A patient who showed a pathologically complete response after undergoing treatment with XELOX plus bevacizumab for synchronous liver metastasis of grade H2 from sigmoid colon cancer.

We herein report the case of a patient who showed a pathological complete response after undergoing chemotherapy with capecitabine, oxaliplatin and bevacizumab. The patient presented with synchronous solitary liver metastasis from sigmoid colon cancer. The maximum diameter of the liver deposit was 5.7 cm and the grade of the liver metastasis was H2 according to the Japanese classification. Deferred hepatectomy after sigmoidectomy was performed, followed by the administration of neoadjuvant chemotherapy. After undergoing sigmoidectomy, the patient received 1,000 mg/m(2) of capecitabine and 130 mg/m(2) of oxaliplatin without bevacizumab as the first cycle of chemotherapy followed by eight cycles of chemotherapy with bevacizumab (7.5 mg/kg) every three weeks. The liver deposit was reduced to 2.2 cm in diameter and the patient showed a partial response to chemotherapy. The patient then underwent metastasectomy of segment 8 of the liver instead of the central hepatectomy that was possibly needed before chemotherapy. Histopathologically, the tumor consisted of fibrous tissue, and no cancer cells were detected in the resected specimen. A pathological complete response in a patient with H2 liver metastasis is considered rare and suggests that capecitabine, oxaliplatin and bevacizumab are efficacious as neoadjuvant chemotherapy.

Methylation of the HACE1 gene is frequently detected in hepatocellular carcinoma.

BACKGROUND/AIMS: Recently, it has been reported that HACE1, the E3 ubiquitin ligase, is epigenetically inactivated in human Wilms' tumors and HACE 1 expression was also down-regulated in colorectal and gastric carcinomas. METHODOLOGY: In this study, methylation status of the HACE1 gene was examined in primary carcinomas and the corresponding normal tissues derived from 27 patients with HCC using quantitative methylation-specific PCR (qMSP). RESULTS: Methylation of the HACE1 gene was detected in 18 out of the 27 (67%) HCCs, suggesting that the methylation of HACE1 was frequently observed in HCC. The clinicopathological data were then correlated with these results. In the value of serum AFP (α-fetoprotein), a significant difference was observed (p=0.0025). CONCLUSIONS: All stages of HCCs presented HACE1 methylation, indicating that the HACE1 gene has been methylated from the early stages of HCCs.

Methylation of the UNC5C gene is frequently detected in hepatocellular carcinoma.

BACKGROUND/AIMS: Recently, we detected that UNC5C expression was downregulated in colon and gastric cancer. METHODOLOGY: In the present study, the methylation status of the UNC5C gene was examined in primary carcinomas and the corresponding normal tissues derived from 42 patients with HCC. RESULTS: Methylation of the UNC5C gene was detected in 11 out of the 42 (26%) HCCs, suggesting that the methylation of UNC5C was frequently observed in HCCs. The clinicopathological data were correlated with the methylation results. CONCLUSIONS: TNM stage 1 HCC presented UNC5C methylation, indicating that the UNC5C gene has been methylated from the early stages of HCC.

Methylation of the WNT5A gene is frequently detected in early gastric carcinoma.

BACKGROUND/AIMS: Recently, it has been reported that WNT5A methylation was frequently detected in colorectal cancers. However, the relationship between the WNT5A methylation and the characteristics of gastric cancer remains unknown. METHODOLOGY: Methylation status of the WNT5A gene was examined in primary carcinomas and the corresponding normal tissues derived from 38 patients with gastric cancer using quantitative methylation-specific PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Aberrant methylation of the WNT5A gene was detected in 7 out of the 38 (18%) primary gastric carcinomas, suggesting that the methylation of WNT5A is observed in gastric carcinomas as well as colorectal ones. The clinicopathological data were correlated with the methylation results. A significant difference was observed in the extent of tumor (p=0.0226). Moreover, a trend was shown towards early TNM stages in methylated tumors (p=0.209). CONCLUSIONS: WNT5A was more frequently methylated in early gastric carcinomas.

Down-regulation of EGFL8: a novel biomarker for advanced gastric cancer.

BACKGROUND: Recently, we have reported an important role of epidermal growth factor-like domain 8 (EGFL8) in the progression of colorectal cancer (CRC) and documented EGFL8 to be a novel prognostic biomarker for this malignancy. However, the function of EGFL8 in the other human gastroenterological malignancies such as gastric cancer remains largely unknown. PATIENTS AND METHODS: EGFL8 expression in 53 cases of gastric cancer and the corresponding normal tissues were determined by quantitative real-time PCR and the EGFL8 down-regulation score for each patient was calculated. Subsequently, the correlations between EGFL8 down-regulation score and the clinicopathological features of gastric cancer were evaluated. RESULTS: EGFL8 expression was significantly lower in the gastric cancer tissues than the corresponding normal tissues (p=0.0001) and the down-regulation of EGFL8 was evident in 73.6% (39/53) of the gastric carcinomas. More importantly, EGFL8 down-regulation was correlated significantly with peritoneal dissemination (p=0.037) and high TNM stage (p=0.025) of gastric cancer. CONCLUSION: The down-regulation of EGFL8 might be a novel biomarker for advanced gastric cancer.

Down-regulation of EGFL8: a novel prognostic biomarker for patients with colorectal cancer.

BACKGROUND: In a previous study, we reported a critical role of epidermal growth factor-like domain 7 (EGFL7) in the metastasis of hepatocellular carcinoma (HCC) and documented it to be a prognostic biomarker as well as a potential therapeutic target for HCC. However, the role of EGFL8, the only known paralog of EGFL7, in human malignancies is currently unclear. PATIENTS AND METHODS: EGFL8 expression in 101 cases of colorectal cancer (CRC) patients was determined by quantitative reverse transcription-polymerase chain reaction and the clinicopathological features of the CRC patients were correlated with the EGFL8 down-regulation scores. In addition, the survival curve and Cox regression model were also employed to assess the prognostic value of EGFL8 down-regulation. RESULTS: EGFL8 was significantly decreased in CRC tissues (p<0.0001) and the down-regulation of EGFL8 was evidenced in 74.3% (75/101) of the CRC patients. EGFL8 down-regulation correlated significantly to distant metastasis (p=0.038) and high TNM stage (p=0.012) of CRC. The CRC patients with high EGFL8 down-regulation showed either poorer disease-free survival (p=0.0167) or poorer overall survival (p=0.0310) than those with low EGFL8 down-regulation. Multivariable analysis identified EGFL8 down-regulation as an independent prognostic factor for CRC patients (hazard ratio, 12.974; p=0.037). CONCLUSION: The reduced expression of EGFL8 is closely related to metastastic potential and poor prognosis of CRC, suggesting the down-regulation of EGFL8 as a novel prognostic biomarker for CRC patients.

[Complete response to S-1/CDDP combination in a patient with obstructive jaundice secondary to lymph node metastasis by gastric cancer - a case report].

A 55-year-old woman was found to have a type-4 lesion centered on the greater curvature of the lower portion of her stomach during an upper gastrointestinal endoscopic examination.A diagnosis of inoperable advanced gastric carcinoma [type 4, tub 2/por, T3 (SE), N3, H0, P1, cStage IV], complicated by pyloric stenosis, liver dysfunction, and obstructive jaundice untreatable by bile drainage, was made.After obtaining the informed consent of the patient and her family and explain- ing that under the circumstances surgery was not indicated, chemotherapy [S-1 (granules) 80 mg/m2, CDDP 60 mg/m2] was selected. After starting treatment, an improvement in liver dysfunction and jaundice was observed, and at the start of the second course, the patient had become capable of oral feeding.The patient was discharged after completion of the second course. No choices associated with evidence exist for treatment of patients with inoperable advanced gastric cancer (complicated by obstructive jaundice), who are not elderly and have good performance status (PS).We report this case in which improvement of activity of daily living (ADL) was achieved relatively safely by treatment with S-1/CDDP, together with a brief discussion based on the literature.

MACC 1 as a marker for vascular invasive hepatocellular carcinoma.

BACKGROUND: Recently, metastasis associated with colon cancer 1 (MACC1) gene was identified by genome-wide search for differentially expressed genes in human colon cancer tissues and metastases. Previously, MACC1 expression was examined in colorectal carcinomas and gastric carcinomas and was found to show significant correlation with peritoneal dissemination. PATIENTS AND METHODS: In this study, MACC1 expression was analyzed in 60 samples (tumor and the surrounding non-tumorous liver tissue) collected from 30 patients with hepatocellular carcinoma (HCC) using quantitative real-time polymerase chain reaction (QRT-PCR). Results. MACC1 expression score (tumor:normal) in primary HCC was between 0.01 and 4.59 (average±SD=0.68±0.94). Subsequently, clinicopathological data were correlated with the MACC1 expression. It was found that MACC1 expression showed significant correlation with vascular invasion and α-fetoprotein level (p=0.034, p=0.0098, respectively). CONCLUSION: These results suggest that MACC1 is more frequently expressed in vascular invasive HCC and may serve as a new parameter for the prognostic prediction of HCC.

Aberrant methylation of the Vimentin gene in hepatocellular carcinoma.

BACKGROUND: Recently, it was shown that the Vimentin gene, usually activated in mesenchymal cells, was highly methylated in colorectal carcinoma. MATERIALS AND METHODS: The methylation status of the Vimentin gene was examined in primary carcinomas and the corresponding normal tissues derived from 43 patients with hepatocellular carcinoma (HCC) using quantitative methylation-specific PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Aberrant methylation of the Vimentin gene was detected in 24 out of the 43 (56%) primary HCC. This result suggested that the aberrant methylation of the Vimentin gene was frequent in HCC. Subsequently, clinicopathological data were correlated with the methylation status. A significant difference was observed in the value of alpha-fetoprotein (AFP) (p=0.045), maximal tumor size (p=0.048) and TNM stage (p=0.043) between the methylation-positive and -negative cases. CONCLUSION: Aberrant methylation of Vimetin might be an early event in the course of hepatocarcinogenesis.

Methylation of OSMR gene is frequently observed in non-invasive colorectal cancer.

BACKGROUND: Recently, it has been reported that oncostatin M receptor-ß (OSMR) is frequently methylated in primary colon cancer tissues, but not in normal tissues. We examined the methylation status of the OSMR gene in primary carcinomas and the corresponding normal tissues derived from 56 patients with colorectal cancer. PATIENTS AND METHODS: The methylation status of the OSMR gene was examined in primary carcinomas and corresponding normal tissues derived from 56 patients with colorectal cancer using quantitative methylation-specific PCR (qMSP), and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Methylation of the OSMR gene was detected in 18 out of the 56 (32%) primary colon carcinomas. The clinicopathological data were then compared with the methylation results. A significant difference was observed in regard to the extent of tumour (p=0.0442). These results indicated that OSMR was more frequently methylated in non-invasive colorectal carcinomas. CONCLUSION: OSMR may act as a tumour suppressor in colorectal carcinoma and OSMR methylation may play an important role in non-invasive colorectal cancer.

TIP60 as a potential marker for the malignancy of gastric cancer.

BACKGROUND: Recently, it has been shown that the loss of the human histone acetyl transferase, TIP60, led to an accumulation of double-strand DNA breaks and has been linked to a growing number of cancer types. MATERIALS AND METHODS: TIP60 expression levels were examined in 46 gastric cancer samples using a quantitative real-time polymerase chain reaction (QRT-PCR). Subsequently, clinicopathological data were correlated with the TIP60 expression score. RESULTS: A down-regulation of the TIP60 gene was observed in 28 out of 46 (61%) specimens of primary gastric cancer. TIP60 down-regulation showed significant correlation with patient age (p=0.0224), depth of tumor invasion (p=0.0401) and lymph node metastasis (p=0.0481). CONCLUSION: The down-regulation of TIP60 is important for the malignant pathway of gastric carcinogenesis.

Downregulation of Mus81 as a novel prognostic biomarker for patients with colorectal carcinoma.

The Mus81 gene encodes a critical endonuclease involved in DNA repair and tumor suppression. Our previous study has shown reduced expression of Mus81 in hepatocellular carcinoma and its association with the metastatic potential and prognosis of hepatocellular carcinoma. However, the role of Mus81 in colorectal carcinoma is currently unknown. We therefore carried out the present study to explore the correlation between Mus81 expression and the progression of colorectal carcinoma. Mus81 expression in 92 cases of colorectal carcinoma and matched normal tissues was determined by quantitative real-time polymerase chain reaction. Our results showed that Mus81 expression in colorectal carcinoma tissues was significantly reduced compared with the corresponding normal tissues (P < 0.001) and the downregulation of Mus81 (decreased by more than 50%) was found in 60.9% (56/92) of colorectal carcinoma. Moreover, Mus81 downregulation correlated significantly to hepatic metastasis (P = 0.019) and a high TNM stage (P = 0.025) of colorectal carcinoma. In addition, the decrease of Mus81 was also detected in 10 cases of hepatic metastasis tissues compared with the corresponding primary colorectal carcinoma tissues (P = 0.016). More importantly, colorectal carcinoma patients with apparent Mus81 downregulation have shown significantly poorer overall survival than those with little Mus81 downregulation (P = 0.0374). Also, multivariable Cox regression analysis identified Mus81 downregulation as an independent prognostic factor for colorectal carcinoma (hazard ratio, 1.678; P = 0.040). In conclusion, the reduced expression of Mus81 is closely related to hepatic metastasis and poor prognosis of colorectal carcinoma, indicating Mus81 as a novel prognostic marker for colorectal carcinoma.

Down-regulation of Mus81 as a potential marker for the malignancy of gastric cancer.

BACKGROUND: The Mus81 gene encodes a critical endonuclease involved in DNA repair and tumor suppression. In the present study, the role of Mus81 in gastric cancer was explored. MATERIALS AND METHODS: Mus81 expression in 53 cases of gastric cancer and the corresponding normal tissues was determined by quantitative real-time PCR. The correlations between Mus81 down-regulation and the clinicopathological data were also evaluated. RESULTS: Mus81 expression was significantly lower in gastric cancer tissues than the corresponding normal tissues (p = 0.018) and the down-regulation of Mus81 occurred in 51% (27/53) of the gastric carcinomas. More importantly, Mus81 down-regulation correlated significantly to invasion depth (p = 0.015) and poorly-differentiated type (p = 0.016) of gastric cancer. CONCLUSION: Mus81 might be a potential marker for the malignancy of gastric cancer.

Detection of vimentin (VIM) methylation in the serum of colorectal cancer patients.

AIM: Detection of colorectal cancer using serum assay of vimentin methylation. MATERIALS AND METHODS: We attempted to detect vimentin methylation in the serum of colorectal cancer patients using quantitative methylation-specific polymerase chain reaction (qMSP). RESULTS: Of 44 colorectal cancer patients, 4 (9%) exhibited methylation of the vimentin gene in their serum DNA by qMSP. Interestingly, methylation was significantly found in the serum of patients with liver metastasis, peritoneal dissemination, and distant metastasis (p = 0.026, p = 0.0029 and p = 0.0063, respectively), suggesting that vimentin methylation in serum might be detected more frequently in patients with advanced colorectal cancer. CONCLUSION: The high sensitivity of qMSP makes it possible to detect smaller amounts of tumor DNA in the serum, suggesting that qMSP can be used as a screening method for cancer.

Methylation of the TFPI2 gene is frequently detected in advanced gastric carcinoma.

BACKGROUND: Recently, Glockner et al. identified the methylation of TFPI2 as a frequent event in human colorectal cancer using a gene expression array-based strategy. MATERIALS AND METHODS: Methylation status of the TFPI2 gene was examined in primary carcinomas and the corresponding normal tissues derived from 38 patients with gastric cancer using quantitative methylation-specific PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Aberrant methylation of the TFPI2 gene was detected in 7 out of 38 (18%) primary gastric carcinomas, suggesting that the methylation of TFPI2 is frequently observed in gastric carcinomas. The clinicopathological data were correlated with the methylation results. A significant difference was observed in maximal tumour size (p=0.0084), extent of tumour (p=0.0068), and TNM stage (p=0.0392). CONCLUSION: TFPI2 is frequently methylated in advanced gastric carcinomas.

MACC 1 as a marker for peritoneal-disseminated gastric carcinoma.

BACKGROUND: Recently, metastasis associated with the colon cancer 1 (MACC1) gene was identified by genome-wide search for differentially expressed genes in human colon cancer tissues and metastases. Previously, the MACC1 expression levels were examined in colorectal carcinomas and it was found that MACC1 expression showed significant correlation with peritoneal dissemination and higher stage of TNM classification. MATERIALS AND METHODS: In this study, MACC1 expression levels were analysed in 41 gastric cancer samples using quantitative real-time polymerase chain reaction (QRT-PCR). Results. Distribution of MACC1 expression scores in primary gastric carcinomas was between 0.01 and 4.36 (average ± SD was 1.34 ± 1.31). Subsequently, clinicopathological data were correlated with the MACC1 expression. It was found that MACC1 expression showed significant correlation with peritoneal dissemination (p=0.038). CONCLUSION: These results suggest that MACC1 is more frequently expressed in peritoneal-disseminated gastric carcinomas and may serve as a new parameter for the prognostic prediction of gastric cancer.

MACC1 as a marker for advanced colorectal carcinoma.

BACKGROUND: Recently, Stein et al. identified the metastasis-associated in colon cancer 1 (MACC1) gene by genome-wide search for differentially expressed genes in human colon cancer tissues and metastases. PATIENTS AND METHODS: We analyzed MACC1 expression levels in 52 colorectal cancer samples using quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: We found that MACC1 expression showed significant correlation with peritoneal dissemination (p=0.042) and higher stage of TNM classification (p=0.007). CONCLUSION: These results suggest that MACC1 is more frequently expressed in advanced colorectal carcinomas.

Methylation of the p16 gene is frequently detected in lymphatic-invasive gastric cancer.

BACKGROUND: A tumor suppressor gene, p16, was found to harbor promoter methylation associated with the loss of protein expression in cancer cells, suggesting that p16 inactivation due to promoter methylation may be important for gastric tumorigenesis. PATIENTS AND METHODS: The methylation status of the p16 gene was examined in primary carcinomas and the corresponding normal tissues derived from 49 patients with gastric cancer using quantitative methylation-specific PCR (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Aberrant methylation of the p16 gene was detected in 17 out of the 49 (34%) primary gastric carcinomas, suggesting that the aberrant methylation of p16 is frequently observed in gastric carcinomas. The clinicopathological data were then correlated with these results. Significant differences were observed with lymphatic invasion (p=0.046) and tumor site (p=0.010). CONCLUSION: p16 might act as a tumor suppressor in gastric carcinomas and appears to be more frequently methylated in lymphatic-invasive gastric carcinomas.

Demethylation of the CD133 gene is frequently detected in early gastric carcinoma.

BACKGROUND: Recently, it has been reported that colorectal carcinoma is created and propagated by a small number of undifferentiated tumorigenic CD133(+) cells. Furthermore, it has been reported that CD133 expression is directly regulated by epigenetic modifications. Therefore, it is possible that CD133 expression by gene demethylation is related to colorectal and gastric carcinogenesis. MATERIALS AND METHODS: The methylation status of the CD133 gene was examined in primary carcinomas and the corresponding normal tissues derived from 36 patients with gastric cancer using quantitative methylation-specific polymerase chain reaction (qMSP) and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Demethylation of the CD133 gene was detected in 14 out of the 36 (39%) primary gastric carcinomas, suggesting that the demethylation of CD133 is frequently observed in gastric carcinomas. The clinicopathological data were correlated with the demethylation results. A significant decrease of CD133 methylation was observed in the extent of tumor (p=0.0421). Moreover, a trend was shown toward smaller maximal tumor size in tumors with demethylated CD133 (p=0.0556). CONCLUSION: CD133 appears to be frequently demethylated in early gastric carcinomas.

Methylation of TFPI2 gene is frequently detected in advanced well-differentiated colorectal cancer.

BACKGROUND: Recently, it has been reported that TFPI2 (tissue factor pathway inhibitor-2), a Kunitz-type serine proteinase inhibitor, is frequently methylated in human colorectal cancer using a gene expression array-based strategy. The aim of this study therefore was to examine whether the TFPI2 methylation in surgically removed colorectal cancers was correlated to the clinicopathological features. MATERIALS AND METHODS: The methylation status of the TFPI2 gene was examined in primary carcinomas and corresponding normal tissues derived from 50 patients with colorectal cancer using quantitative methylation-specific PCR (qMSP), and the correlation between the methylation status and the clinicopathological findings was evaluated. Results. Methylation of the TFPI2 gene was detected in 31 out of the 50 (62%) primary colon carcinomas, suggesting that the methylation of TFPI2 is frequently observed in colorectal cancer. The clinicopathological data were compared with these results. Significant differences were observed between methylation of TFPI2 and histology (p=0.0053) or lymph node metastasis (p=0.0396). These results indicated that TFPI2 was more frequently methylated in well-differentiated advanced colorectal carcinomas. CONCLUSION: TFPI2 may act as a tumour suppressor in colorectal carcinomas and TFPI2 methylation may present a potential risk of malignancy in colorectal cancer.