Effect of proton pump inhibitors on the development of hypomagnesemia induced by panitumumab.

Panitumumab, a therapeutic agent for unresectable advanced/recurrent colorectal cancer, is a human IgG2 monoclonal antibody that binds to and inhibits the activity of the epidermal growth factor receptor (EGFR). The onset of hypomagnesemia is a known side effect of anti-EGFR inhibitors, including panitumumab, and it is thought that inhibition of reabsorption of Mg in renal tubules is one of the causes. In addition, recent reports have shown that long-term administration of proton pump inhibitors (PPIs) reduces serum magnesium levels. Therefore, in this study, 102 patients who received oral PPIs treated with panitumumab were classified into a PPI combination group and a PPI non-combination group, and the effect of PPIs on the development of grade 2 or higher hypomagnesemia was investigated. The incidence of hypomagnesemia in the PPI combination group (46.9%, 15/32) was higher than that in the PPI non-combination group (25.7%, 18/70). A comparison of the backgrounds of the two groups of patients showed a significant difference in serum albumin levels. PPI administration was significantly associated with panitumumab-induced hypomagnesemia development when adjusted for known risk factors, serum albumin level, renal function, and oral magnesium oxide tablets in Cox proportional hazards regression analysis (hazard ratio 2.09; 95% confidence interval 1.03-4.22; P =0.040). These results indicate that detailed monitoring of serum magnesium levels is recommended for patients treated with panitumumab and co-administration of PPIs.

Structure-behaviour correlations between two genetically closely related snail species.

Species, through their structure and composition, have evolved to respond to environmental constraints. Predator-prey interactions are among environmental pressures that can lead to speciation, but it remains unclear how this pressure can be related to the material structure and performance. Recently, two land snails, Karaftohelix editha and Karaftohelix gainesi, were found to exhibit divergent phenotypes and responses to predation despite sharing the same habitat and most of their genome. Indeed, under attack from a beetle, K. editha snails retract into their shell whereas K. gainesi snails swing their shell. In this paper, we looked at the microstructure, composition, morphology and mechanics of the shells of those two species and discuss potential relationships between material structure and the snail defence behaviour. The results of this study provide additional arguments for the role of predator-prey interactions on speciation, as well as an unusual approach for the design of biomimetic structures adapted to a particular function.

Right hepatic artery interruption and prostaglandin E1 in total or proximal pancreatectomy for pancreatobiliary malignancy.

BACKGROUND/AIMS: Advanced hepato-biliary-pancreatic malignancy can frequently involve the hepatic artery. We evaluated the use of prostaglandin E1 in total or proximal pancreatectomy with the right hepatic artery interruption. METHODOLOGY: A Consecutive seven of 117 patients (6.0%) in whom the right hepatic artery was interrupted and not reconstructed were reviewed retrospectively. Four of them received prostaglandin E1 (10-20 ng/kg/min) until the fifth postoperative day, while, the remaining three did not. The effect of prostaglandin E1 was compared concerning complication and hepatic function. RESULTS: The right hepatic artery was intentionally resected because of cancer invasion in five patients with biliary tract carcinoma, while, accidentally transected in two with pancreatic carcinoma. Operative deaths did not occur. The biliary leakage was identified in one patient treated without prostaglandin E1. Although a marked rise in glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase levels was observed, hepatic dysfunction was successfully treated conservatively in all patients. The glutamic oxaloacetic transaminase and lactate dehydrogenase values were significantly lower (P < 0.05) in patients treated with prostaglandin E1 compared with those without prostaglandin E1. CONCLUSIONS: The prostaglandin E1 infusion can be helpful for biliary anastomosis and hepatic function in radical hepato-biliary-pancreatic surgery with the right hepatic artery interruption.

Jejunal interposition to prevent postgastrectomy syndromes.

BACKGROUND: Postgastrectomy syndromes include reflux gastritis and oesophagitis, dumping syndrome, intractable diarrhoea and afferent loop syndrome. To prevent such syndromes, since January 1994 jejunal interposition has been used following distal gastrectomy. The aim of this study was to evaluate the benefit of this procedure. METHODS: A consecutive series of 42 patients who underwent distal gastrectomy for gastric cancer was studied. Twenty-two patients had a Billroth I procedure before January 1994, and 20 patients had isoperistaltic jejunal interposition using a 10-12-cm segment after January 1994. RESULTS: The mean operating time was 260 min for Billroth I and 352 min for jejunal interposition. No serious postoperative complications arose. Reflux gastritis occurred in 19 patients after Billroth I but in none after jejunal interposition. Five patients in the Billroth I group had complaints consistent with dumping syndrome, compared with none after jejunal interposition. The barium gastric emptying time was significantly shorter after Billroth I (mean(s.d.) 269(225)s) than after jejunal interposition (736(479) s) (P < 0.01). CONCLUSION: Jejunal interposition prevented reflux gastritis and inhibited rapid gastric emptying. Postgastrectomy syndromes were effectively prevented by this reconstruction procedure.

Hepatic LDL receptor mRNA in rats is increased by dietary mushroom (Agaricus bisporus) fiber and sugar beet fiber.

Plasma cholesterol concentration is reduced by feeding some dietary fibers and mushroom fruit body, but the mechanism is not fully understood. We examined the effects of mushroom (Agaricus bisporus) fiber and sugar beet fiber on serum cholesterol and hepatic LDL receptor mRNA in rats. Rats were fed a cholesterol-free diet with 50 g/kg cellulose powder (CP), 50 g/kg mushroom (Agaricus bisporus) fiber (MSF) or 50 g/kg sugar beet fiber (BF) for 4 wk. There were no significant differences in the body weight, food intake and cecum weight among the groups. The relative liver weight in the CP group was significantly greater than that in the MSF and BF groups. The cecal pH in the CP and MSF groups was significantly higher than that in the BF group. Cecal acetic acid, butyric acid and total short-chain fatty acid (SCFA) concentrations in the BF group were significantly higher than those in the other groups. The serum total cholesterol, VLDL + intermediate density lipoprotein (IDL) + LDL cholesterol concentrations in the CP group were significantly greater than those in the MSF and BF groups. The HDL cholesterol concentration in the MSF group was significantly lower than that in the CP group. The hepatic LDL receptor mRNA level in the MSF and BF groups was significantly higher than that in the CP group. The results of this study demonstrate that mushroom fiber and sugar beet fiber lowered the serum total cholesterol level by enhancement of the hepatic LDL receptor mRNA.

Patterns of lymph node metastasis in carcinoma of the ampulla of Vater.

BACKGROUND/AIMS: Identification of lymph node metastasis may guide surgical therapy. The aim of this study was to clarify the lymphatic spread in ampullary carcinoma in relation to local tumor extent (pT category in the pTNM classification). METHODOLOGY: The distribution and number of lymph node metastases were histologically examined in 35 patients with ampullary carcinoma. RESULTS: Lymph node metastases were present in 10 of 15 patients (67%) with pT2 tumor and in 10 of 11 (91%) with pT3 tumor. Nodal involvement was not identified in 9 patients with pT1 tumor. The incidence of node-positive patients was higher in pT2 and pT3 tumors than in pT1 tumors (P < 0.01). The total number of positive nodes per node-positive patient was greater in pT3 tumors than in pT2 tumors (mean 3.50 vs. 1.30, P < 0.001). All node-positive patients had metastasis to the posterior pancreaticoduodenal node. The number of positive nodes per node-positive patient in both the posterior pancreaticoduodenal and the superior mesenteric region was greater in pT3 tumors than in pT2 tumors (P < 0.01 and P < 0.05). CONCLUSIONS: With increasing pT category in ampullary carcinoma, lymphatic spread extended from the posterior pancreaticoduodenal region to the superior mesenteric nodes.

Laparoscopic cholecystectomy in the treatment of patients with gall bladder cancer.

BACKGROUND: Surgical procedures based on the depth of the primary tumor invasion (pT category) have been proposed in the treatment of gallbladder cancer (GBC). Trocar site metastases have been reported in patients who underwent laparoscopic cholecystectomy (LC) for preoperatively undiagnosed GBC. STUDY DESIGN: The aim of this study was to clarify the role of LC as a surgical strategy for GBC. From 1986 to 1998, 56 patients with GBC underwent surgical resection. Survival rates were compared retrospectively according to pT category and use of LC. RESULTS: Five-year survival was 91% for pT1 (n = 13), 64% for pT2 (n = 25), 34% for pT3 (n = 14), and 0% for pT4 tumors (n = 4; p<0.0001). LC was performed on 11 patients (4 with pT1, 5 with pT2, and 2 with pT3 tumors). Of the seven patients with pT2 or pT3 tumors, three underwent a second radical operation, three had an open radical operation to which the procedure was converted from LC, and one underwent no additional procedures. For pT1 tumors, one patient died of trocar site metastasis from bile spillage after LC. For pT2 or pT3 tumors, 5-year survival was 63% for radical surgery (n = 35) and 0% for cholecystectomy alone (n = 4; p<0.05). For pT2 or pT3 tumors treated by radical surgery, 5-year survival was 75% for laparoscopic approach (n = 6) and 60% for open surgery (n = 29; not significant). CONCLUSIONS: LC may help to establish the diagnosis and to determine the surgical strategy for undiagnosed GBC. It is important to prevent spillage or implantation of malignant cells during LC. For pT2 or pT3 tumors diagnosed laparoscopically, a second or converted open radical surgery is necessary.

Treatment for extrahepatic metastasis of hepatocellular carcinoma following successful hepatic resection.

BACKGROUND/AIMS: Recent advances in both the diagnosis and treatment of hepatocellular carcinoma (HCC) have improved its prognosis. Intrahepatic recurrence after hepatectomy can be treated with repeated hepatectomy, transhepatic arterial embolization (TAE), percutaneous ethanol injection therapy (PEIT), or microwave coagulo-necrotic therapy. However, treatment for extrahepatic recurrence is also important in prolonging survival in some patients. METHODOLOGY: After radical hepatectomy in 155 patients, extrahepatic recurrences were found in 15 patients that underwent subsequent treatment. The interval between completing treatment for the primary tumor and the discovery of metastasis, the location and mode of treatment of the metastasis, and the outcomes were analyzed. RESULTS: Distant metastasis was detected at a mean of 7 months after radical resection of the primary tumor. Location of the metastasis included lung, bone, and adrenal gland. Four patients had no intrahepatic recurrence and 11 patients had simultaneous intrahepatic recurrence. Six patients with intrahepatic and extrahepatic recurrence that underwent systemic chemotherapy had poor prognoses, and all died within 12 months as a result of progression of the intrahepatic tumor. Five patients with intra- and extrahepatic recurrence that underwent systemic chemotherapy combined with hepatic arterial infusion chemotherapy had relatively good outcomes; all survived for more than 12 months. CONCLUSIONS: These results suggest that to obtain a good prognosis for extrahepatic metastasis coexisting with intrahepatic recurrence, intrahepatic recurrence should be controlled by locoregional therapy, and extrahepatic metastasis should be controlled by systemic chemotherapy and/or irradiation therapy.

Augmentative effect of cyclosporin A on rat liver regeneration: influence on hepatocyte growth factor and transforming growth factor-beta(1).

We investigated the effect of cyclosporin A (CsA) on rat liver regeneration following partial hepatectomy with reference to cytokine production. Rats were divided into two groups: those without CsA pretreatment (group 1) and those with CsA pretreatment (group 2). Animals were given olive oil vehicle or CsA (10 mg/kg) dissolved in olive oil daily by gavage from 4 to 1 days before hepatectomy. The ratio of regenerating liver weight to initial body weight in group 2 was significantly higher than that in group 1 at 72 h. Although a peak 5-bromo-2-deoxyuridine labeling index was found at 24 h after hepatectomy in both groups, the peak value in the CsA-treated animals was significantly higher than in controls. In both groups, hepatocyte growth factor concentrations in both plasma and liver tissue showed maximal values at 12 h. Liver tissue values in group 2, however, were significantly higher from 1 to 12 h compared to group 1. Transforming growth factor-beta(1) (TGF-beta(1)) concentrations showed minimal serial changes in group 1, while those in liver tissue of group 2 rats were significantly lower than in group 1. Plasma TGF-beta(1) concentrations did not differ. These results suggest that upregulation of hepatic regeneration with CsA pretreatment might be attributed in part to changes in production of these mitogenic and mitoinhibitory cytokines.

Patterns of lymph node metastasis in carcinoma of the distal bile duct.

BACKGROUND/AIMS: The aim of this study was to clarify the lymphatic spread in distal bile duct carcinoma in relation to local tumor extent (pT category). METHODOLOGY: The distribution and number of involved nodes were examined in 42 patients with distal bile duct cancer. RESULTS: Lymph node metastases were present in 25 of 42 patients (60%); 5 of 12 (42%) with pT2 tumors and 20 of 26 (77%) with pT3 tumors. Nodal involvement was not identified in 4 patients with pT1 tumors. The incidence of node positivity was higher in patients with pT3 tumors than in those with pT1 or pT2 tumors (p<0.01 or p<0.05). The total number of positive nodes was greater in patients with pT3 tumors than in those with pT2 tumors (mean: 3.08 vs. 0.75; p<0.01). All node-positive patients had involved nodes in the hepatoduodenal ligament or posterior pancreaticoduodenal region, or both. The number of positive nodes in the superior mesenteric and para-aortic region was greater in patients with pT3 tumors than in those with pT2 tumors (p<0.05). CONCLUSIONS: As tumor invades the pancreas from the distal bile duct, lymphatic spread extends from the hepatoduodenal ligament or posterior pancreaticoduodenal region to the superior mesenteric and para-aortic nodes.

A serosurvey of Borna disease virus infection in wild rats by a capture ELISA.

For a serological diagnostic test for Borna disease (BD), we developed a capture ELISA with specificity and sensitivity based on detection of antibodies against BD virus (BDV) p40 protein. Using our capture ELISA system, the antibody response of rats inoculated intracerebrally with BDV at 4 weeks after birth showed a sharp increase from 1 to 4 weeks postinoculation (p.i.) and a steady level after 5 weeks p.i. To investigate prevalence of BDV infection among wild rats, we examined sera of Rattus norvegicus in Kami-iso town, Oshima district, Hokkaido, suggesting that rats in this area had not been infected by BDV.

The pattern of lymphatic spread in carcinoma of the distal bile duct.

From 1995 to 1996, 20 patients with carcinoma of the distal bile duct (Bi) and 16 with carcinoma of the pancreatic head (Ph) underwent pancreaticoduodenectomy or total pancreatectomy with systematic extended lymphadenectomy. Histopathological specimens were examined with special reference to nodal metastases. Pancreatic parenchymal invasion was present in 10 of 20 patients with Bi. The frequency of nodal involvement in Bi with pancreatic invasion and Ph was significantly greater than in Bi without pancreatic invasion (p<0.05 and p<0.01, respectively). Metastasis to nodes around the superior mesenteric artery or abdominal aorta in Bi with pancreatic invasion occurred more frequently than in Bi without pancreatic invasion (p<0.05), though was not different from the frequency observed in Ph. The pattern of lymphatic spread in distal bile duct carcinoma with pancreatic invasion was practically equal to the mode in carcinoma of the pancreatic head.

Delayed massive intraperitoneal hemorrhage after pancreatoduodenectomy.

Of 144 cases of pancreatoduodenectomy we treated 6 patients (4.2%) with delayed massive bleeding. Massive hemorrhage occurred 14 to 38 days later. Leakage of the pancreatojejunostomy was confirmed in all patients. A "sentinel bleed" was evident in five patients with arterial bleeding. One patient with hemorrhage of the superior mesenteric vein was successfully treated conservatively. One patient with bleeding from the left gastric artery stump survived emergency re-operation. Two of four patients with hemorrhage from the gastroduodenal artery stump were successfully treated with selective embolization of the common hepatic artery. The remaining two patients died of uncontrollable re-bleeding or hepatic failure following hemostasis. Angiography and selective embolization are effective for identification and control of the bleeding site when delayed hemorrhage occurs after pancreatoduodenectomy. Intensive treatment is necessary to compensate for reduced hepatic arterial blood supply in cases requiring surgical or radiological interruption of the common hepatic artery.

Intrahepatic peripheral cholangiocarcinoma: mode of spread and choice of surgical treatment.

BACKGROUND: Classification of macroscopic appearance and standard operative procedures for intrahepatic cholangiocarcinoma (ICC) are still controversial. METHODS: The mode of spread of 12 resected ICCs was examined by light microscopy, and the appropriate operative procedures for the various tumours were considered. RESULTS: Macroscopically, nine tumours were classified as mass-forming type and three as periductal infiltrating type. All patients were treated by major hepatectomy; resection of the extrahepatic bile duct was included in two cases of the periductal infiltrating type. Microscopically, invasion into the portal vein, intrahepatic metastasis and perineural or lymphatic vessel invasion occurred in none, one and all of three tumours of the periductal infiltrating type and in eight, six and six of nine tumours of the mass-forming type. CONCLUSION: ICC of the periductal infiltrating type has a tendency to spread along Glisson's sheath via lymphatic vessels. By contrast, ICC of the mass-forming type tends to invade the liver via the portal vein system; such tumours begin to invade Glisson's sheath through the lymphatic vessels when the tumour has increased in size. Therefore, major hepatectomy with combined resection of the extrahepatic bile duct should be performed for all ICCs of the periductal infiltrating type and for those of the mass-forming type with invasion of Glisson's sheath.

Carcinoid somatostatinoma of the papilla of Vater: a case report.

A 57 year-old Japanese man with a carcinoid somatostatinoma of the papilla of Vater is presented. He was found to have cholecystolithiasis without any symptoms. Physical examination showed no abnormal findings. Routine laboratory data gave normal results, except for glucose intolerance and an elevated somatostatin concentration. A yellowish papillary tumor was found at the papilla of Vater, and histological examination suggested the diagnosis of carcinoid. He underwent a pancreatoduodenectomy in March 1992. The gallbladder contained a single pure cholesterol stone. Histological, immunohistochemical, and electron microscopic studies resulted in the diagnosis of a carcinoid somatostatinoma of the papilla of Vater, without regional lymph node metastases. Post-operative pancreatic juice output from the total pancreatic duct drainage increased to more than 1000 mL/day. Although an anastomotic leakage of the pancreatojejunostomy was noted, the pancreatic fistula closed 8 weeks later. His postoperative somatostatin value was normal. He has been well for 54 months following surgery, without any signs of recurrence.

Para-aortic lymph node metastasis in carcinoma of the distal bile duct.

BACKGROUND/AIMS: Lymph node dissection plays an important role in radical surgery for pancreaticoduodenal carcinomas. The aim of this study was to identify the critical areas of lymph node dissection in carcinoma of the distal bile duct. METHODOLOGY: Between January 1995 and December 1996, 20 consecutive patients with distal bile duct cancer underwent pancreaticoduodenectomy with extended lymph node dissection (including the para-aortic nodes). Histopathologic findings were examined with special reference to lymph node metastasis. RESULTS: Histological evidence of lymph node metastasis was found in 11 patients (55%). The areas with frequent metastases were the posterior pancreaticoduodenal lymph nodes (35%), and the nodes around the hepatoduodenal ligament (35%) and around the common hepatic artery (30%). Para-aortic lymph node involvement was identified in 5 patients (25%). Most of these existed in the inter-aorticocaval space. Pancreatic parenchymal invasion was present in 10 patients. Half of the patients with pancreatic invasion had para-aortic nodal involvement. Para-aortic lymph node metastasis was significantly associated with pancreatic parenchymal invasion (p<0.05). CONCLUSIONS: In carcinoma of the distal bile duct with pancreatic parenchymal invasion, extended lymph node dissection (including para-aortic nodes) should be undertaken because of the relatively high incidence of metastasis.