Shoji Suga

Phase I study of recombinant human tumor necrosis factor

SummaryA phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1x105 units/m2. The dose was escalated up to 16x105 units/m2 according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16x105 units/m2. The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12x105 units/m2 when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5x105 units/m2.

Endoscopic ultrasonography with color Doppler function in the diagnosis of rectal variceal bleeding.

Extraesophagogastric variceal bleeding in patients with portal hypertension is rare, but has been reported after endoscopic injection sclerotherapy (EIS) for esophageal varices. Here, we report rectal variceal hemorrhage following EIS. Endoscopic ultrasonography with color Doppler function (EUSCD) was useful for the diagnosis of rectal varices and complete hemostasis was obtained with EIS. A review of the literature since 1980 revealed a total of 15 patients, including ours, with extraesophagogastric variceal bleeding following EIS. This suggests EIS is the principal emergency treatment for bleeding rectal varices.

Eleven-year survey of safety and efficacy of endoscopic injection sclerotherapy using 2% sodium tetradecyl sulfate and contrast medium.

We conducted a retrospective 11-year survey to evaluate the post-treatment course in 285 patients with esophagogastric varices following administration of endoscopic injection sclerotherapy as an emergency, elective, or prophylactic procedure using freshly prepared 2% sodium tetradecyl sulfate not containing benzyl alcohol. These agents were injected into the varices and the supplying veins under fluoroscopic observation, usually in a single treatment. In all patients the variceal size was greatly reduced following one treatment. The amount of sclerosant necessary to fill the varices and the supplying veins varied widely among the patients. Acute variceal bleeding was controlled in 80 (96.4%) of the 83 patients, and the risk of rebleeding during the first month was 0.0548 in the emergency procedures. The serious complication of perforation was observed in one patient. The cause of death was established in the 122 patients who died and included esophageal variceal bleeding in eight (6.6%) and gastric variceal bleeding in one (0.8%). The overall 50% survival period was 5 years and 4 months. Multivariate analysis disclosed that the factors with the greatest negative effect on survival were poor hepatic status and the presence of hepatocellular carcinoma. The method of preparation and the procedure itself may be considered safe and effective in the treatment of esophagogastric varices.

Color Doppler-enhanced Endoscopic Ultrasonographic Diagnosis of Upper Gastrointestinal Submucosal Lesions

Abstract: We investigated the usefulness of color Doppler‐enhanced endoscopic ultrasonography for the assessment of upper gastrointentinal tract submucosal lesions. The subjects were 61 patients with endoscopically detected lesions : five extraluminal, four solitary varices, 26 leiomyomas, seven leiomyosarcomas, five aberrant pancreata, five cysts, three granular cell tumors, three lipomas, two schwannomas and one fibroma. Lesions were confirmed by surgery, biopsy or angiography, as appropriate. The ultrasonographic appearance of the lesions and their locations within the five‐layered structure of the wall are described. For leiomyomatous tumors less than 5 cm including leiomysarcoma, the presence of turbulent, pulsatile flow, as demonstrated on fast Fourier transform analysis, was associated with a sensitivity of 100% (7/7) and a specificity of 77.8% (7/9). We speculate that the flow pattern is related to abnormal vessels in the malignant tumors. Evaluation of the ultrasonographic characteristics of leiomyomatous tumors utilizing the pulsatile wave pattern may allow the diagnosis of leiomyosarcoma. Color Doppler‐enhanced endoscopic ultrasonography is potentially useful in the preoperative diagnosis of submucosal lesions involving the upper gastrointestinal tract.

Studies on the designing of chemotherapy for gastric cancer in man, based on the tumor tissue concentration of anticancer agents

Summary5-fluorouracil analogs investigated in this study include a combination of uracil and Ftorafur (UFT), Ethyl (±)-t-butoxy-5 -fluoro-hexahydro-2,4-dioxopyrimidine r-5-carboxylate (TAC-278), and 5′-deoxy-5-fluorouridine (5′-DFUR). In a total of 45 patients with gastric cancer, tumor tissue level of 5-fluorouracil (5-FU) was determined at 2, 4, 6, 8, and 12 hours following the oral administration of drug, using a resected stomach specimen as material. As a result, it was demonstrated that oral administration of 200 mg/m2 of UFT maintained above 0.05jΜg/g (minimum inhibitory concentration: MIC) of 5-FU in tumor tissues over 12 hours in 11 of 13 patients. On the contrary, 133 mg/m2 of TAC-278, and 200mg/m2 or 300mg/m2 of 5′-DFUR (which is activated by thymidine phosphorylase in man) did not produce an effective 5-FU concentration in tumor tissues. Serum 5-FU level was high in order of TAC-278, UFT, and 5′-DFUR. Clinical response rates obtained with UFT (200mg/m2 twice a day), or TAC-278 (133–200mg/m2, 3 times daily) were 27.5% (49 of 178 cases), and 8.3% (3 of 36 cases, by Koyama et al.), respectively. Fisher’s direct probability test revealed that there was a significant difference (p<0.05) between them in the response rate. It was considered that the measurement of concentration of anticancer drugs in tumor tissues might provide us useful information for the designing of chemotherapy of gastric cancer.

Relationship between initial clinical findings and prognosis of gastric ulcers

Most gastric ulcer patients can be successfully treated by medical regimen, although a failure may be encountered in some instances and the recurrence not infrequently. This report describes the clinical course of gastric ulcer particularly in relation to its characters at the first examination. Three hundreds and fifty-five patients with gastric ulcer were studied. Cure rate of the present series was 24% within a month, 59% within 2 months, 73% within 3 months and 84% within 6 months. When age factor was considered, however, the cure rate within 3 months was 83% in ulcer patients younger than 29 years old, 83% in the thirties, 64% in the forties, 65% in the sixties and 78 in the olders than 70 years. Ulcers in the hyper and normoacidics healed most rapidly, the same cure rate of 79% being obtained within 3 months. In contrast, it was 48% and 69% in the achlorohydrics and hypoacidics, respectively. When cure rate was examined in relation to the initial X-ray findings, 76% of the ulcers without and 74% of the ulcers with radiated mucosal folds healed within 3 months; however, only 58.5% of the ulcers associated with marked radiated mucosal folds healed. Seventy-six per cent of the ulcers smaller than LOcm in diameter on roentgenograms, and 69% of the ulcers larger than 1.Ocm in diameter healed within 3 m o n t h s . Similar cure rate were also observed when ulcers were divided into two groups, i .e. ones shallower than 0.5 cm and the others deeper than 0.5 cm. The three month-cure rate, obtained according to the characters of ulcer base, was 76%, 73% and 65% in faintly coated, thickly coated and blood-tinged or dirty necrotic base, respec. tively. When the presence or absence and the degree of marginal elevation were considered, the 3-month-cure rate was 85% in the ulcers without the elevation and 54% and 51% in the ulcers with moderate and marked elevation. The 3-m0nth-cure rate in the ulcers without Henning sign was 84% as compared with 66% in those with Henning sign. Among the 106 patients who were reexamined within a year af ter healing, 35% were found to have recurred ulcers. Among these cases, however, the recurrence rate was 31% in those which required less than 3 months for the first heal ing and 60% in those which required more than 3 but less than 6 months. However, the recurrence rate appeared steadily to increase as the time elapsed after the first healing, as shown by 52% and 56% within 2 years and 3 years after the first healing. Similarly, a relation of the initial clinical findings to recurence rate was also investigated but no particular relation was noted.

Lactic dehydrogenase activity in gastric juice of patients with gastric cancer, gastric ulcer, duodenal ulcer and gallstone

Gastric biopsies were preformed on 93 patients with various gastric disorders and 6 or 7 mucosal specimens were obtained from the gastric body of the each patients. Several biopsy specimens were homogenized and offered for assay of acid and alkaline phosphodiesterase activities. The results of enzymic determination were compared with gastric acidity, gastrocamera and gastric biopsy findings. The Following results were obtained: 1. High activities of mucosal phosphodiesterase were more frequently observed in anacidic group. 2. It was seen that some correlation existed between the degrees of mucosal atrophic change and the mucosal enzyme activities. 3. No significant difference was found between the mucosal acid and alkaline phosphodiesterase activities. 4. Both phosphodiesterase activities were relatively low in gastric ulcer and high in gastric cancer or polyp, It was perhaps caused of mucosal atrophic changes.