• Asian Pacific Journal of Cancer Prevention
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• v.15 no.3
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• pp.1441-1446
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• 2014

Squamous cell/adenosquamous carcinoma (SC/ASC) of the gallbladder are rare tumors and there are few clinical reports in the literature. Herein we report our clinical experience with 46 patients with SC/ASC and 80 with adenocarcinoma (AC). Expression of EphB1 and Ephrin-B in each tumor was determined using immunohistochemical methods for determination of correlations with prognosis. There was no difference in EphB1 and Ephrin-B expression between SC/ASC and AC tumors (P>0.05), but greater expression in those less than 3 cm in diameter, stage I or II (TNM stage), with no lymph node metastases, with no local invasion and treated with radical resection was apparent. Expression of EphB1 (P<0.05) and Ephrin-B (P<0.01) was higher in well differentiated than in poorly differentiated AC tumors. Kaplan-Meier survival analysis indicated that degree of differentiation, tumor diameter, lymph node metastases, local invasion, surgical approach and expression rate of EphB1 and Ephrin-B were closely related to the survival of SC/ASC (P<0.05) and AC patients (P<0.01). Patients with tumors that positive expressed EphB1 and Ephrin-B, whether it is SC/ASC ($P_{SC/ASC}$ =0.000) or AC ($P_{AC}$ =0.000 or $P_{AC}$ =0.002) had longer survival than those negative expression. Cox multivariate analysis indicated a negative correlation between expression of EphB1 or Ephrin-B and overall survival. Hence, EphB1 and Ephrin-B could be regarded as independent good prognostic factorsand important biological markers for SC/ASC and AC of gallbladder.

• Radiation Oncology Journal
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• v.30 no.4
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• pp.218-225
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• 2012

Purpose: The relationship between treatment outcomes, alteration of the expression of biological markers, and tumor volume response during radiotherapy (RT) in patients with uterine cervical cancer was analyzed. Materials and Methods: Twenty patients with cervical squamous cell carcinoma received definitive RT with (n = 17) or without (n = 3) concurrent chemotherapy. Tumor volumes were measured by three serial magnetic resonance imaging scans at pre-, mid-, and post-RT. Two serial punch biopsies were performed at pre- and mid-RT, and immunohistochemical staining for cyclooxygenase (COX)-2 and epidermal growth factor receptor was performed. The median follow-up duration was 60 months. Results: The median tumor volume response at mid-RT (V2R) was 0.396 (range, 0.136 to 0.983). At mid-RT, an interval increase in the distribution of immunoreactivity for COX-2 was observed in 8 patients, and 6 of them showed poor mid-RT tumor volume response ($V2R{\geq}0.4$). Four (20%) patients experienced disease progression after 10 to 12 months (median, 11 months). All 4 patients had poor mid-RT tumor volume response (p = 0.0867) and 3 of them had an interval increase in COX-2 expression. Overall survival (OS) and progression-free survival (PFS) decreased in patients with $V2R{\geq}0.4$ (p = 0.0291 for both). An interval increase in COX-2 expression at mid-RT was also associated with a decreased survival (p = 0.1878 and 0.1845 for OS and PFS, respectively). Conclusion: Poor tumor volume response and an interval increase in COX-2 expression at mid-RT decreased survival outcomes in patients with uterine cervical cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.10
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• pp.4281-4287
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• 2014

Background: Methylation of tumor suppressor genes has been investigated in all kinds of cancer. Tumor specific epigenetic alterations can be used as a molecular markers of malignancy, which can lead to better diagnosis, prognosis and therapy. Therefore, the aim of this study was to evaluate the association between gene hypermethylation and expression of fragile histidine triad (FHIT), glutathione S-transferase P1 (GSTP1) and p16 genes and various clinicopathologic characteristics in primary non-small cell lung carcinomas (NSCLC). Materials and Methods: The study included 28 primary non-small cell lung carcinomas, where an additional 28 tissue samples taken from apparently normal safety margin surrounding the tumors served as controls. Methylation-specific polymerase chain reaction (MSP) was performed to analyze the methylation status of FHIT, GSTP1 and p16 while their mRNA expression levels were measured using a real-time PCR assay with SYBR Green I. Results: The methylation frequencies of the genes tested in NSCLC specimens were 53.6% for FHIT, 25% for GSTP1, and 0% for p16, and the risk of FHIT hypermethylation increased among patients with NSCLC by 2.88, while the risk of GSTP1 hypermethylation increased by 2.33. Hypermethylation of FHIT gene showed a highly significant correlation with pathologic stage (p<0.01) and a significant correlation with smoking habit and FHIT mRNA expression level (p<0.05). In contrast, no correlation was observed between the methylation of GSTP1 or p16 and smoking habit or any other parameter investigated (p>0.05). Conclusions: Results of the present study suggest that methylation of FHIT is a useful biomarker of biologically aggressive disease in patients with NSCLC. FHIT methylation may play a role in lung cancer later metastatic stages while GSTP1 methylation may rather play a role in the early pathogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7351-7355
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• 2014

Background: Laryngeal carcinogenesis is a multifactorial process that has not been fully elucidated. Despite extensive research, reliable markers with diagnostic and prognostic value are still lacking. It was recently reported that an elevated preoperative neutrophil-to-lymphocyte ratio (NLR) may correlate with an increased risk of recurrence, tumor aggressiveness and poorer prognosis in various malignancies. The aim of this study was to examine whether NLR could be used as an inflammatory marker to differentiate laryngeal squamous cell carcinoma (LSCC) patients from benign laryngeal lesion (BLL) and precancerous laryngeal lesion (PLL) patients. Materials and Methods: This retrospective study was performed on 209 patients admitted to a tertiary referral center with laryngeal lesions and undergoing biopsies to establish their histopathological diagnosis. We reviewed the patient files for their clinical, histopathological and laboratory data. The patients were divided into three groups according to their histopathological findings, as BLL, PLL and LSCC groups. The patients in the PLL group were also divided into three subgroups as mild, moderate and severe dysplasia/carcinoma in situ (CIS) subgroups. The groups were compared for NLR and the other laboratory data. Results: The mean NLRs of the BLL, PLL and the LSCC groups were $2.12{\pm}0.86$, $2.32{\pm}0.68$ and $3.46{\pm}1.51$, respectively, and the difference was statistically significant (p=0.001). The mean NLRs of the patients with PLL and LSCC were significantly higher than the patients with BLL (p=0.031 and p=0.001, respectively). The mean NLRs were similar among mild dysplasia, moderate dysplasia and severe dysplasia / CIS groups (p>0.05). Conclusions: To our knowledge, this is the first study investigating NLR in BLL, PLL and LSCC. NLR is an inexpensive, reproducible and widely available blood test, and could be a useful inflammatory marker to differentiate LSCC from BLL and PLL.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.17
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• pp.7097-7103
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• 2014

Over-expression of de novo lipogenesis (DNL) genes is associated with the prognosis of various types of cancers. However, the effects of single nucleotide polymorphisms (SNPs) in these genes on recurrence and survival of non-small cell lung cancer (NSCLC) patients after surgery are still unknown. In this study, a total of 500 NSCLC patients who underwent surgery treatment were included. Eight SNPs in 3 genes (ACACA, FASN and ACLY) of the DNL pathway were examined using the Sequenom iPLEX genotyping system. Multivariate Cox proportional hazards regression and Kaplan-Meier curves were used to analyze the association of SNPs with patient survival and tumour recurrence. We found that two SNPs in the FASN gene were significantly associated with the recurrence of NSCLC. SNP rs4246444 had a significant association with lung cancer recurrence under additive model (hazard ratio [HR], 0.82; 95% confidence interval [95%CI], 0.67-1.00; p=0.05). Under the dominant model, rs4485435 exhibited a significant association with recurrence (HR, 0.75; 95%CI, 0.56-1.01; p=0.05). Additionally, SNP rs9912300 in ACLY gene was significantly associated with overall survival in lung cancer patients (HR, 1.41; 95%CI, 1.02-1.94, p=0.04) under the dominant model. Further cumulative effect analysis showed moderate dose-dependent effects of unfavorable SNPs on both survival and recurrence. Our data suggest that the SNPs in DNL genes may serve as independent prognostic markers for NSCLC patients after surgery.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.20
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• pp.8893-8900
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• 2014

Dysregulated expression of microRNAs (miRNAs) has been shown to be closely associated with tumor development, progression, and carcinogenesis. However, their clinical implications for gastric cancer remain elusive. To investigate the hypothesis that genome-wide alternations of miRNAs differentiate gastric cancer tissues from those matched adjacent non-tumor tissues (ANTTs), miRNA arrays were employed to examine miRNA expression profiles for the 5-pair discovery stage, and the quantitative real-time polymerase chain reaction (qRTPCR) was applied to validate candidate miRNAs for 48-pair validation stage. Furthermore, the relationship between altered miRNA and clinicopathological features and prognosis of gastric cancer was explored. Among a total of 1,146 miRNAs analyzed, 16 miRNAs were found to be significantly different expressed in tissues from gastric cancer compared to ANTTs (p<0.05). qRT-PCR further confirmed the variation in expression of miR-193b and miR-196a in the validation stage. Down-expression of miR-193b was significantly correlated with Lauren type, differentiation, UICC stage, invasion, and metastasis of gastric cancer (p<0.05), while over-expression of miR-196a was significantly associated with poor differentiation (p=0.022). Moreover, binary logistic regression analysis demonstrated that the UICC stage was a significant risk factor for down-expression of miR-193b (adjusted OR=8.69; 95%CI=1.06-56.91; p=0.043). Additionally, Kaplan-Meier survival curves indicated that patients with a high fold-change of down-regulated miR-193b had a significantly shorter survival time (n=19; median survival=29 months) compared to patients with a low fold-change of down-regulated miR-193b (n=29; median survival=54 months) (p=0.001). Overall survival time of patients with a low fold-change of up-regulated miR-196a (n=27; median survival=52 months) was significantly longer than that of patients with a high fold-change of up-regulated miR-196a (n=21; median survival=46 months) (p=0.003). Hence, miR-193b and miR-196a may be applied as novel and promising prognostic markers in gastric cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.13
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• pp.5239-5243
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• 2014

Background: The prognosis of young colorectal cancer (CRC) patients has been addressed by several studies but with contradictory results. The aim of the present study was to evaluate the clinico-pathological features of young Saudi patients with CRC in addition to displaying their survival outcome. Materials and Methods: In this retrospective study, young CRC patients (${\leq}40$ years) diagnosed between 2007 and 2011 from 4 centres in western Saudi Arabia, were included. Clinico-pathological features, tumor markers, dates of disease relapse and death were collected. Survival parameters were compared with those of older Saudi patients, reported in previous studies. Results: One hundred and sixteen young patients with CRC were identified (32.2% rectal, 67.8% colon). Some 44% were metastatic while 32.7% had stage III at diagnosis. Patients with grade 3 tumors made up 29.4% of the total while 49.5% had positive lymphovascular invasion (LVI), 56% had a lymph node (LN) ratio ${\geq}0.2$ and 40.2% were K-ras mutant. Median disease-free survival (DFS) and overall survival (OS) in non-metastatic cases were 22.8 and 49.6 months respectively with better median DFS in K-ras wild compared to mutant patients (28.5 vs 20.9 months, p=0.005). In metastatic cases, median OS was 19.5 months. These survival outcomes are inferior compared to those of older Saudi patients reported in prior studies. Conclusions: Young CRC patients present more commonly with advanced stage and a high incidence of adverse prognostic factors such as LVI and high LN ratio. Young CRC patients seem to have worse survival compared to older Saudi patients.

• Journal of Life Science
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• v.27 no.10
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• pp.1225-1231
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• 2017

Disruptive expression patterns of the circadian clock genes are highly associated with many human diseases, including cancer. Cell cycle and proliferation is linked to a circadian rhythm; therefore, abnormal clock gene expression could result in tumorigenesis and malignant development. The molecular network of the circadian clock is based on transcriptional and translational feedback loops orchestrated by a variety of clock activators and clock repressors. The expression of 10~15% of the genome is controlled by the overall balance of circadian oscillation. Among the many clock genes, Period 1 (Per1) and Period 2 (Per2) are clock repressor genes that play an important role in the regulation of normal physiological rhythms. It has been reported that PER1 and PER2 are involved in the expression of cell cycle regulators including cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors. In addition, correlation of the down-regulation of PER1 and PER2 with development of many cancer types has been revealed. In this review, we focused on the molecular function of PER1 and PER2 in the circadian clock network and the transcriptional and translational targets of PER1 and PER2 involved in cell cycle and tumorigenesis. Moreover, we provide information suggesting that PER1 and PER2 could be promising therapeutic targets for cancer therapies and serve as potential prognostic markers for certain types of human cancers.

• Tuberculosis and Respiratory Diseases
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• v.68 no.4
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• pp.212-217
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• 2010

Background: Acyl protein thioesterase-1 (APT1) is a cytosolic protein that may function in the depalmitoylation of numerous proteins, including the Ras family. However, the clinical role of depalmitoyl thioesterase in human cancer is not known. We evaluated the APT1 expression in lung cancer tissue and its clinicopathological findings according APT1 expression pattern. Methods: APT1 expression was examined by immunohistochemistry in the tumor tissue from 79 patients, who had undergone curative surgical removal of the primary lesion; all patients had been diagnosed with stage I non-small cell lung cancer between 1993 and 2004, at Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. Results: The APT1 expression was seen in 50 out of 79 (63.3%) cases. The positive APT1 expression was significantly related with histologic subtype and T stage, but was not influenced by differentiation. The positive APT1 expression was not significantly related to patient age, gender, or smoking history. The median follow-up duration was 10.0 years; the 5-year survival rate was 71.0%. The positive APT1 expression group showed significantly worse overall survival and worse disease-free survival without statistical significance. Conclusion: We conclude that positive APT1 expression in stage I lung cancer after surgery is closely associated with overall survival. To evaluate APT1 as a prognostic marker in lung cancer, comprehensive studies on advanced stage cases are needed.

• Journal of Gastric Cancer
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• v.1 no.2
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• pp.92-99
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• 2001

Purpose: E-cadherin is an adhesion molecule essential for tight connection between cells, forming the cadherin/catenin complex. Truncated $\beta$-catenin disrupts the interaction between E-cadherin and $\alpha$-catenin, leading to the loss of intercellular adhesion. Met protein, the hepatocyte growth factor receptor, plays important roles in signal transduction. We investigated the relationships between the expressions of E-cadherin, $\beta$-catenin, and c-met protein and the clinicopathological and prognostic parameters in gastric adenocarcinomas. Materials and Methods: The patterns of E-cadherin, $\beta$-catenin, and c-met protein expression were studied using immunohistochemistry in formalin-fixed, paraffin-embedded archival tissues from 76 surgically resected gastric adenocarcinomas. Results: Increased expressions of E-cadherin, $\beta$-catenin, and c-met were more significantly correlated in early gastric cancers (EGC) than in advanced gastric cancers (AGC) (P=0.002, P=0.003 and P=0.026). The positive immunoreactivities of all three markers were markedly lower in signet ring-cell type and poorly differentiated type lesions than in intestinal-type lesions. Decreased expression of the $\beta$-catenin protein correlated well with increased tumor invasion depth (P=0.039), and increased lymph node metastasis correlated well with reduced expression of c-met (P=0.046). Conclusion: In gastric cancers, reduced expressions of the E-cadherin, $\beta$-catenin, and c-met proteins may play some role in poorer tumor differentiation, deeper tumor invasion, and increased lymph node metastasis. Also, the c-met gene is thought to play a specific role in the mechanism of the yet unknown catenin action.