Yoshimasa Miyauchi

Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium

Twenty‐four patients with various solid tumors including metastatic liver cancer and cancer of the lung, gallbladder, and pancreas were treated with a lipophilic macromolecular drug, copoly(styrene‐maleic acid) conjugated neocarzinostatin (SMANCS). The drug was dissolved in a lipid contrast medium Lipiodol and administered by catheterizing the respective feeding arteries under x‐ray monitoring. The advantages of this therapy include: (1) selective deposition of Lipiodol with the anti‐cancer drug in the target tumor, (2) a pronounced and long‐lasting anti‐cancer effect, (3) enhanced visulization of the tumor on x‐ray examinations for a prolonged period which also facilitated the long‐term follow‐up, (4) semiquantitative evaluation of the dosage regimen by x‐ray examination before further administration, (5) general applicability due to procedural simplicity, and (6) little side effect. Since the amount of Lipiodol and SMANCS used per administration for a patient (1.0–5.0 ml; 1.0–5.0 mg) was far less that the anticipated toxicity (LD50 of Lipiodol = 95 ml/60 kg, dog, intravenously; and that of SMANCS = 3.4 mg/kg, mouse, IV), no deleterious effects to such critical organs as the brain, heart, lung, liver, or kidneys were observed upon radiologic and general clinical examination.

Studies on anticancer treatment with an oily anticancer drug injected into the ligated feeding hepatic artery for liver cancer

In six adult patients with nonresectable liver cancer, as well as in mature New Zealand white rabbits with implanted VX2 carcinoma in the liver, the artery feeding the hepatic lobe with the malignant lesion was ligated, and an oily contrast medium (Lipiodol Ultra‐Fluid) was injected into the hepatoproximal lumen of the ligated artery of the liver with carcinoma. The oily contrast medium was detected in all the branches of the artery injected, and thereafter was found only in tumor tissue for 7 days experimentally and for 16 months clinically. Taking advantage of this phenomenon, the therapeutic effect of the injection of an oily anticancer drug (bleomycin oil suspension) into the hepatoproximal lumen of the ligated hepatic artery was investigated in rabbits with VX2 carcinoma of the liver. The mean concentration level of bleomycin in the tumor tissue was 2.4 ± 0.4 μg/g 1 week after the injection of bleomycin oil suspension (1.5 mg potency/kg) in three rabbits. However, its concentration level in nontumorous tissue of the liver was undetectably low in two rabbits, but 0.6 μg/g in the third rabbit. The group of rabbits receiving an injection of bleomycin oil suspension into the ligated artery had a significantly longer mean survival time than those of the experimental group receiving an injection of saline solution of bleomycin into the ligated artery as well as the three other groups treated (P < 0.02, N = 5 for each group). It may be concluded that an oily anticancer drug injected into the hepatoproximal lumen of the ligated hepatic artery can intensify the anticancer effects of a ligation of the hepatic artery for liver cancer. Cancer 52:2193‐2200, 1983.

Combination of intraoperative radiation with resection of Cancer of the pancreas

SummaryThe utility of intraoperative radiation therapy (IORT) as an adjuvant to the surgical resection of pancreatic cancer was studied. In 1976, as our first trial with this combined therapy, we applied IORT with 30 Gy of electron beam with 8 MeV to 15 patients to prevent local recurrence around the celiac axis and superior mesenteric artery after standard pancreatectomy. However, the combined therapy did not show an improvement in survival rate as compared to that of 19 patients with standard operation alone. Autopsies of three patients with the combined therapy did not show involved lymph nodes in the radiation field, but did show local recurrence around the aorta outside the radiation field.By comparison, we performed extended operation without IORT on nine patients, with almost complete dissection of the lymph nodes around the aorta, from the diaphragm to the level of the inferior mesenteric artery. This extended surgery did not improve survival time, and autopsy showed local recurrence in spite of the dissection of lymph nodes.Therefore, since 1984, we have performed IORT with a dose of 30 Gy, 9 MeV, and an extended radiation field from the diaphragm above to the inferior mesenteric artery below, following extended operation on 14 patients. The five-year cumulative survival rate of these cases was 33.3%. Four autopsies showed improvement of local control rate. No radiation-related complications were noticed postoperatively in patients who underwent extended IORT following pancreatectomy. We were encouraged to continue this approach for the cure of pancreatic cancer.

Glutamine-Supplemented Parenteral Nutrition Improves Gut Mucosa Integrity and Function in Endotoxemic Rats

The effects of glutamine-supplemented parenteral nutrition on protein metabolism, small intestinal mucosal metabolism, morphology, and barrier function were studied in endotoxin-treated rats. Forty-six male Wistar rats were randomized to two groups of 23 animals each and received total parenteral nutrition solutions supplemented with either glutamine (GLN group) or glycine (GLY group) at 2% wt/vol. Endotoxemia was induced by continuous intravenous infusion of endotoxin at a dose of 2 mg/kg per day throughout the 4-day study period. The GLN group had a less-negative cumulative nitrogen balance (-14.0 +/- 132.8 mg of nitrogen in the GLN group and -86.8 +/- 161.7 mg of nitrogen in the GLY group, p < .05) and less cumulative excretion of urinary 3-methylhistidine (2910 +/- 593 nmol) than the GLY group (4447 +/- 933 nmol, p < .01). Jejunal mucosal glutaminase activity and the arterio-portal venous blood glutamine concentration differences were significantly higher in the GLN group compared with the GLY group (15.6 +/- 2.3 vs 11.1 +/- 1.9 mumol/g per minute, p < .05, and 181 +/- 52 vs 147 +/- 36 nmol/mL, p < .05, respectively). The morphology of the jejunal mucosa in the GLN group was significant for having greater mucosal weight (23.4 +/- 3.1 vs 17.6 +/- 2.5 mg/cm), villus height (445 +/- 75 vs 357 +/- 57 microns), crypt depth (197 +/- 34 vs 161 +/- 28 microns), and wall thickness (751 +/- 77 vs 648 +/- 102 microns) than the GLY group (p < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of ischemia and reflow-induced liver injury by an SOD derivative that circulates bound to albumin

Ischemia followed by reflow often results in tissue injury. Although reactive oxygens seem to play an important role in the pathogenesis of postischemic reflow-induced tissue injury, the mechanism and an efficient way to inhibit oxidative injury are not known. We studied the mechanism by which hepatic transport function was inhibited by a transient occlusion followed by reflow of the portal vein and hepatic artery by using a superoxide dismutase (SOD) derivative (SM-SOD) which circulates bound to albumin with a half-life of 6 h. Occlusion of the hepatic vessels for 20 min followed by reflow for 60 min significantly inhibited transhepatic transport of cholephilic ligands, such as bromosulfophthalein (BSP) and taurocholic acid. Intravenous administration of SM-SOD markedly inhibited the reflow-induced decrease in transhepatic transport of these ligands. Thiobarbituric acid - reactive metabolites (TBAR) in the liver and plasma remained unchanged during occlusion and reflow, while TBAR in the bile increased significantly. Intravenous injection of SM-SOD inhibited the reflow-induced increase in biliary TBAR. Xanthine oxidase activity in plasma also increased during occlusion and reflow by an SM-SOD-inhibitable mechanism. Polymorphonuclear leukocyte-dependent chemiluminescence of the peripheral blood remained unchanged during occlusion, but increased markedly with time after reflow. SM-SOD also inhibited the increase in chemiluminescence almost completely. These and other results suggested that the superoxide radical and/or its metabolite(s) might play an important role in the pathogenesis of the reflow-induced liver injury and that SM-SOD might be useful for studying the mechanism for tissue injury caused by oxygen toxicity.

Insulin-like Growth Factor-I Prevents Gut Atrophy and Maintains Intestinal Integrity in Septic Rats

BACKGROUND The effects of insulin-like growth factor-I (IGF-I) on gut metabolism, structure, and barrier function as well as its general anabolic effects were investigated in septic rats. METHODS Thirty-three male Wistar rats that underwent cecal ligation were randomly divided into one of the following two groups: (1) received only total parenteral nutrition (control group) or (2) received total parenteral nutrition with IGF-I (IGF group) at a dose of 4 mg/kg/d for 3 days. RESULTS During the 3-day period, the body weight of rats in the IGF group increased significantly over that of rats in the control group (17.1 +/- 2.6 vs 5.8 +/- 4.6 g, p < .01). The total and free IGF-I plasma concentrations were significantly higher in the IGF group than in the control group. The cumulative nitrogen balance was significantly more positive for the IGF group (423.9 +/- 24.3 mg of nitrogen) than for the control group (290.8 +/- 26.0 mg of nitrogen). The weights of thymus, spleen, and kidneys were significantly increased in the IGF group compared with weights in the control group. Treatment with IGF-I improved the gut mucosal weight in all regions of the gut examined, including duodenum, jejunum, ileum, and colon. Histologic and biochemical analyses of the jejunum showed greater villus height and crypt depth and higher mucosal DNA and protein content in the IGF group. The arterial concentration of endotoxin was not significantly different between the two groups, whereas its level in portal blood was significantly lower in the IGF group (23.2 +/- 9.9 pg/mL) than in the control group (95.5 +/- 37.9 pg/mL), an indication that IGF-I treatment decreased the amount of endotoxin that traversed the gut barrier. CONCLUSIONS These results indicate that IGF-I can improve gut metabolism and reduce mucosal atrophy and that it may play a role in maintaining the gut barrier function in sepsis.

Anticancer effects of arterial administration of the anticancer agent SMANCS with lipiodol on metastatic lymph nodes

A new method of arterially administering an oily anticancer agent was successfully established for the selective targeting of metastatic lymph nodes. A high molecular weight anticancer agent, a conjugate of copolymer (styrene maleic acid) to neocarzinostatin (SMANCS) was prepared in our laboratory and dissolved in a lymphographic oily contrast medium, Lipiodol (SMANCS/Lipiodol). SMANCS/Lipiodol was administered intraoperatively to eight patients with colorectal cancer and preoperatively to one patient with gastric cancer with lymph node metastases. In six of the patients with colorectal cancer, the drug was administered via an artery and in the other two patients the drug was injected into the wall of the colon near the primary cancer. In the patient with gastric cancer, the drug was administered via the left gastric artery. Delivery of the drug to the lymph nodes was examined roentgenologically and the anticancer effect was examined histologically. The results showed that SMANCS/Lipiodol could be delivered to the metastatic lymph node via the artery, but it could not be delivered to the metastatic lesion of the lymph node via the lymphatic route. In the patient with gastric cancer, SMANCS/Lipiodol preoperatively administered via an artery was found to remain selectively in a metastatic lymph node and an anticancer effect was histologically proved in all three of the metastatic lymph nodes.

Surfactant therapy for pulmonary edema due to intratracheally injected bile acid.

Intratracheally injected bile acid has been shown to produce severe pulmonary edema. We investigated the therapeutic effect of an exogenous surfactant for aspirated bile acid. Anesthetized rabbits were injected intratracheally with 1 ml/kg body weight of taurocholic acid, diluted to 0.6% with normal saline solution. After the injection of taurocholic acid, the Pao2 values decreased, the Paco2 values increased, and abnormal shadows appeared in chest x-rays. After surfactant injection, the rabbits improved, but pulmonary edema recurred after one hour. After additional injection of the surfactant, the improved condition was sustained for 6 h. All animals in the untreated group died within 5 h and were shown to have severe pulmonary edema. Conversely, microscopic examination revealed no pulmonary edema in animals surviving 6 h after surfactant treatment. Thus, exogenous surfactant can prevent damage to the lung caused by intratracheally injected bile acid.

A method for safe pancreaticojejunostomy

We devised a new technique to increase the safety of pancreaticojejunostomy in patients with an extended operation for pancreatic cancer. This new pancreaticojejunostomy was created by end-to-side anastomosis with four layers about 7 cm distal to the jejunal stump. The cut surface of the pancreas was placed on the seromuscular coat of the ventral aspect of the jejunum to cover the posterior surface of the anastomosis, and the anastomosis between the pancreas and the jejunum was created using fibrin glue. The pancreatic duct was intubated with a silicone tube, and its stenting tube was brought out through a opening in the jejunum. The anterior surface of the pancreaticojejunostomy was covered by the proximal jejunum as a serosal patch. We used this technique in seven patients. No patient developed an anastomotic leak or any other complication. The anastomosis is covered by the jejunum and is not open to the peritoneum. This new technique of pancreaticojejunostomy may reduce the risk of pancreatic leak, especially when an extended operation is performed.

Endotoxemia and Intestinal Mucosal Dysfunction after the Relief of Obstructive Jaundice by Internal and External Drainage in Rats

We studied the effects of external and internal biliary drainage on the development of endotoxemia in a rat model of obstructive jaundice. Male Donryu rats were allocated to four groups: sham operation, common hepatic bile duct ligation (BDL), internal or external biliary drainage after BDL, and biliary drainage after BDL with oral endotoxin administration. Portal and systemic blood endotoxin concentrations were measured and the histomorphology of the intestinal mucosa was examined. Portal endotoxemia was observed 7 days after BDL and both portal and systemic endotoxemia were observed after 14 days. Portal endotoxemia was reversed by both internal and external biliary drainage and systemic endotoxemia was prevented. The ratio of villous height to crypt depth in the mucosa of the terminal ileum was decreased in rats with external drainage. Oral administration of endotoxin induced marked disruption of the mucosal epithelium in rats with external biliary drainage, but not in rats with internal biliary drainage. Significant increases in portal and systemic blood endotoxin concentrations were observed only in the external drainage group after oral endotoxin administration. The relief of biliary obstruction effectively relieved portal endotoxemia. External biliary drainage, however, has the potentially deleterious effect of disrupting the intestinal mucosa, which may promote the development of endotoxemia. These findings have implications for the use of biliary drainage procedures to reduce postoperative complications in jaundiced patients.