Clinical and experimental studies of intraperitoneal lipolysis and the development of clinically relevant pancreatic fistula after pancreatic surgery.

BACKGROUND: Visceral obesity is one of the risk factors for clinically relevant pancreatic fistula after pancreatic resection. The objective of this study was to evaluate the impact of intraperitoneal lipolysis on postoperative pancreatic fistula. METHODS: The degree of intraperitoneal lipolysis was investigated by measuring the free fatty acid concentration in drain discharge in patients after pancreatic resection. An experimental pancreatic fistula model was prepared by pancreatic transection, and the impact of intraperitoneal lipolysis was evaluated by intraperitoneal administration of triolein (triglyceride) with, or without orlistat (lipase inhibitor). RESULTS: Thirty-three patients were included in the analysis. The free fatty acid concentration in drain discharge on postoperative day 1 was significantly associated with the development of a clinically relevant pancreatic fistula (P = 0·004). A higher free fatty acid concentration in drain discharge was associated with more visceral adipose tissue (P = 0·009). In the experimental model that included 98 rats, intraperitoneal lipolysis caused an increased amount of pancreatic juice leakage and multiple organ dysfunction. Intraperitoneal administration of a lipase inhibitor reduced lipolysis and prevented deterioration of the fistula. CONCLUSION: Intraperitoneal lipolysis significantly exacerbates pancreatic fistula after pancreatic resection. Inhibition of lipolysis by intraperitoneal administration of a lipase inhibitor could be a promising therapy to reduce clinically relevant postoperative pancreatic fistula. Surgical relevance Clinically, there are two types of pancreatic fistula after pancreatic resections: harmless biochemical leak and harmful clinically relevant pancreatic fistula. Visceral obesity is one of the known risk factors for clinically relevant pancreatic fistula; however, the underlying mechanisms remained to be elucidated. Patients with clinically relevant pancreatic fistula had a higher free fatty acid concentration in the drain discharge, suggesting a relationship between intraperitoneal lipolysis and pancreatic fistula. The experimental model of pancreatic fistula demonstrated that intraperitoneal lipolysis caused deterioration in pancreatic fistula, suggesting that intraperitoneal lipolysis is one of the mechanisms that drives biochemical leakage to clinically relevant pancreatic fistula. Intraperitoneal administration of a lipase inhibitor prevented lipolysis as well as pancreatic fistula deterioration in the experimental model, suggesting a future clinical application for lipase inhibitors in prevention of clinically relevant pancreatic fistula.

Henoch-Schönlein Purpura After Living Donor Liver Transplantation: Report of the First Case.

Henoch-Schönlein purpura (HSP) is a systemic vasculitis affecting the small vessels that mainly presents in children and young adults. It is characterized by tissue deposition of immunoglobulin A (IgA) immune complexes with the classic manifestations of purpura, arthritis, arthralgia, and gastrointestinal and renal involvements. We report a case of HSP nephritis that occurred 2 years after living-donor liver transplantation (LDLT). After pulse steroid administration, the patient's symptoms disappeared and blood markers normalized. To the best of our knowledge, this is the first HSP case to be reported in a liver transplant recipient.

'Artery-first' approaches to pancreatoduodenectomy.

BACKGROUND: The technique of pancreatoduodenectomy (PD) has evolved. Previously, non-resectability was determined by involvement of the portal vein-superior mesenteric vein. Because venous resection can be achieved safely and with greater awareness of the prognostic significance of the status of the posteromedial resection margin, non-resectability is now determined by involvement of the superior mesenteric artery (SMA). This change, with a need for early determination of resectability before an irreversible step, has promoted the development of an 'artery-first' approach. The aim of this study was to review, and illustrate, this approach. METHODS: An electronic search was performed on MEDLINE, Embase and PubMed databases from 1960 to 2011 using both medical subject headings and truncated word searches to identify all published articles that related to this topic. RESULTS: The search revealed six different surgical approaches that can be considered as 'artery first'. These involved approaching the SMA from the retroperitoneum (posterior approach), the uncinate process (medial uncinate approach), the infracolic region medial to the duodenojejunal flexure (inferior infracolic or mesenteric approach), the infracolic retroperitoneum lateral to the duodenojenunal flexure (left posterior approach), the supracolic region (inferior supracolic approach) and through the lesser sac (superior approach). CONCLUSION: The six approaches described provide a range of options for the early determination of arterial involvement, depending on the location and size of the tumour, and before the 'point of no return'. Whether these approaches will achieve an increase in the proportion of patients with negative margins, improve locoregional control and increase long-term survival has yet to be determined.

Laparoscopic common hepatic artery ligation and staging followed by distal pancreatectomy with en bloc resection of celiac artery for advanced pancreatic cancer.

INTRODUCTION: Adeno-carcinomas of pancreatic body are usually asymptomatic and progress to advanced stage with involvement of major arteries. Resection of advanced cancer along with en bloc resection of a common hepatic artery and celiac trunk enables a "curative" resections and only possible treatment. However, the celiac axis resection always has a risk of compromising blood supply to liver, resulting in the hepatic insufficiency. We evaluated practicability of a two-stage procedure for the advanced pancreases body cancer, laparoscopic clamping of a common hepatic artery followed by open distal pancreatectomy with en bloc celiac arterial resection to prevent the hepatic insufficiency. MATERIALS AND SURGICAL TECHNIQUE: Seventy-five-year-old woman diagnosed with a 50-mm pancreatic body mass, invading splenic artery, common hepatic artery, splenic vein, and portal vein at the confluence. STAGE-1: At laparoscopy, after confirming absence of the peritoneal, superficial liver metastases and negative peritoneal cytology; we approached the common hepatic artery through the lesser sac and ligated. STAGE-2: Her liver function tests were normal after 2 weeks, and CT angiography showed complete blockage of the common hepatic artery with sufficient collateral circulation to the liver through inferior pancreatico-duodenal artery and gastro-duodenal artery. We performed an open distal pancreatectomy with en bloc resection of celiac artery. Histopathology examination confirmed R0 resection. DISCUSSION: The celiac axis resection with distal pancreatectomy improves the chance of R0 resection and potentially, survival of the patient. Preoperative laparoscopic ligation of the common hepatic artery is a safe, effective, and in-expensive technique to prevent postoperative hepatic insufficiency and improves the safety of en bloc celiac artery resection with a distal pancreatectomy. Also these patients have high risk of peritoneal dissemination. Diagnostic laparoscopy is useful to detect occult metastasis, which are missed by per-operative CT scan.

Diffusion-weighed MR imaging of pancreatic carcinoma.

PURPOSE: The aim of this study was to demonstrate the feasibility of body diffusion-weighted (DW) MR imaging in the evaluation of a pancreatic carcinoma. MATERIAL AND METHODS: In nine normal volunteers and in eight patients with pancreatic carcinoma, DW images were obtained on the axial plane scanning with a multisection spin-echo-type single-shot echo planar sequence with a body coil. Moreover, we measured the apparent diffusion coefficient (ADC) value in a circular region of interest (ROI) within the normal pancreas, pancreatic carcinoma, and tumor-associated chronic pancreatitis. RESULTS: On the DW images, all eight carcinomas were clearly shown as high signal intensity relative to the surrounding tissue. The ADC value (x10(-3) mm(2)/s) in the carcinoma was 1.44 +/- 0.20, which was significantly lower compared to that of normal pancreas (1.90 +/- 0.06) and tumor-associated chronic pancreatitis (2.31 +/- 0.18). CONCLUSION: Diffusion-weighted (DW) images can be helpful in detecting the pancreatic carcinoma and accessing the extent of the tumor.

Current topics on precursors to pancreatic cancer.

Prognosis of invasive pancreatic ductal adenocarcinoma is bleak and the vast majority of patients with pancreatic cancer die of their disease. The detection and treatment of the non-invasive precursor lesions of pancreatic cancer offer the opportunity to cure this devastating disease and therefore great efforts are being made to identify the precursors to pancreatic cancer. Several distinct precursor lesions have been identified. Mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and pancreatic intraepithelial neoplasias (PanINs) all harbor varying degrees of dysplasia and stepwise accumulation of genetic alterations, suggesting progression of these lesions from benign toward malignant neoplasms. MCNs have a characteristic ovarian-type stroma. About one-third of MCNs are associated with invasive carcinoma of ductal phenotype. IPMNs are recently established clinical entity with characteristic features of mucin hypersecretion and duct dilatation. Some IPMNs are associated with invasive carcinoma and IPMNs are recognized precursors to pancreatic cancer. PanINs are microscopic proliferative lesions arising from any parts of the pancreatic duct system. Low grade PanINs are commonly found in pancreatic ducts of elder individuals, while high grade PanINs, previously called carcinoma in situ/severe ductal dysplasia, may eventually give rise to invasive pancreatic cancer. Appropriate clinical managements are requisite for patients with MCNs, IPMNs and PanINs. Further investigation of these precursor lesions is expected to reduce the mortality from pancreatic cancer.

Correlations of hemoglobin index (IHb) of gastric mucosa with Helicobacter pylori (H. pylori) infection and inflammation of gastric mucosa.

BACKGROUND: Helicobacter pylori (H. pylori) infection causes various gastric diseases, among them H. pylori-associated gastritis characterized by diffuse redness of the gastric mucosa. The haemoglobin index (IHb) of the fundic mucosa is an objective parameter of the extent of mucosal redness, but it is unclear whether or not IHb can be used as a diagnostic marker for H. pylori infection. The purpose of this investigation was to evaluate the correlations between IHb of the fundic mucosa and H. pylori infection, inflammatory cell infiltration, and inflammatory mediator production. METHODS: IHb of the fundic mucosa was measured in 108 patients with various gastric diseases (group 1), and values were compared between H. pylori-positive and H. pylori-negative patients. Fifteen patients with H. pylori infection from group 1 underwent H. pylori eradication therapy and IHb was measured before and after treatment. Both IHb and inflammatory cell infiltration were assessed in 61 patients (group 2). In 31 patients from group 2, the expression of interleukin (IL)-8 and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) was assayed in gastric biopsy specimens by the reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: IHb levels were significantly higher in H. pylori-positive patients than in H. pylori-negative patients (P < 0.001). IHb was decreased at one month after the eradication of H. pylori (P < 0.001). IHb was higher in patients with infiltration by both mononuclear cells and neutrophils (P < 0.001). There was a significant correlation between the IHb level and the expression of IL-8 mRNA (P < 0.001), as well as between IHb and iNOS mRNA expression (P < 0.05). CONCLUSIONS: There were significant correlations between IHb of the gastric mucosa and H. pylori infection, inflammatory cell infiltration, and IL-8/iNOS mRNA expression, suggesting that IHb is a reliable marker of H. pylori infection for use during follow-up endoscopy after H. pylori eradication therapy.

Effects of diversion and reperfusion of pancreaticobiliary juice on amylase release from isolated rat pancreas.

Diversion of pancreaticobiliary juice from the small intestine results in resetting of the normal negative-feedback regulation of exocrine pancreatic secretion. The mechanism by which this process occurs is not well understood. To examine this regulatory process, we investigated the effects of pancreaticobiliary juice diversion and reperfusion on exocrine pancreas using isolated rat pancreatic acini. Two groups of rats were surgically prepared for pancreaticobiliary juice diversion and reperfusion. Both groups received a liquid diet via a duodenal cannula and saline by intravenous infusion for 24 hours following surgery. Forty-eight hours after the surgery and infusions, the rats were sacrificed, and acinar cells were quickly isolated from each pancreas. Amylase release from isolated acini was measured in response to doses of cholecystokinin octapeptide (CCK-8) and carbachol. Acinar cell receptor binding was measured by using CCK-8 labeled with iodine 125 and N-tritium-methscopolamine bromide as radioligands. Amylase release in response to both CCK-8 and carbachol was significantly decreased in the diversion group when compared with that of the reperfusion group. Receptor binding sites of CCK-8 and methscopolamine bromide were similar in the diversion and reperfusion groups. The results suggest that cholecystokinin- and carbachol-mediated amylase response is affected by pancreaticobiliary juice diversion through a process that most likely involves alteration of post-receptor-mediated intracellular signaling pathways.

Case report of pediatric laparoscopic splenectomy with technical review.

Laparoscopic splenectomy has been accepted as a feasible extension of minimally invasive surgery, which has undergone dramatic improvements in both technology and instrumentation. We performed a laparoscopic splenectomy in a 7-year-old girl with hereditary spherocytosis. The patient recovered rapidly and returned to unrestricted activities quickly. The appropriate positioning of each laparoscopic port is essential for a good operative view and smooth access. It is also important to dissect the hilum of the spleen meticulously. Laparoscopic splenectomy in the pediatric age group appears to be another promising extension of laparoscopic surgery.

Inhibition of nitric oxide synthase causes cardiac phenotypic modulation in rat.

Cardiac gene expressions of collagen and contractile proteins were examined in rats treated with a nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), for 3 weeks. The rats became hypertensive, which caused left ventricular hypertrophy. Among the mRNAs examined, beta-myosin heavy chain was increased and alpha-myosin heavy chain was decreased in both left and right ventricles, whereas skeletal alpha-actin and atrial natriuretic polypeptide were increased in the left ventricle only. Furthermore, coadministration of losartan with L-NAME lowered blood pressure and caused regression of left ventricular hypertrophy, but did not affect beta- and alpha-myosin heavy chain mRNA levels, indicating that L-NAME directly regulates beta- and alpha-myosin heavy chain mRNA.

Solitary cavernous hemangioma of the duodenum: report of a case.

Vascular lesions of the duodenum, including hemangioma, are rare causes of gastrointestinal bleeding. We herein describe a 52-year-old woman with a solitary cavernous hemangioma of the duodenum that caused chronic gastrointestinal bleeding. Repeated upper gastrointestinal endoscopy and a barium meal study revealed a solitary vascular tumor in the fourth portion of the duodenum, although the initial investigations including selective angiography were unsuccessful. A wedge resection of the duodenum was performed and microscopical examination showed a cavernous hemangioma. Vascular lesions should therefore also be considered in the differential diagnosis of patients with gastrointestinal bleeding of unknown origin.

Effects of diet on cholecystokinin-stimulated amylase secretion by pancreatic Acini and amylase mRNA levels in rat pancreas.

To investigate the mechanisms by which dietary compositions regulate the exocrine pancreas, we examined the effects of no-fat diet (NFD) and high-fat diet (HFD) on cholecystokinin (CCK)-stimulated amylase secretion from rat pancreatic acini. Rats were maintained for 4 weeks on NFD or HFD, which contained 0 or 45% fat and 58 or 29% carbohydrates, respectively. Pancreatic acini were isolated and stimulated by graded doses of CCK for 30 min. Maximal CCK-stimulated amylase secretion by pancreatic acini from rats on NFD (23.1 +/- 4.3 U/mg protein at 10(-10) M) was significantly higher than that of HFD (5.5 +/- 1.6 U/mg protein at 10(-10) M). In contrast, expressed as a percentage of the initial content, maximal CCK-stimulated amylase secretion by pancreatic acini from rats on NFD (15.0 +/- 0.8%) tended to be lower than that from rats on HFD (28.1 +/- 3.5%). To study further the effects of the diets on amylase mRNA levels, another group of rats was maintained on the respective diets for 4 weeks, sacrificed, and total pancreatic RNA isolated. Amylase mRNA levels in rats on NFD were 2.5 times higher than in rats on HFD. The results suggest that alterations in CCK-stimulated amylase secretion by pancreatic acini, as well as modifications in pancreatic amylase expression, may be involved in the mechanisms by which the exocrine pancreas adapts to diet.

Protective effects of endothelin-1 on acute pancreatitis in rats.

Endothelin-1, a 21-residue peptide isolated from vascular endothelial cells, has a broad spectrum of actions. To clarify the involvement of endothelin-1 in acute pancreatitis, we examined the effects of endothelin-1 and its receptor antagonist BQ-123 on cerulein-induced pancreatitis in rats. Rats were infused intravenously with heparin-saline (control), endothelin-1 (100 pmol/kg/hr), cerulein (5 micrograms/kg/hr), or cerulein plus endothelin-1 for 3.5 hr. In another experiment, cerulein or cerulein plus BQ-123 (3 mg/kg/hr) was infused. Infusion of cerulein caused hyperamylasemia and pancreatic edema. Endothelin-1, when infused with cerulein, decreased the extent of pancreatic edema with a significant increase in the pancreatic dry- to wet-weight ratio. Histological changes induced by cerulein were markedly attenuated when endothelin-1 was given with cerulein. In contrast, endothelin-receptor blockade with BQ-123 further augmented pancreatic edema caused by cerulein. The extent of inflammatory cell infiltration was greater than BQ-123 was given with cerulein. Endothelin-1 or BQ-123 had no influence on hyperamylasemia. This study suggests that endothelin-1 has protective effects on experimental acute pancreatitis.

Carbachol and cholecystokinin enhance accumulation of nicotine in rat pancreatic acinar cells.

Nicotine is a possible risk factor for chronic pancreatitis and pancreatic cancer. To study the loci where nicotine might exert its effect, we examined interactions between nicotine and rat pancreatic acini. When pancreatic acini were incubated with [3H]nicotine, [3H]nicotine levels in pancreatic acini were increased in time-and dose-dependent manners, and the t1/2 for dissociation of [3H]nicotine was 63.8 min. At 4 degrees C, the association of [3H]nicotine was 33% of the association at 37 degrees C. Unlabeled nicotine had no significant effect on the accumulation of [3H]nicotine. In addition, surface-bound [3H]nicotine was not detected when acini were washed in a low-pH solution or when they were trypsinized. These results suggest that the accumulation of nicotine may be a biological phenomenon and that [3H]nicotine does not bind to surface receptors of acinar cells, but accumulates intracellularly. The addition of verapamil (0.1 mM) or 12-O-tetradecanoylphorbol-13-acetate (1 microM) had no effect on [3H]nicotine association, while 4-bromo-A23187 (2 microM) or EGTA (10 mM) significantly increased the accumulation of [3H]nicotine. Carbachol and cholecystokinin significantly enhanced the accumulation of [3H]nicotine in a dose-dependent manner. Taken together, the increasing effects of carbachol and cholecystokinin on the accumulation of nicotine may explain, at least in part, the mechanisms involved in the multiplicative effects of the combination of two risk factors, smoking habit and high-fat or high-protein diets, on human pancreatic diseases.

Role of angiotensin II in extracellular matrix and transforming growth factor-beta 1 expression in hypertensive rats.

The in vivo effects of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]- L-prolyl-L-phenylalanine), an angiotensin converting enzyme inhibitor, and SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1- yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), an angiotensin AT1 receptor antagonist, were examined on the cardiac and aortic gene expressions of extracellular matrices and TGF-beta 1 in young spontaneously hypertensive rats (SHR). In SHR, types I and III collagen mRNAs were increased in the left ventricle, and in contrast, fibronectin, collagen IV, and transforming growth factor-beta 1 (TGF-beta 1) mRNAs were increased in aorta, compared with those in Wistar-Kyoto rats. All the enhanced mRNAs in both organs in SHR were significantly inhibited by the short-term treatment with the above two drugs. Thus, angiotensin AT1 receptor may play an important role in the regulation of extracellular matrices and TGF-beta 1 expressions in SHR.

Pancreatic exocrine deficiency after partial pancreatectomy in conscious dogs.

OBJECTIVE: To describe the secretory responses to physiological stimulation of the exocrine pancreas after partial pancreatectomy in conscious animals. DESIGN: Controlled study. MATERIAL: Thirteen mongrel dogs. INTERVENTIONS: Partial pancreatectomy (n = 4), and creation of gastric and pancreatic (Herrera) fistulas (n = 13). Collections of duodenal juice at 15 minute intervals after an oral meal or during intraduodenal infusion of sodium oleate, and blood samples. MAIN OUTCOME MEASURES: Protein concentration in duodenal juice and cholecystokinin 33/39 concentrations in plasma one and three months after partial pancreatectomy, and secretion of fluid by the pancreas. RESULTS: Pancreatic protein output after a meal was significantly reduced at one and three months in dogs after partial pancreatectomy compared with control animals. Protein output in response to an intraduodenal infusion of oleate was also reduced at both time points. In contrast, secretion of fluid after a meal or during infusion of oleate was unchanged by removal of the distal lobe. There was no correlation between the effects of partial pancreatectomy on protein output and plasma concentrations of cholecystokinin 33/39. CONCLUSION: Pancreatic exocrine deficiency, particularly the reduction in secretion of protein, results directly from the partial pancreatectomy and persists for at least three months after the operation.

Microcirculatory response of the pancreas to feeding, sham feeding, and truncal vagotomy in conscious dogs.

In this study, changes in the microcirculatory dynamics of the pancreas in response to normal feeding, sham feeding, and truncal vagotomy were investigated to elucidate the involvement of a neural mechanism in the physiological modulation of pancreatic blood flow in the conscious state. Continuous measurement of changes in the microcirculation of the pancreas was performed in conscious dogs by the thermoelectric method. A meat meal was given to six normal dogs, seven dogs constructed with external esophagostomy (sham feeding), and four dogs with truncal vagotomy. In response to normal feeding, pancreatic blood flow attained the peak increase of 65.2 +/- 6.2%, showing a significant and biphasic response until approximately 120 min. After sham feeding, pancreatic blood flow was significantly increased with peak values of 89.0 +/- 19.0%, but thereafter showed a rapid decrease, returning to the basal level already at 7.2 +/- 1.1 min. Although truncal vagotomy significantly and greatly reduced the peak increase of pancreatic blood flow to 28.2 +/- 5.1%, blood flow showed still a significant and sustained elevation above basal. This study provides evidence for the involvement of the neural mechanism in the physiological modulation of the microcirculation of the pancreas in the conscious state. The results strongly suggest that the cephalic phase of the increase in pancreatic blood flow is vagally mediated.