Dose-related increases in quantitative values for altered hepatocytic foci and cytochrome P-450 levels in the livers of rats exposed to phenobarbital in a medium-term bioassay

The dose-response relationship between liver tumor promoting activity and cytochrome P-450 (CYP) induction by phenobarbital sodium (PB) was investigated using the liver medium-term bioassay system of Ito. Two weeks after a single dose of N-nitrosodiethylamine (DEN) (200 mg/kg body weight, i.p.), rats were given PB at dietary levels of 500, 250, 125, 60, 30, 15 and 8_parts per million (ppm) for 6 weeks. All rats were subjected to partial hepatectomy at week 3, and were killed at week 8. Quantitative values for glutathione S-transferase placental form positive hepatocytic (GST-P⁺) foci were increased in the high dose groups dose-dependently. In contrast, the values in the low dose groups were rather lower than that of the control. CYP2B1, 2C6 and 3A2 were predominantly immunostainable in hepatocytes around the central vein. While Western blotting revealed CYP2B1 and 2C6 proteins to be increased with strict dose-dependence, CYP3A2 was only elevated at high doses. Thus, a good correlation between increase of GST-P⁺ foci and CYP3A2 induction was observed, as well as with CYP2B1 and 2C6 in high dose groups.     

Laparoscopic management of common bile duct stones: transcystic approach and choledochotomy

The purpose of this study was to review our experience with laparoscopic common bile duct (CBD) exploration by the transcystic approach and choledochotomy. We selected the transcystic approach for patients whose CBD stones were less than five in number and smaller than 9 mm in diameter, and whose CBD was less than 15 mm in diameter on cholangiograms. Among 217 patients with CBD stones treated laparoscopically, the transcystic approach was performed successfully in 91 of 104 patients in whom it was attempted (87.5%). The other 126 patients underwent laparoscopic choledochotomy, followed by ductal closure with transcystic drainage in 59, T-tube drainage in 46, primary ductal closure in 19, and choledochoduodenostomy in 1. Choledochotomy was converted to open surgery in only 1 patient. The transcystic approach was associated with shorter hospital stay and less morbidity than choledochotomy. However, choledochotomy also had an acceptably low rate of complications. Bile leaks occurred more frequently in those with primary ductal closure than in those with transcystic drainage or T-tube drainage. Residual stones were found in 2 patients with the transcystic approach and in 10 with choledochotomy. The residual stones were removed through the T-tube tract by choledochoscopy in 7 of these 10 patients. From these results we conclude that laparoscopic management of CBD stones is feasible for almost all patients with CBD stones. It is considered to be safe and effective and has the advantage of being a single-stage procedure. Received: July 7, 2000 / Accepted: October 26, 2000     

Isolation of a Novel Gene Showing Reduced Expression in Metastatic Colorectal Carcinoma Cell Lines and Carcinomas

To investigate genes involved in mctastatic stages of cancer, we analyzed expression of mRN As in three cell lines derived from murine colon adenocarcinoma 26 by means of a differential display method. Each of these lines exhibits distinct metastatic characteristics. Among many bands representing different expression patterns in the display, we confirmed by northern analysis that a gene corresponding to one amplified fragment, termed grm2 (gene related to metastasis 2), was expressed more abundantly in NL4, the derivative with the lowest metastatic potential, than in cell lines NL17, an experimentally metastatic derivative, and in NL22, a spontaneously metastatic derivative. Using thegrm.2 fragment as a probe, we isolated murine cDNA clones and subsequently human cDNA clones corresponding to the GRM2 gene. The human and mouse homologues both encode proteins of 600 amino-acid residues, which show weak homologies to proteins belonging to the myosin family. When we examined the expression levels of this novel gene in human colon cancers and in corresponding metastatic foci, we found that in more than half of these tissues, expression was significantly reduced in association with malignant potential. Our resultsimply that in humans the GRM2 gene product may regulate the metastatic phenotype of some colorectal cancers.     

Inhibitory Effect of a Somatostatin Analogue (SMS 201–995) on the Growth of Androgen-dependent Mouse Mammary Tumor (Shionogi Carcinoma 115)

The influence of a soinatostatin analogue, SMS 201–995 (SMS), on the growth of an androgen-dependent mouse mammary tumor, Shionogi carcinoma 115 (SC115), was studied. Treatment of SC11S tumor-transplanted male mice with s.c. injections of SMS (0.04, 0.2,1, and 5 μg twice a day) resulted in a dose-dependent inhibition of tumor growth. The growth-inhibitory effect of SMS reached its peak at a dose of 1 μg twice a day. SMS was found not to elicit its growth-inhibitory effect through lowering plasma testosterone levels or down-regulating androgen receptor of SC115 tumors. Since specific binding sites for somatostatin were not observed in the membrane fractions of SC115 tumors and SMS did not inhibit the proliferation of primarily cultured SC115 tumor cells, a direct inhibitory mechanism of SMS on SC115 tumors was unlikely to be operative. Since SMS is a very potent inhibitor of growth hormone (GH) secretion, it was speculated that SMS might inhibit the growth of SC115 tumors indirectly through down-regulation of plasma GH levels. This possibility was evaluated by studying the influence of GH replacement on the growth of SC115 tumors grown in SMS-treated mice. GH replacement was done both in a male secretory pattern (intermittent injection, human GH 500 μg/kg twice a day) and in a female secretory pattern (continuous infusion, 1000 μg/kg/day). Intermittent injections of GH fully restored the growth of SC115 tumors in the SMS-treated mice to that in the normal controls but continuous infusion of GH was without effect. These results suggest that SMS inhibits the growth of SC115 tumors through suppression of GH secretion, and that the mode of GH administration is an important determinant of its action on SC115 tumor growth.     

Bcl-2 expression in cholangiocellular carcinoma is inversely correlated with biologically aggressive phenotypes

bcl-2 is known to play a crucial role in modulating carcinoma progression as well as in inhibiting apoptosis. However, its expression and clinical significance for cholangiocellular carcinoma (CCC) remains unclear. In the present study, we immunohistochemically investigated bcl-2 expression in 41 CCC. Thirteen cases (31.7%) were classified as bcl-2 positive, because more than 10% of the carcinoma cells expressed bcl-2. The expression of bcl-2 was inversely related to lymph node metastasis, vascular invasion, perineural invasion, the Ki-67 labeling index, aberrant p53 expression and the incidence of apoptotic cells. Furthermore, well or moderately differentiated carcinoma more frequently expressed bcl-2. These results suggest that downregulation of bcl-2 expression is strongly linked to highly biologically aggressive phenotypes of CCC.     

In vivo gene transfer into the adult mammalian central nervous system by continuous injection of plasmid DNA–cationic liposome complex

Previously reported methods of liposome-mediated direct in vivo gene transfer have been inefficient, especially when performed with highly differentiated, quiescent cells of the adult mammalian central nervous system (CNS). We have therefore improved these procedures based upon a novel concept. Following continuous injection of plasmid DNA–cationic liposome complex which contained a reporter gene encoding E. coli β-galactosidase into the striatum of adult rats, the expression of transgene was dramatically elevated without any adverse effects. This new technique may enable a wide application of liposome-mediated gene transfer technology not only to basic analysis of gene functions in the brain but also for clinical treatment of certain CNS disorders.     

A case of anal fistula cancer probably developing from intraluminal dissemination of rectal cancer

A 63-year-old man with a history of anal fistula was admitted to our hospital because the anal pain didn't disappear after the operation. On digital examination, a hard mass measuring 3.0 cm in diameter was found at the anal canal. Biopsy of the mass showed moderately differentiated adenocarcinoma. Colonoscopy revealed another rectal cancer at 15 cm from anal verge. Biopsy of the tumor also showed moderately differentiated adenocarcinoma, resembling the anal canal tumor. Because the histological findings of both tumors were nearly identical, we considered that cancer cells from the rectal cancer had been implanted and developed the metastatic tumor in the anal fistula. The patient underwent anterior resection for the rectal cancer, and a local resection for the anal canal cancer. Immunohistochemical staining for Ki-67, p53, Muc2, CD10, CK-7, and CK-20 revealed similar patterns in both tumors. Additionally, genetic analysis for p53, K-ras, and MSI revealed similar patterns in both tumors. We may suggest from these results that cancer cells from the rectal cancer had been implanted and developed the metastatic tumor in the anal canal.     

A case of successful treatment using "wrapping therapy" for huge hepatocellular carcinoma

This case is about a male in his 50's. In May 2004, he consulted a nearby doctor with abdominal pain and was pointed out a huge mass in the liver. He was diagnosed as hepatocellular carcinoma over 10 cm in diameter with chronic hepatitis type B. Because the tumor concurred with intra-hepatic metastasis along with lymph node metastasis, we planned transhepatic arterial embolization (TAE) as a first choice of treatment and performed twice. However, because of the tail inside part of the tumor was supplied from the gastroduodenal artery (GDA) and right gastroepiploic artery (RGEA) which were nutrient arteries, an effective TAE was impossible. The enhancement lesion that seemed viable was shown by enhanced CT. Therefore, a wrapping therapy (surgical decollateralization+silicon membrane sheeting) was performed under laparotomy for the purpose of cutting off blood supply to the part of the viable lesion in August of the same year. The tail inside part of the tumor that seemed viable fell into necrosis by wrapping alone, and the serum PIVKA-II level decreased within normal limit. As of ten months after the treatment, the patient is still alive without aggravation.     

A case report of complete obstruction of the left main bronchus caused by recurrent esophageal carcinoma with pulmonary embolism of right lung after surgery for esophageal cancer

A 54-year-old woman complained of dyspnea, due to complete obstruction of the left main bronchus caused by recurrent esophageal carcinoma, was transferred to our department about two months after curative resection (with preoperative chemotherapy for T4 cancer) in July 2004. She suddenly developed a severe shortness of breath with anxiety, and arterial blood gas analysis revealed a PaO2 of 25 mmHg (FiO2 1.0). The presence of pulmonary embolism was diagnosed by pulmonary perfusion scintigraphy. Thrombolytic therapy with urokinase was started to keep the air way. Fogarty catheter and bronchoscopic Nd-YAG laser treatment was performed. After that, an expandable metallic stent (EMS) was placed at the site of obstruction without any troubles, and there was a striking improvement in her condition of respiration and atelectasis. The radiation therapy was initiated and completed safely. The tumor lesion had disappeared on CT scan after the radiation therapy (a total dose of 50 Gy). We experienced a case that could be rescued from an advanced respiratory failure caused by one side air way obstruction and another side's blood circulation disorder.