[A case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion].

A 63-year-old man was admitted with left pleural effusion, and an amylase level of 30994IU/l. A diagnosis of pancreaticopleural fistula was made, based on the findings of magnetic resonance cholangiopancreatography and endoscopic retrograde pancreatography (ERP). After the placement of an endoscopic naso-pancreatic drainage tube, the pleural effusion markedly reduced. When ERP was performed for internal drainage, the main pancreatic duct and stricture were biopsied and showed pancreatic ductal adenocarcinoma histologically. CT revealed a mass in the head of the pancreas. He underwent pylorus-preserving pancreaticoduodenectomy. To the best of our knowledge this is the first case of pancreatic carcinoma presenting as pancreaticopleural fistula with pancreatic pleural effusion. Clinicians should pay attention to the possible presence of cancer and pancreaticopleural fistula in patients with pancreatic pleural effusion.

Effects of bone marrow and hepatocyte transplantation on liver injury.

BACKGROUND: The therapeutic effects of bone marrow and hepatocyte transplantation were investigated regarding the treatment of retrorsine-partial hepatectomy-induced liver injury. METHODS: Analbuminemic F344alb rats were given two doses of retrorsine 2 wk apart, followed 4 wk later by transplantation with F344 rat bone marrow cells or hepatocytes immediately after a two-thirds hepatectomy. The survival rate, liver regeneration rate, liver functions, albumin-positive hepatocytes, and normal albumin gene sequences in the liver and serum albumin levels were investigated in the recipients. RESULTS: Although 65% retrorsine/partial hepatectomy-treated F344alb died between 1 and 11 d after the partial hepatectomy, only 27.5% of the animals died following bone marrow transplantation, and 50% with hepatocyte transplantation. Both bone marrow and hepatocyte transplantation ameliorated acute liver injury after a partial hepatectomy. Bone marrow transplantation yielded a very small increase in the number of albumin-positive hepatocytes in the liver, while hepatocyte transplantation resulted in massive replacement of the liver tissues by the donor hepatocytes associated with an elevation of serum albumin after an extended time. CONCLUSIONS: Both bone marrow and hepatocyte transplantation could prevent acute hepatic injury, conceivably due to a paracrine mechanism.

"Tension-free" herniorrhaphy for groin hernias in patients with cirrhosis: report of four cases.

Tension-free herniorraphies were carried out using either the Mesh Plug repair (M-P) or Perfix plug technique (P-P) in four patients with cirrhosis. Three patients had a lateral inguinal hernia, and the other had bilateral inguinal and femoral hernias. The patients' ages ranged from 55 to 80 years. The Child-Pugh classifications showed that one was A, two were B, and one was C. The main complaint in two patients was a difficult reduction and the others had discomfort. An M-P was performed in the three patients with inguinal hernias and an M-P was performed for the femoral hernias and a P-P for the inguinal hernias in the patient with both inguinal and femoral hernias. Two patients had fluid collection under the incision and one of them required a single puncture. However, the others had no related complications after the operation. One patient died due to liver failure without recurrence of the groin hernias 31 months after the operation. The others had no recurrence and no related symptoms from 5 to 52 months after the operation.

[Survey of oxaliplatin-associated peripheral sensory neuropathy using an interview-based questionnaire in patients with advanced colorectal cancer].

In performing FOLFOX chemotherapy (infusional 5-FU/LV with oxaliplatin) for advanced colorectal cancer, the neurotoxicity of oxaliplatin (L-OHP) is the dose-limiting factor. A retrospective study of 25 consecutive patients, receiving modified FOLFOX6 (mFOLFOX6) for advanced colorectal cancer, was conducted. From March 2006 to February 2008, we investigated the process of development of sensory neuropathy by adverse effect grading and our original interview-based intake about the afflicted regions. Neurotoxicity developed in 21 cases (84%) after 6 courses and the cumulative L-OHP dose was 410 mg/m(2) in median. In 11 cases (52%), it developed from the fingers, while in 8 cases (38%), it occurred from the fingers and toes simultaneously. It developed from the toes or tongue only in one case each. In 6 cases (55%), in which it occurred from the fingers, the symptom aggravated to grade 2 (G2) according to the Neurotoxicity Criteria of DEBIOPHARM (DEBNTC). On the other hand, in cases of coexpression of the fingers and toes, 7 cases (88%) developed G2 neuropathy, among one of whom suffered from grade 3 (G3). The coexistence of diabetes mellitus without neuropathy had no influence on the development of the neurotoxicity in the grading of DEB-NTC. One month after the last mFOLFOX6 therapy, neurotoxicity newly developed in one case, and was aggravated in two cases two months after cessation of the chemotherapy. Therefore, careful observation of the course should be continued even after the end of mFOLFOX6 therapy. Our results suggest that L-OHP neurotoxicity develops on fingers or fingers and toes simultaneously in most cases. And when it occurred on fingers and toes simultaneously, it would aggravate to G2 or G3 during the chemotherapy. The interviewed-based intake about the afflicted region, such as ours, can be used to predict the deterioration of the neurotoxicity.

Colonic vascular conductance increased by Daikenchuto via calcitonin gene-related peptide and receptor-activity modifying protein 1.

BACKGROUND: Daikencyuto (DKT) is a traditional Japanese medicine (Kampo) and is a mixture of extract powders from dried Japanese pepper, processed ginger, ginseng radix, and maltose powder and has been used as the treatment of paralytic ileus. DKT may increase gastrointestinal motility by an up-regulation of the calcitonin gene-related peptide (CGRP). CGRP is also the most powerful vasoactive substance. In the present study, we investigated whether DKT has any effect on the colonic blood flow in rats. MATERIALS AND METHODS: Experiments were performed on fasted anesthetized and artificially ventilated Wistar rats. Systemic mean arterial blood pressure and heart rate were recorded. Red blood cell flux in colonic blood flow was measured using noncontact laser tissue blood flowmetry, and colonic vascular conductance (CVC) was calculated as the ratio of flux to mean arterial blood pressure. We examined four key physiological mechanisms underlying the response using blocker drugs: CGRP1 receptor blocker (CGRP(8-37)), nitric oxide synthase inhibitor, vasoactive intestinal polypeptide (VIP) receptor blocker ([4-Cl-DPhe6, Leu17]-VIP), and substance P receptor blocker (spantide). Reverse transcription-polymerase chain reaction was used for the detection of mRNA of calcitonin receptor-like receptor, receptor-activity modifying protein 1, the component of CGRP 1 receptor and CGRP. After laparotomy, a cannula was inserted into the proximal colon to administer the DKT and to measure CVC at the distal colon. RESULTS: Intracolonal administration of DKT (10, 100, and 300 mg/kg) increased CVC (basal CVC, 0.10 mL/mmHg) from the first 15-min observation period (0.14, 0.17, and 0.17 mL/mmHg, respectively) and with peak response at either 45 min (0.17 mL/mmHg by 10 mg/kg), or 75 and 60 min (0.23 and 0.21 mL/mmHg by 100 and 300 mg/kg, respectively). CGRP(8-37) completely abolished the DKT-induced hyperemia, whereas nitric oxide synthase inhibitor partially attenuated the DKT-induced hyperemia. [4-Cl-DPhe6, Leu17]-VIP and spantide did not affect the hyperemia. Japanese pepper significantly increased CVC at 45 min or later, whereas ginseng radix only showed a significant increase at 15 min. Reverse transcription-polymerase chain reaction showed that mRNA for calcitonin receptor-like receptor, receptor-activity modifying protein 1, and CGRP were expressed in rat colon and up-regulated by DKT. CONCLUSIONS: The present study demonstrated that DKT increased CVC, which was mainly mediated by CGRP and its receptor components.

[Two cases of pancreatic tumor with von Hippel-Lindau disease].

Von Hippel-Lindau disease (VHL disease) is an inherited neoplasia syndrome. VHL disease which frequently complicates pancreatic lesions is rarely diagnosed by existence of pancreatic involvements. We report two cases of VHL disease with pancreatic lesions. The first patient was a 40-year-old woman. Adrenal pheochromocytoma, spinal hemangioblastoma and pancreatic endocrine tumor were resected. The second case was a 68-year-old woman with past surgical histories included cerebellar and spinal hemangioblastoma. Subtotal pancreatectomy was performed for multiple serous cystadenoma. IPMN which has been never reported as pancreatic involvement of VHL disease were documented by imaging diagnosis in the first case, and by histological examination in the second case. We considered VHL disease from coexistent multiple tumors include pancreatic involvements and finally diagnosed by genetic examination in both cases. Care should be taken regarding the patient's right for treatment against for the genetic disease. We hold a genetic conference composed of multidisciplinary team. Consequently we detected another VHL disease patient from patient's family.

Low selection of preneoplastic hepatocytes after treatment with the 2-acetylaminofluorene diet-partial hepatectomy regimen in the liver of hepatocarcinogenesis-resistant DRH strain rats.

In hepatocarcinogenesis-resistant DRH rats, preneoplastic hepatocytic lesions are smaller than those of usual rats during carcinogenesis. When preneoplastic hepatocytes from DRH and Donryu (original strain of DRH) were reciprocally transplanted into the livers of DRH and Donryu treated with 2-acetylaminofluorene (2-AAF) diet/two-thirds hepatectomy (PH), the Donryu cells formed small colonies within the DRH liver, whereas the DRH cells formed large colonies within the Donryu liver. The DRH liver showed less degree of oval cell proliferation after treatment with 2-AAF and PH, and DRH hepatocytes were more resistant to the growth-inhibitory effect of 2-AAF after PH. Furthermore, DRH hepatocytes were generally resistant to cytotoxicity of hepatotoxins. The tissue environment of the DRH liver, therefore, is less effective for selective growth of preneoplastic hepatocytes during the carcinogen treatment, which is probably a major cause of the hepatocarcinogenesis-resistance in DRH rats.

Regeneration of the abdominal postganglionic sympathetic system.

The abdominal sympathetic system is unique in that its postganglionic axons do not directly innervate gastrointestinal smooth muscle layers but exert their effects through the enteric nervous system. The purpose of the present study was to examine the ability of neurons in abdominal sympathetic ganglia to regenerate after axonal injury and to determine whether reinnervation occurs after the removal of ganglia. Axons from the celiac ganglion and superior mesenteric ganglion complex (CG/SMG) of adult female BALB/c mice were crushed or the ganglion complex was removed. Immunohistochemistry, western blotting and in situ hybridization were performed to examine the changes in tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP-43) in the duodenum and the sympathetic ganglia. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling and injection of the tracer dye, fluorogold were also performed. After crushing the nerve, TH in the duodenum disappeared and reappeared within 90 days. In the CG/SMG, TH decreased and increased as in the duodenum, while the expression of GAP-43 changed in the opposite direction. Nerve crushing caused cell death to limited number of neurons in the CG/SMG. The removal of CG/SMG decreased TH in the duodenum and stomach, but 180 days later TH-positive innervation was recovered. Fluorogold injection revealed that the inferior mesenteric ganglion reinnervated the stomach. Therefore, postganglionic sympathetic nerves in the abdomen are able to regenerate and reinnervation occurs even after the removal of sympathetic ganglia.

[A case of liver cysts with Em18-WB was useful for differential diagnosis].

A 72-year-old woman with multilocular liver cysts was admitted. This lesions seemed to be an alveolar hydatid disease. Two methods of Western blotting were used for serologic diagnosis. One method recognizes antigens of crude extracts of Echinococcus multilocularis (EM). The other method recognizes a purified antigen (Em18) of EM. Her serum only reacted with the former method and never reacted with Em18 antigen. Eighteen months after first admission, she had an operation. The resected specimen was diagnosed with simple cysts. Western blotting using Em18 antigen could greatly facilitate the differential diagnosis of simple liver cyst and alveolar hydatid disease.

Allogeneic hepatocyte transplantation: Contribution of Fas-Fas ligand interaction to allogeneic hepatocyte rejection.

Hepatocyte transplantation is a potential therapeutic modality for overcoming the shortage of liver donors, and the clinical application of allogeneic hepatocyte transplantation has been considered. However, there are two major problems with allogeneic hepatocyte transplantation: protection of transplanted hepatocytes from rejection and stimulation of the rapid proliferation of surviving cells. Without immunosuppression, allogeneic hepatocytes are rapidly rejected within a few days after transplantation, even though it is relatively easy to induce immunotolerance after allogeneic whole liver transplantation. Accordingly, different rejection mechanisms seem to operate after allogeneic hepatocyte transplantation and whole liver transplantation. To overcome the rejection of transplanted hepatocytes, induction of donor-specific unresponsiveness to graft without compromising the host immune system would be ideal. We previously reported that the Fas-Fas ligand system plays a critical role in the CD28-independent pathway of hepatocyte rejection. Therefore, blockade of rejection using CTLA4 immunoglobulin (CTLA4Ig) or anti-CD80/86 monoclonal antibodies and anti-FasL monoclonal antibody may prolong the survival of transplanted allogeneic hepatocytes. Furthermore, administration of hepatocyte growth factor (HGF) can promote the proliferation of allogeneic hepatocytes and this may lead to the development of a functioning liver substitute.

Prognostic Significance of the Labeling of Adnab-9 in Pancreatic Intraductal Papillary Mucinous Neoplasms.

First described as a distinct entity in the early1980s (1), pancreatic ductal neoplasms with mucinhypersecretion have been increasingly recognized.This motivated the World Health Organization(WHO) reclassification proposal in 1996 (2), which separated them from mucinous cystic neoplasms.These tumors are now (3) termed intraductal papillarymucinous neoplasms (IPMN). Despite a burgeoningvolume of recent literature devoted to thiscondition, little is known of the pathogenesis ofIPMN,which is believed to constitute 10% of mucinproducingpancreatic tumors and 1% of pancreaticcancers (4). IPMN presents diagnostic and therapeuticchallenges to the clinician because it representsa histologic spectrum of morphology, from thebenign adenoma to invasive carcinoma. The initialhistological and morphological features of IPMN oftenunderestimate its invasive potential (5), and may notaccurately predict survival. Conversely, it may oftenbe difficult to differentiate benign from malignantlesions (5-7). In the most advanced stages, when aninvasive carcinoma is present, IPMN can be indistinguishablefrom common pancreatic ductal cancer(PC), yet with aggressive surgical management, theprognosis for patients with IPMN is far better (6,7).The availability of a prognostic indicator, independentfrom the pathological stage, may help to directtherapy.

[A case report of advanced cardiac cancer showing a complete response to TS-1 as neoadjuvant chemotherapy].

A 69-year-old female had complaints of vomiting, appetite loss and feeling of pharyngeal obstruction. She was diagnosed with a 3'-shaped advanced cardiac cancer with esophageal invasion. A biopsy revealed poorly differentiated adenocarcinoma. The tumor was T3 (SE) N2, Stage IIIB indicating a poor prognosis. After informed consent, TS-1 was administrated as preoperative chemotherapy. Chemotherapy with TS-1 was very effective, and the tumor noticeably decreased. Next, total gastrectomy was performed. Histopathological findings revealed that the primary tumor and lymph node had become scarred and fibrous, indicating a complete response (Grade 3). In the future, TS-1 can be expected to display efficacy in neoadjuvant chemotherapy for patients with advanced gastric cancer who have poor prognoses.

[Two cases of stage IV type 4 gastric cancer with good response to TS-1].

We report two patients with Type 4 gastric cancers having multiple lymph node metastasis and carcinomatosa which responded well to TS-1. After administration of TS-1 orally for two courses, both patients showed improved extension of the gastric wall and almost complete reduction of metastatic lymph nodes. In case 2, colonic stenosis due to peritonum carcinomatosa disappeared after chemotherapy with TS-1. Total gastrectomy was performed in both patients in accordance with their wishes. It was confirmed histopathologically that TS-1 was effective against the primary sites and lymph node metastasis. Both patients are well without recurrence and continue taking TS-1.

Preventive effect of urinary trypsin inhibitor on the development of liver fibrosis in mice.

Urinary trypsin inhibitor (UTI) is a serine protease inhibitor produced in the liver that inhibits the production and activation of various cytokines, notably transforming growth factor-ß (TGF-ß), which are associated with the progression of liver fibrosis. However, the various roles of endogenous UTI in liver fibrosis have not been examined. This study, therefore, examined the long-term effects of UTI deficiency during both steady-state conditions and thioacetamide (TA)-induced liver fibrosis. Furthermore, the effects of continuous exogenous UTI administration were examined. Analyses of liver fibrosis marker, hyaluronic acid (HA), TGF-ß concentrations and histological findings at 30 weeks of age showed that homozygous UTI-knockout (KO) mice had higher HA and TGF-ß concentrations than did heterozygous UTI-KO mice and wild-type mice, although there was no histological evidence of liver fibrosis in these mice. TA treatment for 20 weeks also resulted in greater HA and TGF-ß levels in homozygous mice than in heterozygous and wild-type mice. Furthermore, homozygous mice had more severe liver fibrosis based on histological analyses. HA and TGF-ß levels were lower in homozygous UTI-KO mice that were continuously administered UTI versus those given distilled water. These findings indicate that UTI deficiency leads to the production of HA and hepatic TGF-ß and that administering exogenous UTI can ameliorate these changes. We conclude that endogenous UTI is produced in the liver to suppress the production and activation of TGF-ß and that administering exogenous UTI may be therapeutically beneficial for preventing liver fibrosis.

Multifocal pancreatic intraepithelial neoplasia (PanIN) lesions of the branch ducts associated with lobular parenchymal atrophy in a Japanese patient diagnosed to have familial pancreatic cancer.

This report presents a case of Japanese familial pancreatic cancer (FPC) with multifocal pancreatic intraepithelial neoplasia (PanIN) lesions of the branch ducts probably associated with lobular parenchymal atrophy. The risk of pancreatic cancer is significantly increased in those associated with FPC, and this risk increases with increasing numbers of affected first-degree relatives, but there have been four Japanese cases reported. A 63-year-old Japanese male was referred to the hospital for evaluation and treatment of a pancreatic head tumor. His family history included pancreatic cancer in two-first-degree relatives and three-second-degree relatives. A pylorus-preserving pancreatoduodenectomy with a regional lymphadenectomy and intraoperative radiotherapy were performed. The histological findings of the main tumor showed a moderately differentiated tubular adenocarcinoma in the head of the pancreas without metastasis of the resected lymph nodes. Interestingly, multifocal PanIN lesions in the branch ducts were individually developed and some of these lesions were probably associated with small lesions of lobular parenchymal atrophy. He remained in good condition for 37 months after the operation. Although the concept of FPC has not been clearly established in Japan, nationwide registries of FPC are probably useful for management of FPC patients.

Pylorus-preserving total pancreatectomy for an intraductal papillary-mucinous neoplasm of the pancreas.

BACKGROUND/PURPOSE: Total pancreatectomy (TP) is rarely performed to treat invasive ductal carcinoma of the pancreas, due to the associated markedly impaired quality of life and poor prognosis after the resection. Intraductal papillary-mucinous neoplasm (IPMN) of the pancreas is characterized by extensive intraductal spread and a favorable outcome even when presenting at an invasive stage. We herein reappraise the role of pylorus-preserving total pancreatectomy (PPTP) as a viable alternative pancreatic resection modality for borderline and malignant IPMN. METHODS: A total of five patients with IPMN underwent PPTP and their clinical follow-up data were reviewed. RESULTS: TP was performed due to recurrent IPMN in the remnant pancreas after distal pancreatectomy in three patients and due to massive involvement of the entire pancreas in the others. All patients were treated by the pylorus-preserving method, while the spleen was also preserved in one patient. The surgical margins were negative and no metastasis to the resected lymph nodes was evident, based on histological examinations. One patient underwent a re-operation due to postoperative intraabdominal bleeding, while another patient required tubedrainage for left pleural effusion. Three of the four patients who underwent PPTP with a splenectomy experienced postoperative gastric ulcer, which were controlled by medication. One patient died due to suicide 16 months after the PPTP. All the others were doing well without recurrence at periods of 62 to 127 months after the PPTP. CONCLUSIONS: PPTP is therefore considered to be indicated as an effective treatment for borderline or malignant IPMN with extensive involvement, when the patient's condition permits, in order to achieve complete resection of the IPMN.

A malignant nonfunctioning pancreatic endocrine tumor with a unique pattern of intraductal growth.

The intraductal growth of nonfunctioning pancreatic endocrine tumors (NFPTs) is considered to be rare, and in our survey of the English-language literature, we found only three cases to have been described previously. We herein report the case of a 36-year-old man with a malignant NFPT that uniquely grew within the lumen of the main pancreatic duct (MPD) and completely obstructed the MPD, as shown by endoscopic retrograde pancreatography (ERP). Endoscopic ultrasonography clearly detected the tumor with intraductal growth. In addition, positron emission tomography (PET), using 18F-fluorodeoxyglucose (FDG) and computed tomography (CT) with the same scanner (FDG-PET/CT) showed enhanced uptake of FDG in the tumor. A pylorus-preserving pancreaticoduodenectomy and regional lymphadenectomy were performed under the preoperative diagnosis of an NFPT. Microscopically, positive immunoreactions for synaptophisin and vasoactive intestinal peptide indicated neuroendocrine differentiation of the tumor, while in addition, metastasis to a lymph node along the common hepatic artery was also observed. The patient has survived for 6 months after the surgery without any evidence of recurrence or metastasis. Both ERP and FDG-PET/CT were thus found to be useful for predicting the malignant potential of an NFPT in the preoperative diagnosis.

Mucinous carcinoma of Vater's ampulla with a unique extension along the main pancreatic duct.

We report a case of mucinous carcinoma of Vater's ampulla with a unique extension along only the main pancreatic duct (MPD) and microinvasion to the pancreas. A 52-year-old man was referred to our hospital for the evaluation and treatment of acute pancreatitis. Abdominal computed tomography (CT) demonstrated swelling in the head of the pancreas with a mass in the duodenum. Hypotonic duodenography and endoscopic examination revealed a well-defined mass, measuring about 25 mm in size, in Vater's ampulla. A biopsy specimen of the tumor showed moderately differentiated adenocarcinoma. A pylorus-preserving pancreaticoduodenectomy with a regional lymphadenectomy was performed, under a preoperative diagnosis of adenocarcinoma of Vater's ampulla with direct invasion into the head of the pancreas. The resected specimen of the duodenum confirmed the presence of the mass, which measured 22 x 15 mm in size, in Vater's ampulla. Microscopically, the tumor consisted of two components: moderately differentiated adenocarcinoma in the peripheral region of the tumor Vater's papilla and mucinous carcinoma in the central region of the tumor. The mucinous carcinoma component uniquely extended along only the MPD with microinvasion to the pancreas. Immunohistochemically, both the moderately differentiated adenocarcinoma and the mucinous carcinoma were positive for cytokeratin 20 (CK20) and negative for cytokeratin 7 (CK7) which is the pattern of intestinal-type carcinoma of Vater's ampulla. We concluded that the original site of this tumor may have been the duodenal epithelium of Vater's ampulla originally moderately differentiated adenocarcinoma-which subsequently changed to mucinous carcinoma that extended along only the MPD with microinvasion to the pancreas.

Gallbladder carcinoma associated with occult pancreatobiliary reflux in the absence of pancreaticobiliary maljunction.

We herein report a case of gallbladder carcinoma associated with occult pancreatobiliary reflux (PR) in the absence of pancreatobiliary maljunction. A 67-year-old woman was referred to our hospital for the evaluation and treatment of a gallbladder tumor. Ultrasonography and computed tomography showed a nodular lesion in the fundus of the gallbladder, indicating the possibility of a gallbladder carcinoma. Endoscopic ultrasonography showed the nodular tumor and thickness of the surrounding epithelium. Endoscopic retrograde cholangiopancreatography revealed a normal pancreaticobiliary junction without the common channel and a slight dilatation of the common bile duct (15 mm in diameter). An open cholecystectomy and partial resection of the liver bed of the gallbladder with regional lymphadenectomy was performed. A C-tube was inserted from the cut end of the cystic duct into the common bile duct to prevent bile stasis. Biliary amylase and lipase levels sampled in the gallbladder were 2604 IU/l and 775 IU/l, respectively. Biliary amylase level in the bile collected from the C-tube in the common bile duct was 119 550 IU/l on postoperative day (POD) 6 and 22 265 IU/l on POD 12. These observations suggested that PR was present in this patient. The histopathological findings of the resected specimen showed a well-differentiated adenocarcinoma of the gallbladder with invasion to the muscle layer and no metastasis of the resected lymph nodes. A high index of nuclear staining for MIB-I in the cancer cells (about 10%) was exhibited, and a few cells in the normal epithelium also stained positive.

Low p38 MAPK and JNK activation in cultured hepatocytes of DRH rats; a strain highly resistant to hepatocarcinogenesis.

DRH rats are a hepatocarcinogenesis-resistant strain isolated from hepatocarcinogenesis-sensitive Donryu rats, and the liver of DRH shows less histological damage and fewer/smaller neoplastic hepatic lesions by the treatment with hepatocarcinogens. To investigate the mechanism of the resistance, the properties of hepatocytes of DRH and Donryu were compared. In primary culture, DRH hepatocytes exhibited higher proliferation and less apoptosis than Donryu hepatocytes in the presence of EGF and insulin. However, such difference was not correlated to the degree of DNA damage associated with cell culture or cell cycle checkpoint function. Although the mitogen-activated protein kinases [EGF receptor (EGFR) and extracellular signal regulating kinases (ERK1/2)] were activated to the same degree, the stress-activated protein kinases [p38 mitogen-activated protein kinase (p38) and c-jun N-terminal kinase (JNK)] were activated to a lesser degree in the DRH hepatocytes. Treatment with 2-acetylaminofluorene (2-AAF) in vivo also resulted in less JNK and p38 activation in the DRH livers. Furthermore, apoptosis signal-regulating kinase 1 (ASK1) was inhibited by the lysate from the DRH but not by the Donryu hepatocytes. The low activation of the stress-activated protein kinases may be linked to the resistance to cellular stress, which may underlie the hepatocarcinogenesis-resistance in DRH rats.