Over-expression of S100A2 in pancreatic cancer correlates with progression and poor prognosis.

Controversy exists regarding the clinical significance of S100A2 in the progression of tumours. In pancreatic cancer, little is known about the role of S100A2. The aim of this study was to clarify the clinical significance of S100A2 expression in pancreatic carcinogenesis. We microdissected invasive ductal carcinoma (IDC) cells from 22 lesions, pancreatic intraepithelial neoplasia (PanIN) cells from five lesions, intraductal papillary mucinous neoplasm (IPMN) cells from 38 lesions, pancreatitis-affected epithelial (PAE) cells from 16 lesions, and normal ductal cells from 18 normal pancreatic tissues. S100A2 expression in 14 pancreatic cancer cell lines, microdissected cells and formalin-fixed paraffin-embedded (FFPE) samples was examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Microdissection analyses revealed that IDC cells expressed higher levels of S100A2 than did IPMN, PAE or normal cells (all comparisons, p < 0.007). Cell lines from metastatic sites expressed higher levels of S100A2 than those from primary sites. PanIN cells expressed higher levels of S100A2 than normal cells (p = 0.018). IDC cells associated with poorly differentiated adenocarcinoma expressed higher levels of S100A2 than did IDC cells without poorly differentiated adenocarcinoma (p = 0.006). Analyses of FFPE samples revealed that levels of S100A2 were higher in samples from patients who survived < 1000 days after surgery than in those from patients who survived > 1000 days (p = 0.043). Immunohistochemical analysis was consistent with qRT-PCR. S100A2 may be a marker of tumour progression or prognosis in pancreatic carcinogenesis and pancreatic cancer.

Electrical activation of common bile duct nerves modulates sphincter of Oddi motility in the Australian possum.

BACKGROUND: Sphincter of Oddi (SO) motility is regulated by extrinsic and intrinsic nerves. The existence of neural circuits between the SO and the proximal extrahepatic biliary tree has been reported, but they are poorly understood. Using electrical field stimulation (EFS), we determined if a neural circuit exists between the common bile duct (CBD) and the SO in anaesthetized Australian brush-tailed possums. METHODS: The gallbladder, cystic duct or CBD were subjected to EFS with a stimulating electrode. Spontaneous SO phasic waves were measured by manometry. RESULTS: EFS at sites on the distal CBD (12-20 mm proximal to the SO), but less commonly at more proximal CBD, evoked a variety of responses consisting of an excitatory and/or inhibitory phase. Bi-phasic responses consisting of an excitation followed by inhibition were the most common. Tri-phasic responses were also observed as well as excitation or inhibition only. These evoked responses were blocked by topical application of local anaesthetic to the distal CBD or transection of the CBD. EFS at sites on the gallbladder body, neck or cystic duct did not consistently evoke an SO response. Pretreatment with atropine or guanethidine reduced the magnitude of the evoked response by about 50% (p<0.05), pretreatment with hexamethonium had no consistent effect and pretreatment with a nitric oxide synthase inhibitor increased the response. DISCUSSION: A neural circuit(s) between the SO and the distal CBD modulates SO motility. Damage to this area of the CBD during bile duct exploration surgery could adversely affect SO motility.

Effect of prepyloric gastric transection and anastomosis on sphincter of Oddi cyclic motility in conscious dogs.

PURPOSE: We previously reported significant changes in sphincter of Oddi cyclic motility after proximal duodenal transection and anastomosis. However, the role of intrinsic myoneural continuity between the antrum and duodenum in this respect is not understood. The aim of this study was to elucidate the effects of prepyloric gastric transection on sphincter of Oddi motility in animals in the conscious state. METHODS: Pressures in the bile duct, duodenum, stomach, and sphincter of Oddi and their response to an injection of cholecystokinin-octapeptide were measured in four conscious dogs, with a duodenal cannula, before and after gastric transection and anastomosis 1.5 cm proximal to the pylorus. RESULTS: Gastric transection did not affect the initiation and propagation of the gastroduodenal migration motor complex. Biliary pressure (5.7 +/- 0.15 to 5.5 +/- 0.2 mmHg; P = 0.91), sphincter of Oddi basal pressure (10.6 +/- 0.3 to 10.7 +/- 0.2 mmHg; P = 0.97), and amplitude (26.0 +/- 1.2 to 32.9 +/- 1.7 mmHg; P = 0.304) did not change after gastric transection. Biliary pressure decreased from phase II to phase III of the duodenal migrating motor complex. Cholecystokinin-octapeptide inhibited sphincter of Oddi phasic waves before and after gastric transection. CONCLUSIONS: Intrinsic myoneural transection at the prepyloric region does not influence sphincter of Oddi cyclic motility. Preservation of pyloroduodenal myoneural continuity in pylorus-preserving gastrectomy would be beneficial to maintain normal sphincter of Oddi motility.

Carcinoma arising in choledochocele.

BACKGROUND AND STUDY AIMS: Choledochocele has a potential for carcinogenesis, but no report has described malignant changes of the choledochocele in relation to pancreaticobiliary reflux because its anatomic form does not fit the criteria of pancreaticobiliary malunion (PBM). The aims of this study were to analyze the amylase level in bile in patients with choledochocele and to clarify whether the presence of a choledochocele predisposed to carcinoma. PATIENTS AND METHODS: Records of 2826 patients who had undergone endoscopic retrograde cholangiopancreatography between 1995 and 1999 were reviewed for the presence of choledochocele and/or periampullary carcinoma. As an evidence of pancreaticobiliary reflux, amylase activity was examined in common duct bile obtained at surgery or by endoscopy. The prevalence of periampullary carcinoma was compared between patients with and without choledochocele. RESULTS: A total of 11 patients were diagnosed as having a choledochocele. The amylase level in bile was higher in patients with choledochocele (120,922 +/- 62,269 IU/l; n = 4) than in previously examined patients with functioning gallbladders (15 +/- 24 IU/l; n = 10, P = 0.005). The prevalence of periampullary carcinoma in patients with choledochocele (27%, 3/11) was significantly higher than that in those without choledochocele (0.9%, 26/2815; P<0.0002). CONCLUSION: The bile analysis of the present study presents one possible explanation for the predisposition to carcinoma in choledochocele as bile containing amylase may stagnate in the choledochocele and then carcinoma may develop in the inner epithelium of the choledochocele by the same mechanism as that leading to carcinogenesis in patients with PBM.

Is peripapillary choledochoduodenal fistula an indication for endoscopic sphincterotomy?

BACKGROUND: Most patients with a peripapillary choledochoduodenal fistula undergo fistulotomy by endoscopic sphincterotomy for the treatment of bile duct stones. However, whether sphincterotomy should be performed in patients with the fistula but without stones is controversial. METHODS: Among 165 patients in whom a benign peripapillary choledochoduodenal fistula was diagnosed at ERCP, the clinical outcome was retrospectively analyzed and compared between those who underwent fistulotomy by endoscopic sphincterotomy (group 1) and those whose fistula was left untreated (group 2). All patients with hepatolithiasis, residual stones, biliary diversion, or transduodenal papilloplasty were excluded (32, leaving 133). Fistulas were divided into types I and II according to the location of the fistula (Ikeda classification). RESULTS: Follow-up data collected during a median period of 124 months were available for 127 of 133 patients (95%), 76 in group 1 and 53 in group 2. Late complications were bile duct stone recurrence (17 patients), acute cholangitis (7 patients), and biliary carcinoma (2 patients). The incidence of stone recurrence was not significantly different between the 2 groups (p = 0.1). In group 2, 4 patients (8%) with an untreated type II fistula had 1 to 3 episodes of presumed reflux cholangitis, which resolved quickly with conservative treatment. CONCLUSIONS: Endoscopic sphincterotomy is not always necessary for peripapillary choledochoduodenal fistulas if bile duct stones are absent because reflux cholangitis is a relatively rare complication that can be easily managed.

Manometric evidence of improved early gastric stasis by erythromycin after pylorus-preserving pancreatoduodenectomy.

Gastric stasis is a frequent complication of pylorus-preserving pancreatoduodenectomy (PPPD). We demonstrated that it might be attributable to delayed recovery of phase III activity of the gastric migrating motor complex due to low concentrations of plasma motilin caused by resection of the duodenum. Leucine 13-motilin is effective for treating gastric stasis, but it is not yet available for clinical use. Whether erythromycin would improve early gastric stasis after PPPD was tested clinically and by manometry. A manometric tube assembly and a gastrostomy tube were inserted in the stomach of 10 patients at PPPD for pressure recording from the gastric antrum and jejunum and for gastric juice drainage, respectively. After baseline recording, erythromycin 5 mg/kg was given intravenously on day 14 and saline as a placebo on day 17 every 4 hours four times a day. The daily volume of gastric juice output and the gastric motility index were measured. The mean period until the return of gastric phase III was 31 +/- 1 days. Erythromycin significantly increased the gastric motility index from 7.9 +/- 1.3 mmHg to 15.7 +/- 1.8 mmHg (p = 0.0005), whereas saline did not (7.2 +/- 1.6 mmHg to 6.5 +/- 1.2 mmHg; p = 0.21). Erythromycin significantly decreased the gastric juice output from 1,080 +/- 190 ml to 738 +/- 199 ml (p < 0.0001), but the saline injections did not (1,064 +/- 174 ml to 1,115 +/- 189 ml; p = 0.35). Erythromycin, a universally available motilin agonist, is a safe, effective, potent drug for the treatment of early gastric stasis after PPPD.

Sphincter of Oddi contractile function after balloon dilation: detailed manometric evaluation in conscious dogs.

BACKGROUND: Endoscopic balloon dilation is under investigation as a treatment modality for bile duct stones. It may have an advantage of preserving the sphincter of Oddi function, but little is known about sphincter of Oddi cyclic motility after dilation. METHODS: Four dogs with a duodenal cannula underwent sphincter of Oddi dilation and repeated manometry to assess sphincter of Oddi cyclic motility until 3 months after dilation. Histologic changes in the sphincter of Oddi were examined in another group of four dogs. RESULTS: Motility index (sum of amplitude of sphincter of Oddi phasic waves counted per minute) and basal pressure decreased on day 3. Sphincter of Oddi amplitude during phase III of the duodenal migrating motor complex tended to be increased on day 3 and decreased to the minimum on day 21. Thereafter, it gradually recovered to baseline. By histology, severe acute inflammation was present in the sphincter of Oddi muscle layer on day 3. However, basal pressure remained significantly low even 3 months after dilation. CONCLUSIONS: Sphincter of Oddi amplitude is incompletely reduced on day 3 after balloon dilation. Sphincter of Oddi basal pressure and motility index in the early phase of sphincter of Oddi cyclic motility remain low for at least 3 months after dilation. Further long-term follow-up is necessary to determine whether sphincter of Oddi function is actually preserved.

Sphincter of Oddi motility in patients with hepatolithiasis and common bile duct stones.

The purpose of this study was to explore a difference in sphincter of Oddi (SO) motor activity among patients with intrahepatic (I, N = 5), intra- and extrahepatic (IE, N = 15), and common bile duct (CBD, N = 6) stones. Interdigestive motility of the SO and duodenum was studied by pneumohydraulic infusion manometry via the percutaneous route. SO phasic contractions showed a cyclic change in concert with the duodenal migrating motor complex (MMC) in all these patients. There was no significant difference in the cycle length, frequency, or amplitude of the SO phasic waves among the three groups throughout the whole cycle. The SO basal pressure during duodenal phases I and II of the duodenal MMC was significantly lower in patients with the IE type of hepatolithiasis than in those with the I type (P = 0.04), but there was no significant difference during phase III between the two groups. The SO basal pressure during phases I and II of the CBD group was also significantly lower than that of the I group (P = 0.02). The significance became even more prominent (P = 0.001) when a subgroup of patients with a dilated CBD (diameter > 1 cm) was examined. Lower basal pressure in the IE group or CBD group than in the I group suggested that stones in the common duct might injure or irritate the SO and cause SO dysfunction. In the subgroup with dilated CBD, which may have resulted from repeated and severe SO injury, the statistics became more prominent.

Transactivation mechanisms of mouse clock transcription factors, mClock and mArnt3.

BACKGROUND: The Arnt3 (also termed as BMAL1 or MOP3)/Clock heterodimer is a positive regulator of circadian rhythm and activates the transcription of target genes such as per1 and vasopressin. RESULTS: We investigated the transcriptional mechanism of mArnt3/mClock heterodimer. While mClock did not possess any distinct activation domain, mArnt3 contained a transcriptional activation domain at the most C-terminal end, the activity of which was not expressed, even in the one hybrid system, until it was bound by mClock. It has been suggested that mClock plays a regulatory or structural role in exerting a transcription enhancing effect of the mArnt3/mClock heterodimer. Deletion proceeding from amino acids 559-492 of mClock markedly reduced the transactivation activity of mArnt3/mClock heterodimer, in consistence with the results of the Clock-delta 19 mutant. Yeast and mammalian two-hybrid systems revealed that CBP and p300 interacted with mArnt3 via the CREB binding domain. The In vivo interaction between mArnt3 and CBP was confirmed by the GST pull down assay. CONCLUSION: Taken together, these results suggest that the mArnt3/mClock heterodimer exerted its transactivation activity via CBP or p300 interacting with mArnt3 in the heterodimer with mClock playing a structural or regulatory role in the transactivation process.

Effects of proximal duodenal transection and anastomosis on interdigestive sphincter of Oddi cyclic motility in conscious dogs.

Gallstones formed after gastrectomy are bilirubinate stones probably associated with biliary stasis and infection. Effects of proximal duodenal transection performed during gastrectomy on interdigestive sphincter of Oddi cyclic motility possibly relevant to this phenomenon were investigated in four conscious dogs. Although the cyclic change in sphincter motility was still in concert with the duodenal migrating motor complex after duodenal transection, the mean period was shortened (p < 0.02), and the frequency (p < 0.005) and amplitude (p < 0.001) of sphincter phasic waves during phase III were decreased. The cyclic variation of basal pressure disappeared, and the mean basal pressure throughout the cycle was significantly reduced (p < 0.003). Transient inhibition of sphincter and duodenal contractions normally seen during phase III disappeared. Duodenal transection reversed the response of the sphincter to cholecystokinin-octapeptide from inhibition to stimulation and from reduction of the basal pressure to elevation. These data suggest that duodenal transection produces significant changes in interdigestive sphincter of Oddi motility, possibly contributing to augmented duodenobiliary reflux and then lithogenesis. Myoneural continuity between the stomach and sphincter of Oddi at the proximal duodenum may play an important role in maintaining normal biliary dynamics.

Pain associated with phase III of the duodenal migrating motor complex in patients with postcholecystectomy biliary dyskinesia.

BACKGROUND: Correlation between various gastrointestinal events and particular aspects of the migrating motor complex has been reported. This study correlates postcholecystectomy pain to variations in biliary pressure associated with the duodenal motor cycle. METHODS: In 18 patients with postcholecystectomy pain and 10 control subjects, biliary and duodenal pressures were recorded simultaneously with microtransducers. After recording a spontaneous cycle, morphine was administered to induce a premature phase III and spasm of the sphincter of Oddi, and then cerulein was administered to stop the spasm. RESULTS: Transient but significant elevations of biliary pressure occurred at duodenal phase III in both groups, but a greater percentage of the patients developed pain during phase III (89% vs. 20%, p<0.01). Morphine produced premature phase III and biliary pressure elevation, which were accompanied by pain more frequently in the patients than in the control subjects (78% vs. 30%, p<0.05). Biliary pressure dropped after the cerulein injection, relieving the pain in 13 of 14 patients and in 2 of 3 control subjects who had morphine-induced pain. The phase III-related pain was relieved by endoscopic sphincterotomy in 14 of 15 patients. CONCLUSIONS: The cyclic elevation of biliary pressure in coordination with phase III of the duodenal motor cycle may contribute to the development of pain in patients with postcholecystectomy biliary dyskinesia.

Endoscopic retrograde cholangiopancreatography in infants and children.

A single institutional experience with endoscopic retrograde cholangiopancreatography (ERCP) in pediatric patients was reviewed, focusing on the method of anesthesia, choice of an endoscope, indications, and complications. The medical records of 50 ERCPs performed in 42 infants and children (14 male and 28 female) were reviewed retrospectively. The patients' ages ranged from 57 days to 15 years. Forty-four ERCPs were diagnostic and 6 were therapeutic, including incision of choledochocele, and sphincterotomy and extraction of pancreatic stones. All procedures were successful. The most common indication for ERCP was to evaluate congenital biliary dilatation, in 28 patients (67%). Mild cholangitis occurred as a complication in 1 patient, but was alleviated with medication. A conventional duodenoscope could be used in patients older than 10 years. A pediatric duodenoscope was always used in patients under 1 year of age. Either type was chosen individually for those aged 1 to 10 years depending on the purpose, diagnostic or therapeutic. It is noteworthy that ERCP and/or sphincterotomy in a 1-year-old infant and two 2-year-old children were safely performed with the conventional endoscope. General anesthesia was employed in those younger than 9 years and intravenous sedation and local anesthesia in those older than 11 years. For children aged 9 to 11 years, anesthesia was chosen individually. We concluded that ERCP is a relatively easy and safe technique even for infants and children when performed by skilled hands with an appropriate duodenoscope under suitable anesthesia. The minimum age for use of the conventional duodenoscope may be 1 year.

Reconstruction of an object from its noisy Fourier modulus: ideal estimate of the object to be reconstructed and a method that attempts to find that estimate.

In general, the problem of reconstructing an object from its Fourier modulus has no solution when the Fourier modulus is contaminated by noise. Therefore a quasi solution, which we call the ideal estimate of the object to be reconstructed, is defined here based on the concept of territories of the convergence objects of the error-reduction algorithm, and a method that attempts to find that solution is presented. Keeping in mind that the ideal estimate is one of the output-stagnation objects of the hybrid input-output algorithm, we modify the hybrid input-output algorithm so that the output-stagnation objects can be located even when the value of the feedback parameter is not infinitesimally small, and this modified algorithm is combined with the hybrid input-output algorithm itself. The results of computer simulations carried out to test the performance of the proposed method are shown.

Long-term consequence of endoscopic sphincterotomy for bile duct stones.

BACKGROUND: There are many reports of early- and intermediate-term results of endoscopic sphincterotomy. However, few data are available on long-term clinical outcome of endoscopic sphincterotomy for removal of common bile duct stones. METHODS: Of 419 patients who underwent endoscopic sphincterotomy, follow-up data were obtained in 410 patients (98%). The period ranged from 1 month to 20 years (average 122 months). RESULTS: Late complications included recurrence of stones (12.3%), acute cholangitis, acute cholecystitis (22% of 32 patients with gallstones, 0% of 88 patients without gallstones), new gallstone formation (6 patients), liver abscess (5 patients), and biliary carcinoma (8 patients). All of the recurrent stones were bilirubinate irrespective of the type of stone at sphincterotomy. Cholangitis and liver abscess occurred in 31% and 11%, respectively, of patients with residual intrahepatic stones but not in patients with complete intrahepatic stone clearance. CONCLUSIONS: Late complications occur in a considerable proportion of patients after endoscopic sphincterotomy for the treatment of common bile duct stones, including stone recurrence, acute cholecystitis (which occurs only in patients with gallstones), liver abscess in patients with residual intrahepatic stones, and biliary carcinoma. The fact that the recurrent stones are invariably of the bilirubinate type, irrespective of the type of stones at initial treatment, suggests that bacterial infestation due to ablation of the sphincter mechanism may have a causative role.

Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock.

We isolated a cDNA clone encoding a polypeptide of 626 amino acids containing basic helix-loop-helix (bHLH) and PAS domains from a mouse cDNA library of P19 cells. This protein, termed Arnt3, showed the highest similarity to Arnt and Arnt2 in the bHLH and PAS regions. Arnt3 mRNA was expressed in brain, skeletal muscle, 13.5-day embryos, and P19 cells treated with retinoic acid. The partner PAS proteins of Arnt3 were searched for by the two-hybrid system in yeast, and HIF-1 alpha, HLF, and Clock among various bHLH/PAS proteins were found. Gel mobility shift analysis using nuclear extracts from 293T cells cotransfected with Arnt3 and HIF-1 alpha (or HLF) expression plasmids revealed that these complexes specifically bound the hypoxia-response element (HRE). Coexpression of Arnt3 and HIF-1 alpha (or HLF) in Arnt-deficient c4 cells enhanced transcription of a reporter gene driven by the HRE sequences. We also showed that Arnt3 contained an activation domain at the C-terminal region and a repression domain between the PAS-A and PAS-B regions.

Adenosquamous carcinoma of the pancreas: report of two cases.

Adenosquamous carcinoma of the pancreas is a rare variant of pancreatic exocrine carcinoma. We herein report two patients with this entity. One patient was a 60-yr-old Japanese man complaining of a palpable mass, 5.5 cm in the greatest diameter, in the epigastrium. Serum CA 19-9 was increased (2010 U/ml). Ultrasonography and computed tomography showed a mass in the pancreatic tail with central necrosis and invading the posterior wall of the stomach. Angiography showed an encasement of the splenic artery and complete obstruction of the splenic vein. Distal pancreatectomy, splenectomy, and partial resection of the stomach were done. The patient died of uncontrolled bleeding from the duodenal ulcer four months after operation. The other patient was a 73-yr-old man who presented with jaundice. The CA 19-9 was also elevated (354.8 U/ml). Ultrasonography showed a pancreatic head mass of heterogeneous echogeneity and computed tomography demonstrated a cystic mass with an enhanced rim, indicating necrosis in the tumor center. Angiography showed a hypervascular mass in the head of the pancreas. Pylorus-preserving pancreatoduodenectomy was done, but the patient died of multiple liver metastases 10 months after the operation. From our experience with the two patients, the presence of central necrosis in an infiltrative huge pancreatic tumor seems to be suggestive of the diagnosis of adenosquamous carcinoma of the pancreas.

Long-term results of surgical treatment of thumb polydactyly.

One hundred thirteen hands exhibiting thumb polydactyly were treated and followed up for an average of 49 months. Of these, 109 hands were treated by resection of a supernumerary hypoplastic thumb. Radial thumbs were resected in 107 hands and ulnar thumbs in 2 hands. Four hands were treated using a modified Bilhaut procedure. According to a modified Tada's evaluation, the results were evaluated as good in 97 hands, fair in 12 hands, and poor in 4 hands. Patients and/or their parents were satisfied with the results in 100 hands and dissatisfied with the results in 13 hands. The factors that influenced the surgical results were analyzed. The incidence of unsatisfactory results was relatively high in Wassel types 3, 5, and 6 and triphalangeal-type thumb polydactyly. It was higher when the ulnar digit was removed than when the radial digit was removed. The results for those patients treated between 1983 and 1991 were better than for those treated between 1976 and 1982. The type of deformity, type of procedure, and skillfulness of the surgeon were factors in the results after surgery.

Video-assisted thoracoscopic resection of a mediastinal cyst: report of a case.

Video-assisted endoscopic surgery has recently been expanding its potential, which is shown by our report herein describing the case of a 23-year-old woman for whom successful thoracoscopic resection of a mediastinal cystic lesion was carried out. The patient's postoperative course was uneventful with minimal pain and a prompt recovery. Histological examination confirmed that the lesion was a benign cystic teratoma. We believe that video-assisted thoracoscopic surgery will become the standard procedure for most mediastinal cystic lesions in the future.