High frequency of bone recurrence as an initial recurrence site after radical surgery in T1N3 gastric cancer: a propensity score matching analysis.

PURPOSE: T1 gastric cancer (GC) with seven or more metastatic lymph nodes is extremely rare, and very few clinical studies have been conducted to evaluate the clinicopathological features of their recurrence. METHODS: We retrospectively analyzed the outcomes of T1 GC and T2-4 GC patients who had multiple nodal metastases after radical surgery from 2006 to 2020. Propensity score matching was performed to compare the two groups of patients. RESULTS: After propensity score matching, 18 of 22 patients in the T1 group and 36 of 144 patients in the T2-4 group were selected. Recurrence occurred in six patients (33.3%) in the T1 group. In the T1 group, the most common site of initial recurrence was bone (15.0%). The prevalence of bone recurrence was significantly higher in the T1 group than in the T2-4 group (P = 0.02). The median interval time between radical surgery and bone recurrence was 24 months, and the median survival time after bone recurrence was 14 months. CONCLUSION: Bone recurrence was more frequently identified as an initial recurrence site in T1 GC cases with multiple metastases after radical surgery compared with that in T2-4 GC cases. Careful attention should be paid to postoperative bone recurrence in the long-term postoperative course of these patients.

Long-term Outcomes of Laparoscopic Versus Open Surgery for Clinical Stage II/III Gastric Cancer: A Multicenter Cohort Study in Japan (LOC-A Study).

OBJECTIVE: A large-scale multicenter historical cohort study was conducted to investigate the efficacy of laparoscopic gastrectomy (LG) in comparison to open gastrectomy (OG) for locally advanced gastric cancer. BACKGROUND: LG is now practiced widely, but its applicability for advanced gastric cancer is still controversial. As oncologic outcomes of randomized trials are still pending, there is an urgent need for information that would be relevant to current practice. METHODS: Through a consensus meeting involving surgeons and biostatisticians, 30 preoperative variables possibly influencing the choice of surgical approach and associated with outcome were identified to enable rigorous estimation of propensity scores. A total of 1948 consecutive patients who underwent gastrectomy for clinical stage II/III gastric adenocarcinoma between 2008 and 2014 were identified, and their clinical data were collected from 8 participating hospitals. After propensity score matching, 610 cases (OG = 305, LG = 305) were finally selected for comparison of long-term outcomes. RESULTS: In the propensity-matched OG and LG populations, the mean observation period was 3.5 and 3.4 years, and the 5-year overall survival was 53.0% and 54.2%, respectively. The hazard ratio (LG/OG) for overall survival was 1.01 (95% confidence interval, 0.80-1.29), and noninferiority of LG was demonstrated statistically as the upper 95% confidence limit was less than the prespecified margin (1.33). The recurrence rate was 30.8% and 29.8% for OG and LG, respectively, and the hazard ratio for recurrence was 0.98 (95% confidence interval, 0.74-1.31). The patterns of recurrence in the 2 groups were similar. CONCLUSIONS: This observational study strictly adjusted for confounding factors has provided evidence to suggest that LG is oncologically comparable to OG for locally advanced gastric cancer. The validity of this result will be examined in ongoing randomized trials.

Calpain inhibitor calpeptin suppresses pancreatic cancer by disrupting cancer-stromal interactions in a mouse xenograft model.

Desmoplasia contributes to the aggressive behavior of pancreatic cancer. However, recent clinical trials testing several antifibrotic agents on pancreatic cancer have not shown clear efficacy. Therefore, further investigation of desmoplasia-targeting antifibrotic agents by another mechanism is needed. Calpeptin, an inhibitor of calpains, suppressed fibroblast function and inhibited fibrosis. In this study, we investigated the anticancer effects of calpeptin on pancreatic cancer. We investigated whether calpeptin inhibited tumor progression using a mouse xenograft model. We used quantitative RT-PCR to evaluate the expression of calpain-1 and calpain-2 mRNA in pancreatic cancer cells (PCCs) and pancreatic stellate cells (PSCs). We also undertook functional assays, including proliferation, migration, and invasion, to evaluate the inhibitory effects of calpeptin on PCCs and PSCs. Quantitative RT-PCR indicated that PCCs and PSCs expressed calpain-2 mRNA. Calpeptin reduced tumor volume (P = 0.0473) and tumor weight (P = 0.0471) and inhibited the tumor desmoplastic reaction (P < 0.001) in xenograft tumors in nude mice. Calpeptin also inhibited the biologic functions of PCCs and PSCs including proliferation (P = 0.017), migration (P = 0.027), and invasion (P = 0.035) in vitro. Furthermore, calpeptin reduced the migration of PCCs and PSCs by disrupting the cancer-stromal interaction (P = 0.0002). Our findings indicate that calpeptin is a promising antitumor agent for pancreatic cancer, due not only to its suppressive effect on PCCs and PSCs but also its disruption of the cancer-stromal interaction.

Laparoscopy-Assisted Distal Gastrectomy for the Eldest Elderly Patients with Gastric Cancer.

BACKGROUND/AIMS: The number of the eldest elderly (aged 85 years and older) patients with gastric cancer has been rising in Japan. Laparoscopy-assisted distal gastrectomy (LADG) has been accepted as a less invasive treatment for gastric cancer. The purpose of this study is to evaluate the efficacy and safety of LADG for eldest elderly patents. METHODOLOGY: From January 2006 to July 2010, 262 patients underwent LADG for gastric cancer. Of these, 9 patients were 85 years old and over (eldest elderly group) and the remaining 253 patients were younger than 85 years (control group). Clinicopathological characteristics and operative outcomes were analyzed. RESULTS: Among clinicopathological characteristics analyzed in this study (gender, body mass index, co-morbidity, American Society of Anesthesiologists physical status and tumor status), only gender showed a significant difference between the eldest elderly and the control groups. There were no significant differences in operation time, blood loss, postoperative complication and postoperative hospital stay between the 2 groups. No serious complications or mortality were found in the eldest elderly group. CONCLUSIONS: It is suggested that LADG is a safe and efficient procedure for the treatment of gastric cancer, even in eldest elderly patients.

Midkine mRNA is overexpressed in pancreatic cancer.

PURPOSE: Midkine (MK) has been reported to be a possible molecular marker for the diagnosis of pancreatic cancer. We investigated the feasibility of quantitative analysis of MK mRNA by quantitative real-time RT-PCR (qRT-PCR) as a promising tool for the diagnosis of pancreatic cancer. RESULTS: We found that pancreatic cancer tissues expressed significantly higher levels of MK mRNA than intraductal pancreatic mucinous neoplasm (IPMN) and non-neoplastic pancreatic tissues (P < 0.05); in contrast, we did not find any differences in MK mRNA expression between IPMN and non-neoplastic pancreatic tissues. Additionally, we observed that poorly differentiated carcinoma samples expressed higher levels of MK mRNA than well-differentiated carcinoma samples, although a significant difference was not observed. CONCLUSIONS: The present data suggests that quantitative analysis of MK mRNA provides an objective and sensitive evaluation and may be a promising modality for the diagnosis of pancreatic cancer and the prediction of its prognosis.

Prevention of iatrogenic bile duct injuries in difficult laparoscopic cholecystectomies: is the naso-biliary drain the answer?

BACKGROUND: Prevention of iatrogenic injuries is of paramount importance in difficult laparoscopic cholecystectomies (LC). The objective of this study was to analyze the effectiveness of cholangiography using a pre-inserted endoscopic naso-biliary drain (ENBD) for navigation during difficult cholecystectomies. METHODS: The study design was a retrospective case analysis. In 508 patients who underwent LC in a tertiary referral university hospital from 1996 through 2007, difficult cholecystectomy was anticipated in 26 patients due to possibly aberrant biliary anatomy (four patients), unclear cystic duct anatomy during magnetic resonance cholangiopancreatography (MRCP) and/or endoscopic retrograde cholangiopancreatography (ERCP) (three patients), and acute cholecystitis (19 patients). An ENBD was inserted during ERCP prior to LC for cholangiography (ENBDC) to facilitate safe dissection during LC. Prevalence of biliary complications was assessed as the main outcome measurement. RESULTS: The majority (68%) of the patients who underwent ENBDC had complicated cholecystitis. Advanced technical expertise was not required for insertion of an ENBD. In retrospect, ENBDC was useful in prevention of a possible catastrophe in 69% of cases. Open conversion was necessary in five patients and biliary complications occurred in five patients only in the non-ENBD group. There were no procedure-related complications. One limitation of the study was that it was not randomized and there was no comparison with patients without ENBDC. CONCLUSIONS: ENBDC is a useful and safe tool in the prevention of iatrogenic bile duct injuries in LC.

Internal hernia after laparoscopic gastrectomy with Roux-en-Y reconstruction for gastric cancer.

BACKGROUND/OBJECTIVE: Laparoscopic gastrectomy (LG) is increasingly used to treat gastric cancer. Simultaneously, internal hernia (IH) has been reported after LG with Roux-en-Y reconstruction (RY). The aim of this study was to investigate IH after LG with RY for gastric cancer. METHODS: This study included 15 patients with IH from a database of 355 consecutive patients who underwent LG with RY for gastric cancers. We retrospectively analyzed IH incidence and clinical characteristics by operative procedures. RESULTS: The total incidence of IH was 4.2%. The incidence of IH at Petersen's defect tended to decrease with modifications to the reconstruction methods, but not significantly so. The incidence of IH at jejunojejunostomy mesenteric defect significantly decreased with closure of this defect (p = 0.01). The incidence of IH at transverse mesocolic defect was 1.3% in patients who underwent retrocolic RY; emergent small-bowel resection was only required in two cases of herniation through this defect after laparoscopic total gastrectomy. CONCLUSION: Retrocolic RY with appropriate closure of defects can reduce IH incidence at Petersen's defect and at jejunojejunostomy mesenteric defect. Although the IH incidence at the transverse mesocolic defect is not particularly high, the possibility of herniation through this defect should be kept in mind.

Successful video-assisted thoracoscopic surgery in prone position in patients with esophageal cancer and aberrant right subclavian artery: report of three cases.

BACKGROUND: An aberrant right subclavian artery (ARSA) with an associated nonrecurrent right inferior laryngeal nerve (NRILN) is a relatively rare anomaly that occurs at a frequency of 0.3 to 2.0% of the general population. NRILN has been mainly documented in the head and neck region; it has been rarely described in patients with esophageal cancer, especially those undergoing thoracoscopic surgery. Video-assisted thoracoscopic surgery for esophageal cancer (VATS-E) is becoming more widespread as a reliable minimally invasive surgical procedure associated with reduced perioperative complications. CASE PRESENTATION: Herein, we report three cases of esophageal cancer with ARSA and NRILN which underwent successful VATS-E. Case 1, a 53-year-old male who had early stage esophageal cancer was performed VATS-E. Upper gastrointestinal (GI) series showed "Bayonet sign" (T1aN0M0, pStageIA in UICC). Case 2, a 75-year-old male who had advanced esophageal cancer was performed neoadjuvant chemotherapy and following VATS-E. This case had right thoracic duct and "Bayonet sign" on upper GI series (T1bN2M0, pStage IIIA in UICC). Case3, a 72-year-old male who had advanced esophageal cancer was performed neoadjuvant chemotherapy and following VATS-E (T3N2M0, pStageIIIB in UICC). All of these three cases were performed VATS-E and discharged without any complication. CONCLUSION: VATS-E in the prone position is a feasible procedure that can reduce the risk of complications with an enlarged and clear view, and knowledge of this type of anomaly is very important for surgeons who perform esophagectomy.

Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL.

Metastasis is the main cause of cancer-associated death, and metastasis of pancreatic cancer remains difficult to treat because of its aggressiveness. MicroRNAs (miRNAs) play crucial roles in the regulation of various human transcripts, and many miRNAs have been reported to correlate with cancer metastasis. We identified an anti-metastatic miRNA, miR-5100, by investigating differences in miRNA profiling between highly metastatic pancreatic cancer cells and their parental cells. Overexpression of miR-5100 inhibited colony formation (P<0.05), cell migration (P<0.0001) and invasion (P<0.0001) of pancreatic cancer cells. In addition, we identified a possible target of miR-5100, podocalyxin-like 1 (PODXL), and demonstrated miR-5100 directly binds to the 3' untranslated region of PODXL and post-transcriptionally regulates its expression in pancreatic cancer cells. Silencing PODXL resulted in diminished cell migration (P<0.0001) and invasion (P<0.05). We also clarified the close relationship between expression of PODXL in human pancreatic cancer specimens and liver metastasis (P=0.0003), and determined that post-operative survival was longer in the low-PODXL expression group than in the high-PODXL expression group (P<0.05). These results indicate that miR-5100 and PODXL have considerable therapeutic potential for anti-metastatic therapy and could be potential indicators for cancer metastases in patients with pancreatic cancer.

Biliary sphincter motility after neural isolation of the pancreatoduodenal region in conscious dogs.

BACKGROUND: Several neural and hormonal factors are known to affect the motility of the sphincter of Oddi. However, the precise mechanisms of the control of sphincter motility have not been completely explored. We investigated the relationship of canine biliary sphincter motility when it is extrinsically denervated by neural isolation of the pancreatoduodenal region. METHODS: Interdigestive and postprandial sphincter motility in a denervated pancreatoduodenal segment and effects of cholecystokinin-octapeptide were studied in 7 conscious dogs. Data were compared with those of 7 neurally intact control dogs. RESULTS: After extrinsic denervation of the pancreatoduodenal region, sphincter motility exerted a cyclic change in concert with the duodenal myoelectric cycles; this change involved short cyclic bursts of motor activity, which gradually increased in intensity. The increase in the cyclic bursts of motor activity was also cyclic and associated with an increase in the plasma motilin concentration. Neural isolation of the pancreatoduodenal region increased sphincter basal pressure and motility index (integral per minute). In the denervated biliary sphincter, the feeding pattern and temporary inhibitory effect of feeding, as seen in controls, were absent, which suggests the role of extrinsic nerves in delivering bile into the duodenum after feeding. In the denervated dogs, cholecystokinin-octapeptide caused excitation of the sphincter activity, instead of relaxation observed in controls. CONCLUSIONS: Extrinsic innervation to the pancreatoduodenal region has an inhibitory effect on biliary sphincter motility. Abnormalities in extrinsic innervation to the biliary sphincter might increase the resistance of the sphincter to the bile flow and induce bile stagnation.

Comparison of recovery of gastric phase III motility and gastric juice output after different types of gastrointestinal reconstruction following pylorus-preserving pancreatoduodenectomy.

BACKGROUND: Early gastric stasis is a frequent complication of pylorus-preserving pancreatoduodenectomy (PPPD). However, few reports have addressed this phenomenon in relation to the type of gastrointestinal reconstruction. We compared gastrointestinal motility and gastric juice output after two different types of gastrointestinal reconstruction following PPPD, end-to-side duodenojejunostomy after pancreaticojejunostomy and hepaticojejunostomy (group 1) and end-to-end duodenojejunostomy before pancreaticojejunostomy and hepaticojejunostomy (group 2). METHOD: In a total of 25 patients, 10 in group 1 and 15 in group 2, who underwent PPPD, manometry was repeated to assess gastric and jejunal motility until the first occurrence of phase III activity of gastric cyclic motor activity (CMA). The plasma level of motilin was measured in each phase of the gastric CMA and compared between the two groups. The daily volume of gastric juice output through a gastrostomy tube was also recorded for comparison. RESULT: There was no significant difference in the time period for recovery of gastric phase III activity and gastric juice output between the two groups. However, abnormal contractions with an increased basal pressure appeared frequently in the afferent jejunal loop only in group 1. The plasma motilin level after PPPD showed no apparent cyclic change even after the recovery of gastric phase III in either group. CONCLUSION: Gastrointestinal reconstructive procedures have almost no effect on the recovery of gastric CMA. The plasma motilin concentration does not play a major role in the recovery of gastric CMA in the early postoperative period after PPPD.

Triangulating stapling technique for esophagogastrostomy after minimally invasive esophagectomy.

BACKGROUND: The triangulating stapling technique is one of the reconstruction methods used that provides favorable surgical outcomes in several areas of the digestive tract. However, the results in the cervical esophagogastric anastomosis are not well documented. METHODS: Using a prospectively maintained comprehensive database, we reviewed the surgical results of 160 consecutive patients who underwent minimally invasive esophagectomy followed by cervical triangulating stapling esophagogastrostomy during 2 periods from May 2002 to May 2012 so as to determine the efficacy of the triangulating stapling technique using 2 different types of stapling devices. RESULTS: The rates of anastomotic leakage and stricture in this series were low (1% and 15%, respectively). The rate of anastomotic stricture was significantly reduced when a linear stapler with a cutting knife was used (9%). A logistic regression analysis showed a reduction of anastomotic stricture to be significantly associated with the use of only a linear stapler with a cutting knife. CONCLUSION: Cervical esophagogastric anastomosis by the triangulating stapling technique is safe and feasible. We consider a linear stapling device equipped with a cutting knife to be more suitable for performing the triangulating stapling technique.

Prospectively isolated cancer-associated CD10(+) fibroblasts have stronger interactions with CD133(+) colon cancer cells than with CD133(-) cancer cells.

Although CD133 has been reported to be a promising colon cancer stem cell marker, the biological functions of CD133+ colon cancer cells remain controversial. In the present study, we investigated the biological differences between CD133+ and CD133- colon cancer cells, with a particular focus on their interactions with cancer-associated fibroblasts, especially CD10+ fibroblasts. We used 19 primary colon cancer tissues, 30 primary cultures of fibroblasts derived from colon cancer tissues and 6 colon cancer cell lines. We isolated CD133+ and CD133- subpopulations from the colon cancer tissues and cultured cells. In vitro analyses revealed that the two populations showed similar biological behaviors in their proliferation and chemosensitivity. In vivo analyses revealed that CD133+ cells showed significantly greater tumor growth than CD133- cells (P=0.007). Moreover, in cocultures with primary fibroblasts derived from colon cancer tissues, CD133+ cells exhibited significantly more invasive behaviors than CD133- cells (P<0.001), especially in cocultures with CD10+ fibroblasts (P<0.0001). Further in vivo analyses revealed that CD10+ fibroblasts enhanced the tumor growth of CD133+ cells significantly more than CD10- fibroblasts (P<0.05). These data demonstrate that the in vitro invasive properties and in vivo tumor growth of CD133+ colon cancer cells are enhanced in the presence of specific cancer-associated fibroblasts, CD10+ fibroblasts, suggesting that the interactions between these specific cell populations have important roles in cancer progression. Therefore, these specific interactions may be promising targets for new colon cancer therapies.

MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance.

Due to the poor prognosis of pancreatic cancer, novel diagnostic modalities for early diagnosis and new therapeutic strategy are urgently needed. Recently, microRNA-21 (miR-21) was reported to be strongly overexpressed in pancreatic cancer as well as in other solid cancers. We investigated the functional roles of miR-21, which have not been fully elucidated in pancreatic cancer. miR-21 expression was assessed in pancreatic cancer cell lines (14 cancer cell lines, primary cultures of normal pancreatic epithelial cells and fibroblasts, and a human normal pancreatic ductal epithelial cell line) and pancreatic tissue samples (25 cancer tissues and 25 normal tissues) by quantitative real-time reverse transcription-PCR amplification. Moreover, we investigated the proliferation, invasion, and chemoresistance of pancreatic cancer cells transfected with miR-21 precursor or inhibitor. miR-21 was markedly overexpressed in pancreatic cancer cells compared with nonmalignant cells, and miR-21 in cancer tissues was much higher than in nonmalignant tissues. The cancer cells transfected with the miR-21 precursor showed significantly increased proliferation, Matrigel invasion, and chemoresistance for gemcitabine compared with the control cells. In contrast, inhibition of miR-21 decreased proliferation, Matrigel invasion, and chemoresistance for gemcitabine. Moreover, miR-21 positively correlated with the mRNA expression of invasion-related genes, matrix metalloproteinase-2 and -9, and vascular endothelial growth factor. These data suggest that miR-21 expression is increased in pancreatic cancer cells and that miR-21 contributes to the cell proliferation, invasion, and chemoresistance of pancreatic cancer.

Effect of atropine on the biomechanical properties of the oesophageal wall in humans.

Recently, we reported a novel ultrasound technique to assess biomechanical properties of the oesophagus in human subjects. In the present study, we use the technique, in combination with atropine, to determine the active and passive biomechanical properties of the oesophagus in normal healthy humans. A manometric catheter equipped with a high-compliance bag and a high-frequency intraluminal ultrasonography probe was used to record pressure and oesophageal geometry. Oesophageal distensions with either isovolumic (5-20 ml water) or with isobaric (10-60 mmHg) technique were performed. Intra-bag pressure and ultrasound images of the oesophagus were recorded simultaneously. Following injection of atropine (15 microg kg-1, I.V.), the oesophageal distensions were repeated. The oesophageal wall compliance, circumferential wall tension, stress, strain and elastic modulus were calculated. Atropine resulted in an increase in the oesophageal wall compliance during isobaric distension, but no change in compliance was observed during isovolumic distension. The stress-strain relationship was found to be linear during both types of distension, before as well as after atropine. The Young's modulus, which is the slope of a linear stress-strain relationship, was significantly higher after atropine in the isovolumic study but not in the isobaric study. The stress-strain relationship of the active component (muscle contraction) was different during isovolumic and isobaric distensions but the passive components were similar. The passive and active stress-strain relationships of the human oesophagus resemble those of other soft biological tissues. Furthermore, the method of oesophageal distension has significant influence on the active but not the passive biomechanical properties due to a strain-rate effect.

Effect of truncal vagotomy on sphincter of oddi cyclic motility in conscious dogs.

OBJECTIVE: To evaluate the effects of truncal vagotomy at the diaphragmatic level on the sphincter of Oddi (SO) motility. SUMMARY BACKGROUND DATA: Cholelithiasis is a well-known late complication after gastrectomy and/or vagotomy. The mechanism of gallstone formation is only partly understood, and few studies address the effects of vagotomy on SO cyclic motility in conscious subjects. METHODS: In conscious dogs, SO motility was recorded by retrograde infusion manometry through a duodenal cannula before and after bilateral truncal vagotomy at the diaphragmatic level. Effects of cholecystokinin-octapeptide and feeding were also evaluated before and after vagotomy. RESULTS: SO cyclic motility and the gastroduodenal migrating motor complex continued to occur during postvagotomy fasting. Intermittent inhibitions of the SO and duodenal contractions disappeared during phase 3 of the migrating motor complex. SO basal pressure significantly decreased, whereas the amplitude significantly increased. Cholecystokinin-octapeptide inhibited SO contractions before and after vagotomy. The amplitude of SO contractions increased and their frequency decreased after feeding; however, these effects disappeared after vagotomy. CONCLUSIONS: SO cyclic motility and the effects of feeding change after truncal vagotomy at the diaphragmatic level. These facts may at least partly explain gallstone formation after gastric surgery and/or vagotomy.

Severe localized stenosis and marked dilatation of the main pancreatic duct are indicators of pancreatic cancer instead of chronic pancreatitis on endoscopic retrograde balloon pancreatography.

BACKGROUND: Differentiation between benign and malignant localized stenoses of the main pancreatic duct is difficult by pancreatography. METHODS: A total of 48 patients with such localized stenosis who underwent endoscopic retrograde balloon pancreatography with abdominal compression were retrospectively studied. The following were examined: (1) diameter of the stenotic, prestenotic, and poststenotic ductal segments; (2) ratios of prestenotic/poststenotic, stenotic/prestenotic, and stenotic/poststenotic ductal segments; (3) length of stenosis and steepness of transition to the stenosis (proximal angle, distal angle); and (4) main duct and branch findings for peristenotic segments. RESULTS: The stenosis was diagnosed as caused by chronic pancreatitis in 27 patients and pancreatic cancer in 21 by histopathology, cytology, or clinical follow-up. The prestenotic/poststenotic ductal segments ratio and proximal angle were greater in pancreatic cancer compared with chronic pancreatitis. Severe stenosis (stenotic ductal segments less than 20% of prestenotic or poststenotic ductal segments); moderate (prestenotic ductal segments 2.5 to 3.5 times larger than poststenotic ductal segments), and severe (prestenotic ductal segments more than 3.5 times larger than poststenotic ductal segments) dilatation of the proximal duct were more frequent in pancreatic cancer than in chronic pancreatitis. Multivariate regression analyses showed that severe stenosis and dilatation were independently significant parameters that indicated a diagnosis of pancreatic cancer. Various combinations of severe stenosis, proximal dilatation, and double duct sign gave high predictive values. CONCLUSIONS: Severe stenosis, marked proximal dilatation, double duct sign, and combinations of these findings are useful indicators of malignant localized stenosis of the pancreatic duct.