Adjuvant hepatic arterial infusion pump chemotherapy and resection versus resection alone in patients with low-risk resectable colorectal liver metastases - the multicenter randomized controlled PUMP trial.

BACKGROUND: Recurrences are reported in 70% of all patients after resection of colorectal liver metastases (CRLM), in which half are confined to the liver. Adjuvant hepatic arterial infusion pump (HAIP) chemotherapy aims to reduce the risk of intrahepatic recurrence. A large retrospective propensity score analysis demonstrated that HAIP chemotherapy is particularly effective in patients with low-risk oncological features. The aim of this randomized controlled trial (RCT) --the PUMP trial-- is to investigate the efficacy of adjuvant HAIP chemotherapy in low-risk patients with resectable CRLM. METHODS: This is an open label multicenter RCT. A total of 230 patients with resectable CRLM without extrahepatic disease will be included. Only patients with a clinical risk score (CRS) of 0 to 2 are eligible, meaning: patients are allowed to have no more than two out of five poor prognostic factors (disease-free interval less than 12 months, node-positive colorectal cancer, more than 1 CRLM, largest CRLM more than 5 cm in diameter, serum Carcinoembryonic Antigen above 200 µg/L). Patients randomized to arm A undergo complete resection of CRLM without any adjuvant treatment, which is the standard of care in the Netherlands. Patients in arm B receive an implantable pump at the time of CRLM resection and start adjuvant HAIP chemotherapy 4-12 weeks after surgery, with 6 cycles of floxuridine scheduled. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, hepatic PFS, safety, quality of life, and cost-effectiveness. Pharmacokinetics of intra-arterial administration of floxuridine will be investigated as well as predictive biomarkers for the efficacy of HAIP chemotherapy. In a side study, the accuracy of CT angiography will be compared to radionuclide scintigraphy to detect extrahepatic perfusion. We hypothesize that adjuvant HAIP chemotherapy leads to improved survival, improved quality of life, and a reduction of costs, compared to resection alone. DISCUSSION: If this PUMP trial demonstrates that adjuvant HAIP chemotherapy improves survival in low-risk patients, this treatment approach may be implemented in the standard of care of patients with resected CRLM since adjuvant systemic chemotherapy alone has not improved survival. TRIAL REGISTRATION: The PUMP trial is registered in the Netherlands Trial Register (NTR), number: 7493 . Date of registration September 23, 2018.

The association between portal system vein diameters and outcomes in acute pancreatitis.

BACKGROUND/OBJECTIVES: Acute pancreatitis (AP) progresses to necrotizing pancreatitis in 15% of cases. An important pathophysiological mechanism in AP is third spacing of fluids, which leads to intravascular volume depletion. This results in a reduced splanchnic circulation and reduced venous return. Non-visualisation of the portal and splenic vein on early computed tomography (CT) scan, which might be the result of smaller vein diameter due to decreased venous flow, is associated with infected necrosis and mortality in AP. This observation led us to hypothesize that smaller diameters of portal system veins (portal, splenic and superior mesenteric) are associated with increased severity of AP. METHODS: We conducted a post-hoc analysis of data from two randomized controlled trials that included patients with predicted severe and mild AP. The primary endpoint was AP-related mortality. The secondary endpoints were (infected) necrotizing pancreatitis and (persistent) organ failure. We performed additional CT measurements of portal system vein diameters and calculated their prognostic value through univariate and multivariate Poisson regression. RESULTS: Multivariate regression showed a significant inverse association between splenic vein diameter and mortality (RR 0.75 (0.59-0.97)). Furthermore, there was a significant inverse association between splenic and superior mesenteric vein diameter and (infected) necrosis. Diameters of all veins were inversely associated with organ failure and persistent organ failure. CONCLUSIONS: We observed an inverse relationship between portal system vein diameter and morbidity and an inverse relationship between splenic vein diameter and mortality in AP. Further research is needed to test whether these results can be implemented in predictive scoring systems.

Randomized clinical trial of extended versus single-dose perioperative antibiotic prophylaxis for acute calculous cholecystitis.

BACKGROUND: Many patients who have surgery for acute cholecystitis receive postoperative antibiotic prophylaxis, with the intent to reduce infectious complications. There is, however, no evidence that extending antibiotics beyond a single perioperative dose is advantageous. This study aimed to determine the effect of extended antibiotic prophylaxis on infectious complications in patients with mild acute cholecystitis undergoing cholecystectomy. METHODS: For this randomized controlled non-inferiority trial, adult patients with mild acute calculous cholecystitis undergoing cholecystectomy at six major teaching hospitals in the Netherlands, between April 2012 and September 2014, were assessed for eligibility. Patients were randomized to either a single preoperative dose of cefazolin (2000 mg), or antibiotic prophylaxis for 3 days after surgery (intravenous cefuroxime 750 mg plus metronidazole 500 mg, three times daily), in addition to the single dose. The primary endpoint was rate of infectious complications within 30 days after operation. RESULTS: In the intention-to-treat analysis, three of 77 patients (4 per cent) in the extended antibiotic group and three of 73 (4 per cent) in the standard prophylaxis group developed postoperative infectious complications (absolute difference 0·2 (95 per cent c.i. -8·2 to 8·9) per cent). Based on a margin of 5 per cent, non-inferiority of standard prophylaxis compared with extended prophylaxis was not proven. Median length of hospital stay was 3 days in the extended antibiotic group and 1 day in the standard prophylaxis group. CONCLUSION: Standard single-dose antibiotic prophylaxis did not lead to an increase in postoperative infectious complications in patients with mild acute cholecystitis undergoing cholecystectomy. Registration number: NTR3089 (www.trialregister.nl).

Volume matters in the systemic treatment of metastatic pancreatic cancer: a population-based study in the Netherlands.

PURPOSE: In pancreatic surgery, a relation between surgical volume and postoperative mortality and overall survival (OS) has been recognized, with high-volume centers reporting significantly better survival rates. We aimed to explore the influence of hospital volume on administration of palliative chemotherapy and OS in the Netherlands. METHODS: Patients diagnosed between 2007 and 2011 with metastatic pancreatic cancer were identified in the Netherlands Cancer Registry. Three types of high-volume centers were defined: high-volume (1) incidence center, based on the number of patients diagnosed with metastatic pancreatic cancer, (2) treatment center based on number of patients with metastatic pancreatic cancer who started treatment with palliative chemotherapy and (3) surgical center based on the number of resections with curative intent for pancreatic cancer. Independent predictors of administration of palliative chemotherapy were evaluated by means of logistic regression analysis. The multivariable Cox proportional hazard model was used to assess the impact of being diagnosed or treated in high-volume centers on survival. RESULTS: A total of 5385 patients presented with metastatic pancreatic cancer of which 24 % received palliative chemotherapy. Being treated with chemotherapy in a high-volume chemotherapy treatment center was associated with improved survival (HR 0.76, 95 % CI 0.67-0.87). Also, in all patients with metastatic pancreatic cancer, being diagnosed in a high-volume surgical center was associated with improved survival (HR 0.74, 95 % CI 0.66-0.83). CONCLUSIONS: Hospital volume of palliative chemotherapy for metastatic pancreatic cancer was associated with improved survival, demonstrating that a volume-outcome relationship, as described for pancreatic surgery, may also exist for pancreatic medical oncology.

Metal or plastic stents for preoperative biliary drainage in resectable pancreatic cancer.

INTRODUCTION: In pancreatic cancer, preoperative biliary drainage (PBD) increases complications compared with surgery without PBD, demonstrated by a recent randomised controlled trial (RCT). This outcome might be related to the plastic endoprosthesis used. Metal stents may reduce the PBD-related complications risk. METHODS: A prospective multicentre cohort study was performed including patients with obstructive jaundice due to pancreatic cancer, scheduled to undergo PBD before surgery. This cohort was added to the earlier RCT (ISRCTN31939699). The RCT protocol was adhered to, except PBD was performed with a fully covered self-expandable metal stent (FCSEMS). This FCSEMS cohort was compared with the RCT's plastic stent cohort. PBD-related complications were the primary outcome. Three-group comparison of overall complications including early surgery patients was performed. RESULTS: 53 patients underwent PBD with FCSEMS compared with 102 patients treated with plastic stents. Patients' characteristics did not differ. PBD-related complication rates were 24% in the FCSEMS group vs 46% in the plastic stent group (relative risk of plastic stent use 1.9, 95% CI 1.1 to 3.2, p=0.011). Stent-related complications (occlusion and exchange) were 6% vs 31%. Surgical complications did not differ, 40% vs 47%. Overall complication rates for the FCSEMS, plastic stent and early surgery groups were 51% vs 74% vs 39%. CONCLUSIONS: For PBD in pancreatic cancer, FCSEMS yield a better outcome compared with plastic stents. Although early surgery without PBD remains the treatment of choice, FCSEMS should be preferred over plastic stents whenever PBD is indicated. TRIAL REGISTRATION NUMBER: Dutch Trial Registry (NTR3142).

Hospital of diagnosis and likelihood of surgical treatment for pancreatic cancer.

BACKGROUND: Surgical resection for pancreatic cancer offers the only chance of cure. Assessment of the resectability of a pancreatic tumour is therefore of great importance. The aim of the study was to investigate whether centre of diagnosis influences the likelihood of surgery and whether this affects long-term survival. METHODS: Patients diagnosed with non-metastasized pancreatic cancer (M0) between 2005 and 2013 in the Netherlands were selected from the Netherlands Cancer Registry. Hospitals were classified as a pancreatic centre (at least 20 resections/year) or a non-pancreatic centre (fewer than 20 resections/year). The relationship between centre of diagnosis and likelihood of surgery was analysed by multivariable logistic regression. Influence of centre on overall survival was assessed by means of multivariable Cox regression analysis. RESULTS: Some 8141 patients were diagnosed with non-metastasized pancreatic cancer, of whom 3123 (38·4 per cent) underwent surgery. Of the 2712 patients diagnosed in one of 19 pancreatic centres, 52·4 per cent had exploratory laparotomy compared with 31·4 per cent of 5429 patients diagnosed in one of 74 non-pancreatic centres (P < 0·001). A pancreatectomy was performed in 42·8 and 24·6 per cent of the patients respectively (P < 0·001). Multivariable analysis revealed that patients diagnosed in a pancreatic centre had a higher chance of undergoing surgery (odds ratio 2·21, 95 per cent c.i. 1·98 to 2·47). Centre of diagnosis was not associated with improved long-term survival (hazard ratio 0·95, 95 per cent c.i. 0·91 to 1·00). CONCLUSION: Patients with non-metastasized pancreatic cancer had a greater likelihood of having surgical treatment when the diagnosis was established in a pancreatic centre.

Survival after resection of perihilar cholangiocarcinoma-development and external validation of a prognostic nomogram.

BACKGROUND: The objective of this study was to derive and validate a prognostic nomogram to predict disease-specific survival (DSS) after a curative intent resection of perihilar cholangiocarcinoma (PHC). PATIENTS AND METHODS: A nomogram was developed from 173 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC), New York, USA. The nomogram was externally validated in 133 patients treated at the Academic Medical Center (AMC), Amsterdam, The Netherlands. Prognostic accuracy was assessed with concordance estimates and calibration, and compared with the American Joint Committee on Cancer (AJCC) staging system. The nomogram will be available as web-based calculator at mskcc.org/nomograms. RESULTS: For all 306 patients, the median overall survival (OS) was 40 months and the median DSS 41 months. Median follow-up for patients alive at last follow-up was 48 months. Lymph node involvement, resection margin status, and tumor differentiation were independent prognostic factors in the derivation cohort (MSKCC). A nomogram with these prognostic factors had a concordance index of 0.73 compared with 0.66 for the AJCC staging system. In the validation cohort (AMC), the concordance index was 0.72, compared with 0.60 for the AJCC staging system. Calibration was good in the derivation cohort; in the validation cohort patients had a better median DSS than predicted by the model. CONCLUSIONS: The proposed nomogram to predict DSS after curative intent resection of PHC had a better prognostic accuracy than the AJCC staging system. Calibration was suboptimal because DSS differed between the two institutions. The nomogram can inform patients and physicians, guide shared decision making for adjuvant therapy, and stratify patients in future randomized, controlled trials.

Ruptured hepatic artery aneurysm: an unusual presentation of polyarteritis nodosa.

A 52-year-old woman presented with severe acute right upper quadrant abdominal pain and signs of intra-abdominal haemorrhage. CT and selective angiography revealed a ruptured right hepatic artery aneurysm and diffuse aneurysmatic disease involving most intra-abdominal organs, suggestive of polyarteritis nodosa. Although treatment with high-dose steroids was initiated, the patient died of progressive bowel ischaemia.

Systematic review of innovative ablative therapies for the treatment of locally advanced pancreatic cancer.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) is associated with a very poor prognosis. Current palliative (radio)chemotherapy provides only a marginal survival benefit of 2-3 months. Several innovative local ablative therapies have been explored as new treatment options. This systematic review aims to provide an overview of the clinical outcomes of these ablative therapies. METHODS: A systematic search in PubMed, Embase and the Cochrane Library was performed to identify clinical studies, published before 1 June 2014, involving ablative therapies in LAPC. Outcomes of interest were safety, survival, quality of life and pain. RESULTS: After screening 1037 articles, 38 clinical studies involving 1164 patients with LAPC, treated with ablative therapies, were included. These studies concerned radiofrequency ablation (RFA) (7 studies), irreversible electroporation (IRE) (4), stereotactic body radiation therapy (SBRT) (16), high-intensity focused ultrasound (HIFU) (5), iodine-125 (2), iodine-125-cryosurgery (2), photodynamic therapy (1) and microwave ablation (1). All strategies appeared to be feasible and safe. Outcomes for postoperative, procedure-related morbidity and mortality were reported only for RFA (4-22 and 0-11 per cent respectively), IRE (9-15 and 0-4 per cent) and SBRT (0-25 and 0 per cent). Median survival of up to 25·6, 20·2, 24·0 and 12·6 months was reported for RFA, IRE, SBRT and HIFU respectively. Pain relief was demonstrated for RFA, IRE, SBRT and HIFU. Quality-of-life outcomes were reported only for SBRT, and showed promising results. CONCLUSION: Ablative therapies in patients with LAPC appear to be feasible and safe.

Non-radical resection versus bypass procedure for pancreatic cancer - a consecutive series and systematic review.

BACKGROUND: Most survival studies comparing non-radical resections to bypass surgery in patients with pancreatic cancer often do not differentiate between an R1 and R2 resection. The aim of this study was to evaluate whether non-radical R1 and R2 resections have better postoperative outcomes and survival compared to a palliative bypass. METHODS: A single center cohort study was performed analyzing mortality, morbidity and 1-year survival after R1 (tumor cells within 1 mm from the circumferential margin), R2 and bypass surgery in patients with pancreatic cancer. For the systematic review, studies were identified comparing R1 or R2 resections with bypass, in patients with pancreatic cancer. Postoperative outcomes were compared including the cohort study. RESULTS: The cohort study (n=405) showed higher morbidity rates after R1 (n=191) and R2 (n=11) resections compared to bypass (52% and 73% vs. 34%, p < 0.01). In-hospital mortality did not differ (overall 1.7%). 1-year survival rates were 71%, 46% and 32% after R1, R2 resection and bypass (p=0.6 between R2 and bypass). The systematic review identified 8 studies, after including the cohort study 1535 patients were analyzed. Increased morbidity after R1-R2 resection (48%) compared to bypass (30-34%) was found. Median survival was 14-18 months after R1 resection vs. 9-13 months after bypass and 8.5-11.5 months after R2 resection vs. 7.5-10.7 months after bypass. CONCLUSION: An R2 resection should be avoided in patients with pancreatic cancer due to its poor prognosis. Survival benefit after an R1 resection, as compared to bypass surgery, justifies a resection despite the increased morbidity rate.

Impact of lymph node ratio on survival in patients with pancreatic and periampullary cancer.

BACKGROUND: According to some studies, the number of lymph nodes with metastases in relation to the total number of removed lymph nodes, the lymph node ratio (LNR), is one of the most powerful predictors of survival after resection in patients with pancreatic cancer. However, contradictory results have been reported, and small sample sizes of the cohorts and different definitions of a microscopic positive resection margin (R1) hamper the interpretation of data. METHODS: The predictive value of LNR for 3-year survival was assessed using a Cox proportional hazards model. From 1992 to 2012, all patients with pancreatic and periampullary cancer operated on with pancreatoduodenectomy were selected from a database. Clinicopathological characteristics were analysed. Microscopic positive resection margin was defined as the microscopic presence of tumour cells within 1 mm of the margins. A nomogram was created. RESULTS: Some 760 patients were included. Predictive factors for death in 350 patients with pancreatic ductal adenocarcinoma included in the nomogram were: R1 resection (hazard ratio (HR) 1·55, 95 per cent c.i. 1·07 to 2·25), poor tumour differentiation (HR 2·78, 1·40 to 5·52), LNR above 0·18 (HR 1·75, 1·13 to 2·70) and no adjuvant therapy (HR 1·54, 1·01 to 2·34). The C statistic was 0·658 (0·632 to 0·698), and calibration was good (Hosmer-Lemeshow χ(2) = 5·67, P =0·773). LNR and poor tumour differentiation (HR 4·51 and 3·30 respectively) were also predictive in patients with distal common bile duct (CBD) cancer. LNR, R1 resection and jaundice were predictors of death in patients with ampullary cancer (HR 7·82, 2·68 and 1·93 respectively). CONCLUSION: LNR is a common predictor of poor survival in pancreatic, distal CBD and ampullary cancer.

Systematic review of five feeding routes after pancreatoduodenectomy.

BACKGROUND: Current European guidelines recommend routine enteral feeding after pancreato-duodenectomy (PD), whereas American guidelines do not. The aim of this study was to determine the optimal feeding route after PD. METHODS: A systematic search was performed in PubMed, Embase and the Cochrane Library. Included were studies on feeding routes after PD that reported length of hospital stay (primary outcome). RESULTS: Of 442 articles screened, 15 studies with 3474 patients were included. Data on five feeding routes were extracted: oral diet (2210 patients), enteral nutrition via either a nasojejunal tube (NJT, 165), gastrojejunostomy tube (GJT, 52) or jejunostomy tube (JT, 623), and total parenteral nutrition (TPN, 424). Mean(s.d.) length of hospital stay was shortest in the oral diet and GJT groups (15(14) and 15(11) days respectively), followed by 19(12) days in the JT, 20(15) days in the TPN and 25(11) days in the NJT group. Normal oral intake was established most quickly in the oral diet group (mean 6(5) days), followed by 8(9) days in the NJT group. The incidence of delayed gastric emptying varied from 6 per cent (3 of 52 patients) in the GJT group to 23.2 per cent (43 of 185) in the JT group, but definitions varied widely. The overall morbidity rate ranged from 43.8 per cent (81 of 185) in the JT group to 75 per cent (24 of 32) in the GJT group. The overall mortality rate ranged from 1.8 per cent (3 of 165) in the NJT group to 5.4 per cent (23 of 424) in the TPN group. CONCLUSION: There is no evidence to support routine enteral or parenteral feeding after PD. An oral diet may be considered as the preferred routine feeding strategy after PD.

Impact of nationwide centralization of pancreaticoduodenectomy on hospital mortality.

BACKGROUND: The impact of nationwide centralization of pancreaticoduodenectomy (PD) on mortality is largely unknown. The aim of this study was to analyse changes in hospital volumes and in-hospital mortality after PD in the Netherlands between 2004 and 2009. METHODS: Nationwide data on International Classification of Diseases, ninth revision (ICD-9) code 5-526 (PD, including Whipple), patient age, sex and mortality were retrieved from the independent nationwide KiwaPrismant registry. Based on established cut-off points of annually performed PDs, hospitals were categorized as very low (fewer than 5), low (5-10), medium (11-19) or high (at least 20) volume. A subgroup analysis based on a cut-off age of 70 years was also performed. RESULTS: Some 2155 PDs were included. The number of hospitals performing PD decreased from 48 in 2004 to 30 in 2009 (P = 0·011). In these specific years, the proportion of patients undergoing PD in a medium- or high-volume centre increased from 52·9 to 91·2 per cent (P < 0·001). Nationwide mortality rates after PD decreased from 9·8 to 5·1 per cent (P = 0·044). The mortality rate during the 6-year period was 14·7, 9·8, 6·3 and 3·3 per cent in very low-, low-, medium- and high-volume hospitals respectively (P < 0·001). The difference in mortality between medium- and high-volume centres was statistically significant (P = 0·004). The volume-outcome relationship was not influenced by age (P = 0·467). The mortality rate after PD in patients aged at least 70 years was 10·4 per cent compared with 4·4 per cent in younger patients (P < 0·001). CONCLUSION: With nationwide centralization of PD, the in-hospital mortality rate after this procedure decreased. Further centralization of PD is likely to decrease mortality further, especially in the elderly.

Effects of adjustable gastric banding on gastroesophageal reflux and esophageal motility: a systematic review.

Controversial opinions exist concerning the effect of laparoscopic adjustable gastric banding on gastroesophageal reflux. MEDLINE and EMBASE databases were searched for relevant studies on patients undergoing adjustable gastric banding. Data are expressed in mean (range). Twenty studies were identified with a total of 3307 patients. The prevalence of reflux symptoms decreased postoperatively from 32.9% (16-57) to 7.7% (0-26.9) and medication use from 27.5% (16-38.5) to 9.5% (3.1-19.2). Newly developed reflux symptoms were found in 15% (6.1-20) of the patients. The percentage of esophagitis decreased postoperatively from 33.3% (19.4-61.6) to 27% (2.3-60.8). Newly developed esophagitis was observed in 22.9% (0-38.4). Pathological reflux was found in 55.8% (34.9-77.4) preoperatively and postoperatively in 29.4% (0-41.7) of the patients. Lower esophageal sphincter pressures increased from 12.9 to 16.9 mmHg (11.3-21.4). Lower esophageal sphincter relaxation decreased from 100% to 79.7% (58-86). The percentage of dysmotility increased from 3.5% (0-10) to 12.6% (0-25). Adjustable gastric banding has anti-reflux properties resulting in resolution or improvement of reflux symptoms, normalized pH monitoring results and a decrease of esophagitis on short term. However, worsening or newly developed reflux symptoms and esophagitis are found in a subset of patients during longer follow-up.

[Obtaining medical ethical approval for a multicentre, randomised study: prospective evaluation of a ponderous process]. / Her verkrijgen van medisch-ethische goedkeuring voor een multicentrische, gerandomiseerde trial: prospectieve evaluatie van een moeizaam proces.

OBJECTIVE: To evaluate the procedure to obtain medical ethical approval for a multicentre study in the Netherlands. DESIGN: Prospective and descriptive. METHOD: The application procedure for medical ethical approval of a nationwide randomised multicentre trial (the 'Pancreatitis: surgical necrosectomy versus step up approach' (PANTER)-trial) from the ethics committees (EC) of 9 Dutch hospitals during 2004-2007, was prospectively evaluated. Several predefined variables regarding the duration of the ethical review process, the time invested and material and the type of queries raised by the ECs in all centres were collected. RESULTS: Primary approval by the central EC of the coordinating hospital was obtained after 192 days. The duration of the review process for each of the 18 local participating centres was 105 days (range: 35-361). The maximum review term of 30 days, as defined in the national guideline, was reached by only one centre. It took two years to obtain approval for all participating centres. A median of 14 different documents (range: 5-23) were submitted to the EC of each participating centre. A total of 8314 A4 size papers (about 42 kg) were sent by post, 172 telephone calls were made and 136 e-mail messages were sent by the research fellow coordinating the application procedure. Of the local ECs in the participating centers, 95% requested additional revision of the patient information sheet and 78% requested changes in the informed consent form. CONCLUSION: Obtaining medical ethical approval for this multicentre trial in the Netherlands was a long and inefficient process, requiring a considerable investment of time and resources. Streamlining the application procedure may lead to a substantial reduction in the current unnecessary delay of starting a multicentre study.

[Probiotic prophylaxis in patients with predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial]. / Probioticaprofylaxe bij voorspeld ernstige acute pancreatitis: een gerandomiseerde, dubbelblinde, placebogecontroleerde trial.

OBJECTIVE: To evaluate whether enteral prophylaxis with probiotics in patients with predicted severe acute pancreatitis prevents infectious complications. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. METHOD: A total of 296 patients with predicted severe acute pancreatitis (APACHE II score > or = 8, Imrie score > or = 3 or C-reactive protein concentration > 150 mg/l) were included and randomised to one of two groups. Within 72 hours after symptom onset, patients received a multispecies preparation of probiotics or placebo given twice daily via a jejunal catheter for 28 days. The primary endpoint was the occurrence of one of the following infections during admission and go-day follow-up: infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis or infected ascites. Secondary endpoints were mortality and adverse reactions. The study registration number is ISRCTN38327949. RESULTS: Treatment groups were similar at baseline with regard to patient characteristics and disease severity. Infections occurred in 30% of patients in the probiotics group (46 of 152 patients) and 28% of those in the placebo group (41 of 144 patients; relative risk (RR): 1.1; 95% CI: 0.8-1.5). The mortality rate was 16% in the probiotics group (24 of 152 patients) and 6% (9 of 144 patients) in the placebo group (RR: 2.5; 95% CI: 1.2-5.3). In the probiotics group, 9 patients developed bowel ischaemia (of whom 8 patients died), compared with none in the placebo group (p = 0.004). CONCLUSION: In patients with predicted severe acute pancreatitis, use of this combination of probiotic strains did not reduce the risk of infections. Probiotic prophylaxis was associated with a more than two-fold increase in mortality and should therefore not be administered in this category of patients.

Antimicrobial activity of a multispecies probiotic (Ecologic 641) against pathogens isolated from infected pancreatic necrosis.

AIMS: Although probiotic prophylaxis has been suggested to prevent small bowel bacterial overgrowth, bacterial translocation and infection of pancreatic necrosis in severe acute pancreatitis, limited data are available on their antimicrobial activity. METHODS AND RESULTS: Using the well-diffusion method, we studied the antimicrobial properties of a multispecies probiotic product (Ecologic 641) against a collection of pathogens cultured from infected pancreatic necrosis. All individual probiotic strains included in the multispecies preparation were able to inhibit the growth of the pathogens to some extent. However, the combination of the individual strains (i.e. the multispecies preparation) was able to inhibit all pathogenic isolates. Probiotic-free supernatants adjusted to pH 7 were not able to inhibit pathogen growth. CONCLUSION: Ecologic 641 is capable of inhibiting growth of a wide variety of pathogens isolated from infected pancreatic necrosis. The antimicrobial properties are to a large extent explained by the production of organic acids. SIGNIFICANCE AND IMPACT OF THE STUDY: Ecologic 641 is currently being used in a Dutch nationwide double-blind, placebo-controlled, randomized multicentre trial in patients with predicted severe acute pancreatitis.

Intense adrenal enhancement in patients with acute pancreatitis and early organ failure.

Intense adrenal enhancement has previously been reported in patients with hypovolemic and septic shock. The purpose of this study was to assess whether this computed tomography (CT) finding is also observed in patients presenting with severe acute pancreatitis and early organ failure. A retrospective analysis of a prospectively collected database was performed. Out of 38 consecutive patients with predicted severe acute pancreatitis, 3 patients showed intense bilateral adrenal enhancement on early CT. All patients had early multiple organ failure and subsequently died. In two cases, pathologic correlation was obtained. Intense adrenal enhancement may be a new prognostic indicator in patients with acute pancreatitis, particularly when organ failure is present at the time of CT examination. Further studies are necessary to confirm this observation.