Impact of nationwide enhanced implementation of best practices in pancreatic cancer care (PACAP-1): a multicenter stepped-wedge cluster randomized controlled trial.

BACKGROUND: Pancreatic cancer has a very poor prognosis. Best practices for the use of chemotherapy, enzyme replacement therapy, and biliary drainage have been identified but their implementation in daily clinical practice is often suboptimal. We hypothesized that a nationwide program to enhance implementation of these best practices in pancreatic cancer care would improve survival and quality of life. METHODS/DESIGN: PACAP-1 is a nationwide multicenter stepped-wedge cluster randomized controlled superiority trial. In a per-center stepwise and randomized manner, best practices in pancreatic cancer care regarding the use of (neo)adjuvant and palliative chemotherapy, pancreatic enzyme replacement therapy, and metal biliary stents are implemented in all 17 Dutch pancreatic centers and their regional referral networks during a 6-week initiation period. Per pancreatic center, one multidisciplinary team functions as reference for the other centers in the network. Key best practices were identified from the literature, 3 years of data from existing nationwide registries within the Dutch Pancreatic Cancer Project (PACAP), and national expert meetings. The best practices follow the Dutch guideline on pancreatic cancer and the current state of the literature, and can be executed within daily clinical practice. The implementation process includes monitoring, return visits, and provider feedback in combination with education and reminders. Patient outcomes and compliance are monitored within the PACAP registries. Primary outcome is 1-year overall survival (for all disease stages). Secondary outcomes include quality of life, 3- and 5-year overall survival, and guideline compliance. An improvement of 10% in 1-year overall survival is considered clinically relevant. A 25-month study duration was chosen, which provides 80% statistical power for a mortality reduction of 10.0% in the 17 pancreatic cancer centers, with a required sample size of 2142 patients, corresponding to a 6.6% mortality reduction and 4769 patients nationwide. DISCUSSION: The PACAP-1 trial is designed to evaluate whether a nationwide program for enhanced implementation of best practices in pancreatic cancer care can improve 1-year overall survival and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03513705. Trial opened for accrual on 22th May 2018.

Pancreatic ductal adenocarcinoma and chronic pancreatitis may be diagnosed by exhaled-breath profiles: a multicenter pilot study.

BACKGROUND: The diagnosis of pancreatic adenocarcinoma and chronic pancreatitis often rely on expensive and invasive diagnostic approaches, which are not always discriminative since patients with chronic pancreatitis and pancreatic adenocarcinoma may present with similar symptoms. Volatile organic compounds (VOCs) in expired breath, could be used as a non-invasive diagnostic biological marker for detection of pancreatic pathology. Detection and discrimination of pancreatic pathology with an electronic nose has not yet been reported. PURPOSE: The objective of this pilot study was to determine the diagnostic potential of an electronic nose to identify pancreatic adenocarcinoma and chronic pancreatitis by analyzing volatile organic compoundg (VOC) profiles in exhaled air. PATIENTS AND METHODS: In a multicenter study, the exhaled air of 56 chronic pancreatitis patients, 29 pancreatic adenocarcinoma patients, and 74 disease controls were analyzed using an electronic nose based on 3 metal oxide sensors (MOS). The measurements were evaluated utilizing an artificial neural network. RESULTS: VOC profiles of chronic pancreatitis patients could be discriminated from disease controls with an accuracy of 0.87 (AUC 0.95, sensitivity 80%, specificity 92%). Also, VOC profiles of patients with pancreatic adenocarcinoma differed from disease controls with an accuracy of 0.83 (AUC 0.87, sensitivity 83%, specificity 82%). Discrimination between chronic pancreatitis and pancreatic adenocarcinoma showed an accuracy of 0.75 (AUC 0.83, sensitivity 83%, specificity 71%). CONCLUSION: An electronic nose may be a valuable diagnostic tool in diagnosis of pancreatic adenocarcinoma and chronic pancreatitis. The current study shows the potential of an electronic nose for discriminating between chronic pancreatitis, pancreatic adenocarcinoma and healthy controls. The results from this proof-of-concept study warrant external validation in larger cohorts.

The revised Atlanta criteria more accurately reflect severity of post-ERCP pancreatitis compared to the consensus criteria.

Background and objective: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most prevalent complication after ERCP with an incidence of 3.5%. PEP severity is classified according to either the consensus criteria or the revised Atlanta criteria. In this international cohort study we investigated which classification is the strongest predictor of PEP-related mortality. Methods: We reviewed 13,384 consecutive ERCPs performed between 2012 and 2017 in eight hospitals. We gathered data on all pancreatitis-related adverse events and compared the predictive capabilities of both classifications. Furthermore, we investigated the correlation between the two classifications and identified reasons underlying length of stay. Results: The total sample consisted of 387 patients. The revised Atlanta criteria have a higher sensitivity (100 vs. 55%), specificity (98 vs. 72%) and positive predictive value (58 vs. 5%). There is a significant difference (p < 0.001) between the two classifications. In 124 patients (32%), the length of stay was influenced by concomitant diseases. Conclusion: The revised Atlanta classification is superior in predicting mortality and better reflects PEP severity. This has important implications for researchers, clinicians and patients. For the diagnosis of PEP pancreatitis, the consensus criteria remain the golden standard. However, the revised Atlanta criteria are preferable for defining PEP severity.

[Symptomatic gallstone disease: an indication for surgery]. / Symptomatisch galsteenlijden: een operatie-indicatie.

Three patients, men in the ages of 58, 66 and 56 years, respectively, had experienced 'warning colics' a considerable time before gallstone complications or severe recurrent colic. Ultrasonographically proven gallstones had not led to cholecystectomy. The 58-year-old man died of sepsis due to infected pancreatic necrosis; the other men underwent laparoscopic cholecystectomy, after which they recovered fully. Approximately 10-5% of the adult Dutch population have gallstones, but only 10% will develop symptoms. The annual risk for developing complicated gallstone disease is 1-2% in asymptomatic gallstone carriers. Of patients admitted with complicated gallstone disease, 58% have had prior 'warning colics'. Complicated gallstone disease can be prevented by timely treatment after recognition of warning colics. Cholecystectomy is indicated in patients with intermittent upper-abdominal pain and proven gallstones or sludge.

Review article: agents affecting gall-bladder motility--role in treatment and prevention of gallstones.

Various agents may either enhance or impair post-prandial gall-bladder motility, and they are identified in this review. When studying the impact of medication on gall-bladder motility, the effects on interdigestive gall-bladder and intestinal motility should also be taken into account. Patients at high risk of gallstone disease, and patients who are treated chronically with gall-bladder motility inhibiting drugs, may benefit from improved gall-bladder motility using a prokinetic agent. However, there are no long-term studies to prove that such a strategy prevents gallstone formation.

New strategies for the treatment of gallstone disease.

BACKGROUND: Symptomatic gallstones are generally accepted as being the indication for cholecystectomy. Generally, severe abdominal pain in epigastrium and in the right upper abdominal quadrant, and lasting for more than 15 min, is thought to be caused by gallstones. However, many patients with other abdominal complaints undergo cholecystectomy and are satisfied with the outcome of surgery. Possible ways to improve the results of cholecystectomy are discussed. METHODS: Review of previous work by the authors. RESULTS: The introduction of laparoscopic cholecystectomy has even led to an increase in cholecystectomies; in a higher complication rate; and in increased costs of the treatment of gallstone disease. Because of faster recovery, 70% of symptomatic gallstone patients are able and willing to undergo laparoscopic cholecystectomy in day care. Cholecystectomy after sphincterotomy and stone extraction in patients who have stones in the gallbladder was demonstrated to prevent gallstone-related symptoms in at least 40% of patients. If the gallbladder had to be removed later for symptomatic disease, however, this did not result in a higher rate of conversions and complications. Because of shortage in operation capacity in The Netherlands, there is a considerable delay between the diagnosis of symptomatic stones and cholecystectomy. Better selection of patients for cholecystectomy will not only improve the results of cholecystectomy, it will also reduce the number of cholecystectomies and patients on waiting lists. Delay of cholecystectomy is associated with more complications, longer operative times, higher conversion rates to open cholecystectomy and prolonged hospitalization. The efficacy of the bile salt ursodeoxycholic acid in preventing gallstone-related pain attacks and complications in patients with contraindications for operation or waiting to undergo cholecystectomy should be investigated further, since two retrospective studies have demonstrated favourable outcomes for this strategy. CONCLUSION: The results of cholecystectomy are likely to be improved by better selection of patients, prevention of delay of the procedure and possibly treatment with ursodeoxycholic acid.

Acute idiopathic pancreatitis: does it really exist or is it a myth?

BACKGROUND: Acute pancreatitis is a severe disease with considerable morbidity and mortality. Gallstones and alcohol abuse are the most frequent causes (75% of patients). Other well-known causes are: hyperlipidemia, hypercalcaemia, abdominal surgery and drugs. In 10%-40% of patients however, no cause is identified after initial diagnostic evaluation: acute idiopathic pancreatitis. Identifying a cause in these patients is important, since the recurrence rate is high. METHODS: A systematic review of the current literature was performed to identify possible causes, diagnoses and treatment options of acute idiopathic pancreatitis. Relevant literature was found via Pubmed. RESULTS: The presence of microlithiasis or biliary sludge is an important cause of acute 'idiopathic' pancreatitis (up to 80% of patients). Microlithiasis and sludge can be detected by transabdominal/endoscopic ultrasonography, ERCP or polarizing light microscopy of bile. Cholecystectomy is the treatment of choice, whereas endoscopic sphincterotomy and ursodeoxycholic acid maintenance therapy are effective alternatives. Sphincter of Oddi dysfunction can be identified as the cause of acute 'idiopathic' pancreatitis in up to 30% of patients. Manometry of Oddi's sphincter is the gold standard for its diagnosis. Endoscopic sphincterotomy prevents recurrence in most patients. Anatomic abnormalities such as major papilla stenosis, pancreas divisum, pancreatic duct strictures and tumours may also cause acute 'idiopathic' pancreatitis. Endoscopic sphincterotomy and surgery are effective treatments. Finally, genetic screening may reveal gene mutations as the cause of acute 'idiopathic' pancreatitis. CONCLUSIONS: Acute 'idiopathic' pancreatitis is a severe disease with a high recurrence rate. Extensive diagnostic investigations may lead to a cause in >90% of patients.

Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease.

In the formation of cholesterol gallstones, cholesterol hypersecretion into bile causing cholesterol supersaturation and crystallization appears to be the primary factor, with disturbed gallbladder and intestinal motility as secondary factors. Although intestinal uptake mechanisms have not yet been fully elucidated, the HDL receptor scavenger receptor B1 (SRB1) may be involved. Since HDL-cholesterol, both from the intestine and peripheral sources, is the preferred type of cholesterol for biliary secretion, increased HDL transport to the liver can also cause cholesterol hypersecretion in bile. In the hepatocyte, bile formation is regulated by several transmembrane proteins, all belonging to the ABC family. A change in the activity in one of these proteins can have a profound impact on biliary lipid secretion. The bile salt export pump (BSEP or ABCB11) regulates the excretion of bile salts into bile and mutations cause severe cholestasis. The second ABC transporter, ABCB4 (MDR3) regulates the secretion in bile of phosphatidylcholine (PC), while ABCG5/G8 is active in the excretion of cholesterol and sterols into bile. These transporters also facilitate transport of sterols back into the intestinal lumen. Mutations in either of these genes cause sitosterolaemia with increased absorption of plant sterols and cholesterol. Until now, evidence for a genetic background of human gallstone disease is mostly indirect and based on ethnic differences. Only two single gene defects are associated with gallstones. One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver. Recently, several common DNA polymorphisms in the ABCG8 gene were discovered that are associated with variations in plasma sterols, which could also influence biliary cholesterol secretion, but there is still a paucity of human studies.

Indomethacin disrupts the protective effect of phosphatidylcholine against bile salt-induced ileal mucosa injury.

BACKGROUND: Indomethacin (Indo) exerts local toxic effects on small intestinal mucosa, possibly in association with hydrophobic bile salts. We investigated the potential toxic effects of Indo on ileal mucosa and the role of phosphatidylcholine (PC). MATERIALS AND METHODS: Transmucosal resistance and Na-fluorescein permeability of ileal mucosa segments from female Wistar rats were determined in Ussing chambers during a 30-min incubation with model systems containing: control-buffer, taurodeoxycholate (TDC), Indo, TDC-Indo, TDC-PC, or TDC-PC-Indo. Decrease of resistance and increase of permeability were considered as parameters for mucosal injury. After incubation in Ussing chambers, the histopathology was examined to quantify the extent of mucosal injury. Also, in CaCo-2 cells, LDH-release was determined as a measure of cytotoxicity, after incubation with various model systems. RESULTS: Decrease of resistance and increase of permeability were highest in systems containing TDC-Indo (P < 0.01). Phosphatidylcholine protected against the cytotoxic effects of TDC in absence of Indo only. Extent of mucosal injury by histological examination was also highest in systems containing TDC-Indo (P = 0.006). Again, PC exhibited protective effects in absence of Indo only. The LDH-release by CaCo2-cells was strongest in TDC-Indo systems (P < 0.001). CONCLUSIONS: Indomethacin disrupts protective effects of PC against bile salt-induced ileal mucosa injury. This finding is relevant for small intestinal injury induced by non-steroidal anti-inflammatory drugs.

Cholesterol saturation rather than phospholipid/bile salt ratio or protein content affects crystallization sequences in human gallbladder bile.

BACKGROUND: In model biles, cholesterol crystallization (an important factor in gallstone formation) mainly depends on phospholipid/bile salt ratios with characteristic sequences of plate-like (monohydrate) vs. non-plate-like (presumed anhydrous: arcs, needles, tubules, spirals) cholesterol crystals. We now investigate whether the same phenomenon occurs in human bile. METHODS: Appearances of plate-like and non-plate-like cholesterol crystals were determined in filtered bile of 80 cholesterol gallstone patients, and related to biliary lipid and pro-nucleating protein composition. RESULTS: Non-plate-like crystals appeared before plate-like crystals in 9 biles, on the same day in 24 biles, and after plate-like crystals in 31 biles. In 16 biles only plate-like crystals were observed. Crystal sequences did not depend on biliary lipid or protein composition. Cholesterol saturation indexes were higher in biles with than without non-plate-like crystals (150 +/- 6 vs. 125 +/- 12, P = 0.02). In contrast, phospholipid/(bile salt + phospholipid) ratios, bile salt species, phospholipid classes, concentrations of mucin, IgG, IgM, IgA, haptoglobin and alpha-1 acid glycoprotein did not differ. CONCLUSIONS: Cholesterol crystallization sequences in human bile depend on cholesterol saturation index rather than on phospholipid/bile salt ratio.

Absence of apolipoprotein E4 genotype, good gallbladder motility and presence of solitary stones delay rather than prevent gallstone recurrence after extracorporeal shock wave lithotripsy.

BACKGROUND/AIMS: Extracorporeal shock wave lithotripsy (ESWL) with adjuvant bile salt dissolution therapy may be successful in selected gallstone patients, but the considerable risk of recurrence is a major drawback. Apolipoprotein E4 genotype and impaired gallbladder motility have been identified as major risk factors for recurrence during short-term follow up. We have now examined their relevance during long-term follow up. METHODS: Eighty-four cholesterol gallstone patients (55 solitary and 29 multiple (two to ten) stones) were followed prospectively up to 10 years after complete stone disappearance. Various potential risk factors for recurrence were evaluated. RESULTS: Gallstone recurrence was found in up to 80% of patients at 10 years follow-up. Absence of the apolipoprotein epsilon4 allele, initial solitary stones, good gallbladder emptying (i.e. minimal postprandial volume < or = 6 ml) and 2-year postdissolution ursodeoxycholic acid prophylaxis (in ten patients) all delayed but did not prevent recurrence. In contrast, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was identified as an independent protective factor, with greatly decreased recurrence (at 10 years: 58 vs 93% in non-NSAID users, P = 0.03). CONCLUSIONS: Non-apolipoprotein E4 genotype, presence of solitary stones and good gallbladder emptying delay rather than prevent recurrence after initially successful ESWL. Regular use of NSAIDs may prevent recurrence.

The effect of acute oral erythromycin on gallbladder motility and on upper gastrointestinal symptoms in gastrectomized patients with and without gallstones: a randomized, placebo-controlled ultrasonographic study.

OBJECTIVE: Gastrectomy might be a risk factor for cholelithiasis and gallbladder stasis might play a major role. We studied fasting and postprandial gallbladder motility with 600 mg oral erythromycin or placebo in gastrectomized patients (with and without gallstones) and controls. METHODS: Seventeen patients operated on for gastric cancer (subtotal gastrectomy: n = 10, total gastrectomy: n = 7) were compared with 20 sex- and body-size matched healthy controls. Subjects randomly received erythromycin or placebo 30 min before the ingestion of a standard 200 ml liquid test meal. Gallbladder volume was estimated by ultrasonography until 120 min after test meal. A visual analog scale monitored GI perception of appetite, satiety, nausea, abdominal fullness and epigastric pain. RESULTS: Gastrectomized patients had increased fasting gallbladder volume (35.9 +/- 3.4 ml versus 21.0 +/- 1.4 ml, p = 0.0005) with faster postmeal emptying (T/2 14.8 +/- 1.1 min versus 23.5 +/- 1.5 min, p = 0.00019) than controls. Six patients developed small and asymptomatic gallstones, which did not influence gallbladder motility. In these patients, fasting gallbladder volume increased with time after surgery (r = +0.82, p = 0.047). Perception of satiety, abdominal fullness, and epigastric pain after ingestion of the test meal were all significantly greater in patients than in controls. Erythromycin significantly enhanced gallbladder emptying during fasting (p = 0.001) and postprandially in both patients and controls (0.002 < p < 0.017) and significantly reduced postmeal satiety and epigastric discomfort in gastrectomized patients. CONCLUSIONS: Increased fasting volume might be a form of stasis, predisposing patients to gallstone formation. Erythromycin improves fasting and postprandial gallbladder emptying and decreases upper GI symptoms in gastrectomized patients.