PURPOSE: Increasing experimental evidence indicates that abnormal expression of c-kit may be implicated in the pathogenesis of a variety of solid tumors. It has been reported that over 70% of small cell lung cancer (SCLC) contain the c-kit receptor. In the present study, a c-kit analysis has been extended to non-small cell lung cancer (NSCLC). The expressions of p53, vascular endothelial growth factor (VEGF) and cd34, in addition to c-kit, were evaluated to investigate the correlations between these proteins and to determine their potential relationships with the clinicopathological data. MATERIALS AND METHODS: Paraffin-embedded tumor sections, obtained from 147 patients with NSCLC, were immunohistochemically investigated using anti-c-kit, anti- p53, anti-VEGF and anti-cd34 antibodies. RESULTS: c-kit was expressed in 40 (27%) of the tumors examined: 27% of the adenocarcinomas, 27% of the squamous cell carcinomas and 29% of the undifferentiated carcinomas. p53 and VEG F immunoreactivities were present in 107 (73%) and 110 (75%) carcinomas, respectively. Anti-cd34 was negative in all samples. No associations were established among these proteins. The c-kit, however, showed a strong correlation with the T factor: T1 (n=11), 0%; T2 (n=49), 16% and T3 (n=87), 37% (p=.006). CONCLUSION: It is suggested that in NSCLC c-kit is expressed relatively frequently and may become a therapeutic target for the patients with inoperable or recurrent c-kit positive tumors. The alterations in p53 probably constitute an early event, whereas the activated c-kit may contribute to tumor progression.
Adenocarcinoma ; Antibodies ; Carcinoma ; Carcinoma, Non-Small-Cell Lung ; Carcinoma, Squamous Cell ; Humans ; Immunohistochemistry ; Lung Neoplasms* ; Lung* ; Proto-Oncogene Proteins c-kit ; Small Cell Lung Carcinoma ; Vascular Endothelial Growth Factor A

PURPOSE: Caspase-3 is a cysteine protease that plays an important role in the process of apoptotic cell death, but little has been studied clinically on caspase-3 in lung cancer. Increased c-myc expression can result in mitosis or apoptosis, and its contribution to the pathogenesis and prognosis of lung cancer has gained interest. In the present study, the expressions of caspase-3 and c-myc, along with their possible correlations with prognostic variables, were analyzed in resected non-small cell lung carcinomas (NSCLC). MATERIALS AND METHODS: Archival tumor tissues from 147 previously untreated NSCLC patients were examined by immunohistochemistry for the expressions of caspase-3 and c-myc proteins. Clinical information was obtained through the computerized retrospective database from the tumor registry. RESULTS: The expressions of caspase-3 and c-myc were detected in 60 (88/147) and 16% (24/147) of tumors, respectively. No association was found between caspase-3 and c-myc expressions. A multivariate analysis demonstrated the N status and pathologic stage to be significantly correlated with poor survival (p-value=.018 and .002, respectively), but positive expression of caspase-3 was associated with a good prognosis (p=.03). CONCLUSION: Our data suggest the involvement of caspase-3 in the tumorigenesis of NSCLC. It is also noteworthy that caspase-3 expression might be a favorable prognostic indicator in these tumors.
Apoptosis ; Carcinogenesis ; Carcinoma, Non-Small-Cell Lung* ; Caspase 3* ; Cell Death ; Cysteine Proteases ; Humans ; Immunohistochemistry ; Lung ; Lung Neoplasms ; Mitosis ; Multivariate Analysis ; Prognosis ; Proto-Oncogene Proteins c-myc ; Retrospective Studies

PURPOSE: When used in the second-line setting, single- agent chemotherapy has produced response rates of more than 10% or median survival times greater than 4 months. We studied the safety and efficacy of using second-line single docetaxel (75 mg/m2) for advanced NSCLC patients who were previously treated with platinum-based chemotherapy in Korea. MATERIALS AND METHODS: Thirty-three patients with advanced NSCLC received chemotherapy from May 2002 to January 2005. We retrospectively reviewed the charts of these patients. The patients received 75 mg/m2 of doxetaxel on day 1 and this was repeated at 3-week intervals. RESULTS: The median age was 63 years (range: 42~77 years); 16 patients had adenocarcinoma and 8 patients had squamous cell carcinoma. The median number of cycles was 4 (range: 1~7 cycles). Of the 33 patients, 6 patients had partial responses, 13 patients had stable disease and 14 patients had progressive disease. The response rate was 18.2%. The median overall survival was 11 months (range: 7~15 months), and the median progression free survival was 5 months (range: 3~7 months). The median response duration was 5 months (range: 4~9 months). A total of 137 cycles were evaluated for toxicity. We observed grade 3 or 4 neutropenia in 79 cycles (57.6%), grade 3 or 4 leukopenia in 46 cycles (33.6%), and grade 3 febrile neutropenia in 2 cycles (1.5%). The median nadir day was day 9 (range: day 5~19), and the median number of G-CSF injections was 2 (range: 0~6). The most common non-hematologic toxicities were myalgia/arthralgia and neurotoxicity, but any grade 3 or 4 non-hematologic toxicity was not observed. The major toxicity of this therapy was neutropenia. The absolute neutrophil count decreased relatively rapidly, but neutropenic fever or related infection was rare. There were no treatment-related deaths. CONCLUSION: These results revealed a satisfactory response rate (18.2%) with using docetaxel as the second- line chemotherapy for NSCLC. The second-line docetaxel was an active and well-tolerated regimen in patients with advanced NSCLC pretreated with platinum-based chemotherapy.
Adenocarcinoma ; Carcinoma, Non-Small-Cell Lung* ; Carcinoma, Squamous Cell ; Disease-Free Survival ; Drug Therapy* ; Febrile Neutropenia ; Fever ; Granulocyte Colony-Stimulating Factor ; Humans ; Korea ; Leukopenia ; Neutropenia ; Neutrophils ; Retrospective Studies

PURPOSE: To analyze the response, toxicity, patterns of failure and survival rate of patients with locally advanced non-small cell lung cancer who were treated with concurrent chemoradiotherapy with weekly paclitaxel. MATERIALS AND METHODS: Twenty-three patients with locally advanced non-small cell lung cancer patients who received radical chemoradiotherapy from October 1999 to September 2004 were included in this retrospective study. Patients received total 55.4~64.8 (median 64.8) Gy (daily 1.8 Gy per fraction, 5 days per weeks) over 7~8 weeks. 50 or 60 mg/m2 of paclitaxel was administered on day 1, 8, 15, 22, 29 and 36 of radiotherapy. Four weeks after the concurrent chemoradiotherapy, three cycles of consolidation chemotherapy consisted of paclitaxel 135 mg/m2 and cisplatin 75 mg/m2 was administered every 3 weeks. RESULTS: Of the 23 patients, 3 patients refused to receive the treatment during the concurrent chemoradiotherapy. One patient died of bacterial pneumonia during the concurrent chemoradiotherapy. Grade 2 radiation esophagitis was observed in 4 patients (17%). Sixteen patients received consolidation chemotherapy. During the consolidation chemotherapy, 8 patients (50%) experienced grade 3 or 4 neutropenia and one of those patients died of neutropenic sepsis. Overall response rate for 20 evaluable patients was 90% including 4 complete responses (20%) and 14 partial responses (70%). Among 18 responders, 9 had local failure, 3 had local and distant failure and 2 had distant failure only. Median progression-free survival time was 9.5 months and 2-year progression-free survival rate was 19%. Eleven patients received second-line or third-line chemotherapy after the treatment failure. The median overall survival time was 21 months. 2-year and 5-year survival rate were 43% and 33%, respectively. Age, performance status, tumor size were significant prognostic factors for progression-free survival. CONCLUSION: Concurrent chemoradiotherapy with weekly paclitaxel revealed high response rate and low toxicity rate. But local failure occurred frequently after the remission and large tumor size was a poor prognostic factor. Further investigations are needed to improve the local control.
Carcinoma, Non-Small-Cell Lung* ; Chemoradiotherapy* ; Cisplatin ; Consolidation Chemotherapy ; Disease-Free Survival ; Drug Therapy ; Esophagitis ; Humans ; Neutropenia ; Paclitaxel* ; Pneumonia, Bacterial ; Radiotherapy ; Retrospective Studies ; Sepsis ; Survival Rate ; Treatment Failure ; Treatment Outcome*

BACKGROUND: Thymidylate synthase (TS) catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), and this is an essential step in DNA biosynthesis. The present investigation was designed to determine the expression of TS in the patients with non-small cell lung cancer (NSCLC) and to assess the possible associations between the TS status and the p53 or proliferative index (PI). METHODS: The archival tumor tissues from 56 previously untreated NSCLC patients were examined by immunohistochemistry for TS, p53 and Ki-67. RESULTS: Forty-one men and 15 women (age range: 35 to 79 years, mean age: 62 years) were included in this study. The TS expression was high in 40 patients (71.4%) and low in 16 patients (28.6%). The aberrant expression of p53 was detected in 35 patients (62.5%). The mean PI for all the patients was 31.4+/-12.1. The TS-high tumors tended to be more poorly differentiated (p=0.069). The TS expression by a semiquantitative fourscale grading system was significantly correlated with the PIs (p=0.003). No correlation was established between the TS expression and the p53 status (p=0.806) or survival (p=0.951). CONCLUSIONS: TS was not confirmed to be a useful marker for determining the prognosis of NSCLC patients. However, our data suggest that the tumor cells with higher TS expression have a higher proliferative activity.
Carcinoma, Non-Small-Cell Lung* ; Deoxyuridine ; DNA ; Female ; Humans ; Immunohistochemistry ; Lung Neoplasms ; Male ; Methylation ; Prognosis ; Thymidine ; Thymidylate Synthase*

PURPOSE: To evaluate the response rates, toxicitiesy, and survival rates, to vinorelbine (Navelbine(R)), cisplatin and ifosfamide combination chemotherapy, of the patients with inoperable NSCLC (stage III and IV), who received vinorelbine (Navelbine(R)), cisplatin, ifosfamide combinationthe mentioned chemotherapy every 4 weeks. MATERIALS AND METHODS: This study included 26 patients with inoperable NSCLC (stage III and IV), who attended St. Vincent's Hospital Bbetween April 1999 and December 2001, 26 patients were included at St.Vincent's Hospital. The chemotherapy regimen consisted of vinorelbine (25 mg/m2 on days 1 and 8), ifosfamide (1,500 mg/m2 on days 1- and 2 with mesna), and cisplatin (30 mg/m2 on days 1- to 3). The cycles were administered every 4 weeks. A 25% reduction in the doses reduction was applied into subsequent courses if there werewas grade 3~4 neutropenia. RESULTS: The median age was 63 (range, 44~73) years and the male : to female ratio was 19 : 7. One patient had stage IIIa, 6 had stage IIIb and 19 had stage IV. Twenty two patients had an ECOG performance status of 0 or 1, andwith 4 hadhave one of 2. Eighteen of the patients had adenocarcinoma, 7 had squamous cell carcinomas, and 1 had an undifferentiated NSCLC. Two patients were innot able to be evaluatedble due to follow-up loss. Among Of the 24 patients able to be evaluatedble patients, 1 patient had a complete response and 9 patients hada partial responses, and thewith an overall response rate wasof 41.7%. During a total of 104 cycles, grade 3 neutropenia occurred in 29%, grade 4 neutropenia in 12%, grade 3~4 thrombocytopenia in 4%, grade 3 anemia in 11%, and grade 3~4 mucositis in 2%. The mean time to progression was 6.4 months (range 1~13) and the median overall survival was 10 months (range 1.5~32). CONCLUSION: The combination of vinorelbine, ifosfamide and cisplatin, in the dose and schedule employed in this study, shows an response rate of 41.7%, but, because grade 3- or 4 neutropenia occurred in 41%, a careful investigation is needed.
Adenocarcinoma ; Anemia ; Appointments and Schedules ; Carcinoma, Non-Small-Cell Lung ; Carcinoma, Squamous Cell ; Cisplatin* ; Drug Therapy ; Drug Therapy, Combination* ; Female ; Follow-Up Studies ; Humans ; Ifosfamide* ; Lung Neoplasms* ; Lung* ; Male ; Mucositis ; Neutropenia ; Survival Rate ; Thrombocytopenia