• Tuberculosis and Respiratory Diseases
• /
• v.67 no.5
• /
• pp.413-421
• /
• 2009

Background: MicroRNAs (miRNAs) play an important role in the regulation of cell proliferation, apoptosis, development and differentiation. Several studies have shown that aberrant expression of miRNAs is involved in cancer development and progression by regulating the expression of proto-oncogenes or tumor suppressor genes. In this study, we investigated miRNA expression profiles in Korean patients with non-small cell lung cancer (NSCLC). Methods: We performed miRNA microarray analysis containing 60~65 bp oligonucleotide probes representing human 318 miRNAs and validated the results of the microarray with Northern blot analysis or quantitative RT-PCR. Next, we examined the correlation between miRNA expression and the target gene transcriptional profile using a human whole-genome-expression microarray. Results: We showed that 35 miRNAs were expressed differentially in the NSCLCs and corresponding non-malignant lung tissues. We showed that 35 miRNAs were expressed differentially in the NSCLCs and corresponding nonmalignant lung tissues. Thirteen of the 35 differentially expressed miRNAs were newly identified in the present study. Of the 35 miRNAs, 2 (miR-371 and miR-210) were over-expressed in lung cancers, and 33 miRNAs, including miR-145, were under-expressed in lung cancers. miR-99b expression consistently showed a negative correlation with FGFR3 expression. Conclusion: Albeit a small number of patients were examined, these results suggest that miRNA expression profiles in Korean lung cancers may be somewhat different from the expression profiles reported on lung cancers in Western populations. The findings suggest that miR-99b might be a tumor suppressor through its up-regulation of FGFR3.

• Tuberculosis and Respiratory Diseases
• /
• v.56 no.6
• /
• pp.646-656
• /
• 2004

Background : The aim of this study was to elucidate the mediastinal lymphatic drainage of nonsmall- cell lung cancer (NSCLC). Methods : We retrospectively analyzed the frequency of enlarged mediastinal lymph node (LN) in 256 NSCLC patients with N2 or N3 diseases on CT scan, especially with respect to the location of primary tumor. Results : In 57 patients with right upper lobe (RUL) tumors, right lower paratracheal LN (89.5%) was the most commonly enlarged, followed by subcarinal LN (54.4%). In 61 patients with left upper lobe (LUL) tumors, left lower paratracheal (70.5%) and subaortic LNs (52.5%) were commonly enlarged. Subcarinal LN enlargement without ipsilateral superior mediastinal LN enlargement was rarely found in both upper lobe tumors; RUL 8.8%, LUL 6.6%. In patients with right or left lower lobe (RLL or LLL) tumors, the most commonly enlarged LN was subcarinal; 88.2%, 65.7%, respectively. In RLL tumors with both subcarinal and superior mediastinal LN enlargements, the frequency of ipsilateral superior mediastinal LN involvement was similar to that of bilateral superior mediastinal involvement. In LLL tumors with both subcarinal and superior mediastinal LN enlargements, bilateral superior mediastinal involvement was more frequent than ipsilateral superior mediastinal involvement. Conclusion : The results of this study suggest that both upper lobe tumors are mainly drained directly to ipsilateral superior mediastinal LNs, and that both lower lobe lesions are drained to superior mediastinal LN via subcarinal LNs.

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

• Radiation Oncology Journal
• /
• v.27 no.4
• /
• pp.228-239
• /
• 2009

Purpose: 4DCT scans performed for radiotherapy were retrospectively analyzed to assess the possible benefits of respiratory gating in non-small cell lung cancer (NSCLC) and established the predictive factors for identifying patients who could benefit from this approach. Materials and Methods: Three treatment planning was performed for 15 patients with stage I~III NSCLC using different planning target volumes (PTVs) as follows: 1) PTVroutine, derived from the addition of conventional uniform margins to gross tumor volume (GTV) of a single bin, 2) PTVall phases (patient-specific PTV), derived from the composite GTV of all 6 bins of the 4DCT, and 3) PTVgating, derived from the composite GTV of 3 consecutive bins at end-exhalation. Results: The reductions in PTV were 43.2% and 9.5%, respectively, for the PTVall phases vs. PTVroutine and PTVgating vs. PTVall phases. Compared to PTVroutine, the use of PTVall phases and PTVgating reduced the mean lung dose (MLD) by 18.1% and 21.6%, and $V_{20}$ by 18.2% and 22.0%, respectively. Significant correlations were seen between certain predictive factors selected from the tumor mobility and volume analysis, such as the 3D mobility vector, the reduction in 3D mobility and PTV with gating, and the ratio of GTV overlap between 2 extreme bins and additional reductions in both MLD and $V_{20}$ with gating. Conclusion: The additional benefits with gating compared to the use of patient-specific PTV were modest; however, there were distinct correlations and differences according to the predictive factors. Therefore, these predictive factors might be useful for identifying patients who could benefit from respiratory-gated radiotherapy.

• Journal of Korean Neurosurgical Society
• /
• v.64 no.6
• /
• pp.983-994
• /
• 2021

Objective : The effectiveness of gamma knife radiosurgery (GKR) in the treatment of brain metastases is well established. The aim of this study was to evaluate the efficacy and safety of maximizing the radiation dose in GKR and the factors influencing tumor control in cases of small and medium-sized brain metastases from non-small cell lung cancer (NSCLC). Methods : We analyzed 230 metastatic brain tumors less than 5 mL in volume in 146 patients with NSCLC who underwent GKR. The patients had no previous radiation therapy for brain metastases. The pathologies of the tumors were adenocarcinoma (n=207), squamous cell carcinoma (n=18), and others (n=5). The radiation doses were classified as 18, 20, 22, and 24 Gy, and based on the tumor volume, the tumors were categorized as follows : small-sized (less than 1 mL) and medium-sized (1-3 and 3-5 mL). The progression-free survival (PFS) of the individual 230 tumors and 146 brain metastases was evaluated after GKR depending on the pathology, Eastern Cooperative Oncology Group (ECOG) performance score (PS), tumor volume, radiation dose, and anti-cancer regimens. The radiotoxicity after GKR was also evaluated. Results : After GKR, the restricted mean PFS of individual 230 tumors at 24 months was 15.6 months (14.0-17.1). In small-sized tumors, as the dose of radiation increased, the tumor control rates tended to increase (p=0.072). In medium-sized tumors, there was no statistically difference in PFS with an increase of radiation dose (p=0.783). On univariate analyses, a statistically significant increase in PFS was associated with adenocarcinomas (p=0.001), tumors with ECOG PS 0 (p=0.005), small-sized tumors (p=0.003), radiation dose of 24 Gy (p=0.014), synchronous lesions (p=0.002), and targeted therapy (p=0.004). On multivariate analyses, an improved PFS was seen with targeted therapy (hazard ratio, 0.356; 95% confidence interval, 0.150-0.842; p=0.019). After GKR, the restricted mean PFS of brain at 24 months was 9.8 months (8.5-11.1) in 146 patients, and the pattern of recurrence was mostly distant within the brain (66.4%). The small and medium-sized tumors treated with GKR showed radiotoxicitiy in five out of 230 tumors (2.2%), which were controlled with medical treatment. Conclusion : The small-sized tumors were effectively controlled without symptomatic radiation necrosis as the radiation dose was increased up to 24 Gy. The medium-sized tumors showed potential for symptomatic radiation necrosis without signifcant tumor control rate, when greater than 18 Gy. GKR combined targeted therapy improved the tumor control of GKR-treated tumors.

• Journal of Chest Surgery
• /
• v.42 no.2
• /
• pp.206-213
• /
• 2009

Background: Previous series have suggested that younger patients with primary lung cancer exhibit a more aggressive disease course with a worse prognosis, as compared to older patients, although this issue is still debatable. Material and Method: We reviewed the medical records of 79 patients (32 patients 50 years and younger (Group I) and 47 patients 70 years and older (Group II)) who underwent curative resection for primary lung cancer between July 2000 and June 2008. Result: The median age of the patients was 46.5 years in Group I and this was 73 years in Group II. The older patients were more likely to have major comorbidities (44% versus 77%, respectively; p=0.003). Histological examinations identified that the minor histological types (excluding non-small cell lung cancer (NSCLC)) were predominantly found in the Group I patients (16% versus 2%, respectively; p=0.037). For the TNM staging of the NSCLC, with excluding the minor histologic types, a higher proportion of patients had stage III disease in Group I (33% versus 13%, respectively; p=0.038). There was no significant difference in major morbidity (16% versus 30%, respectively; p=0.148) and operative mortality (0% versus 4.3%; p=0.512) between the groups. The mean follow-up interval was 33 months (range: $1{\sim}98$ months) for patients in both groups. For the patients with NSCLC, the five-year overall survival rate was 52.3% for Group I and 53.7% for Group II (p=0.955). The rate of freedom from recurrence at five years was significantly lower for the Group I patients than for the Group II patients (39.4% versus 70.4%, respectively; p=0.027), and only being a member of Group I impacted recurrence, based on the Cox proportional hazard analysis (p=0.034). Of the patients who had recurrence, four patients in Group I underwent aggressive surgical treatment. All of these patients exhibited long-term survival (range: $46{\sim}87$ months). Conclusion: In our study, the early outcome and long-term survival were similar for the younger and older patients after curative resection of primary lung cancer. However, we think that younger patients require meticulous follow-up as they had a tendency to proceed to surgery with advanced stage disease, a higher recurrence rate than did the older patients and the survival rates were improved, even for the recurred cases, with early aggressive treatment.

• Asian Pacific Journal of Cancer Prevention
• /
• v.14 no.7
• /
• pp.4421-4426
• /
• 2013

Objective: The present study employed 5-aza-2'-deoxycytidine (5-Aza-CdR) to treat non-small cell lung cancer (NSCLC) cell line A549 to investigate the effects on proliferation and expression of the TFPI-2 gene. Methods: Proliferation was assessed by MTT assay after A549 cells were treated with 0, 1, 5, 10 ${\mu}mol/L$ 5-Aza-CdR, a specific demethylating agent, for 24, 48 and 72h. At the last time point cells were also analyzed by flow cytometry (FCM) to identify any change in their cell cycle profiles. Methylation-specific polymerase chain reaction (MSPCR), real time polymerase chain reaction(real-time PCR) and western blotting were carried out to determine TFPI-2 gene methylation status, mRNA expression and protein expression. Results: MTT assay showed that the growth of A549 cells which were treated with 5-Aza-CdR was significantly suppressed as compared with the control group (0 ${\mu}mol/L$ 5-Aza-CdR). After treatment with 0, 1, 5, 10 ${\mu}mol/L$ 5-Aza-CdR for 72h, FCM showed their proportion in G0/G1 was $69.7{\pm}0.99%$, $76.1{\pm}0.83%$, $83.8{\pm}0.35%$, $95.5{\pm}0.55%$ respectively (P<0.05), and the proportion in S was $29.8{\pm}0.43%$, $23.7{\pm}0.96%$, $15.7{\pm}0.75%$, $1.73{\pm}0.45%$, respectively (P<0.05), suggesting 5-Aza-CdR treatment induced G0/G1 phase arrest. MSPCR showed that hypermethylation in the promoter region of TFPI-2 gene was detected in control group (0 ${\mu}mol/L$ 5-Aza-CdR), and demethylation appeared after treatment with 1, 5, 10 ${\mu}mol/L$ 5-Aza-CdR for 72h. Real-time PCR showed that the expression levels of TFPI-2 gene mRNA were $1{\pm}0$, $1.49{\pm}0.14$, $1.86{\pm}0.09$ and $5.80{\pm}0.15$ (P<0.05) respectively. Western blotting analysis showed the relative expression levels of TFPI-2 protein were $0.12{\pm}0.01$, $0.23{\pm}0.02$, $0.31{\pm}0.02$, $0.62{\pm}0.03$ (P<0.05). TFPI-2 protein expression in A549 cells was gradually increased significantly with increase in the 5-Aza-CdR concentration. Conclusions: TFPI-2 gene promoter methylation results in the loss of TFPI-2 mRNA and protein expression in the non-small cell lung cancer cell line A549, and 5-Aza-CdR treatment could induce the demethylation of TFPI-2 gene promoter and restore TFPI-2 gene expression. These findings provide theoretic evidence for clinical treatment of advanced non-small cell lung cancer with the demethylation agent 5-Aza-CdR. TFPI-2 may be one molecular marker for effective treatment of advanced non-small cell lung cancer with 5-Aza-CdR.

• Tuberculosis and Respiratory Diseases
• /
• v.45 no.5
• /
• pp.984-991
• /
• 1998

Background: The 3p deletions has been shown to be the most frequent alteration in lung cancers, strongly suggesting the presence of at least one tumor suppressor gene in this chromosomal region. However, no solid candidate for the tumor suppressor gene(s) on 3p has as yet been identified. Recent attention has focused on a candidate 3p14.2 tumor suppressor gene, FHIT, which is located in a region that is homozygously deleted in multiple tumor cell lines and disrupted by the hereditary renal cell carcinoma t(3;8) chromosomal translocation breakpoint FHIT also spans FRA3B, the most common fragile sites in the human genome. In the present study, we have analyzed expression of the FHIT gene in lung cancer cell lines. Methods: RNA from 21 lung cancer cell lines (16 NSCLC, 5 SCLC) were extracted using standard procedures. Random-primed. first strand cDNAs were synthesized from total RNA and PCR amplication of coding exons 5 to 9 was performed. The RT-PCR products were electrophoresed in 1.5% ethidium bromide-stained agarose gels. Results: 12 of 21(57%) lung cancer cell lines exhibited absent or aberrant FHIT expression [7 of 16(44%) of non-small cell lung cancer and 5 of 5(100%) of small cell lung cancer cell lines]. Conclusion: The result shows that abnormal transcription of the FHIT gene is common in human lung cancer cell lines, especially in small cell lung cancer.

• Radiation Oncology Journal
• /
• v.33 no.2
• /
• pp.89-97
• /
• 2015

Purpose: To evaluate the treatment results in early stage non-small cell lung cancer patients who have undergone fiducial-less CyberKnife radiosurgery (CKRS). Materials and Methods: From June 2011 to November 2013, 58 patients underwent CKRS at Asan Medical Center for stage I lung cancer. After excluding 14 patients, we retrospectively reviewed the records of the remaining 44 patients. All analyses were performed using SPSS ver. 21. Results: The median age at diagnosis was 75 years. Most patients had inoperable primary lung cancer with a poor pulmonary function test with comorbidity or old age. The clinical stage was IA in 30 patients (68.2%), IB in 14 (31.8%). The mean tumor size was 2.6 cm (range, 1.2 to 4.8 cm), and the tumor was smaller than 2 cm in 12 patients (27.3%). The radiation dose given was 48-60 Gy in 3-4 fractions. In a median follow-up of 23.1 months, local recurrence occurred in three patients (2-year local recurrence-free survival rate, 90.4%) and distant metastasis occurred in 13 patients. All patients tolerated the radiosurgery well, only two patients developing grade 3 dyspnea. The most common complications were radiation-induced fibrosis and pneumonitis. Eight patients died due to cancer progression. Conclusion: The results showed that fiducial-less CKRS shows comparable local tumor control and survival rates to those of LINAC-based SABR or CKRS with a fiducial marker. Thus, fiducial-less CKRS using Xsight lung tracking system can be effectively and safely performed for patients with medically inoperable stage I non-small cell lung cancer without any risk of procedure-related complication.

• Journal of Chest Surgery
• /
• v.34 no.12
• /
• pp.924-929
• /
• 2001

Backgroun : The long-term survival after operation of patients with lung cancer invading the chest wall is known to be related to regional nodal involvement, completeness of resection and depth of chest wall involvement. In this study results of complete resection are reviewed to determine survival charateristics. Material and Method: Of 680 consecutive patients who were operated on for primary non-small cell carcinoma between 1988 and 1998, we retrospectively reviewed 55 patients(8.0%) who had complete resection for lung cancer invading the chest wall or parietal pleura. Result: Resection of the chest wall was on bloc in 29 patients(47.3％), and extrapleural in 26(52.7％). In the patients undergoing extrapleural resection, the depth of chest wall invasion was confined to the parietal pleura in all patients(100%). In the patients underging en bloc resection, the pathologic depth of invasion was into the parietal pleura alone in 9(31.0%) and into the chest wall in 20(69.0%). The follow-up rate of these patients was 100%. Hospital mortality was 5.4%(n=3). The actuarial 5-year survival rate was 26% for all hospital survivors(n=52). The actuarial 5-year survival rate of patients with T3N0M0 disease(29%) was better than that of T3N2M0 disease(18%), however, there was no significant(p=0.30) difference. The depth of chest wall invasion had no statistically significant effect on survival in our series, neither for patients with involved lymphatic metastasis nor for those without(p=0.99). Conclusion: These observations indicate that the good five year survival in patients with T3 NSCLC invading the chest wall resulted from complete resection. Survival of patients with lung cancer invading the chest wall after complete resection is dependent on the extent of nodal involvement and much less so on the depth of chest wall invasion.