[Present status of laparoscopic surgery for gastrointestinal neoplasms].
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Colonic Neoplasms↗
Biomedical subjects
Yoshihide Otani
Publications and source records attributed to Yoshihide Otani.
Chemosensitivity testing--present and future in Japan.
Radical surgery with extended lymph node dissection is the first and only curative treatment of gastrointestinal cancer. Although the combined cancer chemotherapy has achieved 30%-50% response rates, a controversy still remains over the significance of the adjuvant cancer chemotherapy after surgery. To break through this limitation, we have introduced the chemosensitivity test to evaluate the appropriate adjuvant cancer chemotherapy for advanced gastrointestinal cancer. Our plural studies indicated that the chemosensitivity test would be useful in evaluating the appropriated adjuvant chemotherapy by increasing survival in the sensitive group. Recently, the molecular targets have been clarified for the conventionally available antitumor agents, e.g., thymidylate synthetase for 5-fluorouracil, ATP-binding cassette transporters for anthracyclines, glutathione-related detoxification for platins, and topoisomerase I for CPT-11, which will be applied for dinical use in evaluating the appropriate cancer chemotherapy. The chemosensitivity test is approved as "advanced clinical medicine" by the Japanese Ministry of Health, Welfare, and Labor in five institutes at present. Because complete dissection and chemosensitivity test-guided adjuvant chemotherapy will result in a survival benefit for patients with advanced gastrointestinal cancer, this test should be approved as "social insurance" for further wide clinical application.
Antineoplastic Agents↗
Possible chemoresistance-related genes for gastric cancer detected by cDNA microarray.
To identify chemoresistance-related genes of gastric cancer, we utilized cDNA microarray technology. Thirty-five gastric cancer specimens surgically resected at our institute between 1998 and 1999 were studied for quantification of expression of 6300 genes by means of oligonucleotide microarray methods, and the results were evaluated in comparison with the chemoresistance of the specimens, which was determined by MTT (tetrazolium-based 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. Inhibition rates (IR) were determined for cisplatin (DDP), 5-fluorouracil (5-FU), mitomycin C or doxorubicin. IR of 60% or more was regarded as sensitive to each agent, and IR of less than 40% was defined as resistant. Clustering was successfully completed for DDP, resulting in selection of 23 candidates as DDP-resistance-related genes, including vascular permeability factor, 2 membrane transporting subunits, and retinoblastoma-binding protein-1. In addition, further selection of DDP-resistance-related genes was performed according to these criteria: 1) Expression of the gene can be detected in more than 70% of resistant tumors. 2) Expression can be detected in less than 30% of sensitive tumors. 3) Expression in tumors is more than twice that of normal mucosa in more than 50% of specimens. Then, metallothionein-IG and heparin-binding epidermal growth factor-like growth factor (HB-EGF) were identified as candidate DDP-resistance-related genes. When known DDP-resistance-related genes were analyzed according to the MTT assay result, families of glutathione-S-transferase and cyclooxygenase-2 genes were also evaluated as resistance-related genes. For 5-FU resistance, dihydropyrimidine dehydrogenase and HB-EGF-like growth factor genes were also suggested to be resistance-related genes. The present study demonstrated that oligonucleotide microarrays can provide information regarding chemoresistance factors in cancer.
Antineoplastic Agents↗
Rare case of early mucosal gastric cancer presenting with metastasis to the bulbar conjunctiva.
Early gastric cancer has an excellent outcome following surgical treatment. In particular, mucosal gastric cancer (m-cancer) very rarely results in metastatic dissemination and may be successfully treated by local surgical resection. We report a 64-year-old Japanese woman who presented with a recurrent cystic lesion on the left bulbar conjunctiva, with a biopsy specimen revealing metastatic signet-ring cell carcinoma. Gastrointestinal investigations revealed an early gastric cancer in the lesser curvature of the stomach. Biopsy specimen of the gastric lesion indicated poorly differentiated adenocarcinoma, which was identical to findings in the lesion in the bulbar conjunctiva. She underwent a distal gastrectomy and made an uneventful recovery. Histopathological analysis indicated a gastric signet-ring cell carcinoma that was limited to the mucosal layer, without evidence of lymphatic spread. Although the exact mechanism of metastatic dissemination to the bulbar conjunctiva is unclear, this case is very unusual, because ocular metastases almost invariably occur in the context of documented and established malignant disease. This is, to our knowledge, the first reported case of a patient with gastric mucosal cancer who presented with a conjunctival metastatic deposit and who subsequently received curative surgical treatment for both conditions.
Adenocarcinoma↗
Minimally invasive surgery for gastric carcinoid tumor.
Minimally invasive laparoscopic wedge resection for gastric mucosal carcinoma and submucosal tumor was first performed in Keio University hospital in 1992. Since then, 172 gastric tumor patients, including four cases of carcinoid tumor, have been successfully treated at the Keio University hospital using this procedure. No local disease recurrence or distant metastases have been observed in follow-ups over as long as 10 years. Chronic atrophic gastritis patients with carcinoid tumors occurring secondary to hypergastrinemia are candidates for the minimally invasive surgery. With careful patient selection according to tumor size, depth of invasion, and histopathological findings of malignancy grade, endoscopic and laparoscopic therapy for these patients can be a safe, curative, and minimally invasive procedure.
Carcinoid Tumor↗
Matrix metalloproteinase inhibitor, marimastat, decreases peritoneal spread of gastric carcinoma in nude mice.
Marimastat, a matrix metalloproteinese inhibitor, was examined for the ability to prevent peritoneal dissemination of a human gastric cancer xenograft, TMK-1. Even with novel approaches such as molecular targeting of cancer chemotherapy, peritoneal dissemination of gastric cancer has little sensitivity to anticancer drugs, and it is impossible to inhibit its growth completely. Intraperitoneal injection of TMK-1 into nude mice at 5 x 10( 5) cells / body resulted in carcinomatous peritonitis that mimicked clinical cases. Continuous administration of marimastat (18 mg / kg / day) from 24 h after the tumor inoculation successfully inhibited the growth of peritoneal dissemination nodules. Combined administration of marimastat (18 mg / kg / day) and mitomycin C (MMC, 2 mg / kg) showed synergistic inhibition of growth of peritoneal dissemination, being superior to MMC alone (2 mg / kg). Although marimastat alone could not increase survival time with statistical significance, combined administration of marimastat and MMC had a survival benefit with statistical significance. The combination of marimastat and MMC increased the preventive effect on peritoneal dissemination. Marimastat seems to be a candidate for the prevention of peritoneal spread of gastric carcinoma.
Animals↗
Arteriovenous shunting blood flow is intravitally observed in the stomach after thermal injury in rats.
Microcirculatory disturbance of the gastric wall is a crucial factor in the development of gastric mucosal lesions induced by Helicobacter pylori, anti-inflammatory drugs and stress. Opening of the arteriovenous shunting channel after thermal injury is one of the possible mechanisms to reduce mucosal blood flow. However, no in vivo observation of arteriovenous shunting blood flow in the stomach has been reported. To assess gastric microcirculatory disturbance, especially arteriovenous shunting blood flow after thermal injury by in vivo microsciopy, male Wistar rats were anesthetized and thermal injury was inflicted on the back skin. Gastric microvascular images were observed by in vivo microscopy. Rolling of leukocytes labelled with carboxyfluorescein diacetate, succinimidyl ester were counted and blood flow dynamics were observed by flow of a micro dye, monastral blue B (MBB). The endothelial damage was assessed by deposits of MBB 5 min after the administration. Arteriovenous shunting blood flow is difficult to detect by normal methods, but it could be observed by How of MBB after thermal injury. Statistical analysis showed a significant difference in the ratio of arteriovenous shunting blood flow detection between the control (no injury) (0%; n = 15) and thermal injury (5 hrs after thermal injury) (28.6%; n = 14) groups. In the thermal injury group, the percentage of rolling leukocytes and the area of monastral blue B deposits increased, and the venular walls tended to be irregular. The total length of erosion increased time-dependently after thermal injury, and the length at 5 hrs was approximately 2 times larger than that at 2 hrs. Arteriovenous shunting blood flow is intravitally observed after thermal injury. A-V shunting blood flow can be a cause of mucosal hypoperfusion. It is suggested that the microcirculatory disturbance seen 5 hrs after thermal injury is contributed to the final step of erosion formation.
Animals↗
[A novel combined chemotherapy using TS-1 and low-dose cisplatin against liver metastasis of gastric cancer].
We used a novel combination chemotherapy of TS-1 and low-dose cisplatin (CDDP) with 4 gastric cancer patients with liver metastases (one far advanced and 3 recurrent patients). TS-1 was administered at 80 mg-120 mg/body/day, twice daily for 3 weeks followed by a 2-week interval as one cycle, and CDDP was administered at 6 mg/m2/day div, for 5 days followed by a 2-day interval (1 cycle for an inpatient) or at 6 mg/m2/day div, at 5 times for 2-3 weeks (1 cycle for an outpatient). Efficacy and toxicity were evaluated after 3-6 cycles of the regimen, as long as the patients tolerated the regimen without severe side effects. This regimen resulted in 1 complete response, 2 partial responses and 1 progressive disease, showing a 75% efficacy rate. One patient experienced grade 2 nausea from this regimen, which was ameliorated by means of prolonging the interval of CDDP-administration. Thus, the regimen is useful to maintain patients' quality of life without severe adverse effects, and has a high efficacy in gastric cancer patients with liver metastases.
Administration, Oral↗
Surgically treated Cronkhite-Canada syndrome associated with gastric cancer.
Cronkhite-Canada syndrome is generally accepted to be a benign disorder, with 374 reported cases to the present. Worldwide, there have been 18 previously reported cases of Cronkhite-Canada syndrome associated with gastric cancer. In this report we describe a case of a 52-year-old man with the clinical features of Cronkhite-Canada syndrome combined with gastric cancer. Although the gastric tumor was located at the antrum of the stomach, we performed a total gastrectomy because of the edematous swelling and high risk of malignancy in the remnant stomach. As Cronkhite-Canada syndrome may be a premalignant condition for gastric cancer, as well as for colorectal cancer, we suggest periodic examination of the stomach, colon, and rectum for patients with Cronkhite-Canada syndrome.
Journal Article↗
Pyrimidine nucleoside phosphorylase and dihydropyrimidine dehydrogenase indicate chemosensitivity of human colon cancer specimens to doxifluridine and 5-fluorouracil, respectively.
We have assessed pyrimidine nucleoside phosphorylase (PyNPase) and dihydropyrimidine dehydrogenase (DPD) activity to compare the chemosensitivity of 5-fluorouracil (5-FU) and doxifluridine (5'-DFUR). Tumor samples were prepared from fresh surgical specimens of 28 patients with advanced colon carcinoma. The activity levels of the two enzymes were assessed as indicators of chemosensitivity to 5'-DFUR and 5-FU. PyNPase activity was analyzed using the HPLC method, and DPD activity was assessed according to the methods of Naguib et al. (1985). A histoculture drug response assay (HDRA) was conducted according to the methods described by Furukawa et al. (1992). The mean and standard deviation of PyNPase activity in the tumor tissue was 110 +/- 48.6 &mgr;g 5-FU/mg protein/h, which was statistically higher than the corresponding value obtained in normal tissue (60 +/- 43.1 &mgr;g 5-FU/mg protein/h) (P < 0.005). When chemosensitivity to the two drug forms was compared in 16 samples obtained from 16 cases with colon cancer, 1 specimen was sensitive to both drug forms, 3 specimens were exclusively sensitive to 5'-DFUR, 5 specimens were exclusively sensitive to 5-FU, and the other 7 specimens were insensitive to both drugs, without significance. High PyNPase activity was associated with a high chemosensitivity to 5'-DFUR, and high DPD activity correlated with a low chemosensitivity to 5-FU. However, the converse relationship was not found. We suggest that the activity of PyNPase and DPD represents a reliable indicator for the chemosensitivity of colon cancer to 5'-DFUR and 5-FU, respectively.
Journal Article↗
Docetaxel enhances the cytotoxicity of anthracyclines by increasing intracellular drug accumulation.
We assessed the combined antitumor activity of docetaxel and doxorubicin (DXR) and tetrahydropyranyl-adriamycin (THP) using the human breast carcinoma cell lines R-27 and MDA-MB-231. Synergistic antitumor activity was observed for both combined docetaxel and DXR, and docetaxel and THP against R-27 cells when contacted simultaneously. However, only additive effects were observed against MDA-MB-231 cells. Intracellular concentrations of DXR and THP in R-27 cells were significantly increased by docetaxel pretreatment, however, this increase was not observed in MDA-MB-231 cells, which exhibited only additive sensitivity to the treatment. Thus, docetaxel increased the antitumor activity of anthracyclines by increasing their intracellular concentrations.
Antineoplastic Combined Chemotherapy Protocols↗
Different pathways of 5-fluorouracil metabolism after continuous venous or bolus injection in patients with colon carcinoma: possible predictive value of thymidylate synthetase mRNA and ribonucleotide reductase for 5-fluorouracil sensitivity.
BACKGROUND: The mode of action of 5-fluorouracil (5-FU) was evaluated in patients with advanced colon cancer treated preoperatively with 5-FU. PATIENTS AND METHODS: After obtaining informed consent, 30 patients were randomized into three groups: untreated controls (n = 16), continuous intravenous infusion of 5-FU for 5 days at a dose of 320 mg/m2 (CIV group, n = 6), or bolus intravenous injection of 5-FU for 5 days at the same dose (bolus group, n = 8). Surgically-resected samples were analyzed by 3-(4,5dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to detect sensitivity to 5-FU. Samples were also assayed for thymidylate synthetase (TS) activity, levels of 5-FU RNA (F-RNA), ribonucleotide reductase (RNR) activity, and TS mRNA levels expressed as the ratio of TS mRNA to beta-actin mRNA. RESULTS: While similar levels of TS inhibition were observed in the civ and bolus groups, F-RNA levels were significantly increased in the bolus group. The TS mRNA ratio was significantly higher in the 5-FU-resistant group than 5-FU-sensitive group. In the control group, the 5-FU-sensitive group showed higher RNR enzymatic activity compared to the 5-FU-resistant group. CONCLUSION: Our results suggested that the method of administration resulted in the induction of different 5-FU metabolic pathways. High TS mRNA and low RNR activity may be concerned with 5-FU-resistance in patients with advanced colon carcinoma.
Colonic Neoplasms↗
Independent antitumor spectrum of UCN-01 (7-hydroxystaurosporine) against gastric and colorectal cancers as detected by MTT assay.
To evaluate the clinical usefulness of 7-hydroxystaurosporine (UCN-01), we compared the antitumor spectrum of UCN-01 with those of conventional antitumor agents against 40 fresh gastric and 40 fresh colorectal cancer specimens using the MTT assay. At a cut-off concentration of 30 micrograms/ml, UCN-01 showed a higher efficacy rate than mitomycin C (MMC), cisplatin, and 5-fluorouracil (5-FU) against both gastric and colorectal cancers. With respect to the gastric cancer specimens, the antitumor spectrum of UCN-01 was independent from those of the other agents, while the patterns of antitumor effects of the conventional agents all correlated significantly with each other. For the colorectal cancer specimens, the pattern of UCN-01-sensitivity did not correlate with the patterns for 5-FU or MMC. In conclusion, UCN-01 may be useful for clinical application against gastric and colorectal cancer due to its different antitumor spectrum from conventionally available agents.
Aged↗
Preoperative combination chemotherapy with S-1 and low dose cisplatin against highly advanced gastric carcinoma.
We performed preoperative chemotherapy with S-1 and low-dose CDDP (TSLD) to treat 9 patients of highly advanced gastric cancer. Five cases showed significant effect with severe fibrosis diagnosed as grade 1b-2 effect in histology, and all 9 cases showed at least grade 1a effect in either primary lesion or lymph node. While toxicity of less than grade 3 (gastrointestinal disorder and/or bone marrow suppression) were observed in 5 out of 9 cases (55.6%), no symptom was observed in 3 out of the 5 patients. We conclude that the TSLD is useful to control highly advanced gastric cancer.
Adenocarcinoma↗
Antitumor activity of doxorubicin in combination with docetaxel against human breast cancer xenografts.
In this study we assessed the in vivo antitumor activity of combined docetaxel (DOCE) and doxorubicin (DXR) treatment using 2 human breast carcinoma cell xenografts (R-27 and MX-1) in the nude mouse model. The transplanted tumors were allowed to reach exponential growth, whereupon 10 or 40 mg DOCE per kg alone (i.p.), 8 mg DXR per kg alone (i.v.), or 10 mg/kg DOCE (i.p.) and 8 mg/kg of DXR (i.v.), in the sequence of DOCE followed by DXR, were administered. The in vivo antitumor activity of combined DOCE and DXR was synergistic against R-27 and additive against MX-1. P-glycoprotein (P-gp) was detected immunohistochemically, and was highly expressed in R-27, but not in MX-1. In conclusion, DOCE may increase the antitumor activity of DXR against P-gp-positive breast cancer xenografts, such that the DOCE and DXR combination may be a useful treatment in clinical breast cancer.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Cancer chemotherapy chemosensitivity testing is useful in evaluating the appropriate adjuvant cancer chemotherapy for stages III/IV gastric cancers without peritoneal dissemination.
BACKGROUND: Because of the low chemosensitivity of gastric cancer to conventional antitumor agents, the role of adjuvant chemotherapy for patients with advanced gastric cancer is controversial. We have previously proposed the necessity to evaluate the appropriateness of particular adjuvant cancer chemotherapies in individual advanced gastric cancer patients using chemosensitivity testing. In the present study, we compared the chemosensitivity and clinical outcomes of patients with Stages III and IV gastric cancer. PATIENTS AND METHODS: A total of 282 patients with advanced gastric cancer were analyzed retrospectively in terms of chemosensitivity as detected by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and survival outcome after surgery. Patients were split into groups according to Stage III or IV gastric cancer, then categorized into those that received surgery without chemotherapy (surgery-alone), and those that received adjuvant chemotherapy, for which all the evaluable cases were further divided into sensitive and resistant cases as determined by MTT assay. RESULTS: For Stage III gastric cancer patients, the sensitive group had a more favorable survival outcome than the other two groups. For Stage IV gastric cancer patients, the sensitive groups, had a more favorable survival outcome than the other two groups, but only in the absence of peritoneal dissemination. CONCLUSION: Chemosensitivity testing, based on the MTT assay, was useful in evaluating the appropriate cancer chemotherapy for patients with Stages III/IV gastric cancer without peritoneal dissemination.
Aged↗
Alteration of DNA methylation status induced by epidermal growth factor in gastric cancer cell line, MKN-74.
DNA methylation dynamics are an important key to understanding various biological events, particularly regulation of gene expressions. To test the hypothesis that epidermal growth factor (EGF) signaling may influence DNA methylation status in cancer cells, which will show several altered biological characters compared with those before EGF-stimulation, we evaluated DNA methylation status with/without EGF-stimulation. The specific alteration of biological character in the gastric cancer cell line, MKN-74, by EGF was demonstrated by DNA synthesis, apoptosis and morphology, revealing that high concentrations of EGF (10 nM) altered the morphology accompanying a moderate increase of cell growth with induction of apoptosis, while low concentrations of EGF (0.1 nM) induced a high increase of cell growth without either morphological change or apoptosis. Although DNA synthesis is almost the same between 0.1 nM of EGF (164%) and 10 nM of EGF (172%), 0.1 nM of EGF showed higher methyltransferase activity than 10 nM of EGF did with a significant difference. In addition, the studies for both the methyl-base uptake into DNA incorporated with DNA synthesis and the methyl-base accepting capacity in DNA showed that a high concentration of EGF (10 nM) induced the demethylated status of the DNA compared with that of 0.1 nM EGF. Thus, we demonstrated that DNA methylation status is affected by EGF-stimulation with alteration of cell biological character.
Adenocarcinoma↗
The inhibitory effect of matrix metalloproteinase inhibitor ONO-4817 on lymph node metastasis in tongue carcinoma.
BACKGROUND: ONO-4817 is a novel matrix metalloproteinase (MMP) inhibitor which has a broad inhibitory spectrum for MMPs. We investigated the inhibitory effect of ONO-4817 on cervical lymph node metastasis of tongue carcinoma. MATERIALS AND METHODS: HSC-3-M3, a cell line derived from human tongue carcinoma with high metastatic potential for lymph node, was used. The direct cytotoxicity of ONO-4817 was assessed by MTT assay and the gelatinolytic activity by gelatin zymography and film in situ zymography (FIZ). The inhibitory effect on lymph node metastasis was examined by orthotopic implantation model with nude mice. RESULTS: ONO-4817 had no direct cyototoxicity on HSC-3-M3 cells. Gelatin zymography and FIZ demonstrated a suppression of MMP-9 activation and a marked inhibition of gelatinolysis. Additionally, a suppression of cervical lymph node metastasis was shown by therapeutic experiment. CONCLUSION: The MMP inhibitor, ONO-4817, is a candidate for adjunctive therapy of cervical lymph node metastasis in tongue carcinoma.
Animals↗