• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.6149-6154
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• 2015

Background: There is no suggested molecular indicator for the determination of which patients will benefit from anti-angiogenetic treatment in metastatic colorectal cancers. Materials and Methods: In this study, VEGF and $HIF-1{\alpha}$ expression and their clinical significance were studied in tumor tissues of patients with colorectal cancer receiving bevacizumab-based treatment. VEGF and $HIF-1{\alpha}$ were assessed by immunohistochemistry in the primary tumors of 53 metastatic colorectal cancer patients receiving chemotherapy in combination with first line bevacizumab. Results: The clinical benefit rate in the low-VEGF expression group was 38%, while it was 62% in the high expression group. While the median progression-free survival (PFS) was 10 months in the high-VEGF expression group, it was 8 months in the low-VEGF expression group (p = 0.009). The median overall survival (OS) was found to be 26 months vs 15 months. Thus, when VEGF was strongly expressed it was in favor of that group and the difference was statistically significant (p = 0.03). High VEGF expression rate was an independent factor that correlated with OS or PFS (p=0.016 and 0.009, respectively). Conclusions: The data showed that VEGF may have predictive value for determining the treatment of CRC.

• Journal of Physiology & Pathology in Korean Medicine
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• v.23 no.5
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• pp.1041-1048
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• 2009

The development of skin metastasis is usually a morbid prognostic feature although they occur infrequently. Adenocarcinomas account for up to about 70% of all metastatic skin cancer. In general, adenocarcinomas are the most difficult metastatic tumor to accurately identify the primary site because they don't have distinctive histological features. For this reason, immunohistochemistry have been used to help identify the origin of metastatic adenocarcinomas. This study performed immunohistochemical staining with metastatic adenocarcinomas of the skin using a variety of antisera to find out characteristic immunohistochemical findings of them. This study was made upon the 29 cases of metastatic adenocarcinomas of the skin, which had been confirmed histopathologically in Chonbuk National University Hospital from January, 1986 to April, 2006, Paraffin blocks were colledted and homemade tissue arrays were made. We performed immunohistochemical staning using 12 antibodies (MUC1, 2, 5AC, 6, cytokeratin (CK) 7, 20, thyroid transcription factor-1 (TTF-1), estrogen receptor (ER), progesterone receptor (PR), beta-catenin, cox-2, claudin-1). The mean age at the time of diagnosis was 60.7 years and the male to female ratio was 1.2:1.0. The most common primary site was lung, followed by stomach and colorectum. MUC1 was expressed by most colorectal, breast and lung adenocarcinoma. MUC2 was expressed infrequently. MUCSAC was expressed by most gastric and colorectal cancer MUC6 was not specific of any primary site in this series. CK7+/CK20+immunophenotype was observed in gastric, lung, colorectal adenocarcinoma. CK7+/CK20- immunophenotype was observed in breast, lung, endometrial, uterine cervical, bile duct adenocarcinoma, while CK7-/CK20+ immunophenotype was observed only in colorectal adenocarcinoma. This results show the utility of TTF-1 to confirm the pulmonary origin. On the other hand ER and PR were not useful markers to assess the origin of primary tumor in this series.

• Biomedical Science Letters
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• v.8 no.3
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• pp.137-142
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• 2002

The expression of CD44v is known as a marker of cancer progression and its metastasis in colorectal cancer. It has been known that CD44 variant containing sequences encoded by exon 11 (v6) confer metastatic potential to human colorectal cancer cells. The role of CD44 standard (CD44s) and CD44v6 in colorectal cancer was investigated in this study by immunohistochemical staining of the primary tumors obtained from the colorectal cancer patients. Immunohistochemical staining was performed in 40 patients with colorectal cancer who underwent curative surgery at Keimyung University hospital. The expression CD44s and CD44v6 was observed in 24/40 (60%) and 13/40 (32.5%) respectively. The expression of CD44v6 had correlation with TNM stage (P＜0.05), however CD44s had not any correlation with clinicopathological parameters. These results suggest that CD44v6 expression may give an information for tumor progression than decreased expression of CD44s in colorectal cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.6
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• pp.2437-2444
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• 2012

Tumor metastasis remains the principal cause of treatment failure and poor prognosis in patients with colorectal cancer. It is a multistage process which includes proteolysis, motility and migration of cells, proliferation in a new site, and neoangiogenesis. A crucial step in the process of intra- and extra-vasation is the activation of proteolytic enzymes capable of degrading the extracellular matrix (ECM). In this stage, urokinase plasminogen activator receptor (uPAR) and matrix metalloproteinases (MMPs) are necessary. Micrometastases need the presence of growth factor and vascular growth factor so that they can form macrometastasis. In addition, cell adhesion molecules (CAMs) and guanine nucleotide exchange factors (GEFs) play important roles in the progression of colorectal cancer and metastatic migration. Further elucidation of the mechanisms of how these molecules contribute will aid in the identification of diagnostic and prognostic markers as well as therapeutic targets for patients with colorectal metastasis.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6559-6564
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• 2014

Objective: To evaluate the efficacy and safety of bevacizumab in the treatment of patients with metastatic colorectal cancer (mCRC). Methods: In a single-center, observational study of 91 Chinese patients with mCRC who received bevacizumab in combination with chemotherapy was conducted. Objective response rates (ORRs), progression-free survival (PFS), overall survival (OS) and adverse events were recorded, and the relationships between various clinical factors and PFS or OS were evaluated by Cox proportional hazards models. Results: Treatment with bevacizumab and chemotherapy was effective and tolerable. Univariate analysis showed that PFS and OS were significantly associated with the Eastern Cooperative Oncology Group performance status (ECOG-PS) score, duration of bevacizumab exposure, and whether chemotherapy was continued after discontinuation of bevacizumab treatment. A multivariate analysis showed that the duration of bevacizumab exposure and whether chemotherapy was continued after discontinuation of bevacizumab were independent prognostic factors for PFS and OS. Conclusion: In Chinese mCRC population, the shorter the duration of exposure to bevacizumab and chemotherapy, the worse the prognosis is.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.7
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• pp.3157-3161
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• 2014

Background: Unlike for fit elderly metastatic colorectal cancer (mCRC) patients, general approaches to initial treatment for the frail older mCRC patients are not clear. Our aim was to evaluate the efficiency and safety of first-line single-agent treatment in one such group. Materials and Methods: We retrospectively evaluated mCRC patients aged 70 or older with an Eastern Cooperative Oncology Group performance score of 2. They had no prior treatment and underwent first-line single-agent capecitabine or other monotherapies until disease progression or unacceptable toxicity. Results: Thirty-six patients were included. Most (n:28, 77.8%) were treated with capecitabine. One patient achieved a complete response and 5 patients had a partial response for an overall response rate of 16.6%. Twelve patients (33.3%) remained stable. Median progression free survival was 5 months (confidence interval (CI), %; 3.59-6.40) and median overall survival was 10 months (95 CI%; 8.1-11.8). Grade 3-4 toxicity was found in 6 patients (16.6%). Febrile neutropenia was not observed and there were no toxicity-associated deaths. Conclusions: Capecitabine is a safe chemotherapeutic agent with moderate activity for first-line treatment of older metastatic colorectal cancer patients with limited performance status.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.14
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• pp.5923-5931
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• 2015

Background: Registry data from four major public hospitals indicate trends over three decades from 1980 to 2010 in treatment and survival from colorectal cancer with distant metastases at diagnosis (TNM stage IV). Materials and Methods: Kaplan-Meier product-limit estimates and Cox proportional hazards models for investigating disease-specific survival and multiple logistic regression analyses for indicating first-round treatment trends. Results: Two-year survivals increased from 10% for 1980-84 to 35% for 2005-10 diagnoses. Corresponding increases in five-year survivals were from 3% to 16%. Time-to-event risk of colorectal cancer death approximately halved (hazards ratio: 0.48 (0.40, 0.59) after adjusting for demographic factors, tumour differentiation, and primary sub-site. Survivals were not found to differ by place of residence, suggesting reasonable equity in service provision. About 74% of cases were treated surgically and this proportion increased over time. Proportions having systemic therapy and/or radiotherapy increased from 12% in 1980-84 to 61% for 2005-10. Radiotherapy was more common for rectal than colonic cases (39% vs 7% in 2005-10). Of the cases diagnosed in 2005-10 when less than 70 years of age, the percentage having radiotherapy and/or systemic therapy was 79% for colorectal, 74% for colon and 86% for rectum (&RS)) cancers. Corresponding proportions having: systemic therapies were 75%, 71% and 81% respectively; radiotherapy were 24%, 10% and 46% respectively; and surgery were 75%, 78% and 71% respectively. Based on survey data on uptake of offered therapies, it is likely that of these younger cases, 85% would have been offered systemic treatment and among rectum (&RS) cases, about 63% would have been offered radiotherapy. Conclusions: Pronounced increases in survivals from metastatic colorectal cancer have occurred, in keeping with improved systemic therapies and surgical interventions. Use of radiotherapy and/or systemic therapy has increased markedly and patterns of change accord with clinical guideline recommendations.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5941-5944
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• 2014

Purpose: To highlight the potential factors that could predict the response rate of patients with metastatic colorectal cancer (mCRC) treated with pemetrexed combined chemotherapy after first- or second-line chemotherapy using the FOLFOX regimen. Materials and Methods: Between January 2007 and July 2014, 54 patients diagnosed and pathologically-confirmed with advanced colorectal cancer in Jiangsu Cancer Hospital and Research Institute, were enrolled. They received pemetrexed at a dose of $500mg/m^2$ by 10 minute infusion on day 1, repeated every 3 weeks. Doses were modified depending on nadir counts of blood cells. Combined chemotherapeutic agents included irinotecan, lobaplatin, carboplatin, oxaliplatin, gemcitabine, cis-platinum or bevacizumab. Multiple variables (age, sex, hemoglobin, platinum drugs combined, metastasis sites, LDH, ALP, CEA>40 ug/ml) reported earlier were selected. We used logistic regression analysis to evaluate relationships between these and tumor response. Results: On multivariable analysis, we found that age was significant in predicting the responsiveness to pemetrexed (p<0.05) combined with oxaliplatin. We did not find any other factors which were significantly associated with the response rate to chemotherapy with pemetrexed and irinotecan. Conclusions: By multivariate analysis, we found that age had significant impact on the responsiveness of pemetrexed when combined with oxaliplatin. Additional research based on genomic properties of host and tumors are needed to clarify markers for better selection of patients who could benefit from pemetrexed combined chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.4117-4123
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• 2016

Background: Methylation of promoter 2 of the SHP1 gene is epithelial cell specific, with reported potential as a lymph node metastatic marker. Objective: To demonstrate SHP1-P2 methylation-specific quantitative PCR effectiveness in detecting colorectal cancer (CRC) DNA in lymph nodes. Materials and Methods: SHP1-P2 methylation levels were measured in lymph nodes of CRC patients and compared with pathological findings and patient prognosis. Results: Lymph nodes of CRC metastatic patients without microscopically detectable cancer cells had higher SHP1-P2 methylation levels than lymph nodes of controls (p<0.001). In addition, a higher SHP1-P2 methylation level was associated with a shorter duration until adverse disease events, metastasis, recurrence and death (r2 = 0.236 and p value = 0.048). Studying two cohorts of 74 CRC patients without microscopic lymph node metastases showed that only the cohort containing samples with high SHP1-P2 methylation levels had a significant hazard ratio of 3.8 (95%CI = 1.02 to 14.2). Conclusions: SHP1-P2 methylation PCR can detect CRC DNA in lymph nodes even if cancer cells are not visible under a microscope, confirming applicability as a potential universal lymph node metastatic marker.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.7
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• pp.3015-3021
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• 2015

Background: Colorectal cancer (CRC) is a major cause of mortality in developed countries, and it is the third most frequent malignancy in Turkey. There are many biological, genetic, molecular, and tissue-derived prognostic factors for CRCs. In this study, we evaluated prognostic factors in patients who were metastatic at diagnosis or progressed to metastatic disease during follow-up. Patients and Methods: This study included 116 patients with malignancies either in the colon or rectum. Of these, 65 had metastatic disease at diagnosis, and 51 progressed to metastatic disease during the course of the disease. The parameters evaluated were age, gender, comorbidity, performance status and stage of the disease at the beginning, localization, history of surgery, chemotherapy regimen, response to first-line treatment, K-RAS status, site and number of metastases, expression of tumor predictors (CEA, CA19-9), and survival times. A multivariate analysis conducted with factors that considered statistically significant in the univariate analysis. Findings: Median age was 56 (32-82) years and the male/female ratio was 80/36. Eleven patients were at stage II, 40 at stage III, and 65 at stage IV at diagnosis. Twenty three patients had tumor in the right colon, 48 in the left colon, and 45 in the rectum. Ninety seven patients were operated, and 27 had surgical metastasectomy. Ninety three patients received targeted therapy. At the end of follow-up, 61 patients had died, and 55 survived. Metastatic period survival times were longer in the adjuvant group, but the difference did not reach the level of statistical significance (adjuvant group: median 29 months, metastatic group: median 22 months; p=0.285). In the adjuvant group before the metastatic first-line therapy, CEA and CA 19-9 levels were significiantly lower compared to the metastatic group (p<0.005). We also found that patients with elevated tumor predictor (CEA, CA 19-9) levels before the first-line therapy had significiantly poorer prognosis and shorter survival time. Survival was significiantly better with the patients who were younger than 65 years of age, had better initial performance status, a history of primary surgery and metastatectomy, and single site of metastasis. Those who benefitted from the first-line therapy were K-RAS wild type and whose tumor markers (CEA, CA 19-9) were not elevated before the first line therapy. Conclusions: Among the patients with metastatic CRC, those who benefited from first-line therapy, had history of metastasectomy, were K-RAS wild type and had low CA 19-9 levels before the first-line therapy, showed better prognosis independent of other factors.