S-1 and oxaliplatin versus tegafur-uracil and leucovorin as post-operative adjuvant chemotherapy in patients with high-risk stage III colon cancer: updated 5-year survival of the phase III ACTS-CC 02 trial.

BACKGROUND: The ACTS-CC 02 trial demonstrated that S-1 plus oxaliplatin (SOX) was not superior to tegafur-uracil and leucovorin (UFT/LV) in terms of disease-free survival (DFS) as adjuvant chemotherapy for high-risk stage III colon cancer (any T, N2, or positive nodes around the origin of the feeding arteries). We now report the final overall survival (OS) and subgroup analysis according to the pathological stage (TNM 7th edition) for treatment efficacy. PATIENTS AND METHODS: Patients who underwent curative resection for pathologically confirmed high-risk stage III colon cancer were randomly assigned to receive either UFT/LV (300 mg/m2 of UFT and 75 mg/day of LV on days 1-28, every 35 days, five cycles) or SOX (100 mg/m2 of oxaliplatin on day 1 and 80 mg/m2/day of S-1 on days 1-14, every 21 days, eight cycles). The primary endpoint was DFS and the patients' data were updated in February 2020. RESULTS: A total of 478 patients in the UFT/LV group and 477 patients in the SOX group were included in the final analysis. With a median follow-up time of 74.3 months, the 5-year DFS rate was 55.2% in the UFT/LV group and 58.1% in the SOX group [stratified hazard ratio (HR) 0.92; 95% confidence interval (CI) 0.76-1.11; P = 0.3973], and the 5-year OS rates were 78.3% and 79.1%, respectively (stratified HR 0.97; 95% CI 0.76-1.24; P = 0.8175). In the subgroup analysis, the 5-year OS rates in patients with T4N2b disease were 51.0% and 64.1% in the UFT/LV and SOX groups, respectively (HR 0.72; 95% CI 0.40-1.31). CONCLUSION: Our final analysis reconfirmed that SOX as adjuvant chemotherapy is not superior to UFT/LV in terms of DFS in patients with high-risk stage III colon cancer. The 5-year OS rate was similar in the UFT/LV and SOX groups.

Tumour characteristics, treatment patterns and survival of patients aged 80 years or older with colorectal cancer.

AIM: This study aimed to clarify tumour characteristics and treatment patterns for patients with colorectal cancer aged 80 years or older and the impact of age on survival using a large-scale cancer registry database. METHOD: The database was used to identify 40 851 colorectal cancer patients who underwent surgery between 1995 and 2004. Patients were stratified into four age groups (< 50, 50-64, 65-79, ≥ 80 years). Demographics, tumour characteristics, treatment pattern and survival were compared between age groups. Additionally, the impact of lymph node dissection and adjuvant chemotherapy on survival was studied using the propensity score-matching method. RESULTS: In the over 80 age group, patients were more commonly female, with right colon cancer, multiple primary cancers, history of colorectal cancer, high serum carcinoembryonic antigen values, large tumour, undifferentiated histology, and more frequent pT3/pT4 tumours. In contrast, metastatic disease, central lymph node dissection and adjuvant chemotherapy were less frequent. Overall survival and cancer-specific survival decreased with increasing age for any stage. Multivariate analysis showed age to be an independent predictor of overall survival (hazard ratio 1.45, 95% CI 1.34-1.58, P < 0.001). In the propensity score-matched cohort, overall survival of the patients with central node dissection and having adjuvant chemotherapy was significantly better than for those without. This difference was not statistically significant in patients aged 80 and above. CONCLUSION: This study showed a significant difference in tumour characteristics and treatment patterns in patients aged 80 and above. Even after adjustment for clinicopathological factors, the difference in survival persisted and age was considered a robust prognostic factor.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

Incorporation of apical lymph node status into the seventh edition of the TNM classification improves prediction of prognosis in stage III colonic cancer.

BACKGROUND: The node classification outlined in the seventh edition of the TNM classification is based solely on the number of metastasized lymph nodes. This study examined the prognostic value of apical lymph node (ALN) metastasis and the additional value of incorporating ALN status into a risk model based on the seventh edition. METHODS: This was a cohort study of patients with stage III colonic cancer who underwent tumour resection with dissection of regional (including apical) lymph nodes at 71 hospitals across Japan between 2000 and 2002. The main exposure was pathologically confirmed ALN metastasis, and the primary endpoint was cancer-specific death. RESULTS: ALN metastasis was present in 113 (8·3 per cent) of 1355 patients. During 5356 patient-years of follow-up (median 5·0 years), 221 instances (16·3 per cent) of cancer-specific death were observed. After adjustment for tumour and node classification (as described in the seventh edition of the TNM classification) and other prognostic factors, ALN metastasis was found to be independently associated with cancer-specific death (hazard ratio 2·29, 95 per cent confidence interval (c.i.) 1·49 to 3·52). Incorporation of ALN metastasis into the prognostic model based on the seventh edition of the TNM classification significantly improved discriminative performance for cancer-specific death (difference in concordance index 0·0146, 95 per cent c.i. 0·0030 to 0·0262) and risk reclassification for cancer-specific death at 5 years (category-free net reclassification improvement 19·4 (95 per cent c.i. 5·0 to 33·4) per cent). CONCLUSION: Assessment of ALN metastasis provided independent prognostic information beyond that achievable with the seventh edition of the TNM classification in patients with stage III colonic cancer.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis. METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated. RESULTS: Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively. CONCLUSION: Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

Evaluation of the seventh edition of the tumour, node, metastasis (TNM) classification for colon cancer in two nationwide registries of the United States and Japan.

AIM: The new TNM classification is currently being implemented. We evaluated the TNM-7 staging system based on the two nationwide colon cancer registries in the United States and Japan to clarify whether this system better stratifies patients' prognoses than the TNM-6 did and to determine whether stratification can be effectively simplified. METHODS: The Surveillance, Epidemiology, and End Results population-based data from 1988 to 2001 for 50139 colon cancer patients and the multi-institutional registry data from the Japanese Society for Cancer of the Colon and Rectum from 1984 to 1994 for 10754 patients were analysed. We devised a modified version of the TNM-7 staging system to allow simpler classification of the TN categories and compared the TNM-6, TNM-7, modified TNM-7, and the Dukes staging system based on survival curves and objective statistical tests such as likelihood ratio χ(2) tests, Akaike's information criterion, and Harrell's c-index. RESULTS: The TNM-7 was superior to the TNM-6 in all objective statistical tests in the United States (c-index; 0.700 vs 0.696, P<0.001) as well as in the Japan data sets (0.732 vs 0.729, P=0.035). The modified TNM-7 is much simpler, but it nevertheless showed similar values to those of the original TNM-7 (c-index; the United States 0.702, Japan 0.733). CONCLUSIONS: The new TNM-7 is complicated but better at stratifying patients than the TNM-6 in the United States and Japan, and could be effectively simplified.

Colorectal cancer in Japan.

There is the increase in colorectal cancer incidence in Japan. The increase in the rate of colon cancer compared with rectal cancer was noticed. The proximal migration of the tumor site from the left colon to right colon is shown in the study. The evident shift toward earlier stage was clearly revealed. According to the extended lymph node resection, the improvement of overall 5-year survival rate from 55% to 69% is important trend.

Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability.

BACKGROUND & AIMS: Methylation of the hMLH1 promoter region has been suggested to cause microsatellite instability (MSI) in sporadic colorectal carcinoma (CRC). We studied the methylation profile in a wide region of the hMLH1 promoter and compared with the hMLH1 protein expression and MSI status in 88 cases of sporadic CRC. METHODS: Na-bisulfite treatment and polymerase chain reaction single-strand conformation polymorphism analysis was performed using 5 sets of polymerase chain reaction primers spanning the promoter region of the hMLH1 to examine methylation status. Results were compared with immunostaining using anti-hMLH1 monoclonal antibody and MSI status of the tumor samples. RESULTS: Methylation status was classified as full or partial methylation. Full methylation indicates the methylation of all CpG sites in the examined regions. Methylation of the hMLH1 promoter was observed in 88.9% (16 of 18) of CRCs showing high frequency MSI (MSI-H), among which 89% (14 of 16) had full methylation with reduced hMLH1 protein expression. All cases showing full methylation were proximal colon tumors with MSI-H. In cases with partial methylation, only the upstream region of the hMLH1 promoter was methylated. Partial methylation was also shown in 33.3% (6 of 18) of the normal mucosa of MSI-H cases. Frequencies of methylation were significantly correlated with female gender (P = 0.0009) and aging (P = 0.007). CONCLUSIONS: Full methylation of the hMLH1 promoter region and subsequent gene inactivation may play a crucial role in the carcinogenesis of MSI-H CRCs in the proximal colon. Methylation upstream of the hMLH1 promoter appears to be an early event in the carcinogenesis of MSI-H tumors.

Colorectal cancer statistics in Japan: data from JSCCR registration, 1974-1993.

Japanese colorectal cancer statistics from 1974 to 1993 are reported, based on the accumulated data registered by the member institutions of the Japan Society for Cancer of the Colon and Rectum (JSCCR). Both colon and rectal cancers were more prevalent in men than in women. In both sexes, colonic cancers were more prevalent than rectal cancers, and a greater increasing trend was seen in colonic cancers. Moderately differentiated adenocarcinoma seemed to have increased in recent years. The resectability and operative death rates improved slightly, but the ratio of stage I + II/III + IV cancers (both colonic and rectal) did not change at all during the 20-year period reported. The yearly improved survival in both colonic and rectal cancers, particularly in stages II and III, may well reflect improved surgical techniques.

5-fluorouracil sensitivity and dihydropyrimidine dehydrogenase activity in advanced gastric cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme of 5-fluorouracil (5-FU) catabolism. Several studies have demonstrated the clinical importance of DPD in cancer patients, suggesting that the efficacy of 5-FU may be related to DPD activity in tumor tissue. In the present study, DPD activity and chemosensitivity to 5-FU were evaluated in advanced gastric cancer. MATERIALS AND METHODS: Thirty-four gastric cancers from 32 patients were studied and chemosensitivity to 5-FU was evaluated by histoculture drug response assay. RESULTS AND CONCLUSION: DPD activity and tumor inhibition of 5-FU among all cases showed no significant correlation, but among 14 histologically differentiated cases significant correlation was observed. DPD activity may be useful in determining the 5-FU sensitivity of differentiated gastric cancer.

Immuno-localization of sulphonylurea receptor 1 in rat pancreas.

AIMS/HYPOTHESIS: A sulphonylurea receptor, SUR1, and an inward rectifier potassium channel, Kir6.2, reconstitute the ATP-sensitive K(+) channel that mediates glucose-induced insulin secretion in pancreatic beta cells. We reported previously that Kir6.2 were localized at insulin-, glucagon-, and somatostatin-producing cells. In this new study we aimed to determine the distribution of SUR1 in rat pancreatic islets and to suggest the location of the ATP-sensitive K(+) channels in the islet. METHODS: Western blot analysis was carried out using two anti-SUR1 antibodies, which had been raised against different portions of rat SUR1. SUR1, Kir 6.2, and islet hormones were then localized by indirect immunofluorescence staining of the cryosections of rat pancreas. RESULTS: In Western blot analysis, each of the anti-SUR1 antibodies detected a band at 140 kDa, which is close to the predicted molecular weight of SUR1, in the homogenate of isolated pancreatic islets. Double immunofluorescence staining of cryosections showed that SUR1 occurred all over the islets, and that SUR1 colocalized with insulin, glucagon, somatostatin, and pancreatic polypeptide. Kir6.2 was also shown to be present in pancreatic polypeptide cells. CONCLUSION/INTERPRETATION: Together with our previously reported data, the above findings indicate that K(ATP) channels comprising SUR1 and Kir6.2 occur not only in beta cells but also in the alpha, delta, and pancreatic polypeptide cells of the pancreatic islets, suggesting that therapeutic sulphonylureas could act on these cells directly. [Diabetologia (1999) 42: 1204-1211]

Effects of chronic liver diseases on mitochondrial DNA transcription and replication in human liver.

To evaluate the effects of chronic liver diseases on mitochondrial DNA (mtDNA) transcription and replication, nuclear respiratory factor-1 (NRF-1) mRNA, mitochondrial transcription factor A (mtTFA) mRNA, a RNA component of ribonuclease (RNase) for mitochondrial RNA processing (MRP), mitochondrial cytochrome b mRNA, and mtDNA were measured in normal, chronically viral-hepatitic and cirrhotic human livers. The mRNA levels of the regulatory factors for mitochondrial gene (NRF-1 and mtTFA) and cytochrome b were significantly increased by chronic hepatitis (160, 280, and 175%, respectively) compared with those in normal livers, but were not different between cirrhotic and normal livers. On the other hand, concentrations of mtDNA and RNA component of RNase MRP were not different among normal, chronically hepatitic, and cirrhotic livers. These results suggest that either persistent hepatitis viral infection or repeated cell necrosis and regeneration in chronically hepatitic liver may be associated with increase in mtDNA transcription.

Human livers with cirrhosis and hepatocellular carcinoma have less mitochondrial DNA deletion than normal human livers.

We measured the populations of mutated mitochondrial DNAs with the 7,436 bp or the 4,977 bp deletion from apparently normal human liver and human livers with chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The amount of the mutated mitochondrial DNA was at the same level between normal and chronically hepatitic livers but was significantly lower in human livers with cirrhosis and hepatocellular carcinoma, especially the latter, suggesting that the mutated mitochondrial DNAs may be decreased with the progress of liver disease from chronic hepatitis to cirrhosis and hepatocellular carcinoma. This phenomenon is opposite to that occuring in the ageing process.

Defective insulin secretion and enhanced insulin action in KATP channel-deficient mice.

ATP-sensitive K+ (KATP) channels regulate many cellular functions by linking cell metabolism to membrane potential. We have generated KATP channel-deficient mice by genetic disruption of Kir6.2, which forms the K+ ion-selective pore of the channel. The homozygous mice (Kir6.2(-/-)) lack KATP channel activity. Although the resting membrane potential and basal intracellular calcium concentrations ([Ca2+]i) of pancreatic beta cells in Kir6.2(-/-) are significantly higher than those in control mice (Kir6.2(+/+)), neither glucose at high concentrations nor the sulfonylurea tolbutamide elicits a rise in [Ca2+]i, and no significant insulin secretion in response to either glucose or tolbutamide is found in Kir6.2(-/-), as assessed by perifusion and batch incubation of pancreatic islets. Despite the defect in glucose-induced insulin secretion, Kir6.2(-/-) show only mild impairment in glucose tolerance. The glucose-lowering effect of insulin, as assessed by an insulin tolerance test, is increased significantly in Kir6.2(-/-), which could protect Kir6.2(-/-) from developing hyperglycemia. Our data indicate that the KATP channel in pancreatic beta cells is a key regulator of both glucose- and sulfonylurea-induced insulin secretion and suggest also that the KATP channel in skeletal muscle might be involved in insulin action.

A case of solitary metastatic pancreatic cancer from rectal carcinoma: a case report.

A 79 year-old male who had undergone resection of the rectum for rectal cancer was shown to have metastasis to the pancreas 11 years after surgery. The metastatic lesion was located at the tail and body of the pancreas, and was resected with distal pancreatectomy. The same patient also had metastasis to the lung 8 years after initial rectal surgery. Therefore, the course of metastasis to the pancreas was suggested to be from the metastatic lung tumor to the pancreas by hematogenous spread. The patient was considered disease-free 8 months after the pancreatectomy. Recent advances in the technology of diagnostic imaging have facilitated the selection of surgical therapy for metastasis to the pancreas in rectal cancer patients after follow-up by imaging diagnosis.

Noc2, a putative zinc finger protein involved in exocytosis in endocrine cells.

We have cloned a cDNA encoding a novel protein of 302 amino acids (designated Noc2, no C2 domain) that has 40.7% amino acid identity with and 77.9% similarity to the N-terminal region of rabphilin-3A, a target molecule of Rab3A. However, unlike rabphilin-3A, Noc2 lacks two C2 domains that are thought to interact with Ca2+ and phospholipids. Noc2 is expressed predominantly in endocrine tissues and hormone-secreting cell lines and at very low levels in brain. Immunoblot analysis of subcellular fractions of the insulin-secreting cell line MIN6 and immunocytochemistry reveal that Noc2 is a 38-kDa protein present in the cytoplasm. Overexpression of Noc2 in PC12 cells cotransfected with growth hormone enhances high K+-induced growth hormone secretion. Screening a mouse embryonic cDNA library with the yeast two-hybrid system shows that Noc2 interacts with the LIM domain-containing protein zyxin, a component of the cytoskeleton, and this interaction is further confirmed by the coimmunoprecipitation experiment. Accordingly, Noc2 is probably involved in regulated exocytosis in endocrine cells by interacting with the cytoskeleton.

Overview of colorectal cancer in Japan: report from the Registry of the Japanese Society for Cancer of the Colon and Rectum.

BACKGROUND AND PURPOSE: In Japan, the incidence of colorectal cancer has increased remarkably since World War II, and interest in this cancer has grown rapidly among Japanese clinicians and pathologists. As a result, the Japanese Society for Cancer of the Colon and Rectum started a multi-institutional registry of colorectal cancer in 1980. The purpose of this report is to present an overview of the actual state of surgical and pathologic aspects of colorectal cancer treated in the leading hospitals in Japan. MATERIALS AND METHODS: Registry files of clinical and pathologic findings for 38,369 patients treated between 1974 and 1986 with five-year follow-up information and 26,360 patients treated between 1991 and 1994 with no follow-up information were reviewed. RESULTS: Numbers of registered patients have increased annually, reflecting a trend toward an increasing incidence of this cancer in Japan. Colon cancer increased more than rectal cancer in both genders. Resection of the primary lesion was achieved in more than 97 percent of patients who underwent surgical operation recently. The curative resection rate has improved from 65.1 to 79.1 percent for colon cancer and from 71.4 to 80.4 percent for rectal cancer between the 1974 and 1979 and the 1991 and 1994 periods, and operative mortality of those has decreased from 1.8 and 2 percent to 0.5 and 0.5 percent, respectively. There was a trend toward a decrease in locally advanced cancer in terms of cancer invasion into the bowel wall. Stage IV colon cancer also decreased from 22.9 to 16.6 percent with time. The five-year survival rate of each pTNM stage has gradually been improving and was especially evident for patients with Stages I, II, and III of rectal cancer. Overall five-year survival rates for colorectal cancer patients currently exceeds 60 percent. CONCLUSION: The overall incidence of colorectal cancer and the ratio of colon cancer to rectal cancer patients in Japan are increasing. Results of surgical treatment are satisfactory with respect to curative resection rate, operative mortality, and the five-year survival rate. Registry data of the Japanese Society for Cancer of the Colon and Rectum are useful for reporting the actual state of diagnosis, treatment, and end results of colorectal cancer in Japan.

Kir6.1: a possible subunit of ATP-sensitive K+ channels in mitochondria.

We have investigated the subcellular localization of the inwardly rectifying K+ channel subunit Kir6.1 (uKATP-1). Immunoblot analysis of the mitochondrial fractions prepared from rat skeletal muscle and liver detected a single band of Kir6.1 at 51 kDa, the intensity of which was stronger than that found in the total homogenate of each tissue. By immunofluorescence staining, the labelling for Kir6.1 was observed as a dispersed array of fine dots throughout all the tissues examined in the rat, including skeletal muscle, cardiac muscle, liver, and pancreas. Electron-microscopic examination revealed that the punctate staining distribution was due to a specific labelling of Kir6.1 in the mitochondria. Immuno-positive colloidal gold particles were scattered over the mitochondria, suggesting that Kir6.1 was located on the inner membrane. Although gold particles were not observed at plasma membrane, a 47 kDa protein was detected in the isolated plasma membrane vesicles by immunoblot analysis against Kir6.1. These results suggest that Kir6.1 might be a subunit of the ATP-sensitive K+ channel in the mitochondrion, as well as in the plasma membrane.