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1.  Near-infrared fluorescence cholangiography assisted laparoscopic cholecystectomy versus conventional laparoscopic cholecystectomy (FALCON trial): study protocol for a multicentre randomised controlled trial 
BMJ Open  2016;6(8):e011668.
Misidentification of the extrahepatic bile duct anatomy during laparoscopic cholecystectomy (LC) is the main cause of bile duct injury. Easier intraoperative recognition of the biliary anatomy may be accomplished by using near-infrared fluorescence (NIRF) imaging after an intravenous injection of indocyanine green (ICG). Promising results were reported for successful intraoperative identification of the extrahepatic bile ducts compared to conventional laparoscopic imaging. However, routine use of ICG fluorescence laparoscopy has not gained wide clinical acceptance yet due to a lack of high-quality clinical data. Therefore, this multicentre randomised clinical study was designed to assess the potential added value of the NIRF imaging technique during LC.
Methods and analysis
A multicentre, randomised controlled clinical trial will be carried out to assess the use of NIRF imaging in LC. In total, 308 patients scheduled for an elective LC will be included. These patients will be randomised into a NIRF imaging laparoscopic cholecystectomy (NIRF-LC) group and a conventional laparoscopic cholecystectomy (CLC) group. The primary end point is time to ‘critical view of safety’ (CVS). Secondary end points are ‘time to identification of the cystic duct (CD), of the common bile duct, the transition of CD in the gallbladder and the transition of the cystic artery in the gallbladder, these all during dissection of CVS’; ‘total surgical time’; ‘intraoperative bile leakage from the gallbladder or cystic duct’; ‘bile duct injury’; ‘postoperative length of stay’, ‘complications due to the injected ICG’; ‘conversion to open cholecystectomy’; ‘postoperative complications (until 90 days postoperatively)’ and ‘cost-minimisation’.
Ethics and dissemination
The protocol has been approved by the Medical Ethical Committee of Maastricht University Medical Center/Maastricht University; the trial has been registered at The findings of this study will be disseminated widely through peer-reviewed publications and conference presentations.
Trial registration number
PMCID: PMC5013353  PMID: 27566635
Near-Infrared Fluorescence Imaging (NIRF); Indocyanine Green (ICG); Laparoscopic Cholecystectomy (LC); Critical View of Safety (CVS); Bile duct Injury
2.  Outcomes of Distal Pancreatectomy for Pancreatic Ductal Adenocarcinoma in the Netherlands: A Nationwide Retrospective Analysis 
Annals of Surgical Oncology  2015;23:585-591.
Large multicenter series on outcomes and predictors of survival after distal pancreatectomy (DP) for pancreatic ductal adenocarcinoma (PDAC) are scarce.
Adults who underwent DP for PDAC in 17 Dutch pancreatic centers between January 2005 and September 2013 were analyzed retrospectively. The primary outcome was survival, and predictors of survival were identified using Cox regression analysis.
In total, 761 consecutive patients after DP were assessed, of whom 620 patients were excluded because of non-PDAC histopathology (n = 616) or a lack of data (n = 4), leaving a total of 141 patients included in the study [45 % (n = 63) male, mean age 64 years (SD = 10)]. Multivisceral resection was performed in 43 patients (30 %) and laparoscopic resection was performed in 7 patients (5 %). A major complication (Clavien–Dindo score of III or higher) occurred in 46 patients (33 %). Mean tumor size was 44 mm (SD 23), and histopathological examination showed 70 R0 resections (50 %), while 30-day and 90-day mortality was 3 and 6 %, respectively. Overall, 63 patients (45 %) received adjuvant chemotherapy. Median survival was 17 months [interquartile range (IQR) 13–21], with a median follow-up of 17 months (IQR 8–29). Cumulative survival at 1, 3 and 5 years was 64, 29, and 22 %, respectively. Independent predictors of worse postoperative survival were R1/R2 resection [hazard ratio (HR) 1.6, 95 % confidence interval (CI) 1.1–2.4], pT3/pT4 stage (HR 1.9, 95 % CI 1.3–2.9), a major complication (HR 1.7, 95 % CI 1.1–2.5), and not receiving adjuvant chemotherapy (HR 1.5, 95 % CI 1.0–2.3).
Survival after DP for PDAC is poor and is related to resection margin, tumor stage, surgical complications, and adjuvant chemotherapy. Further studies should assess to what extent prevention of surgical complications and more extensive use of adjuvant chemotherapy can improve survival.
PMCID: PMC4718962  PMID: 26508153
3.  Sarcopenia, obesity and sarcopenic obesity: effects on liver function and volume in patients scheduled for major liver resection 
Sarcopenia, obesity and sarcopenic obesity have been linked to impaired outcome after liver surgery. Preoperative liver function of sarcopenic, obese and sarcopenic-obese patients might be reduced, possibly leading to more post-operative morbidity. The aim of this study was to explore whether liver function and volume were influenced by body composition in patients undergoing liver resection.
In 2011 and 2012, all consecutive patients undergoing the methacetin breath liver function test were included. Liver volumetry and muscle mass analysis were performed using preoperative CT scans and Osirix® software. Muscle mass and body-fat% were calculated. Predefined cut-off values for sarcopenia and the top two body-fat% quintiles were used to identify sarcopenia and obesity, respectively. Histologic assessment of the resected liver gave insight in background liver disease.
A total number of 80 patients were included. Liver function and volume were comparable in sarcopenic(-obese) and non-sarcopenic(-obese) patients. Obese patients showed significantly reduced liver function [295 (95–508) vs. 358 (96–684) µg/kg/h, P = 0.018] and a trend towards larger liver size [1694 (1116–2685) vs. 1533 (869–2852) mL, P = 0.079] compared with non-obese patients. Weight (r = −0.40), body surface area (r = −0.32), estimated body-fat% (r = −0.43) and body mass index (r = −0.47) showed a weak but significant negative (all P < 0.05) correlation with liver function. Moreover, body-fat% was identified as an independent factor negatively affecting the liver function.
Sarcopenia and sarcopenic obesity did not seem to influence liver size and function negatively. However, obese patients had larger, although less functional, livers, indicating dissociation of liver function and volume in these patients.
PMCID: PMC4458081  PMID: 26136191
Sarcopenia; Obesity; L3 skeletal muscle index; Body fat percentage; Liver function; LiMAx; Volumetry
4.  Obstructive putty-like cast of the biliary tree 
A 62-year-old woman was presented at the emergency department with cholangiosepsis. She had a history of liver metastases for which she had a left hemihepatectomy and loco regional recurrence at the liver hilum for which she received chemoradiation therapy MR-imaging of the liver showed multiple intrahepatic fluid collections/abscesses, together with significantly dilated intrahepatic bile ducts. For her significant hepatic function impairment she received antibiotic treatment and percutaneous drainage. The differential diagnosis was local tumor recurrence or post radiation fibrosis causing outflow obstruction centrally in the liver hilum. During the admission the serum bilirubin values kept rising. During surgery surgeons decided to perform a hepatotomy and connect a loop of the jejunum directly on the liver parenchyma, in order to allow better drainage. Intra operatively, after the hepatotomy, we encountered green-brownisch putty-like material. By traction a ‘cast’ of a large part of the biliary tree was removed.
PMCID: PMC3954996  PMID: 24696838
Biliary tree; obstruction; cast; jaundice; cholangiosepsis
5.  Real-Time In Vivo Imaging of Early Mucosal Changes during Ischemia-Reperfusion in Human Jejunum 
PLoS ONE  2012;7(6):e39638.
Background and study aims
Small intestinal ischemia-reperfusion (IR) is a frequent, potentially life threatening phenomenon. There is a lack of non-invasive diagnostic modalities. For many intestinal diseases, visualizing the intestinal mucosa using endoscopy is gold standard. However, limited knowledge exists on small intestinal IR-induced, early mucosal changes. The aims of this study were to investigate endoscopic changes in human jejunum exposed to IR, and to study concordance between endoscopic appearance and histology.
Patients and methods
In 23 patients a part of jejunum, to be removed for surgical reasons, was isolated and selectively exposed to ischemia with 0, 30 or 120 minutes of reperfusion. In 3 patients, a videocapsule was inserted in the isolated segment before exposure to IR, to visualize the mucosa. Endoscopic view at several time points was related to histology (Heamatoxylin & Eosin) obtained from 20 patients.
Ischemia was characterized by loss of villous structure, mucosal whitening and appearance of punctate lesions. This was related to appearance of subepithelial spaces and breaches in the epithelial lining in the histological view. Early during reperfusion, the lumen filled with IR-damaged, shed cells and VCE showed mucosal erosions, hemorrhage and intraluminal debris. At 60 minutes of reperfusion, the only remaining signs of IR were loss of villous structure and small erosions, indicating rapid mucosal healing.
This study shows a unique, real-time in vivo endoscopic view of early mucosal changes during IR of the human small intestine. Future studies should evaluate its usefulness in diagnosis of patients suspected of IR.
PMCID: PMC3382139  PMID: 22745799
6.  Open versus laparoscopic left lateral hepatic sectionectomy within an enhanced recovery ERAS® programme (ORANGE II – Trial): study protocol for a randomised controlled trial 
Trials  2012;13:54.
The use of lLaparoscopic liver resection in terms of time to functional recovery, length of hospital stay (LOS), long-term abdominal wall hernias, costs and quality of life (QOL) has never been studied in a randomised controlled trial. Therefore, this is the subject of the international multicentre randomised controlled ORANGE II trial.
Patients eligible for left lateral sectionectomy (LLS) of the liver will be recruited and randomised at the outpatient clinic. All randomised patients will undergo surgery in the setting of an ERAS programme. The experimental design produces two randomised arms (open and laparoscopic LLS) and a prospective registry. The prospective registry will be based on patients that cannot be randomised because of the explicit treatment preference of the patient or surgeon, or because of ineligibility (not meeting the in- and exclusion criteria) for randomisation in this trial. Therefore, all non-randomised patients undergoing LLS will be approached to participate in the prospective registry, thereby allowing acquisition of an uninterrupted prospective series of patients. The primary endpoint of the ORANGE II trial is time to functional recovery. Secondary endpoints are postoperative LOS, percentage readmission, (liver-specific) morbidity, QOL, body image and cosmetic result, hospital and societal costs over 1 year, and long-term incidence of incisional hernias. It will be assumed that in patients undergoing laparoscopic LLS, length of hospital stay can be reduced by two days. A sample size of 55 patients in each randomisation arm has been calculated to detect a 2-day reduction in LOS (90% power and α = 0.05 (two-tailed)).
The ORANGE II trial is a multicenter randomised controlled trial that will provide evidence on the merits of laparoscopic surgery in patients undergoing LLS within an enhanced recovery ERAS programme.
Trial registration NCT00874224.
PMCID: PMC3409025  PMID: 22559239
Laparoscopy; Open liver resection; Hepatectomy; ERAS; Left lateral sectionectomy; RCT
7.  Total Intermittent Pringle Maneuver during Liver Resection Can Induce Intestinal Epithelial Cell Damage and Endotoxemia 
PLoS ONE  2012;7(1):e30539.
The intermittent Pringle maneuver (IPM) is frequently applied to minimize blood loss during liver transection. Clamping the hepatoduodenal ligament blocks the hepatic inflow, which leads to a non circulating (hepato)splanchnic outflow. Also, IPM blocks the mesenteric venous drainage (as well as the splenic drainage) with raising pressure in the microvascular network of the intestinal structures. It is unknown whether the IPM is harmful to the gut. The aim was to investigate intestinal epithelial cell damage reflected by circulating intestinal fatty acid binding protein levels (I-FABP) in patients undergoing liver resection with IPM.
Patients who underwent liver surgery received total IPM (total-IPM) or selective IPM (sel-IPM). A selective IPM was performed by selectively clamping the right portal pedicle. Patients without IPM served as controls (no-IPM). Arterial blood samples were taken immediately after incision, ischemia and reperfusion of the liver, transection, 8 hours after start of surgery and on the first post-operative day.
24 patients (13 males) were included. 7 patients received cycles of 15 minutes and 5 patients received cycles of 30 minutes of hepatic inflow occlusion. 6 patients received cycles of 15 minutes selective hepatic occlusion and 6 patients underwent surgery without inflow occlusion. Application of total-IPM resulted in a significant increase in I-FABP 8 hours after start of surgery compared to baseline (p<0.005). In the no-IPM group and sel-IPM group no significant increase in I-FABP at any time point compared to baseline was observed.
Total-IPM in patients undergoing liver resection is associated with a substantial increase in arterial I-FABP, pointing to intestinal epithelial injury during liver surgery.
Trial Registration NCT01099475
PMCID: PMC3265485  PMID: 22291982
8.  Prospective Volumetric Assessment of the Liver on a Personal Computer by Nonradiologists Prior to Partial Hepatectomy 
World Journal of Surgery  2010;35(2):386-392.
A small remnant liver volume is an important risk factor for posthepatectomy liver failure. ImageJ and OsiriX® are both free, open-source image processing software packages. The aim of the present study was to compare ImageJ and OsiriX® in performing prospective computed tomography (CT) volumetric analysis of the liver on a personal computer (PC) in patients undergoing major liver resection.
Patients scheduled for a right hemihepatectomy were eligible for inclusion. Two surgeons and one surgical trainee measured volumes of total liver, tumor, and future resection specimen prospectively with ImageJ and OsiriX®. A radiologist also measured these volumes with CT scanner-linked Aquarius iNtuition® software. Resection volumes were compared with the actual weights of the liver specimens removed during surgery, and differences between the measured liver volumes were analyzed.
A total of 15 patients (8 men, 7 women) with a median age of 63 years (48–79 years) were included. There was a significant correlation between the measured weights of resection specimens and the volumes calculated prospectively with ImageJ and OsiriX® (r = 0.89; r = 0.83, respectively). There was also a significant correlation between the volumes measured with radiological software iNtuition® and the volumes measured with ImageJ and OsiriX® (r = 0.93; r = 0.95, respectively).
There were no major differences in total liver volumes, resection volumes, or tumour volumes for these three software packages. Prospective hepatic CT volumetry with ImageJ or OsiriX® is reliable and can be accurately used on a PC by nonradiologists. ImageJ and OsiriX® yield results comparable to the radiological software iNtuition®.
PMCID: PMC3017311  PMID: 21136056
9.  Virtual Liver Resection and Volumetric Analysis of the Future Liver Remnant using Open Source Image Processing Software 
World Journal of Surgery  2010;34(10):2426-2433.
After extended liver resection, a remnant liver that is too small can lead to postresection liver failure. To reduce this risk, preoperative evaluation of the future liver remnant volume (FLRV) is critical. The open-source OsiriX® PAC software system can be downloaded for free and used by nonradiologists to calculate liver volume using a stand-alone Apple computer. The purpose of this study was to assess the accuracy of OsiriX® CT volumetry for predicting liver resection volume and FLVR in patients undergoing partial hepatectomy.
Preoperative contrast-enhanced liver CT scans of patients who underwent partial hepatectomy were analyzed by three observers. Two surgical trainees measured the total liver volume, resection volume, and tumor volume using OsiriX®, and a radiologist measured these volumes using CT scanner-linked Aquarius iNtuition® software. Resection volume was correlated with prospectively determined resection weight, and differences in the measured liver volumes were analyzed. Interobserver variability was assessed using Bland–Altman plots.
25 patients (M/F ratio: 13/12) with a median age of 61 (range, 34–77) years were included. There were significant correlations between the weight and volume of the resected specimens (Pearson’s correlation coefficient: R2 = 0.95). There were no major differences in total liver volumes, resection volumes, or tumor volumes for observers 1, 2, and 3. Bland–Altman plots showed a small interobserver variability. The mean time to complete liver volumetry for one patient using OsiriX® was 19 ± 3 min.
OsiriX® liver volumetry performed by surgeons is an accurate and time-efficient method for predicting resection volume and FLRV.
PMCID: PMC2936678  PMID: 20652701
10.  Enterocyte Shedding and Epithelial Lining Repair Following Ischemia of the Human Small Intestine Attenuate Inflammation 
PLoS ONE  2009;4(9):e7045.
Recently, we observed that small-intestinal ischemia and reperfusion was found to entail a rapid loss of apoptotic and necrotic cells. This study was conducted to investigate whether the observed shedding of ischemically damaged epithelial cells affects IR induced inflammation in the human small gut.
Methods and Findings
Using a newly developed IR model of the human small intestine, the inflammatory response was studied on cellular, protein and mRNA level. Thirty patients were consecutively included. Part of the jejunum was subjected to 30 minutes of ischemia and variable reperfusion periods (mean reperfusion time 120 (±11) minutes). Ethical approval and informed consent were obtained. Increased plasma intestinal fatty acid binding protein (I-FABP) levels indicated loss in epithelial cell integrity in response to ischemia and reperfusion (p<0.001 vs healthy). HIF-1α gene expression doubled (p = 0.02) and C3 gene expression increased 4-fold (p = 0.01) over the course of IR. Gut barrier failure, assessed as LPS concentration in small bowel venous effluent blood, was not observed (p = 0.18). Additionally, mRNA expression of HO-1, IL-6, IL-8 did not alter. No increased expression of endothelial adhesion molecules, TNFα release, increased numbers of inflammatory cells (p = 0.71) or complement activation, assessed as activated C3 (p = 0.14), were detected in the reperfused tissue.
In the human small intestine, thirty minutes of ischemia followed by up to 4 hours of reperfusion, does not seem to lead to an explicit inflammatory response. This may be explained by a unique mechanism of shedding of damaged enterocytes, reported for the first time by our group.
PMCID: PMC2737143  PMID: 19753114
11.  Rapid Reversal of Human Intestinal Ischemia-Reperfusion Induced Damage by Shedding of Injured Enterocytes and Reepithelialisation 
PLoS ONE  2008;3(10):e3428.
Intestinal ischemia-reperfusion (IR) is a phenomenon related to physiological conditions (e.g. exercise, stress) and to pathophysiological events (e.g. acute mesenteric ischemia, aortic surgery). Although intestinal IR has been studied extensively in animals, results remain inconclusive and data on human intestinal IR are scarce. Therefore, an experimental harmless model for human intestinal IR was developed, enabling us to clarify the sequelae of human intestinal IR for the first time.
Methods and Findings
In 30 patients undergoing pancreatico-duodenectomy we took advantage of the fact that in this procedure a variable length of jejunum is removed. Isolated jejunum (5 cm) was subjected to 30 minutes ischemia followed by reperfusion. Intestinal Fatty Acid Binding Protein (I-FABP) arteriovenous concentration differences across the bowel segment were measured before and after ischemia to assess epithelial cell damage. Tissue sections were collected after ischemia and at 25, 60 and 120 minutes reperfusion and stained with H&E, and for I-FABP and the apoptosis marker M30. Bonferroni's test was used to compare I-FABP differences. Mean (SEM) arteriovenous concentration gradients of I-FABP across the jejunum revealed rapidly developing epithelial cell damage. I-FABP release significantly increased from 290 (46) pg/ml before ischemia towards 3,997 (554) pg/ml immediately after ischemia (p<0.001) and declined gradually to 1,143 (237) pg/ml within 1 hour reperfusion (p<0.001). Directly after ischemia the intestinal epithelial lining was microscopically normal, while subepithelial spaces appeared at the villus tip. However, after 25 minutes reperfusion, enterocyte M30 immunostaining was observed at the villus tip accompanied by shedding of mature enterocytes into the lumen and loss of I-FABP staining. Interestingly, within 60 minutes reperfusion the epithelial barrier resealed, while debris of apoptotic, shedded epithelial cells was observed in the lumen. At the same time, M30 immunoreactivity was absent in intact epithelial lining.
This is the first human study to clarify intestinal IR induced cell damage and repair and its direct consequences. It reveals a unique, endogenous clearing mechanism for injured enterocytes: rapid detachment of damaged apoptotic enterocytes into the lumen. This process is followed by repair of the epithelial continuity within an hour, resulting in a normal epithelial lining.
PMCID: PMC2561292  PMID: 18927609
12.  Liver Volumetry Plug and Play: Do It Yourself with ImageJ 
World Journal of Surgery  2007;31(11):2215-2221.
A small remnant liver volume is an important risk factor for posthepatectomy liver failure and can be predicted accurately by computed tomography (CT) volumetry using radiologic image analysis software. Unfortunately, this software is expensive and usually requires support by a radiologist. ImageJ is a freely downloadable image analysis software package developed by the National Institute of Health (NIH) and brings liver volumetry to the surgeon’s desktop. We aimed to assess the accuracy of ImageJ for hepatic CT volumetry.
ImageJ was downloaded from Preoperative CT scans of 15 patients who underwent liver resection for colorectal cancer liver metastases were retrospectively analyzed. Scans were opened in ImageJ; and the liver, all metastases, and the intended parenchymal transection line were manually outlined on each slice. The area of each selected region, metastasis, resection specimen, and remnant liver was multiplied by the slice thickness to calculate volume. Volumes of virtual liver resection specimens measured with ImageJ were compared with specimen weights and calculated volumes obtained during pathology examination after resection.
There was an excellent correlation between the volumes calculated with ImageJ and the actual measured weights of the resection specimens (r² = 0.98, p < 0.0001). The weight/volume ratio amounted to 0.88 ± 0.04 (standard error) and was in agreement with our earlier findings using CT-linked radiologic software.
ImageJ can be used for accurate hepatic CT volumetry on a personal computer. This application brings CT volumetry to the surgeon’s desktop at no expense and is particularly useful in cases of tertiary referred patients, who already have a proper CT scan on CD-ROM from the referring institution. Most likely the discrepancy between volume and weight results from exsanguination of the liver after resection.
PMCID: PMC2039862  PMID: 17726630
13.  Perioperative strategy in colonic surgery; LAparoscopy and/or FAst track multimodal management versus standard care (LAFA trial) 
BMC Surgery  2006;6:16.
Recent developments in large bowel surgery are the introduction of laparoscopic surgery and the implementation of multimodal fast track recovery programs. Both focus on a faster recovery and shorter hospital stay.
The randomized controlled multicenter LAFA-trial (LAparoscopy and/or FAst track multimodal management versus standard care) was conceived to determine whether laparoscopic surgery, fast track perioperative care or a combination of both is to be preferred over open surgery with standard care in patients having segmental colectomy for malignant disease.
The LAFA-trial is a double blinded, multicenter trial with a 2 × 2 balanced factorial design. Patients eligible for segmental colectomy for malignant colorectal disease i.e. right and left colectomy and anterior resection will be randomized to either open or laparoscopic colectomy, and to either standard care or the fast track program. This factorial design produces four treatment groups; open colectomy with standard care (a), open colectomy with fast track program (b), laparoscopic colectomy with standard care (c), and laparoscopic surgery with fast track program (d). Primary outcome parameter is postoperative hospital length of stay including readmission within 30 days. Secondary outcome parameters are quality of life two and four weeks after surgery, overall hospital costs, morbidity, patient satisfaction and readmission rate.
Based on a mean postoperative hospital stay of 9 +/- 2.5 days a group size of 400 patients (100 each arm) can reliably detect a minimum difference of 1 day between the four arms (alfa = 0.95, beta = 0.8). With 100 patients in each arm a difference of 10% in subscales of the Short Form 36 (SF-36) questionnaire and social functioning can be detected.
The LAFA-trial is a randomized controlled multicenter trial that will provide evidence on the merits of fast track perioperative care and laparoscopic colorectal surgery in patients having segmental colectomy for malignant disease.
PMCID: PMC1693570  PMID: 17134506

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