• Asian Pacific Journal of Cancer Prevention
• /
• v.15 no.14
• /
• pp.5793-5798
• /
• 2014

Background: Golgi phosphoprotein-3 (GOLPH3) is implicated in cancer development and progression. The aim of this study was to evaluate the prognostic significance of GOLPH3 protein and its association with tumor angiogenesis in patients with early-stage NSCLC. Materials and Methods: Immunohistochemistry was performed to determine GOLPH3 protein expression and allow assessment of intratumoral microvessel density (MVD) by counting CD-34 positive immunostained endothelial cells. Correlations of expression with MVD, clinicopathologic features and clinical prognosis were analyzed. Results: A notably higher level of GOLPH3 expression was found in early-stage NSCC tissues at the protein level. However, we do not find any correlation between GOLPH3 expression and clinicopathologic features (p>0.05), although higher MVD was positively associated with GOLPH3 overexpression (p<0.001). Expression of GOLPH3 was found to be an independent prognostic factor in early-stage NSCLC patients, those expressing high levels of GOLPH3 exhibiting a substantially lower 5-year overall survival than GOLPH3-negative patients (adjusted HR =1.899, 95% CI: 1.021-3.532, p=0.043). Conclusions: High expression of the GOLPH3 protein is common in early-stage NSCC, and is closely associated with tumor progression, increased tumor angiogenesis, and poor survival. We conclude a possibility of its use as a diagnostic and prognostic marker in early-stage NSCC patients.

• Brain Tumor Research and Treatment
• /
• v.6 no.2
• /
• pp.54-59
• /
• 2018

Background Leptomeningeal metastasis (LM) is an uncommon, but devastating complication of advanced cancer and has no standard treatment. Herein, we analyzed the clinical characteristics and outcomes of patients with solid tumors who were diagnosed with LM. Methods Between January 2007 and December 2017, we retrospectively analyzed the medical records of patients with solid tumors who were diagnosed with LM. Results A total of 58 patients were enrolled in this study. The median age of patients was 51 years (range, 27-72 years), and 62.1% had a poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) (>2). The common types of primary tumor were breast cancer (39.7%), gastric cancer (25.9%), and non-small cell lung cancer (20.7%). Forty-two patients (72.4%) were diagnosed with LM by MRI of the brain and/or spine and cerebrospinal fluid (CSF) analysis, 14 were diagnosed by CSF analysis alone, and 2 were diagnosed by MRI alone. Treatments for LM were performed in 53 patients (91.4%), and best supportive care was provided for 5 patients (8.6%). Intrathecal chemotherapy, radiotherapy, and systemic chemotherapy were administered in 43 (74.1%), 17 (29.3%), and 24 (41.4%) patients, respectively. The median overall survival of the entire cohort was 2.4 months (95% confidence interval, 1.0-3.7). In the analysis of prognostic factors for survival, a good ECOG PS (${\leq}2$), administration of systemic chemotherapy after LM diagnosis, and a prior history of brain radiation were associated with prolonged survival. Conclusion Although the prognosis of LM in patients with solid tumors is poor, systemic chemotherapy might improve survival in selected patients with a good PS.

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

• Journal of Chest Surgery
• /
• v.41 no.4
• /
• pp.447-456
• /
• 2008

Background: Caspase-3 is a cysteine protease that plays a major role in the process of apoptotic cell death. The dysregulated expression of c-myc contributes to the tumorigenesis in a variety of human cancers. The aim of this study was to investigate the expressions of caspase-3 and c-myc and their significances as prognosis markers in patients with completely resected non-small cell lung cancer (NSCLC). Material and Method: A total 130 consecutive patients who had undergone complete resection without pre-operative radio-therapy or chemotherapy between May 1996 and December 2003 for NSCLC were retrospectively reviewed. The median follow-up period of the patients was 50 months (range: $3{\sim}128$ months). The expressions of caspase-3 and c-myc were immuno-histochemically examined, and these were correlated with the clinico-pathologic data. Result: The prevalence of caspase-3 and c-myc expressions in the patients was 68% (88/130) and 59% (77/130), respectively. Significant association was found between the frequency of the expressions of caspase-3 and c-myc (p=0.025). The caspase-3 and c-myc expressions were not significantly associated with the prognosis in all the patients. However, according to stages, a positive caspase-3 expression was significantly correlated with a favorable prognosis for patients with stage IIIa disease (median survival period: 35 months vs. 10 months, p=0.021). Multivariate analysis showed the pathologic stage to be significantly correlated with a good prognosis in all the patients (p=0.024), and with a positive caspase-3 expression, well differentiated tumor and negative neuronal invasion in the patients with stage llla disease (p=0.005, p=0.003, p=0.004, respectively). Conclusion: Caspase-3 and c-myc were frequently expressed in NSCLC, suggesting its possible involvement in tumor development. The caspase-3 expression, as determined with performing immunohistochemical staining, may be a favorable prognostic indicator in patients with completely resected NSCLC an advanced stage (IIIa).

• Asian Pacific Journal of Cancer Prevention
• /
• v.16 no.16
• /
• pp.7071-7076
• /
• 2015

Epidermal growth factor receptor (EGFR) is one of the targeted molecular markers in many cancers including lung malignancies. Gefitinib and erlotinib are two available therapeutics that act as specific inhibitors of tyrosine kinase (TK) domains. We performed a case-control study with formalin-fixed paraffin-embedded tissue blocks (FFPE) from tissue biopsies of 167 non-small cell lung carcinoma (NSCLC) patients and 167 healthy controls. The tissue biopsies were studied for mutations in exons 18-21 of the EGFR gene. This study was performed using PCR followed by DNA sequencing. We identified 63 mutations in 33 men and 30 women. Mutations were detected in exon 19 (delE746-A750, delE746-T751, delL747-E749, delL747-P753, delL747-T751) in 32 patients, exon 20 (S786I, T790M) in 16, and exon 21 (L858R) in 15. No mutations were observed in exon 18. The 63 patients with EFGR mutations were considered for upfront therapy with oral tyrosine kinase inhibitor (TKI) drugs and have responded well to therapy over the last 15 months. The control patients had no mutations in any of the exons studied. The advent of EGFR TKI therapy has provided a powerful new treatment modality for patients diagnosed with NSCLC. The study emphasizes the frequency of EGFR mutations in NSCLC patients and its role as an important predictive marker for response to oral TKI in the south Indian population.

• Korean Journal of Radiology
• /
• v.22 no.5
• /
• pp.829-839
• /
• 2021

Objective: To compare the diagnostic performance of contrast-enhanced radial T1-weighted gradient-echo 3-tesla (3T) magnetic resonance imaging (MRI) and computed tomography (CT) for the detection of visceral pleural surface invasion (VPSI). Visceral pleural invasion by non-small-cell lung cancer (NSCLC) can be classified into two types: PL1 (without VPSI), invasion of the elastic layer of the visceral pleura without reaching the visceral pleural surface, and PL2 (with VPSI), full invasion of the visceral pleura. Materials and Methods: Thirty-three patients with pathologically confirmed VPSI by NSCLC were retrospectively reviewed. Multidetector CT and contrast-enhanced 3T MRI with a free-breathing radial three-dimensional fat-suppressed volumetric interpolated breath-hold examination (VIBE) pulse sequence were compared in terms of the length of contact, angle of mass margin, and arch distance-to-maximum tumor diameter ratio. Supplemental evaluation of the tumor-pleura interface (smooth versus irregular) could only be performed with MRI (not discernible on CT). Results: At the tumor-pleura interface, radial VIBE MRI revealed a smooth margin in 20 of 21 patients without VPSI and an irregular margin in 10 of 12 patients with VPSI, yielding an accuracy, sensitivity, specificity, positive predictive value, negative predictive value, and F-score for VPSI detection of 91%, 83%, 95%, 91%, 91%, and 87%, respectively. The McNemar test and receiver operating characteristics curve analysis revealed no significant differences between the diagnostic accuracies of CT and MRI for evaluating the contact length, angle of mass margin, or arch distance-to-maximum tumor diameter ratio as predictors of VPSI. Conclusion: The diagnostic performance of contrast-enhanced radial T1-weighted gradient-echo 3T MRI and CT were equal in terms of the contact length, angle of mass margin, and arch distance-to-maximum tumor diameter ratio. The advantage of MRI is its clear depiction of the tumor-pleura interface margin, facilitating VPSI detection.

• 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.

• Radiation Oncology Journal
• /
• v.17 no.3
• /
• pp.195-202
• /
• 1999

Purpose : We peformed this study to evaluate the prognostic factors and the effect of induction chemotherapy in locally advanced non-small cell lung cancer (NSCLC). Materials and Methods : A retrospective analysis was done for 130 patients with locally advanced NSCLC treated with curative radiotherapy alone or induction chemo-radiotherapy from January 1986 to October 1996. Eighty-five patients were treated with radiotherapy alone, forty-five with induction chemotherapy and radiotherapy. Age, sex, performance status, histopathologic type, and stage were evenly distributed in both groups. The patients were treated with 6 MV or 10 MV X-ray. Conventional fractionation with daily fraction size 1$.8\~2.0$ Gy was done. Of the patients, 129 patients received total dose above 59.6 Gy ($56\~66$ Gy, median 60 Gy). Induction chemotherapy regimen were CAP (Cyclo-phosphamide, Adriamycin, Cisplatin) in 6 patients, MVP (Mitomycin, Vinblastine, Cisplatin) in 9 patients, MIC (Mitomycin, Ifosfamide Cisplatin) in 13 patients, and EP (Etoposide, Cisplatin) in 17 patients. Chemotherapy was done in $2\~5$ cycles (median 2). Results : Overall 1-, 2-, and 3-year survival rate (YSR) for all patients were $41.5\%,{\;}13.7\%,{\;}and{\;}7\%$, respectively (median survival time 11 months). According to treatment modality, median survival time, overall 1-, 2-, and 3-YSR were 9 months, $32.9\%,{\;}10.\5%,{\;}6\%$ for radiotherapy alone group, and 14 months, $57.8\%,{\;}20\%,{\;}7.6\%$ for induction chemotherapy group, respectively (f=0.0005). Complete response (CR) to overall treatments was $25\%$ (21/84) in radiotherapy alone and $40.5\%$ (17/42) in induction chemotherapy group (p=0.09). The Prognostic factors affecting overall survival were hemoglobin level (p=0.04), NSE (neuron-specific enolase) level (p=0.004), and respense to overall treatment(p=0.004). According to treatment modalities, NSE (neuron-specific enolase) (p=0.006) and response to overall treatment (p=0.003) were associated with overall survival in radiotherapy alone group, and response to overall treatment (p=0.007) in induction chemotherapy group. The failure Pattern analysis revealed no significant difference between treatment modalities. But, in patients with CR to overall treatment, distant metastasis were found in 11/19 patients with radiotherapy alone, and 3/13 patients with induction chemotherapy and radiotherapy (p=0.07). Locoregional failure patterns were not different between two groups (10/19 vs 6/13). Conclusion : Induction chemotherapy and radiotherapy achieved increased 2YSR compared to radiotherapy alone, At least in CR patients, there was decreased tendency in distant metastasis with induction chemotherapy. But, locoregional failures and long-term survival were not improved. Thus, there is need of more effort to increasing local control and further decreasing distant metastasis.

• Nuclear Medicine and Molecular Imaging
• /
• v.40 no.3
• /
• pp.163-168
• /
• 2006

Purpose: Incidence of lung canter in patients with idiopathic pulmonary fibrosis (IPF) is known to be higher than that in general population. However, it is difficult to discriminate pulmonary nodule in patients with IPF, because underlying IPF can be expressed as lung nodules. We evaluated the diagnostic performance of FDG PET in discriminating lung nodule in patients with IPF. Methods: We retrospectively reviewed 28 lung nodules in 16 subjects (age; $67.53{\pm}9.53$, M:F=14:2). Two patients had previous history of malignant cancer (small cell lung cancer and subglottic cancer). The diagnostic criteria on chest CT were size, morphology and serial changes of size. FDG PET was visually interpreted, and maximal SUV was calculated for quantitative analysis. Results: from 28 nodules, 18 nodules were interpreted as benign nodules, 10 nodules as malignant nodules by histopahthology or follow-up chest CT. The sensitivity and specificity of FDG PET were 100% and 94.4%, while those of CT were 70.0% and 44.4%, respectively. Malignant nodule was higher maxSUV than that of benign lung nodules ($7.68{\pm}3.96\;vs.\;1.22{\pm}0.65$, p<0.001). Inflammatory lesion in underlying IPF was significantly lower maxSUV than that of malignant nodules ($1.80{\pm}0.43$, p<0.001). The size of malignant and benign nodule were $23.95{\pm}10.15mm\;and\;10.83{\pm}5.23mm$ (p<0.01). Conclusion: FDG PET showed superior diagnostic performance to chest CT in differentiating lung nodules in patients with underlying IPF. FDG PET could be used to evaluate suspicious malignant lung nodule detected by chest in patients with IPF.

• Progress in Medical Physics
• /
• v.26 no.2
• /
• pp.79-86
• /
• 2015

The purpose of this study is to evaluate efficacy and feasibility of adaptive radiotherapy according to tumor volume change (TVC) in early stage non-small cell lung cancer (NSCLC) using stereotactic body radiotherapy (SBRT). Twenty-two lesions previously treated with SBRT were selected. SBRT was usually performed with a total dose of 48 Gy or 60 Gy in four fractions with an interval of three to four days between treatments. For evaluation of TVC, gross tumor volume (GTV) was contoured on each cone-beam computed tomography (CBCT) image used for image guidance. Intensity modulated radiotherapy (IMRT) planning was performed in the first CBCT (CBCT1) using a baseline plan. For ART planning (ART), re-optimization was performed at $2^{nd}$, $3^{rd}$, and $4^{th}$ CBCTs (CBCT2, CBCT3, and CBCT4) using the same angle and constraint used for the baseline plan. The ART plan was compared with the non-ART plan, which generated copying of the baseline plan to other CBCTs. Average GTV volume was 10.7 cc. Average TVC was -1.5%, 7.3%, and -25.1% in CBCT2, CBCT3, and CBCT4 and the TVC after CBCT3 was significant (p<0.05). However, the nine lesions were increased GTV in CBCT2. In the ART plan, $V_{20\;Gy}$, $D_{1500\;cc}$, and $D_{1000\;cc}$ of lung were significantly decreased (p<0.05), and $V_{30\;Gy}$ and $V_{32\;Gy}$ of the chest wall were also decreased (p<0.05). While D min of planning target volume (PTV) decreased by 8.3% in the non-ART plan of CBCT2 compared with the baseline plan in lesions with increased tumor size (p=0.021), PTV coverage was not compromised in the ART plan. Based on this result, use of the ART plan may improve target coverage and OAR saving. Thus ART using CBCT should be considered in early stage NSCLC with SBRT.