Mitsuo Ninomiya

Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma

Background. In patients with hepatocellular carcinoma (hepatoma), the rate of recurrent and second primary hepatomas is high despite surgical resection and percutaneous ethanol-injection therapy. We developed an acyclic retinoid, polyprenoic acid, that inhibits hepatocarcinogenesis in the laboratory and induces differentiation and apoptosis in cell lines derived from human hepatoma. In a randomized, controlled study, we tested whether the compound reduced the incidence of recurrent and second primary hepatomas after curative treatment. Methods. We prospectively studied 89 patients who were free of disease after surgical resection of a primary hepatoma or the percutaneous injection of ethanol. We randomly assigned the patients to receive either polyprenoic acid (600 mg daily) or placebo for 12 months. We studied the remnant liver by ultrasonography every three months after randomization. The primary end point of the study was the appearance of a histologically confirmed recurrent or new hepatoma. Results. Treatment with polyprenoic acid significantly reduced the incidence of recurrent or new hepatomas. After a median follow-up of 38 months, 12 patients in the polyprenoic acid group (27 percent) had recurrent or new hepatomas as compared with 22 patients in the placebo group (49 percent, P = 0.04). The most striking difference was in the groups that had second primary hepatomas-7 in the group receiving polyprenoic acid as compared with 20 in the placebo group (P=0.04 by the log-rank test). Cox proportional-hazards analysis demonstrated that as an independent factor, polyprenoic acid reduced the occurrence of second primary hepatomas (adjusted relative risk, 0.31 ; 95 percent confidence interval, 0.12 to 0.78). Conclusions. Oral polyprenoic acid prevents second primary hepatomas after surgical resection of the original tumor or the percutaneous injection of ethanol.

Inhibitory Effects of (—)‐Epigallocatechin Gallate on Spontaneous Hepatoma in C3H/HeNCrj Mice and Human Hepatoma‐derived PLC/PRF/5 Cells

The inhibitory effect of (—)‐epigallocatechin gallate (EGCG), a main constituent of Japanese green tea, on spontaneous hepatoma in C3H/HeNCrj mice was investigated. A total of 72 mice were divided into three groups; the control group without EGCG, and two experimental groups receiving 0.05% (w/w) or 0.1% EGCG in drinking water. EGCG reduced the incidence of hepatoma‐bearing mice from 83.3% (control) to 56.0% (0.05% EGCG) and 52.2% (0.1% EGCG), and also reduced the average number of hepatomas per mouse from 1.83 (control) to 0.72 (0.05% EGCG) and 0.91 (0.1% EGCG) at week 65. Ridit analysis of the distribution of the number of hepatomas in each group revealed that EGCG significantly increased the rate of mice without hepatoma in the two EGCG groups as compared to the control. EGCG did not affect body weight gain, food consumption or any serum biochemical parameter. EGCG inhibited the growth and secretion of α‐fetoprotein by human hepatoma‐derived PLC/PRF/5 cells without decreasing their viability. These results indicate that EGCG may be a practical, nontoxic preventive agent against human hepatoma.

Inhibition of ornithine decarboxylase induction by retinobenzoic acids in relation to their binding affinities to cellular retinoid-binding proteins.

SummaryRetinobenzoic acids induce differentiation of human promyelocytic leukemia cells (HL-60). Like retinoic acid, 14 retinobenzoic acids inhibited the induction of ornithine decarboxylase (ODC) by teleocidin in mouse skin. The mechanism(s) of inhibition of ODC induction by 7 retinobenzoic acids, Am 80, Am 81, Am 580, Am 590, Am 68, Sa 80, and Ch 55 was compared with those by all-trans-retinoic acid and the arotinoid compound 19. Application of 114 nmol of Am 80, Am 81, Am 580, Am 590, Am 68, Sa 80, or Ch 55, 10 min before 11.4 nmol of teleocidin, resulted in 76.7%, 82.0%, 76.2%, 28.3%, 48.4%, 58.6%, and 85.1% inhibition of ODC induction, respectively. Since all-trans-retinoic acid and compound 19 were also inhibitory, we determined whether retinobenzoic acids bind to cellular retinoic acid-binding protein (CRABP) isolated from bovine adrenal glands. Am 80 and Am 580 inhibited the specific binding of 3H-retinoic acid to CRABP, but also showed less affinity than authentic unlabeled retinoic acid and compound 19. Am 81, Am 590, Am 68, Sa 80, and Ch 55 at up to 10 μM were not effective competitors of the binding of either 3H-retinoic acid or 3H-retinol. These results suggest that the inhibition of ODC induction can be mediated by pathways that do not involve CRABP or the cellular retinol-binding protein.

Inhibitory effects of synthetic acidic retinoid and polyprenoic acid on the development of hepatoma in rats induced by 3'-methyl-N, N-dimethyl-4-aminoazobenzene.

SummaryA study was conducted to investigate the inhibitory effects of acidic retinoid (trimethylmethoxyphenyl analog of retinoic acid ethylester or TMMP) and polyprenoic acid (3, 7, 11, 15tetramethyl-2, 4, 6, 10, 14-hexadecapentaenoic acid or E-5166) on the development of hepatoma induced by 3′-methyl-N, N-dimethyl-4-aminoazobenzene (3′-MeDAB) in rats. Morphometric analysis of liver specimens was employed to evaluate the antitumor effects of the compounds in detail, and revealed significant decreases in the number and area of tumors in the TMMP- and E-5166-treated groups. As for adverse effects, retarded growth and marked hypertriglyceridemia were observed only in TMMPtreated rats. During the hepatocarcinogenesis, cellular retinoid-binding protein, F-type or CRBP(F) and cellular retinoic acid-binding protein or CRABP newly appeared in the tumor tissue, particularly in hyperplastic nodules which are the precancerous state of hepatoma. These results suggest that the polyprenoic acid is a good candidate for clinical chemoprevention of hepatoma, targetting its precancerous stage when intracellular receptors for acidic retinoid have emerged.

Inhibitory Effect of Sarcophytol A on Development of Spontaneous Hepatomas in Mice

The inhibitory effect of sarcophytol A, a cembrane‐type diterpene isolated from a marine soft coral, Sarcophyton glaucum, on development of spontaneous hepatomas was investigated in C3H/HeNCrj mice. A total of 80 mice were divided equally into two groups. The experimental and control groups were given basal diets with and without 0.01% sarcophytol A, respectively. At week 65 of the experiment, mice were examined for hepatomas. The percentages of hepatoma‐bearing mice of the subgroup with three or more tumors and the tumor diameters of the group treated with sarcophytol A were smaller than those of the control group. Ridit analysis revealed that these differences were statistically significant. The body weight gain, and the food intake were not significantly different between these two groups. Analysis of blood serum revealed that feeding the diet containing 0.01% sarcophytol A for 65 weeks did not show any adverse effects. These results suggest that sarcophytol A inhibits the development of spontaneous hepatomas without toxicity, and should he considered as a possible cancer chemopreventive agent for hepatomas in humans.

Human papillomavirus type 16-positive esophageal papilloma at an endoscopic injection sclerotherapy site

Human papillomavirus infection is important for both the development of papilloma and the progression of the papilloma-carcinoma sequence in the cervix, larynx, lung, and colon. Esophageal squamous cell papilloma is rare but important as a possible precancerous lesion. Esophageal papilloma has previously been thought to develop mainly as a result of chemical irritation by chronic gastroesophageal reflux. However, a few recent studies suggested a role for papillomavirus infection in esophageal tumorigenesis, although the exact route of transmission and invasion of the virus has not been fully elucidated. A case of esophageal squamous papilloma at the site of endoscopic injection sclerotherapy (EIS) for varices is reported. Papilloma development was followed up clinically during a 2-year period, and the papilloma was removed by endoscopic mucosal resection. Histological examination of the tissue confirmed the diagnosis of squamous cell papilloma. DNA analysis of the tumor showed integration of papillomavirus type 16 but not types 18 and 33. The surrounding normal mucosa did not contain any of the three virus types. Injury such as ulceration resulting from EIS may have provided a locus susceptible to the viral infection. The clinical course after EIS should be monitored carefully to detect papilloma formation.

Plasma retinol transport system and taste acuity in patients with obstructive jaundice

Preliminary Topics 1. Efficacy and safety of ESWL: Experimental data 2. Indication of ESWL: Patients and gallstones 3. Gallstone imaging 4. Clinical data on ESWL 5. Comparison of various lithotriptors 6. Adjuvant bile acid therapy 7. Recurrence of gallstones after successful ESWL: Prevention and management 8. Use of ESWL for bile duct stones 9. Other biliary lithotripsy: Percutaneous and endoscopic approachesA study was conducted to elucidate the correlation between the plasma retinol transport system and taste acuity in patients with obstructive jaundice (OJ). Plasma levels of retinol, retinol-binding protein (RBP), transthyretin (TTR) and holo-RBP (retinol-RBP complex unbound to TTR), as well as the threshold of taste acuity, were determined in 8 cases with OJ (6 cases with common bile duct cancer and 2 cases with pancreas head cancer) and in 20 apparently healthy volunteers. These parameters were also measured serially in patients with OJ before and after percutaneous transhepatic biliary drainage (PTBD). Plasma levels of retinol, RBP and TTR were significantly decreased in every patients with OJ as compared with healthy controls, whereas changes in holo-RBP levels were not consistent. Taste acuity was found to be reduced in patients with decreased holo-RBP levels, while the acuity was preserved well in patients whose holo-RBP levels remained normal. Impaired taste acuity was rapidly improved in every patients after treatment with PTBD, significantly correlating with the recovery of plasma RBP and holo-RBP levels, and with the reduction of plasma total bilirubin levels. These results suggest that taste acuity is affected by the plasma retinol transport system, including serum levels of holo-RBP, from which retinol is delivered, presumably through a receptor-mediated manner, to the taste buds.

The clearance rate of retinyl ester from plasma distinguishes patients with idiopathic portal hypertension from those with liver cirrhosis

Abstract A study was conducted to investigate alterations in the clearance rate of chylomicron remnant from plasma in patients with liver cirrhosis and idiopathic portal hypertension. Chylomicron remnant was labeled with retinyl palmitate which was orally administered at a dose of 0.14 mg/kg body weight. Blood samples were drawn serially up to 6 h after the oral administration, and plasma retinyl palmitate levels were determined by high performance liquid chromatography. Kinetics of plasma disappearance curves of retinyl palmitate were analyzed assuming a three compartment model which consists of chylomicron, chylomicron remnant and low density lipoprotein (LDL) pools. Retinyl palmitate was found to be removed from plasma through the latter two compartments, which fractional efflux rate constants were designated as 12 and 13, respectively. 12 was reduced significantly in both liver cirrhosis (1.4 × 10 −2 /min, median, n = 30) and idiopathic portal hypertension (3.1 × 10 −2 , n = 5) as compared with the control (4.0 x 10 −2 , n = 6).13 in idiopathic portal hypertension (6.8 × 10 −3 /min) was significantly elevated, while that in liver cirrhosis (1.9 × 10 −3 ) was decreased when compared to the control (5.0 × 10 −3 ). Such opposite alterations in l 3 may be brought about by the decrease in the number of the responsible receptor (possibly apoB/E receptor) in liver cirrhosis and by the up-regulation of the receptor in idiopathic portal hypertension. The alterations in l 3 are also suggested to help distinguish idiopathic portal hypertension from liver cirrhosis.

Effect of Endoscopic Injection Sclerotherapy on Acute Bleeding from Esophageal Varices in Cirrhotic Patients with Advanced Hepatocellular Carcinoma

Abstract: The effect of endoscopic injection sclerotherapy (EIS) on acute bleeding from esophageal varices in sixteen cirrhotic patients with advanced hepatocellular carcinoma (HCC) was analysed using the Cox proportional hazard model. Only EIS was found to have independently and significantly affected the survival rate (P = 0.0385), while clinical variables such as the extent of HCC, the presence of ascites and portal thrombosis, laboratory data and therapeutic modalities other than EIS showed no significant effect. EIS should be considered one of the treatments of choice when a cirrhotic patient with advanced HCC has acute bleeding from his/her esophageal varices.

A Case of Duodenal Crohn's Disease Associated with Ampullar Insufficiency and Cholangitis

Abstract: A 67‐year‐old Japanese woman with duodenal Crohns disease developed cholangitis. Radiographic and endoscopic examinations revealed a marked stenosis of the third portion and a dilatation of the second portion of the duodenum. The endoscopic and histopathological observations showed this disease affected the Vaters papilla. Duodenoscopic manometry indicated a reduced pressure of the phasic sphincter of Oddi, indicating ampullar insufficiency. E. coli was found in the bile culture as the infecting organism. The authors suggest that the cholangitis in this patient was caused by the reflux of duodenal contents into the biliary tract.