Taiichi Otani

Treatment of Pancreatic Cancer: The Role of Surgery

Pancreatic cancer shows an aggressive growth behavior which results in an extremely poor prognosis. It is presently the 4th to 5th leading cause of cancer-related deaths in Western countries with an incidence of 8–10 new cases per 100,000 inhabitants. Since current conservative oncological therapies fail to influence the long-term outcome, curative resection remains the only possibility with a potential for cure. During the past decades, a considerable decrease in postoperative mortality after pancreatic resection and a significant increase in the resection rate have been achieved. Although several types of pancreatic resection have evolved, standard procedures are the classical Whipple resection for cancers of the pancreatic head and left resection for cancers of pancreatic body and tail. Since the pylorus-preserving Whipple resection and extended Whipple resection are still debated as better alternatives to the classical Whipple procedure, large, controlled clinical trials in patients need to be conducted to reach reliable conclusions. However, there is mounting evidence that the pylorus-preserving Whipple procedure offers a better postoperative outcome than the classical Whipple operation without compromising radicality and thereby the long-term prognosis. Despite the progress in surgical treatment of pancreatic cancer, the overall prognosis following resection remains unsatisfactory to date. It is hoped that progress in multimodality treatment and modern therapies, resulting from both clinical and advanced basic research, can improve the prognosis of this malignancy in the near future.

The pH modulator chloroquine blocks trypsinogen activation peptide generation in cerulein-induced pancreatitis.

Introduction and Aims We examined the effects of a weak base, chloroquine, on the trypsinogen processing in cerulein-induced pancreatitis. Methodology Immunofluorescence studies were performed using newly generated affinity-purified antibodies to the trypsinogen activation peptide (TAP). Results The present study showed that chloroquine pretreatment blocked intracellular TAP generation in cerulein-induced pancreatitis. Conclusion These results indicate that intracellular trypsinogen activation, which plays an important role in acute pancreatitis, requires a low-pH compartment, as well as serine protease activity.

Distribution of a synthetic protease inhibitor in rat pancreatic acini after supramaximal secretagogue stimulation

Protease inhibitors may have a beneficial effect in acute pancreatitis. The effects of E3123, a new low molecular weight protease inhibitor, on the ultrastructure of isolated pancreatic acini were examined using transmission electron microscopy. Acini supramaximally stimulated with cerulein (10−8 M) formed large cytoplasmic vacuoles similar to those generated in the cerulein-induced in vivo model of pancreatitis. Pretreatment of isolated acini with E3123 significantly reduced the size and number of vacuoles associated with cerulein treatment. The distribution of 3H-E3123 in acinar cells was examined using a pulse-chase protocol and electron microscopic autoradiography. Cellular levels of 3H-E3123 increased about 30-fold in acinar cells treated with cerulein (10−8 M) compared to unstimulated controls. In cerulein-treated acini examined after a 5-min chase, 47.4% of the autoradiographic grains were associated with the rough endoplasmic reticulum and 13.2% were associated with zymogen granules. After 30 min of incubation, the grains associated with the endoplasmic reticulum decreased to 18.5% but increased to 26.3% over zymogen granules. Thus, E3123 is taken up by the acinar cell and follows a cellular itinerary similar to that of newly synthesized secretory proteins. One potential conclusion from these studies is that the ability of E3123 to reduce the formation of vacuoles in supramaximally stimulated acini may be due to its inhibition of proteases within the secretory pathway.

Smallest Todani's type II choledochal cyst

A choledochal cyst is defined as an isolated or combined congenital dilation of the extra hepatic or intrahepatic biliary tree. Todani and colleagues proposed the five types of congenital choledochal cysts which have gained widespread acceptance. Type II choledochal cyst, a diverticulum of common bile duct, is rarest, and most reported cases of Type II were as large as several centimeters in size. We herein report the case of a small Type II choledochal cyst which was resected at pancreatoduodenectomy for carcinoma of the papilla of Vater. A 58-year-old Japanese male was referred to our hospital for the evaluation of jaundice. Preoperative cholangiogram via the percutaneous transhepatic biliary drainage tube revealed a complete obstruction at the narrow terminal segment. Furthermore, a small diverticular protrusion was demonstrated on the lower part of the common bile duct. The resected specimen showed a 2.2 x 1.7 x 1.2 cm carcinoma of the major papilla, and a deep, 2 mm in diameter and 5 mm in depth, depression on the posterior wall of the common bile duct. The anomalous pancreatobiliary duct was not seen. The deep depression was confirmed microscopically to penetrate the fibromuscular layer of the common bile duct and diagnosed as a Todanis Type II choledochal cyst. To our knowledge, the current case is the smallest Type II choledochal cyst which was completely resected.

Intracellular activation of trypsinogen in rat pancreatic acini after supramaximal secretagogue stimulation: cysteine protease and serine protease activity.

Objective: The aim of the study was to explore the mechanism by which trypsinogen becomes activated during acute pancreatitis. Methods: Given the ability of cholecystokinin (CCK) to induce pancreatitis in vivo, the effects of high-dose CCK on preparations of isolated pancreatic acini were examined using immunofluorescence techniques for the detection of trypsinogen activation. Acini were pretreated with weak base or serine or cysteine protease inhibitors before CCK hyperstimulation. Results: CCK was found to stimulate the generation of trypsinogen activation peptide (TAP), a marker for trypsinogen processing. The generation of TAP was inhibited by pretreatment with a weak base, chloroquine (40 &mgr;mol/L). TAP generation was also inhibited by pretreatment with serine protease inhibitor FUT-175 (1 &mgr;mol/L) but not cysteine protease inhibitor E64 (0.1 mmol/L) or E64-d (0.1 mmol/L). Although treatment with a high dose of E64-d (1 mmol/L) reduced activation, it also caused cell injury. Conclusions: High-dose CCK stimulated the intracellular activation of trypsinogen within isolated pancreatic acini. This event appears to require an acidic subcellular compartment and serine protease activity. The role for thiol proteases in this model remains unclear.Abbreviations: Asp - aspartic acid, CA1 - carboxypeptidase A1, CCK - cholecystokinin, CCK-8 - cholecystokinin octapeptide, DMSO - dimethyl sulfoxide, EGTA - ethylene glycol-bis(&bgr;-aminoethyl ether)-N,N,N&vprime;,N&vprime;-tetraacetic acid, HEPES - N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid, LDH - lactate dehydrogenase, Lys, lysine, PCA1 - procarboxypeptidase A1, PMSF - &agr;-phenyl-methyl sulfonyl fluoride, TAP - trypsinogen activation peptide

Intraoperative direct pancreatography using ultrasound-guided puncture for accessory duct sphincteroplasty in a patient with pancreas divisum.

Pancreas divisum is a common anomaly of the pancreas and has been reported to cause pancreatitis. Transduodenal accessory duct sphincteroplasty is an effective treatment in patients with recurrent acute pancreatitis, but the preoperative diagnosis is not always definite, and it is sometimes difficult to identify the accessory papilla during the operation in these cases. We report here intraoperative direct pancreatography using ultrasound-guided puncture for accessory duct sphincteroplasty, which is useful for verifying the diagnosis of pancreas divisum and locating the accessory papilla.

A cystic duct with no visible signal on magnetic resonance cholangiography is associated with laparoscopic difficulties: an analysis of 695 cases

AbstractBackground/aims We investigated the association between the magnetic resonance cholangiography (MRC) results and surgical difficulties and bile duct injuries during laparoscopic cholecystectomy (LC).MethodsMRC was performed on 695 consecutive patients before LC. We divided the patients into two groups (visible cystic duct group and “no signal” cystic duct on MRC group) and compared them with regard to the length of the operation, conversion rate to open cholecystectomy (OC) and rate of bile duct injury.ResultsThe “no signal” cystic duct on MRC group had a longer operation and higher rate of conversion to OC compared with the visible cystic duct group. However, there was no statistically significant difference in the occurrence rate of bile duct injury between the two groups.ConclusionsThe “no signal” cystic duct on MRC group was associated with laparoscopic difficulties, but not with an increased rate of biliary injury. When a visible cystic duct is not observed on MRC an early conversion to open surgery may avoid a bile duct injury during LC.