• Radiation Oncology Journal
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• v.24 no.4
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• pp.230-236
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• 2006

$\underline{Purpose}$: 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. $\underline{Materials\;and\;Methods}$: 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 $55.4{\sim}64.8$ (median 64.8) Gy (daily 1.8 Gy per fraction, 5 days per weeks) over $7{\sim}8$ weeks. 50 or $60\;mg/m^2$ 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 $135\;mg/m^2$ and cisplatin $75\;mg/m^2$ was administered every 3 weeks. $\underline{Results}$: 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. $\underline{Conclusion}$: 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.

• Tuberculosis and Respiratory Diseases
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• v.44 no.3
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• pp.516-524
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• 1997

Background : Cancer invasion and metastasis require the dissolution of the extracellular matrix in which several proteolytic enzymes are involved. One of these enzymes is the urokinase-type plasminogen activator(u-PA), and plasminogen activator inhibitors(PAI-1, PAI-2) also have a possible role in cancer invasion and metastasis by protection of cancer itself from proteolysis by u-PA. It has been reported that the levels of u-PA and plasminogen activator inhibitors in various cancer tissues are significantly higher than those in normal tissues and have significant correlations with tumor size and lymph node involvement. Here, we measured the concentration of plasma u-PA and PAI-1 antigens in the patients with lung cancer and compared the concentration of them with histologic types and staging parameters. Methods : We measured the concentration of plasma u-PA and PAI-1 antigens using commercial ELISA kit in 37 lung cancer patients, 21 benign lung disease patients and 24 age-matched healthy controls, and we compared the concentration of them with histologic types and staging parameters in lung cancer patients. Results : The concentration of u-PA was $1.0{\pm}0.3ng/mL$ in controls, $1.0{\pm}0.3ng/mL$ in benign lung disease patients and $0.9{\pm}0.3ng/mL$ in lung cancer patients. The concentration of PAI-1 was $14.2{\pm}6.7ng/mL$ in controls, $14.9{\pm}6.3ng/mL$ in benign lung disease patients, and $22.1{\pm}9.8ng/mL$ in lung cancer patients. The concentration of PAI-1 in lung cancer patients was higher than those of benign lung disease patients and controls. The concentration of u-PA was $0.7{\pm}0.4ng/mL$ in squamous cell carcinoma, $0.8{\pm}0.3ng/mL$ in adenocarcinoma, 0.9ng/mL in large cell carcinoma, and $1.1{\pm}0.7ng/mL$ in small cell carcinoma. The concentration of PAI-1 was $22.3{\pm}7.2ng/mL$ in squamous cell carcinoma, $22.6{\pm}9.9ng/mL$ in adenocarcinoma, 42 ng/mL in large cell carcinoma, and $16.0{\pm}14.2ng/mL$ in small cell carcinoma. The concentration of u-PA was 0.74ng/mL in stage I, $1.2{\pm}0.6ng/mL$ in stage II, $0.7{\pm}0.4ng/mL$ in stage IIIA, $0.7{\pm}0.4ng/mL$ in stage IIIB, and $0.7{\pm}0.3ng/mL$ in stage IV. The concentration of PAI-1 was 21.8ng/mL in stage I, $22.7{\pm}8.7ng/mL$ in stage II, $18.4{\pm}4.9ng/mL$ in stage IIIA, $25.3{\pm}9.0ng/mL$ in stage IIIB, and $21.5{\pm}10.8ng/mL$ in stage IV. When we divided T stage into T1-3 and T4, the concentration of u-PA was $0.8{\pm}0.4ng/mL$ in T1-3 and $0.7{\pm}0.4ng/mL$ in T4, and the concentration of PAI-1 was $17.9{\pm}5.6ng/mL$ in T1-3 and $26.1{\pm}9.1ng/mL$ in T4. The concentration of PAI-1 in T4 was significantly higher than that in T1-3. The concentration of u-PA was $0.8{\pm}0.4ng/mL$ in M0 and $0.7{\pm}0.3ng/mL$ in M1, and the concentration of PAI-1 was $23.6{\pm}8.3ng/mL$ in M0 and $21.5{\pm}10.8ng/mL$ in M1. Conclusions : The plasma levels of PAI-1 in lung cancer were higher than benign lung disease and controls, and the plasma levels of PAI-1 in T4 were significantly higher than T1-3. These findings suggest involvement of PAI-1 with local invasion of lung cancer, but it should be confirmed by the data on comparison with pathological staging and tissue level in lung cancer.

• Tuberculosis and Respiratory Diseases
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• v.41 no.4
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• pp.339-353
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• 1994

Background : The p53 gene codes for a DNA-binding nuclear phosphoprotein that appears to inhibit the progression of cells from the G1 to the S phase of the cell cycle. Mutations of the p53 gene are common in a wide variety of human cancers, including lung cancer. In lung cancers, point mutations of the p53 gene have been found in all histological types including approximately 45% of resected NSCLC and even more frequently in SCLC specimens. Mutant forms of the p53 protein have transforming activity and interfere with the cell-cycle regulatory function of the wild-type protein. The majority of p53 gene mutations produce proteins with altered conformation and prolonged half life; these mutant proteins accumulate in the cell nucleus and can be detected by immunohistochemical staining. But protein overexpression has been reported in the absence of mutation. p53 protein overexpression or gene mutation is reported poor prognostic factor in breast cancer, but in lung cancer, its prognostic significance is controversial. Method : We investigated the p53 abnormalities by nucleotide sequencing, polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP), and immunohistochemical staining. We correlated these results with each other and survival in 75 patients with NSCLC resected with curative intent. Overexpression of the p53 protein was studied immunohistochemically in archival paraffin- embedded tumor samples using the D07(Novocastra, U.K.) antibody. Overexpression of p53 protein was defined by the nuclear staining of greater than 25% immunopositive cells in tumors. Detection of p53 gene mutation was done by PCR-SSCP and nucleotide sequencing from the exon 5-9 of p53 gene. Result: 1) Of the 75 patients, 36%(27/75) showed p53 overexpression by immunohistochemical stain. There was no survival difference between positive and negative p53 immunostaining(overall median survival of 26 months, disease free median survival of 13 months in both groups). 2) By PCR-SSCP, 27.6%(16/58) of the patients showed mobility shift. There was no significant difference in survival according to mobility shift(overall median survival of 27 in patients without mobility shift vs 20 months in patients with mobility shift, disease free median survival of 8 months vs 10 months respectively). 3) Nucleotide sequence was analysed from 29 patients, and 34.5%(10/29) had mutant p53 sequence. Patients with the presence of gene mutations showed tendency to shortened survival compared with the patients with no mutation(overall median survival of 22 vs 27 months, disease free median survival of 10 vs 20 months), but there was no statistical significance. 4) The sensitivity and specificity of immunostain based on PCR-SSCP was 67.0%, 74.0%, and that of the PCR-SSCP based on the nucleotide sequencing was 91.8%, 96.2% respectively. The concordance rate between the immunostain and PCR-SSCP was 62.5%, and the rate between the PCR-SSCP and nucleotide sequencing was 95.3%. Conclusion : In terms of detection of p53 gene mutation, PCR-SSCP was superior to immunostaining. p53 gene abnormalities either overexpression or mutation were not a significant prognostic factor in NSCLC patients resected with curative intent. However, patients with the mutated p53 gene showed the trends of early relapse.

• Tuberculosis and Respiratory Diseases
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• v.66 no.3
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• pp.178-185
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• 2009

Background: Epigallocatechin-3-gallate (EGCG) is the major catechin in green tea, and has shown antiproliferative, antiangiogenic, antimetastatic and cell cycle pertubation activity in various tumor models. Hypoxia can be induced because angiogenesis is insufficient for highly proliferating cancer. Hypoxia-inducible factor-1$\alpha$ (HIF-1$\alpha$) and its downstream target, vascular endothelial growth factor (VEGF), are important for angiogenesis, tumor growth and metastasis. The aim of this study was to determine how hypoxia could cause changes in the cellular phenomena and microenvironment in a non-small cell culture system and to examine the effects of EGCG on a HIF-1$\alpha$ and VEGF in A549 cell line. Methods: A549 cells, a non-small cell lung cancer cell line, were cultured with DMEM and 10% fetal bovine serum. A decrease in oxygen tension was induced using a hypoxia microchamber and a $CO_2-N_2$ gas mixture. Gas analysis and a MTT assay were performed. The A549 cells were treated with EGCG (0, 12.5, 25, 50 ${\mu}mol/L$), and then examined by real-time-PCR analysis of HIF-1$\alpha$, VEGF, and $\beta$-actin mRNA. Results: Hypoxia reduced the proliferation of A549 cells from normoxic conditions. EGCG inhibited HIF-1$\alpha$ transcription in A549 cells in a dose-dependent manner. Compared to HIF-1$\alpha$, VEGF was not inhibited by EGCG. Conclusion: HIF-1$\alpha$ can be inhibited by EGCG. This suggests that targeting HIF-1$\alpha$ with a EGCG treatment may have therapeutic potential in non-small cell lung cancers.

• Journal of Chest Surgery
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• v.30 no.9
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• pp.899-907
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• 1997

Recently, primary lung cancer has increased markedly in incidence & prevalence in korea. Prom July 1979 to June 1996, 183 patients were diagnosed and operated for primary non-small cell lung cancer, and evaluated clinically. 1. There were 164 males and 19 females(M:P=8.6: 1), and the peak incidence of age was 50th and 60th decade of life(73.7%). 2. Most of symptoms were respiratory, whitch were cough(44.8%), chest pain(30.1%), dyspnea(20.8%), hemoptysis or blood tinged sputum(19.7%), sputum(15.3%), and asymptomatic cases were 12.0%. 3. Histopathologically, sguamous cell carcinoma was 68.9%, adenocarcinoma 19.7%, bronchioloalveol r cell carcinoma 2.2%, adenosguamous cell carcinoma 1.6%, and large cell carcinoma 7.7%. 4. In the operation, pneumonectomy was 41.0%, lobectomy 42.1%, bilobectomy 13.1%, stagmentectomy or wedge resection 1.6%, and explore tharacotomy 2.2%, and the overall resectability was 97.8%. 5. Postoperative complications were developed in 31.9%, and operative mortality was 1.6%. 6. In postoperative stagings, stage I was 38.3%, stage H 14.8%, stage llla 31.1%, and stage IIIb 15.8%. 7. The overall cumulative survival rates were 1 year 77.8%, 3 year 42.7%, and 5 year 39.5%. The 5 year survival rate according to stage were stage 153.0%, stage H 46.5%, stage I[la 28.2%, and stage IIIb 13.8%(p<0.05), according to operation method were lobectomy 45.0%, and pneumonectomy 30.3%(p<0.05), and according to mediastinal involvement were Nl 32.0%, and N2 11.1%(p<0.05). The 5 year survival rate according to histologic type were squamous cell carcinoma 43.1%, adenocarcinoma 23.3%, and large cell carcinoma 30.3 (p>0.05).

• Radiation Oncology Journal
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• v.26 no.3
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• pp.160-165
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• 2008

Purpose: In cases of locally advanced non-small cell lung cancer (NSCLC), concurrent chemoradiotherapy(CCRT) is the leading therapeutic modality. However, much controversy exists about the chemotherapeutic regimens and radiation methods. Materials and Methods: During concurrent chemoradiotherapy, three or four cycles of gemcitabine ($500\;mg/m^2$) and cisplatin ($30\;mg/m^2$) were administered every two weeks while 50.4 Gy of irradiation was administered in 28 fractions (once/day, 5 treatment days/week) to the tumor site, mediastinum, and the involved lymph node region. In addition, a booster irradiation dose of 18 Gy in 10 fractions was administered to the primary tumor site unless the disease progressed. Two or three cycles of consolidation chemotherapy were performed with gemcitabine ($1,200\;mg/m^2$, $1^{st}$ and 8th day) and cisplatin ($60\;mg/m^2$) every three weeks. Results: A total of 29 patients were evaluable for modality response. Response and treatment toxicities were assessed after concurrent chemoradiotherapy and consolidation chemotherapy, respectively. One patient (4%) achieved a complete response; whereas 20 patients (69%) achieved a partial response after concurrent chemoradiotherapy. Following the consolidation chemotherapy, three patients (10.3%) achieved complete responses and 21 patients (72.4%) achieved partial responses. The median follow-up period was 20 months (range $3{\sim}39$ months) and the median survival time was 16 months (95% CI; $2.4{\sim}39.2$ months). The survival rates in one, two, and three years after the completion of treatment were 62.7%, 43.9%, and 20%, respectively. Complications associated to this treatment modality included grade 3 or 4 esophagitis, which occurred in 15 patients (51.7%). In addition, an incidence of 24% for grade 3 and 14% for grade 4 neutropenia. Lastly, grade 2 radiation pneumonitis occurred in 6 patients (22%). Conclusion: The response rate and survival time of concurrent chemoradiotherapy with biweekly gemcitabine ($500\;mg/m^2$) and cisplatin ($30\;mg/m^2$) were encouraging in patients with locally advanced NSCLC. However, treatment related toxicities were significant, indicating that further modification of therapy seems to be warranted.

• Tuberculosis and Respiratory Diseases
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• v.60 no.3
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• pp.304-313
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• 2006

Background : Heme oxygenase-1 (HO-1) is an inducible enzyme that catalyzes the oxidative degradation of heme to form biliverdin, carbon monoxide (CO), and free iron. The current evidence has indicated a critical role of HO-1 in cytoprotection and also in other, more diverse biological functions. It is known that the high expression of HO-1 occurs in various tumors, and that HO-1 has an important role in rapid tumor growth because of its antioxidative and antiapoptotic effects. Therefore, the role of HO-1 was analyzed in human lung cancer cell lines, and especially in the A549 cell line. Material and Methods : Human lung cancer cell lines, i.e., A549, NCI-H23, NCI-H157 and NCI-H460, were used for this study. The expression of HO-1 in the untreated state was defined by Western blotting. ZnPP, which is the specific HO inhibitor we used, and the viability of cells were tested for by conducting MTT assaysy. The HO enzymatic activity, as determined via the bilirubin level, was also indirectly measured. Moreover, the generation of intracellular hydrogen peroxide (H2O2) was monitored fluorimetrically with using a scopoletin-horse radish peroxidase (HRP) assay and 2',7'-dichlorofluorescein diacetate (DCFH-DA). We have also transfected small HO-1 interfering RNA (siRNA) into A549 cells, and the apoptotic effects were evaluated by flow cytometric analysis and Western blotting. Results : The A549 cells had a greater expression of HO-1 than the other cell lines, whereas ZnPP significantly decreased the viability of the A549 cells more than the viability of the other lung cancer cells in a dose-dependant fashion. Consistent with the viability, the HO enzymatic activity also was decreased. Moreover, intracellular H2O2 generation via ZnPP was induced in a dose-dependent manner. Apoptotic events were, then induced in the HO-1 siRNA transfected A549 cells. Conclusion : HO-1 provides new important insights into the possible molecular mechanism of the antitumor therapy in lung cancer.

• Radiation Oncology Journal
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• v.13 no.4
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• pp.311-319
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• 1995

Purpose : To evaluate the survival and prognostic factors in patients with stage III non-small cell lung cancer treated with curative radiotherapy alone or combined with chemotherapy Materials and Methods : A retrospective analysis was undertaken of 35 patients who had locally advanced non-small-cell lung cancer and treated with curative radiotherapy in Department of Therapeutic Radiology, Kangdong Sacred Heart Hospital, from January 1991 through December 1993. According to AJCC staging, 15 patients were stage IIIA, and 20 were stage IIIB. Radiotherapy was delivered with 1 8-2 Gy per fraction/day. 5 days per week using 6 MV X-ray, to a total dose ranging from 48.8 Gy to 66.6 Gy (median, 61.2 Gy) in 4 to 9 weeks. Ten patients received neoadjuvant or concurrent chemotherapy with FIP (5-FU, ifosfamide, and cisplatin) or FP (5-FU and cisplatin) Results : For all Patients, median survival was 6 months. 1-year and 2-year survival rates were 23.3% and 6.7%, respectively The median survival was 8 months in stage IIIA and 5.5 months in stage IIIB. In patients treated with radiation therapy alone, median survival was 5 months and 1-year survival rate was 9%. In patients who received chemotherapy, median survival was 11 months and 1-year survival rate was 60%. The difference of survival between these two groups was statistically significant (p=0.03). Total radiation dose, degree of response, and Post-treatment ECOG score were also significantly associated with survival. But it was not affected by age, sex, pretreatment ECOG score, presence or absence of weight loss, tumor location. pathologic type, N stage, and degree of response to treatment. Conclusion : Conventional radiotherapy alone is unlikely to achieve long term survival in patients with stage III NSCLC. Radiotherapy with altered fractionation schedule or multimodality treatment combined with surgery and/or chemotherapy should be considered if feasible.

• Radiation Oncology Journal
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• v.22 no.1
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• pp.1-10
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• 2004

Locally advanced (Stage III) non-small cell lung cancer (NSCLC) accounts for approximately one third of all cases of NSCLC. Few patients with locally advanced NSCLC present with disease amenable to curative surgical resection. Historically, these patients were treated with primary thoracic radiation therapy (RT) and had poor long term survival rates, due to both progression of local disease and development on distant metastases. Over the last two decades, the use of multidisciplinary approach has improved the outcome for patients with locally advanced NSCLC. Combined chemoradiotherapy is the most favored approach for treatment of locally advanced unresectable NSCLC. There are two basic treatment protocols for administering combined chemotherapy and radiation, sequential versus concurrent. The rationale for using chemotherapy is to eliminate subclinical metastatic disease while improving local control. Sequential use of chemotherapy followed by radiotherapy has improved median and long term survival compared to radiation therapy alone. This approach appears to decrease the risk of distant metastases,, but local failure rates remain the same as radiation alone. Concurrent chemoradiotherapy has been studied extensively. The potential advantages of this approach may include sensitization of tumor cells to radiation by the administration of chemotherapy, and reduced overall treatment time compared to sequential therapy; which is known to be important for improving local control in radiation biology. This approach Improves survival primarily as a result of improved local control. However, it doesn't seem to decrease the risk of distant metastases probably because concurrent chemoradiation requires dose reductions in chemotherapy due to increased risks of acute morbidity such as acute esophageal toxicity. Although multidisciplinary therapy has led to improved survival rates compared to radiation therapy alone and has become the new standard of care, the optimal therapy of locally advanced NSCLC continues to evolve. The current issues in the multidisciplinary management of locally advanced NSCLC will be reviewed in this report.

• Tuberculosis and Respiratory Diseases
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• v.45 no.1
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• pp.68-76
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• 1998

Background: Patients with centrally recurred bronchogenic carcinoma make a complaint of many symptoms like hemoptysis, cough & dyspnea. At these conditions, the goal of treatment is only to relieve their symptoms. High dose rate brachytherapy(HDR-BT) is the palliative treatment modality of centrally located endobronchial tumor regardless of previous external irradiation(XRT) on the same site in symptomatic patients. Methods: We studied the effects of HDR-BT in 26 patients with symptomatic recurrent lung cancer. Patients(male: 24, mean age: 54yrs)were treated with HDR-BT underwent bronchoscopic placement of $^{192}Ir$ HDR after loading unit(Gammamed$^{(T)}$, Germany) to deliver 500cGY intraluminal irradiation at a depth of 1cm every lwk on 3 occasions. Evaluation at base line and 4wks after HDR brachytherapy included chest X-ray, bronchscopy, symptoms (Standadized Scale for dyspnea,cough,hemoptysis), and Karnofsky performance scale. Results: Endobronchial obstruction was improved in 11/26 patients(37%). Atelectasis in chest X-ray was improved in 5/15 patients(33%). Hemoptysis, dyspnea & cough were improved in 5/10 patients (50%), 5/8 patients (62%) & 10/18 patients (56%) respectively. Karnofsky performance status was changed from 76.4 scores in pretreatment to 77.6 scores after treatment. During HDR-BT, massive hemoptysis (2 patients) and pneumothorax(1 patient) were occurred as complications. Conclusion: We concluded that HDR-BT gave additional benefits for the control of symptoms and general performance and endobronchial obstruction & atelectasis. And HDR-BT will be an additional treatment for the recurrent and endobronchial obstructive lung cancer.