• Radiation Oncology Journal
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• v.16 no.3
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• pp.275-282
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• 1998

Purpose : The effect of hyperfractionated radiotherapy on locally advanced non-small lung cancer was studied by a retrospective analysis. Materials & Methods : We analyzed sixty one patients of biopsy-confirmed, IIIA and IIIB non-small cell lung cancer. Using the ECOG performance scale, all the patients were scored less than 2. They were treated by curative hyperfractionated radiotherapy alone from Oct. 1992 to Oct. 1995 at the Department of Radiation Oncology. All the patients received 120cGy b.i.d with more than 6 hours interval between each fraction. The total dose of radiation was reached up to 6400-7080 cGy with a mean dose of 6934 cGy. The results were analyzed retrospectively. Results : The overall survival rate was 53 1$\%$ in 1 year, 9.9$\%$ in 2 years with a median survival time (MST) of 13.9 months. The progression free survival (PFS) rate was 37.0$\%$ in 1 year, 8.9$\%$ in 2 years. Twenty two Patients were classified as complete responders to this treatment and their MST was 19.5 months When this was compared with that of partial responders (MST: 11 7months), it was statistically significant (p=0.0003). Twenty nine patients of stage IIIA showed a better overall survival rate (1yr 63.3$\%$, 2yr 16.8$\%$) than IIIB patients (1yr 43.3$\%$, 2yr 3.6$\%$), which was also statistically significant (p=0.003). Patients with adenocarcinoma showed a better survival rate (1yr 64.3$\%$, 2yr 21.4$\%$) than that of squamous cell counterpart (1yr 49.4$\%$, 2yr 7.4$\%$), although this was not significant statistically (p=0.61). Two patients developed fatal radiation-induced pneumonia right after the completion of the treatment which progressed rapidly and they all died within 2 months. One patient developed radiation-induced fibrosis after 13 months. He refused further treatment and died soon after the development of fibrosis. Conclusion : Among locally advanced NSCLC, hyperfractionated radiotherapy was effective on stage IIIA patients by increasing MST with acceptable toxicities. Acute radiation-induced pneumonia should be carefully monitored and must be avoided during or after this treatment.

• Tuberculosis and Respiratory Diseases
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• v.57 no.4
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• pp.336-344
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• 2004

Background : Immunotherapy for cancer has not been successful because of several obstacles in tumor and its environment. Inappropriate secretions of cytokines and growth factors by tumors cause substantial changes in the immune responses against tumors, affording the tumors some degree of protection from immune attack. Uteroglobin (UG, Clara cell secretory protein) has been known to have anti-inflammatory, immunomodulatory and anti-cancer activities. However, in lung cancer cells, UG expression is decreased. This study investigated the role of UG in the immunomodulation of lung cancer. Methods : The UG protein was overexpressed by Adenovirus(Ad)-UG transduction in non-small cell lung cancer cell lines. The concentration of Prostaglandin $E_2$ ($PGE_2$) was measured by Enzyme Immunoassay (EIA). Peripheral blood mononuclear cells (PBMC) from whole blood were prepared with Ficoll. PBMC were cultured in RPMI 1640, supernatant of A549, or A549 with UG or NS-398. Concentration of Th 1 type and Th 2 type cytokines from PBMC were measured by ELISA. Results : UG suppressed $PGE_2$, Cyclooxygenase-2 (COX-2) product. Both Th1 type such as Interleukin-2 (IL-2), Interferon-${\gamma}$ (IFN-${\gamma}$) and Tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and Th2 type cytokines such as IL-10 and Tumor growth factor-${\beta}$ (TGF-${\beta}$) were increased when PBMC were cultured with supernatant of non small lung cancer cells. UG and COX-2 inhibitor, NS-398 induced normal immune response of PBMC. Although Th 1 type cytokines were increased, Th 2 type cytokines were reduced by UG. Conclusion : UG suppressed PGE2, COX-2 product. Supernatant of NSCLC induced imbalance of immune response of PBMC. However, UG reversed this imbalance. These results suggest that UG may be used in the development of immunotherapy for lung cancer.

• Tuberculosis and Respiratory Diseases
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• v.66 no.4
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• pp.274-279
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• 2009

Background: Uteroglobin (UG) is a secretary protein that has strong immunomodulatory properties, and which is synthesized in most epithelia including lung tissue. Overexpression of UG is associated with decreased expression of cyclooxygenase (COX)-2 and suppression of cancer cell growth. Indoleamine 2,3-dioxygenase (IDO) catalyzes tryptophan along the kynurenine pathway, and both the reduction in local tryptophan and the production of tryptophan metabolites contribute to the immunosuppressive effects of IDO. Methods: In this study, we investigated the pattern of expression of COX-2 and IDO, and the effect of UG transduction in the expression of COX-2 and IDO in several non-small cell lung cancer cell lines, especially A549. Results: Both COX-2 and IDO were constitutionally expressed in A549 and H460 cells, and was reduced by UG transduction. In A549 cells, the slightly increased expression of COX-2 and IDO with the instillation of interferon-gamma (IFN-$\gamma$) was reduced by UG transduction. However, the reduced expression of COX-2 and IDO by UG transduction was not increased with IFN-$\gamma$ instillation in A549 cells. In both the A549 COX-2 sense and the A549 COX-2 anti-sense small interfering RNA (siRNA)-transfected cells, IDO was expressed; expression was reduced by UG transduction, irrespective of the expression of COX-2. Conclusion: The results suggest that the anti-proliferative function of UG may be associated with the immune tolerance pathway of IDO, which is independent of the COX-2 pathway.

• 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.

• Journal of Chest Surgery
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• v.40 no.6 s.275
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• pp.428-434
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• 2007

Background: Recent studies have suggested that UFT may be an effective adjuvant therapy for completely resected IB (pT2N0) non-small cell lung cancer (NSCLC). We designed this study to clarify the feasibility of performing adjuvant chemotherapy with UFT for completely resected IB nor-small cell lung cancer, Material and Method: We randomly assigned patients suffering with completely resected IB non-small cell lung cancer to receive either UFT 3g for 2 year or they received no treatment. All patients had to be followed until death or the cut-off date (December 31 2006). Result: From June 2002 through December 2004, 64 patients were enrolled. Thirty five patients were assigned to receive UFT (the UFT group) and 29 patients were assigned to observation (the control group). A follow-up surrey on the 3 year survival rate was successfully completed for all the patients. The median follow-up time for all the patients was 32.8 months. In the UFT group, the median time of administration was 98 weeks (range: $2{\sim}129$ weeks). The rate of compliance was 88.2% at 6 months, 87.5% at 12 months, 80.6% at 18 month and 66.7% at 24 months. Seven recurrences (24.1%) occurred in the control group and six (17.1%) occurred in the UFT group (p=0,489). The three-year disease free survival rate was 71.3% for the control group and 82.0% for the UFT group (p=0.331). On the subgroup analysis, the three-year disease free survival rate for the patients with adenocacinoma was 45.0% for the control group and 75.2% for the UFT group (p=0.121). The three-year disease free survival rate for the patients with non-adenocarcinoma was 88.1% for the control group and 88.9% for the UFT group (p=0.964), Conclusion: Postoperative oral administration of UFT was well-tolerated. Adjuvant chemotherapy with UFT for completely resected pT2N0 adenocarcinoma of the lung could be expected to improve the disease free survival, but this failed to achieve statistical significance. A prospective randomized study for a large number of patients will be necessary.

• Journal of Chest Surgery
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• v.42 no.6
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• pp.725-731
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• 2009

Background: Lobectomy and more extended anatomic resection are regarded as standard treatment for stage Ia non-small cell lung cancer, but approximately 15~40% of patients suffer from treatment failures such as cancer recurrence or death. The authors analyzed types and causes of treatment failures in surgically treated cases of stage Ia non small cell lung cancer. Material and Method: We retrospectively reviewed the medical records of 156 patients who had undergone complete resection for stage Ia NSCLC between Jan 1992 and Aug 2005. Patients were divided into two different treatment failure groups: cancer-related deaths and non-cancer-related deaths. Risk factors were analyzed in each group by the Kaplan-Meyer survival method and the Cox proportional hazard model. Result: Among the 156 patients, 93 were males; the mean age was 61. The median follow-up period was 33.8 months. The 5 year survival rate was 87.6%. Microscopic lympho-vascular permeation was reported in 10 patients. Recurrence was reported in 19 patients and 12 patients died due to recurrent lung cancer. Noncancer related deaths occurred in 16 patients. Risk factors for cancer recurrence and cancer related death were microscopic lympho-vascular permeation (HR=6.81, p=0.007, HR=7.81, p<0.001); for non-cancer related death, risk factors were pneumonectomy (HR=25.92, p=0.001) and postoperative cardiopulmonary complications (HR=29.67, p=0.002). Conclusion: After complete resection of stage Ia non small cell lung cancer patients, mortality includes not only cancer related deaths but also cancer unrelated deaths. Adjuvant chemotherapy is advised for patients who show microscopic lympho-vascular permeation, which is a risk factor for recurrence and for cancer related death. Patients who had pneumonectomy or who suffered from cardiac or respiratory complications need meticulous care in order to reduce comorbidity-induced death.

• Journal of Chest Surgery
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• v.39 no.2 s.259
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• pp.106-110
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• 2006

Background: Bronchioloalveolar carcinoma (BAC) is an uncommon primary malignancy of the lung, and it accounts for $2{\~}14\%$ of all pulmonary malignancies. According to World Health Organization (WHO) categorisation, BAC is a subtype of adenocarcinoma. The current definition of BAC includes the following: malignant neoplasms of the lung that have no evidence of extrathoracic primary adenocarcinoma, an absence of a central bronchogenic source, a peripheral parenchymal location, and neoplastic cells growing along the alveolar septa. Previous reports had demonstrated a better prognosis following surgery for patients affected by BAC than those affected by other type of non-small cell lung cancer (NSCLC). We aim to analyse Asan Medical Center experiences of BAC. Material and Method: Between 1990 and 2002, 31 patients were received operations for BAC. We analyse retrosepectively sex, age, disease location, preoperative clinical stage, postoperative pathologic stage & complications, survival according to medical record. Result: There were 12 men and 19 women, the average age was 61.09$\pm$10.63 ($31{\~}79$) years. Tumor locations were 7 in RUL, 1 in RML, 4 in RLL, 8 in LUL, 11 in LLL. Operations were 28 lobectomies, 2 pneumonectomies. Postoperative pathologic stage were 12 T1N0M0, 15 T2N0M0, 1 T1N1M0, 1 T1N2M0, 1 T2N2M0, 1 T1N0M1. Mortality were 4 cases ($12.9\%$) and there were no early mortality. Cancer free death was 1 cases, other 3 were cancer related deaths. All of them were affected by distal metastasis and received chemotherapy and each metastatic locations were right rib, brain, and both lung field. The average follow up periods were 50.87$\pm$24.77 months. The overall 3, 5-year survival rate among all patients was $97.1\%,\;83.7\%$, stage I patients overall 2, 5year survival rate was $96.3\%$. The overall disease free 1, 2, 5-year survival rate among all patients was $100\%,\;90\%,\;76\%$ and 2, 5-year survival rate in cases of stage I was $96.4\%,\;90.6\%$. 7 cases ($22.58\%$) were chemotherapies, 1 case ($3.22\%$) was radiation therapy, and 2 cases ($6.45\%$) were chemoradiation therapies. Metastatic locations were 3 cases in lung, 1 case in bone, 1 cases in brain. Conclusion: BAC has a favourable survival and low recurrence rate compare with reported other NSCLC after operative resections.

• Radiation Oncology Journal
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• v.11 no.2
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• pp.295-301
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• 1993

Since Jan. 1991 a prospective randomized study for Stage III unresectable non small cell lung cancer (NSCLC) has been conducted to evaluate the response rate and tolerance of induction chemotherapy with MVP followed by hyperfractionated radiotherapy and evaluate the efficacy of maintenance chemotherapy in Asan Medical Center. All patients in this study were treated with hyperfractionated radiotherapy (120 cGy/fx BID, 6480 cGy/54 fx) following 3 cycles of induction chemotherapy, MVP (Mitomycin C 6 $mg/m^2,$ Vinblastin 6 $mg/m^2,$ Cisplatin 60 $mg/m^2$) and then the partial and complete responders from induction chemotherapy were randomized to 3 cycles of adjuvant MVP chemotherapy group and observation group. 48 patients were registered to this study until December 1992; among 48 patients 3 refused further treatment after induction chemotherapy and 6 received incomplete radiation therapy because of patient's refusal, 39 completed planned therapy. Twenty-three $(58\%)$ patients including 2 complete responders showed response from induction chemotherapy. Among the 21 patients who achieved a partial response after induction chemotherapy,1 patient rendered complete clearance of disease and 10 patients showed further regression of tumor following hyperfractionated radiotherapy. Remaining 10 patients showed stable disease or progression after radiotherapy. Of the sixteen patients judged to have stable disease or progression after induction chemotherapy, seven showed more than partial remission after radiotherapy but nine showed no response in spite of radiotherapy. Of the 39 patients who completed induction chemotherapy and radiotherapy, 25 patients $(64\%)$ including 3 complete responders showed more than partial remission. Nineteen patients were randomized after radio-therapy. Nine Patients were allocated to adjuvant chemotherapy group and 4/9 showed further regression of tumor after adjuvant chemotherapy. For the time being, there is no suggestion of a difference between the adjuvant chemotherapy group and observation group in distant metastasis rate and survival. Median survival time was 13 months. Actuarial survival rates at 6,12 and 18 months of 39 patients who completed this study were $84.6\%,\;53.7\%\;and\;40.3\%,$ respectively. The partial and complete responders from induction chemotherapy showed significantly better survival than non-responders (p=0.028). Incidence of radiation pneumonitis in this study group was less than that in historical control group inspite of induction chemotherapy. All patients tolerated hypertractionated radiotherapy without definite increase of acute complications compared with conventional radiotherapy group. The longer follow up is needed to evaluate the efficacies of induction and maintenance chemotherapy and survival advantage by hyperfractionated radiotherapy but authors are encouraged with an excellent tolerance, higher response rate and improvement of one year survival rate in patients of this study.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7195-7200
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• 2014

Background: The aim of this study was to evaluate how CYP2C19 affects icotinib and metabolite' exposure, and to determine whether the exposure and EGFR genotype influences survival time, tumor metastasis and adverse drug reactions. Materials and Methods: 274 NSCLC patients who accepted 125mg icotinib/t.i.d. were chosen from a phase III study. Blood samples were obtained in $672^{nd}$ ($4^{th}$ week) and $1,680^{th}$ hours ($10^{th}$ week), and plasma was used to quantify the concentration of icotinib and blood cells were sampled to check the genotypes. Clinical data were also collected at the same time, including EGFR genotypes. Plasma concentrations were assessed by HPLC-MS/MS and genotype by sequencing. All data were analyzed through SPSS 17.0 and SAS 9.2. Results: CYP 2C19 genotypes affected bio-transformation from icotinib to M24 and M26, especially in poor-metabolisers. Higher icotinib concentrations (>1000 ng/mL) not only increased patient PFS and OS but also reduced tumor metastasis. Patients with mutant EGFR experienced a higher median PFS and OS (234 and 627 days), especially those with the 19del genotype demonstrating higher PR ratio. Patients who suffered grade II skin toxicity had a higher icotinib exposure than those with grade I skin toxicity or no adverse effects. Liver toxic reactions might occur in patients with greater M20 and M23 plasma concentrations. Conclusions: CYP2C19 polymorphisms significantly affect icotinib, M24 and M26 exposure. Patients with mutant EGFR genotype and higher icotinib concentration might have increased PFS and OS and lower tumor metastasis. Liver ADR events and serious skin effects might be respectively induced by greater M20, M23 and icotinib concentrations.

• Journal of Chest Surgery
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• v.43 no.5
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• pp.506-512
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• 2010

Background: This study was designed to evaluate the FDG uptake ratio of mediastinal node and primary tumors using integrated PET/CT imaging combined with Glut-1 expression of the primary tumor in order to predict the N2 status more accurately in NSCLC patients. Material and Method: Patients who underwent integrated PET/CT scanning with a detectable mSUV for both primary tumors and mediastinal lymph nodes were eligible for this study. The FDG uptake ratio between the mediastinal node and the primary tumor was calculated. Result: The average mSUV of primary tumors and mediastinal nodes were, respectively, $7.4{\pm}2.2$ and $4.2{\pm}2.2$ in N2-positive patients and $7.6{\pm}3.7$ and $2.8{\pm}6.9$ in N2-negative patients. The mean FDG uptake ratio of mediastinal node to primary tumor were $0.58{\pm}0.23$ for malignant N2 lymph nodes and $0.45{\pm}0.20$ for benign lymph nodes (p<0.05). Models which combined Glut-1 expression with an FDG ratio have better diagnostic power than models that use the FDG uptake ratio alone. Conclusion: In some patients with a previous history of pulmonary tuberculosis or other inflammatory lung diseases, an FDG uptake ratio combined with Glut-1 expression may be useful in diagnosing mediastinal node metastasis more exactly.