Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

The influence of aging on the effectiveness of heat stress in preventing disuse muscle atrophy.

This study examined the aging effect on disuse muscle atrophy prevention using heat stress. Wistar rats aged 7 and 60 weeks were divided into three groups as follows: control, immobilized (Im), and immobilized and heat stressed (ImH). Heat stress was given by immersing the hindlimbs in hot water (42 °C) for 60 min, once in every 3 days and the gastrocnemius (GAS) and soleus (SOL) muscles were extracted after 14 days. Muscle-fiber types were classified using ATPase staining. Heat shock protein 70 (HSP70) was assessed through Western blotting. In GAS muscle of both groups and SOL muscle of 7-week-old rats, the fiber diameter of each muscle type in the ImH group significantly increased compared with that in the Im group. However, this could not be observed in the SOL muscle of the 60-week-old rats. The increased percentage of type-I fibers and variability of types I and II muscle-fiber diameter were evident in the SOL muscle of the 60-week rats. HSP70 was significantly elevated in the ImH group compared with in the Im group in both muscle types of both age groups. Thus, effectiveness of heat stress in the prevention of disuse muscle atrophy appears unsatisfactory in aging muscle fibers.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Dietary fiber showed no preventive effect against colon and rectal cancers in Japanese with low fat intake: an analysis from the results of nutrition surveys from 23 Japanese prefectures.

BACKGROUND: Since Fuchs' report in 1999, the reported protective effect of dietary fiber from colorectal carcinogenesis has led many researchers to question its real benefit. The aim of this study is to evaluate the association between diet, especially dietary fiber and fat and colorectal cancer in Japan. METHODS: A multiple regression analysis (using the stepwise variable selection method) was performed using the standardized mortality ratios (SMRs) of colon and rectal cancer in 23 Japanese prefectures as objective variables and dietary fiber, nutrients and food groups as explanatory variables. RESULTS: As for colon cancer, the standardized partial correlation coefficients were positively significant for fat (1,13, P = 0.000), seaweeds (0.41, P = 0.026) and beans (0.45, P = 0.017) and were negatively significant for vitamin A (-0.63, P = 0.003), vitamin C (-0.42, P = 0.019) and yellow-green vegetables (-0.37, P = 0.046). For rectal cancer, the standardized partial correlation coefficient in fat (0.60, P = 0.002) was positively significant. Dietary fiber was not found to have a significant relationship with either colon or rectal cancers. CONCLUSIONS: This study failed to show any protective effect of dietary fiber in subjects with a low fat intake (Japanese) in this analysis, which supports Fuchs' findings in subjects with a high fat intake (US Americans).

An individual patient data meta-analysis of long supported adjuvant chemotherapy with oral carmofur in patients with curatively resected colorectal cancer.

To reappraise the benefits of the long supported chemotherapy with carmofur, a meta-analysis based on individual patient data from the three clinical trials was performed by pooling 614 patients from three trials, there is a statistically significant survival benefit (2p=0.032) and disease-free survival (DFS) benefit (2p=0.021) for carmofur; and a highly significant advantage for carmofur in DFS (2p=0.0004) and in survival (2p=0.004) in Dukes' C patients. This IPD meta-analysis strongly suggested an effect of oral carmofur in a long supported chemotherapy for curatively resected colorectal carcinoma.

Relationship between mineral and trace element concentrations in drinking water and gastric cancer mortality in Japan.

It is well known that the incidence and mortality from gastric cancer in Japan are the highest in the world. This is thought to be due, in part, to dietary habit, including a high salt intake. There are, however, no epidemiological reports to describe the relationship between ingestion of mineral and trace elements and gastric carcinogenesis. In this study, we determined the concentrations of 14 elements in drinking water from 34 water treatment plants in Aomori Prefecture, Japan, and studied how element concentrations were geographically associated with gastric cancer mortality rate. Gastric cancer mortality was calculated from the data of the Annual Aomori Health Report. Multiple regression analysis (stepwise method of decreasing the number of variables) was performed by using age-adjusted mortality of gastric cancer by gender as objective variables and each element concentration as an explanatory variable. The standardized partial regression coefficient was significant in men for zinc (-0.59, P = 0.004), lead (1.01, P = 0.013), strontium (1.23, P = 0.007), and selenium (-1.62, P = 0.004), whereas it was significant in women for lead (-0.65, P = 0.022), strontium (0.51, P = 0.035), and gold (0.70, P = 0.019). It is suggested that selenium and zinc may aid in the prevention of gastric carcinogenesis. However, the significant relationship of sodium (a component of salt) to gastric carcinogenesis was not observed, although many previous epidemiological studies in Japan have shown this relationship.

Circadian rhythm-modulated chemotherapy with high dose 5-fluorouracil against gastrointestinal cancers: evaluation and case report.

Circadian variations in chemotherapy toxicity and antitumor effects were investigated in experimental and clinical studies. In the experimental study, Balb/c mice bearing murine colon carcinoma Colon 26 were treated with 4 injections of 5-fluorouracil (5-FU) (80 mg/kg) at 0000 Hours After Light On (HALO), 0600 HALO, 1200 HALO and 1800 HALO. The antitumor effect of treatment at 0000 HALO (early resting phase) group was significantly better with lower toxicity than the 1200 HALO (early activity phase) group, resulting in significantly longer survival (p < 0.05). In the clinical study, the effect of circadian rhythm-modulated 5-FU plus leucovorin therapy was evaluated in an end-stage patient with recurrent gastric carcinoma. After continuous weekly infusion of 5-FU (1000 mg/m2/day x 2) was stopped because of its gastrointestinal toxicity, circadian rhythm-modulated chemotherapy (CRMC) was performed changing the dose of 5-FU to 666 mg/m2/day during the daytime (0500 to 1700) and to 1333 mg/m2/day from evening to night (1700 to 0500). The patient persevered with the 23 CRMC course without any signs of severe side effects and survived for nearly a year, suggesting the potential effect of CRMC in minimizing toxicity and prolonging survival.

Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patient data meta-analysis of randomized trials.

BACKGROUND: Oral 5-fluorouracil and its prodrugs (tegafur, carmofur) is now being studied for adjuvant chemotherapy of curatively resected colorectal cancers. To evaluate the effect of these oral fluoropyrimidines (o-FPs), an individual patient data (IPD) meta-analysis of randomized clinical trials was performed in Japan as an inter-trialist group study. METHODS: Data from the three clinical trials in which postoperative adjuvant therapy with o-FPs was compared with surgery alone in patients with colorectal cancer were sought. IPD from a total of 4960 patients with follow-up periods of at least 5 years were analyzed. RESULTS: The results of the meta-analysis on an 'intention to treat' basis demonstrated a significant benefit of o-FPs in terms of the disease-free survival (DFS) of the total patients [risk ratio (RR) 0.830, 95% confidence interval (CI) 0.742-0.929, P = 0.001]. o-FPs were also demonstrated to be effective for survival in rectal cancer (RR 0.857, 95% CI 0.734-0.999, P = 0.049) and in Dukes'C colorectal cancer (RR 0.828, 95% CI 0.711-0.965, P = 0.016). CONCLUSION: The results suggest the advantage of long term o-FPs, possibly with the injection of mitomycin C, for prognosis for curatively resected colorectal cancer patients.

[Surgery and multidisciplinary treatment for colorectal cancer].

Evaluation of surgery and multidisciplinary treatment for colorectal cancer was performed based on the review of the results of clinical trials. Although most improvement in prognosis for colorectal cancer patients was obtained by the development of surgical techniques until the mid-70's, further extended surgery could not have demonstrated the obvious improvement in survival after the 80's. In this regard, various multidisciplinary treatments were evaluated by a meta-analysis of clinical trials. Among those modalities, preoperative irradiation for rectal cancer, postoperative adjuvant chemotherapy for resected colorectal cancer and biochemical modulation of 5-fluorouracil by methotrexate or leucovorin for advanced colorectal cancers proved to be significantly effective for improvement of prognosis. Clinical trials of immunochemotherapy using either levamisole or PSK for resected colorectal cancers, a trial of hepatic artery infusion for liver metastasis, and a trial of an adjuvant monoclonal antibody treatment, were also reported to demonstrate significant effects. For further progress in multidisciplinary treatment for colorectal cancers, standardization of the appropriate surgical technique for each stage of the disease is much anticipated.

Imaging of recurrent intestinal carcinoma with indium-111-labeled anti-carcinoembryonic antigen monoclonal antibody CEA102.

CEA102 is a mouse immunoglobulin G1 monoclonal antibody (mAb) that detects an epitope of carcinoembryonic antigen (CEA). The biodistribution and imaging characteristics of indium-111-labeled (111-In)-mAb CEA102 were studied in 1 primary and 9 extrahepatic recurrent intestinal carcinoma patients. Evaluation included antibody pharmacokinetics and assessment of antibody distribution in surgical specimens, in comparison with whole body imaging using a gamma camera, and imaging with single photon emission computed tomography. Selective mAb CEA102 localization to tumor tissue was demonstrated in 7 patients with tumors over 2 cm in size, and the external images correlated well with the results of surgical inspection, pathological examination, and tissue radioactivity measurements. Tumor:serum ratios ranged from 0.20:1 to 3.22:1, and serial biodistribution study of "regions of interest" also demonstrated a high radioactivity in the tumor. These results indicated the potential exploitability of the 111-In-labeled mAb CEA102 in radioimmunodetection of primary and extrahepatic recurrence of CEA-positive intestinal carcinomas.

Effects of dietary supplementation with lactosucrose (4G-beta-D-galactosylsucrose) on cecal flora, cecal metabolites, and performance in broiler chickens.

The effects of dietary lactosucrose on cecal flora, cecal metabolites, and performance were studied in eight 20-d-old and eight 62-d-old broiler chickens fed a basal diet (control) or a diet with .15% lactosucrose added. On Day 20 of age, the frequency of occurrence of lecithinase-negative clostridia were decreased (P < .05) by lactosucrose consumption. On Day 62 of age, the numbers of bifidobacteria were increased (P < .05) by lactosucrose consumption, but the counts of lecithinase-positive clostridia, including Clostridium perfringens, bacteriodaceae, and staphylococci, total anaerobic bacteria, and the frequency of occurrence of pseudomonads were decreased (P < .05). No detectable change was observed in counts of other organisms throughout the experimental period. Cecal concentration of ammonia (P < .01), phenol (P < .05), and cresol (P < .05) were decreased on Day 62 of lactosucrose consumption. Acetic acid and butyric acid were increased (P < .01 and P < .05, respectively) on Day 62 of lactosucrose consumption. Environmental ammonia and odor of chicken ceca were greatly reduced by lactosucrose consumption.

Efficacy of immunochemotherapy as adjuvant treatment after curative resection of gastric cancer. Study Group of Immunochemotherapy with PSK for Gastric Cancer.

In Japan the standard adjuvant treatment after resection of gastric cancer is intravenous mitomycin plus oral fluorouracil. We have assessed the efficacy of protein-bound polysaccharide (PSK) in addition to standard chemotherapy in patients who had undergone curative gastrectomy at 46 institutions in central Japan. 262 patients were randomly assigned standard treatment alone or with PSK. The minimum follow-up time was 5 years (range 5-7 years). PSK improved both the 5-year disease-free rate (70.7 vs 59.4% in standard treatment group, p = 0.047) and 5-year survival (73.0 vs 60.0%, p = 0.044). The two regimens had only slight toxic effects, consisting of nausea, leucopenia, and liver function impairment, and there were no significant differences between the groups. The treatments were clinically well tolerated and compliance was good. Addition of PSK to adjuvant chemotherapy with mitomycin and fluorouracil is beneficial as treatment after curative gastrectomy.

[Antipyretic effects of traditional Chinese medicines in bacterial endotoxin-induced febrile rabbits].

The antipyretic effects of oral administration of eight traditional Chinese medicines (dried extracts) were tested in febrile rabbits injected with bacterial pyrogen, lipopolysaccharide (LPS) 0.05 micrograms/kg (i.v.). The traditional Chinese medicines were given 0.6-2 g/10 ml/kg (p.o.) simultaneously with LPS. The most potent antipyretic effect was observed in Dai-jyoki-to (Ta-chen-chi-tang). The moderate antipyretic effects were observed in Toki-syakuyaku-san (Tang-kuei-shao-yao-san) and Syo-saiko-to (Hssiao-chai-hu-tang). Koso-san (Hsiang-su-san), Oren-gedoku-to (Huang-lien-chieh-tu-tan), Gorei-san (Wu-ling-san), Kakkon-to (Ko-ken-tang) and Byakkoka-ninjin-to (Pai-hu-chia-jen-sheng-tang) showed no effects.

[A randomized controlled trial of surgical adjuvant therapy with mitomycin C, 5-fluorouracil and OK-432 in patients with gastric cancer].

The effect of postoperative immunochemotherapy with mitomycin C (MMC), 5-fluorouracil (5-FU) and OK-432 was evaluated as an adjuvant therapy after curative resection for gastric cancer. Immediately after surgery, patients were randomly allocated to the following three treatments: (A) chemotherapy with MMC and 5-FU (32 cases); (B) chemoimmunotherapy with MMC, 5-FU and OK-432 (33 cases); and (C) surgery alone as control (34 cases). There were no significant differences in the background factors influencing survival time among the groups, and there was no dose-distribution of chemotherapeutic agents between groups A and B. While the differences were not statistically significant, the survival rate and disease-free interval of group B were better than those of groups A or C. Side effects such as gastroenteric disorder, leukopenia (less than 3,000/mm3), thrombocytopenia (less than 7 X 10(4)/mm3) and increase of serum transaminase level (GPT greater than or equal to 100 units) were less frequently observed in group B than in group A. The results of the present study seemed to indicate that chemoimmunotherapy with OK-432 may be effective for surgical adjuvant therapy.