A phase II study of bevacizumab with modified OPTIMOX1 as first-line therapy for metastatic colorectal cancer: the TCOG-GI 0802 study.

BACKGROUND: Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)). METHODS: Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease. RESULTS: The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths. CONCLUSIONS: Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer.

Serum vimentin methylation as a potential marker for colorectal cancer.

AIMS: The present study aimed to examine the feasibility of detecting vimentin (VIM) methylation in the serum of patients with colorectal cancer (CRC) and to determine the effectiveness of a relatively simple, inexpensive, and non-invasive test performed in combination with the conventional carcinoembryonic antigen analysis. MATERIALS AND METHODS: VIM methylation in the serum DNA of 242 patients with CRC was measured by a quantitative methylation-specific polymerase chain reaction. RESULTS: A significantly higher positive rate was obtained for VIM methylation than for carcinoembryonic antigen or carbohydrate antigen 19-9 in stage 0, I, and II patients. The combination of all three markers yielded similar sensitivity for patients with disease of stage 0: 57.1%, I: 36.1%, II: 45.2%, and III: 55.4%, whereas the sensitivity reached 85.7% for patients with stage IV disease. CONCLUSION: VIM methylation of serum DNA may be a useful marker for the early detection of CRC.

p16 Methylation is frequently detected in the serum of metastatic colorectal cancer patients.

For the purpose of detection of colorectal cancers, we tried to detect p16 methylation in the serum of colorectal cancer patients using quantitative methylation-specific polymerase chain reaction (qMSP). Out of 211 serum samples derived from colorectal cancer patients, 14 (7%) exhibited p16 methylation in their serum DNA by qMSP. After completion of qMSP analysis in all specimens, clinicopathological data were correlated with the molecular analysis. Interestingly, a significant difference was observed in the presence of distant metastasis (P = 0.0420). Moreover, a trend was shown toward preferentially developing lymph node metastasis (P = 0.0547), thus suggesting that p16 methylation in serum could be detected more frequently in metastatic colorectal cancer patients. High sensitivity of qMSP makes it possible to detect smaller amounts of tumor DNA in the serum. In principle, the methylation status of a primary tumor is not required in advance to detect circulating tumor DNA, suggesting that qMSP can be used as a screening method for cancer.

[Efficacy and safety of cetuximab+irinotecan for unresectable advanced or recurrent colorectal cancer].

BACKGROUND: In July 2008, cetuximab treatment for unresectable advanced or recurrent colorectal cancer was approved in Japan, but there have been few reports on this therapy in Japan. PURPOSE: We retrospectively analyzed the efficacy and safety of cetuximab(Cmab)+irinotecan(CPT-11)for unresectable advanced or recurrent colorectal cancer from October 2008 to April 2010 at 5 centers in the Kanagawa region. PATIENTS AND METHODS: The number of patients enrolled was 38, all of whom were treated after second-line therapy. RESULTS: The RR was 24%. DCR was 68%. TTF was 105 days and OS was 242 days. CONCLUSION: At 5 centers, Cmab+CPT-11 was an effective and safe treatment after second-line therapy.

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.

Heterozygous loss of NF2 is an early molecular alteration in well-differentiated papillary mesothelioma of the peritoneum.

Well-differentiated papillary mesothelioma of the peritoneum (WDPMP) is a rare disease, and many cases are either benign neoplasms or low-graded malignancies; however, a few cases show rapid progressive clinical courses. No effective therapy has yet been established for WDPMP, and the molecular basis of WDPMP tumorigenesis has never been reported. This study shows the malignant transformation of WDPMP in a Japanese female patient, who was alive for 54 months after the initial diagnosis by a laparoscopic biopsy. A molecular analysis of single nucleotide polymorphisms (SNPs), which were located in the neurofibromatosis type 2 (NF2) gene, a tumor suppressor gene assigned to chromosome 22q12.3, revealed the loss of heterozygosity (LOH) of the NF2 gene. Furthermore, SNP analyses determined that LOH was observed in the IL17RA (22q11.1), CHECK2 (22q12.1), and SHANK3 (22q13.3) genes, thus suggesting that NF2 loss occurred through 22q deletions or monosomy 22. The LOH of the NF2 gene was observed in an early stage of WDPMP, thus indicating that LOH of the NF2 gene is an early molecular alteration, and NF2 loss is a molecular mechanism associated not only with malignant pleural mesothelioma, but also with WDPMP.

FBN2 methylation is detected in the serum of colorectal cancer patients with hepatic metastasis.

BACKGROUND, MATERIALS AND METHODS: For the purpose of colorectal cancer detection, we investigated fibrillin-2 (FBN2) methylation in the serum of colorectal cancer patients using quantitative methylation-specific polymerase chain reaction (qMSP). RESULTS: Out of 78 patients with colorectal cancer, 49 (63%) exhibited methylation of FBN2 in their tumor tissue DNA, suggesting that FBN2 methylation frequently exists in colorectal cancer. We next examined the methylation status of FBN2 in the serum DNA of patients with colorectal cancer. Out of 49 serum samples, four (8%) exhibited FBN2 methylation in their serum DNA by qMSP, suggesting that FBN2 methylation exists in the serum of colorectal cancer patients. After completion of qMSP analysis in all specimens, clinicopathological data were correlated with the molecular analysis findings. Interestingly, methylation of FBN2 was found in the serum DNA of male (p=0.0167) patients, and in those with hepatic metastasis (p<0.0001). CONCLUSIONS: The clinical sensitivity of this assay can be potentially improved by incorporating other common genetic targets such as p53 and KRAS. Advances in technology which will permit for rapid detection of an array of specific mutations and methylation would enhance the utility of this approach.

Expression levels of thymidylate synthase, dihydropyrimidine dehydrogenase, and thymidine phosphorylase in patients with colorectal cancer.

BACKGROUND: Predictors of the response of colorectal cancer to chemotherapy remain poorly understood. We analyzed the mRNA expression levels of enzymes related to sensitivity to 5-fluorouracil derivatives in patients with colorectal cancer. PATIENTS AND METHODS: Danenberg tumor profile method (DTP) was used in order to measure mRNA expression levels of thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), and thymidine phosphorylase (TYMP) from 180 patients with colorectal cancer. The relations of expression levels with clinicopathological factors and outcomes were studied. RESULTS: Higher TYMS expression was associated with greater age, DPYD expression with greater age, poorer differentiation and low invasion, and TYMP expression with poorer differentiation and lack of peritoneal metastasis. DPYD expression positively correlated with TYMP expression. In patients with stage IV disease, high DPYD or TYMP expression was associated with poor outcomes. CONCLUSION: mRNA expression of TYMS, DPYD, and TYMP is associated with distinct characteristics and may be useful for predicting survival in patients with stage IV colorectal cancer.

Methylation of the DFNA5 gene is frequently detected in colorectal cancer.

BACKGROUND: Recently, the human deafness, autosomal dominant 5 gene, DFNA5, has frequently been detected in cancer tissues. The methylation status of the DFNA5 gene in colorectal cancer was examined and was compared to the clinocopathological findings. MATERIALS AND METHODS: Eighty-five tumor samples and corresponding normal tissues were obtained from patients with colorectal cancer who underwent surgery at our hospital. The methylation status of the DFNA5 gene in these samples was examined by quantitative methylation-specific PCR (qMSP). Subsequently, the clinicopathological findings were correlated with the methylation status of the DFNA5 gene. RESULTS: DFNA5 gene methylation was found in 29 (34%) out of the 85 colorectal carcinomas, suggesting that it was frequently observed in colorectal cancer. A significant correlation with methylation was observed for lymphatic vessel invasion and TNM stage (p=0.0268 and p=0.0189, respectively). CONCLUSION: DFNA5 might act as a tumor suppressor gene and DFNA5 gene methylation might play an important role in the development of colorectal cancer. Our data implicate DFNA5 gene methylation as a novel molecular biomarker in colorectal cancer.

Methylation of TFPI2 no longer detected in the serum DNA of colorectal cancer patients after curative surgery.

In our previous study, we used quantitative methylation-specific polymerase chain reaction (qMSP) to examine the methylation status of tissue factor pathway inhibitor 2 (TFPI2) in the preoperative serum DNA of 215 colorectal cancer patients and found that TFPI2 was methylated in serum DNA from 39 of these patients. In this study, we examined postoperative serum DNA, obtained within one month after surgery from 38 out of the 39 patients and found that TFPI2 was methylated in the serum DNA of only 18 (47%) of these patients, suggesting that TFPI2 methylation in the serum of the remaining colorectal cancer patients was abolished by surgical tumor reduction. Next, we examined the correlation between the presence of TFPI2 methylation in postoperative serum DNA and residual cancer status after surgery. If R0 (no residual cancer) operations were successfully performed, TFPI2 methylation was not detected in postoperative serum. However, if R2 (obvious residual cancer) operations were performed, 17 (77%) out of 22 postoperative sera, still exhibited TFPI2 methylation. Taken together, our results confirm that detection of methylated TFPI2 in serum DNA was derived from colorectal cancer and could serve as a marker of surgical outcome.

Detection of vimentin methylation in the serum of patients with gastric cancer.

AIM: Detection of gastric cancer using serum assay of vimentin methylation. METHODS: A quantitative methylation-specific polymerase chain reaction assay was used to detect vimentin gene (VIM) methylation in the serum of 71 patients with gastric cancer. RESULTS: Mean VIM methylation in cancer patients (0.304 ± 0.558) was significantly higher than that in healthy donors (0.011 ± 0.015, p=0.018). The sensitivity of VIM methylation (33.8%) was similar to the one of carbohydrate antigen 19-9 (CA19-9) (25.4%), higher than the one of carcinoembryonic antigen (CEA) (12.7%), and significantly higher than the sensitivity of both markers for patients with stage I and IV disease (p=0.010 and 0.044, respectively). At all stages, the sensitivity of a combination of markers was higher than the sensitivity of any in isolation marker and was similar for stages I, II and III, reaching 76.9% for stage IV disease. CONCLUSION: VIM methylation may represent a useful marker for the detection of tumor DNA in the serum of patients with gastric cancer.

[Significance of Onodera's prognostic nutritional index for treating unresectable or recurrent colorectal cancer with chemotherapy].

We analyzed the relationship between Onodera's prognostic nutritional index(PNI), classified by serum albumin level, lymphocyte level, and clinicopathological features, in 46 patients with unresectable or recurrent colorectal cancer being treated with chemotherapy.Onodera 's PNI was distributed between 29.7 and 56.1(average 45.4±6.8 ).Onodera 's PNI showed a significant correlation with performance status and surgery before chemotherapy(p=0.002 and 0.002, respectively).Next, all patients were divided into two groups according to their Onodera's PNI values, based on the receiver operator characteristic curve.We found that Onodera's PNI showed a significant correlation with overall survival times(median survival time, 548 days(Onodera's PNI<47.8 ), 902 days(Onodera's PNI≥47.8 ), p=0.00065 ).This PNI could be a prognostic factor and a very useful objective screening tool for assessing the nutritional condition of those with unresectable or recurrent colorectal cancer being treated with chemotherapy.

Detection of TFPI2 methylation in the serum of gastric cancer patients.

BACKGROUND: Methylation of tissue factor pathway inhibitor-2 (TFPI2) has been detected in the stool of colorectal cancer patients. Using quantitative methylation-specific polymerase chain reaction (qMSP), 39 out of 215 (18%) patients exhibited TFPI2 methylation in their serum DNA, suggesting that a significant number of methylated TFPI2 existed in colorectal cancer patients' sera. MATERIALS AND METHODS: Methylation status of the TFPI2 gene was examined in sera derived from 73 patients with gastric cancer using qMSP and the correlation between the methylation status and the clinicopathological findings was evaluated. RESULTS: Out of 73 serum samples, 7 (10%) exhibited TFPI2 methylation in their serum DNA by qMSP, suggesting that TFPI2 methylation existed in the serum of gastric cancer patients. After completion of qMSP analysis of all specimens, clinicopathological data were correlated with the molecular analysis. TFPI2 methylation was significantly more frequently found in serum of patients with lymph node metastasis (p=0.0040) and distant metastasis (p=0.0115). CONCLUSION: In principle, knowledge of the methylation status of a primary tumor is not required in advance in order to be able to detect circulating tumor DNA. Therefore, qMSP could be used as a cancer screening method.

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.

Methylation of the homeobox gene, HOPX, is frequently detected in poorly differentiated colorectal cancer.

BACKGROUND: Homeodomein only protein x (HOPX) gene methylation has frequently been detected in cancer tissues. The methylation status of the HOPX gene in colorectal cancer was examined and compared to the clinocopathological findings. MATERIALS AND METHODS: Eighty-nine tumor samples and corresponding normal tissues were obtained from colorectal cancer patients who underwent surgery at our hospital. The methylation status of the HOPX gene in these samples was examined by quantitative methylation-specific PCR (qMSP). Subsequently, the clinicopathological findings were correlated with the methylation status of the HOPX gene. RESULTS: HOPX gene methylation was found in 46 (52%) out of the 89 colorectal carcinomas, suggesting that it was frequently observed in colorectal cancer. A significant increase of methylation was observed in the poorly differentiated carcinomas (p=0.0049). CONCLUSION: HOPX gene methylation could play an important role for the development of colorectal cancer and is closely related to the histological type.

Detection of TFPI2 methylation in the serum of colorectal cancer patients.

We examined whether TFPI2 methylation can be used as a molecular marker for colorectal cancers by detecting TFPI2 methylation in colorectal cancer patients' sera by using quantitative methylation-specific polymerase chain reaction (qMSP). The qMSP analysis showed that 39 of 215 (18%) patients exhibited TFPI2 methylation in their serum DNA, suggesting that TFPI2 methylation frequently existed in colorectal cancer patients' sera. After completion of qMSP analysis, clinicopathological data were correlated with molecular data. TFPI2 methylation was significant in the sera of patients with large (p = 0.0022), poorly differentiated carcinoma (p = 0.0164), deep invasion (p = 0.0002), lymph node metastasis (p = 0.0147), or distant metastasis (p < 0.0001). Moreover, TFPI2 methylation was observed more frequently according to the progression of TNM stage, suggesting that serum TFPI2 methylation could be detected more easily in patients with advanced colorectal cancer. We also examined whether serum TFPI2 methylation would be useful in the detection of colorectal cancer, compared to the conventional tumor markers. Detection rates of colorectal cancer using the tumor markers TFPI2 methylation, CEA and CA19-9, in the serum were 18%, 33%, and 17%, respectively. In cases where we combined all three markers, the detection rate was 42%. High sensitivity of qMSP enables detection of smaller amounts of serum tumor DNA. In principle, the methylation status of a primary tumor is not required in advance to detect circulating tumor DNA, suggesting the potential of qMSP as a cancer screening method.

[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.