Early and delayed Tc-99m ECD brain SPECT in SLE patients with CNS involvement.

We compared early and delayed Tc-99m ECD SPECT scans in 32 SLE patients (Group 1, definite neuropsychiatric disorders; Group 2, minor neurologic symptoms or normal) with those of normal controls by visual inspection and semi-quantitative evaluation. With visual interpretation, 13 out of 14 patients in Group 1 (93%) and 7 out of 18 patients in Group 2 (39%) had diffuse uneven decrease in early scans. Seven patients in Group 2 (39%) who had normal early scans demonstrated focal decrease in the medial frontal lobe in delayed scans. With cerebral region to cerebellar ratios, in early scans, the medial frontal lobe in Group 1 and Group 2 was significantly lower than in normal controls, and lateral frontal lobe and occipital lobes in Group 1 were significantly lower than in normal controls. Nevertheless, in delayed scans, every cortical region except for the parietal lobe in Groups 1 and 2 was significantly lower than in normal controls. The retention rates in all regions in SLE patients were significantly lower than in normal controls. No case showed SPECT improvement on follow-up studies in either group in spite of clinical improvement. Delayed Tc-99m ECD brain SPECT of high sensitivity might be useful in detecting CNS involvement. Although the SPECT findings did not correlate with the neuropsychiatric symptoms, early and delayed Tc-99m ECD SPECT seems to provide useful objective diagnostic information in SLE patients.

[Clinical usefulness of MRI in acute phase of spinal multiple sclerosis--influence of high-dose steroid therapy in acute phase].

Magnetic resonance imaging (MRI) is useful for detecting spinal cord lesions in multiple sclerosis (MS). In this study, we have examined MRI for 14 patients (26 cases) with clinically definite MS and investigated the correlations between neurological and MRI findings before and after high-dose corticosteroid therapy (pulse therapy). High signal intensity areas on T2-weighted images (T2WI) were found in 25 of 26 cases. In 22 cases spinal level of clinically suspected lesions were involved in these high intensity areas. T1-weighted images (T1WI) after intravenous gadolinium with diethylenetriamine pentaacetic acid (Gd-DTPA) were also obtained and in 12 of 17 cases before pulse therapy, the symptoms and enhancement of lesions correlated well. The symptoms regressed in all cases after pulse therapy, and high-intensity areas in T2WI became less distinct. Gd-DTPA enhanced areas disappeared in 6 cases and became smaller in 3 of 12 cases. Additional pulse therapy in 3 cases effectively diminished the enhanced areas in these cases. In one patient who had repeated pulse therapy, MRI showed no enhancement. In two other patients who continued on decreased steroid dose had relapses, pulse therapy was therefore started again, providing a good recovery both clinically and radiologically. The changes of MRI findings and clinical course suggest that the pathological changes in spinal MS may be caused not only by demyelination but also by parenchymal edema. Clinical and MRI concordance was significantly better with Gd-DTPA enhanced T1WI than the high-intensity areas in T2WI. Contrast enhancement gives more information about disease activity and the reaction to therapy.

Cardiac preservation is enhanced in a heterotopic rat transplant model by supplementing the nitric oxide pathway.

Nitric oxide (NO) is a novel biologic messenger with diverse effects but its role in organ transplantation remains poorly understood. Using a porphyrinic microsensor, the first direct measurements of coronary vascular and endocardial NO production were made. NO was measured directly in the effluent of preserved, heterotopically transplanted rat hearts stimulated with L-arginine and bradykinin; NO concentrations fell from 2.1 +/- 0.4 microM for freshly explanted hearts to 0.7 +/- 0.2 and 0.2 +/- 0.08 microM for hearts preserved for 19 and 38 h, respectively. NO levels were increased by SOD, suggesting a role for superoxide-mediated destruction of NO. Consistent with these data, addition of the NO donor nitroglycerin (NTG) to a balanced salt preservation solution enhanced graft survival in a time- and dose-dependent manner, with 92% of hearts supplemented with NTG surviving 12 h of preservation versus only 17% in its absence. NTG similarly enhanced preservation of hearts stored in University of Wisconsin solution, the clinical standard for preservation. Other stimulators of the NO pathway, including nitroprusside, L-arginine, or 8-bromoguanosine 3',5' monophosphate, also enhanced graft survival, whereas the competitive NO synthase antagonist NG-monomethyl-L-arginine was associated with poor preservation. Likely mechanisms whereby supplementation of the NO pathway enhanced preservation included increased blood flow to the reperfused graft and decreased graft leukostasis. NO was also measured in endothelial cells subjected to hypoxia/reoxygenation and detected based on its ability to inhibit thrombin-mediated platelet aggregation and serotonin release. NO became undetectable in endothelial cells exposed to hypoxia followed by reoxygenation and was restored to normoxic levels on addition of SOD. These studies suggest that the NO pathway fails during preservation/transplantation because of formation of oxygen free radicals during reperfusion, which quench available NO. Augmentation of NO/cGMP-dependent mechanisms enhances vascular function after ischemia and reperfusion and provides a new strategy for transplantation of vascular organs.

New three-dimensional moving field radiation therapy for brain tumors.

A new modified rotation radiation method called "three-dimensional moving field radiation therapy" is described. The new method uses rotation in many planes while maintaining the the same isocenter to achieve a good spatial dose distribution. This delivers a high dose to tumors and spares the surrounding normal structures. This easy method can be carried out using the equipment for conventional rotation radiation therapy. The new method was superior to the one plane rotation radiation therapy using a physical phantom with film, a chemical phantom using the iodine-starch reaction, and a new biological model using tumor cells. Treatment of six brain tumors irradiated with total air doses of 50-60 Gy caused no hair loss or radiation necrosis.

A case of combined primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia.

A rare case of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia is described in a 49-year-old Japanese diabetic woman. Primary biliary cirrhosis was diagnosed by characteristic liver histology and positive serum mitochondrial antibody test. Ulcerative colitis was diagnosed by typical findings of barium enema and colonoscopy, negative fecal test for pathogens and compatible rectal histology. Chronic myelocytic leukemia was determined by representative hematologic findings and positive result for Ph1 chromosome. This is the first case with combination of primary biliary cirrhosis, ulcerative colitis and chronic myelocytic leukemia.

[Awareness and electromyograph biofeedback in the acquisition of control of a novel muscular activity].

Two experiments were conducted to examine what kind of awareness to the internal control process should be encouraged in order to effectively acquire the control of a novel muscular activity with electromyograph (EMG) biofeedback. The m. auricularis posterior (the muscle to draw an ear backward) was selected as the target muscle of this study. Experiment I investigated the relation between control ability and awareness of the target muscle activity. Results showed that subjects who were able to move their ears could be aware of the target muscle activity more precisely than those who were unable to do it. In experiment II, 32 undergraduate and graduate students who could not move their ears were required to activate their left m. auricularis posterior. Results provided evidences supporting the hypothesis that, in the initial stage of the acquisition of control, subjects who were encouraged to be aware of ways and feelings of striving (efferent process) and were given EMG feedback signals from the target muscle could acquire the control of the target muscle activity more effectively than those who were encouraged to be aware of a bodily feeling brought about by the striving (afferent process) and who were given no EMG feedback signals.

Influence of local hyperthermia on the healing of small intestinal anastomoses in the rat.

Peritoneal hyperthermia may have a role in limiting serosal metastatic disease. When applied to the peritoneal cavity immediately after surgery, it is important to know the optimum temperature, and to investigate the subsequent healing of intestinal anastomoses. To study the first problem, local hyperthermia was applied to the intestinal loop of rats for 30 min. Treatment at 46.0 degrees C or 45.0 degrees C resulted in 100 per cent and 90 per cent mortality respectively, but 100 per cent survival was obtained at 44.0 degrees C. To study the second problem rats with intestinal anastomoses were studied in three groups: group A, local hyperthermia (44.0 degrees C x 30 min) applied to the intestinal loop containing the anastomosis; group B, local hyperthermia (44.0 degrees C x 30 min) applied using saline supplemented with mytomycin C (10 mg/l); group C (controls) no thermal treatment was applied. Anastomotic healing was assessed by breaking strength and histological examination. On the third day after operation, the breaking strength of anastomoses decreased to the lowest values in each group, but no statistically significant differences were noted. On the seventh and 14th day, increased resistance to breaking developed in all three groups and was greatest in the thermally treated groups. Histological findings supported these results. Local hyperthermia up to 44.0 degrees C x 30 min had no adverse effects on the healing of intestinal anastomoses.

The effects of hyperthermia on the cell cycle of Ehrlich ascites cancer cells in vivo.

The effects of hyperthermia on the cell cycle of Ehrlich ascites cancer cells were studied, and these effects simultaneously evaluated in terms of prolonging the survival of test mice inoculated with tumor cells from heat-treated mice. DDY mice bearing Ehrlich ascites cancer cells were placed in a water bath at 37 degrees C, 39 degrees C, 41 degrees C, 42 degrees C. The heating of mice at 41 degrees C, 42 degrees C and 43 degrees C induced the accumulation of cancer cells at the G2M phase of the cell cycle with many cells exhibiting polyploidy (16 C). The extent of accumulation increased as the temperature of incubation was raised, however the interrupted cell cycle resumed 120 hours after heating. The retransplantation of cells from the heat-treated mice revealed that the mice which were inoculated with Ehrlich ascites cancer cells from mice heated at 43 degrees C survived longer, while the mice which were inoculated with Ehrlich ascites cancer cells from mice heated at 39 degrees C survived for only a slightly shorter time than those which were inoculated with cells from mice heated at 37 degrees C.

The influence of hyperthermia in vitro on the functions of peritoneal macrophages in mice.

Total-body hyperthermia (TBHT) as a treatment for cancer may lead to a reduction in the host's immunocompetence as a result of the direct effects of heat on the immune system. Thus, we studied the influences of hyperthermia in vitro on the function of peritoneal macrophages from mice. Peritoneal macrophages from C3H/HeN mice were heated in vitro for 3 hr at 37, 39, 40, 41 or 42 degrees C. After exposure to heat, the phagocytic ability of the macrophages, as well as results of the nitroblue tetrazolium (NBT) reduction test and the cytotoxicity test were examined. The changes in all these parameters showed almost the same pattern: a tendency for macrophage functions to be potentiated up to 40 degrees C, and a tendency towards inhibited functioning at temperatures above 41 degrees C. Although augmented functions of macrophages were observed after exposure to mild hyperthermia (less than 40 degrees C), the possibility of TBHT (42 degrees C)-induced inhibition of macrophage function must be further investigated in clinical trials of TBHT therapy for cancer.

[Intra-hepato-arterial chemotherapy combined with hyperthermic treatment: clinical results of metastatic cancer of the liver and effects on correct (but not at all necessary) hepatic blood flow].

In treating cancerous metastases to the liver, we combined hyperthermic treatment with chemotherapy via the intra-hepato-arterial injection (IHAI) of cis-diamminedichloroplatinum (II) plus 5-fluorouracil. The subjects were 14 patients having metastases to the liver: 3 from gastric cancer and 11 from colorectal cancer. In metastases of colorectal origin, the response rate (partial response) was 55%; the 1-year survival rate was 80%; the 50%-survival period was 23 months. The response rate and the 50%-survival period in metastases of gastric origin were 67% and 11 months, respectively. When IHAI chemotherapy was combined with hyperthermic treatment, antitumor effects were generated in 3 of 6 metastatic patients from colorectal cancer, who had received no benefit from the IHAI chemotherapy alone. Better results were produced by thermochemotherapy than by IHAI chemotherapy alone. Hepatic blood flow, which influences the antitumor effect of hyperthermic treatment or chemotherapy, was measured using the 133Xe clearance method. Over the long term, the hepatic blood flow, especially that of the portal-venous route, showed a decreasing tendency after repeated sessions of the present regimen. This fact suggests the increased retainability of arterial-injected carcinostatics in cancerous tissues.

Acquisition of self-control of a novel muscular activity with EMG and video feedback.

To examine the acquisition of voluntary control of a novel muscular activity from the initial stage to the self-control stage, the m. auricularis posterior, which had generally degenerated and had nearly lost its function of drawing an auricle backward in the human body, was selected as a target muscle to be studied. One female undergraduate student who could not move her auricles intentionally was required to activate her left m. auricularis posterior and underwent rest, pretest, training, and posttest sessions once a day for five days. At the subject's request, the electromyograph (EMG) from her left m. auricularis posterior on an oscillograph was provided for her as the feedback signal on each training trial. The picture of her left ear on television was handled in the same way. The EMG measures indicated that the subject could learn to activate her left m. auricularis posterior differentially. The number of training trials on which the subject requested the feedback signals suggested that EMG feedback signal was more useful to her than the video and that the usefulness of the feedback signals varied as the training sessions advanced. It was also concluded from analysis of the self-report data that the acquisition process of self-control of a novel muscular activity could be divided into at least four stages.

Hyperthermic peritoneal perfusion combined with anticancer chemotherapy as prophylactic treatment of peritoneal recurrence of gastric cancer.

We have conducted a clinical trial to evaluate the effectiveness of continuous hyperthermic peritoneal perfusion with mitomycin C (CHPP-M) as prophylactic treatment of peritoneal recurrence of gastric cancer. Between January 1983 and October 1985, 82 patients with macroscopic serosal invasion but no macroscopic peritoneal metastasis undergoing potentially curative resection of gastric cancer, were divided into two groups by random sampling: 42 patients were scheduled to receive CHPP-M, while 40 would not receive such treatment. The CHPP-M was administered immediately after closure of the abdomen following gastric resection, while the patient was still on the operating table under general anesthesia. The 5-year survival rate (71.5% of the patients in the CHPP-M group was higher than that (59.7%) of those in the control group. Although postoperative follow-up periods are not long enough, the longer survival obtained in the patients treated with CHPP-M should be emphasized, since no effective means of preventing peritoneal recurrence of gastric cancer is so far available.

The effect of angiotensin II on blood flow in tumours during localized hyperthermia.

The selective enhancement of drug delivery to tumours is an important factor in the effectiveness of thermochemotherapy as well as in standard normothermal chemotherapy. We have attempted to clarify experimentally using AH 100B tumour-bearing rats whether or not a selective increase in blood flow in tumours can be produced under specific conditions of local hyperthermia by administration of angiotensin (AGT II). AGT II (2 micrograms/kg/min) produced an elevation of blood pressure (ca. 150 mm Hg) when local hyperthermia, at 41, 43, and 45 degrees C, was induced. Furthermore, at 41 and 43 degrees C a selective increase in blood flow in tumours resulted from the AGT II-induced hypertension. By contrast, a decrease in blood flow was observed at 45 degrees C both in tumour and in muscle. These results indicate that AGT II-induced hypertension and the resultant selective increase in drug delivery to tumours during the initial phase of heating may result in an augmentation of the anticancer effects of thermochemotherapy.

[Acquisition of the control of a novel muscular activity by electromyograph biofeedback].

Present study aimed at to examine the process that people acquire the control of a novel muscular activity, of which they have had little experience of voluntary control, by electromyograph (EMG) biofeedback. Thirty undergraduate students who were unable to move their ears served as subjects. They were asked to give tension unto the m. auricularis posterior (the muscle to draw an ear backward). A factorial design was employed with two levels of strategy (transferring, non-transferring) and three methods of how to provide with the EMG feedback signals from the m. auricularis posterior during training session (no-feedback, biofeedback, intermittent biofeedback). The experiment was consisted of four sessions: rest, pre-test, training, and post-test. Main results were as follows: (1) Two groups, which subjects used the transferring strategy and the feedback signals, significantly increased the integrated EMG of the m. auricuralis posterior from pre- to post-tests. (2) Furthermore, the EMG-increase was significantly greater in one group, which feedback signals were intermittently given at every other training trial, than another group, which feedback signals were given at all trials. (3) It was also found that no increase of awareness to the muscular tension occurred despite the increase of EMG activity.

[Hepatic arterial chemotherapy combined with hyperthermia or arterial embolization in unresectable liver tumor].

Fifty-four patients with unresectable malignant liver tumors (14 of hepatocellular carcinoma, 40 of metastasis to the liver from gastric or colo-rectal cancer) were treated with intra-hepato-arterial (IHA) injections of cis-diamminedichloroplatinum (II) (CDDP) plus 5-fluorouracil (5-FU). In 32 of the patients, the liver tumors were detected synchronously with the diagnosis of the primary cancers, which were resected palliatively. Therapeutic schedules consisted of bolus injections of CDDP (50 mg/body/week) and 5-FU (250 mg/body/day) [Regimen I], and CDDP (50 mg/body/10-14 days) and 5-FU (100 mg/body/day) [Regimen II]. In 48 patients treated with IHA chemotherapy only, a partial response (PR) was obtained in 6 of 14 (43%) evaluable patients for Regimen I and in 11 of 30 (37%) patients for Regimen II. The dose-limiting factor for treatment with CDDP was bone marrow toxicity, but this toxicity was remarkably alleviated in Regimen II without any decrease in antitumor effectiveness. In 13 patients, other modalities, such as total-body hyperthermia (4 patients), radiofrequency capacitive local hyperthermia (5), and temporary arterial embolization (4), were combined with IHA chemotherapy. PR was obtained in 7 of 13 (54%) patients with the combined therapy. This combined therapy was efficacious in 7 patients in whom no desired results were obtained by IHA chemotherapy only. The survival rate was 50% at 12 months. IHA chemotherapy with CDDP plus 5-FU, especially when according to Regimen II, appears to be a strongly recommended strategy for treatment of unresected primary or metastatic liver tumor. Further, addition of the hyperthermia or the arterial embolization might enhance the antitumor effect of IHA chemotherapy.

Experimental studies of the effects of local hyperthermia on blood flow, oxygen pressure and pH in tumors.

The heat-induced environmental changes in tumor tissues are considered to influence the antitumor effect of hyperthermia or hyperthermochemotherapy, which is believed to complement the direct lethal effect of heat on tumor cells. The effects of local hyperthermia on the blood flow, oxygen pressure and pH in tissues were investigated using AH-100B tumor bearing rats, by immersing the tumor in a water bath at 41 degrees, 43 degrees and 45 degrees C. These parameters were measured in the marginal and deeper sites of the tumor mass, and in the normal muscle adjacent to the tumor. During immersion at 41 degrees C, blood flow in the tissue was increased at each site, and during immersion at 43 degrees C, tissue blood flow increased initially at each site, but decreased with time to rates below that of the unheated tissue. During immersion at 45 degrees C, the blood flow decreased markedly in each tissue. The changes in oxygen pressure and pH in each tissue were similar to those observed in the blood flow during localized heating at 41 degrees, 43 degrees and 45 degrees C. In local thermochemotherapy, the initial stage of hyperthermic treatment seems to be the most suitable time for administering carcinostatics, since it is the time when tumor blood flow has not yet decreased.

[Hyperthermia adjunct to surgery in the treatment of scirrhous carcinoma of the stomach].

In approximately 80% of patients with scirrhous carcinoma of the stomach, recurrence of cancers occurs even after potentially curative resection, and recurrence most frequently occurs in the form of peritoneal metastasis. Such recurrence may be attributable to possible intraperitoneal dissemination of malignant cells already present at the time of surgery. We performed intraoperative peritoneal cytology on patients with scirrhous carcinoma of the stomach. Free cancer cells were demonstrated in the Douglas cavity in 16 of 32 (50%) patients who underwent potentially curative gastrectomy. The postoperative 5-year survival rate was 23% in patients without detectable free cancer cells in the peritoneal cavity, compared with only 9% in patients with microscopic evidence of intraperitoneal free cancer cells. Therefore, we have applied hyperthermic continuous peritoneal perfusion (CHPP) on patients with scirrhous carcinoma of the stomach in order to develop a surgical adjuvant therapy effective for the prevention of recurrence of peritoneal involvement. The results obtained so far from our study have shown an increased 3-year survival rate of patients undergoing potentially curative gastrectomy, but no improvement of therapeutic outcome in terms of postoperative 5-year survival.

[Clinical results and problems of total-body thermochemotherapy].

The clinical results and problems of extracorporeally-induced total-body thermochemotherapy (TBHT) for recurrent cancer are presented. A total of 127 hyperthermic treatments were performed in 45 patients who had undergone unsuccessful conventional systemic anticancer chemotherapy. Partial response was observed in 11 of 34 evaluable patients (32%). In analysing the anticancer effects of TBHT according to cancer site, a high efficacy was observed in patients with their main tumor in the lung, liver and lymph nodes. The anticancer effects were most enhanced when TBHT was performed in combination with cisplatin and 5-fluorouracil. In order to augment the anticancer effects of TBHT, the choice of combined agents and administration timing are important. A useful method for determining the thermochemosensitivity of individual cancer cells to agents selected for drug treatment is the human tumor clonogenic assay. Furthermore, the usefulness of angiotensin II-induced hypertensive chemotherapy during TBHT for augmenting selective drug delivery to cancer tissue is stressed.

Prophylactic therapy for peritoneal recurrence of gastric cancer by continuous hyperthermic peritoneal perfusion with mitomycin C.

Continuous hyperthermic peritoneal perfusion (CHPP) with a solution that contains mitomycin C (CHPP-M) has been clinically introduced as a prophylactic treatment for peritoneal recurrence of gastric cancer with serosal invasion. Two studies, each with a treated and a control group, were performed. In the historical control study the postoperative 3-year survival rate of patients (73.7%) in the treated group (n = 38) was significantly higher than the survival rate (52.7%) of those in the control group (n = 55) (P less than 0.04). In the random control study the survival rate (83%) of patients in the treated group (n = 26) was also higher than that (67.3%) of those in the control group (n = 21) in the 30 months that followed gastric surgery. However, there was no significant difference. In the historical control study with respect to the postoperative complications, anastomotic leak was observed in 8.5% of patients who were given CHPP-M and 12.8% patients who did not have CHPP-M. In the random control study anastomotic leak was observed in 3.1% of patients who had CHPP-M and 7.1% of patients who did not have CHPP-M. The incidence of adhesive ileus in patients having CHPP-M did not increase in historical or random control groups. Postoperative prolonged intestinal paresis or chemical peritonitis were not induced by CHPP-M. These results indicate that CHPP-M is a simple, safe, and readily available prophylactic therapy for peritoneal recurrence that may follow gastric cancer surgery.