• Journal of Chest Surgery
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• v.57 no.4
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• pp.351-359
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• 2024

Background: Major pulmonary resection after neoadjuvant concurrent chemoradiation therapy (nCCRT) is associated with a substantial risk of postoperative complications. This study investigated postoperative complications and associated risk factors to facilitate the selection of suitable surgical candidates following nCCRT in stage IIIA-N2 non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective analysis of patients diagnosed with clinical stage IIIA-N2 NSCLC who underwent surgical resection following nCCRT between 1997 and 2013. Perioperative characteristics and clinical factors associated with morbidity and mortality were analyzed using univariable and multivariable logistic regression. Results: A total of 574 patients underwent major lung resection after induction CCRT. Thirty-day and 90-day postoperative mortality occurred in 8 patients (1.4%) and 41 patients (7.1%), respectively. Acute respiratory distress syndrome (n=6, 4.5%) was the primary cause of in-hospital mortality. Morbidity occurred in 199 patients (34.7%). Multivariable analysis identified significant predictors of morbidity, including patient age exceeding 70 years (odds ratio [OR], 1.8; p=0.04), low body mass index (OR, 2.6; p=0.02), and pneumonectomy (OR, 1.8; p=0.03). Patient age over 70 years (OR, 1.8; p=0.02) and pneumonectomy (OR, 3.26; p<0.01) were independent predictors of mortality in the multivariable analysis. Conclusion: In conclusion, the surgical outcomes following nCCRT are less favorable for individuals aged over 70 years or those undergoing pneumonectomy. Special attention is warranted for these patients due to their heightened risks of respiratory complications. In high-risk patients, such as elderly patients with decreased lung function, alternative treatment options like definitive CCRT should be considered instead of surgical resection.

• Radiation Oncology Journal
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• v.31 no.4
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• pp.247-251
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• 2013

Purpose: This study aimed to investigate efficient approaches for determining internal target volume (ITV) from four-dimensional computed tomography (4D CT) images used in stereotactic body radiotherapy (SBRT) for patients with early-stage non-small cell lung cancer (NSCLC). Materials and Methods: 4D CT images were analyzed for 15 patients who received SBRT for stage I NSCLC. Three different ITVs were determined as follows: combining clinical target volume (CTV) from all 10 respiratory phases ($ITV_{10Phases}$); combining CTV from four respiratory phases, including two extreme phases (0% and 50%) plus two intermediate phases (20% and 70%) ($ITV_{4Phases}$); and combining CTV from two extreme phases ($ITV_{2Phases}$). The matching index (MI) of $ITV_{4Phases}$ and $ITV_{2Phases}$ was defined as the ratio of $ITV_{4Phases}$ and $ITV_{2Phases}$, respectively, to the $ITV_{10Phases}$. The tumor motion index (TMI) was defined as the ratio of $ITV_{10Phases}$ to $CTV_{mean}$, which was the mean of 10 CTVs delineated on 10 respiratory phases. Results: The ITVs were significantly different in the order of $ITV_{10Phases}$, $ITV_{4Phases}$, and $ITV_{2Phases}$ (all p < 0.05). The MI of $ITV_{4Phases}$ was significantly higher than that of $ITV_{2Phases}$ (p < 0.001). The MI of $ITV_{4Phases}$ was inversely related to TMI (r = -0.569, p = 0.034). In a subgroup with low TMI (n = 7), $ITV_{4Phases}$ was not statistically different from $ITV_{10Phases}$ (p = 0.192) and its MI was significantly higher than that of $ITV_{2Phases}$ (p = 0.016). Conclusion: The $ITV_{4Phases}$ may be an efficient approach alternative to optimal $ITV_{10Phases}$ in SBRT for early-stage NSCLC with less tumor motion.

• Journal of Chest Surgery
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• v.44 no.1
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• pp.32-38
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• 2011

Background: Surgical treatment of stage I non-small cell lung cancer (NSCLC) can be performed either by thoracotomy or by employing video-assisted thoracic surgery (VATS). The aim of this study was to evaluate the feasibility of VATS lobectomy for pathologic stage I NSCLC. Material and Methods: Between December 2003 and December 2007, 529 patients with pathologic stage I NSCLC underwent lobectomies (373 thoracotomy, 156 VATS). Patients in both groups were selected after being matched by age, gender and pathologic stage using propensity score method, to create two comparable groups: thoracotomy and VATS groups, and the overall survival, recurrence-free survival, complication and length of hospitalization were compared between these two groups. Results: After the patients were matched by age, gender and pathologic stage, 272 patients remained eligible for analysis, 136 in each group (mean age of 59.5 years; 70 men, 66 women; 80 stage IA, 56 stage IB). There was no statistical difference in other preoperative clinical characteristics between the two groups. No hospital mortality was observed in both groups. Overall 3-year survival rate was 97.4% in thoracotomy group and 96.6% in VATS groups (p=0.76). During the follow-up, 20 patients (14.7%) developed recurrence in thoracotomy group, including loco-regional recurrence in 7, distant metastasis in 13. In VATS group, 13 patients (9.6%) developed recurrence, including loco-regional recurrence in 4, distant metastasis in 9. Three-year recurrence-free survival rate was 81.8% in thoracotomy group and 85.3% in VATS groups (p=0.43). There was no significant difference in postoperative complications between thoracotomy and VATS groups (30 cases in 22 patients vs. 19 cases in 17 patients, p=0.65, odds ratio=1.19). The mean hospital stay of VATS group was 2 days shorter than that of thoracotomy group ($8.8{\pm}6.5$ days vs. $6.3{\pm}3.3$ days, p<0.05). Conclusion: VATS lobectomy for pathologic stage I lung cancer is a feasible operation with shorter hospitalization, while surgical outcome is comparable to thoracotomy lobectomy.

• Journal of Microbiology and Biotechnology
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• v.25 no.5
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• pp.648-657
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• 2015

H9, a novel herbal extract, demonstrated cytotoxicity in A549 non-small cell lung cancer (NSCLC) cell lines. In this study, we investigated whether H9, and/or co-treatment with an anticancer drug, pemetrexed (PEM), inhibited tumor growth in BALB/c nude mice models bearing A549 NSCLC cells. The mice were separated into groups and administered H9 and PEM for 2 weeks. Protein and mRNA levels were detected using western blotting and reverse transcription polymerase chain reaction, respectively; immunohistochemistry (IHC) was also performed on the tumor tissues. H9 and co-treatment with PEM induced the cleavage of proapoptotic factors, such as caspase-3, caspase-8, caspase-9, and poly(ADP)-ribose polymerase (PARP). Expression levels of cell-death receptors involving Fas/FasL, TNF-related apoptosisinducing ligands (TRAIL), and TRAIL receptors were increased by H9 and co-treatment with PEM. Furthermore, analysis of levels of cell-cycle modulating proteins indicated that tumor cells were arrested in the G1/S phase. In addition, the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt survival signaling pathways were inhibited by H9 and co-treatment with PEM. In conclusion, H9 and co-treatment with PEM inhibited tumor growth in BALB/c nude mice models bearing A549 NSCLC cells. These results indicate that H9 and co-treatment with PEM can be used as an anticancer therapy in NSCLC.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.1837-1840
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• 2012

Background: In spite of the fact that platinum-based doublets are considered the standard therapy for patients with advanced non-small-cell lung cancer (NSCLC), no elderly-specific platinum based prospective phase III regimen has been explored. The aim of this retrospective singlecenter study was to evaluate the efficacy and side effects of cisplatin-based therapy specifically for the elderly. Methods: Patients receiving platinum-based treatment were divided into three groups. In the first group (GC), Gemcitabine was administrated at 1000 $mg/m^2$ on days 1, 8 and cisplatin was added at 75 $mg/m^2$ on day 1. In the second group (DC), 75 $mg/m^2$ docetaxel and cisplatin were administered on day 1. The third group (PC) received 175 mg of paclitaxel and 75 mg of cisplatin on day 1. These treatments were repeated every three weeks. Result: GC arm had 36, the DC arm 42 and the PC arm 29 patients. Grade III-IV thrombocytopenia was higher in the GC arm (21.2% received GC, 2.8% received DC, and 3.8% received PC), while sensory neuropathy was lower in patients with GC arm (3.0%, 22.2%, and 23.1% received GC, DC and PC, respectively). There were no statistically significant difference in the response rates among the three groups (p>0.05). The median Progression-free survival (PFS) was 5.0 months and the median Overall survival (OS) in each group was 7.1, 7.4 and 7.1 months, respectively (p>0.05). Conclusion: The response rate, median PFS and OS were similar among the three treatment arms. Grade III-IV thrombocytopenia was higher in the GC arm, while the GC regimen was more favorable than the other cisplatin-based treatmetns with regard to sensory neuropathy.

• Tuberculosis and Respiratory Diseases
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• v.65 no.2
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• pp.105-109
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• 2008

Background: Fascin is an actin-bundling protein that plays an important role in cellular motility. Fascin is normally expressed in the neuronal and mesenchymal cells and its expression is low or absent in the epithelia. However, an overexpression of fascin has been linked to the invasive behavior of some neoplasms such as breast, stomach and ovarian tumors. In this study, we evaluated the expression of fascin and its prognostic significance in stage I non-small cell lung cancer (NSCLC). Methods: Immunohistochemical staining for fascin was performed on the paraffin-embeded tissue sections of 81 cases of resected NSCLC. Staining of more than 5% of the tumor cells was recorded as positive immunoreactivity. Results: Fascin expression was seen in 73% (59/81) of the cases and this was more frequently seen in squamous cell carcinoma than in adenocarcinoma (93% vs 42%). There were no significant correlations of fascin immunoreactivity with tumor recurrence and overall survival. Conclusion: The expression rate of fascin was relatively high in NSCLC, but this was without prognostic significance. The exact clinical role of fascin should be defined through further investigations.

• Journal of Chest Surgery
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• v.38 no.1 s.246
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• pp.38-43
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• 2005

Matrix metalloproteinase-2 (MMP-2) is a class of proteolytic enzymes that digest collagen type IV and other components of the basement membrane. It plays a key role in the local invasion and the formation of distant metastases by various malignant tumors. The aim of this study was to evaluate the activity of MMP-2 and its significance as a prognostic marker in resected stage I non-small cell lung cancer (NSCLC). Material and Method: In this study we obtained fresh-frozen samples of tumor and non-tumor tissues from 34 patients with stage I NSCLC who underwent resection without preoperative radiotherapy or chemotherapy. After the extraction of total protein from tissue samples, MMP-2 activities were assessed by gelatin-substrate-zymography. The activities were divided into the higher or lower groups. Result: The MMP-2 activities were higher in tumor tissues than in non-tumor tissues. The MMP-2 activity of non-tumor tissues in recurrent group was higher than in non-recurrent group (p<0.01). Also the patients with higher MMP-2 activity of non-tumor tissues showed poor 5 year survival (p<0.01). Conclusion: This result indicates that the higher level of MMP-2 activity in the non-tumor tissue is associated with the recurrence and survival after the resection of stage I NSCLC. Therefore, MMP-2 activity in the non-tumor tissue could be used as a potential prognostic marker for the resected stage I-NSCLC.

• Tuberculosis and Respiratory Diseases
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• v.48 no.1
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• pp.24-32
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• 2000

Purpose: Microsatellite instability(MSI) is frequently used as an indicator of microsatellite mutator phenotype(MMP) tumors. MSI has been observed in a percentage of non-small cell lung cancer(NSCLC). However, its role in tumorigenesis of NSCLC remains unknown. The frequency and pattern of MSI in NSCLC were evaluated and clinical parameters of MSI-positive tumors with those of MSS(microsatellite stable) tumors were compared. Materials and Methods: Twenty surgically resected NSCLCs were analyzed for 15 microsatellite markers located at chromosomes 3p and 9p. The peripheral blood lymphocytes of patients were used as the source of the normal DNA. Results: 1) Of 20 cases, 8(40%) demonstrated MSI. 2) Instability was observed more frequently in tri- and tetra-nucleotide repeats than in dinucleotide repeats. In all cases, instability appeared as a shift of individual allelic bands. 3) LDH was observed in 10(50%) of 20 tumors analyzed. 4) Of 20 cases, MSI-H tumor(showing MSI in the majority of markers) was absent. There were 5 MSI-L tumors(showing MSI in a greater than 10% of markers). 5) No significant difference was observed between MSI-L tumors and MSI-negative tumors in terms of clinicopathologic features such as pack-year history of smoking, histologic subtype, and(delete) stage of disease. There was also no significant difference in the incidence of LDH in relation to the status of MSI. Conclusion: These data strongly suggest that MSI plays different roles in lung and colon cancer. MMP pathway appears to be far less important in the tumorigenesis of NSCLC, caused mainly by cigarette smoke, with little familial tendency.

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

• Biomolecules & Therapeutics
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• v.30 no.1
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• pp.19-27
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• 2022

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase widely expressed in many cancers such as non-small cell lung cancer (NSCLC), pancreatic cancer, breast cancer, and head and neck cancer. Mutations such as L858R in exon 21, exon 19 truncation (Del19), exon 20 insertions, and others are responsible for aberrant activation of EGFR in NSCLC. First-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib have clinical benefits for EGFR-sensitive (L858R and Del19) NSCLC patients. However, after 10-12 months of treatment with these inhibitors, a secondary T790M mutation at the gatekeeper position in the kinase domain of EGFR was identified, which limited the clinical benefits. Second-generation EGFR irreversible inhibitors (afatinib and dacomitinib) were developed to overcome this T790M mutation. However, their lack of selectivity toward wild-type EGFR compromised their clinical benefits due to serious adverse events. Recently developed third-generation irreversible EGFR TKIs (osimertinib and lazertinib) are selective toward driving mutations and the T790M mutation, while sparing wild-type EGFR activity. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S, the key residue cysteine that forms covalent bonds with irreversible inhibitors. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are not effective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism.