Histomorphologic and molecular phenotypes predict gemcitabine response and overall survival in adenocarcinoma of the ampulla of Vater.

BACKGROUND: The need for adjuvant chemotherapy after resection of ampullary cancer (PapCa) remains undefined. Recent data suggest that a different epithelial origin of PapCa might be associated with different tumor biology. The aim of the present study was to assess the clinical value of morphologic and immunohistochemic subclassification of PapCa into intestinal-type (IT) and pancreaticobiliary-type (PT) to predict chemotherapy response and overall survival (OS). METHODS: Via a prospective database, 112 PapCa were identified, of which 95 could be included in the present study. Those were compared with 206 matching patients with periampullary pancreatic cancer (ie, pancreatic ductal adenocarcinoma, PDAC). IT and PT PapCa were classified morphologically, and tissue microarray was prepared with immunohistochemistry for CK7, CK20, MUC2, CDX2, ß-Catenin, and Villin. Multivariate survival analysis was performed. RESULTS: OS of PT patients was less compared with IT patients (25 vs 98 months; P < .001), whereas it was comparable with patients with PDAC (25 vs 14 months; P = .123). PT patients receiving adjuvant gemcitabine chemotherapy featured improved OS (32 vs 13 months; P = .013), whereas gemcitabine tended to be associated with decreased OS in IT patients (35 vs 112 months; P = .193). Besides histopathologic classification, expression of CK7 and MUC2 were important prognostic variables. PT patients with CK7-positivity or MUC2-negativity were segregated into an even poorer prognostic group. CONCLUSION: PapCa is not a separate tumor entity. We demonstrate important differences between IT-PapCa and PT-PapCa not only in long-term survival but also in response to adjuvant gemcitabine. Tumor biology and clinical course of PT tumors resemble those of PDAC. PT tumors should therefore be treated like PDAC.

Topical application of nitrates onto the papilla of Vater: manometric and clinical results.

BACKGROUND AND STUDY AIMS: Systemic administration of nitrates inhibits motility of the sphincter of Oddi (SO) but is hampered by a decrease of the arterial blood pressure. We evaluate whether topical application of glyceril trinitrate (GTN) onto the papilla can facilitate cannulation of the common bile duct during routine endoscopic retrograde cholangiopancreatography (ERCP) and compare the effect of topical GTN with that of isosorbide dinitrate (ISDN) on SO motility. PATIENTS AND METHODS: A total of 80 patients undergoing routine ERCP for suspected biliary obstruction received topical application of either saline (n = 40) or 10 mg of GTN (n = 40) onto the papilla of Vater in a randomized, double-blind fashion. Thereafter, selective bile-duct cannulation was attempted with a 0.035" hydrophilic guide wire. In another trial, 16 biliary type III patients underwent endoscopic SO-manometry and received in a randomized fashion either 10 mg of GTN (n = 8) or 10 mg of ISDN (n = 8) which was infused topically onto the papilla via the manometric catheter. Thereafter, the manometric recording was continued for a further 5 minutes. RESULTS: A spontaneous opening of the papilla with concurrent transpapillary bile flow was observed in 24/40 patients after topical GTN, and in only 8/40 patients after topical saline (P < 0.01). However, neither the number of cannulation attempts nor the time until successful cannulation differed significantly between the groups. In addition, the pre-cut rate was nearly identical in the two groups. Topical GTN showed no significant influence on the mean arterial blood pressure. The SO-baseline pressure was significantly lowered by topical GTN (28.2+/-12.9 mm Hg before ISDN vs. 22.5+/-13.7 mmHg after P<0.01). The phasic SO motility was also strongly inhibited by both drugs. However, the effect of GTN completely wanes after 3 minutes, whereas ISDN inhibited SO motility for > 5 minutes in all patients. CONCLUSIONS: Both topically administered GTN and ISDN evoked a profound inhibition of SO motility, but the effect of ISDN was longer lasting than that of GTN. However, locally administered GTN did not facilitate selective bile-duct access during routine ERCP.

Effects of caloric stimuli on frog ampullar receptors.

The observation that caloric nystagmus can be evoked even in microgravity conditions argues against Barany's convective theory. To justify this result, gravity-independent mechanisms (mainly endolymphatic volume changes and direct action of the temperature on vestibular sensors) are believed to contribute to caloric-induced activation of vestibular receptors. To define the importance of both gravity-dependent and gravity-independent mechanisms, the posterior semicircular canal of the frog was thermally stimulated by a microthermistor positioned close to the sensory organ. The stimulus produced a gravity-dependent transcupular pressure difference that, depending on the position of the heater, could result in either excitation or inhibition of ampullar receptor sensory discharge. When the heater was positioned on the ampulla, or when the canal rested on the horizontal plane, no responses could be evoked by thermal stimuli. These results suggest that, in our experimental conditions (DeltaT up to 1.5 degrees C), neither a thermally induced expansion of the endolymph nor a direct action of the temperature on vestibular sensors play any major role.

Normal Vaterian sphincter complex: evaluation of morphology and contractility with dynamic single-shot MR cholangiopancreatography.

OBJECTIVE: The objective of this study was to assess the usefulness of dynamic single-shot MR cholangiopancreatography in the evaluation of the morphology and contractility of the normal Vaterian sphincter complex and to assess whether i.v. injection of glucagon can improve visualization. SUBJECTS AND METHODS: Sixty patients without signs of Vaterian sphincter complex dysfunction were studied. A fast single-shot MR imaging sequence was used to obtain 20 consecutive images of the Vaterian sphincter complex during successive episodes of breathholding. In patients of group A (n = 30), 10 images were obtained before and 10 after i.v. administration of a sphincter-relaxing agent (glucagon). In the patients of group B (n = 30), no glucagon was administered. The degree of visualization of the Vaterian sphincter complex was assessed. RESULTS: Overall, the morphology and contractility of the Vaterian sphincter complex was adequately assessed in 57 patients (95%). However, the number of repetitions required to obtain this result varied greatly (mean, seven; range, two to 18). Glucagon had no apparent effect on the visibility of the most distal portion of the common bile duct. CONCLUSION: Nonvisualization of the most distal portion of the common bile duct on MR cholangiopancreatography studies is a normal variant that can simulate disease. Obtaining serial breath-hold images using a single-shot technique is helpful to avoid diagnostic errors.

[Experimental biliary reconstruction with a Dacron graft which preserves the function of papilla Vater].

Roux-en-Y cholangiojejunostomy has been widely accepted as a method of biliary reconstruction after resection of the bile duct, however complications such as cholestasis, cholangitis and peptic ulcer attributable to the loss of papillary functions are frequently encountered after this procedure. In this point of view, the author experimentally studied biliobiliary anastomosis with a Dacron vascular graft to preserve normal bile passage through the duodenal papilla. End-to-end choledocho-graft-choledochostomy with a Dacron vascular graft coated with collagen (Hemashield) was carried out in 10 pigs. Out of them three died of complications during the 13th to 26th the POD, and seven were sacrificed 6 weeks after the operation. Two weeks after biliary grafting (n = 3) the grafts were surrounded by thin fibrous tissue and microscopically collagen fibers infiltrating into pores of the graft were noted, however after 6 weeks the grafts were spontaneously detached from the bile duct and floated in bile. The covered fibrous tissue was remained and the anastomotic site was replaced with soft granulation tissue, where infiltration of inflammatory cells were microscopically noted. Caliber of the anastomotic site was not smaller and but for slight elevation of total bile acid level blood biochemistry did not show cholestasis and cholangitis. The papillary function was manometrically well maintained. A Dacron graft shielded by collagen seemed to be inadequate material as a permanent bile duct graft, however granulation tissue after spontaneous removal of the graft may be covered with biliary epithelium, and may heal maintaining normal papillary function.

Cholinergic nerve-mediated excitation in the guinea pig choledochoduodenal junction activated by distension.

The electrical basis of propulsive contractions in the guinea pig choledochoduodenal junction (CDJ), which are triggered by distension, was investigated using intracellular microelectrode recording techniques. The isolated CDJ was placed in a continuously perfused tissue chamber at 37 degrees C. Membrane potential was recorded from smooth muscle cells in either the ampulla or in the upper CDJ (upper junction) regions, which were immobilized by pinning. Distension of the upper junction (20-30 s) by increasing intraductal hydrostatic pressure (mean elevation: 2.0 +/- 0.3 kPa, n = 13) triggered "transient depolarizations" (TDs: < 5 mV in amplitude and 2-5 s in duration) and action potentials in the circular muscle layer of the ampulla. The frequency of TDs in the ampulla was increased from 2.2 +/- 0.2 to 15.9 +/- 2.2 min-1 (n = 13) during distension. Simultaneous impalements of cells in the longitudinal and circular muscle layers in the ampulla revealed that subthreshold TDs in the circular layer were associated with an increased rate of action potential discharge in the longitudinal layer. Atropine (Atr; 1.4 x 10(-6) M) and tetrodotoxin (TTX; 3.1 x 10(-6) M blocked the distension-evoked increase in TD frequency, without affecting the frequency of ongoing TDs. The sulfated octapeptide of cholecystokinin (1-5 x 10(-8) M) increased the amplitude of TDs recorded in the circular muscle layer of the ampulla and increased action potential discharge rate. In separate recordings, radial stretch of the ampulla region increased the rate of discharge of action potentials in the smooth muscle of the upper junction.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of feeding and secretin administration on the pancreaticoduodenal papilla of conscious dogs.

The aim of this study was to define the functional role of the pancreaticoduodenal papilla (PDP) in the regulation of pancreatic outflow into the duodenum in response to feeding and secretin administration in conscious dogs. The canine model we developed allowed for measurement of the pancreatic ductal pressure and pancreatic outflow simultaneously in a physiological state without interfering with the flow of pancreatic juice via the intact sphincter of the duodenal papilla. Feeding increased the pancreatic outflow from 2.8 +/- 0.2 to 13.4 +/- 1.3 ml/15 min with a slight increase in the pancreatic ductal pressure from 8.5 +/- 0.6 to 13.7 +/- 1.4 cmH2O. The administration of secretin increased the pancreatic outflow from 2.8 +/- 0.2 to 12.7 +/- 1.0 ml/15 min without increasing the pancreatic ductal pressure. The viscosity of the pancreatic juice increased during exposure to food, but decreased following food intake and secretin administration, after which the PDP seemed to dilate by about 40% of the fasting value. The results suggest that PDP changes its opening to maintain the pancreatic ductal pressure below a certain level, even if pancreatic secretion into the pancreatic duct increases due to food intake and secretin administration.

[Prospects of intraoperative dynamic cholangio-manometry by tensor detectors with graphic recording of pressure function]. / Perspektivy intraoperatsionnoi dinamicheskoi kholangiomanometrii tenzornymi datchikami s graficheskoi registratsiei funktsii davleniia.

Intraoperative cholangio-manometry with a miniature tensor sensor and graphic recording of the results were conducted to study the function of the major duodenal papilla in 53 patients. A periodical activity of the ampulla of the papilla was revealed, which was characterized by certain values of the peak and basal pressure, and duration of contraction and relaxation periods. The numerical values and the pattern of the pressure curve differed in patients with obstructive cholecystitis, biliary pancreatitis, and a concrement incarcerated in the ampulla of the papilla. The informativeness of the study increases with the use of the glucagon test.

Time-series analysis of myoelectric cycling of sphincter of Oddi: evidence of cycling during fed state.

The sphincter of Oddi (SO) in the fasted opossum exhibits spontaneous cyclic spikeburst activity that is temporally related to the interdigestive migrating myoelectric complex (MMC) of the small intestine. After feeding, the cyclic activity is apparently disrupted. Our aim was to use time-series analysis to mathematically describe the periodic behavior of the fasted state and to determine whether this periodicity is present after feeding. Five opossums were chronically prepared with bipolar electrodes secured to the SO. With the animals fasted and conscious, myoelectric activity was recorded for at least two MMC cycles after which they were fed 170 kcal of cream. Spikeburst frequency data were analyzed by fast Fourier transform (FFT) and by digital band-pass filtering. Results from FFT analysis showed an intense low-frequency peak during the fasted state which persisted but was markedly depressed during the fed state. Analysis of the data after filtering also showed persistent sinusoidal activity at the MMC frequency after feeding, although the waveform was significantly depressed by both peak-to-peak amplitude and root mean square amplitude analysis. Recovery to normal fasting cyclic behavior with recovery of both FFT and filtered data was observed. We conclude that in the opossum the cyclic nature of the SO myoelectric activity observed during the fasted state persists after feeding, but is inhibited and masked by an increase in overall spikeburst activity.

Substance P stimulates the opossum sphincter of Oddi in vitro.

We have previously shown that substance P (SP) regulates sphincter of Oddi (SO) motility in vivo. However, its mechanism of action remains unclear. Our aim was to develop an in vitro model to measure spikeburst (SB) an contractile frequency (CMC) of the SO and to characterize further SP effects. In 16 opossums, SO rings were excised, mounted within a Kreb's tissue bath with bipolar electrodes and force transducers, allowed to equilibrate, and exposed to increasing SP concentrations with washout between each test solution. Spikeburst and CMC frequencies were recorded on a polygraph, quantitated, expressed as differences before and during SP, and statistically analyzed with Student's test. Although SP induced a significant concentration-dependent increase in phasic SB frequency and CMC, the amplitude of concentrations was not affected by SP. A close correlation was found between basal and SP-stimulated SB and CMC, suggesting myoelectric and mechanical coupling. Previous exposure of SO to SP antagonist [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-SP significantly decreased the response to SP. Tetrodotoxin (TTX), did not affect the delta CMC response to SP. In conclusion an in vitro preparation was developed to study the effect of SP on the SO. Substance P increased SB and CMC of the SO in a concentration-dependent fashion, thus acting as a stimulatory peptide. Perfusion of SO rings with SP antagonist had no effect on basal CMC but significantly inhibited the action of SP in a competitive manner. The effect of SP was not altered by TTX. These data suggest that the action of SP on the SO is primarily myogenic.

Pancreatitis after sphincter of Oddi manometry.

The nature, frequency, severity, and possible causes of complications after 207 sphincter of Oddi manometry measurements were studied in 146 patients. Acute pancreatitis was diagnosed in 6% (12 of 207) of the investigations and in 8% (12 of 146) of the patients examined. The pancreatitis was mild in all patients. After cannulation of the pancreatic duct, acute pancreatitis occurred in 10 of 95 (11%) patients compared with one of 93 (1%) when the manometry catheter entered the bile duct only (p less than 0.02). Seven (58%) of the patients who developed acute pancreatitis, however, were found to be suffering from chronic pancreatitis. Some 26% of all sphincter of Oddi manometry measurements on patients with this diagnosis were complicated by an acute attack of pancreatitis compared with 3% (p less than 0.001) in patients without signs of chronic pancreatitis. In all patients the pancreatitis developed within three hours of manometry. We conclude that pancreatitis may occasionally follow sphincter of Oddi manometry measurement, even in patients without pancreaticobiliary disease, and that underlying chronic pancreatitis constitutes a definite risk. Sphincter of Oddi manometry measurement in control subjects should therefore be performed only in centres where the safety of the procedure has been established, and the presence of chronic pancreatitis should be excluded beforehand. Cannulation of the pancreatic duct should be avoided. Manometry can be safely performed, however, as an outpatient procedure.

Rabbit sphincter of Oddi has a certain autonomy: characteristic features.

Simultaneous recordings of electromyography and manometry were obtained from rabbit sphincter of Oddi (SO) and duodenum. Three different patterns of activity were observed in SO and in duodenum: 1) a low-amplitude (less than 3 cm H2O) pattern of background oscillations with 2) superimposed high-amplitude (4-20 cm H2O) contractions and 3) occasional complex contractions consisting of an elevation of the basal pressure with superimposed smaller contractions. A certain SO autonomy was evident: 57.6% of SO pressure peaks could not be assigned to any duodenal activity. The distribution of SO pressure peak amplitudes could not be described by a simple normal distribution. The distribution of SO pressure peak amplitudes with concomitant duodenal activity differed from the overall distribution (p less than 0.001). Whereas a substantial part of SO pressure peaks greater than 4 cm H2O had no or low-amplitude corresponding duodenal pressure activity, duodenal pressure peaks greater than 4 cm H2O almost invariably were associated with SO pressure peaks. It is concluded that rabbit SO does possess a certain autonomy, but at the same time a close functional connection exists between the two compartments.

Rabbit sphincter of Oddi and duodenum are regulated by slow waves with a common basic-mode activity.

Simultaneous recordings of pressure and slow-wave activity were obtained from the sphincter of Oddi (SO) and the duodenum in anesthetized rabbits. Histographic analysis of the recordings was performed when the following criteria were fulfilled: 1) slow waves must be present in the EMG recordings from both compartments; and 2) only pressure recordings with sufficient pressure activity (greater than 50 peaks in 10 min) would be considered. Of 12 animals fulfilling the criteria for histographic analysis of 4 channels, a common basic-mode activity was found in all channels in 9 animals (75%). Of three animals fulfilling the criteria for histographic analysis of three channels, a common basic-mode activity was seen in all channels in all animals (100%). A correlation between the amplitude of the slow waves and the amplitude of the elicited pressure peaks in the SO was significant at a 5% level or better in 12 animals (80%). In some of the animals episodes of low-amplitude pressure activity was observed in the SO, occurring synchronously with slow waves devoid of spike activity. It is concluded that rabbit SO and duodenum are paced by slow waves with a common basic-mode activity in most animals. Slow waves may not only be the chief determinant of the contractile rhythm but may also have a certain influence on the force of the individual SO contractions. It is suggested that slow waves per se may be able to mediate contractile activity.

Sphincter of Oddi cyclic motility. Effect of translocation of the papilla in opossums.

The role of myoneural continuity between the sphincter of Oddi and duodenum in coordinating sphincter cyclic motility and the duodenal migrating myoelectric complex was studied in conscious opossums. Five animals underwent implantation of the duodenal papilla into the jejunum. Myoelectric recording was obtained from the sphincter, duodenum, and jejunum in these animals and from 5 other animals as controls. The mean spike frequency of the sphincter of controls was 1.6 per min during phase I, 4.2 per min during phase II, 11.0 per min during phase III, and 3.6 per min during phase IV of the duodenal migrating myoelectric complex. After translocation of the papilla, the spike rates during phase II (2.2 per min) and phase III (2.8 per min) were lower than in controls (p less than 0.02), while those during phases I and IV remained unchanged. Feeding disrupted the migrating myoelectric complex and increased sphincter spike activity in both groups; however, the plateau frequency after feeding was lower after the translocation. These data suggest that the duodenum does not control cyclicity of sphincter motility but sphincter-duodenal intrinsic myoneural continuity is important in the increase in sphincter spike activity during phases II and III and after feeding.

The propulsive behavior of the opossum sphincter of Oddi.

This study investigates whether the phasic contractions of the opossum sphincter of Oddi (SO) delay bile flow by acting as a resistor or facilitate bile flow by acting as a pump. The common bile duct (CBD) and an adjacent segment of duodenum from eight opossums were studied in a propulsion evaluation system in vitro. This system required the production of hydrostatic work by the SO to transfer fluid from the CBD to the duodenum when the pressure in the duodenum was equal or greater than the pressure in the CBD. Fluid movement from the CBD to duodenum and duodenum to CBD was studied at pressure gradients up to 50 cmH2O before and after sodium nitroprusside (10(-7) M) inhibition of smooth muscle contractile activity. All preparations propelled fluid from the CBD to the duodenum against a pressure gradient ranging from 10 to 50 cmH2O. The SO emptied the CBD in a monoexponential fashion, with a time constant of 1.52 +/- 0.7 min, until CBD pressure was reduced to 8.5 +/- 3.2 cmH2O, when propulsion ceased. Superimposed on the CBD pressure waveform were pressure pulses of 1-2 cmH2O in amplitude that resulted from the contractions of the SO. CBD pressure was higher at the start than at the end of a periodic pressure pulse, whereas CBD pressure was stable between pulses. The frequency of the pressure pulses was greatest at the maximal CBD pressure (9.4/min) and decreased significantly when the basal pressure was reached (1.5/min, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Sphincter of Oddi manometry in healthy volunteers.

In this study we describe in detail the characteristics of sphincter of Oddi motor function in a large group of healthy subjects. Studies were obtained in 50 healthy volunteers. The findings showed a sphincter of Oddi segment that had a basal pressure of 14.8 +/- 6.3 mm Hg (X +/- SD). Phasic contractions were superimposed on the basal pressure. They had an amplitude of 119.7 +/- 32 mm Hg, a duration of 4.7 +/- 1 sec, and a frequency of 5.7 +/- 1.2 contractions/min. In 40 subjects the propagation sequence of phasic contractions could be evaluated and were simultaneous in 53%, antegrade in 35%, and retrograde in 11% of the waves. In 20 subjects, pressure measurements done at the common bile duct sphincter waves. In 20 subjects, pressure measurements done at the common bile duct sphincter were similar to those obtained at the pancreatic duct sphincter. In 10 subjects, pressure values obtained at the common bile duct sphincter within a week were similar. Our study should help to establish standards for normal manometric values of the sphincter of Oddi and emphasizes the importance of having a healthy volunteer group from which to obtain the normal values of sphincter of Oddi motor function.

Papilla of Vater: structure and function.

The papilla of Vater is involved in the regulation of bile flow (inhibition and facilitation) into the duodenum and the prevention of reflux into the bile and pancreatic duct system. These functions are achieved by a special muscular, neural and mucosal structure of the papilla of Vater. The mucosa of the papilla of Vater consists of a complicated system of mucosal folds which can function as an anti-reflux valve or might even participate in the regulation of bile outflow. The smooth muscle of the sphincter of Oddi differs anatomically and embryologically from the surrounding duodenal muscle. It shows spontaneous electrical and mechanical activity acting independently from the duodenum but integrated into the overall function of the gastrointestinal tract by myogenic mechanisms, extrinsic and intrinsic nerves and circulating hormones. A spontaneous myogenic electrical activity propagates distally and leads to distally propagating phasic contractions. With endoscopic manometry in humans these phasic contractions as well as basal tone, bile duct pressure and pancreatic duct pressure can be measured. Changes of the basal tone and the phasic activity will alter the flow resistance thus regulating bile flow and inducing gallbladder filling. The most characteristic feature of the sphincter of Oddi is the inhibitory effect of cholecystokinin, which is a powerful contractor of the gallbladder, on the sphincter of Oddi motor activity. Cholecystokinin released in response to intra-duodenal fat and other nutrients might be the physiological stimulus of the increased bile flow post-prandially. The function of other hormones is still rather speculative and their physiological significance awaits further confirmation.

Inhibition of sphincter of Oddi motility in Australian possum by cholic acid.

The effect of intravenous administration of cholic acid on sphincter of Oddi (SO) and gallbladder motility was studied. Bolus doses of cholic acid, 20 to 60 mg/kg, produced inhibition of SO wave frequency, a fall in gallbladder pressure and enhanced bile flow. However, hydrocortisone, 10 and 20 mg/kg, produced comparable elevation in bile flow with no effect on SO and gallbladder motility. The effect of cholic acid on SO motility was not influenced by prior treatment with atropine. Phentolamine or propranolol administration did not influence SO wave frequency SO wave frequency, but subsequent injection of cholic acid resulted in a decrease in SO wave frequency. Gallbladder pressure was not influenced by atropine, phentolamine, or propranolol, and these agents did not influence the cholic acid-induced fall in gallbladder pressure. These findings suggest that bile acids influence the motility of the biliary tract.