Surgical risk assessment for super-elderly patients.

AIM: Super-elderly patients are often frail and the decision on surgical indications remains a difficult issue. The purpose of this study was to provide a certain preoperative surgical risk assessment tool for super-elderly people. METHODS: We selected 112 individuals who were super-elderly patients aged >90 years who had surgeries under general anesthesia in our department. Based on the quality of the postoperative outcome of each case, we categorized these patients into two groups: good and poor groups. We evaluated the fundamental examination items, such as American Society of Anesthesiologists physical status, skeletal muscle mass index and so on, and a couple of the well-known risk score systems represented by Estimation of Physiology Ability and Surgical Stress. RESULTS: A total of 85 of the 112 patients belonged to the good group and the rest belonged to the poor group. The quality of postoperative outcome is well characterized by Estimation of Physiology Ability and Surgical Stress (P = 0.001). Receiver operating characteristic analysis of Estimation of Physiology Ability and Surgical Stress for the quality of postoperative outcome shows sensitivity of 0.83 and specificity of 0.61. Multivariate logistic regression analysis showed that skeletal muscle mass index and American Society of Anesthesiologists physical status are prominent as the risk determinants affecting the quality of postoperative outcome. A scoring system based on the skeletal muscle mass index, which is a good index of sarcopenia, and American Society of Anesthesiologists physical status, named the "SAP score" has the following characteristics. P-value <0.001, sensitivity 0.76 and specificity 0.91. CONCLUSIONS: Informed consent based on the risk score might be able to reduce the regrettable situation where it would have been better to have had surgery or not to have had surgery. Geriatr Gerontol Int 2022; 22: 271-277.

[Induction chemotherapy with S-1/oxaliplatin prevented colostomy in a patient with advanced rectal cancer].

A 72-year-old woman was admitted to our hospital with bloody stools and constipation. She was diagnosed with advanced lower rectal cancer with multiple liver and pulmonary metastases. Because the rectal cancer was located 2 cm from the anal verge, we suggested she undergo an abdominoperineal resection(Miles operation), but she refused to undergo a colostomy. Then, 6 courses of chemotherapy with S-1/oxaliplatin(SOX)were administered, and the local tumor, liver metastases, and pulmonary metastases were all significantly decreased in size(reduction rate 60%). After chemotherapy, she chose to undergo low anterior resection(LAR), D2. Postoperative recovery was uneventful, and she currently has stable disease with adjuvant SOX chemotherapy. Induction SOX chemotherapy was considered to be useful for maintaining the quality of life(QOL) in a patient with advanced rectal cancer.

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.

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 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.

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.

[Diamine oxidase as blood biomarker in rats and humans to GI tract toxicity of fluorouracil anti-cancer drugs].

Diarrhea is a side effect of a 5-fluorouracil (5-FU) anti-cancer drug-induced intestinal mucosal disorder, which sometimes becomes more severe. Blood diamine oxidase (DAO; EC1. 4. 3. 6) activity is reported to be significantly correlated with activity in the small intestinal mucosal tissue, and to be a reliable indicator of small intestinal mucosal integrity and maturity. Here, we investigated whether blood DAO activity can be a biomarker for the gastrointestinal (GI) mucosal disorder caused by 5-FU anti-cancer drugs, both in rats and humans. From results of the rat study, the degree of jejunal mucosal disorder caused by the 5-FU anti-cancer drug was well correlated with a decrease in blood DAO activity. Clinically, 12 out of 28 patients (43%) administered 5-FU anti-cancer drug suffered from diarrhea. The plasma DAO activity within one week of the onset of diarrhea significantly decreased compared with that before the administration. Furthermore, before drug administration, plasma DAO activity in patients suffering from diarrhea was higher than those in patients without diarrhea. Although DAO activity differs by the individual, it is a useful biomarker for estimating the degree of intestinal mucosal disorder, and possibly for estimating manifestations of diarrhea induced by 5-FU anti-cancer drug administration.

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.