Journal of Pathology and Translational Medicine

Reviews

Current status and future perspectives of liquid biopsy in non-small cell lung cancer: Sunhee Chang, Jae Young Hur, Yoon-La Choi, Chang Hun Lee, Wan Seop Kim; J Pathol Transl Med. 2020;54(3):204-212. Published online April 15, 2020; DOI: https://doi.org/10.4132/jptm.2020.02.27

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With advances in target therapy, molecular analysis of tumors is routinely required for treatment decisions in patients with advanced non-small cell lung cancer (NSCLC). Liquid biopsy refers to the sampling and analysis of circulating cell-free tumor DNA (ctDNA) in various body fluids, primarily blood. Because the technique is minimally invasive, liquid biopsies are the future in cancer management. Epidermal growth factor receptor (EGFR) ctDNA tests have been performed in routine clinical practice in advanced NSCLC patients to guide tyrosine kinase inhibitor treatment. In the near future, liquid biopsy will be a crucial prognostic, predictive, and diagnostic method in NSCLC. Here we present the current status and future perspectives of liquid biopsy in NSCLC.

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PD-L1 Testing in Non-small Cell Lung Cancer: Past, Present, and Future: Hyojin Kim, Jin-Haeng Chung; J Pathol Transl Med. 2019;53(4):199-206. Published online May 2, 2019; DOI: https://doi.org/10.4132/jptm.2019.04.24; Correction in: J Pathol Transl Med 2020;54(2):196

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Abstract PDF

Blockade of the programmed cell death-1 (PD-1) axis has already been established as an effective treatment of non-small cell lung cancer. Immunohistochemistry (IHC) for programmed death-ligand 1 (PD-L1) protein is the only available biomarker that can guide treatment with immune checkpoint inhibitors in non-small cell lung cancer. Because each PD-1/PD-L1 blockade was approved together with a specific PD-L1 IHC assay used in the clinical trials, pathologists have been challenged with performing various assays with a limited sample. To provide a more unified understanding of this, several cross-validation studies between platforms have been performed and showed consistent results. However, the interchangeability of assays may be limited in practice because of the risk of misclassification of patients for the treatment. Furthermore, several issues, including the temporal and spatial heterogeneity of PD-L1 expression in the tumor, and the potential for cytology specimens to be used as an alternative to tissue samples for PD-L1 testing, have still not been resolved. In the future, one of the main aims of immunotherapy research should be to find a novel predictive biomarker for PD-1 blockade therapy and a way to combine it with PD-L1 IHC and other tests.

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Original Articles

Association between Expression of 8-OHdG and Cigarette Smoking in Non-small Cell Lung Cancer: Ae Ri An, Kyoung Min Kim, Ho Sung Park, Kyu Yun Jang, Woo Sung Moon, Myoung Jae Kang, Yong Chul Lee, Jong Hun Kim, Han Jung Chae, Myoung Ja Chung; J Pathol Transl Med. 2019;53(4):217-224. Published online March 11, 2019; DOI: https://doi.org/10.4132/jptm.2019.02.20

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Abstract PDF

Background
Exposure to cigarette smoking (CS) is a major risk factor for the development of lung cancer. CS is known to cause oxidative DNA damage and mutation of tumor-related genes, and these factors are involved in carcinogenesis. 8-Hydroxydeoxyguanosine (8-OHdG) is considered to be a reliable biomarker for oxidative DNA damage. Increased levels of 8-OHdG are associated with a number of pathological conditions, including cancer. There are no reports on the expression of 8-OHdG by immunohistochemistry in non-small cell lung cancer (NSCLC).
Methods
We investigated the expression of 8-OHdG and p53 in 203 NSCLC tissues using immunohistochemistry and correlated it with clinicopathological features including smoking.
Results
The expression of 8-OHdG was observed in 83.3% of NSCLC. It was significantly correlated with a low T category, negative lymph node status, never-smoker, and longer overall survival (p < .05) by univariate analysis. But multivariate analysis revealed that 8-OHdG was not an independent prognostic factor for overall survival in NSCLC patients. The aberrant expression of p53 significantly correlated with smoking, male, squamous cell carcinoma, and Ki-67 positivity (p < .05).
Conclusions
The expression of 8-OHdG was associated with good prognostic factors. It was positively correlated with never-smokers in NSCLC, suggesting that oxidative damage of DNA cannot be explained by smoking alone and may depend on complex control mechanisms.

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Human Leukocyte Antigen Class I and Programmed Death-Ligand 1 Coexpression Is an Independent Poor Prognostic Factor in Adenocarcinoma of the Lung: Yeon Bi Han, Hyun Jung Kwon, Soo Young Park, Eun-Sun Kim, Hyojin Kim, Jin-Haeng Chung; J Pathol Transl Med. 2019;53(2):86-93. Published online January 14, 2019; DOI: https://doi.org/10.4132/jptm.2018.12.26

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Abstract PDF

Background
Both human leukocyte antigen (HLA) class I and programmed death-ligand 1 (PD-L1) molecules are known to play important roles in cancer immunity. In this study, we evaluated HLA class I expression in resected adenocarcinoma of the lung, and investigated its prognostic impact in correlation with PD-L1 expression.
Methods
HLA class I and PD-L1 expression was evaluated by immunohistochemistry in a total of 403 resected lung adenocarcinomas using tissue microarray. Correlations between the expression of HLA class I/PD-L1 and clinicopathologic features and prognostic significance were analyzed.
Results
HLA class I expression was reduced in 91.6% of adenocarcinoma, and more frequently reduced in patients with younger age, absence of vascular invasion, and low pathologic stage (p = .033, p = .007, and p = .012, respectively). Positive PD-L1 expression in tumor cells was 16.1% (1% cut-off), and associated with poor differentiation, presence of vascular invasion and nodal metastasis (p < .001, p = .002, and p = .032, respectively). On survival analysis, HLA class I or PD-L1 expression alone did not show any statistical significance. On the integrated analysis, HLA class I (+)/PD-L1 (+) subgroup showed a significantly shorter overall survival than other groups (p = .001). Multivariate analysis revealed that coexpression of HLA class I and PD-L1 was an independent poor prognostic factor of lung adenocarcinoma. (p < .001; hazard ratio, 6.106; 95% confidence interval, 2.260 to 16.501).
Conclusions
Lung adenocarcinoma with coexpression of HLA class I and PD-L1 was associated with poor prognosis. This subgroup may evade immune attack by expressing PD-L1 protein despite HLA expression.

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Prognostic and Clinical Significance of Human Leukocyte Antigen Class I Expression in Breast Cancer: A Meta-Analysis
Weiqiang Qiao, Zhiqiang Jia, Wanying Guo, Qipeng Liu, Xiao Guo, Miao Deng
Molecular Diagnosis & Therapy.2023; 27(5): 573. CrossRef
Loss of HLA-class-I expression in non-small-cell lung cancer: Association with prognosis and anaerobic metabolism
Ioannis M. Koukourakis, Alexandra Giatromanolaki, Achilleas Mitrakas, Michael I. Koukourakis
Cellular Immunology.2022; 373: 104495. CrossRef

Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung: Hyun Min Koh, Hyo Jung An, Gyung Hyuck Ko, Jeong Hee Lee, Jong Sil Lee, Dong Chul Kim, Jung Wook Yang, Min Hye Kim, Sung Hwan Kim, Kyung Nyeo Jeon, Gyeong-Won Lee, Se Min Jang, Dae Hyun Song; J Pathol Transl Med. 2019;53(1):13-22. Published online November 26, 2018; DOI: https://doi.org/10.4132/jptm.2018.11.12

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Abstract PDF

Background
S100A8 and S100A9 have been gaining recognition for modulating tumor growthand metastasis. This study aimed at evaluating the clinical significance of S100A8 and S100A9 innon-small cell lung cancer (NSCLC).
Methods
We analyzed the relationship between S100A8and S100A9 expressions, clinicopathological characteristics, and prognostic significance in tumorcells and peritumoral inflammatory cells.
Results
The positive staining of S100A8 in tumorcells was significantly increased in male (p < .001), smoker (p = .034), surgical method other thanlobectomy (p = .024), squamous cell carcinoma (SQCC) (p < .001) and higher TNM stage (p = .022)compared with female, non-smoker, lobectomy, adenocarcinoma (ADC), and lower stage. Theproportion of tumor cells stained for S100A8 was related to histologic type (p < .001) and patientsex (p = .027). The proportion of inflammatory cells stained for S100A8 was correlated with patientage (p = .022), whereas the proportion of inflammatory cells stained for S100A9 was correlatedwith patient sex (p < .001) and smoking history (p = .031). Moreover, positive staining in tumorcells, more than 50% of the tumor cells stained and less than 30% of the inflammatory cellsstained for S100A8 and S100A9 suggested a tendency towards increased survivability in SQCCbut towards decreased survivability in ADC.
Conclusions
S100A8 and S100A9 expressions might be potential prognostic markers in patients with NSCLC.

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Gene expression related to lung cancer altered by PHMG-p treatment in PBTE cells
Yoon Hee Park, Sang Hoon Jeong, Hyejin Lee, Cherry Kim, Yoon Jeong Nam, Ja Young Kang, Jin Young Choi, Yu-Seon Lee, Su A. Park, Jaeyoung Kim, Eun-Kee Park, Yong-Wook Baek, Hong Lee, Ju-Han Lee
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Yanhong Liu, Lan Gao, Yanru Fan, Rufei Ma, Yunxia An, Guanghui Chen, Yan Xie
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S100A8 and S100A9 in Cancer
Yu Chen, Yuzhen Ouyang, Zhixin Li, Xiufang Wang, Jian Ma
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Gene expression of S100a8/a9 predicts Staphylococcus aureus-induced septic arthritis in mice
Meghshree Deshmukh, Santhilal Subhash, Zhicheng Hu, Majd Mohammad, Anders Jarneborn, Rille Pullerits, Tao Jin, Pradeep Kumar Kopparapu
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The S100 protein family in lung cancer
Ting Wang, Ge Du, Dong Wang
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Hong-Yan Liu, Hui-Xian Xiang, Ying Xiang, Zheng Xu, Chun-Mei Feng, Jun Fei, Lin Fu, Hui Zhao
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Saliva proteomic analysis reveals possible biomarkers of renal cell carcinoma
Xiao Li Zhang, Zheng Zhi Wu, Yun Xu, Ji Guo Wang, Yong Qiang Wang, Mei Qun Cao, Chang Hao Wang
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An Huang, Wei Fan, Jiacui Liu, Ben Huang, Qingyuan Cheng, Ping Wang, Yiping Duan, Tiantian Ma, Liangyue Chen, Yanping Wang, Mingxia Yu
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Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01): Bo Mi Ku, Mi Hwa Heo, Joo-Hang Kim, Byoung Chul Cho, Eun Kyung Cho, Young Joo Min, Ki Hyeong Lee, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Tae Jung Kim, Ho Yun Lee, Hojoong Kim, Kyung-Jong Lee, Myung-Ju Ahn; J Pathol Transl Med. 2018;52(3):148-156. Published online March 26, 2018; DOI: https://doi.org/10.4132/jptm.2018.03.12

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Background
Non-small cell lung cancer (NSCLC) is a common type of cancer with poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to evaluate the clinical adequacy of molecular testing using next-generation sequencing (NGS) for small biopsy samples and characterize the mutational landscape of Korean patients with advanced NSCLC.
Methods
DNA was extracted from small biopsy samples of 162 patients with advanced NSCLC. Targeted NGS of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2.
Results
The median age of patients was 64 years (range, 32 to 83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range, 1 to 21 mutated genes). Mutations were found in 41 genes. Three of the most frequently mutated genes were TP53 (151, 93.2%), KDR (104, 64.2%), and epidermal growth factor receptor (EGFR; 69, 42.6%). We also observed coexistence of EGFR and other oncogene (such as KRAS, PIC3CA, PTEN, and STK11) mutations. Given that 69.6% (48/69) of EGFR mutant patients were treated with EGFR tyrosine kinase inhibitors, EGFR mutant status had higher prognostic ability in this study.
Conclusions
These results suggest that targeted NGS using small biopsy samples is feasible and allows for the detection of both common and rare mutations in NSCLC.

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Prognostic Significance of Aquaporin 5 Expression in Non-small Cell Lung Cancer: Young Min Jo, Tae In Park, Hwa Young Lee, Ji Yun Jeong, Won Kee Lee; J Pathol Transl Med. 2016;50(2):122-128. Published online February 8, 2016; DOI: https://doi.org/10.4132/jptm.2015.10.31

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Background
Aquaporins are water channel proteins that play a major role in the movement of water in various human tissues. Recently, it has been found that aquaporins have influence in the carcinogenesis of human malignancies. We analyzed the prognostic impact of aquaporin 5 (AQP5) in non-small lung cancer (NSCLC). Methods: Seventy-six cases of NSCLC were studied, including 44 cases of adenocarcinoma (ADC) and 32 cases of squamous cell carcinoma (SQCC). Tissue microarray was constructed and immunohistochemical staining for AQP5 was performed. Results: AQP5 was positive in 59.2% of the total enrolled NSCLCs (63.7% in ADC and 53.1% in SQCC). The difference in expression of AQP5 according to the histologic grade of the tumor was significant (p<.047), but not in a serial order. When ADC and SQCC were separately evaluated, no significant difference was observed according to the histologic grade of the tumor (p=.076 in ADC and p=.631 in SQCC). No difference was observed between AQP5 expression and other demographic data and tumor characteristics. Disease-free survival (DFS) was higher in AQP5 negative cases than positive cases in ADC (p=.047), but no significance was found in SQCC (p=.068). We were unable to find a significance between AQP5 overexpression and overall survival in either ADC (p=.210) or SQCC (p=.533). Conclusions: AQP5 expression is associated with DFS in ADC of the lung and tumor grade of NSCLC. The present study suggests that AQP5 can be a prognostic factor of NSCLC.

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Ian M. Smith, Shohini Banerjee, Allison K. Moses, Kimberly M. Stroka
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Lukasz Jaskiewicz, Anna Romaszko-Wojtowicz, Anna Doboszynska, Agnieszka Skowronska
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Ekta Yadav, Niket Yadav, Ariel Hus, Jagjit S. Yadav
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Combined Systematic Review and Transcriptomic Analyses of Mammalian Aquaporin Classes 1 to 10 as Biomarkers and Prognostic Indicators in Diverse Cancers
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Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung
Hyun Min Koh, Hyo Jung An, Gyung Hyuck Ko, Jeong Hee Lee, Jong Sil Lee, Dong Chul Kim, Jung Wook Yang, Min Hye Kim, Sung Hwan Kim, Kyung Nyeo Jeon, Gyeong-Won Lee, Se Min Jang, Dae Hyun Song
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Ahmed E Hegab, Mari Ozaki, Naofumi Kameyama, Jingtao Gao, Shizuko Kagawa, Hiroyuki Yasuda, Kenzo Soejima, Yongjun Yin, Robert D Guzy, Yoshikazu Nakamura, David M Ornitz, Tomoko Betsuyaku
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Wei Wang, Qing Li, Tao Yang, Dongsheng Li, Feng Ding, Hongzhi Sun, Guang Bai
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Qing Li, Tao Yang, Dongsheng Li, Feng Ding, Guang Bai, Wei Wang, Hongzhi Sun
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Clinicopathologic Implication of Ezrin Expression in Non-small Cell Lung Cancer: Ho Won Lee, Eui Han Kim, Mee-Hye Oh; Korean J Pathol. 2012;46(5):470-477. Published online October 25, 2012; DOI: https://doi.org/10.4132/KoreanJPathol.2012.46.5.470

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Abstract PDF

Background

Ezrin, a member of the ezrin-radixin-moesin family, is implicated in tumor progression, metastatic dissemination, and adverse outcomes, in several cancer types. In this study, we explored the clinicopathological significance of ezrin expression in non-small cell lung carcinomas (NSCLCs).

Methods

Immunohistochemical analysis of tissue microarray with 112 surgically resected NSCLC specimens, was performed to examine the ezrin expression. We also correlated ezrin expression with other clinicopathological features and prognosis.

Results

The ezrin-positive group revealed significantly higher correlation with pleural invasion (p=0.016) and pathologic stage (p=0.050). Univariate survival analysis showed that ezrin-positive group had a significantly shorter cancer-specific survival than ezrin-negative group (p=0.016). Meanwhile, female (p=0.030), no pleural invasion (p=0.023), no lymphatic invasion (p=0.026), and early pathologic stage (p=0.008) significantly correlated with longer survival. Multivariate survival analysis showed that variables such as ezrin positivity (p=0.032), female (p=0.035), and early pathologic stage (p=0.001) were independent prognostic factors for NSCLC.

Conclusions

Ezrin might be a molecular marker to predict poor prognosis of NSCLC.

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The Histone Acetyltransferase hMOF is Overexpressed in Non-small Cell Lung Carcinoma.: Joon Seon Song, Sung Min Chun, Ji Young Lee, Dong Kwan Kim, Yong Hee Kim, Se Jin Jang; Korean J Pathol. 2011;45(4):386-396.; DOI: https://doi.org/10.4132/KoreanJPathol.2011.45.4.386

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Abstract PDF

BACKGROUND
One of the histone acetyltransferases (HATs) family of proteins, human MOF (hMOF, MYST1), is involved in histone H4 acetylation, particularly at lysine 16 (H4K16Ac), an epigenetic mark of active genes. Dysregulation of the epigenetic mark influences cellular biology and possibly leads to oncogenesis. We examined the involvement of hMOF and H4K16Ac in primary non-small cell lung cancer (NSCLC).
METHODS
Reverse transcription polymerase chain reaction using fresh-frozen lung cancer tissues and lung cancer cell lines and immunohistochemistry for hMOF and H4K16Ac via tissue microarray of 551 formalin-fixed paraffin-embedded NSCLC tissue blocks were conducted.
RESULTS
hMOF mRNA was frequently overexpressed in lung cancer tissues, compared with normal lung tissues (10/20, 50%). NSCLC tissues were positive for hMOF in 37.6% (184/489) and H4K16Ac in 24.7% (122/493) of cases. hMOF protein expression was tightly correlated with the H4K16Ac level in tumors (p<0.001). Knockdown of hMOF mRNA with siRNA led to a significant inhibition of growth in the Calu-6 cell line.
CONCLUSIONS
hMOF was frequently expressed in NSCLC and was correlated with H4K16Ac. To our knowledge, this is the first study that has focused on the expression status of HATs and hMOF in NSCLC. Our results clearly suggest a potential oncogenic role of the gene and support its utility as a potential therapeutic target.

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Clinicopathological Significance of S100A4 Expression in Non-small Cell Lung Carcinomas.: Eun Ah Jung, Hyun Deuk Cho, Ji Hye Lee, Mee Hye Oh; Korean J Pathol. 2010;44(5):477-482.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.5.477

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Abstract PDF

BACKGROUND
S100A4 has been implicated in invasion and metastasis of various malignant tumors. The aim of this study was to investigate whether or not S100A4 plays an important role in non-small cell lung carcinomas (NSCLCs).
METHODS
Sixty-seven patients with NSCLC including 37 with squamous cell carcinomas (SCCs) and 30 with adenocarcinomas (ADs) who had undergone surgical resection were analyzed. S100A4 expression was analyzed by immunohistochemistry using tissue microarray blocks.
RESULTS
S100A4 expression was positive in 56 (83.6%) of 67 NSCLC cases. ADs were more frequently S100A4 positive than SCCs (p = 0.017). However, no significant correlation was observed between S100A4 expression and age, gender, pT, pN or tumor, node and metastasis (TNM) stage. Two distant metastatic cases revealed an S100A4 positive reaction. Kaplan-Meier survival curves with the log-rank test showed no correlation with 3-year survival (p = 0.782) or 5-year survival (p = 0.227) in either group of patients according to S100A4 expression.
CONCLUSIONS
S100A4 expression was not correlated with age, gender, pT, pN or TNM stage or survival in patients with NSCLCs. Therefore, S100A4 expression may not be useful as a prognostic marker for NSCLCs. However, S100A4 expression showed a higher positivity in ADs than in SCCs.

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Clinicopathological and prognostic value of S100A4 expression in non-small cell lung cancer: a meta-analysis
Jing Zhang, Yanhui Gu, Xiaoli Liu, Ximin Rao, Guichuan Huang, Yao Ouyang
Bioscience Reports.2020;[Epub] CrossRef
S100A4 promotes endometrial cancer progress through epithelial-mesenchymal transition regulation
TENG HUA, SHUANGGE LIU, XIAOYAN XIN, LIQIONG CAI, RUI SHI, SHUQI CHI, DILU FENG, HONGBO WANG
Oncology Reports.2016; 35(6): 3419. CrossRef
Prognostic value of cytoplasmic expression of S100A4 protein in endometrial carcinoma
HYE IN CHONG, JEONG HEE LEE, MAN SOO YOON, DONG SOO SUH, KYUNGBIN KIM, JEE YEON KIM, KYUNG UN CHOI
Oncology Reports.2014; 31(6): 2701. CrossRef
Clinical significance of E-cadherin, β-catenin, vimentin and S100A4 expression in completely resected squamous cell lung carcinoma
Hua Zhang, Jun Liu, Dongsheng Yue, Liuwei Gao, Daowei Wang, Hongdian Zhang, Changli Wang
Journal of Clinical Pathology.2013; 66(11): 937. CrossRef
Expression of S100A4, ephrin-A1 and osteopontin in non-small cell lung cancer
Ane Kongsgaard Rud, Marius Lund-Iversen, Gisle Berge, Odd Terje Brustugun, Steinar K Solberg, Gunhild M Mælandsmo, Kjetil Boye
BMC Cancer.2012;[Epub] CrossRef
Clinicopathologic Implication of Ezrin Expression in Non-small Cell Lung Cancer
Ho Won Lee, Eui Han Kim, Mee-Hye Oh
Korean Journal of Pathology.2012; 46(5): 470. CrossRef

Expression of p63 and its Isoform, deltaNp63, in Non-Small Cell Lung Carcinoma.: Ick Doo Kim, Dong Hoon Shin, Kyung Un Choi, Do Youn Park, Gi Yeong Huh, Mee Young Sol, Min Ki Lee, Young Dae Kim, Chang Hun Lee; Korean J Pathol. 2009;43(4):321-328.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.4.321

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Abstract PDF: BACKGROUND
Several studies have been conducted on the role of the p63 gene family in non-small cell lung carcinoma (NSCLC). Nevertheless, the role of these genes in the development and progression of NSCLC remains controversial. This study was designed to examine the expression and clinicopathologic significance of the p63 family in NSCLC.
METHODS
Immunohistochemical staining was performed on 92 cases of NSCLC (47 squamous cell carcinomas [SqCCs] and 45 adenocarcinomas [ACs]) using tissue microarray blocks. The results were analyzed and correlated with clinicopathologic data. RESULTS: The expression of delta Np63 (Delta Np63) was elevated in SqCC (39/47), but not in AC (2/45; p<0.01). Both p63 and Delta Np63 had high expression in 39 SqCCs; p63 and Delta Np63 also had a similar geomorphologic distribution in most positive tumors. The expression of Delta Np63 was correlated with histologic type, gender, pT stage, p53 expression, and p63 expression. pT and pN stages were independent factors in survival (p<0.05, respectively).
CONCLUSIONS
The major p63 isoform in NSCLC, Delta Np63, had a strong correlation with p53 and p63, and was exclusively expressed in SqCC. However, our findings suggest that Delta Np63 was not an independent prognostic factor for NSCLC.

Expression of p53 and Vascular Endothelial Growth Factor mRNA in Angiogenesis of Non-Small Cell Lung Carcinoma.: Jun Seog Kim, Tae In Park, Myoung Hoon Lee, Eun Kyoung Kwak, Ji Young Park, Jung Sik Kwak, Jong Min Chae; Korean J Pathol. 2003;37(1):35-40.

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Abstract PDF: BACKGROUND
Angiogenesis is one of the most important factors in the progression and me-tastasis of malignancies. Angiogenesis is a multistep process requiring the interaction of numerous factors able to stimulate the growth and development of new vessels. But, understanding of the mechanism involved in VEGF expression is unclear.
METHODS
Expressions of p53 and VEGF, and neovasculiarization were examined in 19 cases of surgically resected non-small cell carcinoma of the lung by the immunohistochemical staining. Furthermore, VEGF mRNA expressions were quantified in all cases using the real-time quantitative RT-PCR. These results were compared with clinicopathologic parameters such as histologic grade and stage.
RESULTS
Tumors with high aberrant p53 expressions showed significantly higher VEGF mRNA ex-pressions and microvessel counts than those with low p53 expressions. Expressions of p53 as well as VEGF and micovessel counts were closely associated with the tumor stage, but not with the histologic grade and other clinical parameters.
CONCLUSIONS
These results suggest that aberrant p53 expression may play a role in the regulation of VEGF expression and may be involved in controlling angiogenesis in non-small cell carcinoma of the lung.

An Analysis of HER-2/neu, ERCC1, and GST-pi in Advanced Non-Small Cell Lung Cancer Patients Who are Treated with Platinum-based Chemotherapy.: Kyung Jin Seo, Byoung Yong Shim, Hoon Kyo Kim, Ji Han Jung, Jinyoung Yoo, Seok Jin Kang, Kyo Young Lee; Korean J Pathol. 2008;42(6):327-334.

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Abstract PDF: BACKGROUND
Platinum-based chemotherapy has shown to be an effective first-line treatment for patients with advanced stage, unresectable non-small cell lung cancer (NSCLC). We evaluated the response rate to combination chemotherapy with cisplatin and taxane, and the significance of the HER-2/neu, ERCC1, and GST-pi status as predictive markers for the tumor response. METHODS: The HER-2/neu, ERCC1, and GST-pi status were analyzed in the biopsy specimens obtained from 35 patients with advanced stage NSCLC prior to cisplatin plus either paclitaxel or docetaxel chemotherapy. RESULTS: The response rate of the tumors to combination chemotherapy was 62.9% (22/35). HER-2/neu was amplified in 51.4% (18/35) of the tumors, and this was observed exclusively in patients with progressive disease (p=0.014). ERCC1 was overexpressed in 77.2% of the specimens (27/35), and this showed a tendency to correlate with the tumor response (p=0.057). GST-pi was detected in 85.7% of the specimens (30/35). Seventy-seven percent of the patients with a negative HER-2/neu and positive ERCC1 status showed a partial response, which was in contrast to only a 25% response rate for the patients with a positive HER-2/neu and negative ERCC1 status (p=0.006). The overall survival was prolonged in the patients without HER-2/neu amplification (15 vs 8.5 months, respectively, p=0.008). On multivariate analysis, the HER-2/neu status remained the significant predictor of survival (p=0.005). CONCLUSIONS: A combination of the ERCC1, HER-2/neu status may define a subset of patients with the most favorable response to combination chemotherapy regimens for treating advanced NSCLC.

Expression of p73 in Non-small Cell Lung Carcinomas.: Ji Han Jung, Gyeongsin Park, Chan Kwon Jung, Hyun Joo Choi, Jinyoung Yoo, Seok Jin Kang, Kyo Young Lee; Korean J Pathol. 2007;41(2):109-115.

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Abstract PDF: BACKGROUND
The p73 is a recently identified homologue of the tumor suppressor gene, p53, and it has been found to induce apoptosis and inhibit cell proliferation. However, its role in the development of tumors is unclear. This study examined the expression of p73 in patients with non-small cell lung carcinomas (NSCLCs) to determine its clinical significance and association with the expressions of p53, pRb, and mdm2.
METHODS
A total of 183 NSCLCs were analyzed immunohistochemically using a tissue microarray.
RESULTS
The p73 protein was expressed in the cell nuclei in 156 (85.2%) out of the 183 cases. There was no correlation between the p73 expression and the clinicopathological variables. However, there was a correlation between the p73 expression and the mdm2 and pRb expressions. Multivariate Cox survival analysis identified tumor size and lymph node metastasis to be independent prognostic factors, but the p73 expression was not found to be associated with the patients' survival.
CONCLUSIONS
p73 is commonly expressed in NSCLC and it might, in conjunction with pRb and mdm2, be involved in the development of these tumors.

The Expression of Telomerase Reverse Transcriptase Protein is an Independent Prognostic Marker in Early Stage Non-Small Cell Lung Carcinomas.: Ji Han Jung, Chan Kwon Jung, Ahwon Lee, Gyeongsin Park, Jinyoung Yoo, Kyo Young Lee; Korean J Pathol. 2007;41(2):95-102.

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Abstract PDF: BACKGROUND
The catalytic subunit of telomerase, hTERT (telomerase reverse transcriptase), is one of the most important components of telomerase, and performs a pivotal role in the mechanism underlying the regulation of telomerase activity in cellular immortalization and carcinogenesis. The principal objective of this study was to investigate hTERT expression in patients with non-small cell lung carcinomas (NSCLCs), and to evaluate its clinical significance and association with the expression of p16 and p53.
METHODS
Using tissue microarray, the protein expression profiles of hTERT, p16 and p53 were investigated via immunohistochemistry in 167 samples of NSCLCs.
RESULTS
Expression was observed in 54.5% (91/167) of the tumors, which were predominantly squamous cell carcinomas. Patients evidencing hTERT expression in their tumors exhibited significantly poorer survival rates than did patients without hTERT expression in early-stage NSCLCs (p=0.0125). According to the results of our Cox regression analysis, hTERT expression proved to be an independent prognostic factor (p=0.006), particularly for squamous cell carcinomas (p=0.019). hTERT expression was not correlated with p16 expression, but was rather associated with the expression of p53 (p=0.002).
CONCLUSIONS
Our results show that hTERT may perform a function in the progression of NSCLC, and that its detection may be useful in predicting the prognosis of NSCLC patients in the early stages of the disease, as well as in the development of a targeted therapy in these tumors.

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