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Background: The current use of prophylactic antibiotics for lung cancer surgery requires modification in aging individuals with impaired lung function. A sustained-release formulation of azithromycin (AZM-SR) could help resolve some of these challenges with its sustained antibacterial and anti-inflammatory effects. The aim of this study was to examine the safety and efficacy of AZM-SR in lung cancer surgery as well as its anti-inflammatory effect., Methods: Fifty patients were included in the study, and AZM-SR was administered 1 day prior to the surgery. The clinical course, including postoperative complications, was monitored, and the concentration of AZM, bacterial culture, and inflammatory cytokine levels of resected lung specimens were evaluated., Results: No side effects related to AZM-SR were observed. Five cases of postoperative pneumonia (10%) were observed; technical issues were involved in 3 cases. All patients recovered well. Four cases showed positive bacterial culture upon lung tissue examination; however, this was not significantly correlated with postoperative complications. A negative correlation was observed between AZM concentration in lung tissue and interleukin-6 (IL-6) expression., Conclusions: Prophylactic utilization of AZM-SR in lung cancer surgery seems feasible. The anti-inflammatory effect of AZM might contribute additional beneficial effects in the perioperative management of lung cancer surgery.

Background/aim: Malignant pleural mesothelioma (MPM) is an intractable cancer, and causes of its malignant transformation are not well known. Adenosine deaminase acting on RNA (ADAR) is an RNA-editing enzyme that converts adenosine into inosine in double-stranded RNAs potentially involved in malignant development., Materials and Methods: To examine the role of ADAR1 and ADAR2 in MPM, small interfering RNAs (siRNAs) against ADAR1 or ADAR2 were used., Results: Transfection of siRNA against ADAR2 suppressed proliferation, motility, and invasiveness of MPM cells expressing both ADAR1 and ADAR2; however, siRNA against ADAR1 did not affect these cellular activities. Overexpression of ADAR2, that was incapable of binding to RNA, suppressed growth, motility, and invasion of MPM cells. However, overexpression of ADAR2 that had no enzyme activity did not alter the malignant properties of MPM cells., Conclusion: Enhancement of the malignant characteristics of cultured MPM cells via ADAR2 was independent of RNA-editing activity., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Adjuvant vinorelbine and cisplatin chemotherapy is recognized as a standard regimen for patients with completely resected stage II and III non-small cell lung cancer (NSCLC). However, efficacy of adjuvant chemotherapy in Japanese phase III trials with cisplatin-containing regimen has been controversial, and data are limited on the long-term outcome of adjuvant vinorelbine and cisplatin chemotherapy for NSCLC patients., Methods: This was a single-arm phase II study in patients with completely resected pathological stage II or III NSCLC, who had not received prior chemotherapy or radiotherapy. Patients received 4 cycles of vinorelbine [25 mg/m(2) of body surface area (BSA)] and cisplatin (40 mg/m(2) of BSA) on days 1 and 8, every 4 weeks. Primary end point was the 3-year relapse-free survival; secondary end points were overall survival and safety., Results: Between December 2006 and January 2011, 60 patients (40 men and 20 women, median age 64 years) were enrolled; all patients were evaluable for survival and safety. Three-year relapse-free survival rate was 55.0 % (95 % confidence interval 42.4-67.6 %). Three- and five-year overall survival rates were 83.3 and 77.8 %, respectively. There were no chemotherapy-related deaths, and adverse effects were acceptable., Conclusions: Adjuvant vinorelbine and cisplatin chemotherapy was safe and showed a valid relapse-free survival rate. This regimen could be used as a standard regimen and deserves to be a control arm of trials on adjuvant chemotherapy in the Japanese NSCLC patient population.

Introduction: Smoking status is one of the prognostic factors in advanced non-small-cell lung cancer (NSCLC). Currently, adenocarcinoma (Ad) histology is considered a predictive factor in advanced NSCLC. We investigated the correlation between histology or smoking status and survival of NSCLC patients receiving chemotherapy., Methods: We retrospectively reviewed clinical data from stage IIIB or IV NSCLC patients who started first-line chemotherapy at affiliated institutions of West Japan Oncology Group from 2004 to 2005. We also collected information on pack-years of cigarette smoking and years since cessation. Overall survival was compared using log-rank test, and Cox regression analysis was used to identify independent prognostic factors., Results: In total, 2542 consecutive patients were enrolled at 40 institutions. Of those, 71 were excluded because of unknown smoking history. The median overall survival of nonsmoking Ad patients (593 days) was longer than that of smoking Ad, nonsmoking non-Ad, and smoking non-Ad patients (384, 374, and 319 days, respectively; p < 0.001). In Cox regression with sex, age, stage, performance, and treatment as covariates, we found significant interaction (p = 0.039) between histology (Ad/non-Ad) and smoking status (smoker/nonsmoker); smoking conferred a hazard ratio of 1.34 (95% confidence interval, 1.15-1.55) in Ad, but only 0.99 (0.75-1.31) in non-Ad. Higher pack-years and shorter period since cessation were significantly associated with poorer survival in Ad (p < 0.001), but not in non-Ad (p ≥ 0.434)., Conclusion: Ad histology is associated with better prognosis, and only smoking status had a prognostic impact in Ad.

Background: Our aims were to investigate whether the association between smoking and survival is significant when adjusted for prognostic factors including use of epidermal growth factor tyrosine kinase inhibitors and the Glasgow Prognostic Score, an established score for inflammation, and to explore prognostic factors., Methods: We analyzed 244 patients with stage IIIB or IV non-small-cell lung cancer in a registry, including only chemotherapy-receiving outpatients with performance status zero., Results: Of 244 patients, 170 had died and the median follow-up time for the 74 surviving patients was 12.0 months. In multivariate Cox regression, smoker (hazard ratio compared to never-smoker: 1.67, P < 0.01), stage IV (hazard ratio compared to IIIB: 1.72, P < 0.01), and elevated C-reactive protein level (hazard ratio per 1 mg/dL increase: 1.08, P < 0.01) were significantly associated with shorter survival. The association between survival and smoking was significant, even after adjustment for the Glasgow Prognostic Score and regimens of chemotherapy (hazard ratio: 1.72, P = 0.02). In never-smokers, increased neutrophils were a major determinant of shorter survival and the interaction test between smoking and neutrophils was significant (hazard ratio per 1,000/mm(3) increase for smokers: 1.01; hazard ratio per 1,000/mm(3) increase for never-smokers: 1.44, P for interaction <0.01)., Conclusions: Known factors including treatment response or inflammatory process are not responsible for the fact that advanced non-small-cell lung cancer patients without any history of smoking have better survival than those who have smoked.

Background: The purpose of the present study was to improve the prognosis of patients with stage IIIA-N2 non-small cell lung cancer (NSCLC). To achieve that goal, we performed induction chemoradiotherapy followed by surgery., Methods: The criteria for this phase II study were ≤75-year-old patients with pathologically diagnosed stage IIIA-N2 NSCLC who had performance statuses of 0 or 1 with good organ function. Three cycles of chemotherapy with paclitaxel and carboplatin were carried out, with concurrent hyperfractionated irradiation (42 Gy). After re-evaluation, pulmonary resections were considered unless patients showed progressive disease. The primary endpoint was overall survival (OS), and the secondary endpoints were disease-free survival (DFS) and absence of toxicity., Results: All 22 patients enrolled in this study completed the induction chemoradiotherapy without any severe complications. In these 22 patients, the 2- and 5-year OS were 81 and 47%, respectively. There were no therapy-related deaths. Surgery was subsequently performed in 19 patients (86%). Pathological complete responses were seen in 6 patients (27%), while node downstaging was obtained in 10 patients (45%). In the 19 patients who underwent surgery, the 2- and 5-year OS rates were 83 and 62%, respectively, and the 2-year DFS rate was 63%. All 6 patients with pathological complete responses survived without disease. Patients with residual multiple-station N2 showed worse OS and DFS rates than did those with downstaged and single-station N2 (P=0.026 and P<0.0001, respectively)., Conclusions: This trimodal therapy was effective and well tolerated, and it is an acceptable therapeutic option for patients with locally advanced stage IIIA-N2 NSCLC. Patients without persistent multiple-station N2 showed promising survival.

Objective: We conducted a Phase II study to evaluate the efficacy and safety of a weekly combination of carboplatin and irinotecan regimen for patients with extensive disease small-cell lung cancer., Methods: Patients with previously untreated extensive disease small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0, 1 or 2, were enrolled in this trial. Carboplatin area under the curve of two and irinotecan (50 mg/m(2)) were administered on days 1 and 8 every 3 weeks. Treatment was continued up to a maximum of six cycles. The expected response rate was 85%, and this regimen was considered sufficiently positive if >45 responses were observed in the 55 patients., Results: Between December 2003 and September 2006, 56 patients were enrolled and 55 patients were eligible. Of 55 patients, 6 complete remissions and 37 partial remissions were achieved, and the response rate was 78.2% (95% confidence interval: 64.6-87.9). Major Grade 3 or more toxicities were leukocytopenia 3, neutropenia 15, anemia 7, infection 5, diarrhea 3, anorexia 7, nausea 6 and pneumothorax 1. The median survival was 13.9 months (95% confidence interval: 11.8-18.5) and the median progression-free survival was 5.7 months (95% confidence interval: 4.9-7.4)., Conclusions: This Phase II trial of a weekly combination of carboplatin and irinotecan for extensive disease small-cell lung cancer was not positive for a response rate that is considered to be worthy of further Phase III trial.

Purpose: Erlotinib is the first epidermal growth factor receptor-tyrosine kinase inhibitor shown to provide a survival benefit for advanced non-small-cell lung cancer (NSCLC) patients. Adverse drug reactions of erlotinib in Japanese, which may be very different from those in Caucasians because of differences in genetic background, have not been fully reported. Therefore, we aimed to clarify the safety profile of erlotinib., Methods: Forty-eight patients with pretreated NSCLC were treated with erlotinib between March 2008 and January 2009 in this historical cohort study at Kyoto University Hospital Outpatients Oncology Unit. Erlotinib 150 mg/day was administered until progressive disease or discontinuation due to adverse events. The primary endpoint was frequency and degree of adverse events, and secondary endpoints were clinical efficacy including response rate, disease control rate, progression-free survival and overall survival., Results: Of 48 patients, 3 patients experienced erlotinib-induced interstitial pneumonitis, which appeared on day 15 and 70 in 2 patients who recovered and on day 8 in 1 patient who died. The incidences of pruritus, dry skin, diarrhea and stomatitis rapidly increased within 14 days after the start of medication with erlotinib. However, these adverse events were well controllable in outpatients treated with erlotinib. Overall response rate was 10% and disease control rate was 68%. The median progression-free survival was 58 days (95% confidence interval 30-118) and the median overall survival was 229 days (95% confidence interval 135-not available)., Conclusions: Outpatients with NSCLC can be treated with initial administration of erlotinib by careful management.

Background: Combination of erlotinib and bevacizumab is a promising regimen in advanced non-squamous non-small-cell lung cancer (NSCLC). We are conducting a single arm phase II trial which aims to evaluate the efficacy and safety of this regime as a second- or third-line chemotherapy., Methods: Key eligibility criteria were histologically or cytologically confirmed non-squamous NSCLC, stage III/IV or recurrent NSCLC not indicated radical chemoradiation, prior one or two regimen of chemotherapy, age 20 years or more, and performance status of two or less. The primary endpoint is objective response rate. The secondary endpoints include overall survival, progression-free survival, disease control rate and incidence of adverse events. This trial plans to accrue 80 patients based on a two-stage design employing a binomial distribution with an alternative hypothesis response rate of 35% and a null hypothesis threshold response rate of 20%. A subset analysis according to EGFR mutation status is planned., Discussion: We have presented the design of a single arm phase II trial to evaluate the efficacy and safety of combination of bevacizumab and erlotinib in advanced non-squamous NSCLC patients. In particular we are interested in determining the merit of further development of this regimen and whether prospective patient selection using EGFR gene is necessary in future trials., Trial Registration: This trial was registered at the UMIN Clinical Trials Registry as UMIN000004255 (http://www.umin.ac.jp/ctr/index.htm).

Purpose: The purpose of the present phase II study was to evaluate both the efficacy and toxicity of the combination of S-1 and docetaxel in previously treated patients with locally advanced or metastatic non-small cell lung cancer., Methods: Thirty-eight previously treated patients with non-small cell lung cancer were treated with S-1 (80 mg/m(2), days 1-14, oral) and docetaxel (40 mg/m(2), day 1, intravenous) every 3 weeks., Results: No complete response was observed, and seven patients had a partial response, yielding an overall response rate of 18.4% (95% CI, 7.7-34.3%). The median overall survival time and 1-year overall survival rate were 16.1 months and 60%, respectively. The median progression-free survival time was 4.4 months. Myelosuppression was the main toxicity with grade 3 or 4 neutropenia and leukopenia in 50 and 21%, respectively. There was no irreversible toxicity in this study., Conclusions: The combination of S-1 and docetaxel is well tolerable and has substantial activity for patients with locally advanced or metastatic non-small cell lung cancer. A phase III trial comparing docetaxel with or without S-1 would warrant further investigation.

A 58-year-old woman was admitted with refractory fever despite receiving broad-spectrum antibiotics. She had hypoxemia, severe anemia, elevated levels of serum lactic dehydrogenase and soluble interleukin-2 receptor, and a positive direct Coombs test, which suggested an underlying autoimmune hemolytic anemia (AIHA). Chest computed tomography (CT) showed no abnormal findings, but she had hypoxia, and her alveolar-arterial oxygen difference (A-aDO2) was increased. A random transbronchial lung biopsy (TBLB) was performed, and pathological analysis showed massive proliferation of tumor cells in the lumina of the small vessels. Intravascular large B-cell lymphoma (IVLBCL) was diagnosed, and her general status improved after chemotherapy.

Background: Breast cancer resistance protein (BCRP) functions as a drug efflux transporter that mediates drug resistance. Topoisomerase I inhibitors, including 7-ethyl-10-hydroxycamptothecin (SN-38), are substrates effluxed by BCRP. However, it remains unclear whether the overexpression of BCRP induces drug resistance during chemotherapy. The objectives of the current study were to examine a correlation of altered promoter methylation of BCRP with BCRP expression and to investigate the correlation between methylation status according to methylation-specific polymerase chain reaction (MSP) analysis and BCRP expression levels in several small cell and nonsmall cell lung cancer cells., Methods: Non-BCRP-expressing PC-6 cells, which were sensitive to SN-38, were treated with DNA methyltransferase inhibitor to induce BCRP re-expression by means of reverse transcriptase-polymersae chain reaction, Western blot, and flow cytometric analyses. Subsequently, bisulfite sequencing analysis in both PC-6 cells and SN-38-resistant PC-6/SN2-5H, highly expressing BCRP cells was performed to identify the methylated region in the BCRP promoter. Finally, the authors established an MSP method on the basis of methylated and unmethylated DNA sequences., Results: DNA methyltransferase inhibitor treatment of PC-6 cells induced BCRP re-expression at the messenger RNA and protein levels. Bisulfite sequencing analysis revealed that both alleles at all CpG sites were methylated completely in PC-6 cells, whereas alleles at portions of CpG sites in PC-6/SN2-5H cells were unmethylated. There was an inverse correlation between promoter methylation of BCRP determined by MSP and BCRP expression in both small cell and nonsmall cell lung cancer cells., Conclusions: The current results indicated that demethylation of at least 1 allele is necessary for BCRP re-expression and that promoter demethylation of BCRP may be a mechanism of BCRP expression in lung cancer cells.

Background and Objectives: Tissue inhibitor of metalloproteinase-3 (TIMP-3) inhibits the activity of metalloproteinases that play important roles in development and progression of malignant tumors. We conducted a retrospective study of TIMP-3 expression in resected non-small cell lung cancer (NSCLC)., Methods: TIMP-3 expression was examined immunohistochemically in primary tumor specimens from 143 patients who underwent complete resection for NSCLC. Correlations between TIMP-3 expression grade and tumor histology, TNM classification, MMP-2 and MMP-9 expression grade, VEGF expression grade, intra-tumoral microvessel density, proliferative index, apoptosis index, and prognosis were analyzed., Results: TIMP-3 expression was low in 40, moderate in 71, and high in 32 patients. Higher TIMP-3 expression was seen in squamous cell carcinoma than in adenocarcinoma (P = 0.001), and reduced TIMP-3 expression was significantly associated with nodal involvement (P = 0.016) and advanced pathologic stage (P = 0.036). MMP-2 expression was reduced along with enhanced TIMP-3 expression (P = 0.010). The 5-year overall survival rates of low, moderate, and high TIMP-3 patients were 53, 64, and 84%, respectively (P = 0.037). Multivariate analysis confirmed that enhanced TIMP-3 expression was an independent factor for a favorable prognosis (P = 0.037)., Conclusions: TIMP-3 expression status was significantly correlated with pathologic stage and nodal involvement, and was an independent prognostic factor in resected NSCLC.

Background and Objectives: In this paper we examined the influence of epidermal growth factor receptor (EGFR) gene mutations on EGFR expression, downstream mediators, and survival in patients with non-small cell lung cancer (NSCLC)., Methods: We retrospectively analyzed the tumors of 53 patients with completely resected pathological stage I-IIIA NSCLC for the presence of EGFR gene mutations, the expression of EGFR mRNA and protein, phosphoryl-Akt, and phosphoryl-mitogen-activated protein kinase (MAPK) using immunostaining, and patients' prognosis., Results: EGFR mutations were associated with elevations in EGFR mRNA (P = 0.004) and protein (P = 0.029) expression, but not with the expression of phosphoryl-Akt or phosphoryl-MAPK. The 5-year survival rate for all patients who exhibited an EGFR mutation was similar to those who were free of such mutations (71% vs. 56%, P = 0.252). However, the 5-year survival rate of patients with either a stage I adenocarcinoma or large cell carcinoma who had an EGFR mutation was significantly greater than for those who did not have such a mutation (92% vs. 57%, P = 0.037)., Conclusions: EGFR gene mutations were significantly associated with higher EGFR expression, but not with p-Akt or p-MAPK status. In early stage NSCLC, the presence of an EGFR gene mutation bode well for the patient's prognosis.

Purpose: Nitroglycerin may improve the response to chemotherapy in advanced non-small cell lung cancer. The effects and mechanisms of nitroglycerin on the enhancement of chemosensitivity to docetaxel and carboplatin regimen (DCb) in patients with lung adenocarcinoma have not been reported., Experimental Design: Seventeen patients with operable lung adenocarcinoma and stable angina pectoris were selected to investigate the effects of nitroglycerin on immunoreactivity for hypoxia-inducible factor 1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), P-glycoprotein (P-gp), the production of which is regulated by HIF-1, and p53 proteins in their resected tumor by semiquantitative immunohistochemical analyses. Eight of 17 patients were treated with nitroglycerin patches before operation, but 9 of 17 patients were not. Furthermore, to study the relationship between changes in plasma VEGF levels by nitroglycerin treatment and response to DCb, 29 patients with advanced lung adenocarcinoma were treated with nitroglycerin for 3 days before chemotherapy using DCb., Results: The rates of immunoreactive cells for HIF-1alpha, VEGF, and P-gp in tumor tissues treated with nitroglycerin were lower than those without nitroglycerin, but those for p53 were not different between those treated with and without nitroglycerin. Furthermore, the rates of immunoreactive cells for VEGF and P-gp proteins were significantly associated with those for HIF-1alpha in tumor tissue. The magnitude of decrease in plasma VEGF levels after treatment with nitroglycerin was significantly associated with response to DCb in patients with advanced lung adenocarcinoma., Conclusions: Nitroglycerin treatment may improve response to DCb in patients with lung adenocarcinoma, partly through decreasing VEGF and P-gp production via reduction of HIF-1alpha.

Background: Maspin is a member of the serpin (serine protease inhibitor) superfamily, and its exact function in the development and progression of malignant tumors remains controversial, though some experimental studies have revealed potential tumor-suppressor activities. In addition, there have been only a few clinical studies on maspin expression in malignant tumors including non-small cell lung cancer (NSCLC). The purpose of this study was to assess maspin expression and its clinical significance in NSCLC., Methods: A total of 210 consecutive patients with completely resected pathological (p-) stage I-IIIA NSCLC were retrospectively reviewed. Maspin expression along with intratumoral microvessel density, proliferative activity, and p53 status were evaluated immunohistochemically. The incidence of apoptotic cell death was also evaluated., Results: The incidence of strong maspin expression was significantly higher in lung squamous cell carcinoma (56/76, 73.7%; P < .001) than in other histological types. The incidence of aberrant expression of p53 was significantly higher in maspin-strong than in maspin-weak tumors (56.2% and 35.8%, respectively; P = .005). There was no difference in prognosis according to maspin status for all patients. However, for squamous cell carcinoma patients, univariate analysis showed that enhanced maspin expression was a significant factor in predicting a favorable prognosis (5-year survival rates, 70.1% for maspin-strong tumors and 41.5% for maspin-weak tumors; P = .014), which was confirmed in a multivariate analysis (hazard ratio = .475, 95% confidence interval .241-.936; P = .032)., Conclusions: Enhanced maspin expression was a significant and independent factor in predicting a favorable prognosis in lung squamous cell carcinoma.

Background: Reversion-inducing cysteine-rich protein with Kazal motifs (RECK) is a novel membrane-anchored matrix metalloproteinase inhibitor, and experimental studies have shown that RECK can suppress tumor progression through angiogenesis inhibition. We have already revealed that enhanced RECK expression is significantly correlated with a favorable prognosis in non-small-cell lung cancer (NSCLC). In this study, further analyses focused on pN2 disease were conducted to assess the clinical significance of RECK expression., Methods: A total of 118 patients with completely resected pathologic stage IIIA N2 NSCLC were retrospectively examined. RECK expression in the primary tumor, along with involved N2 nodes, was examined immunohistochemically., Results: RECK expression in the primary tumor was strong in 53 patients (44.9%) and was weak in the other 65 patients. The 5-year survival rate of patients with RECK-strong tumor (42.9%) was significantly higher than that of patients with RECK-weak tumor (23.1%; P = .017). Reduced RECK expression significantly correlated with a poor prognosis for patients with a single N2 node involved (P = .019), but not for patients with multiple N2 nodes involved (P = .440). A multivariate analysis confirmed that reduced RECK expression was an independent and significant factor to predict a poor prognosis (P = .031). RECK expression in involved N2 nodes was significantly higher than in primary tumors (P < .001)., Conclusions: RECK status was a novel prognostic factor in pathologic stage IIIA N2 NSCLC.

Purpose: The aim of this study was to evaluate the relationships among [18F]fluorodeoxyglucose ([18F]-FDG) uptake, Glut-1 and HK-II expressions, and grade of inflammation in resected lung lesions., Materials and Methods: Sixty patients had undergone preoperative 18F-FDG-PET imaging and thoracotomy. For semiquantitative analysis of 18F-FDG uptake, partial volume effect corrected maximum standardized uptake values (pSUVs) were calculated. Immunohistochemical staining was performed in resected specimens using anti-Glut-1, anti-HK-II, and anti-proliferative cellular nuclear antigen (PCNA) antibodies, and immunoreactivities were scored as G-, H-, and P-indexes on a five-point scale (0: 0%; 1: 20%, 2: 40%; 3: 60%; 4: 80%, and 5: 100% percentages of strongly immunoreactive cells).Grade of inflammation was also evaluated., Results: The malignant lesions had higher pSUV and higher G- and H- than nonmalignant lesions. pSUVs correlated with the G- (p < .001), H- (p < .01), and P-indexes (p < .01) in malignant lesions. In adenocarcinomas, cancers with lower differentiation showed higher expression of Glut-1 and HK-II than those with higher differentiation. A positive linear regression was observed between pSUVs and the grading of inflammation in nonmalignant lesions (p < .05)., Conclusions: Our study indicates that 18F-FDG uptake in lung cancer correlates well with the Glut-1, HK-II, and PCNA expression. For nonmalignant lesions, the presence of a higher inflammatory process correlated with 18F-FDG uptake.

Purpose: The melanoma differentiation-associated gene-7 (MDA-7) protein, also known as interleukin (IL)-24, is a novel candidate of tumor suppressor that can induce apoptosis experimentally in a variety of human malignant cells including lung cancer cells. However, only one clinical study has documented that MDA-7/IL-24 expression is down-regulated with progression of melanoma. Thus, the present study was conducted to assess the clinical significance of MDA-7/IL-24 expression in non-small cell lung cancer., Experimental Design: A total of 183 consecutive patients with resected pathologic stage I-IIIA, non-small cell lung cancer were retrospectively reviewed, and immunohistochemical staining was used to detect MDA-7/IL-24 expression., Results: MDA-7/IL-24 expression was high in 97 (53.0%) patients and low in the other patients. There was no significant correlation between MDA-7/IL-24 status and any patients' characteristic including pathologic stage. There was no significant difference in tumor angiogenesis or proliferative activity according to MDA-7/IL-24 status, but MDA-7/IL-24-high adenocarcinoma showed a significantly higher incidence of apoptotic tumor cell death than MDA-7/IL-24-low adenocarcinoma. MDA-7/IL-24-high patients seemed to show a favorable postoperative prognosis as compared with MDA-7/IL-24-low patients (5-year survival rates, 75.9% and 62.0%, respectively), although the difference did not reach a statistical significance (P = 0.061). Subset analyses showed that positive MDA-7/IL-24 expression was a significant factor to predict a favorable prognosis in adenocarcinoma (P = 0.033), which was confirmed by a multivariate analysis; there was no difference in the prognosis according to MDA-7/IL-24 status in squamous cell carcinoma., Conclusions: MDA-7/IL-24 status was a significant prognostic factor in lung adenocarcinoma, not in lung squamous cell carcinoma.

Purpose: Experimental studies have revealed that fms-like tyrosine kinase (Flt)-4 plays important roles in lymphangiogenesis in malignant tumors, but the clinical significance remains unclear. We assessed Flt-4 expression in tumor cells and in endothelial cells in correlation with clinical outcomes in non-small cell lung cancer (NSCLC)., Experimental Design: A total of 206 consecutive patients with resected pathological stage I-IIIA NSCLC were reviewed. Expression of Flt-4 was examined immunohistochemically, and Flt-4-positive microvessels were quantitatively evaluated (Flt-4-positive endothelial cell density)., Results: There was no significant correlation between Flt-4-positive endothelial cell density and any characteristic of patients including nodal metastases. A significant correlation between Flt-4-positive endothelial cell density and Flt-4 status in tumor cells was documented (P < 0.001), but there was no significant difference in the mean Flt-4-positive endothelial cell density according to vascular endothelial growth factor-C or -D status in tumor cells. The 5-year survival rate for higher Flt-4-positive endothelial cell density tumor (56.4%) was significantly lower than that of lower Flt-4-positive endothelial cell density tumor (69.0%, P = 0.046); the prognostic significance was enhanced in pIIIA-N2 patients (5-year survival rates, 18.8% for higher Flt-4-positive endothelial cell density tumor and 50.0% for lower Flt-4-positive endothelial cell density tumor, respectively; P = 0.012). A multivariate analysis confirmed that higher Flt-4-positive endothelial cell density was a significant and independent prognostic factor (P = 0.019). CD34-positive vessel density or Flt-4 status in tumor cells was not a significant prognostic factor., Conclusions: Flt-4-positive endothelial cell density, not Flt-4 status in tumor cells, was a significant prognostic factor in NSCLC.

Specimens were obtained from 10 patients with radiological abnormalities involving mediastinal or hilar areas, for histological examination using 19 G transbronchial needle aspiration (TBNA). The tissues examined proved diagnostic in 6 patients (60%) including one with a benign condition (sarcoidosis). Clinical characteristics (sex, age, puncture site, number of specimens, size of radiological abnormalities) in the 6 positive patients were compared with those for the 4 negative patients. No significant differences in the number of specimens or the size of radiological abnormalities were observed between groups. However, a punctured trachea was seen in significantly more cases in the negative group (3/4, 75%) than in the positive group (1/6, 17%; p<0.05). Few minor complications were encountered. The use of a 19 G TBNA appears effective for obtaining tissue for histological examination and diagnosis of benign conditions. Training in this technique should increase the diagnostic utility of the histology needle.

Purpose: The purpose is to assess clinical significance of matrix metalloproteinase (MMP)-2 and MMP-9 status, especially MMP-2 status, in stromal cells in non-small-cell lung cancer (NSCLC) because experimental studies have revealed that stromal MMP-2 plays important roles in progression of malignant tumors, but most clinical studies focused on tumoral MMP-2 expression, not stromal MMP-2 expression., Experimental Design: We conducted a retrospective study on MMP-2 and MMP-9 expression as evaluated immunohistochemically in a total of 218 consecutive patients with completely resected pathological stage I-IIIA, NSCLC., Results: Strong MMP-2 expression in tumor cells and stromal fibroblasts were documented in 54 (24.8%) and 132 (60.6%) patients, respectively. Strong MMP-2 expression in stromal fibroblasts was more frequently seen in squamous cell carcinoma (72.7%) than in adenocarcinoma (54.9%; P = 0.016). Tumors showing strong MMP-2 expression in stromal fibroblasts showed a significantly higher intratumoral microvessel density (IMVD) than weak stromal MMP-2 tumors (mean intratumoral microvessel density, 50.9 versus 32.4, P = 0.003). In addition, postoperative prognosis of strong stromal MMP-2 patients was significantly poorer than that of weak stromal MMP-2 patients (5-year survival rate, 77.5 versus 60.2%, P = 0.032), and the prognostic significance was enhanced in squamous cell carcinoma patients but disappeared in adenocarcinoma patients. Multivariate analyses confirmed that strong stromal MMP-2 expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. In contrast, MMP-2 or MMP-9 status in tumor cells was not a significant prognostic factor., Conclusions: MMP-2 status in stromal fibroblasts, not in tumor cells, was a significant prognostic factor associated with angiogenesis in NSCLC.

Recent experimental studies have revealed that tumour-associated stromal macrophages as well as tumour cells express vascular endothelial growth factor C (VEGF-C), which plays important roles in lymphangiogenesis, which is a critical factor in the progression of many malignant tumours including non-small-cell lung cancer (NSCLC). However, no clinical study on VEGF-C expression in both stromal macrophages and tumour cells has been reported, and we conducted the present study to address the issue in resected NSCLC. A total of 206 patients with completely resected pathologic stage I-IIIA NSCLC were retrospectively reviewed. Expression of VEGF-C in primary lung tumour was assessed immunohistochemically. Expression of VEGF-C in tumour cells was high in 125 patients (60.7%), and that in stromal macrophages was positive in 136 patients (71.2%). The status of VEGF-C in tumour cells or in stromal macrophages was not correlated with nodal status or angiogenesis. The 5-year survival rate of high tumoral VEGF-C patients (60.7%) was significantly lower than that of low tumoral VEGF-C patients (39.3%) (P=0.046), and a multivariate analysis confirmed that tumoral VEGF-C status was a significant and independent prognostic factor. Moreover, tumour showing high VEGF-A and VEGF-C expression in tumour cells showed the poorest prognosis (5-year survival rate, 45.1%). The status of VEGF-C in stromal macrophages was not correlated with the prognosis. In conclusion, tumoral VEGF-C status, not stromal VEGF-C status, was a significant prognostic factor in resected NSCLC.

The reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) was initially isolated as a transformation-suppressor gene by expression cloning and found to encode a membrane-anchored regulator of the matrix metalloproteinases (MMPs). Experimental studies have shown that RECK can suppress tumour - invasion, metastasis and angiogenesis. However, the clinical impact of RECK remains unclear. To assess the clinical significance of RECK-expression in non-small cell lung cancer (NSCLC), a total of 171 patients with completely resected pathological stage (p-stage) I-IIIA NSCLC were retrospectively examined. Expression of RECK and vascular endothelial growth factor (VEGF) in tumour tissues was assessed by immunohistochemical staining (IHS). Intratumoural microvessel density (IMVD), a measurement of angiogenesis, was also determined by IHS using an anti-CD34 antibody. A significant inverse correlation between RECK-expression and tumour angiogenesis was documented; the mean IMVD in tumours with strong RECK-expression (157.1) was significantly lower than that observed in tumours with weak RECK-expression (194.5; P = 0.008). Interestingly, this inverse correlation was seen only when VEGF was strongly expressed, which suggests that RECK could suppress the angiogenesis induced by VEGF. The 5-year survival rate for patients with tumours with strong RECK-expression (75.8%) was significantly higher than that for patients with weakly expressing tumours (54.3%; P = 0.016). Subset analyses showed that the prognostic impact of RECK-status was evident in patients with either adenocarcinoma, poorly differentiated tumours, or p-stage IIIA disease. A multivariate analysis confirmed that reduced RECK-expression was an independent and significant factor in predicting a poor prognosis (P = 0.009; Hazard ratio (HR), 0.474 with a 95% Confidence interval (CI) of 0.271-0.830). In conclusion, RECK-status is a significant prognostic factor correlated with tumour angiogenesis in NSCLC patients.

Objective: To reveal the incidence and clinical significance of mediastinal nodal metastases without N1-station nodal metastases ('skip-N2 metastases') in non-small cell lung cancer (NSCLC)., Methods: A total of 450 NSCLC patients who underwent tumor resection with a systemic mediastinal nodal dissection were retrospectively reviewed. p53 status and proliferative activity represented as proliferative index (PI) were also examined immunohistochemically., Results: Skip-N2 metastases were documented in 49 (13%) patients of all 450 patients; among 334 patients without N1-nodal involvement, 18% patients had skip-N2 metastases. The postoperative survival of skip-N2 patients was almost same as that for patients with metastases to both N1 and N2 nodes. Skip-N2 metastases were significantly more frequent in male patients and squamous cell carcinoma patients. In addition, the mean PI for tumor with skip-N2 metastases was significantly higher than that for any other pathologic nodal (pN)-status diseases. Combined with histologic type and PI, the incidences of skip-N2 metastases for adenocarcinoma showing lower PI were only 5% (7/137) of all patients and 7% (7/94) of patients without N1-nodal involvement., Conclusions: N1 nodal status is not a useful predictor of N2 nodal status in NSCLC, because skip-N2 metastases were documented in 18% patients showing no N1-nodal involvement. However, N1 node-guided dissection might be performed in patients with adenocarcinoma showing lower PI, because the incidence of skip-N2 metastases was extremely low.

Background: Postoperative prognosis for patients with pathologic (p-) stage IIIA-N2 non-small-cell lung cancer (NSCLC) is poor, and significant factors that influence the prognosis remain unclear., Methods: A total of 99 patients who underwent complete resection for p-stage IIIA-N2 NSCLC without any preoperative therapy were retrospectively reviewed. Biological features such as tumor angiogenesis (intratumoral microvessel density [IMVD]), proliferative activity (proliferative index [PI]), and p53 status were also evaluated immunohistochemically., Results: Univariate analysis revealed that the number of involved N2 stations was a significant prognostic factor; 5-year survival rates for a tumor with metastases in single N2 stations, tumor with metastases in two N2 stations, and tumor with metastases in 3 or more N2 stations were 41.6%, 35.3%, and 0.0%, respectively (P =.041) In addition, the 5-year survival rate for cN0-1 disease was significantly higher than that for cN2 disease (41.9% and 25.5%, respectively; P =.048) Tumor angiogenesis and proliferative activity were the most significant prognostic factors; 5-year survival rates for lower-IMDV tumor and higher-IMVD tumor were 53.6% and 15.9%, respectively (P =.002), and those for lower-PI tumor and higher-PI tumor were 47.0% and 20.4%, respectively (P =.019) There was no difference in the postoperative survival between tumor showing aberrant p53 expression and tumor showing no aberrant p53 expression. These results were confirmed by a multivariate analysis., Conclusions: P-stage IIIA-N2 NSCLC cases represented a mixture of heterogeneous prognostic subgroups, and the number of involved N2 stations, cN status, PI, and IMVD were significant predictors of the survival.

UFT is an oral 5-fluorouracil derivative drug that may improve postoperative survival in non-small cell lung cancer (NSCLC), and experimental studies have shown that UFT inhibits tumor angiogenesis. In the present study, therefore, the correlation between tumor angiogenesis (intratumoral microvessel density, IMVD) and the efficacy of UFT in 162 patients with pathologic stage I NSCLC was examined. For higher IMVD tumors (IMVD > or = 20, n = 80), the 5-year survival rate of UFT-treated patients (82.5%) was significantly higher than that of surgery-alone patients (61.8%, P = 0.032). For lower IMVD tumors (n = 82), however, there was no difference in the survival between these groups (5-year survival rates, 84.9% and 82.6%, respectively; P = 0.657). Multivariate analyses confirmed that postoperative UFT administration was effective for higher IMVD tumors (P = 0.046; relative risk [RR] and the 95% confidence interval [CI], 0.288 [0.084-0.979]), but not for lower IMVD tumors (P = 0.616; 0.726 [0.208-2.539]). Moreover, vascular endothelial growth factor (VEGF) status was also a predictive factor. For tumor showing strong VEGF expression (n = 63), UFT administration improved the survival (5-year survival rates of UFT-treated patients and surgery-alone patients, 84.6% and 60.0%, respectively; P = 0.048); for weakly VEGF-expressing tumors (n = 99), UFT administration did not influence the survival (5-year survival rates, 83.4% and 79.1%, respectively; P = 0.455). Multivariate analyses demonstrated that UFT administration seemed to be effective for strong VEGF tumors (P = 0.063; RR and the 95% CI, 0.234 [0.051-10.81]), but not for weak VEGF tumors (P = 0.456; 0.673 [0.293-1.900]). In conclusion, the efficacy of postoperative UFT administration in NSCLC was correlated with tumor angiogenesis.

Many experimental studies have revealed that enhanced thymidylate synthase (TS) expression is significantly correlated with higher proliferative activity of tumor cells, which may account for a poor prognosis of high-TS patients. However, only a few clinical studies have focused on the correlation between TS status and cell proliferation. Therefore, we assessed the correlation between TS expression and proliferative index (PI) as a marker of cell proliferation or p53 status in a total of 109 patients with completely resected pathologic stage I, non-small cell lung cancer (NSCLC). PI was defined as the percentage of tumor cells with positive staining against proliferative cell nuclear antigen (PCNA). The mean PIs of TS-high and TS-low tumors were 48.2% and 34.4% respectively, showing a significantly higher proliferative activity of TS-high tumor (P=0.020); when stratified according to histological type, the difference was significant in adenocarcinoma (P=0.038), but not in squamous cell carcinoma. There was no significant correlation between TS expression and p53 status. In conclusion, tumor cells with higher TS expression have higher proliferative activity in NSCLC, especially in adenocarcinoma.

The prognosis in cases of advanced lung cancer with poor performance status is poor. We report here a patient with advanced non-small cell lung cancer of performance status 3 who had severe cancer-induced pain, which was not controlable with morphine and radiation therapy. The cancer was successfully treated by oral administration of gefitinib (250 mg/day) without serious adverse effects of worsening of quality of life. Not only was the tumor controlled but rapid relief of severe cancer-induced pain was achieved.

Glomeruloid microvascular proliferation (GMP) is a focal proliferative budding of endothelial cells (ECs) resembling a renal glomerulus. Whereas some experimental and clinical studies have suggested recently that GMPs indicate an aggressive angiogenic phenotype, the incidence and clinical significance of GMPs remains unclear. Thus, we conducted a retrospective study on GMPs in a total of 236 patients with completely resected pathological (p-) stage I-IIIA NSCLC. ECs were highlighted with immunohistochemical staining using an anti-CD34 antibody, and GMPs were defined as focal glomerulus-like aggregates of closely associated and multilayer CD34-positive ECs. Expression of vascular endothelial growth factor, angiopoietin (Ang)-1, and Ang-2 was also examined immunohistochemically. GMPs were positive in 60 (25.4%) patients, and the incidence was not correlated with age, gender, histological type, or p-stage. The mean intratumoral microvessel densities for GMP-negative tumor and GMP-positive tumor were 178.2 and 184.1, respectively, showing that the incidence of GMPs was not correlated with intratumoral microvessel density (P = 0.676). There was no correlation between vascular endothelial growth factor expression and the incidence of GMPs, but GMPs were more frequently seen in Ang-1-positive tumor than in Ang-1-negative tumor. The 5-year survival rate of GMP-positive patients was 54.2%, which was significantly lower than that of GMP-negative patients (72.3%; P = 0.016). The 5-year survival rate of higher-MVD patients (71.5%) seemed to be lower than that of the lower-MVD patients (63.7%), but the difference did not reach a statistical significance (P = 0.137). A multivariate analysis confirmed that the presence of GMPs was a significant prognostic factor (P = 0.003), whereas MVD was not. In conclusion, GMPs indicate an aggressive angiogenic phenotype associated with a poor prognosis in NSCLC.

A 69-year-old man had undergone low anterior resection and a right lobe resection of the liver for rectum cancer and metastatic liver tumor at the age of 66 years. He presented at our hospital because of an abnormal shadow on a CT chest scan, which indicated a tumor shadow 2.5 cm in size in the lingular lobe and enlarged hilar and mediastinal lymph nodes. A bronchoscopic tumor biopsy revealed pulmonary metastasis from the rectum cancer. Bronchoscopic examination also identified an endobronchial squamous cell lung cancer, which almost completely obstructed the orifice of B1 and B2. We concluded that the patient had squamous cell lung cancer with metastases in the mediastinal lymph nodes. He was initially treated with weekly chemotherapy with carboplatin (AUC 1.25) and paclitaxel (70 mg/m2). The endobronchial tumor was markedly reduced in size after 2 weeks of the chemotherapy. Furthermore, after 6 weeks of the chemotherapy, the tumor had disappeared completely, and 11 days later, lower division segmentectomy and hilar and mediastinal lymph node dissection were performed. Pathological examination revealed no metastases in the lymph nodes. The patient has continued to receive chemotherapy as an outpatient and has been well without recurrence of any metastases for over 16 months.

Only a few clinical studies have documented a significant correlation between intratumoral microvessel density (IMVD), a measurement of angiogenesis, and apoptotic index (AI), an incidence of apoptosis, although many experimental studies have confirmed that insufficient angiogenesis induces accelerated apoptotic cell death. In the present study, therefore, to assess AI in correlation with IMVD in resected non-small cell lung cancer, a total of 236 patients with pathologic stage I to IIIa were reviewed. IMVDs were determined immunohistochemically with an antibody against a pan-endothelial marker, CD34 (CD34-IMVD), and an antibody against a proliferation-related endothelial marker, CD105 (CD105-IMVD). AI was defined as the number of tumor cells positive for the terminal deoxynucleotidyl tranferase-mediated dUTP-biotin nick end-labeling staining per 1000 tumor cells. When CD34 was used as a marker of angiogenesis, the mean AIs for the lower-IMVD and the higher-IMVD patients were 20.1 and 17.5, respectively, demonstrating no significant difference between the lower- and the higher-IMVD patients. In contrast, when CD105 was used, the mean AI for the lower-IMVD patients was significantly higher than that for the higher-IMVD patients (22.0 and 15.6, respectively; P=0.019). There was no significant correlation between proliferative activity and CD34-IMVD or CD105-IMVD. These results demonstrated that that decreased angiogenesis may induce enhanced apoptotic tumor-cell death without affecting cell proliferation.

Angiopoietin (Ang)-1 and -2 have been recently identified as potent angiogenic factors which function in concert with vascular endothelial growth factor (VEGF), but no detailed clinical study on Ang expression has been reported. To assess the clinical significance of Ang expression in non-small cell lung cancer (NSCLC), a total of 236 patients with pathological stage-I-IIIA disease were retrospectively reviewed. Expression of Ang-1, Ang-2, or VEGF was examined immunohistochemically; intratumoral microvessel density (IMVD) was examined with immunohistochemical staining against CD34, a marker of pan-endothelial cells (CD34-IMVD), and that against CD105, a marker of proliferative endothelial cells (CD105-IMVD). Positive expression of Ang-1 and that of Ang-2 were seen in 101 (42.8%) and 40 patients (16.9%), respectively. There was no significant correlation between Ang-1 expression and CD34-IMVD or CD105-IMVD. In contrast, the average CD105-IMVD for Ang-2-positive tumor was significantly higher than that for Ang-2-negative tumor (56.7 versus 38.5; P = 0.032). More interestingly, such an angiogenic effect of Ang-2 was seen only when VEGF expression was high; when VEGF expression was high, the average CD105-IMVD for Ang-2-positive tumor was significantly higher than that for Ang-2-negative tumor (89.1 versus 63.6; P = 0.045); when VEGF expression was low, the average CD105-IMVD for Ang-2-positive tumor and that for Ang-2-negative tumor were almost the same (27.4 and 27.1, respectively). Moreover, positive expression of Ang-2, not Ang-1, was a significant factor to predict a poor postoperative survival (5-year survival rates for Ang-2-positive patients and -negative patients were 53.5 and 70.3%, respectively; P = 0.027), which was confirmed by a multivariate analysis. The influence of Ang-2 status on postoperative survival was enhanced when VEGF expression was high. That said, the 5-year survival of Ang-2-positive and VEGF-high patients was extremely low (41.4%) as compared with that for Ang-2-negative and VEGF-low patients (66.6%), as compared with that for Ang-2-positive and VEGF-low patients (63.6%), and as compared with that for Ang-2-negative and VEGF-low patients (71.8%). In conclusion, positive Ang-2 expression was significantly correlated with a poor prognosis, as well as with aggressive angiogenesis in resected NSCLC that was enhanced in the presence of high VEGF expression.

To clarify clinical characteristics and biological features of primary lung carcinoma arising from emphysematous bullae (EB), a total of 50 patients (49 males and one female) among all 1478 patients who underwent operation for primary lung carcinoma cases were reviewed; biological features were examined in 31 patients whose resected specimens were available for immunohistochemical staining (IHS). Thirty-one patients (62.0%) had pathologic stage I disease, and 30 cases (60.0%) had poorly differentiated tumor, demonstrating earlier pathologic stages and poorer cell differentiation of lung carcinoma with EB as compared with that without EB. The mean proliferative index (PI) for carcinoma with EB was 64.0%, which was significantly higher than that for carcinoma without EB (47.2%, P = 0.001); no significant difference in Apoptotic index (AI) was demonstrated. Aberrant p53 expression was less frequent in carcinoma with EB (29.0%) than in carcinoma without EB (47.9%, P = 0.043). Five-year survival rates for carcinoma with and that without EB were 50.3 and 46.9%, respectively, showing no significant difference. Multivariate analysis did not demonstrate that association of EB was a significant prognostic factor. In conclusion, although with the poorer cell differentiation and accelerated proliferative activity of lung carcinoma arising from EB, this does not have a significantly different prognosis than primary lung carcinoma not associated with bullae., (Copyright 2002 Elsevier Science Ireland Ltd.)

Background and Objectives: Dihydropyrimidine dehydrogenase (DPD) activity in tumor cells has been suggested to be one of the factors determining the effectiveness of 5-fluorouracil (5-FU). In the present study, we analyzed DPD expression in tumors and investigated retrospectively the relationship between the efficacy of UFT (Tegafur + Uracil) as adjuvant chemotherapy and DPD expression in nonsmall-cell lung cancer (NSCLC)., Methods: DPD expression of 166 resected p-stage I NSCLC was examined immunohistochemically. Patients who were administered UFT alone as adjuvant therapy comprised the UFT group (n = 54), and those who underwent only surgery comprised the control group (n = 112). DPD expression was categorized as either high or low, according to intensity of staining., Results: DPD expression was high in 98 patients (59.0%) and low in 68 patients (41.0%). Patients with low-DPD tumors who were administered UFT had a significantly better prognosis than those who did not receive adjuvant treatment (P = 0.021). No significant difference was found between the two groups of patients with high-DPD tumors (P = 0.598)., Conclusions: DPD expression may predict the efficacy of UFT after surgery for p-stage I NSCLC. A prospective study is needed to confirm the role of DPD expression as a predictor of UFT efficacy., (Copyright 2002 Wiley-Liss, Inc.)

Purpose: The clinical significance of p21 expression remains unclear, whereas many experimental studies have demonstrated that p21, the product of the WAF1/CIP1/SDI1 gene, plays an important role in regulation of the cell cycle as an inhibitor of cyclin-dependent kinases. The purpose of this study was to clarify the clinical significance in resected non-small-cell lung cancer (NSCLC)., Patients and Methods: A total of 233 consecutive patients with completely resected pathologic stage I to IIIA NSCLC were retrospectively reviewed. Expression of p21 and the status of p53 were examined immunohistochemically. Proliferative activity was also evaluated immunohistochemically. The incidence of apoptotic cell death was evaluated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling staining., Results: Expression of p21 was positive in 120 patients (51.5%). The 5-year survival rate of p21-positive patients was 73.8%, significantly higher than that of p21-negative patients (60.7%; P =.006). Aberrant expression of p53 was positive in 98 patients (42.1%). When combined with p53 status, the prognostic value of p21 status was enhanced: the 5-year survival rate of p21-positive and p53-negative patients was 80.7%, markedly higher than that of p21-negative and p53-positive patients (50.0% for both; P =.001). Multivariate analysis confirmed that positive expression of p21 was a significant factor for predicting a favorable prognosis. There was no significant correlation between p21 expression and p53 status, proliferative activity, or incidence of apoptosis., Conclusion: p21 expression was shown to be an independent prognostic factor in NSCLC.

To evaluate the influence of p53 status on postoperative survival and incidence of apoptosis (apoptotic index, AI) in non-small cell lung cancer (NSCLC), a total of 185 pathologic stage I patients were retrospectively analyzed. It was demonstrated by univariate and multivariate analyses that aberrant expression of p53 was a significant factor to predict a poor prognosis, which was caused by a significantly higher proliferative index (PI) in tumor with aberrant expression of p53 (52.7%) than that in tumor without aberrant expression of p53 (37.9%, P < 0.001). In addition, for tumor without aberrant expression of p53, mean AIs of the lowest-, the lower-, the higher-, and the highest-PI groups were 12.6, 12.9, 31.3, and 35.1, respectively, showing that incidence of apoptosis was markedly increased in response to cell proliferation (P = 0.002). In contrast, for tumor with aberrant expression of p53, no increase in incidence of apoptosis in response to cell proliferation was documented. These results clearly demonstrated that active cell proliferation and reduced apoptotic cell death in response to cell proliferation resulted in the poor postoperative prognosis in tumor with aberrant expression of p53.

Background: Clinical significance of the status of nm23 gene, originally identified as an antimetastatic gene, in non-small cell lung cancer remains unestablished, whereas many clinical studies have demonstrated that reduced nm23 expression is correlated with tumor progression and poor prognosis in a variety of malignant tumors such as breast carcinoma., Methods: nm23 expression was examined immunohistochemically in a total of 117 patients with completely resected pathologic stage I non-small cell lung cancer., Results: nm23 expression was positive in 73 (62.4%) patients, and there was no correlation between nm23 expression and age, sex, performance status, pathologic T factor, histologic type, or degree of cancer cell differentiation. The 5-year survival rates of nm23-positive and nm23-negative patients were 79.7% and 57.8%, respectively, demonstrating a significantly poorer prognosis in nm23-negative patients (p = 0.013), which was confirmed by a multivariate analysis. nm23 was not correlated with the incidence of apoptosis, proliferative activity, or p53 status., Conclusions: nm23 expression was a significant factor for predicting a favorable prognosis, suggesting antimetastatic potential of the nm23 gene in non-small cell lung cancer.

We investigated thymidylate synthase (TS) expression in tumor tissues and examined the relationship between TS expression and post-operative survival in patients with p-stage I adenocarcinoma of the lung. A total of 104 patients, who underwent complete resection for p-stage I adenocarcinoma of the lung, were retrospectively reviewed. TS expression in tumor tissues was evaluated by immunohistochemical staining using rhTS polyclonal antibody. The intensity of immunohistochemical staining was classified into four categories using a visual grading system from 0 to 3. The percentage of each grade of TS staining was 9.6% for Grade 0, 18.3% for Grade 1, 35.6% for Grade 2 and 36.5% for Grade 3. Five-year survival rates of patients with Grade 0 to Grade 3 were 90.0, 83.9, 70.3 and 73.7%, respectively with no significant difference among all groups (P=0.236). When divided into two groups, according to the intensity of the grade, 5-year survival rates of TS low expression group (Grade 0 and Grade 1) and TS high expression group (Grade 2 and Grade 3) were 86.1 and 72.0%, respectively, with a significant difference (P=0.048). In conclusion, high level of TS expression was associated with poor prognosis. Immunohistochemical evaluation of TS expression may be useful to predict survival after complete resection in p-stage I adenocarcinoma of the lung.

Purpose: Angiogenesis is an essential process in the progression of malignant tumors. Whereas pan-endothelial markers, such as CD34, are generally used in evaluation of angiogenesis, pan-endothelial antibodies react with not only "newly forming" vessels but also normal vessels just trapped within tumor tissues. It has been recently reported that anti-CD105 antibody preferentially reacts with "activated" endothelial cells in angiogenic tissues. Thus, the superiority of anti-CD105 monoclonal antibody (mAb) in evaluation of angiogenesis of non-small cell lung cancer (NSCLC) was assessed., Experimental Design: A total of 236 patients with resected NSCLC were retrospectively reviewed. Intratumoral microvessel density (IMVD) was determined with an anti-CD34 mAb (CD34-IMVD) and with an anti-CD105 mAb (CD105-IMVD)., Results: The mean CD34-IMVD and CD105-IMVD were 179.9 and 41.6, respectively. Whereas CD34-IMVD was significantly correlated with the expression of vascular endothelial growth factor (P = 0.003), CD105-IMVD was more closely correlated with vascular endothelial growth factor expression (P < 0.001). The 5-year survival rate of the lower CD105-IMVD patients was 74.9%, significantly higher than that of the higher CD105-IMD patients (60.4%, P = 0.018). Whereas the 5-year survival rate of the lower CD34-IMVD patients seemed higher than that of the higher CD34-IMVD patients (63.7%), the difference did not reach a statistical significance (P = 0.137). Multivariate analysis confirmed that higher CD105-IMVD was a significant factor to predict poor prognosis (P = 0.029), whereas CD34-IMVD was not (P = 0.070)., Conclusions: Anti-CD105 mAb proved to be superior to anti-CD34 mAb in evaluation of angiogenesis in NSCLC.

Objectives: To clarify prognostic factors in resected pathologic (p-) T1-2N1M0 non-small cell lung cancer (NSCLC)., Methods: A total of 95 consecutive patients who underwent complete tumor resection and mediastinal dissection for pT1-2N1M0 NSCLC between 1976 and 1997 were retrospectively reviewed. p53 status and proliferative activity were evaluated immunohistochemically., Results: The extent of N1 stations and p53 status proved to be significant prognostic factors. The 5-year survival rate for tumor without hilar node (#10) involvement was 66%, significantly higher than that for tumor with #10 involvement (39%, P<0.01). The 5-year survival rate for tumor with aberrant p53 expression was 37%, significantly lower than that for tumor without aberrant p53 expression (74%, P<0.01). There proved to be no significant difference in the prognosis between pT1 disease and pT2 disease; the 5-year survival rates for pT1 and pT2 diseases were 62 and 56%, respectively. Age, gender, performance status, grade of tumor differentiation, histological type, or proliferative activity were not significant factors. Multivariate analysis of prognostic factors using Cox's proportional hazard model confirmed these results., Conclusions: Involvement of the hilar node and aberrant p53 expression were significant factors to predict a worse prognosis in resected T1-2N1M0 NSCLC.

Polysialic acid (PSA) is a carbohydrate attached mainly to the neural cell adhesion molecule. Because PSA is composed of a linear homopolymer of alpha-2-8-linked sialic acid residues and has a large negative charge, the presence of PSA attenuates the adhesive property of neural cell adhesion molecule and increases cellular motility. In an earlier study, we demonstrated that PSA and STX, a polysialyltransferase, were associated with tumor progression in non-small cell lung cancer (NSCLC) (F. Tanaka et al., Cancer Res., 60: 3072-3080, 2000). Therefore, in the present study, to assess the prognostic significance of PSA in resected NSCLC, a total of 236 patients who underwent complete resection for pathological (p)-stage I-IIIa disease were reviewed retrospectively. PSA was expressed in 44 of 236 (18.6%) patients, and the expression was correlated with p-stage disease. For all p-stage patients, 5-year survival rates for those with PSA-positive and PSA-negative tumors were 52.1% and 71.3%, respectively, demonstrating a significantly worse prognosis for the PSA-positive patients (P = 0.012). Analysis for only p-stage I patients also demonstrated a significantly worse prognosis for the PSA-positive patients; 5-year survival rates of the PSA-positive and the PSA-negative patients were 45.1% and 83.5%, respectively, (P < 0.001). In addition, there proved to be no difference in the postoperative survival among p-stage I, II, and IIIa patients when PSA expression was positive. Multivariate analysis confirmed that PSA expression was an independent factor to predict poor prognosis in resected NSCLC. These results suggested that PSA could be an important clinical marker and that preoperative induction and/or postoperative adjuvant therapies should be performed for PSA-positive NSCLC, even if the disease is classified as p-stage I.

To examine whether efficacy of postoperative oral administration of UFT, a 5-fluorouracil derivative chemotherapeutic agent, may be influenced by incidence of apoptosis (apoptosis index) or apoptosis-related gene status (p53 and bcl-2) of the tumour, a total of 162 patients with pathologic stage I non-small cell lung cancer were retrospectively reviewed. UFT was administrated postoperatively to 44 patients (UFT group), and not to the other 118 patients (Control group). For all patients, 5-year survival rate of the UFT group (79.9%) seemed higher than that of the Control group (69.8%), although without significant difference (P = 0.054). For patients with higher apoptotic index, 5-year survival rate of the UFT group (83.3%) was significantly higher than that of the Control group (67.6%, P = 0.039); for patients with lower apoptotic index, however, there was no difference in the prognosis between these two groups. Similarly, UFT was effective for patients without p53 aberrant expression (5-year survival rates: 95.2% for the UFT group and 74.3% for the Control group, P = 0.022), whereas not effective for patients with p53 aberrant expression. Bcl-2 status did not influence the efficacy of UFT. In conclusion, apoptotic index and p53 status are useful factors to predict the efficacy of postoperative adjuvant therapy using UFT., (Copyright 2001 Cancer Research Campaign.)

Caspase-3 is a cysteine protease that plays an important role in the process of apoptotic cell death. Whereas many studies on the clinical significance of apoptosis in the therapy of malignant tumors have been reported, little has been studied clinically on caspase-3. In the present study, the clinical significance of caspase-3 expression in resected nonsmall-cell lung cancer (NSCLC) and its correlation with incidence of apoptosis were examined. A total of 118 consecutive patients who had undergone complete resection for pathologic Stage I NSCLC were retrospectively reviewed. Caspase-3 expression was examined immunohistochemically using a polyclonal antibody that recognized uncleaved caspase-3. The 5-year survival rate for patients with strong expression of caspase-3 (66.6%) was significantly lower than that for patients with weak expression (82.1%, P = 0.021). Expression of caspase-3 was not correlated with incidence of apoptosis, proliferative activity, or p53 status. Multivariate analysis confirmed that strong expression of caspase-3 was a significant factor to predict poor prognosis. These results suggest that enhanced expression of "uncleaved" caspase-3, that is, inactivated caspase-3, was correlated with poor prognosis in resected NSCLC., (Copyright 2002 Wiley-Liss, Inc.)

Background: To examine whether biological features of primary tumor can help preoperative evaluation of mediastinal nodal status in non-small cell lung cancer., Methods: A total of 450 patients who underwent tumor resection and mediastinal dissection were reviewed. p53 status and proliferative fraction (PI) were evaluated immunohistochemically., Results: The accuracy of preoperative evaluation of mediastinal nodal status with computed tomography (CT) was 72.2%; mediastinal nodal metastases had not been revealed until operation in 59 patients (13.1%) (false-negative), and no metastasis was revealed in 66 patients (14.7%) although mediastinal nodal enlargement had been demonstrated by CT (false-positive). The number of false-negative patients was significantly larger when p53 aberrant expression was positive or when PI was higher. Combined with p53 status and PI, there were 27 false-negatives (24.1%) among patients with aberrant p53 expression and higher PI, whereas only two false-negatives (1.5%) among those with negative p53 expression and lower PI., Conclusions: Mediastinoscopy may be recommended for tumor showing aberrant p53 expression and higher PI, even when CT demonstrates no mediastinal nodal enlargement.

Objective: To clarify results of surgery for non-small cell lung cancer (NSCLC) based on the new tumor-node-metastasis (TNM) classification revised in 1997 and its time trend., Methods: A total of 921 patients operated from 1980-1994 were retrospectively reviewed. For analysis of time trend, they were grouped into three periods by the year of operation (period (1): 1980-1984, period (2): 1985-1989, and period (3): 1990-19-94)., Results: Concerning patients' characteristics, recent increase in the ratio of patients whose tumor was discovered at mass screening (31% in period (1), 40% in period (2), and 50% in period (3)), and increase in the ratio of p-stage IA patient (16, 20, and 29%, respectively) were marked. Decrease in the ratio of operation-related death and the ratio of exploratory thoracotomy was significant. Concerning level of operation, decrease in the ratio of pneumonectomy, increase in the ration of sublober resection and that of tracheal or bronchoplastic procedures were significant. Postoperative survival for all patients was significantly better in period (2) or (3) than that in period (1); no significant difference was demonstrated between period (2) and (3) (5-year survival rates: 35% for period (1), 56% for period (2), and 56% for period (3)). Stratified p-stage, improvement of postoperative survival in recent years was demonstrated in p-stage IIA, IIB, IIIA, and IIIB diseases., Conclusions: Postoperative survival for all NSCLC patients has been improved with significant increase of early-stage (p-stage IA) patients. Concerning level of resection, recent increase in patients who underwent sublobar resection and bronchoplastic procedures was marked.

Polysialic acid (PSA) is a carbohydrate composed of a linear homopolymer of alpha-2-8-linked sialic acid residues and is mainly attached to the neural cell adhesion molecule (NCAM). Because of the large negative charge of PSA, presence of PSA attenuates the adhesive property of NCAM and increases the cellular motility. PSA expression on NCAM is developmentally regulated, and PSA plays important roles in formation and remodeling of the neural system through regulation of the adhesive property of NCAM. Expression of the polysialated form of NCAM has been also demonstrated in some malignant tumors, such as Wilms' tumor and small cell lung cancer. Despite the possible importance as an onco-developmental antigen, however, significance of PSA expression in most malignant tumors has not been revealed. Therefore, PSA expression in non-small cell lung cancer was assessed in the present study. PSA was expressed only in 5 (20.8%) of 24 pathological stage I cases, whereas it was expressed in most stage IV cases (76.8%, 11 of 14 cases). PSA expression was correlated with nodal metastasis and distant metastasis, but not with local extent of the primary tumor. Next, expression of polysialyltransferase genes (PST and STX genes) which controlled formation of PSA, was examined. The PST gene was constantly expressed in both normal lung tissue and tumor tissue of all cases. In contrast, the STX gene was not expressed in normal lung tissue of any case, and STX gene expression in tumor tissue was closely correlated with tumor progression. The STX gene was expressed only in 1 (4.2%) of 24 stage I cases, whereas it was expressed in most stage IV cases (85.7%, 12 of 14 cases). These results suggested that the PSA and STX genes could be new targets of cancer therapy as well as important clinical markers.