Biomedical subjects

M Kokubun

Publications and source records attributed to M Kokubun.

At least 55 records · Page 3Linked to original sources

PubMed1989

[Pharmacokinetic analysis in intraperitoneal hyperthermic perfusion using mitomycin C in far-advanced gastric cancer].

Postoperative intraperitoneal hyperthermic perfusion (IPHP) using MMC was performed with marked success on 15 gastric cancer patients with peritoneal dissemination or serosal invasion (first surgery group) and on 5 recurrent gastric cancer patients with ascitic retention (recurrent cancer group), and the MMC concentrations was studied in the perfusate and circulating blood. The perfusate contained MMC 10 micrograms/ml at the onset of IPHP, except one recurrent case of 20 micrograms/ml, and IPHP was performed for 120 minutes except in one case given 20 micrograms/ml of MMC. There was little difference in the hepatorenal functions and perfusate temperatures between the first surgery group and the recurrent cancer group. The drug levels were measured by HPLC method with minimal assay levels of 2 ng/ml. Perfusate drug levels in the first surgery group reduced by half at 12 minutes after the start of IPHP, whereas in the recurrent cancer group, they decreased by half about 60 minutes later. Perfusate drug levels in the first surgery group decreased twice as rapidly as in the recurrent cancer group. The area under the curve (AUC) and average drug levels in the first surgery group were 7,900 micrograms.hr/l and 3.3 micrograms/ml, respectively, and those in the recurrent cancer group were 12,620 micrograms.hr/l and 5.3 micrograms/ml, respectively. On the other hand, the drug levels in peripheral blood were almost the same between the two groups. These data suggest that although recurrent gastric cancer is well suited for IPHP because of high AUC, it is worthwhile performing IPHP combined with surgery for gastric cancer with peritoneal seeding, with due consideration for AUC of 7,900 micrograms.hr/l and the average drug level of 3.3 micrograms/ml.

Adult↗

PubMed1989

Pharmacokinetic analysis in intraperitoneal hyperthermic chemotherapy of far-advanced gastric cancer patients.

The pharmacokinetics of mitomycin C (MMC) has been evaluated in 10 far-advanced gastric cancer patients by means of an intraperitoneal hyperthermic perfusion (IPHP) using MMC to prevent and/or treat peritoneal dissemination. Further, misonidazole (MIS), which was used as a thermosensitizer, also was evaluated. The IPHP was performed for 120 min right after surgical procedure, using a closed-circuit with an inflow perfusate temperature from 46.3 approximately 47.5 degrees C and an outflow temperature of 44.0 approximately 46.0 degrees C. The MMC level in the perfusate was 10 micrograms/ml at the onset of IPHP and thereafter decreased to 1.7 +/- 0.4 micrograms/ml minutes later. The average AUC (area under the curve) in the perfusate was 3.3 micrograms/ml during the IPHP. The MMC level in the peripheral blood was 0.15 +/- 0.04 micrograms/ml 30 min after start of the IPHP and increased to 0.18 +/- 0.05 micrograms/ml at the end of IPHP. Additionally, the MIS level in the peripheral blood was 64.7 +/- 10.3 micrograms/ml 60 min after the IPHP, 60.6 +/- 9.2 micrograms/ml at 120 min, and then decreased to 32.8 +/- 10.3 micrograms/ml at 12 hours after IPHP. The AUC was calculated as being 975 micrograms.hr/ml. Again, the level in the portal vein blood was calculated from the peritoneal permeability and the peripheral blood level of the drug. From data, it was concluded that the perfusate and portal vein blood level of MMC, the peripheral blood level of MIS, as well as the perfusate temperature, are important in providing a favorable, safe, antitumoral treatment.

Adult↗

PubMed1989

[Clinical evaluation of intraperitoneal hyperthermic perfusion in far-advanced gastric cancer].

Nineteen far-advanced gastric cancer patients, including peritoneal dissemination, underwent surgical treatment followed by intraperitoneal hyperthermic perfusion (IPHP). Seven of them had cancerous ascites, 5 had ovarial metastasis, and in 7 the primary tumor extended to the adjacent organs. Postoperatively, ascitic effusion was absent after IPHP, and all patients were discharged. The survival of the IPHP group was compared with that of 27 advanced gastric cancer patients with serosal invasion (control group), who underwent gastrectomy without IPHP. In the IPHP group, the average and 50% survival was 400 and 520 days, respectively, and 1-year survival rate was 73.3%, against 273 days, 250 days, and 31.8%, respectively, in controls. The survival rate for the IPHP group was statistically better than that of the control group (p less than 0.01). In patients with peritoneal dissemination, the average survival and 50% survival for the IPHP group was 396 and 380 days, respectively, and 1-year survival rate was 62.5%, against 204 days, 170 days, and 16.6%, respectively, in controls. Based on these results, IPHP was suggested to be effective for gastric cancer with serosal invasion, especially with peritoneal dissemination.

Adult↗

PubMed1989

[Effect of degradable starch microspheres (DSM) on hepatic hemodynamics].

The effect of intra-arterial infusion of degradable starch microspheres (DSM) on hepatic arterial blood flow was measured using a transit-time ultrasonic blood flow meter. Before the infusion of DSM, the mean hepatic arterial flows were 316 +/- 79 ml/min. After infusion, the mean flows decreased to 43 +/- 86 ml/min (86%). RI-angiography using 99mTc-macroaggregated albumin (MAA) was performed to measure hemodynamic changes in the liver. T/N ratio of 99mTc-MAA accumulation was increased from 0.37 to 0.62. Based on the peripheral MMC blood levels after combined infusion with DSM and MMC, the mean AUC with MMC plus DSM was decreased to 55% of that of AUC with MMC alone. These results show that combined use of DSM is effective for intra-arterial chemotherapy against the hepatic cancer.

Hemodynamics↗

PubMed1989

Combined treatment with surgery and intraperitoneal hyperthermic perfusion (IPHP) for far-advanced gastrointestinal cancer with peritoneal seeding.

In 19 patients with advanced gastric carcinoma intraperitoneal hyperthermia combined with mitomycin C was administered. After this therapy in repeated cytological examinations of the peritoneal effusion malignant cells could be determined. From 19 patients 5 died innert the first 10 months. The other patients lived 12 months without recurrence.

Chemotherapy, Cancer, Regional Perfusion↗

PubMed1989

[Polarographic analysis of tumor tissue oxygen tension after hyperthermia combined with misonidazole].

For the purpose to analyse the influence of a thermosensitizing drug, misonidazole (MIS), on tissue oxygen tension (TpO2), TpO2 in human gastric cancer tissue (H-23) was measured by a polarographic method. MIS, 500 mg/kg, was given i.p. and then the heat treatment was done in a water bath at 43.5 +/- 0.1 degrees C for 23 minutes. A second treatment was performed to develop thermotolerance at the following intervals: 24 hours, 72 hours, 5 days, and 7 days. Tumor doubling time was shortest at 72-hour interval, i.e., the maximal thermotolerance of the tumor developed at 72-hour interval, whereas the tumor doubling time in case of combined use of MIS was shortest at 24-hour interval. TpO2 in the 72-hour interval treatment decreased soon after hyperthermia, and returned to a pre-heated value 3 hours after, whereas in the other 3 treatments the recovery time was 6 to 12 hours. On the other hand, in 24-hour interval of the combined use of MIS, the post-thermal value of TpO2 was about a half of the pre-thermal value and recovered 24 hours after. In the 5- and 7-day interval treatments, TpO2 declined notably and did not return to the pre-thermal value during 24 hours. These data suggest that the thermo-sensitizing effects of MIS were brought about by prolonged and extreme decrease in TpO2.

Adaptation, Physiological↗

PubMed1988

Enhancement of hyperthermochemotherapy for human gastric cancer in nude mice by thermosensitization with nitroimidazoles.

Hyperthermia for human gastric cancer xenotransplanted into the hindlegs of nude mice was performed to determine whether misonidazole (MISO) or metronidazole (MTR), derivatives of nitroimidazole, would intensify the antitumour effects of hyperthermia only, or combined with mitomycin C (MMC). MISO, MTR and MMC were given i.p. at doses of 500 mg kg-1, 500 mg kg-1 and 2.0 mg kg-1 respectively, and MISO or MTR was administered 45 min before MMC. Hyperthermia was applied twice at 48 h intervals, by means of a water bath at 43.5 +/- 0.1 degrees C for 23 min. Tumour tripling times following heat alone, MTR plus heat, and MISO plus heat were about 6.7, 8.0 and 7.9 days respectively, compared with 4.6 days for the control, but tumour regression occurred in the heat plus MISO group only. Tumour tripling times for MMC plus heat, MMC plus MTR plus heat, and MMC plus MISO plus heat were 9.6, 11.6 and 17.1 days respectively, compared to 4.6 days for the control and 6.7 days for heat alone. These data suggest that the antitumour activity of MMC plus MISO plus heat is an additive phenomenon.

Animals↗

PubMed1988

Intraperitoneal hyperthermic perfusion combined with surgery effective for gastric cancer patients with peritoneal seeding.

Fifteen patients with far-advanced gastric cancer were given surgical treatment followed by intraperitoneal hyperthermic perfusion (IPHP) with mitomycin C (MMC) and misonidazole (MIS), a thermosensitizing drug. Immediately after extensive resection of the abdominal tumors, a 2-hour IPHP was performed at the inflow temperature of 44.7 to 48.7 C, using equipment designed for treatment of cancerous peritoneal seeding as a closed circuit, and under hypothermic general anesthesia at 30 to 31 C. In nine of the 15 patients with peritoneal seeding and/or ascites, cancerous ascites was absent after this treatment. In all cases, repeated cytologic examinations of the lavage from Douglas's pouch were negative. The postoperative courses were uneventful except for Patients 1 and 10, in whom slight leakage occurred. All patients were discharged and are in good health at the time of this writing, 7.2 +/- 4.6 months after the treatment. The Case 4 Patient recently died in a traffic accident. In all patients, transient hepatic dysfunction and hypoproteinemia occurred after the operation. This extensive surgery combined with IPHP using MMC and MIS was well tolerated and is a safe antitumor treatment for gastric cancer with peritoneal dissemination. Neurotoxicity due to MIS was nil.

Adult↗

PubMed1988

Intravenous insulin infusion system to determine insulin regimen in diabetics.

An algorithm for insulin infusion system to control blood glucose was derived from results of intravenous (i.v.) insulin infusion performed on 10 diabetics. I.v. insulin infusion was done on 14 diabetics for 24 hr using the algorithm, and blood glucose was controlled within the proper range in all cases; mean blood glucose was 130 +/- 42 mg/100 ml. During the examination, 4 of 14 cases did not need insulin infusion from midnight to the morning (type A) and 7 cases needed insulin infusion from midnight to the morning (type B). In 3 cases, insulin infusion was not needed at midnight, but blood glucose rose markedly in the early morning followed by insulin infusion (type C). The insulin regimen was determined according to the amount of insulin infused during the examination, dividing insulin dosages into two separate doses using semilente in the morning and a mixture of regular and lente insulin in the evening. In all the cases of type A and B, blood glucose was controlled well on the calculated regimen of insulin. However, good control of blood glucose was not obtained in 3 diabetics of type C. It is concluded that the algorithm is reliable in the estimation of the insulin infusion rate to control blood glucose in the diabetics, and the insulin regimen calculated from the result of intravenous insulin infusion is proper in about 78% of the diabetics.

Adult↗

PubMed1988

[Chemosensitization with nitroimidazole to human gastric cancer transplanted into nude mice].

Combined chemotherapy for human gastric cancer Transplanted into nude mice has been performed to determine whether misonidazole (MIS) and metronidazole (MTR), derivatives of nitroimidazole, would enhance the antitumor activity of MMC. MTR, 500 mg/kg, MIS 500 mg/kg, and MMC 2.0 mg/kg were administered ip twice during a 48-hour interval. The antitumor efficacies of MMC only, MTR only, or MIS only were seen to be much the same as in the controls. The combined treatment with MMC and MTR surpassed the controls in antitumoral activity after the 12th day, whereas it did not surpass a regimen with MMC alone. The addition of MIS to MMC showed an enhanced antitumoral activity after the 10th day compared to the controls and, further, after the 10th day it exceeded the results of MMC only. Tumor tripling time in cases of MMC only, MTR only, MIS only, MMC plus MTR, and MMC plus MIS was 123, 132, 144, 144, and 178 hours, respectively, compared to 110 hours in the controls. Thus, these results suggest that MIS has a chemosensitizing activity under these conditions, while MTR has little activity.

Animals↗

PubMed1988

[Enhancement of hyperthermochemotherapy with hypoxic cell radiosensitizers].

Hyperthermochemotherapy with hypoxic cell radiosensitizers has been carried out using human gastric cancer xenotransplanted into the nude mouse. Misonidazole (MIS) and metronidazole (MTR), hypoxic cell radiosensitizers, were administered singularly or in combination with an ip dose of 500 mg/kg each, and after 60 minutes, an ip dose of MMC of 2.0 mg/kg was given. Subsequently, hyperthermia was applied, twice at a 48-hour interval, by a water bath at 43.5 +/- 0.1 degrees C for 23 minutes. The antitumor activity of hyperthermia with MTR was similar to that of hyperthermia alone, whereas hyperthermia with MIS surpassed hyperthermia alone, at 0.03237 less than p less than 0.05038. Hyperthermia combined with MIS and MMC enhanced the antitumor effects, as compared to hyperthermia with MMC, and with MMC plus MTR. Tumor volumetric tripling times in case of MMC plus heat, MTR, MMC plus heat, and MIS, MMC plus heat were about 229, 213, and 398 hours, respectively, compared to about 110 hours in the control and 160 hours in the case of hyperthermia alone. Thus, these data suggest that the antitumor efficacy of hyperthermochemotherapy with MIS may be the result of a synergistic phenomenon of thermo-chemosensitization.

Animals↗

PubMed1988

[Repeated intra-arterial chemotherapy combined with mitomycin C and degradable starch microspheres in inoperable metastatic hepatic cancer].

Intra-arterial chemotherapy combined with mitomycin C (MMC) and degradable starch microspheres (DSM) was prescribed repeatedly for 14 patients with inoperable hepatic metastasis. This intra-arterial treatment was repeated 2.7 times on the average. The average dose of DSM and MMC in a single infusion was 685 +/- 201 mg and 13.8 +/- 3.8 mg, respectively. To analyse the degradation time of DSM, MMC concentrations in the peripheral blood were measured by HPLC method. RI-angiography using 99mTc macroaggregated albumin(MAA) was performed to estimate the hemodynamic changes in the liver. Antitumor efficacy was evaluated in terms of tumor regression measured by CT scan. An objective tumor response was observed in 9/14 patients(64.2%): CR 1/14; PR 6/14; MR 2/14. Elevated CEA levels were decreased in 11/12 patients (91.7%). Based on the peripheral MMC blood levels after combined infusion with DSM and MMC, an occlusion of intrahepatic vessels with DSM continued at least for 30 minutes. Again, RI-angiography with 99mTc-MAA plus DSM revealed the increased accumulation in the tumor, compared to 99mTc-MAA only. Side effects possibly attributable to DSM were observed in 14/38 treatments, though they were slight and temporary. Thus, these results indicate that this combined intra-arterial infusion of DSM and MMC achieve, higher regional selectivity.

Combined Modality Therapy↗

PubMed1988

[Extended treatment for gastric cancer patients with peritoneal seeding].

Fourteen patients with far-advanced gastric cancer were treated surgically followed by intraperitoneal hyperthermic perfusion (IPHP) with mitomycin C (MMC) and misonidazole (MIS), a thermosensitizing drug. Immediately after extensive resection of the abdominal tumors, a 2-hour IPHP was performed at the inflow temperature 47.4 +/- 0.5 degrees C and at the outflow temperature 45.3 +/- 0.5 degrees C, using equipment designed for treatment of cancerous peritoneal seeding, as a closed circuit, and under hypothermic general anesthesia at 31.2 +/- 0.5 degrees C. In 6 of the 14 patients, cancerous ascites was absent after IPHP. Repeated cytologic examination of the lavage from pelvic cul-de-sac were negative, in all cases. The postoperative courses were uneventful except for 2 patients, in whom slight leakage occurred. All patients were discharged, and 4 in the 14 patients died of recurrence in the liver, abdominal and/or pleural cavities 8.8 +/- 2.1 months after IPHP. The remaining 10 are in good health 12.1 +/- 3.1 months after IPHP. Transient hepatic dysfunction and hypoproteinemia occurred after hyperthermia in all cases. This extensive surgery combined with IPHP using MMC and MIS was well tolerated and is a safe anti-tumor treatment for gastric cancer with peritoneal dissemination. Neurotoxicity due to MIS was nil.

Combined Modality Therapy↗

PubMed1988

[The relationship between thermotolerance and the tissue oxygen tension in human gastric cancer tissue].

To study the relationship between thermotolerance and post-thermal phenomenon, tumor pO2 (TpO2) in xenoplanted gastric cancer tissue (H-23) has been measured by a polarographic method. The heat treatment was done in a water bath at 43.5 +/- 0.1 degrees C for 23 minutes. In order to produce thermotolerance, the second treatment was carried out at an interval of 24 hours, or, alternatively at 72 hours, or at 5 days or at 7 days. The thermotolerance of the H-23 tumor reached its maximum at the 72 hour-interval and was seen to disappear completely at 7 days. The TpO2 in the H-23 tumor decreased immediately after a single heat treatment and returned to its pre-treated value after 10 hours. In cases of the second heat treatment, the 72-hour interval group returned to its pre-treated value in 2-6 hours, whereas the 24-hour, 5-day, and 7-day interval groups showed a longer recovery time. The relationship between thermotolerance and TpO2 recovery was inverse at r = -0.858 and p = 0.035. Thus, our study suggests that not only is the thermotolerance affected by the alteration of the intra-cellular components, but also by the post-thermal changes in the tumor vessels.

Animals↗

PubMed1987

The presence of an aberrant type of human chorionic gonadotropin in patients with gastric or colorectal cancer.

Beta subunits of human chorionic gonadotropin (beta-hCG) and human chorionic gonadotropin-like substance (hCGLS) were measured radioimmunologically in the serum and malignant tissue from patients with gastrointestinal cancer. Since serum beta-hCG and hCGLS correlate closely to those in cancer tissues, it is assumed that these two gonadotropins originate from cancer tissues. The serum hCGLS levels in 54 patients with gastrointestinal cancer were significantly higher, when compared with the findings in 19 healthy volunteers and 10 peptic ulcer patients. The frequency of high levels of serum hCGLS accounted for 71 per cent of those with operable gastric cancer, 44 per cent of those with inoperable gastric cancer, 100 per cent of those with operable colorectal cancer, and 67 per cent of those with inoperable colorectal cancer. On the contrary, serum beta-hCG levels did not differ between the volunteers and the cancer patients. In the 17 sera and 15 cancer tissues assayed, beta-hCG did not correlate to hCGLS. Moreover, the high levels of beta-hCG in cancer patients occurred in only 1/14 (7.1 per cent) of the assayed serum, and in 5/14 (35.7 per cent) of the cancer tissue. The increased production of these two hCGs may result from neoplastic transformation of an unrestrained fetal genome responsible for hCG production during gestation. It is assumed that the increased producibility of a defective hCG, i.e., an aberrant hCG such as hCGLS, is characteristic of malignant tumors.

Chorionic Gonadotropin↗

PubMed1987

Enhanced antitumor efficacy with a combination of hyperthermochemotherapy and thermosensitization with polyamine antimetabolites in nude mice.

In an attempt to enhance the antitumor effects of hyperthermochemotherapy, methylglyoxal-bis-guanylhydrazone (MGBG) and alpha-difluoromethylornithine (DFMO) were used in combination with hyperthermochemotherapy of 1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU) against human gastric cancer (ST-2) xenotransplanted into nude mice. After priming with DFMO and MGBG, ACNU was given ip and subsequently, a 23 minute-hyperthermia was carried out by placing the leg with the tumor into a water bath of a temperature of 43.5 +/- 0.1 degrees C. The second hyperthermic treatment was given in the same manner after 48 hours. MGBG and DFMO were administered for 4 successive days from the previous day of the first hyperthermia. In mice treated with DFMO plus MGBG, either tumor growth or tumor tripling time was much the same as in the control, while in mice given MGBG, DFMO plus heat, there was a diminution in tumor growth. Hyperthermia together with MGBG, DFMO plus ACNU brought about remarkable antiproliferative effects on ST-2 tumor growth, compared to three regimens with MGBG, DFMO plus heat, MGBG, DFMO plus ACNU, as well as ACNU plus heat. These data suggest that a combination of MGBG with DFMO leads to a favorable thermosensitization to the antitumor efficacy of ACNU.

Animals↗

PubMed1987

Gastric cancer with synchronous unresectable hepatic metastasis and a positive response to chemotherapy--report of two cases.

We report herein the clinical events seen in two longterm survivors of gastric cancer with unresectable synchronous hepatic metastases. Partial gastrectomy was performed against the primary lesion and continuous intra-arterial infusion of anti-tumor drugs, followed by prolonged systemic antitumor drug treatment, were prescribed. A 43-year-old man with moderately-differentiated tubular adenocarcinoma had an uneventful course during his first 21 postoperative months. However, multiple liver metastases became manifest at 24 months and enlargement of the intrahepatic foci led to death 27 months after gastrectomy. A 51-year-old woman with moderately-differentiated tubular adenocarcinoma had an uneventful postoperative course and is now well with no signs of recurrence 6 years and 6 months after gastrectomy.

Adult↗

PubMed1987

[Antitumor effects of polyamine antimetabolites with polyamine-free diet].

To evaluate the antitumor efficacy of polyamine antimetabolites such as methylglyoxal-bis-guanylhydrazone (MGBG), ethylglyoxal-bis-guanylhydrazone (EGBG), and alpha-difluoromethylornithine (DFMO), the combined therapies of polyamine antimetabolites with a polyamine-free diet were studied. The combination of EGBG plus DFMO or MGBG plus DFMO showed a marked suppression of tumor growth with a polyamine-free diet; and, when compared, EGBG was slightly superior to MGBG. The inhibition of DNA biosynthesis was also parallel to the above-mentioned results. Furthermore, from an analysis for polyamine levels in tumor tissues, it was confirmed that the polyamine depletion can be maintained by polyamine antimetabolites in combination with a polyamine-free diet in vivo. Moreover, as EGBG has lesser side effects than MGBG, EGBG might be more suitable for clinical use.

Animals↗