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Biomedical subjects

Yoshihiro Kakeji

Publications and source records attributed to Yoshihiro Kakeji.

At least 37 records · Page 2Linked to original sources
PubMed2005

Expression of aldehyde dehydrogenase 2 in the normal esophageal epithelium and alcohol consumption in patients with esophageal cancer.

Alcohol consumption is a risk factor for esophageal cancer. Acetaldehyde, a highly toxic intermediate produced from ethanol, is converted to acetic acid mainly by aldehyde dehydrogenase 2 (ALDH2) in the metabolic pathway of ethanol. Fifty percent of Japanese have inactive ALDH2 due to genetic polymorphism, which is considered to be a risk factor associated with esophageal cancer. In our previous study, we have demonstrated that ALDH2 is expressed in the esophagus with a considerable variation among individuals. In this study, we further investigated the expression of ALDH2 in esophagus and its relationship with risk factors of esophageal cancer. Tissue specimens resected from 51 patients with esophageal cancer were analyzed by immunohistochemistry using ALDH2-antibody. The immuno-staining of ALDH2 in the esophageal epithelium was compared with both the drinking habit and the occurrence of flushing that is closely associated with the ALDH2 deficiency. ALDH2 was not detectable in 8 (16%) among 51 specimens. All of the 8 patients were non- or light-drinkers but not heavy-drinkers. Among 18 patients showing the high level ALDH2 expression in the esophagus, 15 patients (83%) were heavy-drinkers. Although the relationship between the ALDH2 deficiency and drinking habit is not clear, the patients with ALDH2 deficiency tend to be non- or light drinkers while heavy-drinkers tend to have the active form of ALDH2. These results suggest that both inactive and active forms of ALDH2 are induced in the esophagus by heavy drinking and also support a hypothesis that ALDH2 deficiency might be a high-risk factor of esophageal cancer for the individuals having a heavy-drinking habit. To our knowledge, this is the first study demonstrating the induction of ALDH2 in the esophagus by ethanol consumption.

Alcohol Drinking↗
PubMed2005

Increased antitumor activity in combined treatment TS-1 and docetaxel. A preclinical study using gastric cancer xenografts.

As TS-1 and docetaxel (TXT) have different mechanisms of antitumor activity, the combination therapy is expected to have a higher response. Human gastric cancer xenografts SC-2, St-40, and SC-4 inoculated into nude rats were treated with TS-1 alone (TS-1 12 mg/kg/day, day 1-14), TXT alone (TXT 2 mg/kg/day, day 1 or day 8), and combination of both drugs. TS-1 alone showed antitumor activity against three tumors (growth inhibition rate (IR): SC-2 (38.6 and 40.5%), St-40 (54.5%), SC-4 (55.1%)). TXT was effective with minimal toxicity, especially on day 1 of administration (IR at day 1 administration: SC-2 (51.7%), St-40 (42.1%), SC-4 (46.3%)). In the combined TS-1 and TXT group, antitumor activity increased at day 1 and at day 8 TXT administration (IR at day 1 administration: SC-2 (68.4%), St-40 (72.5%), SC-4 (76.0%)). Weight loss of TS-1 and day 1 TXT administration was the same as that of TS-1 alone. TS-1 and TXT showed no pharmacokinetic interaction. Compared with 5-fluorouracil and cisplatin treatment, combined therapy with TS-1 and TXT showed the same antitumor activity and toxicity. Combined therapy with TS-1 and TXT showed enhanced antitumor activity compared with monotherapy of each drug. The outpatient-based treatment of this combination is worth investigating.

Animals↗
PubMed2005

Genetic polymorphism in cytochrome P450 7A1 and risk of colorectal cancer: the Fukuoka Colorectal Cancer Study.

Bile acids have long been implicated in the etiology of colorectal cancer, but epidemiologic evidence remains elusive. Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the synthesis of bile acids from cholesterol in the liver, and thus may be an important determinant of bile acid production. We examined the association between the CYP7A1 A-203C polymorphism and colorectal cancer. The CYP7A1 A-203C polymorphism was determined by the PCR-RFLP method in 685 incident cases of colorectal cancer and 778 controls randomly selected from a community in the Fukuoka area, Japan. The CC genotype was slightly less frequent in the case group, and the adjusted odds ratio for the CC versus AA genotype was 0.88 (95% confidence interval, 0.65-1.20). In the analysis by subsite of the colorectum, a decreased risk associated with the CYP7A1 CC genotype was observed for proximal colon cancer, but not for either distal colon or rectal cancer. The adjusted odds ratios (95% confidence intervals) of proximal colon cancer for the CC genotype were 0.63 (0.36-1.10) compared with the AA genotype, and 0.59 (0.37-0.96) compared with the AA and AC genotypes combined. A decreased risk of proximal colon cancer in relation to the CC genotype of CYP7A1 A-203C, which probably renders less activity of the enzyme converting cholesterol to bile acids, is new evidence for the role of bile acids in colorectal carcinogenesis.

Adult↗
PubMed2005

Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability.

Microsatellite instability (MSI) is associated with defective DNA mismatch repair in various human malignancies. Using a unique fluorescent technique, we have observed two distinct modes of dinucleotide microsatellite alterations in human colorectal cancer. Type A alterations are defined as length changes of < or =6 bp. Type B changes are more drastic and involve modifications of > or =8 bp. We show here that defective mismatch repair is necessary and sufficient for Type A changes. These changes were observed in cell lines and in tumours from mismatch repair gene-knockout mice. No Type B instability was seen in these cells or tumours. In a panel of human colorectal tumours, both Type A MSI and Type B instability were observed. Both types of MSI were associated with hMSH2 or hMLH1 mismatch repair gene alterations. Intriguingly, p53 mutations, which are generally regarded as uncommon in human tumours of the MSI+ phenotype, were frequently associated with Type A instability, whereas none was found in tumours with Type B instability, reflecting the prevailing viewpoint. Inspection of published data reveals that the microsatellite instability that has been observed in various malignancies, including those associated with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is predominantly Type B. Our findings indicate that Type B instability is not a simple reflection of a repair defect. We suggest that there are at least two qualitatively distinct modes of dinucleotide MSI in human colorectal cancer, and that different molecular mechanisms may underlie these modes of MSI. The relationship between MSI and defective mismatch repair may be more complex than hitherto suspected.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Genetic mutual relationship between PTEN and p53 in gastric cancer.

Both PTEN (encoding phosphate and tensin homologue) and p53 are known as cancer suppressor genes, and they are assumed that their gene mutations and loss of heterozygosity (LOH) occur frequently in various types of carcinoma. In the present study, we investigated both the p53 mutation and LOH of PTEN in 113 gastric cancer patients. We observed the LOH of PTEN in 11.1% of the patients with normal p53s and 46.2% of the patients with p53 gene mutations. The result that LOH of PTEN was frequently observed in the cases with p53 gene mutations and other data in this study suggested that both PTEN and p53 have complimentary roles in gastric carcinoma development.

Aged↗
PubMed2005

p53 mutation profiling of multiple esophageal carcinoma using laser capture microdissection to demonstrate field carcinogenesis.

Inactivation of the p53 tumor suppressor gene is one of the most frequent genetic alterations observed in human esophageal carcinomas. In patients with esophageal carcinoma, one of the significant pathological features of the tumor is the presence of multiple lesions within the esophagus. However, the molecular mechanisms involved in the occurrence of multiple lesions have remained elusive. To characterize p53 alterations in multiple esophageal carcinomas and to study their roles in carcinogenesis, we performed p53 immunohistochemical and p53 mutation analyses using laser capture microdissection on surgically resected human esophageal carcinomas from 11 patients: 9 patients with multiple esophageal carcinomas, 1 with an intramural metastasis lesion within the esophagus and 1 with an intraepithelial carcinoma lesion contiguous to the main lesion. In each of the patients with multiple esophageal carcinomas, we examined samples from 1 main lesion and 1 representative concomitant lesion. Molecular analyses of samples from fresh-frozen normal tissues and tumor tissues of the main lesion (whole tumor) were also performed by the same method. p53 protein accumulation was observed in 16 (72.7%) of 22 lesions from the 11 cases. No p53 mutation was found in normal esophageal tissues. In the 9 cases of multiple esophageal carcinomas, point mutations were detected in the whole tumor in 1 (11.1%) case, in the microdissected tumor samples of main lesions in 3 (33.3%) cases and in the microdissected tumor samples of concomitant lesions in 3 (33.3%) cases. For the microdissected tumor samples, there was a 54.5% (12/22) concordance rate between the results of immunostaining and molecular analysis. In the 8 cases of whole tumors in which a p53 mutation was not observed, 2 cases revealed p53 mutation in the microdissected tumor samples of the main lesion. All 6 cases of multiple esophageal carcinomas that showed a p53 mutation in the microdissected tumor sample had a discordant p53 mutational status between the main and concomitant lesions. In contrast, both the intramural metastasis lesion and the intraepithelial carcinoma contiguous to the main lesion showed p53 mutational patterns identical to those of the main lesions. In conclusion, the analysis of microdissected DNA by laser capture microdissection is useful for characterizing the heterogeneity of the p53 gene mutation in multiple carcinoma lesions that cannot be accurately analyzed in whole esophageal tumor DNA. The finding of different p53 gene mutations among multiple esophageal carcinoma lesions suggest further evidence of multicentric or field carcinogenesis of the human esophagus.

Carcinoma in Situ↗
PubMed2005

Surgical robot setup simulation with consistent kinematics and haptics for abdominal surgery.

Preoperative simulation and planning of surgical robot setup should accompany advanced robotic surgery if their advantages are to be further pursued. Feedback from the planning system will plays an essential role in computer-aided robotic surgery in addition to preoperative detailed geometric information from patient CT/MRI images. Surgical robot setup simulation systems for appropriate trocar site placement have been developed especially for abdominal surgery. The motion of the surgical robot can be simulated and rehearsed with kinematic constraints at the trocar site, and the inverse-kinematics of the robot. Results from simulation using clinical patient data verify the effectiveness of the proposed system.

Biomechanical Phenomena↗
PubMed2005

Tele-surgical simulation system for training in the use of da Vinci surgery.

Laparoscopic surgery including robotic surgery allows the surgeon to be able to conduct minimally invasive surgery. A surgeon is required to master difficult skills for this surgery to compensate for the narrow field of view, limitation of work space, and the lack of depth sensation. To counteract these drawbacks, we have been developing a training simulation system that can allow surgeons to practice and master surgical procedures. In addition, our system aims to distribute a simulation program, to provide a means of collaboration between remote hospitals, and to be able to provide a means for guidance from an expert surgeon. In this paper, we would like to show the surgery simulation for da Vinci surgery, in particular a cholecystectomy. The integral parts of this system are a soft tissue model which is created by the sphere-filled method enabling real-time deformations based on a patient's data, force feedback devices known as a PHANToM and the Internet connection. By using this system a surgeon can perform surgical maneuvers such as pushing, grasping, and detachment in real-time manipulation. Moreover, using the broadband communication, we can perform the tele-surgical simulation for training.

Computer Simulation↗
PubMed2005

A laparoscopic radical prostatectomy assisted by the "ZEUS" robotic system: an initial case report.

A 68-year-old man with prostate cancer, T1cN0M0, was treated with laparoscopic radical prostatectomy (LRP) assisted by the ZEUS robotic system. The ZEUS system was utilized only for vesico-urethral anastomosis, one of the most difficult procedures to perform during LRP. We could complete the vesico-urethral anastomosis using the ZEUS system for 100 min without any intraoperative complications. The urethral catheter was removed 7 days after operation. To our knowledge, this is the initial case of robot-assisted radical prostatectomy using the ZEUS system.

Aged↗
PubMed2005

[Evaluation of positive cases with peritoneal lavage cytology in gastric cancer].

Peritoneal dissemination with advanced gastric cancer is of significant problem. Peritoneal lavage cytology has been an effective method for the detection of early peritoneal dissemination since 1999. The accurate evaluation of peritoneal lavage cytology is unclear except for the same prognosis of peritoneal dissemination. We examined the clinical findings and the prognosis with positive cases in peritoneal lavage cytology. The prognosis of cases with P1CY1 or P2P3 group was poorer than in the P0CY1 or P0, CY1 group. We thus review the evaluation of peritoneal lavage cytology with gastric cancer in the Japanese and English literature. In addition, we describe the diagnosis of early peritoneal dissemination using peritoneal lavage tumor markers or molecular markers of peritoneal lavage.

Adult↗
PubMed2004

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies.

Adenocarcinoma↗
PubMed2004

Prognostic significance of tumor markers in peritoneal lavage in advanced gastric cancer.

OBJECTIVE: Predicting peritoneal dissemination of cancer is very difficult whatever method of examination is used. Recently, a cytological examination of peritoneal lavage has been shown to be a feasible measure to predict an early state of peritoneal seeding. The predictive value of the levels of tumor markers in peritoneal lavage for peritoneal metastasis from gastric carcinoma was thus studied. METHODS: In 229 patients gastric cancer tumor markers, CEA, CA 125, and CA 19-9, in peritoneal lavage were intraoperatively evaluated using a chemiluminescent enzyme immunoassay. RESULTS: CEA in peritoneal lavage at a cutoff level of 0.5 ng/ml showed overall a higher sensitivity of 75.8% at a specificity of 90.8% for a diagnosis of peritoneal dissemination including cytologically positive peritoneal lavage [CY(+)] than CA 125 or CA 19-9 in peritoneal lavage. The CEA level in peritoneal lavage as well as both serosal invasion and the CA 125 level in peritoneal lavage were significant factors for the prediction of peritoneal dissemination including CY(+) with a relative risk of 6.6, 14.1 and 9.4. In patients undergoing curative operations, the recurrence rate for peritoneal dissemination and liver metastasis in cases with CEA levels in peritoneal lavage of > or = 0.5 ng/ml was significantly higher than that in cases with CEA levels of < 0.5 ng/ml (p < 0.0001, p < 0.002). CONCLUSIONS: These finding suggest that the CEA level in peritoneal lavage is thus considered to be a predictor of peritoneal dissemination including CY(+).

Adult↗
PubMed2004

[Anti angiogenesis].

Based on presentations on the basic concepts and scientific rationale of anti-angiogenic approaches to cancer therapy and the possible applications in the area of prostate cancer, gastrointestinal cancer, lung cancer and breast cancer it is easy to conclude that development of anti-angiogenic approaches into clinical therapies is extremely challenging. It is now well established that cancer growth is increased by angiogenic factors and that inhibition of angiogenesis decreases growth and metastatic potential. Anti-angiogenic effect can be obtained through interference with multiple targets. Further development of new strategies involving such novel cancer therapies requires wide reaching development of translational research abilities. However, for moving new therapies into the clinic same rigorous criteria need to be applied as is done for traditional therapies. Angiogenesis appear to be a critical factor for development of prostate, gastric, lung and breast cancers. Development of new anti-angiogenic treatment modalities might become very important in these diseases. A critical requirement for the successful clinical development will be the development of imaging techniques that can help evaluate the effect on blood vessel functionality. Such surrogate markers of anti-angiogenic effect will be essential for optimising molecules and doses.

Angiogenesis Inhibitors↗
PubMed2004

[Current combination chemotherapy containing paclitaxel for advanced, recurrent gastric cancer].

5-FU has been a key chemotherapeutic agent in the treatment of advanced or recurrent gastric cancer. In order to enhance the effect of 5-FU, biochemical modulation or combination chemotherapy has been developed. Although several phase III studies were reported in the 1990s, a standard chemotherapeutic regimen has not been established worldwide. Recently, a newly developed anticancer agent, Paclitaxel, can be clinically used for advanced gastric cancer either as a single agent or in combination with such as 5-FU, cisplatin, and TS-1. It may well further improve the quality of life and prolong the survival of patients with gastric cancer. Further assessment for the well design phase III clinical trials will be necessary to establish the availability of such combination modalities for the treatment of advanced, recurrent gastric cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Cyclin-dependent kinase 1 gene expression is associated with poor prognosis in gastric carcinoma.

PURPOSE: A low expression level of cyclin-dependent kinase (Cdk) inhibitor p27 is associated with high aggressiveness and poor prognosis of various carcinomas. Human Cdk subunit 1 (Cks1), as well as S-phase kinase-associated protein 2 (Skp2), is an essential and specific factor in the p27 proteolysis by SCF(Skp2) ubiquitin ligase. The purpose of this study is to clarify the clinical significance of Cks1 expression and the relationship between Cks1 and p27 expression in gastric carcinomas. EXPERIMENTAL DESIGN: We measured Cks1 expression using quantitative reverse transcription-PCR in 76 human gastric carcinomas and p27 expression using immunohistochemistry in 28 cases. Moreover, we established Cks1- and/or Skp2-transfected gastric carcinoma cell lines and assessed the relationship between Cks1, Skp2, and p27 expression using quantitative reverse transcription-PCR and Western blot analysis. RESULTS: Cks1 high expression was correlated with poor prognosis (P < 0.05) and Cks1 expression was inversely correlated with the expression level of p27 protein in gastric carcinomas (P < 0.05). Using combined Skp2 data [T-a. Masuda, Cancer Res., 62: 3819-3825, 2002], 88.9% of the Cks1/Skp2 double-high cases expressed a low level of p27 protein and showed the poorest prognosis (P < 0.05). Western blot analysis showed that Cks1/Skp2-cotransfected cells expressed a much lower level of p27 protein than the controls. CONCLUSIONS: These findings indicate that Cks1, as well as Skp2, regulates the expression level of p27 protein in gastric carcinomas. Cks1 could play an important role in gastric carcinoma progression and would be a novel target for the treatment of gastric carcinomas as well as a strong prognostic marker.

Aged↗
PubMed2003

S-1 in the treatment of advanced and recurrent gastric cancer: current state and future prospects.

BACKGROUND: S-1 (TS-1) is a novel oral anticancer drug. Because of the excellent results of phase II studies, we continued to prescribe S-1 for advanced or recurrent gastric cancer after we participated in the phase I and II studies. METHODS: Twenty-nine patients with advanced or recurrent gastric cancer were treated with S-1. Clinicopathological features, survival, and adverse reactions were analyzed. RESULTS: One course of treatment consisted of 40, 50, or 60 mg/body twice a day for 28 days followed by withdrawal for 2 weeks. The mean number of treatments was 3.6 courses (range, 1-12 courses). The response rate was 37.9% (11 partial responses [PRs] in 29 patients). Although the response rate of patients who did not receive prior chemotherapy was 47.6% (10 PRs in 21 patients), that of patients with prior chemotherapy was 12.5% (1 PR in 8 patients). The median survival time was 14.1 months, and that of patients who responded to treatment was 22.1 months, which was significantly longer than that of nonresponder patients. One-year and 2-year survivals in the 29 patients were 50.2% and 24.3%, respectively. Adverse reactions were noted in 17 of 29 patients, and the most frequent one was leukocytopenia. Only 2 patients experienced grade 3 leukocytopenia and neutrocytopenia. CONCLUSION: Because of the high response rate and low incidence of severe adverse reactions, S-1 is a first-line chemotherapy that can be used for outpatients, especially for patients without prior chemotherapy. As the response rate for patients with prior chemotherapy was low, combined therapy with S-1 is worth evaluating for these patients.

Adult↗