Publications by authors named "Bert A Bonsing"

91 Publications

Preoperative serum ADAM12 levels as a stromal marker for overall survival and benefit of adjuvant therapy in patients with resected pancreatic and periampullary cancer.

HPB (Oxford) 2021 May 19. Epub 2021 May 19.

Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, University of Amsterdam, the Netherlands. Electronic address:

Background: We evaluated the stroma marker A Disintegrin And Metalloprotease 12 (ADAM12) as a preoperative prognostic and treatment-predictive marker for overall survival (OS) in pancreatic ductal adenocarcinoma (PDAC) and periampullary cancers.

Methods: Materials were derived from the prospective nationwide Dutch Pancreas Biobank (2015-2017). We included patients who underwent resection because of PDAC/periampullary cancer or non-invasive IPMN (control group) and had a preoperative serum sample available. ADAM12 levels were dichotomized using a pre-defined cut-off (316 pg/mL). Univariable and multivariable Cox regression analyses (backward selection) were performed.

Results: Median ADAM12 levels were 161 (IQR 79-352) pg/mL in 215 PDAC and periampullary adenocarcinomas. High ADAM12 levels (>316 pg/mL) predicted poor OS in the total group of pancreatic and periampullary adenocarcinomas (P = 0.04), but not after adjustment. In distal cholangiocarcinoma (n = 33), high ADAM12 levels predicted poor OS in univariable analysis (P = 0.02), but not in PDAC (P = 0.63). PDAC patients (n = 135) with high ADAM12 levels benefited from adjuvant treatment (median OS 27 vs 14 months, P = 0.02), whereas those with low levels did not (21 vs 21 months, P = 0.87).

Conclusion: High circulating ADAM12 levels, as a proxy for activated stroma, predict survival benefit from adjuvant chemotherapy in PDAC, requiring validation in future studies.
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http://dx.doi.org/10.1016/j.hpb.2021.05.001DOI Listing
May 2021

Clinical Perspective on Proteomic and Glycomic Biomarkers for Diagnosis, Prognosis, and Prediction of Pancreatic Cancer.

Int J Mol Sci 2021 Mar 6;22(5). Epub 2021 Mar 6.

Department of Surgery, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical techniques and new (neo)adjuvant chemotherapy regimens. Early detection of PDAC may increase the overall survival. It is furthermore foreseen that precision medicine will provide improved prognostic stratification and prediction of therapeutic response. In this review, omics-based discovery efforts are presented that aim for novel diagnostic and prognostic biomarkers of PDAC. For this purpose, we systematically evaluated the literature published between 1999 and 2020 with a focus on protein- and protein-glycosylation biomarkers in pancreatic cancer patients. Besides genomic and transcriptomic approaches, mass spectrometry (MS)-based proteomics and glycomics of blood- and tissue-derived samples from PDAC patients have yielded new candidates with biomarker potential. However, for reasons discussed in this review, the validation and clinical translation of these candidate markers has not been successful. Consequently, there has been a change of mindset from initial efforts to identify new unimarkers into the current hypothesis that a combination of biomarkers better suits a diagnostic or prognostic panel. With continuing development of current research methods and available techniques combined with careful study designs, new biomarkers could contribute to improved detection, prognosis, and prediction of pancreatic cancer.
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http://dx.doi.org/10.3390/ijms22052655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961509PMC
March 2021

Outcomes of a Multicenter Training Program in Robotic Pancreatoduodenectomy (LAELAPS-3).

Ann Surg 2021 Feb 1. Epub 2021 Feb 1.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands Department of Surgery, Regional Academic Cancer Center Utrecht, UMC Utrecht Cancer Center & St Antonius Hospital Nieuwegein, Utrecht University, Utrecht, the Netherlands Department of Surgery, Erasmus University Medical Center, Rotterdam, the Netherlands Department of Surgery, Amphia Ziekenhuis, Breda, the Netherlands Department of Surgery, OLVG, Amsterdam, the Netherlands Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands Department of Surgery, Medisch Spectrum Twente, Enschede, the Netherlands Department of Surgery, Southampton University Hospital NHS Foundation Trust, Southampton, UK Department of Surgery, Istituto Fondazione Poliambulanza, Brescia, Italy Department of Surgery, Centre Hospitalier Régional Orleans, Orleans, France Department of Surgery, University of Texas, Southwestern, Dallas, TX, USA Department of Surgery, Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Department of Surgery, Northshore University HealthSystem, Chicago, IL, USA.

Objective: To assess feasibility and safety of a multicenter training program in robotic pancreatoduodenectomy (RPD) adhering to the IDEAL framework for implementation of surgical innovation.

Background: Good results for RPD have been reported from single center studies. However, data on feasibility and safety of implementation through a multicenter training program in RPD are lacking.

Methods: A multicenter training program in RPD was designed together with the University of Pittsburgh Medical Center, including an online video bank, robot simulation exercises, biotissue drills, and on-site proctoring. Benchmark patients were based on the criteria of Clavien. Outcomes were collected prospectively (March 2016-October 2019). Cumulative sum (CUSUM) analysis of operative time was performed to distinguish the first and second phase of the learning curve. Outcomes were compared between both phases of the learning curve. Trends in nationwide use of robotic and laparoscopic PD were assessed in the Dutch Pancreatic Cancer Audit.

Results: Overall, 275 RPD procedures were performed in seven centers by 15 trained surgeons. The recent benchmark criteria for low-risk PD were met by 125 (45.5%) patients. The conversion rate was 6.5% (n = 18) and median blood loss 250 ml (IQR 150-500). The rate of Clavien-Dindo grade ≥III complications was 44.4% (n = 122), postoperative pancreatic fistula (grade B/C) rate 23.6% (n = 65), 90-day complication-related mortality 2.5% (n = 7) and 90-day cancer-related mortality 2.2.% (n = 6). Median postoperative hospital stay was 12 days (IQR 8-20). In the subgroup of patients with pancreatic cancer (n = 80), the major complication rate was 31.3% and POPF rate was 10%. CUSUM analysis for operative time found a learning curve inflection point at 22 RPDs (IQR 10-35) with similar rates of Clavien-Dindo grade ≥III complications in the first and second phase (43.4% vs 43.8%, P = 0.956, respectively). During the study period the nationwide use of laparoscopic PD reduced from 15% to 1%, whereas the use of RPD increased from 0% to 25%.

Conclusions: This multicenter RPD training program in centers with sufficient surgical volume was found to be feasible without a negative impact of the learning curve on clinical outcomes.
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http://dx.doi.org/10.1097/SLA.0000000000004783DOI Listing
February 2021

Complications After Major Surgery for Duodenopancreatic Neuroendocrine Tumors in Patients with MEN1: Results from a Nationwide Cohort.

Ann Surg Oncol 2021 Aug 31;28(8):4387-4399. Epub 2021 Jan 31.

Department of Endocrine Surgical Oncology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background: Little is known about complications after major duodenopancreatic surgery for duodenopancreatic neuroendocrine tumors (dpNETs) in multiple endocrine neoplasia type 1 (MEN1). Therefore, the incidence and severity of complications after major surgery for MEN1-related dpNETs were assessed.

Methods: Patients were selected from the population-based Dutch MEN1 database if they had undergone a Whipple procedure or total pancreatectomy from 2003 to 2017. Complications were graded according to the Clavien-Dindo classification (grade III or higher complications were considered a severe complication) and definitions from the International Study Group of Pancreatic Surgery. The Cumulative Complication Index (CCI) was calculated as the sum of all complications weighted for their severity. Univariable logistic regression was performed to assess potential associations between predictor candidates and a severe complication.

Results: Twenty-seven patients (median age 43 years) underwent a major duodenopancreatic resection, including 14 Whipple procedures and 13 total pancreatectomies. Morbidity and mortality were 100% (27/27) and 4% (1/27), respectively. A severe complication occurred in 17/27 (63%) patients. The median CCI was 47.8 [range 8.7-100]. Grade B/C pancreatic fistulas, delayed gastric emptying, bile leakage, hemorrhage, and chyle leakage occurred in 7/14 (50%), 10/27 (37%), 1/27 (4%), 7/27 (26%), 3/27 (11%) patients, respectively. Patients with a severe complication had longer operative time and higher blood loss. After Whipple, new-onset endocrine and exocrine insufficiency occurred in 1/13 and 9/14 patients, respectively.

Conclusions: Major duodenopancreatic surgery in MEN1 is associated with a very high risk of severe complications and cumulative burden of complications and should therefore be reserved for a select subgroup of patients with MEN1-related dpNETs.
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http://dx.doi.org/10.1245/s10434-020-09496-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253708PMC
August 2021

Real-time surgical margin assessment using ICG-fluorescence during laparoscopic and robot-assisted resections of colorectal liver metastases.

Ann Transl Med 2020 Nov;8(21):1448

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Almost a third of the resections in patients with colorectal liver metastases (CRLM) undergoing curative surgery, end up being tumor-margin positive (≤1 mm margin). Near-infrared fluorescent (NIRF) imaging using the fluorescent contrast agent indocyanine green (ICG) has been studied for many different applications. When administered in a relatively low dose (10 mg) 24 hours prior to surgery, ICG accumulated in hepatocytes surrounding the CRLM. This results in the formation of a characteristic fluorescent 'rim' surrounding CRLM when located at the periphery of the liver. By resecting the metastasis with the entire surrounding fluorescent rim, in real-time guided by NIRF imaging, the surgeon can effectively acquire margin-negative (>1 mm) resections. This pilot study aims to describe the surgical technique for using near-infrared fluorescence imaging to assess tumor-margins in patients with CRLM undergoing laparoscopic or robot-assisted resections.

Methods: Out of our institutional database we selected 16 CRLM based on margin-status (R0; n=8, R1; n=8), which were resected by a minimally-invasive approach using ICG-fluorescence. NIRF images acquired during surgery, from both the resection specimen and the wound bed, were analysed for fluorescent signal. We hypothesized that a protruding fluorescent rim at the parenchymal side of the resection specimen could indicate a too close proximity to the tumor and could be predictive for a tumor-positive surgical margin. NIRF images were correlated to final histopathological assessment of the resection margin.

Results: All lesions with a NIRF positive resection plane were reported as having a tumor-positive margin. Lesions that showcased no protruding rim in the wound bed were diagnosed as having a tumor-negative margin in 88% of cases. A 5-step surgical workflow is described to document the NIRF signal was used assess the resection margin for future clinical studies.

Conclusions: The pilot study shows that image-guided surgery using real-time ICG-fluorescence has the potential to aid surgeons in achieving a tumor-negative margin in minimally invasive liver metastasectomies. The national multi-centre MIMIC-Trial will prospectively study the effect of this technique on surgical tumor-margins (Dutch Trial Register number NL7674).
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http://dx.doi.org/10.21037/atm-20-1999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723628PMC
November 2020

Clinical implications of bile cultures obtained during pancreatoduodenectomy: a cohort study and meta-analysis.

HPB (Oxford) 2021 Jul 10;23(7):1123-1133. Epub 2020 Dec 10.

Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: The association between intraoperative bile cultures and infectious complications after pancreatoduodenectomy remains unclear. This cohort study and meta-analysis aimed to determine the predictive role of intraoperative bile cultures in abdominal infectious complications after pancreatoduodenectomy.

Methods: The cohort study included 114 patients undergoing pancreatoduodenectomy. Regression analyses were used to estimate the odds to develop an organ space infection (OSI) or isolated OSI (OSIs without a simultaneous complication potentially contaminating the intraabdominal space) after a positive bile culture. A systematic review and meta-analysis was performed on abdominal infectious complications (Mantel-Haenszel fixed-effect model).

Results: The positive bile culture rate was 61%, predominantly in patients after preoperative biliary drainage (98% vs 26%, p < 0.001). OSIs occurred in 35 patients (31%) and isolated OSIs in nine patients (8%) and were not associated with positive bile cultures (OSIs: odds ratio = 0.6, 95% CI = 0.25-1.23, isolated OSIs: odds ratio = 0.77, 95% CI = 0.20-3.04). In the meta-analysis, 15 studies reporting on 2047 patients showed no association between positive bile cultures and abdominal infectious complications (pooled odds ratio = 1.3, 95% CI = 0.98-1.65).

Conclusion: Given the rare occurrence of isolated OSIs and similar odds for patients with positive and negative bile cultures to develop abdominal infectious complications, routine performance of bile cultures should be reconsidered.
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http://dx.doi.org/10.1016/j.hpb.2020.10.028DOI Listing
July 2021

Pancreatic resection in the pediatric, adolescent and young adult population: nationwide analysis on complications.

HPB (Oxford) 2020 Dec 3. Epub 2020 Dec 3.

Department of Hepatopancreatobiliary Surgery and Liver Transplantation, University of Groningen, University Medical Center Groningen, the Netherlands. Electronic address:

Background: The aim of this study was to determine pancreatic surgery specific short- and long-term complications of pediatric, adolescent and young adult (PAYA) patients who underwent pancreatic resection, as compared to a comparator cohort of adults.

Methods: A nationwide retrospective cohort study was performed in PAYA patients who underwent pancreatic resection between 2007 and 2016. PAYA was defined as all patients <40 years at time of surgery. Pancreatic surgery-specific complications were assessed according to international definitions and textbook outcome was determined.

Results: A total of 230 patients were included in the PAYA cohort (112 distal pancreatectomies, 99 pancreatoduodenectomies), and 2526 patients in the comparator cohort. For pancreatoduodenectomy, severe morbidity (29.3% vs. 28.6%; P = 0.881), in-hospital mortality (1% vs. 4%; P = 0.179) and textbook outcome (62% vs. 58%; P = 0.572) were comparable between the PAYA and the comparator cohort. These outcomes were also similar for distal pancreatectomy. After pancreatoduodenectomy, new-onset diabetes mellitus (8% vs. 16%) and exocrine pancreatic insufficiency (27% vs. 73%) were lower in the PAYA cohort when compared to adult literature.

Conclusion: Pancreatic surgery-specific complications were comparable with patients ≥40 years. Development of endocrine and exocrine insufficiency in PAYA patients who underwent pancreatoduodenectomy, however, was substantially lower compared to adult literature.
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http://dx.doi.org/10.1016/j.hpb.2020.10.029DOI Listing
December 2020

External Validity of the Multicenter Randomized PREOPANC Trial on Neoadjuvant Chemoradiotherapy in Pancreatic Cancer: Outcome of Eligible But Non-Randomized Patients.

Ann Surg 2020 Dec 2. Epub 2020 Dec 2.

Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Objectives: To investigate the accrual proportion and patients' reasons for not participating in the PREOPANC trial on neoadjuvant chemoradiotherapy vs. immediate surgery in resectable and borderline resectable pancreatic cancer, and to compare these patients' outcomes with those of patients who had been randomized in the trial.

Summary Of Background Data: The external validity of multicenter randomized trials in cancer treatment has been criticized for suboptimal non-representative inclusion. In trials, it is unclear how outcomes compare between randomized and non-randomized patients.

Methods: At eight of 16 participant centers, this multicenter observational study identified validation patients, who had been eligible but not randomized during recruitment for the PREOPANC trial. We assessed the accrual proportion, investigated their most common reasons for not participating in the trial, and compared resection rates, radical (R0) resection rates and overall survival (OS) between the validation patients and PREOPANC patients, who had been randomized in the trial to immediate surgery.

Results: In total, 455 patients had been eligible during the recruitment period, 151 of whom (33%) had been randomized. Fifty-five percent of the 304 validation patients had refused to participate. Median OS in the validation group was 15.2 months, against 15.5 months in the PREOPANC group (p = 1.00). The respective resection rates (76% vs. 73%) and R0 resection rates (51% vs. 46%) did not differ between the groups.

Conclusions: The PREOPANC trial included a reasonable percentage of 33% of eligible patients. In terms of the outcomes survival, resection rate, and R0 resection rate, this appeared to be a representative group.
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http://dx.doi.org/10.1097/SLA.0000000000004364DOI Listing
December 2020

Surgical Complications in a Multicenter Randomized Trial Comparing Preoperative Chemoradiotherapy and Immediate Surgery in Patients With Resectable and Borderline Resectable Pancreatic Cancer (PREOPANC Trial).

Ann Surg 2020 Nov 12. Epub 2020 Nov 12.

Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

Objectives: To investigate the effect of preoperative chemoradiotherapy on surgical complications in patients after pancreatic resection for (borderline-)resectable pancreatic cancer.

Summary Of Background Data: Preoperative chemoradiotherapy is increasingly used in patients with (borderline-)resectable pancreatic cancer. Concerns have been raised about the potential harmful effect of any preoperative therapy on the surgical complication rate after pancreatic resection.

Methods: An observational analysis was performed within the multicenter randomized controlled PREOPANC trial (April 2013-July 2017). The trial randomly assigned (1:1) patients to preoperative chemoradiotherapy followed by surgery and the remaining adjuvant chemotherapy or to immediate surgery, followed by adjuvant chemotherapy. The main analysis consisted of a per-protocol approach. The endpoints of the present analyses were the rate of postoperative complications.

Results: This study included 246 patients from 16 centers, of whom 66 patients underwent resection after preoperative therapy and 98 patients after immediate surgery. No differences were found regarding major complications (37.9% vs 30.6%, P = 0.400), postpancreatectomy hemorrhage (9.1% vs 5.1%, P = 0.352), delayed gastric emptying (21.2% vs 22.4%, P = 0.930), bile leakage (4.5% vs 3.1%, P = 0.686), intra-abdominal infections (12.1% vs 10.2%, P = 0.800), and mortality (3.0% vs 4.1%, P = 1.000). There was a significant lower incidence of postoperative pancreatic fistula in patients who received preoperative chemoradiotherapy (0% vs 9.2%, P = 0.011).

Conclusions: Preoperative chemoradiotherapy did not increase the incidence of surgical complications or mortality and reduced the rate of postoperative pancreatic fistula after resection in patients with (borderline-)resectable pancreatic cancer.
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http://dx.doi.org/10.1097/SLA.0000000000004313DOI Listing
November 2020

Intraoperative detection of colorectal and pancreatic liver metastases using SGM-101, a fluorescent antibody targeting CEA.

Eur J Surg Oncol 2021 Mar 2;47(3 Pt B):667-673. Epub 2020 Nov 2.

Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: Fluorescence-guided surgery can provide surgeons with an imaging tool for real-time intraoperative tumor detection. SGM-101, an anti-CEA antibody labelled with a fluorescent dye, is a tumor-specific imaging agent that can aid in improving detection and complete resection for CEA-positive tumors. In this study, the performance of SGM-101 for the detection of colorectal and pancreatic liver metastases was investigated.

Methods: In this open-label, non-randomized, single-arm pilot study, patients were included with liver metastases from colorectal origin and intraoperatively detected liver metastases from pancreatic origin (during planned pancreatic surgery). SGM-101 was administered two to four days before the scheduled surgery as a single intravenous injection. Intraoperative fluorescence imaging was performed using the Quest Spectrum® imaging system. The performance of SGM-101 was assessed by measuring the intraoperative fluorescence signal and comparing this to histopathology.

Results: A total of 19 lesions were found in 11 patients, which were all suspected as malignant in white light and subsequent fluorescence inspection. Seventeen lesions were malignant with a mean tumor-to-background ratio of 1.7. The remaining two lesions were false-positives as proven by histology.

Conclusion: CEA-targeted fluorescence-guided intraoperative tumor detection with SGM-101 is feasible for the detection of colorectal and pancreatic liver metastases.
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http://dx.doi.org/10.1016/j.ejso.2020.10.034DOI Listing
March 2021

Nationwide compliance with a multidisciplinary guideline on pancreatic cancer during 6-year follow-up.

Pancreatology 2020 Dec 10;20(8):1723-1731. Epub 2020 Oct 10.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Background: Compliance with national guidelines on pancreatic cancer management could improve patient outcomes. Early compliance with the Dutch guideline was poor. The aim was to assess compliance with this guideline during six years after publication.

Materials And Methods: Nationwide guideline compliance was investigated for three subsequent time periods (2012-2013 vs. 2014-2015 vs. 2016-2017) in patients with pancreatic cancer using five quality indicators in the Netherlands Cancer Registry: 1) discussion in multidisciplinary team meeting (MDT), 2) maximum 3-week interval from final MDT to start of treatment, 3) preoperative biliary drainage when bilirubin >250 μmol/L, 4) use of adjuvant chemotherapy, and 5) chemotherapy for inoperable disease (non-metastatic and metastatic).

Results: In total, 14 491 patients were included of whom 2290 (15.8%) underwent resection and 4561 (31.5%) received chemotherapy. Most quality indicators did not change over time: overall, 88.8% of patients treated with curative intent were discussed in a MDT, 42.7% were treated with curative intent within the 3-week interval, 62.7% with a resectable head tumor and bilirubin >250 μmol/L underwent preoperative biliary drainage, 57.2% received chemotherapy after resection, and 36.6% with metastatic disease received chemotherapy. Only use of chemotherapy for non-metastatic, non-resected disease improved over time (23.4% vs. 25.6% vs. 29.7%).

Conclusion: Nationwide compliance to five quality indicators for the guideline on pancreatic cancer management showed little to no improvement during six years after publication. Besides critical review of the current quality indicators, these outcomes may suggest that a nationwide implementation program is required to increase compliance to guideline recommendations.
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http://dx.doi.org/10.1016/j.pan.2020.10.032DOI Listing
December 2020

Stage-Specific Value of Carbohydrate Antigen 19-9 and Carcinoembryonic Antigen Serum Levels on Survival and Recurrence in Pancreatic Cancer: A Single Center Study and Meta-Analysis.

Cancers (Basel) 2020 Oct 14;12(10). Epub 2020 Oct 14.

Department of Surgery, Leiden University Medical Center, 2300RC Leiden, The Netherlands.

This study aimed to determine the stage-specific prognostic value of carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) serum levels at diagnosis on overall survival (OS) and time to local recurrence or distant metastases in patients with pancreatic ductal adenocarcinoma (PDAC). Consecutive PDAC patients, discussed at multidisciplinary team meetings from 2013 through 2017, were reviewed. Prognostic factors were stage-specific (resection vs. advanced PDAC) evaluated in Cox proportional hazard models. Additionally, a systematic literature search and meta-analysis was performed, as current literature is lacking a complete overview of used cut-off values and the added value of CEA as prognostic marker. In the retrospective cohort, elevated CA19-9 (>305 kU/L) level was independently associated with poor OS (Hazard ratio (HR): 1.72(1.31-2.26)) and early recurrence (HR: 1.74(1.06-2.86)), whereas CEA was not significantly associated. The meta-analysis showed that both elevated CA19-9 and CEA serum levels were predictors for poor OS (pooled HR: 1.29(1.17-1.42) and HR: 1.51(1.33-1.73), respectively). In the resected cohort, elevated CA19-9 level was significantly associated with early recurrence (pooled HR: 2.41(1.77-3.29)), whereas CEA was not. Elevated CA19-9 serum level appear to be an independent prognostic factor for poor OS and early recurrence in PDAC patients, whereas the prognostic value of CEA is disputable.
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http://dx.doi.org/10.3390/cancers12102970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602123PMC
October 2020

Serum N-Glycome analysis reveals pancreatic cancer disease signatures.

Cancer Med 2020 11 8;9(22):8519-8529. Epub 2020 Sep 8.

Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.

Background &aims: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer type with loco-regional spread that makes the tumor surgically unresectable. Novel diagnostic tools are needed to improve detection of PDAC and increase patient survival. In this study we explore serum protein N-glycan profiles from PDAC patients with regard to their applicability to serve as a disease biomarker panel.

Methods: Total serum N-glycome analysis was applied to a discovery set (86 PDAC cases/84 controls) followed by independent validation (26 cases/26 controls) using in-house collected serum specimens. Protein N-glycan profiles were obtained using ultrahigh resolution mass spectrometry and included linkage-specific sialic acid information. N-glycans were relatively quantified and case-control classification performance was evaluated based on glycosylation traits such as branching, fucosylation, and sialylation.

Results: In PDAC patients a higher level of branching (OR 6.19, P-value 9.21 × 10 ) and (antenna)fucosylation (OR 13.27, P-value 2.31 × 10 ) of N-glycans was found. Furthermore, the ratio of α2,6- vs α2,3-linked sialylation was higher in patients compared to healthy controls. A classification model built with three glycosylation traits was used for discovery (AUC 0.88) and independent validation (AUC 0.81), with sensitivity and specificity values of 0.85 and 0.71 for the discovery set and 0.75 and 0.72 for the validation set.

Conclusion: Serum N-glycome analysis revealed glycosylation differences that allow classification of PDAC patients from healthy controls. It was demonstrated that glycosylation traits rather than single N-glycan structures obtained in this clinical glycomics study can serve as a basis for further development of a blood-based diagnostic test.
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http://dx.doi.org/10.1002/cam4.3439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666731PMC
November 2020

Reliability and Agreement of Radiological and Pathological Tumor Size in patients with MEN1-Related Pancreatic Neuroendocrine Tumors: Results from a Population-Based Cohort.

Neuroendocrinology 2020 Jul 28. Epub 2020 Jul 28.

Background: Pancreatic neuroendocrine tumors (pNETs) have a high prevalence in patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Tumor size is still regarded as the main prognostic factor and therefore used for surgical decision making. We assessed reliability and agreement of radiological and pathological tumor size in a population-based cohort of patients with MEN1-related pNETs.

Methods: Patients were selected from the Dutch MEN1 database if they had undergone a resection for a pNET between 2003 and 2018. Radiological (magnetic resonance imaging (MRI), computed tomography (CT) and endoscopic ultrasonography (EUS)) and pathological tumor size were collected from patient records. Measures of agreement (Bland-Altman plots with limits of agreement (LoA) and absolute agreement) and reliability (Intraclass Correlation Coefficients (ICC) and unweighted Kappa) were calculated for continuous and categorized (< or ≥ 2 cm) pNET size.

Results: In seventy-three included patients, the median radiological and pathological tumor size measured was 22 [3 - 160] and 21 [4 - 200] mm, respectively. Mean bias between radiological and pathological tumor size was -0.2mm and LoA ranged from -12.9 to 12.6mm. For the subgroups of MRI, CT and EUS, LoA of radiological and pathological tumor size ranged from -9.6 to 10.9, -15.9 to 15.8 and -13.9 to 11.0, respectively. ICCs for the overall cohort, MRI, CT and EUS were 0.80, 0.86, 0.75 and 0.76, respectively. Based on the 2 cm criterion, agreement was 81.5%, hence 12 patients (18.5%) were classified differently between imaging and pathology. Absolute agreement and kappa's of MRI, CT and EUS were 88.6%, 85.7%, 75.0% and 0.77, 0.71 and 0.50, respectively.

Conclusion: Within a population-based cohort, MEN1-related pNET size was not systematically over-, or underestimated on preoperative imaging. Based on agreement and reliability measures, MRI is the preferred imaging modality.
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http://dx.doi.org/10.1159/000510514DOI Listing
July 2020

Prophylactic total pancreatectomy in individuals at high risk of pancreatic ductal adenocarcinoma (PROPAN): systematic review and shared decision-making programme using decision tables.

United European Gastroenterol J 2020 10 23;8(8):865-877. Epub 2020 Jul 23.

Department of Surgery, University of Amsterdam, Amsterdam, The Netherlands.

Background: Individuals with a very high lifetime risk of developing pancreatic ductal adenocarcinoma; for example, hereditary pancreatitis and main-duct or mixed-type intraductal papillary mucinous neoplasm, may wish to discuss prophylactic total pancreatectomy but strategies to do so are lacking.

Objective: To develop a shared decision-making programme for prophylactic total pancreatectomy using decision tables.

Methods: Focus group meetings with patients were used to identify relevant questions. Systematic reviews were performed to answer these questions.

Results: The first tables included hereditary pancreatitis and main-duct or mixed-type intraductal papillary mucinous neoplasm. No studies focused on prophylactic total pancreatectomy in these groups. In 52 studies (3570 patients), major morbidity after total pancreatectomy was 25% and 30-day mortality was 6%. After minimally invasive total pancreatectomy (seven studies, 35 patients) this was, respectively, 13% and 0%. Exocrine insufficiency-related symptoms occurred in 33%. Quality of life after total pancreatectomy was slightly lower compared with the general population.

Conclusion: The decision tables can be helpful for discussing prophylactic total pancreatectomy with individuals at high risk of pancreatic ductal adenocarcinoma.
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http://dx.doi.org/10.1177/2050640620945534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707864PMC
October 2020

Nationwide practice and outcomes of endoscopic biliary drainage in resectable pancreatic head and periampullary cancer.

HPB (Oxford) 2021 Feb 16;23(2):270-278. Epub 2020 Jul 16.

Department of Gastroenterology and Hepatology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Background: Guidelines advise self-expanding metal stents (SEMS) over plastic stents in preoperative endoscopic biliary drainage (EBD) for malignant extrahepatic biliary obstruction. This study aims to assess nationwide practice and outcomes.

Methods: Patients with pancreatic head and periampullary cancer who underwent EBD before pancreatoduodenectomy were included from the Dutch Pancreatic Cancer Audit (2017-2018). Multivariable logistic and linear regression models were performed.

Results: In total, 575/1056 patients (62.0%) underwent preoperative EBD: 246 SEMS (42.8%) and 329 plastic stents (57.2%). EBD-related complications were comparable between the groups (44/246 (17.9%) vs. 64/329 (19.5%), p = 0.607), including pancreatitis (22/246 (8.9%) vs. 25/329 (7.6%), p = 0.387). EBD-related cholangitis was reduced after SEMS placement (10/246 (4.1%) vs. 32/329 (9.7%), p = 0.043), which was confirmed in multivariable analysis (OR 0.36 95%CI 0.15-0.87, p = 0.023). Major postoperative complications did not differ (58/246 (23.6%) vs. 90/329 (27.4%), p = 0.316), whereas postoperative pancreatic fistula (24/246 (9.8%) vs. 61/329 (18.5%), p = 0.004; OR 0.50 95%CI 0.27-0.94, p = 0.031) and hospital stay (14.0 days vs. 17.4 days, p = 0.005; B 2.86 95%CI -5.16 to -0.57, p = 0.014) were less after SEMS placement.

Conclusion: This study found that preoperative EBD frequently involved plastic stents. SEMS seemed associated with lower risks of cholangitis and less postoperative pancreatic fistula, but without an increased pancreatitis risk.
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http://dx.doi.org/10.1016/j.hpb.2020.06.009DOI Listing
February 2021

Impact of Complications After Pancreatoduodenectomy on Mortality, Organ Failure, Hospital Stay, and Readmission: Analysis of a Nationwide Audit.

Ann Surg 2020 Jun 3. Epub 2020 Jun 3.

Department of Surgery, Regional Academic Cancer Centre Utrecht, University Medical Centre Utrecht and St Antonius Hospital Nieuwegein, Utrecht, The Netherlands.

Objective: To quantify the impact of individual complications on mortality, organ failure, hospital stay, and readmission after pancreatoduodenectomy.

Summary Of Background Data: An initial complication may provoke a sequence of adverse events potentially leading to mortality after pancreatoduodenectomy. This study was conducted to aid prioritization of quality improvement initiatives.

Methods: Data from consecutive patients undergoing pancreatoduodenectomy (2014-2017) were extracted from the Dutch Pancreatic Cancer Audit. Population attributable fractions (PAF) were calculated for the association of each complication (ie, postoperative pancreatic fistula, postpancreatectomy hemorrhage, bile leakage, delayed gastric emptying, wound infection, and pneumonia) with each unfavorable outcome [ie, in-hospital mortality, organ failure, prolonged hospital stay (>75th percentile), and unplanned readmission), whereas adjusting for confounders and other complications. The PAF represents the proportion of an outcome that could be prevented if a complication would be eliminated completely.

Results: Overall, 2620 patients were analyzed. In-hospital mortality occurred in 95 patients (3.6%), organ failure in 198 patients (7.6%), and readmission in 427 patients (16.2%). Postoperative pancreatic fistula and postpancreatectomy hemorrhage had the greatest independent impact on mortality [PAF 25.7% (95% CI 13.4-37.9) and 32.8% (21.9-43.8), respectively] and organ failure [PAF 21.8% (95% CI 12.9-30.6) and 22.1% (15.0-29.1), respectively]. Delayed gastric emptying had the greatest independent impact on prolonged hospital stay [PAF 27.6% (95% CI 23.5-31.8)]. The impact of individual complications on unplanned readmission was smaller than 11%.

Conclusion: Interventions focusing on postoperative pancreatic fistula and postpancreatectomy hemorrhage may have the greatest impact on in-hospital mortality and organ failure. To prevent prolonged hospital stay, initiatives should in addition focus on delayed gastric emptying.
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http://dx.doi.org/10.1097/SLA.0000000000003835DOI Listing
June 2020

Surgical management and pathological assessment of pancreatoduodenectomy with venous resection: an international survey among surgeons and pathologists.

HPB (Oxford) 2021 Jan 20;23(1):80-89. Epub 2020 May 20.

Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: The aim of this survey was to gain insights in the current surgical management and pathological assessment of pancreatoduodenectomy with portal-superior mesenteric vein resection (VR).

Methods: A systematic literature search was performed to identify international expert surgeons (N = 150) and pathologists (N = 40) who published relevant studies between 2009 and 2019. These experts and Dutch surgeons (N = 17) and pathologists (N = 20) were approached to complete an online survey.

Results: Overall, 76 (46%) surgeons and 37 (62%) pathologists completed the survey. Most surgeons (71%) estimated that preoperative imaging corresponded correctly with intraoperative findings of venous involvement in 50-75% of patients. An increased complication risk following VR was expected by 55% of surgeons, mainly after Type 4 (segmental resection-venous conduit anastomosis). Most surgeons (61%) preferred Type 3 (segmental resection-primary anastomosis). Most surgeons (75%) always perform the VR themselves. Standard postoperative imaging for patency control was performed by 54% of surgeons and 39% adjusted thromboprophylaxis following VR. Most pathologists (76%) always assessed tumor infiltration in the resected vein and only 54% of pathologists always assess the resection margins of the vein itself. Variation in assessment of tumor infiltration depth was observed.

Conclusion: This international survey showed variation in the surgical management and pathological assessment of pancreatoduodenectomy with venous involvement. This highlights the lack of evidence and emphasizes the need for research on imaging modalities to improve patient selection for VR, surgical techniques, postoperative management and standardization of the pathological assessment.
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http://dx.doi.org/10.1016/j.hpb.2020.04.015DOI Listing
January 2021

Treatment and Survival of Elderly Patients with Stage I-II Pancreatic Cancer: A Report of the EURECCA Pancreas Consortium.

Ann Surg Oncol 2020 Dec 9;27(13):5337-5346. Epub 2020 May 9.

Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.

Background: Elderly patients with pancreatic cancer are underrepresented in clinical trials, resulting in a lack of evidence.

Objective: The aim of this study was to compare treatment and overall survival (OS) of patients aged ≥ 70 years with stage I-II pancreatic cancer in the EURECCA Pancreas Consortium.

Methods: This was an observational cohort study of the Belgian (BE), Dutch (NL), and Norwegian (NOR) cancer registries. The primary outcome was OS, while secondary outcomes were resection, 90-day mortality after resection, and (neo)adjuvant and palliative chemotherapy.

Results: In total, 3624 patients were included. Resection (BE: 50.2%; NL: 36.2%; NOR: 41.3%; p < 0.001), use of (neo)adjuvant chemotherapy (BE: 55.9%; NL: 41.9%; NOR: 13.8%; p < 0.001), palliative chemotherapy (BE: 39.5%; NL: 6.0%; NOR: 15.7%; p < 0.001), and 90-day mortality differed (BE: 11.7%; NL: 8.0%; NOR: 5.2%; p < 0.001). Furthermore, median OS in patients with (BE: 17.4; NL: 15.9; NOR: 25.4 months; p < 0.001) and without resection (BE: 7.0; NL: 3.9; NOR: 6.5 months; p < 0.001) also differed.

Conclusions: Differences were observed in treatment and OS in patients aged ≥ 70 years with stage I-II pancreatic cancer, between the population-based cancer registries. Future studies should focus on selection criteria for (non)surgical treatment in older patients so that clinicians can tailor treatment.
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http://dx.doi.org/10.1245/s10434-020-08539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669775PMC
December 2020

Care after pancreatic resection according to an algorithm for early detection and minimally invasive management of pancreatic fistula versus current practice (PORSCH-trial): design and rationale of a nationwide stepped-wedge cluster-randomized trial.

Trials 2020 May 7;21(1):389. Epub 2020 May 7.

Department of Surgery, Regional Academic Cancer Center Utrecht, St. Antonius Hospital and University Medical Center Utrecht, PO Box 85500, Utrecht, 3508, GA, The Netherlands.

Background: Pancreatic resection is a major abdominal operation with 50% risk of postoperative complications. A common complication is pancreatic fistula, which may have severe clinical consequences such as postoperative bleeding, organ failure and death. The objective of this study is to investigate whether implementation of an algorithm for early detection and minimally invasive management of pancreatic fistula may improve outcomes after pancreatic resection.

Methods: This is a nationwide stepped-wedge, cluster-randomized, superiority trial, designed in adherence to the Consolidated Standards of Reporting Trials (CONSORT) guidelines. During a period of 22 months, all Dutch centers performing pancreatic surgery will cross over in a randomized order from current practice to best practice according to the algorithm. This evidence-based and consensus-based algorithm will provide daily multilevel advice on the management of patients after pancreatic resection (i.e. indication for abdominal imaging, antibiotic treatment, percutaneous drainage and removal of abdominal drains). The algorithm is designed to aid early detection and minimally invasive step-up management of postoperative pancreatic fistula. Outcomes of current practice will be compared with outcomes after implementation of the algorithm. The primary outcome is a composite of major complications (i.e. post-pancreatectomy bleeding, new-onset organ failure and death) and will be measured in a sample size of at least 1600 patients undergoing pancreatic resection. Secondary endpoints include the individual components of the primary endpoint and other clinical outcomes, healthcare resource utilization and costs analysis. Follow up will be up to 90 days after pancreatic resection.

Discussion: It is hypothesized that a structured nationwide implementation of a dedicated algorithm for early detection and minimally invasive step-up management of postoperative pancreatic fistula will reduce the risk of major complications and death after pancreatic resection, as compared to current practice.

Trial Registration: Netherlands Trial Register: NL 6671. Registered on 16 December 2017.
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http://dx.doi.org/10.1186/s13063-020-4167-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206814PMC
May 2020

Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial.

J Clin Oncol 2020 06 27;38(16):1763-1773. Epub 2020 Feb 27.

Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Purpose: Preoperative chemoradiotherapy may improve the radical resection rate for resectable or borderline resectable pancreatic cancer, but the overall benefit is unproven.

Patients And Methods: In this randomized phase III trial in 16 centers, patients with resectable or borderline resectable pancreatic cancer were randomly assigned to receive preoperative chemoradiotherapy, which consisted of 3 courses of gemcitabine, the second combined with 15 × 2.4 Gy radiotherapy, followed by surgery and 4 courses of adjuvant gemcitabine or to immediate surgery and 6 courses of adjuvant gemcitabine. The primary end point was overall survival by intention to treat.

Results: Between April 2013 and July 2017, 246 eligible patients were randomly assigned; 119 were assigned to preoperative chemoradiotherapy and 127 to immediate surgery. Median overall survival by intention to treat was 16.0 months with preoperative chemoradiotherapy and 14.3 months with immediate surgery (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; = .096). The resection rate was 61% and 72% ( = .058). The R0 resection rate was 71% (51 of 72) in patients who received preoperative chemoradiotherapy and 40% (37 of 92) in patients assigned to immediate surgery ( < .001). Preoperative chemoradiotherapy was associated with significantly better disease-free survival and locoregional failure-free interval as well as with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. Survival analysis of patients who underwent tumor resection and started adjuvant chemotherapy showed improved survival with preoperative chemoradiotherapy (35.2 19.8 months; 029). The proportion of patients who suffered serious adverse events was 52% versus 41% (096).

Conclusion: Preoperative chemoradiotherapy for resectable or borderline resectable pancreatic cancer did not show a significant overall survival benefit. Although the outcomes of the secondary end points and predefined subgroup analyses suggest an advantage of the neoadjuvant approach, additional evidence is required.
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http://dx.doi.org/10.1200/JCO.19.02274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265386PMC
June 2020

Conditional Survival After Resection for Pancreatic Cancer: A Population-Based Study and Prediction Model.

Ann Surg Oncol 2020 Jul 12;27(7):2516-2524. Epub 2020 Feb 12.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Conditional survival is the survival probability after already surviving a predefined time period. This may be informative during follow-up, especially when adjusted for tumor characteristics. Such prediction models for patients with resected pancreatic cancer are lacking and therefore conditional survival was assessed and a nomogram predicting 5-year survival at a predefined period after resection of pancreatic cancer was developed.

Methods: This population-based study included patients with resected pancreatic ductal adenocarcinoma from the Netherlands Cancer Registry (2005-2016). Conditional survival was calculated as the median, and the probability of surviving up to 8 years in patients who already survived 0-5 years after resection was calculated using the Kaplan-Meier method. A prediction model was constructed.

Results: Overall, 3082 patients were included, with a median age of 67 years. Median overall survival was 18 months (95% confidence interval 17-18 months), with a 5-year survival of 15%. The 1-year conditional survival (i.e. probability of surviving the next year) increased from 55 to 74 to 86% at 1, 3, and 5 years after surgery, respectively, while the median overall survival increased from 15 to 40 to 64 months at 1, 3, and 5 years after surgery, respectively. The prediction model demonstrated that the probability of achieving 5-year survival at 1 year after surgery varied from 1 to 58% depending on patient and tumor characteristics.

Conclusions: This population-based study showed that 1-year conditional survival was 55% 1 year after resection and 74% 3 years after resection in patients with pancreatic cancer. The prediction model is available via www.pancreascalculator.com to inform patients and caregivers.
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http://dx.doi.org/10.1245/s10434-020-08235-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311496PMC
July 2020

Elevated CEA and CA19-9 serum levels independently predict advanced pancreatic cancer at diagnosis.

Biomarkers 2020 Mar 13;25(2):186-193. Epub 2020 Feb 13.

Department of Surgery, Leiden University Medical Center, Leiden, The Netherlands.

It is suggested that tumour markers carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) could be used to predict the stage of pancreatic cancer. However, optimal cut-off values for CEA and CA19-9 are disputable. This study aimed to assess the value of CEA and CA19-9 serum levels at diagnosis of pancreatic ductal adenocarcinoma (PDAC) as predictors for the advanced stage of PDAC in patients discussed at pancreatic multidisciplinary team (MDT) meetings. Patients with suspected PDAC discussed at MDT meetings from 2013 to 2017 were reviewed, in order to determine optimal cut-off values of both CEA and CA19-9. In total, 375 patients were included. Optimal cut-off values for predicting advanced PDAC were 7.0 ng/ml for CEA and 305.0 U/ml for CA19-9, resulting in positive predictive values of 83.3%, 73.6%, and 91.4% for CEA, CA19-9 and combined, respectively. Both tumour markers were independent predictors of advanced PDAC, demonstrated by an odds ratio of 4.21 (95% CI:1.85-9.56;  = 0.001) for CEA and 2.58 for CA19-9 (95% CI:1.30-5.14;  = 0.007). CEA appears to be a more robust predictor of advanced PDAC than CA19-9. Implementing CEA and CA19-9 serum levels during MDT meetings as an additional tool for establishing tumour resectability is worthwhile for tailored diagnostics.
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http://dx.doi.org/10.1080/1354750X.2020.1725786DOI Listing
March 2020

Efficacy and feasibility of stereotactic radiotherapy after folfirinox in patients with locally advanced pancreatic cancer (LAPC-1 trial).

EClinicalMedicine 2019 Dec 19;17:100200. Epub 2019 Nov 19.

Department of Surgery, Erasmus University Medical Center, Rotterdam, Netherlands.

Background: We conducted a multicentre phase II trial to investigate feasibility and antitumor activity of sequential FOLFIRINOX and Stereotactic Body Radiotherapy (SBRT) in patients with locally advanced pancreatic cancer (LAPC), (LAPC-1 trial).

Methods: Patients with biopsy-proven LAPC treated in four hospitals in the Netherlands between December 2014 and June 2017. Patients received 8 cycles of FOLFIRINOX followed by SBRT (5 fractions/8 Gy) if no tumour progression after the FOLFIRINOX treatment was observed. Primary outcome was 1-year overall survival (OS). Secondary outcomes were median OS, 1-year progression-free survival (PFS), treatment-related toxicity, and resection rate. The study is registered with ClinicalTrials.gov, NCT02292745, and is completed.

Findings: Fifty patients were included. Nineteen (38%) patients did not receive all 8 cycles of FOLFIRINOX, due to toxicity ( = 12), disease progression ( = 6), or patients' preference ( = 1). Thirty-nine (78%) patients received the SBRT treatment. The 1-year OS and PFS were 64% (95% CI: 50%-76%) and 34% (95% CI: 22%-48%), respectively. Thirty grade 3 or 4 adverse events were observed during FOLFIRINOX. Two (5%) grade 3 or 4 adverse events after SBRT were observed. Two (5%) patients died due to a gastro-intestinal bleeding within three months after SBRT were observed. Six (12%) patients underwent a resection, all resulting in a complete (R0) resection. Two patients had a complete pathological response.

Interpretation: FOLFIRINOX followed by SBRT in patients with LAPC is feasible and shows relevant antitumor activity. In 6 (12%) patients a potentially curative resection could be pursued following this combined treatment, with a complete histological response being observed in two patients.
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http://dx.doi.org/10.1016/j.eclinm.2019.10.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933188PMC
December 2019

Nationwide trends in incidence, treatment and survival of pancreatic ductal adenocarcinoma.

Eur J Cancer 2020 01 13;125:83-93. Epub 2019 Dec 13.

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands. Electronic address:

Background: In recent years, new treatment options have become available for pancreatic ductal adenocarcinoma (PDAC) including 5-fluorouracil, leucovorin, irinotecan and oxaliplatin. The impact hereof has not been assessed in nationwide cohort studies. This population-based study aimed to investigate nationwide trends in incidence, treatment and survival of PDAC.

Materials And Methods: Patients with PDAC (1997-2016) were included from the Netherlands Cancer Registry. Results were categorised by treatment and by period of diagnosis (1997-2000, 2001-2004, 2005-2008, 2009-2012 and 2013-2016). Kaplan-Meier survival analysis was used to calculate overall survival.

Results: In a national cohort of 36,453 patients with PDAC, the incidence increased from 12.1 (1997-2000) to 15.3 (2013-2016) per 100,000 (p < 0.001), whereas median overall survival increased from 3.1 to 3.8 months (p < 0.001). Over time, the resection rate doubled (8.3%-16.6%, p-trend<0.001), more patients received adjuvant chemotherapy (3.0%-56.2%, p-trend<0.001) and 3-year overall survival following resection increased (16.9%-25.4%, p < 0.001). Over time, the proportion of patients with metastatic disease who received palliative chemotherapy increased from 5.3% to 16.1% (p-trend<0.001), whereas 1-year survival improved from 13.3% to 21.2% (p < 0.001). The proportion of patients who only received supportive care decreased from 84% to 61% (p-trend<0.001).

Conclusion: The incidence of PDAC increased in the past two decades. Resection rates and use of adjuvant or palliative chemotherapy increased with improved survival in these patients. In all patients with PDAC, however, the survival benefit of 3 weeks is negligible because the majority of patients only received supportive care.
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http://dx.doi.org/10.1016/j.ejca.2019.11.002DOI Listing
January 2020

Screening for colorectal cancer after pancreatoduodenectomy for ampullary cancer.

Eur J Surg Oncol 2020 04 11;46(4 Pt A):534-538. Epub 2019 Oct 11.

Department of Surgery, Reinier de Graaf Gasthuis, Delft, the Netherlands.

Background: In some Dutch pancreatic surgery centers, patients who underwent pancreatoduodenectomy (PD) for ampullary cancer undergo surveillance for colorectal cancer (CRC), since an association is suggested in contemporary literature. This study aimed to examine the CRC incidence after PD for ampullary cancer in four pancreatic surgery centers and a Dutch nationwide cohort.

Methods: All patients who underwent resection of ampullary cancer from 2005 through 2017 at four centers were included. All colonoscopies and CRC diagnoses in these patients were recorded. In addition all PDs for ampullary cancer in the Dutch Pathology Registry (2000-2017) were recorded along with the CRC diagnoses and compared with an age, sex, and year-matched cohort.

Results: Out of 287 included patients by the four centers, 11% underwent a colonoscopy within one year after PD. Eight (2.7%) were diagnosed with CRC before PD and two (0.7%), at 14 and 72 months after PD. In the nationwide cohort comparison, the CRC incidence was similar before (2.6% versus 1.9%, P = 0.424) and after surgery (2.1% versus 3.1%, P = 0.237). Within one year after PD, the incidence was 0.3% compared to 0.6% in the matched controls (P = 0.726).

Conclusions: The current study could not find an increased risk of CRC in patients with resected ampullary cancer. Therefore, there is insufficient justification to screen for CRC in patients with resected ampullary cancer.
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http://dx.doi.org/10.1016/j.ejso.2019.10.013DOI Listing
April 2020

The risk of not receiving adjuvant chemotherapy after resection of pancreatic ductal adenocarcinoma: a nationwide analysis.

HPB (Oxford) 2020 02 19;22(2):233-240. Epub 2019 Aug 19.

Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, the Netherlands. Electronic address:

Background: The relation between type of postoperative complication and not receiving chemotherapy after resection of pancreatic ductal adenocarcinoma (PDAC) is unclear. The aim was to investigate which patient factors and postoperative complications were associated with not receiving adjuvant chemotherapy.

Methods: Patients who underwent resection (2014-2017) for PDAC were identified from the nationwide mandatory Dutch Pancreatic Cancer Audit. The association between patient-, tumor-, center-, treatment characteristics, and the risk of not receiving adjuvant chemotherapy was analyzed with multivariable logistic regression.

Results: Overall, of 1306 patients, 24% (n = 312) developed postoperative Clavien Dindo ≥3 complications. In-hospital mortality was 3.5% (n = 46). Some 433 patients (33%) did not receive adjuvant chemotherapy. Independent predictors (all p < 0.050) for not receiving adjuvant chemotherapy were older age (odds ratio (OR) 0.96), higher ECOG performance status (OR 0.57), postoperative complications (OR 0.32), especially grade B/C pancreatic fistula (OR 0.51) and post-pancreatectomy hemorrhage (OR 0.36), poor tumor differentiation grade (OR 0.62), and annual center volume of <40 pancreatoduodenectomies (OR 0.51).

Conclusions: This study demonstrated that a third of patients do not receive chemotherapy after resection of PDAC. Next to higher age, worse performance status and lower annual surgical volume, this is mostly related to surgical complications, especially postoperative pancreatic fistula and post-pancreatectomy hemorrhage.
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http://dx.doi.org/10.1016/j.hpb.2019.06.019DOI Listing
February 2020

Optimizing the timing of colorectal surgery in patients with familial adenomatous polyposis in clinical practice.

Scand J Gastroenterol 2019 Jun 11;54(6):733-739. Epub 2019 Aug 11.

Department of Gastroenterology & Hepatology, Leiden University Medical Centre , Leiden , The Netherlands.

Familial adenomatous polyposis (FAP) is characterized by the development of hundreds of colorectal adenomas in the second decade of life, and prophylactic colectomy is usually performed around age of 20. A common question is the appropriate timing of surgery and which endoscopic findings indicate surgery. All FAP patients known at Leiden University Medical Centre from 1985 onwards were included. The patients were then subdivided into those diagnosed before or after 2000. Patient information included age at diagnosis, colonic phenotype, age at surgery, pathological findings and the outcome of follow-up colonoscopies in whom surgery was postponed. The 72 FAP patients identified consisted of 33 patients diagnosed before (group A) and 39 after (group B) 2000. The median age at diagnosis for patients with classical FAP was 18 in groups A and B. All patients diagnosed before 2000 underwent colorectal surgery versus 68% of those diagnosed >2000. The median age at surgery for classical FAP patients was 19 and 24 years in groups A and B, respectively. In patients with intact colon, the number of adenomas gradually increased over many years. Although most adenomas remained <5 mm, the proportion of 5-15 mm adenomas slowly increased. Only one patient developed a high-grade adenoma. None of the patients developed CRC. Surgery today in FAP is performed less often and at a more advanced age. Our experience also suggests that surgery can be safely postponed in selected patients. The most important endoscopic indication for surgery is substantial number of large adenomas of >5-10 mm.
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http://dx.doi.org/10.1080/00365521.2019.1621930DOI Listing
June 2019

Intraoperative detection of the remnant cystic duct during robot-assisted surgery using near-infrared fluorescence imaging: a case report.

BMC Surg 2019 Aug 7;19(1):104. Epub 2019 Aug 7.

Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2300 RC, Leiden, The Netherlands.

Background: Post cholecystectomy syndrome is characterized as recurrence of symptoms as experienced before cholecystectomy. In rare cases, a remnant cystic duct is causing these symptoms and occasionally surgical resection is performed. During surgery, visualization of the biliary ducts could be difficult due to inflammation and dense adhesions.

Case Presentation: In this article, we presented a 36-year old woman with post-cholecystectomy syndrome in which we evaluated the feasibility of near-infrared (NIR) fluorescence imaging using indocyanine green (ICG) for visualization of the remnant cystic and common bile duct during robot-assisted surgery. Intraoperative visualization of the remnant biliary duct and other important structures was feasible, and resection of the remnant cystic duct was successfully performed under fluorescence guidance, without any complications.

Conclusions: NIR fluorescence imaging of the biliary ducts using ICG does not prolong the operating time, and could potentially decrease the operation time in difficult procedures, because of easy and fast detection of the biliary tract. Furthermore, it is a non-hazardous and non-invasive technique, as it does not require use of radiation and cannot cause bile duct injury. This case illustrated that ICG NIR fluorescence imaging during difficult robot-assisted surgical procedures of the bile ducts is effective and therefore highly recommended.
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http://dx.doi.org/10.1186/s12893-019-0567-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686477PMC
August 2019
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