• 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.

• Radiation Oncology Journal
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• v.27 no.3
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• pp.126-132
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• 2009

Purpose: We wanted to evaluate the prognostic factors for the pathologic N2 non-small cell lung cancer (NSCLC) patients who were treated by postoperative radiotherapy. Materials and Methods: We retrospectively reviewed 112 pN2 NSCLC patients who underwent surgery and postoperative radiotherapy (PORT) From January 1999 to February 2008. Seventy-five (67%) patients received segmentectomy or lobectomy and 37 (33%) patients received pneumonectomy. The resection margin was negative in 94 patients, and it was positive or close in 18 patients. Chemotherapy was administered to 103 (92%) patients. Nine (8%) patients received PORT alone. The median radiation dose was 54 Gy (range, 45 to 66), and the fraction size was 1.8~2 Gy. Results: The 2-year overall survival (OS) rate was 60.2% and the disease free survival (DFS) rate was 44.7% for all the patients. Univariate analysis showed that the patients with multiple-station N2 disease had significantly reduced OS and DFS (p=0.047, p=0.007) and the patients with an advanced T stage ($\geq$T3) had significantly reduced OS and DFS (p<0.001, p=0.025). A large tumor size ($\geq$5 cm) and positive lymphovascular invasion reduced the OS (p=0.035, 0.034). Using multivariate analysis, we found that multiple-station N2 disease and an advanced T stage ($\geq$T3) significantly reduced the OS and DFS. Seventy one patients (63.4%) had recurrence of disease. The patterns of failure were loco-regional in 23 (20.5%) patients, distant failure in 62 (55.4%) and combined loco-regional and distant failure in 14 (12.5%) patients. Conclusion: Multiple involvement of mediastinal nodal stations for the pN2 NSCLC patients with PORT was a poor prognostic factor in this study. A prospective study is necessary to evaluate the N2 subclassification and to optimize the adjuvant treatment.

• 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.

• 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.

• Journal of Chest Surgery
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• v.41 no.5
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• pp.586-590
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• 2008

Background: Non-small cell lung cancer (NSCLC) patients histologically proven to have stage N2 disease by media-stinoscope or thoracoscope underwent subsequent neoadjuvant chemoradiotherapy. This study was designed to find out if there were any differences in survival or recurrence rates between N2 positive and N2 negative patients. Material and Method: Between January 1998 and December 2005, we retrospectively analyzed 69 patients who were divided into three groups. Group A consisted of patients whose N stage was downstaged, group B of patients whose N stage was the same, and Group C of patients who could not undergo surgery because of disease progression during neoadjuvant chemoradiotherapy. We analyzed and compared the mean survival, three-year survival, mean disease-free survival, and three-year disease-free survival rates for the three groups. Result: There were no demographic differences among the groups. The mean survival was 58, 47, and 21 months for groups A, B, and C, respectively. The mean survival was longest in group A, but no statistically significant difference was found on A-B or B-C group comparison (p>0.05). However, a significant difference was noted between group A and group C (p : 0.01). Three-year survival rates were 67%, 41%, and 21.6% for groups A, B, and C, respectively, with a statistical difference similar to that seen in mean survival. The mean disease-free survival was 44 months in group A and 45 months in group B, with no statistically significant difference noted. No significant differences were noted in the three-year disease-free survival rates (55.1%, 46.8%). Conclusion: There were no significant differences in survival or recurrence rates with changes in N stage after neoadjuvant chemoradiotherapy. However, mean survival, three-year survival, and three-year disease-free survival rates tended to be higher in downstaged patients. Nevertheless, the difference was statistically insignificant, and therefore further studies with more patients and longer follow-up are necessary to clarify the positive effects on the survival and prognosis of downstaged patients.

• 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.

• 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.

• The Journal of Korean Society for Radiation Therapy
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• v.26 no.1
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• pp.59-67
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• 2014

Purpose : This study aims to evaluate 3D dosimetric impact for MIP image and each phase image in stereotactic body radiotherapy (SBRT) for lung cancer using volumetric modulated arc therapy (VMAT). Materials and Methods : For each of 5 patients with non-small-cell pulmonary tumors, a respiration-correlated four-dimensional computed tomography (4DCT) study was performed. We obtain ten 3D CT images corresponding to phases of a breathing cycle. Treatment plans were generated using MIP CT image and each phases 3D CT. We performed the dose verification of the TPS with use of the Ion chamber and COMPASS. The dose distribution that were 3D reconstructed using MIP CT image compared with dose distribution on the corresponding phase of the 4D CT data. Results : Gamma evaluation was performed to evaluate the accuracy of dose delivery for MIP CT data and 4D CT data of 5 patients. The average percentage of points passing the gamma criteria of 2 mm/2% about 99%. The average Homogeneity Index difference between MIP and each 3D data of patient dose was 0.03~0.04. The average difference between PTV maximum dose was 3.30 cGy, The average different Spinal Coad dose was 3.30 cGy, The average of difference with $V_{20}$, $V_{10}$, $V_5$ of Lung was -0.04%~2.32%. The average Homogeneity Index difference between MIP and each phase 3d data of all patient was -0.03~0.03. The average PTV maximum dose difference was minimum for 10% phase and maximum for 70% phase. The average Spain cord maximum dose difference was minimum for 0% phase and maximum for 50% phase. The average difference of $V_{20}$, $V_{10}$, $V_5$ of Lung show bo certain trend. Conclusion : There is no tendency of dose difference between MIP with 3D CT data of each phase. But there are appreciable difference for specific phase. It is need to study about patient group which has similar tumor location and breathing motion. Then we compare with dose distribution for each phase 3D image data or MIP image data. we will determine appropriate image data for treatment plan.

• Progress in Medical Physics
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• v.19 no.4
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• pp.263-268
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• 2008

The application of a respiratory gated radiotherpy method to the lung radiation surgery was evaluated compared with the conventional method in which the whole tumor motion range is considered in the delineation of PTV (Planning target volume). The four dimensional CT simulation images were acquired for the five NSCLC (Non-small cell lung cancer) patients for radiation surgery. The respiratory gated plan was prepared with the 50% phase CT images and the conventional method was planned based on the ITV (Internal target volume) which include all the target volumes created in each phase CT images within a whole respiratory period. The DVH (Dose volume histogram) of OAR (Organ at risk) which calculated in each method was compared for the evaluation of the plan properness. The relative decrease of OARs' DVH were verified in the application of respiratory gated method. The average decrease rate were $16.88{\pm}9.97%$ in the bronchus, $34.13{\pm}19.15%$ in the spinal cord, $28.42{\pm}18.49%$ in the chest wall and $32.48{\pm}16.66%$ in the lung. Based on these results, we can verified the applicability and the effectiveness of the respiratory gated method in the lung radiation surgery.