical rating scale (NRS) as well as levels of sleep disturbance, breakthrough pain, end-of-dose failure, patient satisfaction, and overall assessment of drug effectiveness based on investigator evaluation. Of the 648 enrolled patients, 553 patients were included in the full analysis set. The mean pain intensity was significantly decreased from the NRS value of 5.07 ± 1.99 to 2.75 ± 1.94 (mean % change of 42.13 ± 46.53, P < 0.001). The degree of sleep disturbance significantly improved (mean NRS change of 1.61 ± 2.57, P < 0.001), and the incidence of breakthrough pain was significantly decreased (mean NRS change of 1.22 ± 2.30, P < 0.001). The experience of end-of-dose failure also significantly decreased from 4.60 ± 1.75 to 3.93 ± 1.70, P = 0.007). The patient satisfaction rate was 72.7%, and 72.9% of investigators evaluated the study drug as effective. OROS hydromorphone was an effective and tolerable agent for cancer pain management. It effectively lowered pain intensity as well as improved sleep disturbance, breakthrough pain, and end-of-dose failure.