[Efficacy of lidocaine cream in protecting against thermal stress during hyperthermia].

Hyperthermia is performed in combination with chemotherapy as multimodal treatment for recurrent and advanced cancer. It is generally believed that the temperature cannot be raised higher because of thermal stress. In this study, we examined the efficacy of lidocaine cream in protecting against thermal stress during hyperthermia. We devised a new local anesthetic cream containing 5% lidocaine. The subjects were eighteen patients with stomach cancer, liver cancer, or large intestine cancer. This cream was applied locally to the skin with an occlusive dressing for about one hour before hyperthermia was performed, and was wiped away just before hyperthermia. The pain scores in the treatment group were significantly lower than in the no-treatment group (p < 0.05). The scores for sensation of heat in the treatment group were lower, though not to a significant extent, than those in the no-treatment group. No adverse effects were observed. Plasma concentrations of lidocaine were lower than 0.5 microgram/ml, and percutaneous absorption of lidocaine from the lidocaine cream was minimal.

[Indication of percutaneous microwave coagulation therapy for hepatocellular carcinoma].

Multifocal carcinogenesis is caused by a persistent infection of hepatitis viruses, and is considered to be the main cause of post-operational recurrences of hepatocellular carcinoma. It has been generally believed that a single therapeutic modality (including resection therapy) cannot improve the survival rate. In this paper, we describe the efficacy of microwave coagulation therapy and its indications based on an analysis of cases experienced at our institution over a 10-year period. We compared the background factors, recurrence rate, and survival rate of various therapies, and concluded that microwave coagulation therapy is highly effective for tumor coagulation and necrosis. Microwave coagulation therapy is also technically easier than a surgical operation, has fewer complications, and results in an equally good survival rate when compared to hepatectomy. Due to these intrinsic advantages, microwave therapy is useful not only as a treatment after recurrence, but also as a primary therapy of small liver tumors. When the detection rate for small liver tumors increases, microwave coagulation therapy will start to play an even more important role in the treatment strategy for hepatocellular carcinomas as a less invasive option, in addition to laparotomic and percutaneous/laparoscopic surgeries.

Basic knowledge of a microwave tissue coagulator and its clinical applications.

A microwave tissue coagulator originally developed to control hemorrhage during hepatic resection has recently found widespread use in the field of minimally invasive surgery. This surgical tool is based on the principle that by radiating a 2450-MHz (12-cm wavelength) microwave from a monopolar antenna within tissue, the heat generated will be limited to within the electromagnetic field generated around the antenna, leading to coagulation of protein in that field. It is therefore possible to use this monopolar antenna as a surgical electrode. The coagulation field is determined by the relationship between the wavelength frequency, tissue-specific permittivity, antenna length, waveform and output, and duration of the irradiation. Since this technique has been applied to devise a new method of hepatectomy, it has also found use in various other surgical fields, such as gastrointestinal tract endoscopic surgery, laparoscopic surgery, and percutaneous surgery. It has also enhanced therapeutic results, notably in cancer therapy.

Beneficial effects of fructose-1,6-diphosphate infusion on liver regeneration after ischemic liver injury.

The effect of fructose-1,6-diphosphate (FDP) on cellular viability after partial hepatectomy in partial ischemic liver was investigated in rats. The administration of FDP did not increase blood flow in the hepatic tissue; however, it significantly suppressed the elevation of serum liver functions for 24 hours after partial hepatectomy. Levels of DNA synthesis, protein synthesis, and labeling index were significantly higher in the groups administered divided doses of FDP before and after partial hepatic ischemia than in the control group (P less than 0.01). Thus, these findings indicate that FDP has cytoprotective and hepatotrophic effects on liver with ischemic injury and that divided dose administration of FDP is more effective than bolus doses in decreasing damage following ischemic and reperfusion injury.

[Beneficial effects of fructose-1,6-diphosphate infusion on hepatic regeneration after partial hepatectomy by microwave tissue coagulator].

Experiments were performed to explore the effect of microwave tissue coagulator (MTC) on post-lobectomy regeneration of the liver and the regeneration-promoting effect of fructose-1,6-diphosphate (FDP) on heat injury of the liver after 40% hepatectomy in rats. Concerning the effect of MTC on hepatic regeneration, a MTC group showed a significantly higher serum LDH level on post-operative day 2, compared with a simple ligation group. A significant difference in DNA synthesizing activity between two groups was noted only in the peripheral region of regenerating liver tissue. A marked depression was observed on post-operative day 2 in the MTC group, 433 +/- 50 dpm/micrograms DNA as compared to 782 +/- 111 dpm/micrograms DNA in the simple ligation group, and also in respect of protein synthesis and labeling index. Administration of FDP prior to operation brought about a complete inhibition of the serum LDH elevation. DNA synthesis was significantly enhanced in the peripheral region of regenerating liver tissue in rats pretreated with FDP (422 +/- 52, 783 +/- 112 and 912 +/- 115 dpm/micrograms DNA in the saline, FDP 0.25 mmol/kg and FDP 0.8 mmol/kg groups, respectively). Similar trends were observed as to protein synthesis and labeling index. FDP has been proven to be effective on protection of the liver cells as well as on promotion of the liver regeneration following hepatic resection by MTC.

[Successful adoptive immunotherapy with OK432-inducible activated natural killer cells on tumor-bearing mice].

We had demonstrated that the NK cell mediated cytotoxicity of murine spleen cells could be augmented by in vivo prime and subsequent in vitro challenge with the streptococcal preparation OK432, and the cell surface phenotype of induced killer cells was Thy 1+, asialo GM1+, suggesting the activated NK cells (OK-NK cell). The culture supernatants of spleen cells with OK432 possessed the activity of IL-2 and IFN-gamma, and the IL-2 played a major role to induce the OK-NK cells via the production of IFN-gamma. In this study, we examined the effect of adoptive transfer of OK-NK cells on tumor-bearing mice. The mice were implanted SP2 myeloma cells intraperitoneally (i.p.), or C26 colon adenocarcinoma cells subcutaneously (s.c.) to make the models of peritonitis carcinomatosa or solid tumor, and the OK-NK cells were transferred i.p. or i.t., adoptively. By the adoptive transfer of OK-NK cells, the 92% of mice bearing SP2-tumor had be cured. The tumor growth of C26-solid tumor was inhibited, and the survival rate of mice bearing C26-tumor was increased, significantly. The intratumoral remnants of 125I-labelled OK-NK cells were 61.27 and 8% after intratumoral transfer, respectively. By multiple transfer of OK-NK cells the anti-tumor effect was more augmented than that of a single transfer. Thus we recognized the anti-tumor effect of adoptive transfer of OK-NK cells on tumor-bearing mice, and suggested that OK-NK cells could be useful for the therapy of cancer patients.

[Role of interleukin 2 and interferon gamma in induction of activated natural killer cells by the streptococcal preparation OK432].

The natural killer (NK) cell mediated cytotoxicity to syngeneic tumor cells can be augmented by in vivo priming and subsequent in vitro challenge with the streptococcal preparation OK432. Supernatants of coculture of spleen cells with OK432 contained Interleukin 2 (IL-2) and Interferon (IFN), mainly IFN-gamma. As the anti-mouse IFN-gamma monoclonal antibody but not anti-mouse IFN-alpha antibody inhibited the induction of activated NK cells with OK432, the IFN-gamma participated in this response. The incubated spleen cells with IL-2 receptors increased with OK432 treatment by flow cytometry, and the NK cell and IFN activities of supernatants were also abrogated by the treatment with anti-mouse IL-2 receptor monoclonal antibody to block the interaction between IL-2 and these receptors of effector cells. By panning method, it was clarified that the incubated spleen cells with IL-2 receptors were responsible for the production of IFN-r. These results suggest that IL-2 plays a major role to induce the activated NK cells from murine spleen cells primed in vivo and subsequently challenged in vitro with OK432, by the production of IFN-gamma.

[Induction of activated natural killer cells by the streptococcal preparation OK432 (I). Induction from spleen cells of normal or tumor-bearing mouse primed in vivo and subsequently challenged in vitro with OK432].

The present study shows that natural killer cell-mediated cytotoxicity of BALB/c mouse spleen cells to syngeneic tumor cells was augmented by in vivo priming or in vitro stimulation with the streptococcal preparation OK432. The augmentation of spleen cell cytotoxicity to syngeneic tumor cells by in vivo priming alone with OK432 was lower than that obtained by in vitro stimulation alone with OK432. When the murine spleen cells primed in vivo with OK432 were rechallenged in vitro with OK432 at various intervals, the natural cytotoxicity was more strongly enhanced than that seen with in vitro stimulation alone. The cell surface phenotype of killer cells activated with OK432 was Thy1+ and asialo GM1+, suggesting the activated natural killer cell. Mice were transplanted with syngeneic colon adenocarcinoma cells, and primed in vivo with OK432, and then their spleen cells were subsequently challenged in vitro with OK432. These cells displayed a strong cytotoxic activity not only to the transplanted adenocarcinoma cells but also to other syngeneic tumor cells.

Role of interleukin-2 and interferon-gamma in induction of activated natural killer cells from mice primed in vivo and subsequently challenged in vitro with the streptococcal preparation OK432.

The natural-killer(NK)-cell-mediated cytotoxicity to syngeneic tumor cells can be augmented by in vivo priming and subsequent in vitro challenge with the streptococcal preparation OK432. Supernatants of cocultures of spleen cells with OK432 contained interleukin-2 (IL-2) and interferon (IFN), mainly IFN-gamma. As the anti-(mouse IFN-gamma) monoclonal antibody but not anti-(mouse IFN-alpha) antibody inhibited the induction of activated NK cells with OK432, the IFN-gamma participated in this response. The enhancement of NK cell activity and production of IL-2 were partially inhibited by the pretreatment of spleen cells with mitomycin C or irradiation, and were completely abolished by pretreatment with actinomycin D. The IL-2 activity after treatment with various metabolic inhibitors ran parallel to the NK activity in a system augmented with OK432. The activity of incubated spleen cells with IL-2 receptors was increased by OK432 treatment, and the NK cell and IFN activities of supernatants were also abrogated by the treatment with anti-(mouse IL-2 receptor) monoclonal antibody, to block the interaction between IL-2 and these receptors of effector cells. The panning method clarified that the incubated spleen cells with IL-2 receptors are responsible for the production of IFN-gamma. These results suggest that IL-2 plays a major role in inducing the activated NK cells from murine spleen cells primed in vivo and subsequently challenged in vitro with OK432, by the production of IFN-gamma.

Induction of activated natural killer cells from murine spleen cells primed in vivo and subsequently challenged in vitro with the streptococcal preparation OK432.

The present study shows that natural killer cell-mediated cytotoxicity of BALB/c mouse spleen cells to syngeneic tumor cells was augmented by in vivo priming or in vitro stimulation with the streptococcal preparation OK432. The augmentation of spleen cell cytotoxicity to syngeneic tumor cells by in vivo priming alone with OK432 was lower than that obtained by in vitro stimulation alone with OK432. When the murine spleen cells primed in vivo with OK432 were rechallenged in vitro with OK432 at various intervals, the natural cytotoxicity was more strongly enhanced than that seen with in vitro stimulation alone. The cell surface phenotype of killer cells activated with OK432 was Thy 1+ and asialo GM1+, suggesting the activated natural killer cell. Next, mice were transplanted with syngeneic colon adenocarcinoma cells, and primed in vivo with OK432. These spleen cells were subsequently challenged in vitro with OK432. These spleen cells displayed a strong cytotoxic activity not only to the transplanted adenocarcinoma cells but also to other syngeneic tumor cells.

[Analysis of intestinal motility by enteric sound recording system--clinical evaluation of aclatonium napadisilate and prostaglandine F2 alpha on intestinal movement].

In patients with so-called postoperative enteroplegia after laparotomy, effects of aclatonium napadisilate (abbreviated as TM-723 hereinafter) and prostaglandine F2 alpha (abbreviated as PGF2 alpha) on intestinal motility were determined using an enteric sound recording system (phonointestinography) and simultaneously the time required for breaking wind after operation was examined. TM-723 was administered at a dose of 50 mg from the intestinal fistula after dissolved in 5 ml of physiological saline, while PGF2 alpha was administered as an i.v. drip infusion at a dose of 2 mg dissolved in 500 ml of 5% glucose solution. Intestinal movement was determined at McBurney point using the enteric sound recording system developed at our department. The time required for breaking wind after operation was determined in three groups received TM-723, PGF2 alpha and placebo, respectively. No significant intergroup difference was observed. As to effect on intestinal motility, TM-723 increased intestinal motility when it was reduced in so-called postoperative enteroplegia phase. Its efficacy became higher with a decrease in motility. On the contrary, TM-723 rather tended to depress intestinal motility when it was increased. On the other hand, PGF2 alpha tended to increase intestinal motility regardless of motility in enteroplegia phase.

Microwave tissue coagulation applied clinically in endoscopic surgery.

On the basis of the ample basic knowledge acquired by repeated experiments, we applied our microwave tissue coagulator in endoscopic surgery, in a total of 59 patients with benign and malignant lesions encountered during a period of two years beginning in July, 1981. Hemostasis was achieved in 96.5% of all the cases with bleeding lesions in the digestive tract. Stenosis was alleviated in 86% of the cases with esophageal or rectal stenosis. Furthermore, the technique was successfully used for hemostasis and tumor reduction in inoperable early cancer cases. Our device is unique in that the electrode is thrust into tissue, which assures us of a satisfactory result. In this point, it must be clearly distinguished from an electrocoagulator or a laser coagulator, which is associated with a risk of injuring intact tissue. The range of coagulation is adjustable by changing the length of the monopolar antenna and electric output, and by employing a coaxial cable of appropriate thickness. In conclusion, our microwave tissue coagulator can be used easily and safely in clinical endoscopic surgery.