Surgery versus radiochemotherapy for resectable locally invasive pancreatic cancer: final results of a randomized multi-institutional trial.

PURPOSE: Although the outcome of surgery for locally advanced pancreatic cancer remains poor, it is improving, with 5-year survival up to about 10% in Japan. The preliminary results of our multi-institutional randomized controlled trial revealed better survival after surgery than after radiochemotherapy. We report the final results of this study after 5 years of follow-up. METHODS: Patients with preoperative findings of pancreatic cancer invading the pancreatic capsule without involvement of the superior mesenteric or common hepatic arteries, or distant metastasis, were included in this randomized controlled trial, with their consent. If the laparotomy findings were consistent with these criteria, the patient was randomized to a surgery group or a radiochemotherapy group (5-fluorouracil 200 mg/m2/day and 5040 Gy radiotherapy). We compared the mean survival time, 3-and 5-year survival rates, and hazard ratio. RESULTS: The surgery and radiochemotherapy groups comprised 20 and 22 patients, respectively. Patients were followed up for 5 years or longer, or until an event occurred to preclude this. The surgery group had significantly better survival than the radiochemotherapy group (P<0.03). Surgery increased the survival time and 3-year survival rate by an average of 11.8 months and 20%, respectively, and it halved the instantaneous mortality (hazard) rate. CONCLUSION: Locally invasive pancreatic cancer without distant metastases or major arterial invasion is treated most effectively by surgical resection.

Enzyme histochemical analysis of lymphatic vessels in colon carcinoma: occurrence of lymphangiogenesis within the tumor.

BACKGROUND/AIMS: While it is generally recognized that the lymph vessel is absent in solid carcinoma, a few papers have reported the presence of intratumoral lymph vessels. The present study was carried out to clarify whether or not intratumoral lymphangiogenesis occurs. METHODOLOGY: To identify lymphatics in colon carcinomas, tumor-adjoining and normal submucosa, we tried using an enzymatic histochemistry procedure to examine the specific high activity of 5'-nucleotidase that is seen in lymphatic endothelial cells. Additionally, arterioles and venules were identified by alkaline phosphatase and dipeptidyl (amino) peptidase IV staining, respectively. RESULTS: Intratumoral lymphatic vessels were observed in 30 of 34 colon carcinomas (91%), and arterioles were found in all cases. However, no venules were identified within the tumor. The lymphatic density (mean +/- SD vessels/mm2) increased in the order of the submucosa near the tumor (21.9 +/- 9.5), normal submucosa (27.9 +/- 13.8) and tumor tissue (33.9 +/- 25.1). Intratumoral lymphatic density was significantly higher than that in the submucosa near the tumor (P<0.05). Intratumoral lymphatic density is related to arteriolar density (r=0.284, P=0.0012). The ratio of lymphatic/arteriolar density in the tumor was significantly higher than that seen in the submucosa near the tumor (0.78 +/- 0.76 vs. 0.51 +/- 0.36, P<0.05). Intratumoral lymphatic density was relatively higher in cases with lymph node metastasis than in those without metastasis, but was not related to tumor size, depth of tumor invasion, distant metastasis and TNM stage. CONCLUSIONS: Enzyme histochemistry revealed active lymphangiogenesis and the absence of venules within the tumor. Intratumoral lymphatic density was relatively correlated to arteriolar density. Enzyme histochemistry is a simple and quickly processed method that can be used to differentiate lymphatics from arterioles and venules.

Paired-like homeodomain protein ESXR1 possesses a cleavable C-terminal region that inhibits cyclin degradation.

The eukaryotic cell cycle is regulated by sequential activation and inactivation of cyclin-cyclin-dependent kinase (Cdk) complexes. In this work, we screened human cDNAs that can rescue yeast Saccharomyces cerevisiae from lethality caused by ectopic expression of human cyclin E and isolated a cDNA encoding ESXR1, a paired-like homeodomain-containing protein with a unique C-terminal proline-rich repeat region. In adult tissues, ESXR1 is primarily expressed in the testis. We demonstrate that ESXR1 prevents degradation of ubiquitinated cyclins in human cells. Accordingly, elevation of ESXR1 level results in accumulation of cyclin A and cyclin B1 and thereby provokes M-phase arrest. In human cells, the 65-kDa full-length ESXR1 protein is capable of proteolytically processing into N-terminal 45-kDa and C-terminal 20-kDa fragments. The C-terminal fragment, containing a proline-rich repeat region, is localized to the cytoplasm and displays the ability to inhibit cyclin degradation. In contrast, the N-terminal fragment, containing a paired-like homeodomain, is localized exclusively in the nucleus, suggesting that it plays a role in transcription. Our results indicate that proteolytic processing of ESXR1 plays a role in concerted regulation of the cell cycle and transcription in human cells.

Role of thromboxane derived from COX-1 and -2 in hepatic microcirculatory dysfunction during endotoxemia in mice.

Although thromboxanes (TXs), whose synthesis is regulated by cyclooxygenase (COX), have been suggested to promote inflammation in the liver, little is known about the role of TXA(2) in leukocyte endothelial interaction during endotoxemia. The present study was conducted to investigate the role of TXA(2) as well as that of COX in lipopolysaccharide (LPS)-induced hepatic microcirculatory dysfunction in male C57Bl/6 mice. We observed during in vivo fluorescence microscopic study that LPS caused significant accumulation of leukocytes adhering to the hepatic microvessels and non-perfused sinusoids. Levels of serum alanine transaminase (ALT) and tumor necrosis factor alpha (TNF alpha) also increased. LPS raised the TXB(2) level in the perfusate from isolated perfused liver. A TXA(2) synthase inhibitor, OKY-046, and a TXA(2) receptor antagonist, S-1452, reduced LPS-induced hepatic microcirculatory dysfunction by inhibiting TNF alpha production. OKY-046 suppressed the expression of an intercellular adhesion molecule (ICAM)-1 in an LPS-treated liver. In thromboxane prostanoid receptor-knockout mice, hepatic responses to LPS were minimized in comparison with those in their wild-type counterparts. In addition, a selective COX-1 inhibitor, SC-560, a selective COX-2 inhibitor, NS-398, and indomethacin significantly attenuated hepatic responses to LPS including microcirculatory dysfunction and release of ALT and TNF alpha. The effects of the COX inhibitors on hepatic responses to LPS exhibited results similar to those obtained with TXA(2) synthase inhibitor, and TXA(2) receptor antagonist. In conclusion, these results suggest that TXA(2) is involved in LPS-induced hepatic microcirculatory dysfunction partly through the release of TNF alpha, and that TXA(2) derived from COX-1 and COX-2 could be responsible for the microcirculatory dysfunction during endotoxemia.

The expression of pancreatic endocrine markers in centroacinar cells of the normal and regenerating rat pancreas: their possible transformation to endocrine cells.

To determine the progenitor nature of centroacinar cells (CACs), we attempted to compare the expression pattern of endocrine cell markers and PDX-1 (pancreatic duodenal homeobox gene 1) in CACs of both the quiescent and the regenerating rat pancreas. In the normal pancreas, most CACs were relatively small cells with sparse cytoplasm and oval or elongated nuclei. In addition, we noticed a distinct population of a small number of large cells with round nuclei in the centroacinar region. By immunohistochemistry, 0.21% and 0.3% of CACs in normal rat pancreas were respectively found positive for glucagon and insulin, being large CACs and designated as GL-CAC and IL-CAC. They also exhibited the mRNA of each hormone by in situ hybridization (ISH). The ISH signal for glucagon but not insulin was also detected in a subset of small CACs (designated GS-CAC). The expression of PDX-1 was also observed in subsets of small and large CACs (PS-CAC and PL-CAC, respectively). After a 90% pancreatectomy, the relative frequency for GS-CACs, but not those for other CACs, was significantly reduced in two days after surgery. On day 7 after surgery, the number of GS-CACs recovered to preoperative levels, whereas GL-CACs, IL-CACs, PS-CAC, and PL-CAC gradually increased to about double in number. From these results, a portion of CACs was suggested to differentiated into endocrine cells. A possible cell lineage is discussed for endocrine neogenesis during pancreatic regeneration.

Serum alanine aminotransferase levels and survival after hepatectomy in patients with hepatocellular carcinoma and hepatitis C virus-associated liver cirrhosis.

We examined whether sustained alleviation of inflammation as monitored by serum alanine aminotransferase (ALT) levels was associated with longer survival in hepatectomized hepatocellular carcinoma (HCC) patients with hepatitis C virus-associated liver cirrhosis (HCV-LC). Thirty-four hepatectomized patients with HCV-LC and HCC as a single nodule, and for whom more than 5 years had elapsed after the hepatectomy, were studied. They had no histologic evidence of portal or hepatic vein invasion. They were subdivided into two groups according to their serum ALT levels in the 2 years after hepatectomy: the low ALT group comprised 13 patients whose serum ALT levels showed a sustained low level below 80 IU, and the high ALT group comprised 21 patients whose serum ALT levels showed several peaks or plateaus above 80 IU. The patients had been followed-up prospectively with frequent ultrasonography and magnetic resonance imaging or computed tomography for recurrence for > 5 years. The survival period, non-recurrence interval and number of recurrences were observed. Recurrences were treated with transcatheter chemoembolization in all cases. The cumulative survival rate in the low ALT group was significantly better than that in the high ALT group (P < 0.05). The 5-year survival in the low ALT group was as high as 92.3% (12 of 13) compared with 33.3% (7 of 21) in the high ALT group (P < 0.05). The cumulative non-recurrence rate in the low ALT group was also significantly better than that in the high ALT group (P < 0.01). The survival period correlated well with the interval until the first recurrence (r = 0.545, P = 0.006). There was a tendency for the number of recurrences in the low ALT group (1.5 +/- 0.4, mean +/- SE) to be fewer than that in the high ALT group (2.2 +/- 0.4), although this was not significant. Sustained alleviation of inflammation, as indicated by low ALT levels, provides a survival advantage mainly due to the longer non-recurrence interval, and possibly because of fewer recurrences, in hepatectomized HCC patients with HCV-LC.

Efficacy of endoscopic surveillance of the upper gastrointestinal tract following distal gastrectomy for early gastric cancer.

BACKGROUND/AIMS: How endoscopy can be used in the follow-up of the upper gastrointestinal tract in patients who underwent gastrectomy for early gastric cancer remains unclear. METHODOLOGY: Two-hundred and ten patients (137 males and 73 females, aged at initial gastrectomy 27-86, average age 56.5) were followed in the present study. Results of follow-up endoscopy of all patients, pathologic diagnoses of secondary tumors and interval between gastrectomy and detection of secondary tumor were reviewed. Cumulative incidence rate of second tumors in the upper gastrointestinal tract was then analyzed. RESULTS: Secondary tumor was observed by follow-up endoscopy in 7 patients including two gastric, one esophageal, one duodenal carcinoma and 3 gastric adenomas. The interval between initial gastrectomy and diagnosis of secondary tumor ranged from 20 to 71 months (average 51.7 months). All carcinomas were early stage and localized within the mucosa. Three patients with secondary cancer were successfully treated by endoscopic mucosal resection. The cumulative incidence rate of secondary cancer in the gastric remnant, esophagus and duodenum at six years after initial gastrectomy was 1.0, 0.8 and 0.5%, respectively. The overall incidence rate of secondary tumors of the upper gastrointestinal tract at six years after distal gastrectomy was 4.1%. CONCLUSIONS: The present findings indicate that annual follow-up endoscopy of the upper gastrointestinal tract after gastrectomy for early gastric cancer can be introduced to detect carcinoma at an early stage, thus improving the survival rate of gastrectomy patients.

Differentiation and proliferation of endocrine cells in the regenerating rat pancreas after 90% pancreatectomy.

The transplantation of pancreatic tissue has been anticipated to serve as a radical treatment for diabetes mellitus. However, the identification of the stem cells, and elucidation of their differential lineage and controlling mechanisms are prerequisites to ensure effective transplantation. We conducted an immunohistochemical study to determine the proliferation and differentiation dynamics of pancreatic endocrine cells in the rat pancreas 1 to 28 days after a 90% pancreatectomy. Regeneration of endocrine cells started immediately after pancreatectomy. The process of regeneration included the proliferation of preexisting islet cells and neogenesis of endocrine cells from epithelial cells of the most peripheral duct. Intercalated ductal cells and centroacinar cells were speculated to be the major sources of neogenesis, from which islet tissue was formed. Glucagon cells were the first endocrine cells differentiated, some of which transformed to insulin cells by a mechanism of non-replication. These results indicate that endocrine stem cells exist among the intercalated ductal and/or centroacinar cells, and these special regions should be utilized in transplantation for the successful treatment of diabetes.

Induction of specific stress response increases resistance of rat liver allografts to cold ischemia and reperfusion injury.

Heme oxygenase-1 (HO-1) has been shown to increase cellular resistance against oxidative injury, but the functional significance of this is currently obscure. We investigated the protective role of HO-1, induced by tin-protoporphyrin IX (SnPP), in attenuating liver transplantation injury. Lewis rats were intraperitoneally treated with saline as control, 50 micro mol/kg of SnPP, or 2 mg/kg of cycloheximide (CHX) before SnPP injection. Gene expression of HO-1 was induced after either treatment with SnPP- or CHX + SnPP instead of saline, whereas HO-1 protein synthesis was enhanced in Kupffer-like dendritic cells of the SnPP-treated group. Following reperfusion of liver grafts preserved for 30 h, there were fewer intercellular adhesion molecule-1-positive cells in SnPP-treated livers, significantly reduced numbers of dead cells, and enhanced graft viability. The present data suggest that increased synthesis of HO-1 protein by SnPP pre-conditioning is linked to the improved liver graft viability through inhibition of inflammatory adhesion molecules.

Pyrrolidine dithiocarbamate provides protection against hypothermic preservation and transplantation injury in the rat liver: the role of heme oxygenase-1.

BACKGROUND: Pyrrolidine dithiocarbamate (PDTC) represents a class of antioxidants and is a potent inducer of the heme oxygenase-1 (HO-1) gene and an inhibitor of nuclear factor-kappa B (NF-kappa B). We examined the impact of PDTC preconditioning against cold ischemia and reperfusion injury in the rat liver. METHODS: Lewis rats were treated subcutaneously with saline or PDTC solution 24 hours before harvesting. Some animals pretreated with PDTC were also given zinc protoporphyrin IX intravenously immediately after reperfusion. HO-1 expression and enzyme activity in liver tissues were analyzed at different time points after each treatment. After transplantation of 24-hour preserved livers, serum levels of transaminases and gene expression of tumor necrosis factor-alpha, interleukin-1 beta, and NF-kappa B were measured. Animal survival and cellular viability were monitored. RESULTS: HO-1 gene expression and protein synthesis were enhanced in PDTC-treated livers, leading to increased enzyme activity (P <.05). The PDTC treatment group showed lower transaminase levels (P <.05), lower cytokine and NF-kappa B messenger RNA expression (P <.05), and fewer nonviable cells (P <.05) than did the control group, whereas these PDTC effects were abolished with zinc protoporphyrin injection after reperfusion (P <.05). The best animal survival rate was observed in the PDTC group (P <.05). CONCLUSION: PDTC preconditioning reduces inflammatory responses during reperfusion. PDTC appears to exert this protective effect by induction of an antioxidative stress protein and inhibition of proinflammatory cytokines.

First drainage lymph node(s) in gastric cancer: analysis of the topographical pattern of lymph node metastasis in patients with pN-1 stage tumors.

BACKGROUND: We attempted to identify the first lymph node(s) involved in metastasis of gastric cancer by studying the topographical pattern of metastasis to regional lymph nodes in patients with pN-1 stage tumors. MATERIALS AND METHODS: A total of 190 patients (108 males and 82 females; age range, 27 to 83 years; mean, 59.7 years), who had undergone curative resection combined with lymphadenectomy for solitary carcinoma of the stomach and were histologically diagnosed as having pN-1 stage tumors, were enrolled in the present study. The topographical patterns of metastasis to regional lymph nodes were reviewed from the pathology records of these patients. RESULTS: A total of 7561 lymph nodes (mean, 39.8/patient; range 15-99/patient) were dissected and metastasis was histologically observed in 523 nodes (6.9%, mean, 2.7/patient). Although perigastric lymph nodes were a common site of metastasis, the distribution of positive nodes depended on tumor location. As the number of positive nodes increased, a more diffuse pattern of regional involvement was noted. Skip metastasis was identified in 10 (5%) out of 190 patients. This unusual pattern of metastasis was found in 9 (14%) out of 63 patients with single positive nodes, while only one (1%) out of 127 patients with 2-6 positive nodes exhibited this pattern of metastasis. The difference between the two groups was statistically significant (p < 0.0001). CONCLUSION: Although perigastric lymph nodes are important first sites of drainage from pN-1 stage gastric tumors, the pattern of lymph node metastasis varies widely within a regional area even in pN-1 stage patients.

Preconditioning with tin-protoporphyrin IX attenuates ischemia/reperfusion injury in the rat kidney.

BACKGROUND: Heme oxygenase (HO)-1 is induced as a unique stress response and leads to a transient resistance against oxidative damage, including ischemia and reperfusion (I/R) injury. In the present study, we examined whether HO-1 induction may confer a protection against I/R injury in the rat kidney. METHODS: Lewis rats were divided into four groups as follows: (1) vehicle group; (2) group treated with ferri-protoporphyrin IX (hemin), an inducer of HO; (3) group treated with low-dose tin-protoporphyrin IX (SnPP), an inhibitor of HO; and (4) group treated with high-dose SnPP. Renal warm ischemia for 60 minutes was performed 24 hours after each treatment. RESULTS: At 24 hours after treatment, hemin induced a significant increase in renal HO activity, but failed to induce HO-1 protein synthesis. Although both low- and high-dose SnPP reduced HO activity, a marked HO-1 expression was observed only in the high-dose SnPP-treated kidney. Hemin exacerbated the renal function after reperfusion, while high-dose SnPP significantly suppressed the intercellular adhesion molecule (ICAM)-1 expression, the infiltration of ED-1-positive macrophages and the expression of activated caspase-3, which resulted in attenuation of apoptotic cell death and ameliorated I/R injury. CONCLUSION: These results suggest that prior induction of HO-1 protein by high-dose SnPP may lead to anti-inflammatory and antiapoptotic effects on warm renal I/R injury independently of its enzyme activity, and that HO enzyme activation may not always act as an antioxidant, especially under I/R-induced oxidative stress.

Evaluation of the morphology of submucosal tumor invasion and its volume in early gastric cancer.

BACKGROUND: The aim of the present study was to evaluate the clinical importance of the morphology of submucosal tumor invasion and its volume in early gastric cancer. MATERIALS AND METHODS: The subjects were 92 patients with a single lesion of early gastric cancer, who underwent gastrectomy with dissection of lymph nodes, and in whom the lesion was histologically-diagnosed as early gastric cancer with submucosal invasion. The volume of lesions (Vsm, S: < 50 mm3, L: > = 50 mm3) was determined by reconstructing submucosal lesions by the surface rendering method using pathological tissue sections (mean, 3.6 sections/lesion). The relationships between the volume of lesions and lymph node metastasis and between conventional clinicopathological parameters and lymph node metastasis were evaluated. RESULTS: Lymph node metastasis was observed in 18 patients (20%). The depth of submucosal invasion was 1.7 +/- 1.4 mm (mean +/- S.D.; range, 0.2-7.5 mm). sm1 (depth of submucosal tumor invasion < 0.5 mm) was observed in 11 patients (12%), and sm2 (depth of submucosal tumor invasion > = 0.5 mm) in 81 patients (88%). The mean Vsm was 104.1 +/- 215.4 mm3 (0.4-1,730.5 mm3). Fifty-seven patients (62.0%) were in group S, and 35 patients (38.0%) in group L. There was a significant difference between lymph node metastasis and Vsm (S vs. L) alone (p = 0.006). Logistic regression analysis also demonstrated that Vsm alone was correlated with lymph node metastasis (p = 0.005; odds ratio, 1.27; 95% confidence interval, 0.074-0.401). CONCLUSION: The volume of submucosal lesions in early gastric cancer is important for evaluating lymph node metastasis.

Immunohistochemical study of collagen synthesis in an in-vitro model of scirrhous carcinoma of the stomach.

BACKGROUND/AIMS: The mechanisms involved in the unique stromal change that occurs upon cancer invasion are poorly understood in scirrhous carcinoma of the stomach. METHODOLOGY: Three different human gastric cancer cell lines (KATO-III, MKN-28, MKN-45) and human fibroblast cells (TIG-101) were co-cultured three-dimensionally in collagen gels. The gels, in vitro models of gastric cancer, were immunostained by monoclonal antibodies to human placental prolyl 4-hydroxylase (PH, a key enzyme of collagen synthesis) and then examined by light and electron microscopy. RESULTS: Under co-culture of cancer cells and fibroblasts, cytoplasmic staining for PH was observed in both the cancer cells (KATO-III, MKN-28, MKN-45) and fibroblasts. No significant difference in the expression patterns of the alpha- and beta-subunits of PH was observed not only among the KATO-III, MKN-28 and MKN-45 cell lines but also between cancer cells and fibroblasts. CONCLUSIONS: These findings indicate that both cancer cells and fibroblasts can synthesize collagen in gastric cancer models. Moreover, this property may not be a unique characteristic of scirrhous gastric cancer cells, but common to gastric cancer cells and fibroblasts in vitro.

Clinical evaluation of pN-stage (TNM) in gastric cancer: an analysis of distribution of regional lymph nodes in node-positive patients.

BACKGROUND: The aims of the present study were to identify the distribution of regional lymph nodes in gastric cancer patients based on the number of nodes and to assess the influence of the examined area of lymph nodes on the determination of node stage according to TNM in node-positive patients with gastric cancer. MATERIALS AND METHODS: A total of 346 node-positive patients with primary solitary carcinoma of the stomach (210 males and 136 females; age range, 27 to 84 years; mean, 58.5 years), who underwent curative gastric resection combined with D2 or more extended lymph node dissection, were enrolled in the present study. The anatomical distribution of regional lymph nodes at each station classified according to the JCGC was assessed from pathology records. RESULTS: The number of first tier and all regional nodes dissected was < 15 in 7 patients (2%) of all patients and <15 in 37 patients (11%), respectively. Metastasis to first tier nodes was found in 2129 nodes (21%) but not in 8199 nodes (79%) and to second tier nodes in 375 nodes (9%) but not in 4028 nodes (91%), representing a significant difference between the two node groups (p<0.0001). No metastasis to first tier nodes was found in 12 patients (5%) out of 229 patients with pN1 tumor. Similarly, the number of metastases to first tier nodes in 15 patients (21%) out of 73 patients with pN2 tumor and in 13 patients (29%) out of 44 patients with pN3 tumor were 1-6 and 7-15, respectively. CONCLUSION: The present findings suggest that the extent of lymph node dissection does affect node stage as classified according to TNM and that restriction of the number of dissected regional lymph nodes (> or = 15 lymph nodes) may not be essential for practical staging of TNM.

Neutrophil elastase inhibitor attenuates lipopolysaccharide-induced hepatic microvascular dysfunction in mice.

The present study was conducted to elucidate the role of neutrophil elastase in lipopolysaccharide (LPS)-induced hepatic microvascular injury by using in vivo microscopy. The intravenous (i.v.) injection of LPS (0.1 mg/kg) in male C3H/HeN mice caused significant hepatic microcirculatory dysfunction: leukocyte adhesion to the sinusoids as well as to the venule, and reduced sinusoidal perfusion, in comparison with vehicle-treated mice. Concomitantly, the serum alanine aminotransferase (ALT) activity at 4 h after LPS injection was significantly increased. The serum concentrations of tumor necrosis factor (TNFalpha) and interleukin-1beta (IL-1beta) at 1 h and at 4 h after LPS injection, respectively, were significantly elevated. Neutrophil elastase inhibitors, ONO-5046 (30 and 90 mg/kg, i.v., 0 and 2 h after LPS injection) or FK706 (30 and 100 mg/kg, i.v., 0 and 2 h after LPS injection) minimized the LPS-induced hepatic microcirculatory dysfunction in a dose-dependent manner. Treatment with ONO-5046 and FK706 significantly reduced the ALT level as well as the serum concentrations of TNFalpha and IL-1beta. In addition, ONO-5046 and FK706 attenuated both hepatic microcirculatory dysfunction and liver injury mediated by TNFalpha and IL-1beta (10 microg/kg i.v.). Furthermore, both ONO-5046 and FK706 improved human neutrophil elastase (10 microg/kg i.v.)-induced hepatic microcirculatory dysfunction, although neutrophil elastase did not increase the levels of TNFalpha and IL-1beta. These results suggest that neutrophil elastase aggravates the LPS-induced hepatic microvascular dysfunction. Neutrophil elastase inhibitors attenuate hepatic microvascular dysfunction in response to LPS by inhibiting TNFalpha and IL-1beta production. Neutrophil elastase inhibitors also reduce the microvascular dysfunction mediated by TNFalpha and IL-1beta as well as by neutrophil elastase.

Effect of FR167653, a novel inhibitor of tumor necrosis factor-alpha and interleukin-1beta synthesis on lipopolysaccharide-induced hepatic microvascular dysfunction in mice.

Tumor necrosis factor-alpha (TNFalpha) and interleukin-1 (IL-1) have been recognized as key proinflammatory mediators in the pathogenesis of lipopolysaccharide (LPS)-induced liver injury. In the present study we examined the effect of FR167653, a novel inhibitor of TNFalpha and IL-1 synthesis, on the hepatic microvascular response to LPS using in vivo microscopy. Significant hepatic microvascular responses comprising leukocyte adhesion to the sinusoidal wall and central venules and reduced sinusoidal perfusion appeared 2 and 4 h after LPS (0.1 mg/kg, i.v.) injection in male C3H/HeN mice (LPS sensitive) when compared with male C3H/HeJ mice (LPS resistant). The serum concentrations of TNFalpha at 1.5 h and IL-1beta at 4 h after injection of LPS, as determined by enzyme-linked immunosorbent assay, were significantly higher in C3H/HeN mice than in C3H/HeJ mice. Administration of murine TNFalpha or IL-1beta (10 microg/kg., i.v., respectively) in both C3H/HeN and C3H/HeJ mice elicited the hepatic microvascular responses that were similar to those produced by LPS injection in C3H/HeN mice. FR167653 (1 and 10 mg/kg, i.v., 0 and 2 h after LPS injection) significantly reduced leukocyte adhesion and restored sinusoidal perfusion in a dose-dependent manner in C3H/HeN mice 4 h after LPS injection. The levels of TNFalpha, IL-1beta, and alanine aminotransferase also were significantly lower in FR167653-treated endotoxemic C3H/HeN mice than those in vehicle-treated endotoxemic animals. The results suggest that the hepatic microvascular response to LPS is partly mediated by TNFalpha and IL-1beta, and that FR167653 prevents LPS-induced hepatic microcirculatory dysfunction by inhibiting the production of TNFalpha and IL-1beta.

Effects of cortisol administration on hepatic circulation during brain death in rabbits.

BACKGROUND: Hemodynamic instability and endocrinologic alterations during brain death contribute to dysfunction of donor organs. The present study was conducted to examine the effect of cortisol administration on hepatic circulation in brain-dead hypotensive donors. METHODS: Brain death was created by inflating a balloon catheter inserted into the epidural space in rabbits. In another set of experiments, non-brain-dead rabbits were bilaterally adrenalectomized. At 1 hour of equilibration after brain death or adrenalectomy, cortisol at a dose of either 0.05 or 5 mg/kg/hr was given intravenously for 5 hours. RESULTS: The induction of brain death resulted in a significant decrease in mean arterial pressure (MAP), whereas MAP after adrenalectomy was maintained. Both brain death and adrenalectomy caused an approximately 40% decrease in the portal vein blood flow (PVF) and hepatic tissue blood flow (HTF) and a significant increase in serum hyaluronic acid (HA) level as well as alanine aminotransferase (ALT) level. These changes were associated with a substantial decrease in serum cortisol level. Transmission electron microscopic examination showed swollen Kupffer cells with phagocytosis. Cortisol supplement after brain death or adrenalectomy significantly increased PVF and HTF to prevalues without affecting MAP. Both dosing rates of cortisol also significantly decreased serum HA and ALT levels and attenuated Kupffer cell activation. CONCLUSIONS: These results suggest that cortisol administration exhibits beneficial effects on hepatic circulation in hemodynamically unstable brain-dead animals.

Blockade of bradykinin B(2) receptor suppresses acute pancreatitis induced by obstruction of the pancreaticobiliary duct in rats.

1. The involvement of bradykinin (BK) B(2) receptor in acute pancreatitis induced by pancreaticobiliary duct ligation was investigated in rats. 2. The activities of amylase and lipase in the serum, the water content of the pancreas, and vacuolization of the acinar cells were significantly increased 2 h after obstruction of the duct in Sprague-Dawley rats. 3. Elevated serum amylase activity, increased pancreatic oedema, and damage of the pancreatic tissue were significantly less marked in plasma kininogen-deficient, B/N-Katholiek rats than in the normal strain, B/N-Kitasato rats 2 h after the ligation. 4. Obstruction of the pancreaticobiliary duct augmented the level of (1-5)-BK (Arg(1)-Pro(2)-Pro(3)-Gly(4)-Phe(5)), a stable BK metabolite, in the blood from 73.0+/-21.7 pg ml(-1) at 0 h to 149.8+/-38.0 pg ml(-1) at 2 h after the induction of pancreatitis in SD rats. 5. Administration of a BK B(2) receptor antagonist, FR173657 (100 mg kg(-1), p.o.) or Hoe140 (100 nmol kg(-1), s.c.), reduced the elevation of amylase and lipase activities in the serum and of pancreatic water content in a dose-dependent manner. The effective attenuation of oedema formation and vacuolization by the antagonists was also confirmed light-microscopically. In contrast, treatment with gabexate mesilate or indomethacin did not cause significant suppression of the pancreatitis. 6. These findings suggest a possible involvement of kinin B(2) receptor in the present pancreatitis model. Furthermore, they point to the potential usefulness of the B(2) receptor in clinical acute pancreatitis.

Biliary tract cancer treatment: results from the Biliary Tract Cancer Statistics Registry in Japan.

BACKGROUND/PURPOSE: A registry project for cancers of the biliary tract accumulated a total of 11,030 cases for 10 years. In the present study, registered cases were analyzed for information bearing on problems with the treatment of cancer of the biliary tract. The Japanese classification of lymph nodes was also considered on the basis of the results of this study. METHODS: In 11,030 cases, the site of cancer was the gallbladder in 4,774, the bile duct in 4,833, and the papilla of Vater in 1,423. Those cases were analyzed with regard to patient survival according to the stage of disease and the extent of lymph node metastasis. RESULTS: More than 11,000 cases of cancer of the biliary tract have been registered to date from 158 member institutions of the Japanese Society of Biliary Surgery. While the 5-year survival rates for stage I gallbladder cancer and cancer of the papilla were 77% and 75%, respectively, those for stage I hilar or upper bile duct cancer and middle or lower bile duct cancer were 47% and 54%. For stage II and stage III disease, the 5-year survival rates were about 50% for gallbladder cancer and 30% or higher for cancer of the papilla, while survival was only 20% to 30% for bile duct cancer, regardless of specific site. For stage IV, the 5-year survival rate was unexpectedly high, being about 10% or higher for cancers at all sites, with 19% for cancer of the papillary region being the highest. Thus, there still seem to remain surgical indications for stage IV cancers. The lymph node metastasis rate was about 40% for cancers at all sites. Changes in surgical procedures to improve the 5-year survival rate in patients with n2 metastasis or less will be needed. Noncurative resection occurred frequently for cancers at all sites, particularly in cancers of the hilar or upper bile duct, accounting for 60% of cases or more. We have to recognize that measures to reduce inadvertent noncurative resection are fundamental to the treatment of cancer. CONCLUSIONS: Considering the survival results according to specific lymph nodes involved, we concluded that the Japanese classification of lymph nodes, particularly hepatoduodenal ligament lymph nodes, should be reexamined, while another procedure to remove such lymph nodes completely should be developed.