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1.  Evaluation of Matrix Metalloproteinase 7 in Plasma and Pancreatic Juice as a Biomarker for Pancreatic Cancer 
Differentiating between periampullary carcinoma and chronic pancreatitis with an inflammatory mass is difficult. Consequently, 6% to 9% of pancreatic resections for suspected carcinoma are done inappropriately for chronic pancreatitis. Here, we test if matrix metalloproteinase 7 (MMP-7), a secreted protease frequently expressed in pancreatic carcinoma, can be measured in plasma, pancreatic, and duodenal juice, and if it can distinguish between periampullary carcinoma and chronic pancreatitis. Ninety-four patients who underwent pancreatic surgery for a (peri)pancreatic neoplasm (n = 63) or chronic pancreatitis (n = 31) were analyzed. Median plasma MMP-7 levels were significantly higher in carcinoma (1.95 ng/mL; interquartile range, 0.81–3.22 ng/mL) compared with chronic pancreatitis and benign disease (0.83 ng/mL; interquartile range, 0.25–1.21 ng/mL; P < 0.01). MMP-7 levels in pancreatic juice were higher, although not significantly, in carcinoma (62 ng/mg protein; interquartile range, 18–241 ng/mg protein) compared with chronic pancreatitis and benign disease (23 ng/mg protein; interquartile range, 8.5–99 ng/mg protein; P = 0.17). MMP-7 levels in duodenal juice were universally low. At an arbitrary cutoff of 1.5 ng/mL in plasma, positive and negative predictive values were 83% and 57%, respectively, values comparable to those of today’s most common pancreatic tumor marker, carbohydrate antigen 19-9 (CA19-9; 83% and 53%, respectively). Positive and negative likelihood ratios for plasma MMP-7 were 3.35 and 0.52, respectively. The area under the receiver operating characteristic curve for MMP-7 was 0.73 (95% confidence interval, 0.63–0.84) and for CA19-9, 0.75 (95% confidence interval, 0.64–0.85). Combined MMP-7 and CA19-9 assessment gave a positive predictive value of 100%. Thus, plasma MMP-7 levels discriminated between patients with carcinoma and those with chronic pancreatitis or benign disease. The diagnostic accuracy of plasma MMP-7 alone is not sufficient to determine treatment strategy in patients with a periampullary mass, but combined evaluation of plasma MMP-7 with CA19-9 and other markers may be clinically useful.
PMCID: PMC4516164  PMID: 17507610
2.  Endoscopic treatment of post‐surgical bile duct injuries: long term outcome and predictors of success 
Gut  2007;56(11):1599-1605.
To analyse the short and long term outcome of endoscopic stent treatment after bile duct injury (BDI), and to determine the effect of multiple stent treatment.
Design, setting and patients
A retrospective cohort study was performed in a tertiary referral centre to analyse the outcome of endoscopic stenting in 67 patients with cystic duct leakage, 26 patients with common bile duct leakage and 110 patients with a bile duct stricture.
Main outcome measures
Long term outcome and independent predictors for successful stent treatment.
Overall success in patients with cystic duct leakage was 97%. In patients with common bile duct leakage, stent related complications occurred in 3.8% (n = 1). The overall success rate was 89% (n = 23). In patients with a bile duct stricture, stent related complications occurred in 33% (n = 36) and the overall success rate was 74% (n = 81). After a mean follow up of 4.5 years, liver function tests did not identify “occult” bile duct strictures. Independent predictors for outcome were the number of stents inserted during the first procedure (OR 3.2 per stent; 95% CI 1.3 to 8.4), injuries classified as Bismuth III (OR 0.12; 95% CI 0.02 to 0.91) and IV (OR 0.04; CI 0.003 to 0.52) and endoscopic stenting before referral (OR 0.24; CI 0.06 to 0.88). Introduction of sequential insertion of multiple stents did not improve outcome (before 77% vs after 66%, p = 0.25), but more patients reported stent related pain (before 11% vs after 28%, p = 0.02).
In patients with a postoperative bile duct leakage and/or strictures, endoscopic stent treatment should be regarded as the choice of primary treatment because of safety and favourable long term outcome. Apart from the early insertion of more than one stent, the benefit from sequential insertion of multiple stents did not become readily apparent from this series.
PMCID: PMC2095661  PMID: 17595232
3.  Which clinical scenarios do surgeons record as complications? A benchmarking study of seven hospitals 
BMJ Open  2015;5(6):e007500.
To investigate agreement and potential differences in the application and interpretation of the definition among surgical departments of various hospitals.
24 cases were formulated including general, trauma, gastrointestinal and vascular surgery, and based on points of discussion about the definition and ambiguities regarding complication registration as encountered in daily practice. The cases were presented to the surgical staff and residents in seven Dutch hospitals, using the national registration system of complications and an electronic response system.
In total, 134 participants responded. Interpretation differences were particularly found regarding: (1) complications considered as logical consequences of a surgical procedure; (2) complications occurring after radiological interventions; (3) severity criteria such as when to consider a complication as a ‘(probably) permanent damage or function loss’; (4) registering a cancelled operation as a complication and (5) patients with serial complications during hospital stay.
The definition of surgical complications as currently applied in the Netherlands does not ensure a uniform complication registration. Improvement of this registration system is mandatory before benchmarking of these findings in the public domain is appropriate. Modifications of the current definition of a surgical complication, and improved consensus about specific clinical situations and training of surgeons might improve the quality of benchmarking.
PMCID: PMC4458580  PMID: 26033948
4.  Results of percutaneous sclerotherapy and surgical treatment in patients with symptomatic simple liver cysts and polycystic liver disease 
AIM: To evaluate the results of the treatment of simple liver cysts (solitary and multiple) and polycystic liver disease (PLD) using percutaneous sclerotherapy and/or surgical procedures in a single tertiary referral centre.
METHODS: Retrospective analysis of 54 patients referred for evaluation and possible treatment of simple liver cysts (solitary and multiple) and PLD, from January 1997 to July 2006.
RESULTS: Simple liver cysts were treated in 41 pts (76%) with a mean size of 12.6 cm. The most common reason for referral was abdominal pain or discomfort (85%). Percutaneous sclerotherapy was performed as initial treatment in 30 pts, showing cyst recurrence in 6 pts (20%). Surgical treatment was initially performed in 11 pts with cyst recurrence in 3 pts (27%). PLD was treated in 13 pts (24%) with a mean size of the dominant cyst of 13 cm. Percutaneous sclerotherapy for PLD was performed in 9 pts with recurrence in 7 pts (77.8%). Surgical treatment for PLD was undertaken in 4 pts (30.8%) with recurrence in all. Eventually, 2 pts with PLD in the presence of polycystic kidney disease underwent liver- and kidney transplantation because of deterioration of liver and kidney function.
CONCLUSION: The majority of patients with simple liver cysts and PLD are referred for progressive abdominal pain. As initial treatment, percutaneous sclerotherapy is appropriate. Surgical deroofing is indicated in case of cyst recurrence after percutaneous sclerotherapy. However, the results of percutaneous sclerotherapy and surgical treatment for PLD are disappointing. Partial liver resection is indicated when there is suspicion of a pre-malignant lesion.
PMCID: PMC4172617  PMID: 17589926
Simple liver cyst; Polycystic liver disease; Percutaneous sclerotherapy; Deroofing; Complications
5.  Obstructive jaundice due to hepatobiliary cystadenoma or cystadenocarcinoma 
Hepatobiliary cystadenomas (HBC) and cystadenocarcinomas are rare cystic lesions. Most patients with these lesions are asymptomatic, but presentation with obstructive jaundice may occur. The first patient presented with intermittent colicky pain and recurrent obstructive jaundice. Imaging studies revealed a polypoid lesion in the left hepatic duct. The second patient had recurrent jaundice and cholangitis. Endoscopic retrograde cholangiopancreatography (ERCP) showed a cystic lesion at the confluence of the hepatic duct. In the third patient with intermittent jaundice and cholangitis, cholangioscopy revealed a papillomatous structure protruding into the left bile duct system. In the fourth patient with obstructive jaundice, CT-scan showed slight dilatation of the intrahepatic bile ducts and dilatation of the common bile duct of 3 cm. ERCP showed filling of a cystic lesion. All patients underwent partial liver resection, revealing HBC in the specimen. In the fifth patient presenting with obstructive jaundice, ultrasound examination showed a hyperechogenic cystic lesion centrally in the liver. The resection specimen revealed a hepatobiliary cystadenocarcinoma. HBC and cystadenocarcinoma may give rise to obstructive jaundice. Evaluation with cross-sectional imaging techniques is useful. ERCP is a useful tool to differentiate extraductal from intraductal obstruction.
PMCID: PMC4088181  PMID: 17007033
Liver; Hepatobiliary cystadenoma; Cystadenocarcinoma; Obstructive jaundice; Endoscopic retrograde cholangiopancreatography
6.  Quantifying the demand for hospital care services: a time and motion study 
The actual amount of care hospitalised patients need is unclear. A model to quantify the demand for hospital care services among various clinical specialties would avail healthcare professionals and managers to anticipate the demand and costs for clinical care.
Three medical specialties in a Dutch university hospital participated in this prospective time and motion study. To include a representative sample of patients admitted to clinical wards, the most common admission diagnoses were selected from the most recent update of the national medical registry (LMR) of ICD-10 admission diagnoses. The investigators recorded the time spent by physicians and nurses on patient care. Also the costs involved in medical and nursing care, (surgical) interventions, and diagnostic procedures as an estimate of the demand for hospital care services per hospitalised patient were calculated and cumulated. Linear regression analysis was applied to determine significant factors including patient and healthcare outcome characteristics.
Fifty patients on the Surgery (19), Pediatrics (17), and Obstetrics & Gynecology (14) wards were monitored during their hospitalization. Characteristics significantly associated with the demand for healthcare were: polypharmacy during hospitalization, complication severity level, and whether a surgical intervention was performed.
A set of predictors of the demand for hospital care services was found applicable to different clinical specialties. These factors can all be identified during hospitalization and be used as a managerial tool to monitor the patients’ demand for hospital care services and to detect trends in time.
PMCID: PMC4311505  PMID: 25608889
Patient characteristics; Demand for hospital care services; Time and motion research; (Multivariable) regression analysis
9.  Trial-based cost-effectiveness analysis comparing surgical and endoscopic drainage in patients with obstructive chronic pancreatitis 
BMJ Open  2013;3(9):e003676.
Published evidence indicates that surgical drainage of the pancreatic duct was more effective than endoscopic drainage for patients with chronic pancreatitis. This analysis assessed the cost-effectiveness of surgical versus endoscopic drainage in obstructive chronic pancreatitis.
This trial-based cost-utility analysis (ISRCTN04572410) was conducted from a UK National Health Service (NHS) perspective and during a 79-month time horizon. During the trial the details of the diagnostic and therapeutic procedures, and pancreatic insufficiency were collected. The resource use was varied in the sensitivity analysis based on a review of the literature. The health outcome was the Quality-Adjusted Life Year (QALY), generated using EQ-5D data collected during the trial. There were no pancreas-related deaths in the trial. All-cause mortality from the trial was incorporated into the QALY estimates in the sensitivity analysis.
Patients with obstructive chronic pancreatitis.
Primary and secondary outcome measures
Costs, QALYs and cost-effectiveness.
The result of the base-case analysis was that surgical drainage dominated endoscopic drainage, being both more effective and less costly. The sensitivity analysis varied mortality and resource use and showed that the surgical option remained dominant in all scenarios. The probability of cost-effectiveness for surgical drainage was 100% for the base case and 82% in the assessed most conservative case scenario.
In obstructive chronic pancreatitis, surgical drainage is highly cost-effective compared with endoscopic drainage from a UK NHS perspective.
PMCID: PMC3787408  PMID: 24065699
10.  Prognostic Impact of Preoperative Imaging Parameters on Resectability of Hilar Cholangiocarcinoma 
HPB Surgery  2013;2013:657309.
Objectives. To evaluate, in hilar cholangiocarcinoma (HCCA), the prognostic impact of specific preoperative radiologic parameters on resectability, metastases, and yield of laparoscopy, and to evaluate the currently used staging systems. Methods. Consecutive patients with HCCA presenting in our center from January 2003 through August 2010 were evaluated. Suspicion on lymph node metastasis, portal vein and hepatic artery involvement, lobar atrophy, and proximal extent of ductal invasion was scored. The prognostic value of these parameters for predicting resectability, yield of diagnostic laparoscopy, likelihood of metastatic disease, R0 resection, and survival was assessed. The Bismuth-Corlette classification and MSKCC staging system were evaluated. Results. Of all 289 evaluated patients, 158 patients (55%) had unresectable disease based on cross-sectional imaging studies or diagnostic laparoscopy; 131 patients (45%) underwent exploration. 83 patients (64%) underwent resection, of whom 67 (87%) had a radical (R0) resection. Suspicious lymph nodes and involvement of the hepatic artery were important prognostic factors for resectability. Predictive power of the evaluated staging systems was limited. Conclusions. Current staging systems predict resectability, but there is room for improvement. Hepatic artery involvement and nodal status might be important factors for prediction of resectability and should be considered in future staging systems.
PMCID: PMC3687508  PMID: 23861556
12.  Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial 
BMC Gastroenterology  2013;13:49.
In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis.
The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥ 5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria (i.e. need for opioid analgesics) the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥ 4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized (alpha 0.05, power 90%, drop-out 10%).
The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice.
Trial registration
PMCID: PMC3610165  PMID: 23506415
Chronic pancreatitis; Pain; Surgical management; Surgery; Endoscopic treatment; Endoscopy; ERCP; Opioid; Pancreaticojejunostomy; Frey procedure
13.  Explaining the amount of care needed by hospitalised surgical patients: a prospective time and motion study 
Hospitals provide care for patients with a variety of diseases, co-morbidities and complications. The actual amount of care these patients need is unclear. Given the recent developments such as ageing, multi-morbidity and budgetary restraints, a practical explanatory model would avail healthcare professionals and managers in determining the demand and costs for clinical care.
Six surgical wards in a Dutch university hospital participated in this prospective time and motion study. Surgeons, nurses and paramedics recorded the time spent on patient care 24/7 by means of PDAs. The investigators extracted possible determining characteristics from a previous systematic review and expert focus group. Total amount of care needed by the patients was expressed as costs involved in medical and nursing time, surgical interventions and diagnostics. Afterwards the investigators applied linear regression analysis to detect significant independent characteristics.
174 Surgical patients were monitored during their hospital stay. Characteristics significantly influencing the consumed amount of care were: medication during hospitalisation, complications, co-morbidity, medical specialty, age, as well as undergoing surgery and length of stay. Median costs for care were €8.446 per patient admission.
The investigators developed a model that explains the total demand and costs of care needed for surgical patients in a university hospital. The input for this instrument can be derived from readily available data in hospital databases. This makes it a relatively easy instrument to help healthcare professionals and managers appreciate the amount of care needed on (surgical) wards and may be used to appreciate trends in time.
PMCID: PMC3599528  PMID: 23379756
Patient characteristics; Workload; Time and motion research; (multiple) regression analysis
14.  New diagnostic criteria and severity assessment of acute cholecystitis in revised Tokyo guidelines 
The Tokyo Guidelines for the management of acute cholangitis and cholecystitis (TG07) were published in 2007 as the world’s first guidelines for acute cholangitis and cholecystitis. The diagnostic criteria and severity assessment of acute cholecystitis have since been widely used all over the world. A validation study of TG07 has shown that the diagnostic criteria for acute cholecystitis are highly reliable but that the definition of definite diagnosis is ambiguous. In addition, considerable new evidence referring to acute cholecystitis as well as evaluations of TG07 have been published. Consequently, we organized the Tokyo Guidelines Revision Committee to evaluate TG07, recognize new evidence, and conduct a multi-center analysis to revise the guidelines (TG13).
Methods and materials
We retrospectively analyzed 451 patients with acute cholecystitis from multiple tertiary care centers in Japan. All 451 patients were first evaluated using the criteria in TG07. The “gold standard” for acute cholecystitis in this study was a diagnosis by pathology. The validity of TG07 diagnostic criteria was investigated by comparing clinical with pathological diagnosis.
Of 451 patients evaluated, a total of 227 patients were given a diagnosis of acute cholecystitis by pathological examination (prevalence 50.3 %). TG07 criteria provided a definite diagnosis of acute cholecystitis in 224 patients. The sensitivity of TG07 diagnostic criteria for acute cholecystitis was 92.1 %, and the specificity was 93.3 %. Based on the preliminary results, new diagnostic criteria for acute cholecystitis were proposed. Using the new criteria, the sensitivity of definite diagnosis was 91.2 %, and the specificity was 96.9 %. The accuracy rate was improved from 92.7 to 94.0 %. In regard to severity grading among 227 patients, 111 patients were classified as Mild (Grade I), 104 as Moderate (Grade II), and 12 as Severe (Grade III).
The proposed new diagnostic criteria achieved better performance than the diagnostic criteria in TG07. Therefore, the proposed criteria have been adopted as new diagnostic criteria for acute cholecystitis and are referred to as the 2013 Tokyo Guidelines (TG13). Regarding severity assessment, no new evidence was found to suggest that the criteria in TG07 needed major adjustment. As a result, TG07 severity assessment criteria have been adopted in TG13 with minor changes.
PMCID: PMC3429769  PMID: 22872303
Acute cholecystitis; Murphy’s sign; Diagnostic criteria; Severity assessment; Guidelines
15.  New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo guidelines 
The Tokyo Guidelines for the management of acute cholangitis and cholecystitis were published in 2007 (TG07) and have been widely cited in the world literature. Because of new information that has been published since 2007, we organized the Tokyo Guidelines Revision Committee to conduct a multicenter analysis to develop the updated Tokyo Guidelines (TG13).
We retrospectively analyzed 1,432 biliary disease cases where acute cholangitis was suspected. The cases were collected from multiple tertiary care centers in Japan. The ‘gold standard’ for acute cholangitis in this study was that one of the three following conditions was present: (1) purulent bile was observed; (2) clinical remission following bile duct drainage; or (3) remission was achieved by antibacterial therapy alone, in patients in whom the only site of infection was the biliary tree. Comparisons were made for the validity of each diagnostic criterion among TG13, TG07 and Charcot’s triad.
The major changes in diagnostic criteria of TG07 were re-arrangement of the diagnostic items and exclusion of abdominal pain from the diagnostic list. The sensitivity improved from 82.8 % (TG07) to 91.8 % (TG13). While the specificity was similar to TG07, the false positive rate in cases of acute cholecystitis was reduced from 15.5 to 5.9 %. The sensitivity of Charcot’s triad was only 26.4 % but the specificity was 95.6 %. However, the false positive rate in cases of acute cholecystitis was 11.9 % and not negligible. As for severity grading, Grade II (moderate) acute cholangitis is defined as being associated with any two of the significant prognostic factors which were derived from evidence presented recently in the literature. The factors chosen allow severity assessment to be performed soon after diagnosis of acute cholangitis.
TG13 present a new standard for the diagnosis, severity grading, and management of acute cholangitis.
PMCID: PMC3429782  PMID: 22825491
Acute cholangitis; Biliary infection; Diagnostic criteria; Severity assessment; Charcot’s triad
16.  Registration of surgical adverse outcomes: a reliability study in a university hospital 
BMJ Open  2012;2(3):e000891.
Accurate registration of adverse surgical outcomes is essential to detect areas for improvement of surgical care quality. One reason for inaccurate adverse outcome registration may be the method to collect these outcomes. The authors compared the completeness of the national complication registry database (LHCR) as used in our hospital with relevant information from other available resources.
Retrospective reliability analysis.
University hospital.
From the 3252 patients admitted to the surgical wards in 2010, the authors randomly selected a cohort of 180 cases, oversampling those with adverse outcomes. The LHCR contains adverse outcomes as reported during morning hand-offs or in discharge letters. The authors checked if the number and severity of adverse outcomes recorded in the LHCR agreed with those reported in morning hand-offs, discharge letters and medical and nursing files.
In 135 of 180 patients, all resources could be retrieved completely. Fourteen per cent of the patients with adverse outcomes were not recorded in the LHCR. Missing adverse outcomes were all reversible without the need for (re)operation, for example, postoperative pain, delirium or urinary tract complications. Only 38% of these adverse outcomes were reported in the morning hand-offs and discharge letters but were best reported in the medical and nursing files.
Registration of surgical adverse outcomes appears largely depending on the reliability of the underlying sources. For a more complete adverse outcome registration, the authors advocate a better hand-off and additional consultation of the patient's dossier. This extra effort allows for improvement actions to eventually avoid ‘mild’ adverse outcomes patients perceive as important and undesirable.
Article summary
Article focus
How complete is the national surgical complication registry as applied in a university hospital?
Should we use more or other resources to achieve a more complete registry of adverse outcomes?
Key messages
Registration of surgical adverse outcomes largely depends on the reliability of the underlying resources.
Better hand-off and additional consultation of the patient's dossier will increase the reliability.
This extra effort can help avoid ‘mild’ adverse outcomes patients perceive as important and undesirable.
Strengths and limitations of this study
Representative data set from a consistently used registry.
Only inhospital adverse outcomes were taken into account.
PMCID: PMC3367156  PMID: 22637372
17.  Long-term Survival in Hilar Cholangiocarcinoma also Possible in Unresectable Patients 
World Journal of Surgery  2012;36(9):2179-2186.
Radical resection remains the only curative treatment for hilar cholangiocarcinoma (HCCA). Only a limited proportion of patients, however, are eligible for resection. The survival and prognostic factors of these patients are largely unknown. The aim of this study was to evaluate survival and prognostic factors in unresectable patients presenting with HCCA.
We performed a cohort study of the denominator of HCCA patients seen in a tertiary referral center between March 2003 and March 2009. Demographics, treatment, pathology results, and survival were analyzed.
A total of 217 patients with suspected HCCA were identified. Ninety-five patients (40 %) underwent laparotomy, and in 57 (63 %) of these patients resection was performed. Overall median and 5-year survival of resected patients were 37 months and 43 %, respectively, as compared to 13 months and 7 % in unresectable patients. In unresectable patients, median survival was better in patients with locally advanced disease (16 months) as compared to patients with hepatic and extrahepatic metastases (5 and 3 months, p < 0.001). Of the 160 unresectable patients, 17 (10 %) survived longer than 3 years.
Of the patients presenting with HCCA in our center, 26 % proved resectable. The 7 % long-term survival rate of unresectable patients is remarkable and emphasizes the indolent growth of some of these tumors. Patients with metastases had a much worse prognosis with a median of 4 months.
PMCID: PMC3414707  PMID: 22569746
18.  Acute cholecystitis in high risk surgical patients: percutaneous cholecystostomy versus laparoscopic cholecystectomy (CHOCOLATE trial): Study protocol for a randomized controlled trial 
Trials  2012;13:7.
Laparoscopic cholecystectomy in acute calculous cholecystitis in high risk patients can lead to significant morbidity and mortality. Percutaneous cholecystostomy may be an alternative treatment option but the current literature does not provide the surgical community with evidence based advice.
The CHOCOLATE trial is a randomised controlled, parallel-group, superiority multicenter trial. High risk patients, defined as APACHE-II score 7-14, with acute calculous cholecystitis will be randomised to laparoscopic cholecystectomy or percutaneous cholecystostomy. During a two year period 284 patients will be enrolled from 30 high volume teaching hospitals. The primary endpoint is a composite endpoint of major complications within three months following randomization and need for re-intervention and mortality during the follow-up period of one year. Secondary endpoints include all other complications, duration of hospital admission, difficulty of procedures and total costs.
The CHOCOLATE trial is designed to provide the surgical community with an evidence based guideline in the treatment of acute calculous cholecystitis in high risk patients.
Trial Registration
Netherlands Trial Register (NTR): NTR2666
PMCID: PMC3285056  PMID: 22236534
Acute cholecystitis; laparoscopic cholecystectomy; percutaneous cholecystostomy; percutaneous drainage
19.  Failure of available scoring systems to predict ongoing infection in patients with abdominal sepsis after their initial emergency laparotomy 
BMC Surgery  2011;11:38.
To examine commonly used scoring systems, designed to predict overall outcome in critically ill patients, for their ability to select patients with an abdominal sepsis that have ongoing infection needing relaparotomy.
Data from a RCT comparing two surgical strategies was used. The study population consisted of 221 patients at risk for ongoing abdominal infection. The following scoring systems were evaluated with logistic regression analysis for their ability to select patients requiring a relaparotomy: APACHE-II score, SAPS-II, Mannheim Peritonitis Index (MPI), MODS, SOFA score, and the acute part of the APACHE-II score (APS).
The proportion of patients requiring a relaparotomy was 32% (71/221). Only 2 scores had a discriminatory ability in identifying patients with ongoing infection needing relaparotomy above chance: the APS on day 1 (AUC 0.61; 95%CI 0.52-0.69) and the SOFA score on day 2 (AUC 0.60; 95%CI 0.52-0.69). However, to correctly identify 90% of all patients needing a relaparotomy would require such a low cut-off value that around 80% of all patients identified by these scoring systems would have negative findings at relaparotomy.
None of the widely-used scoring systems to predict overall outcome in critically ill patients are of clinical value for the identification of patients with ongoing infection needing relaparotomy. There is a need to develop more specific tools to assist physicians in their daily monitoring and selection of these patients after the initial emergency laparotomy.
Trial registration number
PMCID: PMC3268736  PMID: 22196238
20.  Staging Laparoscopy for Hilar Cholangiocarcinoma: Is it Still Worthwhile? 
Annals of Surgical Oncology  2011;18(9):2647-2653.
This study was designed to evaluate the benefit of staging laparoscopy (SL) in patients with suspected hilar cholangiocarcinoma (HCCA) during the past 10 years. Only 50–60% of patients with HCCA who undergo laparotomy are ultimately amenable to a potentially curative resection. In a previous study, we recommended routine use of SL to prevent unnecessary laparotomies. The accuracy of imaging techniques, however, has significantly improved during the past decade, which is likely to impact the yield and accuracy of SL.
From 2000 to 2010, 195 patients with suspected HCCA were analyzed. The yield and accuracy of SL were calculated by dividing total number of avoided laparotomies by the total number of laparoscopies or by all patients with unresectable disease, respectively. Factors associated with better yield and accuracy were assessed.
Of 195 patients with HCCA, 175 underwent SL. The yield of SL was 14% and the accuracy was 32%. Operative morbidity of SL was 3%, and operative morbidity of laparotomy for unresectable disease was 33%. No clear factors that influenced the yield of SL were found.
Overall yield and accuracy of SL for HCCA in the present series decreased to 14% and 32%, respectively, compared with earlier reports. This finding is likely the result of improved imaging techniques that evolved during the past decade. The place of SL in the workup of patients with HCCA needs to be reconsidered, and one should decide whether the declining additional value of SL still outweighs the drawbacks of SL.
PMCID: PMC3162633  PMID: 21347792
21.  Neoadjuvant chemoradiotherapy has a potential role in pancreatic carcinoma 
Pancreatic cancer has an extremely poor prognosis, only a small minority of patients undergo a resection with curative intent. Chemotherapy and/or radiochemotherapy may improve this by prolonging survival or disease-free interval and improving resectability and the proportion of microscopically complete (R0) resections. With regard to prolonging survival, both in the postoperative adjuvant setting and in locally advanced disease, chemotherapy has a positive but limited effect on survival and may be considered standard. The role of postoperative adjuvant radiochemotherapy remains debatable. For improving resectability/proportion of R0 resections, many studies suggest that the proportion of patients undergoing a resection during exploration and the proportion of R0 resections increase after neoadjuvant radiochemotherapy. This may improve the prognosis of patients with a resectable or borderline resectable pancreatic carcinoma. The effect of neoadjuvant radiochemotherapy, if any, is modest. The search for better combinations, including targeted therapy, must continue. The interpretation of single-arm studies is hampered by (selection) biases. The reporting of pathology and study endpoints should be internationally standardized. To avoid biases in studies of patients with (borderline) resectable tumours, prospective parallel registration of all patients referred for surgery would help. Ultimately, randomized controlled phase III trials should establish the role of neoadjuvant radiochemotherapy. Thus, neoadjuvant radiochemotherapy has a potential benefit in resectable and borderline resectable pancreatic cancer, but better combinations are warranted.
PMCID: PMC3126035  PMID: 21789153
neoadjuvant; pancreatic cancer; radiochemotherapy
22.  Costs of relaparotomy on-demand versus planned relaparotomy in patients with severe peritonitis: an economic evaluation within a randomized controlled trial 
Critical Care  2010;14(3):R97.
Results of the first randomized trial comparing on-demand versus planned-relaparotomy strategy in patients with severe peritonitis (RELAP trial) indicated no clear differences in primary outcomes. We now report the full economic evaluation for this trial, including detailed methods, nonmedical costs, further differentiated cost calculations, and robustness of different assumptions in sensitivity analyses.
An economic evaluation was conducted from a societal perspective alongside a randomized controlled trial in 229 patients with severe secondary peritonitis and an acute physiology and chronic health evaluation (APACHE)-II score ≥11 from two academic and five regional teaching hospitals in the Netherlands. After the index laparotomy, patients were randomly allocated to an on-demand or a planned-relaparotomy strategy. Primary resource-utilization data were used to estimate mean total costs per patient during the index admission and after discharge until 1 year after the index operation. Overall differences in costs between the on-demand relaparotomy strategy and the planned strategy, as well as relative differences across several clinical subgroups, were evaluated.
Costs were substantially lower in the on-demand group (mean, €65,768 versus €83,450 per patient in the planned group; mean absolute difference, €17,682; 95% CI, €5,062 to €29,004). Relative differences in mean total costs per patient (approximately 21%) were robust to various alternative assumptions. Planned relaparotomy consistently generated more costs across the whole range of different courses of disease (quick recovery and few resources used on one end of the spectrum; slow recovery and many resources used on the other end). This difference in costs between the two surgical strategies also did not vary significantly across several clinical subgroups.
The reduction in societal costs renders the on-demand strategy a more-efficient relaparotomy strategy in patients with severe peritonitis. These differences were found across the full range of healthcare resources as well as across patients with different courses of disease.
Trial Registration
PMCID: PMC2911734  PMID: 20507557
23.  Endoscopic and Percutaneous Preoperative Biliary Drainage in Patients with Suspected Hilar Cholangiocarcinoma 
Controversy exists over the preferred technique of preoperative biliary drainage (PBD) in patients with hilar cholangiocarcinoma (HCCA) requiring major liver resection. The current study compared outcomes of endoscopic biliary drainage (EBD) and percutaneous transhepatic biliary drainage (PTBD) in patients with resectable HCCA.
One hundred fifteen consecutive patients were explored for HCCA between 2001 and July 2008 and assigned by initial PBD procedure to either EBD or PTBD.
Of these patients, 101 (88%) underwent PBD; 90 patients underwent EBD as primary procedure, and 11 PTBD. The technical success rate of initial drainage was 81% in the EBD versus 100% in the PTBD group (P = 0.20). Stent dislocation was similar in the EBD and PTBD groups (23% vs. 20%, P = 0.70). Infectious complications were significantly more common in the endoscopic group (48% vs. 9%, P < 0.05). Patients in the EBD group underwent more drainage procedures (2.8 vs. 1.4, P < 0.01) and had a significantly longer drainage period until laparotomy (mean 15 weeks vs. 11 weeks in the PTBD group; P < 0.05). In 30 patients, EBD was converted to PTBD due to failure of the endoscopic approach.
Preoperative percutaneous drainage could outperform endoscopic stent placement in patients with resectable HCCA, showing fewer infectious complications, using less procedures.
PMCID: PMC2793391  PMID: 19756881
Endoscopic; Percutaneous; Biliary drainage; Cholangiocarcinoma; Preoperative
24.  Diagnostic criteria and severity assessment of acute cholecystitis: Tokyo Guidelines 
The aim of this article is to propose new criteria for the diagnosis and severity assessment of acute cholecystitis, based on a systematic review of the literature and a consensus of experts. A working group reviewed articles with regard to the diagnosis and treatment of acute cholecystitis and extracted the best current available evidence. In addition to the evidence and face-to-face discussions, domestic consensus meetings were held by the experts in order to assess the results. A provisional outcome statement regarding the diagnostic criteria and criteria for severity assessment was discussed and finalized during an International Consensus Meeting held in Tokyo 2006. Patients exhibiting one of the local signs of inflammation, such as Murphy’s sign, or a mass, pain or tenderness in the right upper quadrant, as well as one of the systemic signs of inflammation, such as fever, elevated white blood cell count, and elevated C-reactive protein level, are diagnosed as having acute cholecystitis. Patients in whom suspected clinical findings are confirmed by diagnostic imaging are also diagnosed with acute cholecystitis. The severity of acute cholecystitis is classified into three grades, mild (grade I), moderate (grade II), and severe (grade III). Grade I (mild acute cholecystitis) is defined as acute cholecystitis in a patient with no organ dysfunction and limited disease in the gallbladder, making cholecystectomy a low-risk procedure. Grade II (moderate acute cholecystitis) is associated with no organ dysfunction but there is extensive disease in the gallbladder, resulting in difficulty in safely performing a cholecystectomy. Grade II disease is usually characterized by an elevated white blood cell count; a palpable, tender mass in the right upper abdominal quadrant; disease duration of more than 72 h; and imaging studies indicating significant inflammatory changes in the gallbladder. Grade III (severe acute cholecystitis) is defined as acute cholecystitis with organ dysfunction.
PMCID: PMC2784516  PMID: 17252300
Acute cholecystitis; Diagnosis; Severity of illness index; Guidelines; Infection
25.  Diagnostic criteria and severity assessment of acute cholangitis: Tokyo Guidelines 
Because acute cholangitis sometimes rapidly progresses to a severe form accompanied by organ dysfunction, caused by the systemic inflammatory response syndrome (SIRS) and/or sepsis, prompt diagnosis and severity assessment are necessary for appropriate management, including intensive care with organ support and urgent biliary drainage in addition to medical treatment. However, because there have been no standard criteria for the diagnosis and severity assessment of acute cholangitis, practical clinical guidelines have never been established. The aim of this part of the Tokyo Guidelines is to propose new criteria for the diagnosis and severity assessment of acute cholangitis based on a systematic review of the literature and the consensus of experts reached at the International Consensus Meeting held in Tokyo 2006. Acute cholangitis can be diagnosed if the clinical manifestations of Charcot’s triad, i.e., fever and/or chills, abdominal pain (right upper quadrant or epigastric), and jaundice are present. When not all of the components of the triad are present, then a definite diagnosis can be made if laboratory data and imaging findings supporting the evidence of inflammation and biliary obstruction are obtained. The severity of acute cholangitis can be classified into three grades, mild (grade I), moderate (grade II), and severe (grade III), on the basis of two clinical factors, the onset of organ dysfunction and the response to the initial medical treatment. “Severe (grade III)” acute cholangitis is defined as acute cholangitis accompanied by at least one new-onset organ dysfunction. “Moderate (grade II)” acute cholangitis is defined as acute cholangitis that is unaccompanied by organ dysfunction, but that does not respond to the initial medical treatment, with the clinical manifestations and/or laboratory data not improved. “Mild (grade I)” acute cholangitis is defined as acute cholangitis that responds to the initial medical treatment, with the clinical findings improved.
PMCID: PMC2784515  PMID: 17252297
Cholangitis; Diagnosis; Severity of illness index; Guidelines

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