Sohzaburo Kiuchi

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 hypothermie 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 cytologie examinations of the lavage from Douglass 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.

Positive results of combined therapy of surgery and intraperitoneal hyperthermic perfusion for far-advanced gastric cancer.

To evaluate the clinical efficacy of intraperitoneal hyperthermic perfusion (IPHP) for far-advanced gastric cancer, particularly with peritoneal seeding, we investigated the survival times of 59 patients who underwent distal subtotal gastrectomy, total gastrectomy, or total gastrectomy combined with concomitant resection of some of the remaining intra-abdominal organs. In all the 30 patients given IPHP, no cancer cells were present posthyperthermically in the lavage from the Douglas pouch. The 30 patients given IPHP lived longer than the 29 patients not given IPHP (p = 0.001), with a 1-year survival rate of 80.4% in the former group compared to 34.2% in the latter. With respect to a comparison of survival time of patients with peritoneal seeding, 7 patients not given IPHP had a 6-month survival rate of 57.1% and did not survive more than 9 months, whereas 20 patients given IPHP had 1- and 2-year survival rates of 78.7% and 45.0%, respectively; here the difference was significant (p = 0.001). The IPHP and control groups without peritoneal metastasis included 10 and 22 patients, respectively, and the 1-year survival rates are 85.4% and 45.3%, respectively. The survival rates of the former exceeded those of the latter, with p = 0.015 by the generalized Wilcoxon test. Thus this combined therapy offers the promise of extended survival for patients with far-advanced gastric cancer.

Stapled or manual suturing in esophagojejunostomy after total gastrectomy: A comparison of outcome in 379 patients

From January 1983 to December 1989, we performed esophagojejunostomy on 379 patients who underwent total gastrectomy for gastric cancer. A mechanical EEA stapler or conventional manual suturing was used. The clinical outcomes of 199 patients in whom stapling was used (stapler group) and 180 patients in whom manual suturing was done (manual group) were compared. Two of the 199 patients in the stapler group and 3 of the 180 patients in the manual group died of causes directly related to the anastomosis. In the stapler group, 16 stapled anastomoses were formed supradiaphragmatically, and manual suturing was done for 6 patients. The highly placed anastomosis was formed without left thoracotomy or with median sternotomy in 8 of the 16 patients in whom the stapling device was used and in 1 of the 6 patients in whom manual suturing was used. The incidence of anastomotic leakage and stenosis did not differ between the groups. Thus, the mechanical stapler facilitated the construction of a rapid, reliable esophagojejunostomic anastomosis.

Prevention of scald injury on the peritoneo-serosal surface in advanced gastric cancer patients treated with intraperitoneal hyperthermic perfusion

In attempts to avoid the side-effects derived from a scald on the peritoneo-serosal surface during intraperitoneal hyperthermic perfusion (IPHP) for advanced gastric cancer, a randomized study using cimetidine, a histamine H2-receptor antagonist, was carried out on 18 patients with advanced gastric cancer. Cimetidine, 50 mg/kg, was administered intravenously and immediately before IPHP. The background characteristics of the patients and the types of surgical treatment used were almost the same between each group of patients, whether or not cimetidine was given. The perfusion time in the cimetidine and control groups was 123 +/- 9 and 117 +/- 9 min, respectively. The inflow and outflow temperatures of the perfusate were 46.3 +/- 0.4 and 44.2 +/- 0.1 degrees C in the cimetidine group, respectively, whereas in the control group the temperatures were 46.0 +/- 0.3 and 44.1 +/- 0.2 degrees C, respectively. In the nine patients who were given cimetidine, the histamine concentrations in the peripheral blood increased significantly, compared to those in the nine controls; this resulted from the release of histamine into the circulating blood. Higher concentrations of protein were observed in the post-hyperthermic intraperitoneal exudate of the control group for 3-24 h after IPHP and, consequently, post-hyperthermic hypoproteinaemia was remarkable in the control group. These data suggest that when pre-IPHP cimetidine was prescribed for patients with gastric cancer treated with IPHP, the peritoneo-serosal surface was protected from scald injury and the side-effects of IPHP were reduced.

Metabolic changes in cimetidine treatment for scald injury on the peritoneo-serosal surface in far-advanced gastric cancer patients treated by intraperitoneal hyperthermic perfusion

Since pretreatment with cimetidine results in the prevention of scald injury on the peritoneo-serosal surface caused by intraperitoneal hyperthermic perfusion (IPHP) for advanced gastric cancer, the diverse influence of IPHP on patients who were either given or not given cimetidine was studied both during and after IPHP treatment. Cimetidine 50 mg/kg was injected intravenously into 12 patients immediately prior to IPHP. There were no statistical background differences between the cimetidine and control groups (those not given cimetidine). The inflow and outflow temperatures of the hyperthermic perfusate in the control and cimetidine groups were 46.1±0.1°C and 44.1±0.1°C and 46.3±0.1°C and 44.2±0.04°C, respectively. Either the pre-IPHP hypothermia or IPHP in the control group resulted in a considerable increase in serum noradrenaline and adrenaline. The intravenous administration of cimetidine led to a stransient but moderate drop in the mean blood pressure as well as a delayed appearance of high concentrations of noradrenaline and adrenaline, induced by high concentrations of circulating histamine released with cimetidine. These results suggest that the sympathetic nervous responses were activated either by hypothermia or hyperthermia. The transient hypotension and delayed increases of both serum catecholamines were attributed to a marked increase in circulating histamine, released with the intravenous cimetidine.

Augmented antitumour effects of combined treatment with hyperthermia and tumour necrosis factor on human gastric cancer xenotransplanted into nude mice

Hyperthermia combined with recombinant human tumour necrosis factor (rH-TNF) was evaluated for antitumour efficacy in vivo. Use was made of human gastric cancer tissues xenografted into nude mice. When 100, 300, 600, and 1200 units of rH-TNF (2.4 x 10(6) units/mg protein) were given twice intraperitoneally, tumour regression did not occur in any animal. In contrast, a remarkable suppression of tumour growth was observed when 600 and 1200 units of rH-TNF was given in combination with hyperthermia at 43.5 +/- 0.1 degrees C. No effects were evident with the regimen of 100 and 300 units of rH-TNF plus hyperthermia at the same temperature, as compared with evidence obtained with hyperthermia alone. The tumoral blood flow, determined by the hydrogen diffusion method, decreased immediately after hyperthermia alone or hyperthermia plus 1200 units of rH-TNF, whereas a slight decrease was seen after rH-TNF alone. When hyperthermia plus 1200 units of rH-TNF were given, there was a remarkable delay in reversion to pretreatment values of tumoral blood flow, as compared to findings with rH-TNF only or heat only. These results are discussed in relation to the antitumour and side-effects of rH-TNF.

Thermotolerance of xenografted human gastric cancer.

To compare the thermotolerancein vivo of two human gastric cancers with different doubling times, the xenografted tumors were warmed twice at 43.5±0.1°C in a water bath for 20 minutes at a predetermined interval. In the tumors with doubling times of 5.2 and 10.9 days, a 7-day interval heat treatment resulted in a prolongation in tumor tripling times by 156 per cent and 132 per cent, respectively, compared with a single heat treatment for 40 minutes. On the contrary, two heat treatments given at intervals of 3 to 5 days had a short tumor tripling time, compared to that of the 40-minute single treatment. Thus, the thermotolerance of these human gastric cancers gradually increased to a maximum within a 3- to 4-day interval and disappeared completely after a 7-day interval. These results indicate that the times required to reach maximal thermotolerance in these human gastric cancers were longer than those previously demonstrated for human and rodent cancer cell linesin vitro. The development and decay of thermotolerance in these human gastric cancers need to be considered in the design of multiple-fractionated regimens.

Clinical outcome of intraperitoneal hyperthermo-chemotherapy for patients with refractory gastric cancer

The survival time of patients with advanced gastric cancer remains short regardless of whether or not postoperative adjuvant chemotherapy is given. Intra-abdominal spread of cancer cells is inevitable since a sensitive diagnostic to detect a small volume of tumors on the peritoneal surface has not been available. Drugs can be delivered through the circulating blood to the surface of the peritoneum, mesentery, and omentum ; however, an intra-abdominal form of chemotherapy has the dual advantages of a high regional concentration of antitumor drugs and alleviation of systemic side effects [1].

Preventive antitumor treatment for peritoneal recurrence of gastric cancer with serosal invasion.

漿膜浸潤陽性胃癌症例の術後の腹膜再発を予防することを目的として, 腹腔内温熱灌流 (intraperitonealhyperthermic perfusion;以下IPHP) を行うとともに, 腹腔内へrecombinant interleukin-2を投与した. 対象胃癌18例はsell例, sei 7例であり, IPHPはMMC 10μg/mlを含む灌流液の平均流入温47.2℃, 流出温45.1℃ に保ち120分間行った. IPHP直前に体表面冷却により31～32℃ の低体温とし, 術中腹腔内癌細胞陽性14/18例 (77.8%) は, IPHP後に1例を除き陰性となった. 術後第14病日前後よりrecombinant interleukin-2 1000単位の腹腔内投与を14日間行い, 腹腔内浸出液中にNK細胞を認めたので, 腹腔内局所にNK活性の誘導が可能であり, 有効な局所免疫療法であることが示唆された.