A novel radiopaque biodegradable stent for pancreatobiliary applications--the first human phase I trial in the pancreas.

BACKGROUND/AIMS: During the recent years we have developed and experimentally tested a biodegradable stent for pancreatobiliary applications. Such stents may be used in benign strictures or when securing the flow of bile, pancreatic juice or a fluid collection after endoscopic or surgical procedures. The lack of suitable devices has so far prohibited clinical endoscopic or percutaneous tests whereas surgical application has become possible. Recently we described a modified binding (purse string) pancreaticojejunostomy, where a biodegradable stent is introduced to secure the lumen opening when tightening the bowel over the pancreas with a purse string. Although routine use of any stent in pancreaticojejunostomy has been under debate, we used this setting to run for the first phase I human clinical trial with a biodegradable stent in a pancreatobiliary application. METHODS: After 29 pancreaticoduodenectomies, a braided gamma sterilized radiopaque 96L/4D polylactide stent was introduced into the duct of pancreas remnant, which was then sunk into the Roux-Y jejunal limb. Complications, stent disappearance and late anastomotic patency (MRI) were monitored. RESULTS: Hospital mortality was zero. One patient developed Grade C fistula (overall fistula rate 3%). She also developed Grade C hemorrhage and Grade C delayed gastric emptying (DGE). One other patient developed Grade B hemorrhage (overall hemorrhage rate 7%) and B DGE. Three other patients developed clinically significant Grade B-C DGE (5/29=17%). In addition, 10 other patients were not on solid food only on post-operative day 8, and were classified as Grade A DGE (34%). Most of these patients were eating normally and could be discharged from hospital by day 10. Nine out of 26 patients (35%) with negative preoperative trypsinogen test, developed post-operative trypsinogen release suggesting pancreatitis. Within 12 months four patients died and one quitted the study. The stents disappeared in median 3 months. MRI interpretation of the anastomosis failed in one patient having ascites. Of the 23 patients, 13 (57%) had the anastomosis well open, three (13%) had some narrowing, while seven (30%) had the anastomosis obstructed. CONCLUSION: Compared with our previous experiences obtained in pancreaticoduodenectomy, a biodegradable stent is well tolerated in the human pancreatic duct, encouraging further development for future applications and tests in randomized trials.

Pancreatic damage after the first episode of acute alcoholic pancreatitis and its association with the later recurrence rate.

BACKGROUND: Acute alcoholic pancreatitis (AAP) recurs in up to half of the patients, continuous alcohol consumption being an important risk factor. Changes in pancreatic function and morphology after acute pancreatitis have been characterized previously, but their association with later recurrences has not been adequately studied. PATIENTS AND METHODS: In this prospective follow-up study, the pancreatic function of 54 patients (47 males and 7 females) with a median age of 49 years (range 25-71) and morphology (35 patients) were evaluated. Pancreatic morphology was evaluated by secretin-stimulated magnetic resonance pancreatography (SMRP). Patients were evaluated early (baseline) and at 2 years after the first episode of AAP. In order to evaluate later recurrences, the patients were followed for a median of 47 (range 28-66) months. RESULTS: Of the 46 patients without previous diabetes, 17 patients (37%) developed impaired glucose metabolism during the 2 years following the first AAP. The prevalence of exocrine dysfunction decreased from 39% at baseline to 9% at 2 years. Of the patients with severe pancreatitis (n = 13, 24%), 31% had elevated glycosylated haemoglobin levels compared to 7% in patients with mild pancreatitis [p = 0.05, odds ratio (OR): 5.5, 95% confidence interval (CI): 1.04-29.0]. Twenty percent (7/35) of the patients had changes consistent with chronic pancreatitis on baseline SMRP, which persisted in all cases. Of the 29% patients with acute changes on baseline SMRP, the acute changes resolved in 50% and chronic pancreatitis was detected in the remaining 50% at 2 years. Development of chronic changes did not depend on continued alcohol consumption, as it was also found in 3 patients practising complete abstinence following their first attack of AAP. The presence of a chronic pseudocyst at 2 years predicted pancreatitis when compared to patients lacking pseudocyst formation: 4 (80%) versus 5 (17%) (p = 0.01, OR: 20.0, 95% CI: 1.83-219). CONCLUSION: The severity of the first episode of AAP was associated with deteriorated diabetes control, but not with pancreatic exocrine dysfunction at 2 years. The number of patients with chronic changes on SMRP increased independently of alcohol consumption. Chronic pseudocyst formation seen on SMRP 2 years after AAP was significantly associated with recurrence of pancreatitis.

Risk factors for recurrent acute alcohol-associated pancreatitis: a prospective analysis.

OBJECTIVE: In an earlier retrospective study we showed that 46% of patients with acute alcoholic pancreatitis had recurrent attacks within 10-20 years, about 30% having a recurrence during the first 3 years. The aim of this prospective follow-up study was to determine the risk factors associated with recurrences. MATERIAL AND METHODS: Sixty-eight patients, (59 M, 9 F, mean age 46 years, range 25-71 years) who survived their first acute alcohol-induced pancreatitis from January 2001 to January 2004 volunteered to participate in the study. The diagnostic criteria for acute pancreatitis were epigastric pain, serum amylase > 3 times the upper normal range, elevated serum C-reactive protein (CRP), and signs of acute pancreatitis in imaging. Other etiologies were excluded. Alcohol consumption and dependency were detected by the Alcohol Use Disorders Identification Test (AUDIT) and the Short Alcohol Dependence Data (SADD), respectively, and by attempting to evaluate recent use in grams of pure alcohol. Social and demographic data of the patients, smoking, body mass index, and the severity of the pancreatitis were recorded. Serum and fecal markers of the endocrine and exocrine function and secretin-stimulated MRCP were studied. The patients were followed for a median 38 (25-61) months for recurrences, and at the 2-year time-point had a follow-up visit to investigate any changes in alcohol consumption. RESULTS: Seventeen (25%) patients had recurrences of acute alcoholic pancreatitis during the follow-up. Pre-illness alcohol consumption, the severity of the pancreatitis, patient's social or demographic data, pancreatic function tests or morphologic changes in MRCP, or smoking did not correlate with recurrence. None of the 13 patients with consistent total abstinence from alcohol at 2 years developed recurrent pancreatitis compared with 17 out of 51 (33%) patients with at least some alcohol consumption (p = 0.02). Use of other sedatives than alcohol before the first attack of pancreatitis was an independent risk factor associated with recurrence (HR = 6.95, 95% CI 2.45-19.72, p < 0.001). A lower reduction in dependency on alcohol (less decreased SADD points) during 2 years was associated with a higher recurrence rate (HR = 0.921/each reduced point, 95% CI 0.872-0.974, p=0.004). CONCLUSIONS: Contrary to chronic pancreatitis, smoking was not found to be a risk factor for recurrent episodes after the first attack of acute alcoholic pancreatitis. Abstinence from alcohol protects against recurrent pancreatitis. Patients who developed recurrent acute pancreatitis had increased dependency on alcohol, demonstrated by the use of other sedatives in addition to alcohol and supported by the less decreased dependency during the follow-up.

Screening for human cationic trypsinogen (PRSS1) and trypsinogen inhibitor gene (SPINK1) mutations in a Finnish family with hereditary pancreatitis.

OBJECTIVE: Mutations in the cationic trypsinogen gene (PRSS1) have been linked with hereditary pancreatitis (HP). A change in R122H in the third exon is one of the mutations most frequently associated with HP. A mutation N34S in the serine protease inhibitor Kazal type 1 gene has also been shown to be linked with HP. The purpose of this study was to report on the incidence of PRSS1 and SPINK1 mutations in a Finnish family with HP and to correlate the findings to the clinical symptoms. MATERIAL AND METHODS: The study included 36 individuals from one Finnish family with HP (21 M, 15 F, median age 38 years). All individuals underwent abdominal ultrasound and laboratory tests (glucose, faecal elastase-1 test). Blood samples were taken for mutational analysis of PRSS1 (R122H, N29I and A16V) and SPINK1 (N34S). RESULTS: Ten (28%) individuals were affected by mutations: the most frequent mutation was R122H, affecting 8 (22%) individuals; 2 (6%) individuals were affected by the N34S mutation and none by the other tested mutations (N29I and A16V). Four out of eight (50%) R122H-positive individuals had a diagnosis of chronic pancreatitis without other known aetiologies. Four out of five (80%) male individuals with the R122H mutation also had clinical pancreatitis, whereas none of the three mutation-positive females had any signs or symptoms of chronic pancreatitis. The two individuals with the N34S mutation did not have any signs of chronic pancreatitis. CONCLUSIONS: In the investigated Finnish pedigree with HP, the PRSS1 mutation R122H is linked with chronic disease. Although the SPINK1 mutation (N34S) was also observed in two individuals, it was not linked with the disease.

Obstructed pancreaticojejunostomy partly explains exocrine insufficiency after pancreatic head resection.

OBJECTIVE: The majority of patients with long-term survival after pancreatic head resection suffer from pancreatic exocrine insufficiency. The objective of this study was to investigate whether this is due to glandular malfunction or obstructed pancreaticojejunal anastomosis. MATERIAL AND METHODS: Twenty-six patients (10 M, 16 F, mean age 61 years, range 34-81 years) were re-examined a median of 52 months (range 3-76 months) after pancreatic head resection and end-to-end invaginated pancreaticojejunostomy. Pancreatic exocrine function was measured by fecal elastase-1 assay. The size of the pancreatic remnant, glandular secretion and the flow through the anastomosis were analyzed with secretin-stimulated dynamic magnetic resonance pancreatography (D-MRP). RESULTS: All patients had pancreatic exocrine insufficiency, 24 (92%) of them having severe insufficiency. Eighteen patients (69%) reported moderate to severe diarrhea. Lowest fecal elastase-1 concentrations were associated with the initial diagnosis of chronic pancreatitis or ductal adenocarcinoma, suggesting preoperative primary or secondary chronic pancreatitis as important determinants. The size of the remnant gland did not correlate with the fecal elastase-1 concentrations. D-MRP failed in three patients. Severe glandular malfunctions were found in 7 (30%) of the 23 successful D-MRP examinations. The anastomosis was totally obstructed in 5 patients (22%) or partially obstructed in 6 (26%) but remained perfectly open in 5 patients (22%). The five patients with perfect anastomoses had the highest measured median fecal elastase-1 activity. CONCLUSIONS: Although late diarrhea and pancreatic exocrine insufficiency may be partly induced already by the disease treated with resection, at least half may be explained by obstructed anastomosis. To obtain better late functional results, improvements may be required in the surgical techniques.

Complications of palliative hepaticojejunostomy and gastrojejunostomy in unresectable periampullary cancer: patient- and disease-related risk factors.

BACKGROUND/AIMS: Under 20% of the patients with periampullary cancer can be treated with curative resection. When the tumor is only found to be unresectable for cure during the operation, it is generally accepted to perform hepaticojejunostomy on the jaundiced patients. Gastric emptying problems develop after laparotomy in only 7-17% of the patients with unresectable periampullary cancer, which has made the justification of prophylactic gastrojejunostomy less clear. Because the quality of life is the most important aim in palliative surgery, the risks should be minimized. The aim of our study was to evaluate the possible risk factors for the development of complications, after palliative hepaticojejunostomy and gastrojejunostomy in patients whose periampullary tumors were not found to be unresectable for cure until during the operation. METHODOLOGY: Thirty-three patients underwent routine palliative hepaticojejunostomy (Roux-Y) and gastrojejunostomy (retrocolic) and 17 (52%) underwent also operative celiac plexus blockade (50% ethanol ad 20mL both sides), when their periampullary tumor was found not resectable for cure at laparotomy. Jaundice had been relieved preoperatively in 26 (79%) patients, with an endoscopic stent (ERCP-stent) in 13 (39%) patients and with a percutaneous transhepatic drainage (PTD) in 13 (39%) patients. Gastric emptying problems were found preoperatively in 12 (36%) patients: 7 (58%) had verified partial duodenal obstruction and 5 (42%) had only vomiting without anatomical findings. Antimicrobial and antithrombotic prophylaxis was used routinely. Patients were divided into two groups: 1) complication group (n=12, 36%) and 2) no complication group (n=21, 64%). RESULTS: Hospital mortality was 0%. In the complication group the tumor diameter was more often over 4cm compared to the no complication group (10/12 vs. 7/21, p=0.007) and gastric emptying problems were more common in the complication group (7/12 vs. 5/21, p=0.02). We also found a tendency to higher preoperative alkaline phosphatase level in the complication group (mean +/- SEM, [943 +/- 201 vs. 578 +/- 84 IU/L], p=0.06). In multivariate analysis we clarified the influence of gastric emptying problems, tumor size, treatment method of preoperative jaundice (ERCP-stent, PTD), preoperative alkaline phosphatase level and age of the patient on the risk for the development of complications, and found two independent risk factors: patients with symptoms possibly relating to gastric emptying problems developed more complications (OR=6.9, p=0.002), whereas ERCP-stent seemed to protect from complications (OR=0.2, p=0.047). The risk for developing complications in patients with two positive risk factors (gastric emptying problems and unsuccessful ERCP-stent) was 67%, with one positive risk factor 50%, compared to 8% when neither of the two significant risk factors were observed. CONCLUSIONS: Gastric emptying problems and missing ERCP-stent are risk factors for developing complications in patients who undergo palliative hepaticojejunostomy and gastrojejunostomy because of periampullary cancer. These data can be utilized in patient information and when stratifying patients in future trials.