Diagnostic and prognostic biomarkers for progressive fibrosing interstitial lung disease.

No biomarkers have been identified in bronchoalveolar lavage fluid (BALF) for predicting fibrosis progression or prognosis in progressive fibrosing interstitial lung disease (PF-ILD). We investigated BALF biomarkers for PF-ILD diagnosis and prognosis assessment. Overall, 120 patients with interstitial pneumonia who could be diagnosed with PF-ILD or non PF-ILD were enrolled in this retrospective study. PF-ILD was diagnosed according to Cottin's definition. All patients underwent bronchoscopy and BALF collection. We evaluated blood and BALF parameters, high-resolution computed tomography (HRCT) patterns, and spirometry data to identify factors influencing PF-ILD diagnosis and prognosis. On univariate logistic analysis, age, sex, the BALF white blood cell fraction (neutrophil, lymphocyte, eosinophil, and neutrophil-to-lymphocyte ratio), BALF flow cytometric analysis (CD8), and an idiopathic pulmonary fibrosis/usual interstitial pneumonia pattern on HRCT were correlated with PF-ILD diagnosis. Multivariate logistic regression analysis revealed that sex (male), age (cut-off 62 years, area under the curve [AUC] 0.67; sensitivity 0.80; specificity 0.47), white blood cell fraction in BALF (NLR, neutrophil, and lymphocyte), and CD8 in BALF (cut-off 34.2; AUC 0.66; sensitivity, 0.74; specificity, 0.62) were independent diagnostic predictors for PF-ILD. In BALF, the NLR (cut-off 8.70, AUC 0.62; sensitivity 0.62; specificity 0.70), neutrophil count (cut-off 3.0, AUC 0.59; sensitivity 0.57; specificity 0.63), and lymphocyte count (cut-off 42.0, AUC 0.63; sensitivity 0.77; specificity 0.53) were independent diagnostic predictors. In PF-ILD patients (n = 77), lactate dehydrogenase (cut-off 275, AUC 0.69; sensitivity 0.57; specificity 0.78), Krebs von den Lungen-6 (cut-off 1,140, AUC 0.74; sensitivity 0.71; specificity 0.76), baseline forced vital capacity (FVC) (cut-off 1.75 L, AUC 0.71; sensitivity, 0.93; specificity, 0.46), and BALF neutrophil ratio (cut-off 6.0, AUC 0.72; sensitivity 0.79; specificity 0.80) correlated with death within 3 years. The BALF cellular ratio, particularly the neutrophil ratio, correlated with the diagnosis and prognosis of PF-ILD. These findings may be useful in the management of patients with interstitial pneumonia.

Hospital Management and Public Health Role of National Hospitals after Transformation into Independent Administrative Agencies.

The development of medical care, technological advances, and the ageing of society have led to rising medical costs. As a result, there is a demand to improve the efficiency of healthcare delivery systems, including public healthcare institutions, in order to ensure the sustainability of healthcare functions. In 2004, as part of national civil service reform in Japan, national hospitals were merged in order to form the National Hospital Organization (NHO). The NHO used new public management methods and was required to be self-financing and to maintain critical functions under a five-year management plan. The objective of this study was to examine whether the NHO was able to maintain its key function in the national infrastructure in terms of management. An analysis of the business conditions of the NHO was performed based on the financial statements from FY 2004 to FY 2018 using evaluation indexes. In the first and second periods, the NHO achieved its targeted management improvements. However, since FY 2014, even with the utmost restrictions on capital investment, the profits have not increased, and the free cash flow has been negative. Our results suggest that further organizational reforms are needed in order to sustain the NHO infrastructure in the long term and to withstand health crisis management during periods such as the COVID-19 pandemic.

Management evaluation about introduction of electric medical record in the national hospital organization.

Introduction of Electronic Medical Record (EMR) into a hospital was started from 1999 in Japan. Then, most of all EMR company said that EMR improved efficacy of the management of the hospital. National Hospital Organization (NHO) has been promoting the project and introduced EMR since 2004. NHO has 143 hospitals, 51 hospitals offer acute-phase medical care services, the other 92 hospitals offer medical services mainly for chronic patients. We conducted three kinds of investigations, questionnaire survey, checking the homepage information of the hospitals and analyzing the financial statements of each NHO hospital. In this financial analysis, we applied new indicators which have been developed based on personnel costs. In 2011, there are 44 hospitals which have introduced EMR. In our result, the hospital with EMR performed more investment of equipment/capital than personnel expenses. So, there is no advantage of EMR on the financial efficacy.

Significance of pretreatment comorbidities in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitor.

A standard, valid assay of comorbidities for elderly patients with advanced non-small-cell lung cancer (NSCLC) who have received antitumor therapy is needed to provide useful prognostic information. The aim of this study was to analyze prognostic factors and validate classic Charlson comorbidity index (CCI) and comorbidity scores in elderly patients with advanced NSCLC treated with chemotherapy or epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). A retrospective analysis was conducted on 162 patients with advanced NSCLC over 70 years old at diagnosis, who were treated with cytotoxic chemotherapy or with EGFR-TKIs between April 2003 and April 2009 at Kyoto University Hospital. Collected data included clinical assessments, treatments, toxicities, and outcomes. Survival was estimated using the Kaplan-Meier method. Prognostic factors were evaluated with log-rank and Cox regression tests. Based on multivariate analysis, unspecified NSCLC histology [Hazard ratio (HR), 1.631; 95% Confidence interval (CI), 1.184-2.263; P = 0.0016], more than 3 comorbidities (HR, 1.317; 95% CI, 1.020-2.675; P = 0.0350), and a CCI of more than 3 (HR, 1.321; 95% CI, 1.031-1.664; P = 0.0285) were significant independent negative prognostic factors for survival. Our results indicate that CCI and the number of comorbidities are independent predictors of survival in elderly patients undergoing systemic chemotherapy including EGFR-TKIs for advanced NSCLC. These factors should be taken into consideration in the pretreatment assessment as important factors predicting survival outcome.

Clinical significance of epidermal growth factor receptor mutations and insulin-like growth factor 1 and its binding protein 3 in advanced non-squamous non-small cell lung cancer.

This study of patients with advanced non-squamous non-small cell lung cancer (NSCLC) evaluated epidermal growth factor receptor (EGFR) mutation status and two serum markers, serum insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3), for their associations to response to gefitinib therapy and for their prognostic impact. An immunoradiometric assay determined levels of IGF1 and IGFBP3 in serum from 68 patients with advanced non-squamous NSCLC. The peptic nucleic acid locked nucleic acid clamp method determined their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis. Having IGF1-positive serum as determined by the 75th percentile and having wild-type EGFR were both independent negative predictive factors for geftinib treatment by multivariate logistic regression model analysis. Both having serum positive for IGF1 as determined by the 25th percentile and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. We demonstrated that having IGF1-positive serum predicts a negative response to gefitinib therapy independent of EGFR mutational status. We also demonstrated that both IGF1-positive serum and wild-type EGFR were independent poor prognostic factors in patients with non-squamous NSCLC who received gefitinib therapy.

Plasma and pleural fluid pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small-cell lung cancer with pleural effusion.

BACKGROUND: Erlotinib is orally active and selectively inhibits the tyrosine kinase activity of the epidermal growth factor receptor. The pleural space penetration and exposure of erlotinib is poorly understood. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in non-small-cell lung cancer (NSCLC) of malignant pleural effusion (MPE). PATIENTS AND METHODS: We analyzed the PK of erlotinib and OSI-420 on days 1 and 8 after beginning erlotinib therapy in 9 patients with MPE. Their concentrations were determined by high-performance liquid chromatography with ultraviolet detection. Blood samples were obtained five times per day: before administration, and 2, 4, 8, and 24 hours after administration. Pleural effusions were obtained once per day, 2 hours after administration on day 1, and before administration on day 8. The exceptions were cases 2 and 4, which had pleural effusions obtained just before drug administration, and 2, 4, 8, and 24 hours after administration. RESULTS: The mean percentage of penetration from plasma to pleural effusion for erlotinib was 18% on day 1 and 112% on day 8, while these values for OSI-420 were 9.5% on day 1 and 131% on day 8. The area under the drug concentration-time curve of pleural fluid for erlotinib was 28,406 ng-hr/mL for case 2 and 45,906 ng-hr/mL for case 4. CONCLUSIONS: There seems to be a significant accumulation of both erlotinib and OSI-420 in MPE with repeated dosing. Although larger studies will be necessary to determine the true impact of erlotinib MPE accumulation on plasma PK and safety, erlotinib can be administered safely to patients with MPE with respect to efficacy and side effects.

Clinical significance of the ratio between the alpha 2 plasmin inhibitor-plasmin complex and the thrombin-antithrombin complex in advanced non-small cell lung cancer.

The aims of this study are to: (a) confirm the prognostic significance of the procoagulant molecules D dimer, thrombin-antithrombin complex (TAT), and plasmin-α2-plasmin inhibitor complex (PIC); (b) to evaluate hemostatic activation in patients with advanced non-small cell lung cancer (NSCLC); and (c) to delineate the relationships between markers of hemostasis and other clinical characteristics. In this study, a low PIC/TAT ratio and poor PS were significant independent negative prognostic factors for survival in patients with advanced NSCLC. The PIC/TAT ratio may become a surrogate marker for treatment with anticoagulants in the future.

Phase I study of the combination of nedaplatin and gemcitabine in previously untreated advanced squamous cell lung cancer.

PURPOSE: The objectives of this phase I trial were to evaluate the toxicity of the nedaplatin/gemcitabine regimen, determine the maximum tolerated doses (MTDs) of these agents, and observe the anti-tumor effects of this regimen on advanced squamous cell lung cancer. METHODS: Patients with previously untreated advanced squamous cell lung cancer were eligible if they had a performance status of 0 or 1 with adequate organ function. The doses of gemcitabine (days 1 and 8) and nedaplatin (day 8) studied were 800/70, 1,000/80, 1,000/90, and 1,000/100 (mg/m(2)), repeated every 3 weeks. RESULTS: Toxicity and response could be assessed in all 13 patients enrolled. The patients included 12 men and one woman with a median age of 69 years (range 57-81 years). Three patients had stage IIIB disease and 10 patients had stage IV disease. The MTDs were reached at 1,000 mg/m(2) gemcitabine and 80 mg/m(2) nedaplatin. The most frequent toxic effects were thrombocytopenia and neutropenia; grade 3 or 4 thrombocytopenia was observed in 23% of patients, and grade 3 or 4 neutropenia was seen in 46% of patients. Non-hematologic toxicities were mild. Grade 3 fatigue, nausea/vomiting, and appetite loss occurred in two patients. The overall response rate was 62%. CONCLUSIONS: We recommend doses of 800 mg/m(2) gemcitabine and 70 mg/m(2) nedaplatin for phase II study. This combination chemotherapeutic regimen is active and well tolerated.

Association between brain natriuretic peptide and distant metastases in advanced non-small cell lung cancer patients.

This study aimed to investigate the relationship between clinicopathological factors and plasma brain natriuretic peptide (BNP) levels in non-small cell lung cancer (NSCLC) patients. A total of 133 patients with advanced NSCLC were included in this study. The level of BNP was determined at the time of diagnosis. The BNP plasma concentration was measured using a chemiluminescent enzyme immunoassay kit. The univariate relationship between each independent clinicopathological variable and plasma BNP was examined using the Chi-square test. The survival curves were determined using the Kaplan-Meier method. According to the cut-off value of plasma BNP levels (11.5 and 22.4 pg/ml), plasma BNP negatively correlated with the presence of metastases (Chi-square test, p=0.0374 and p=0.0098, respectively). However, no significant association between patient survival time and plasma BNP levels was found. Reduced plasma BNP levels in advanced NSCLC patients with metastases were noted and the possibility was raised that BNP decreases distant metastases of advanced NSCLC patients.

Octreotide, a somatostatin analogue, in the treatment of chylothorax associated with idiopathic fibrosing mediastinitis.

Fibrosing mediastinitis (FM) is a rare benign disorder that is characterized by excessive fibrotic reactions in the mediastinum. FM is associated with various diseases, including Histoplasma capsulatum infection and IgG4-related disease, and may compromise the airways, great vessels, and other mediastinal structures. Chylothorax is not a common manifestation of FM, and there is no standard treatment for FM or chylothorax. Recently, however, somatostatin and octreotide, a somatostatin analogue, were successfully used for the treatment of chylothorax due to various causes, and they are considered as putative therapeutic interventions for chylothorax. Here, we present a 28-year-old Japanese man with chylothorax due to idiopathic FM, who was successfully treated with octreotide. The patient visited our hospital because of dyspnea on exertion. On admission, chest computed tomography revealed pericardial effusion, bilateral pleural effusion, and a mass in the mediastinum. The right pleural effusion appeared chylous, with the triglyceride level of 253 mg/dl. The biopsy specimen from the mediastinal mass showed collagenous fibers and fibroblasts with moderate infiltration of lymphocytes. Neither fungi nor bacteria were cultured from the biopsy specimen. Steroid therapy was not effective. The patient was then treated with subcutaneous octreotide (100 microg three times daily). Five days after starting the treatment, the drained pleural fluid was decreased to approximately 150 ml/day from approximately 1,000 ml/day. The mediastinal mass decreased in size 2 weeks after the initiation of octreotide treatment. After discharge, the patient has received octreotide treatment for 6 months without serious adverse events. We suggest octreotide as a treatment option for FM.

Outcome of Surgical Treatment for Metastatic Vertebra Bone Tumor in Advanced Lung Cancer.

BACKGROUND: Spinal metastases of patients with advanced stage lung cancer are an important target for palliative therapy, because their incidence is high, and they often cause severe symptoms and worsen the quality of life. Surgery is one of the most effective treatment options, but the indication of surgery is unclear as the procedure is invasive and patients with spinal metastasis have a rather short life expectancy. Furthermore, there have been few studies that have focused on lung cancer with poor prognosis. METHODS: We reviewed all of the cases of lung cancer from January 1999 to July 2007 in the Department of Respiratory Medicine, Kyoto University Hospital, Japan. Thirteen patients with metastatic spinal tumor of lung cancer underwent surgery, and all of them had a poor performance status score (3 or 4). RESULTS: Neurological improvement by at least 1 Frankel grade was seen in 10 of 14 cases (71%). Improvement of the movement capacity was noted in 9 of 14 cases (64%), and pain improvement was noted in 12 of 14 (86%). Median postoperative survival was 5 months (1-25 months). In particular, the group with a good postoperative performance status score (0-2) was shown to have a better median postoperative survival of 13 months. CONCLUSIONS: Surgical treatment for symptomatic metastatic spinal tumor of lung cancer can improve quality of life in a substantially high percentage of patients. Surgery should be considered even if preoperative performance status is poor.

Good Clinical Response to Erlotinib in a Non-Small Cell Lung Cancer Patient Harboring Multiple Brain Metastases and a Double Active Somatic Epidermal Growth Factor Gene Mutation.

Recently, 2 small molecule kinase inhibitors (TKIs), targeting epidermal growth factor receptor (EGFR), have proven effective in the treatment of non-small cell lung cancer. However, it is unknown whether the EGFR double activating mutation of L858R in exon 21 and the in-frame deletion in exon 19 is a predictor of the effectiveness of EGFR-TKIs. We report for the first time a case of non-small cell lung cancer with central nervous system metastases harboring a rare EGFR double activating mutation who showed a good clinical response to erlotinib, regardless of his poor performance status, as swallowing is not possible. Therefore, we suggest that erlotinib may become a therapeutic choice in cases of central nervous system metastases even with poor performance status.

Good clinical response to gefitinib in a non-small cell lung cancer patient harboring a rare somatic epidermal growth factor gene point mutation; codon 768 AGC > ATC in exon 20 (S768I).

Recently, two small-molecule kinase inhibitors targeting epidermal growth factor receptor have proven effective in the treatment of non-small cell lung cancer. There are specific activating mutations within the tyrosine kinase domain of epidermal growth factor receptor related to the sensitivity of tyrosine kinase inhibitors. However, it is unknown whether rare mutations in the N-lobe (exons 18-20) and the C-lobe (exon 21) of the epidermal growth factor receptor kinase domain other than L858R in exon 21 and the in-frame deletion in exon 19 may predict the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors. We reported a case of non-small cell lung cancer harboring a rare epidermal growth factor somatic mutation, codon 768 AGC > ATC in exon 20 (S768I), who showed a good clinical response to gefitinib. Therefore, we may suggest that this rare mutation (S768I in exon 20) may not be an insensitive epidermal growth factor receptor somatic mutation in vivo.

Cerebrospinal fluid concentration of erlotinib and its active metabolite OSI-420 in patients with central nervous system metastases of non-small cell lung cancer.

BACKGROUND: Although there have been several reports in which central nervous system (CNS) metastases of non-small cell lung cancer (NSCLC) were improved by erlotinib, cerebrospinal fluid (CSF) penetration of erlotinib in such patients has not been reported. We investigated CSF concentrations of erlotinib and its active metabolite OSI-420. METHOD: We administered 150 mg erlotinib daily to four patients with NSCLC who had CNS metastases, and we investigated plasma pharmacokinetics of erlotinib and OSI-420 on days 1 and 8. In addition, we measured the concentrations of erlotinib and OSI-420 in CSF just before administration of erlotinib on day 8. RESULTS: In all cases except for one case, plasma pharmacokinetics data on day 8 were similar to those previously reported. The mean +/- SD CSF concentrations of erlotinib and OSI-420 were 54 +/- 30 ng/ml and 10.8 +/- 8.2 ng/ml, respectively. The mean +/- SD CSF penetration rates of erlotinib and OSI-420 were 5.1% +/- 1.9% and 5.8% +/- 3.6%, respectively. CSF concentrations of erlotinib exceeded median inhibitory concentration (IC50) of erlotinib in intact tumor cells with wild-type epidermal growth factor receptor gene. CONCLUSION: The CSF penetrations of erlotinib and OSI-420 in patients with NSCLC who had CNS metastases were approximately 5.1% and 5.8%, respectively. This indicates that erlotinib can become a treatment option for CNS metastases of NSCLC.

Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with non-small cell lung cancer and chronic renal failure who are undergoing hemodialysis.

INTRODUCTION: Although erlotinib, an orally active and selective tyrosine kinase inhibitor of epidermal growth factor receptor, is mainly metabolized in the liver, its effectiveness and safety for patients with chronic renal failure (CRF) undergoing hemodialysis (HD) has not been reported. Thus, we investigated the pharmacokinetics (PK) of erlotinib and its active metabolite OSI-420 in such patients with nonsmall cell lung cancer (NSCLC). METHOD: We administered 150 mg erlotinib daily to three patients with NSCLC and CRF undergoing HD (HD group) and five patients with NSCLC and normal organ function (control group) and analyzed the PK of erlotinib and OSI-420. In the HD group, PK analyses were performed on day 1 (off HD), day 8 (off HD), and day 9 (on HD) after starting administration of erlotinib, and in the control group, they were performed on day 1 and day 8. RESULTS: In the HD group, there were little differences in the PK data between day 8 and day 9. The PK data on day 1 and day 8 of the HD group were also similar to those of the control group. There were no serious adverse events in any cases, and one of the HD patients achieved partial response. CONCLUSION: Erlotinib was hardly affected by renal function and HD, which confirms the effectiveness and safety of erlotinib treatment in patients with NSCLC and CRF undergoing HD. Erlotinib can become one treatment option for such patients.

Clinical significance of pretreatment C-reactive protein in patients with advanced nonsquamous, non-small cell lung cancer who received gefitinib.

PURPOSE: We examined patients with advanced nonsquamous, non-small cell lung cancer (NSCLC) to evaluate epidermal growth factor receptor (EGFR) mutation status and serum C-reactive protein (CRP) for their associations with response to gefitinib therapy and for prognostic impacts. METHODS: Serum levels of CRP from 79 Japanese patients with advanced nonsquamous NSCLC were measured before the start of gefitinib. We used the peptic nucleic acid-locked nucleic acid clamp method to determine their EGFR somatic mutation status. We evaluated the relationship between each independent clinicopathological variable and the response to gefitinib therapy and the risk factors associated with prognosis. RESULTS: Having CRP-positive serum and having wild-type EGFR were both independent negative predictive factors for the response to gefitinib treatment by multivariate logistic regression model analysis. Having CRP-positive serum and having wild-type EGFR were significant independent negative prognostic factors for survival based on multivariate analysis. CONCLUSIONS: Having CRP-positive serum predicted a lack of response to gefitinib therapy independent of EGFR mutational status. Both CRP-positive serum and wild-type EGFR were independent poor prognostic factors in patients with nonsquamous NSCLC who received gefitinib therapy.

Retrospective analysis of Japanese patients with relapse or refractory small-cell lung cancer treated with amrubicin hydrochloride.

Amrubicin (AMR) is one of the most active chemotherapeutic agents for small-cell lung cancer (SCLC). Previous phase II studies reported on its effectiveness and severe hematological toxicities. However, AMR has yet to be approved outside Japan. Subsequently, no extensive evidence of its effects exist. Between January 2004 and October 2009, 69 patients received AMR for relapsed SCLC at our hospital. We reviewed these patients, and analyzed the efficacy and hematological toxicities of AMR. There were 27 sensitive relapses (S) and 42 refractory relapses (R). Patients received platinum agents, and 43 and 71% of the patients received etoposide and irinotecan, respectively. The median number of treatment cycles was 3 (range 1-14), and the response rate was 51% (70% in the S and 38% in the R cases, respectively). In patients administered with AMR as second-line therapy, the response rate was 55% and as third-line therapy, 39%. Median progression-free survival time was 3.2 months in the S and 1.9 months in the R patients (p=0.1071). Median survival time from the start of AMR was 6.2 months in the S and 4.8 months in the R cases (p=0.0045). The frequency of grade ≥3 hematological toxicities was leukopenia (41%), neutropenia (51%), anemia (14%), thrombocytopenia (17%) and febrile neutropenia (12%). No treatment-related death was observed. Although hematological toxicities, particularly neutropenia, were severe, AMR showed excellent anti-tumor activity, not only in the S, but also in the R cases, as shown in previous phase II studies. These results warrant further evaluation of AMR in the second-line setting, and also in the first-line setting in both limited- and extensive-stage disease. We conducted a phase II study to assess the efficacy of consolidation chemotherapy with AMR after standard chemoradiation in limited-stage SCLC.

Infectious background of febrile advanced lung cancer patients who received chemotherapy.

The study aimed to determine the diagnostic utility of procalcitonin (PCT) in order to discriminate between infective fever and fever due to inflammation in febrile advanced lung cancer patients treated with cytotoxic chemotherapy. A total of 121 patients with advanced lung cancer, treated with a cytotoxic chemotherapy regimen between September 2007 and September 2008 at Kyoto University Hospital, were recruited. Blood samples were obtained on the first day of the fever. Serum c-reactive protein (CRP) and PCT levels were measured. At least two blood cultures were performed, and sputum was taken for Gram staining and culture. There were 71 episodes in 61 patients in the 12 months of the study, representing 50.4% of our study population. A total of 41 patients (57.7%) were diagnosed with pneumonia using imaging modalities, 6 (8.5%) with bacteremia using blood culture and 4 (5.6%) with urinary tract infections using urine culture. Among the 41 pneumonia cases, culture from sputum revealed pathologic bacteria in 21 (51.2%) and fungal disease in 14 (34.1%) cases. Among the 71 febrile episodes, serum procalcitonin and CRP were measured in 50 episodes. Serum procalcitonin-positive patients showed poor outcomes on antibiotics therapy (Fisher's exact test, p=0.042). Furthermore, serum procalcitonin positivity was able to discriminate infective fever from fever due to inflammation (Chi-square test, p=0.001). We showed the causative organisms of febrile advanced lung cancer patients who received cytotoxic chemotherapy, as well as the possibility of PCT to discriminate infective fever from fever due to inflammation.

Effect of vascular endothelial growth factor polymorphisms on survival in advanced-stage non-small-cell lung cancer.

Polymorphisms have been identified in the vascular endothelial growth factor (VEGF) gene that may affect VEGF production. We hypothesized that such polymorphisms may correlate with survival outcomes among advanced-stage non-small-cell lung cancer (NSCLC) patients. We evaluated the association between VEGF polymorphisms and overall survival among patients with advanced NSCLC who were treated with at least one cytotoxic regimen at Kyoto University Hospital between 2003 and 2008. We investigated the following VEGF polymorphisms: -460T > C (rs833061), +405G > C (rs2010963), +936C > T (rs3025039), -1154G > A (rs1570360), and -2578C > A (rs699947). Analyses of genotype associations with survival outcomes were performed using Cox proportional models, Kaplan-Meier methods, and the log-rank test. There were 126 patients and 80 deaths. On a Cox regression analysis of a current and former smoker (hazards ratio [HR], 1.422; 95% confidence interval [CI], 1.111-1.859; P = 0.0046), poor performance status (PS) (HR, 2.524; 95% CI, 1.483-3.827; P = 0.0019), the VEGF -460CC genotype (HR, 1.719; 95% CI, 1.166-2.390; P = 0.0084), VEGF -1154AA and AG genotypes (HR, 1.482; 95% CI, 1.144-1.897; P = 0.0034), and VEGF -2578AA genotype (HR, 1.797; 95% CI, 1.219-2.495; P = 0.0047) had a significant prognostic effect on survival based on univariate analysis. Based on multivariate analysis of a current and former smoker (HR, 1.407; 95% CI, 1.095-1.840; P = 0.0070), poor PS (HR, 2.249; 95% CI, 1.309-3.468; P = 0.0058), and the VEGF -1154AA and AG genotypes (HR, 1.419; 95% CI, 1.033-1.901; P = 0.0316) were significant independent prognostic factors for survival. In this study, polymorphisms in VEGF may affect survival in advanced NSCLC.