Publications by authors named "Geert Roeyen"

25 Publications

  • Page 1 of 1

Novel combination immunotherapy for pancreatic cancer: potent anti-tumor effects with CD40 agonist and interleukin-15 treatment.

Clin Transl Immunology 2020 15;9(8):e1165. Epub 2020 Aug 15.

Center for Oncological Research (CORE) Integrated Personalized & Precision Oncology Network (IPPON) University of Antwerp Wilrijk Belgium.

Objectives: With the poorest 5-year survival of all cancers, improving treatment for pancreatic cancer is one of the biggest challenges in cancer research. We sought to explore the potential of combining both priming and activation of the immune system. To achieve this, we combined a CD40 agonist with interleukin-15 and tested its potential in pancreatic cancer.

Methods: Response to this combination regimen was assessed in pancreatic ductal adenocarcinoma mouse models, and a thorough analysis of the tumor microenvironment was performed.

Results: We demonstrated profound reduction in tumor growth and increased survival of mice with the majority of mice being cured when both agents were combined, including an unprecedented 8-fold dose reduction of CD40 agonist without losing any efficacy. RNAseq analysis showed involvement of natural killer (NK) cell- and T-cell-mediated anti-tumor responses and the importance of antigen-presenting cell pathways. This combination resulted in enhanced infiltration of tumors by both T cells and NK cells, as well as a striking increase in the ratio of CD8 T cells over Tregs. We also observed a significant increase in numbers of dendritic cells (DCs) in tumor-draining lymph nodes, particularly CD103 DCs with cross-presentation potential. A critical role for CD8 T cells and involvement of NK cells in the anti-tumor effect was highlighted. Importantly, strong immune memory was established, with an increase in memory CD8 T cells only when both interleukin-15 and the CD40 agonist were combined.

Conclusion: These novel preclinical data support initiation of a first-in-human clinical trial with this combination immunotherapy strategy in pancreatic cancer.
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http://dx.doi.org/10.1002/cti2.1165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428816PMC
August 2020

"Does Perioperative Patient Perfusion Obviate the Need for Kidney Machine Perfusion?" A Retrospective Analysis of Patients Receiving a Kidney From "Donation After Circulatory Death" Donors.

Transplant Proc 2020 Dec 24;52(10):2923-2929. Epub 2020 Jun 24.

Department of Nephrology, Antwerp University Hospital, Edegem, Belgium.

Background: Delayed graft function (DGF) remains a clinically relevant problem in the post-transplant period, especially in patients with a renal graft from a "donation after cardiac death" (DCD) donor. Controversy exists around the optimal perioperative fluid therapy in such patients. These patients may benefit from a perioperative saline loading fluid protocol, which may reduce the risk of DGF.

Methods: We compared 2 cohorts of patients who underwent a renal transplantation with a graft from a DCD donor. From January 2003 until December 2012, patients (N = 46) were hemodynamically managed at the discretion of the care-giving physician, without a preoperative fluid administration protocol (first study period). From January 2015 until March 2019 (N = 26), patients received saline loading before, during, and after kidney transplantation according to a well-defined saline loading fluid protocol (second study period). The relationship between the use of this perioperative fluid protocol and DGF was analyzed using univariable and multivariable logistic regression models.

Results: DGF occurred in 11 of 46 (24%) patients in the first study period and in 1 of 26 (4%) in the second study period (P < .05). In a multivariable model, correcting for cold ischemia time and Kidney Donor Risk Index, the use of a saline loading fluid protocol in the perioperative phase was nearly significantly associated with a decrease in DGF (P = .07).

Conclusion: In our DCD transplant population, DGF rates were low. Our data further strongly suggest that implementation of a perioperative saline loading fluid protocol was independently associated with a lower risk of DGF.
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http://dx.doi.org/10.1016/j.transproceed.2020.05.018DOI Listing
December 2020

DNA Methylation Distinguishes Two Subtypes of Pancreatic Neuroendocrine Neoplasms with a Different Prognosis.

Cancers (Basel) 2020 Jun 4;12(6). Epub 2020 Jun 4.

Center for Oncological Research, University of Antwerp and Antwerp University Hospital, 2610 Antwerp, Belgium.

DNA methylation is a crucial epigenetic mechanism for gene expression regulation and cell differentiation. Furthermore, it was found to play a major role in multiple pathological processes, including cancer. In pancreatic neuroendocrine neoplasms (PNENs), epigenetic deregulation is also considered to be of significance, as the most frequently mutated genes have an important function in epigenetic regulation. However, the exact changes in DNA methylation between PNENs and the endocrine cells of the pancreas, their likely cell-of-origin, remain largely unknown. Recently, two subtypes of PNENs have been described which were linked to cell-of-origin and have a different prognosis. A difference in the expression of the transcription factor PDX1 was one of the key molecular differences. In this study, we performed an exploratory genome-wide DNA methylation analysis using Infinium Methylation EPIC arrays (Illumina) on 26 PNENs and pancreatic islets of five healthy donors. In addition, the methylation profile of the region was used to perform subtyping in a global cohort of 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples. In our exploratory analysis, we identified 26,759 differentially methylated CpGs and 79 differentially methylated regions. The gene set enrichment analysis highlighted several interesting pathways targeted by altered DNA methylation, including MAPK, platelet-related and immune system-related pathways. Using the methylation in 83 PNEN, 2 healthy alpha cell and 3 healthy beta cell samples, two subtypes were identified, subtypes A and B, which were similar to alpha and beta cells, respectively. These subtypes had different clinicopathological characteristics, a different pattern of chromosomal alterations and a different prognosis, with subtype A having a significantly worse prognosis compared with subtype B (HR 0.22 [95% CI: 0.051-0.95], = 0.043). Hence, this study demonstrates that several cancer-related pathways are differently methylated between PNENs and normal islet cells. In addition, we validated the use of the methylation status for the subtyping of PNENs and its prognostic importance.
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http://dx.doi.org/10.3390/cancers12061461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352978PMC
June 2020

The art of obtaining a high yield of cell-free DNA from urine.

PLoS One 2020 6;15(4):e0231058. Epub 2020 Apr 6.

Center for Oncological Research Antwerp (CORE), University of Antwerp (UA), Wilrijk, Belgium.

Although liquid biopsies offer many advantages over tissue biopsies, they are not yet standard practice. An important reason for the lack of implementation is the unavailability of well standardized techniques and guidelines, especially for pre-analytical conditions which are an important factor causing the current sensitivity issues. To overcome these limitations, we investigated the effect of several pre-analytical conditions on the concentration of cell-free DNA (cfDNA) and cellular genomic DNA (gDNA) contamination. Urine samples from healthy volunteers (HVs) and cancer patients were collected and processed according to specific pre-analytical conditions. Our results show that in samples with a relatively small volume more than 50% of the cfDNA can be found in the first 50 mL of the urine sample. The total DNA concentration increased again when samples were collected more than 3.5 hours apart. Adding preservative to urine samples is recommended to obtain high concentrations of cfDNA. To remove the cellular content, high speed centrifugation protocols as 4,000g 10min or 3,000g 15min are ideal for urine collected in cfDNA Urine Preserve (Streck). Although this study was a pilot study and needs to be confirmed in a larger study population, clear trends in the effect of several pre-analytical conditions were observed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0231058PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135229PMC
July 2020

Specialized Blood Collection Tubes for Liquid Biopsy: Improving the Pre-analytical Conditions.

Mol Diagn Ther 2020 02;24(1):113-124

Center for Oncological Research (CORE) Antwerp, University of Antwerp (UAntwerp), Universiteitsplein 1, 2610, Wilrijk, Belgium.

Introduction: The potential of circulating cell-free DNA (cfDNA) analysis as a liquid biopsy has led to the development of several specialized measuring tools. Interest in the (pre-)analytical conditions of the liquid biopsy workflow has increased over the past few years.

Methods: In this study, we performed a systematic review of the cfDNA stabilizing efficacy in standard EDTA and specialized blood collection tubes (BCTs), namely CellSave, Norgen, PAXgene, Roche, and Streck tubes, and compared the efficacy of the latter three BCTs in a situation resembling the clinical setting. Blood samples were collected from ten KRAS-mutated metastatic cancer patients and stored for 72 h. During this time, samples were shaken and kept at either 6 °C or at room temperature for 24 h to mimic transport.

Results: We demonstrated that while cfDNA levels in EDTA tubes are only stable for a couple of (≤ 6) hours, they could be sustained for at least 48-72 h in all three specialized BCTs, irrespective of temperature. This timespan enables a fast turnaround time, which is one of the advantages of liquid biopsy.

Conclusions: The choice between these specialized BCTs is less vital when they are processed correctly within a few days.
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http://dx.doi.org/10.1007/s40291-019-00442-wDOI Listing
February 2020

Circulating Cell-Free DNA and RNA Analysis as Liquid Biopsy: Optimal Centrifugation Protocol.

Cancers (Basel) 2019 Mar 30;11(4). Epub 2019 Mar 30.

Center for Oncological Research Antwerp (CORE), University of Antwerp (UAntwerp), 2610 Wilrijk, Belgium.

The combined analysis of circulating cell-free (tumor) DNA (cfDNA/ctDNA) and circulating cell-free (tumor) RNA (cfRNA/ctRNA) shows great promise in determining the molecular profile of cancer patients. Optimization of the workflow is necessary to achieve consistent and reproducible results. In this study, we compared five centrifugation protocols for the optimal yield of both cfDNA/ctDNA and cfRNA/ctRNA. These protocols varied in centrifugation speed, ambient temperature, time, and number of centrifugation steps. Samples from 33 participants were collected in either BD Vacutainer K₂EDTA (EDTA) tubes or cell-free DNA BCT (Streck) tubes. cfDNA concentration and fragment size, and cfRNA concentration were quantitated in all samples by digital droplet PCR (ddPCR) and quantitative PCR (qPCR). The -mutated ctDNA and ctRNA fraction was determined via ddPCR. In EDTA tubes, the protocol generating both plasma and platelets was found to produce high quality cfDNA and cfRNA concentrations. Two-step, high-speed centrifugation protocols were associated with high cfDNA but low cfRNA concentrations. High cfRNA concentrations were generated by a one-step, low-speed protocol. However, this coincided with a high amount of genomic DNA (gDNA) contamination. In Streck tubes, two-step, high-speed centrifugation protocols also generated good quality, high cfDNA concentration. However, these tubes are not compatible with cfRNA analysis.
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http://dx.doi.org/10.3390/cancers11040458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521186PMC
March 2019

Cell-Free DNA From Metastatic Pancreatic Neuroendocrine Tumor Patients Contains Tumor-Specific Mutations and Copy Number Variations.

Front Oncol 2018 1;8:467. Epub 2018 Nov 1.

Center for Oncological Research, University of Antwerp, Antwerp, Belgium.

Detection of tumor-specific alterations in cell-free DNA (cfDNA) has proven valuable as a liquid biopsy for several types of cancer. So far, use of cfDNA remains unexplored for pancreatic neuroendocrine tumor (PNET) patients. From 10 PNET patients, fresh frozen tumor tissue, buffy coat and plasma samples were collected. Whole-exome sequencing of primary tumor and germline DNA was performed to identify tumor-specific variants and copy number variations (CNVs). Subsequently, tumor-specific variants were quantified in plasma cfDNA with droplet digital PCR. In addition, CNV analysis of cfDNA was performed using shallow whole-genome sequencing. Tumor-specific variants were detected in perioperative plasma samples of two PNET patients, at variant allele fractions (VAFs) of respectively 19 and 21%. Both patients had metastatic disease at time of surgery, while the other patients presented with localized disease. In the metastatic patients, CNV profiles of tumor tissue and cfDNA were significantly correlated. A follow-up plasma sample of a metastatic patient demonstrated an increased VAF (57%) and an increased chromosomal instability, in parallel with an increase in tumor burden. We are the first to report the presence of tumor-specific genetic alterations in cfDNA of metastatic PNET patients and their evolution during disease progression. Additionally, CNV analysis in cfDNA shows potential as a liquid biopsy.
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http://dx.doi.org/10.3389/fonc.2018.00467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6221938PMC
November 2018

Pancreaticopleural fistula: a rare cause of pleural empyema.

Acta Chir Belg 2019 Dec 2;119(6):396-399. Epub 2018 May 2.

Department of Hepatobiliary, Transplantation and Endocrine Surgery, University Hospital Antwerp , Antwerp , Belgium.

Pancreaticopleural fistula (PPF) is a rare complication of acute or chronic pancreatitis. When the pancreatic duct disrupts, pancreatic fluid may leak into the retroperitoneum and fistulate into the pleural cavity. Patients usually present with thoracic complaints, making it hard to suspect an abdominal etiology. Although PPF is uncommon, one must consider this diagnosis in patients with thoracic complaints and a history of alcohol abuse or pancreatitis. We present an illustrative case and review of the literature on PPF. A 47-year old man was presented with recurrent PPF due to pancreas divisum, pancreatic stones and chronic exudative pancreatitis, resulting in unilateral empyema. After initial conservative treatment, operative measures were needed. We report omentoplasty against the diaphragmatic hiatus in combination with VATS (video-assisted thoracoscopic surgery) thoracotomy with decortication and debridement as a feasible operative option for resolving PPF. PPF is a rare complication of pancreatitis. The diagnosis is difficult to make and can be confirmed by thoracocentesis and proper imaging, preferably MRCP. Treatment options include conservative, endoscopic (ERCP) or surgical measures. Omentoplasty positioned against the diaphragmatic hiatus is a feasible technique for closure of PPF.
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http://dx.doi.org/10.1080/00015458.2018.1470293DOI Listing
December 2019

Natural killer cells and their therapeutic role in pancreatic cancer: A systematic review.

Pharmacol Ther 2018 09 13;189:31-44. Epub 2018 Apr 13.

Center for Oncological Research, University of Antwerp, Antwerp, Belgium; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, Antwerp, Belgium.

Pancreatic cancer is among the three deadliest cancers worldwide with the lowest 5-year survival of all cancers. Despite all efforts, therapeutic improvements have barely been made over the last decade. Even recent highly promising targeted and immunotherapeutic approaches did not live up to their expectations. Therefore, other horizons have to be explored. Natural Killer (NK) cells are gaining more and more interest as a highly attractive target for cancer immunotherapies, both as pharmaceutical target and for cell therapies. In this systematic review we summarise the pathophysiological adaptions of NK cells in pancreatic cancer and highlight possible (future) therapeutic NK cell-related targets. Furthermore, an extensive overview of recent therapeutic approaches with an effect on NK cells is given, including cytokine-based, viro- and bacteriotherapy and cell therapy. We also discuss ongoing clinical trials that might influence NK cells. In conclusion, although several issues regarding NK cells in pancreatic cancer remain unsolved and need further investigation, extensive evidence is already provided that support NK cell oriented approaches in pancreatic cancer.
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http://dx.doi.org/10.1016/j.pharmthera.2018.04.003DOI Listing
September 2018

Outcomes After Distal Pancreatectomy with Celiac Axis Resection for Pancreatic Cancer: A Pan-European Retrospective Cohort Study.

Ann Surg Oncol 2018 May 12;25(5):1440-1447. Epub 2018 Mar 12.

Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, Amsterdam, the Netherlands.

Background: Western multicenter studies on distal pancreatectomy with celiac axis resection (DP-CAR), also known as the Appleby procedure, for locally advanced pancreatic cancer are lacking. We aimed to study overall survival, morbidity, mortality and the impact of preoperative hepatic artery embolization (PHAE).

Methods: Retrospective cohort study within the European-African Hepato-Pancreato-Biliary-Association, on DP-CAR between 1-1-2000 and 6-1-2016. Primary endpoint was overall survival. Secondary endpoints were radicality (R0-resection), 90-day mortality, major morbidity, and pancreatic fistulae (grade B/C).

Results: We included 68 patients from 20 hospitals in 12 countries. Postoperatively, 53% of patients had R0-resection, 25% major morbidity, 21% an ISGPS grade B/C pancreatic fistula, and 16% mortality. In total, 82% received (neo-)adjuvant chemotherapy and median overall survival in 62 patients with pancreatic ductal adenocarcinoma patients was 18 months (CI 10-37). We observed no impact of PHAE on ischemic complications.

Conclusions: DP-CAR combined with chemotherapy for locally advanced pancreatic cancer is associated with acceptable overall survival. The 90-day mortality is too high and should be reduced. Future studies should investigate to what extent increasing surgical volume or better patient selection can improve outcomes.
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http://dx.doi.org/10.1245/s10434-018-6391-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5891548PMC
May 2018

Prediction of delayed graft function using different scoring algorithms: A single-center experience.

World J Transplant 2017 Oct;7(5):260-268

Department of Nephrology-Hypertension, Antwerp University Hospital, B-2650 Edegem, Belgium.

Aim: To compare the performance of 3 published delayed graft function (DGF) calculators that compute the theoretical risk of DGF for each patient.

Methods: This single-center, retrospective study included 247 consecutive kidney transplants from a deceased donor. These kidney transplantations were performed at our institution between January 2003 and December 2012. We compared the occurrence of observed DGF in our cohort with the predicted DGF according to three different published calculators. The accuracy of the calculators was evaluated by means of the c-index (receiver operating characteristic curve).

Results: DGF occurred in 15.3% of the transplants under study. The c index of the Irish calculator provided an area under the curve (AUC) of 0.69 indicating an acceptable level of prediction, in contrast to the poor performance of the Jeldres nomogram (AUC = 0.54) and the Chapal nomogram (AUC = 0.51). With the Irish algorithm the predicted DGF risk and the observed DGF probabilities were close. The mean calculated DGF risk was significantly different between DGF-positive and DGF-negative subjects ( < 0.0001). However, at the level of the individual patient the calculated risk of DGF overlapped very widely with ranges from 10% to 51% for recipients with DGF and from 4% to 56% for those without DGF. The sensitivity, specificity and positive predictive value of a calculated DGF risk ≥ 30% with the Irish nomogram were 32%, 91% and 38%.

Conclusion: Predictive models for DGF after kidney transplantation are performant in the population in which they were derived, but less so in external validations.
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http://dx.doi.org/10.5500/wjt.v7.i5.260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661123PMC
October 2017

A plea for more practical and clinically applicable criteria defining type 3c diabetes.

Pancreatology 2017 Nov - Dec;17(6):875. Epub 2017 Oct 14.

Department of Endocrinology, Diabetology and Metabolic Diseases, Antwerp University Hospital, Belgium.

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http://dx.doi.org/10.1016/j.pan.2017.10.004DOI Listing
August 2018

Does Kidney Donor Risk Index implementation lead to the transplantation of more and higher-quality donor kidneys?

Nephrol Dial Transplant 2017 Nov;32(11):1934-1938

Department of Hypertension-Nephrology, Antwerp University Hospital, Antwerp, Belgium.

Background: The Kidney Donor Risk Index (KDRI) is a quantitative evaluation of the quality of donor organs and is implemented in the US allocation system. This single-centre study investigates whether the implementation of the KDRI in our decision-making process to accept or decline an offered deceased donor kidney, increases our acceptance rate.

Methods: From April 2015 until December 2016, we prospectively calculated the KDRI for all deceased donor kidney offers allocated by Eurotransplant to our centre. The number of the transplanted versus declined kidney offers during the study period were compared to a historical set of donor kidney offers.

Results: After implementation of the KDRI, 26.1% (75/288) of all offered donor kidneys were transplanted, compared with 20.7% (136/657) in the previous period (P < 0.001). The median KDRI of all transplanted donor kidneys during the second period was 0.97 [Kidney Donor Profile Index (KDPI) 47%], a value significantly higher than the median KDRI of 0.85 (KDPI 34%) during the first period (P = 0.047). A total of 68% of patients for whom a first-offered donor kidney was declined during this period were transplanted after a median waiting time of 386 days, mostly with a lower KDRI donor kidney.

Conclusions: Implementing the KDRI in our decision-making process increased the transplantation rate by 26%. The KDRI can be a supportive tool when considering whether to accept or decline a deceased donor kidney offer. More data are needed to validate this score in other European centres.
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http://dx.doi.org/10.1093/ndt/gfx257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837419PMC
November 2017

The impact of pancreaticoduodenectomy on endocrine and exocrine pancreatic function: A prospective cohort study based on pre- and postoperative function tests.

Pancreatology 2017 Nov - Dec;17(6):974-982. Epub 2017 Sep 9.

Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Belgium.

Background/objectives: Studies reporting on function after pancreatic surgery are frequently based on diabetes history, fasting glycemia or random glycemia. The aim of this study was to investigate prospectively the evolution of pancreatic function in patients undergoing pancreaticoduodenectomy based on proper pre- and postoperative function tests. It was hypothesised that pancreatic function deteriorates after pancreaticoduodenectomy.

Methods: Between 2013 and 2016, 78 patients undergoing pancreaticoduodenectomy for oncologic indications had a prospective evaluation of their endocrine and exocrine pancreatic function. Endocrine function was evaluated with the 75 g oral glucose tolerance test (OGTT) and the 1 mg intravenous glucagon test. Exocrine function was evaluated with a 13C-labelled mixed-triglyceride breath test. Tests were performed pre- and postoperatively.

Results: In 90.5% (19/21) of patients with preoperatively known diabetes, no change in endocrine function was observed. In contrast, endocrine function improved in 68.1% (15/22) of patients with newly diagnosed diabetes. 40% (14/35) of patients with a preoperative normal OGTT or prediabetes experienced deterioration in function. In multivariate analysis, improvement of newly diagnosed diabetes was correlated with preoperative bilirubin levels (p = 0.045), while progression towards diabetes was correlated with preoperative C-peptidogenic index T (p = 0.037). A total of 20.5% (16/78) of patients had pancreatic exocrine insufficiency preoperatively. Another 51.3% (40/78) of patients deteriorated on exocrine level. In total, 64.1% (50/78) of patients required pancreatic enzyme-replacement therapy postoperatively.

Conclusions: Although deterioration of endocrine function was expected after pancreatic resection, improvement is frequently observed in patients with newly diagnosed diabetes. Exocrine function deteriorates after pancreaticoduodenectomy.
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http://dx.doi.org/10.1016/j.pan.2017.09.004DOI Listing
July 2018

Interleukin-15 stimulates natural killer cell-mediated killing of both human pancreatic cancer and stellate cells.

Oncotarget 2017 Aug 25;8(34):56968-56979. Epub 2017 May 25.

Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.

Pancreatic ductal adenocarcinoma (PDAC) is the 4 leading cause of cancer-related death in Western countries with a 5-year survival rate below 5%. One of the hallmarks of this cancer is the strong desmoplastic reaction within the tumor microenvironment (TME), orchestrated by activated pancreatic stellate cells (PSC). This results in a functional and mechanical shield which causes resistance to conventional therapies. Aiming to overcome this resistance by tackling the stromal shield, we assessed for the first time the capacity of IL-15 stimulated natural killer (NK) cells to kill PSC and pancreatic cancer cells (PCC). The potency of IL-15 to promote NK cell-mediated killing was evaluated phenotypically and functionally. In addition, NK cell and immune checkpoint ligands on PSC were charted. We demonstrate that IL-15 activated NK cells kill both PCC and PSC lines (range 9-35% and 20-50%, respectively) in a contact-dependent manner and significantly higher as compared to resting NK cells. Improved killing of these pancreatic cell lines is, at least partly, dependent on IL-15 induced upregulation of TIM-3 and NKG2D. Furthermore, we confirm significant killing of primary PSC by IL-15 activated NK cells in an autologous system. Screening for potential targets for immunotherapeutic strategies, we demonstrate surface expression of both inhibitory (PD-L1, PD-L2) and activating (MICA/B, ULBPs and Galectin-9) ligands on primary PSC. These data underscore the therapeutic potential of IL-15 to promote NK cell-mediated cytotoxicity as a treatment of pancreatic cancer and provide promising future targets to tackle remaining PSC.
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http://dx.doi.org/10.18632/oncotarget.18185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593617PMC
August 2017

Measuring future liver remnant function prior to hepatectomy may guide the indication for portal vein occlusion and avoid posthepatectomy liver failure: a prospective interventional study.

HPB (Oxford) 2017 02 9;19(2):108-117. Epub 2016 Dec 9.

Hepatobiliary, Endocrine and Transplantation Surgery, Antwerp University Hospital, Edegem, Belgium.

Background: Estimation of the future liver remnant function (eFLRF) can avoid post-hepatectomy liver failure (PHLF). In a previous study, a cutoff value of 2.3%/min/m for eFLRF was a better predictor of PHLF than future liver remnant volume (FLRV%). In this prospective interventional study, investigating a management strategy aimed at avoiding PHLF, this cutoff value was the sole criterion assessing eligibility for hepatectomy, with or without portal vein occlusion (PVO).

Methods: In 100 consecutive patients, eFLRF was determined using the formula: eFLRF = FLRV% × total liver function (TLF). Group 1 (eFLRF >2.3%/min/m) underwent hepatectomy without preoperative intervention. Group 2 (eFLRF <2.3%/min/m) underwent PVO and re-evaluation of eFLRF at 4-6 weeks. Hepatectomy was performed if eFLRF had increased to >2.3%/min/m, but was considered contraindicated if the value remained lower.

Results: In group 1 (n = 93), 1 patient developed grade B PHLF. In group 2 (n = 7) no PHLF was recorded. Postoperative recovery of TLF in patients with preoperative eFLRF <2.3%/min/m occurred more rapidly when PVO had been performed.

Conclusion: A predefined cutoff for preoperatively calculated eFLRF can be used as a tool for selecting patients prior to hepatectomy, with or without PVO, thus avoiding PHLF and PHLF-related mortality.
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http://dx.doi.org/10.1016/j.hpb.2016.11.005DOI Listing
February 2017

A Comparison of Cell-Free DNA Isolation Kits: Isolation and Quantification of Cell-Free DNA in Plasma.

J Mol Diagn 2017 01 17;19(1):162-168. Epub 2016 Nov 17.

Center for Oncological Research, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium; Department of Pathology, Antwerp University Hospital, Edegem, Belgium. Electronic address:

The analysis of cell-free DNA (cfDNA) as a sensitive biomarker for cancer diagnosis and monitoring has resulted in a need for efficient and standardized cfDNA isolation. In this study, we compared the isolation efficiency of the QIAamp circulating nucleic acid kit (QIA) with four other cfDNA isolation kits: the PME free-circulating DNA Extraction Kit (PME), the Maxwell RSC ccfDNA Plasma Kit (RSC), the EpiQuick Circulating Cell-Free DNA Isolation Kit (EQ), and two consecutive versions of the NEXTprep-Mag cfDNA Isolation Kit (NpM). cfDNA was isolated from 10 plasma samples, of which five contained KRAS mutated cell-free tumor DNA (ctDNA). Digital droplet PCR was used to quantify the total cfDNA concentration as well as the KRAS mutated ctDNA fraction. cfDNA integrity was assessed with real-time quantitative PCR. The QIA and the RSC kits displayed similar isolation efficiencies of both KRAS mutated ctDNA and nonmutated cfDNA, whereas the yield generated by the PME and NpM kits was significantly lower. Real-time quantitative PCR indicated the presence of digital droplet PCR inhibiting agents in the eluates of the NpM and EQ kits. To conclude, this study presents two highly efficient isolation kits for cfDNA isolation, of which the RSC kit has the advantage of a fully automated protocol over the labor-intensive QIA kit.
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http://dx.doi.org/10.1016/j.jmoldx.2016.09.009DOI Listing
January 2017

Pancreatic exocrine insufficiency after pancreaticoduodenectomy is more prevalent with pancreaticogastrostomy than with pancreaticojejunostomy. A retrospective multicentre observational cohort study.

HPB (Oxford) 2016 12 7;18(12):1017-1022. Epub 2016 Oct 7.

Department of General, Hepatobiliary and Liver Transplantation Surgery, Ghent University Hospital, Belgium.

Objective: Recently, pancreaticogastrostomy (PG) has attracted renewed interest as a reconstruction technique after pancreaticoduodenectomy (PD), as it may imply a lower risk of clinical pancreatic fistula than reconstruction by pancreaticojejunostomy (PJ). We hypothesise that pancreatic exocrine insufficiency (PEI) is more common during clinical follow-up after PG than it is after PJ.

Research Design And Methods: This study compares the prevalence of PEI in patients undergoing PD for malignancy with reconstruction by PG versus reconstruction by PJ. PEI during the first year of follow-up was defined as the intake of pancreatic enzyme replacement therapy (PERT) within one year postoperatively and/or an abnormal exocrine function test.

Results: A total of 186 patients, having undergone surgery at two university hospitals, were included in the study. PEI during the first year postoperatively was present in 75.0% of the patients with PG, compared to 45.7% with PJ (p < 0.001). Intake of PERT within one year after surgery was found to be more prevalent in the PG group, i.e. 75.8% versus 38.5% (p < 0.001). There was a trend towards more disturbed exocrine function tests after PG (p = 0.061).

Conclusions: PEI is more common with PG reconstruction than with PJ reconstruction after pancreaticoduodenectomy for malignancy.
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http://dx.doi.org/10.1016/j.hpb.2016.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5144554PMC
December 2016

Future remnant liver function estimated by combining liver volumetry on magnetic resonance imaging with total liver function on (99m)Tc-mebrofenin hepatobiliary scintigraphy: can this tool predict post-hepatectomy liver failure?

HPB (Oxford) 2016 06 21;18(6):494-503. Epub 2016 Mar 21.

Hepatobiliary, Endocrine and Transplantation Surgery, University Hospital Antwerp, University Antwerp, Belgium.

Introduction: Posthepatectomy liver failure (PHLF) is a major complication after hepatectomy with a high mortality rate and is likely to happen in insufficient liver remnant. We hypothesize that assessment of the estimated future liver remnant function (eFLRF), combining future remnant liver volume (FLRV) with total liver function (TLF), is an accurate formula for prediction of PHLF.

Methods: 88 patients undergoing hepatectomy were included. The ratio of the future liver remnant volume (FLRV%) was measured on MRI. TLF was estimated by liver clearance of (99m)Technetium (Tc)-mebrofenin on hepatobiliary scintigraphy (HBS). eFLRF was calculated by multiplying FLRV% by TLF. Cut-off values of FLRV% and eFLRF predicting PHLF, were defined by receiver-operating-characteristic (ROC) analysis.

Results: PHLF occurred in 12 patients (13%). Perioperative mortality was 5/12 (41%). Multivariate analysis showed that FLRV% cut off at 40% was not an independent predictive factor. eFLRF cut off at 2.3%/min/m(2) was the only independent predictive factor for PHLF. For FLRV% vs. eFLRF, positive predictive value was 41% vs. 92% and Odds Ratio 26 vs. 836.

Conclusion: FRLF measured by combining FLRV% and TLF is a more valuable tool to predict PHLF than FLRV% alone. The cutoff of eFLRF can be used in clinical decision making.
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http://dx.doi.org/10.1016/j.hpb.2015.08.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913132PMC
June 2016

Diabetes mellitus and pre-diabetes are frequently undiagnosed and underreported in patients referred for pancreatic surgery. A prospective observational study.

Pancreatology 2016 Jul-Aug;16(4):671-6. Epub 2016 May 6.

Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Belgium.

Objective: Previous reports on the prevalence of diabetes in pancreatic cancer and chronic pancreatitis patients are based on inconsistent and equivocal criteria. The objective of this study is to prospectively assess with conclusive methods the preoperative glycaemic status of patients undergoing pancreatic surgery. We hypothesise that most of those patients are unaware of these disturbances in glycaemic status and that the prevalence is underestimated.

Methods: During the last 2 years, patients referred for pancreatic surgery and without history of diabetes underwent a prospective preoperative screening with an oral glucose tolerance test (OGTT) and determination of the glycated haemoglobin level (HbA1c). The American Diabetes Association's criteria for diabetes and pre-diabetes were used. Beta-cell function and insulin sensitivity were calculated using HOMA2 indices. Impact on surgical policy has been scored.

Results: 99 patients were screened, 25 had a history of diabetes. The other 74 underwent an OGTT and HbA1c determination. Only 29.7% (22/74) had a normal glucose metabolism, while 8.1% (6/74) had impaired fasting glucose, 21.6% (16/74) had impaired glucose tolerance, 6.7% (5/74) had a combination of both, and 33.8% (25/74) had undiagnosed diabetes. In 15.2% (15/99) of the patients, this preoperative assessment had an impact on surgical policy.

Conclusions: 77.7% of patients referred for pancreatic surgery had some degree of (pre-)diabetes. In 70.3% of patients without a history of diabetes, these disturbances in glucose metabolism are a new finding. Physicians involved in pancreatic surgery should be aware of the frequently undiagnosed (pre-)diabetes and actively check for it. This prevalence is underestimated.
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http://dx.doi.org/10.1016/j.pan.2016.04.032DOI Listing
March 2017

Belgian consensus on chronic pancreatitis in adults and children: statements on diagnosis and nutritional, medical, and surgical treatment.

Acta Gastroenterol Belg 2014 Mar;77(1):47-65

Chronic pancreatitis (CP) is an inflammatory disorder characterized by inflammation and fibrosis, resulting in a progressive and irreversible destruction of exocrine and endocrine pancreatic tissue. Clinicians should attempt to classify patients into one of the six etiologic groups according to the TIGARO classification system. MRI/MRCP, if possible with secretin enhancement, is considered the imaging modality of choice for the diagnosis of early-stage disease.In CP, pain is the most disabling symptom, with a significant impact on quality of life. Pain should be assessed using the Izbicki score and preferably treated using the "pain ladder" approach. In painful CP, endoscopic therapy (ET) can be considered as early as possible. This procedure can be combined with extracorporeal shock-wave lithotripsy (ESWL) in the presence of large (> 4 mm), obstructive stone(s) in the pancreatic head, and with ductal stenting in the presence of a single main pancreatic duct (MPD) stricture in the pancreatic head with a markedly dilated MPD. Pancreatic stenting should be pursued for at least 12 months in patients with persistent pain relief. On-demand stent exchange should be the preferred strategy. The simultaneous placement of multiple, side-by-side, pancreatic stents can be recommended in patients with MPD strictures persisting after 12 months of single plastic stenting. We recommend surgery in the following cases: a) technical failure of ET ; b) early (6 to 8 weeks) clinical failure ; c) definitive biliary drainage at a later time point; d) pancreatic ductal drainage when repetitive ET is considered unsuitable for young patients; e) resection of an inflammatory pancreatic head when pancreatic cancer cannot be ruled out; f) duodenal obstruction. Duodenopancreatectomy or oncological distal pancreatectomy should be considered for patients with suspected malignancy. Pediatricians should be aware of and systematically search for CP in the differential diagnosis of chronic abdominal pain. As malnutrition is highly prevalent in CP patients, patients at nutritional risk should be identified in order to allow for dietary counseling and nutritional intervention using oral supplements. Patients should follow a healthy balanced diet taken in small meals and snacks, with normal fat content. Enzyme replacement therapy is beneficial to symptomatic patients, but also in cases of subclinical insufficiency. Regular follow-up should be considered in CP patients, primarily to detect subclinical maldigestion and the development of pancreatogenic diabetes. Screening for pancreatic cancer is not recommended in CP patients, except in those with the hereditary form.
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March 2014

Pancreaticojejunostomy versus pancreaticogastrostomy reconstruction after pancreaticoduodenectomy for pancreatic or periampullary tumours: a multicentre randomised trial.

Lancet Oncol 2013 Jun 2;14(7):655-62. Epub 2013 May 2.

University Hospitals KU Leuven, Abdominal Surgery, Leuven, Belgium.

Background: Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours.

Methods: Patients aged 18-85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (≤3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778.

Findings: Between June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19.8%) patients in the pancreaticojejunostomy group and 13 (8.0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2.86, 95% CI 1.38-6.17; p=0.002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade ≥3a than in the pancreaticogastrostomy group (39 vs 35).

Interpretation: In patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula.

Funding: Funding Johnson & Johnson Medical Devices, Belgium.
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http://dx.doi.org/10.1016/S1470-2045(13)70126-8DOI Listing
June 2013

Kidney donation after circulatory death in a country with a high number of brain dead donors: 10-year experience in Belgium.

Transpl Int 2012 Aug 13;25(8):857-66. Epub 2012 Jun 13.

Department of Abdominal Transplant Surgery, University Hospitals Leuven, KULeuven, Leuven, Belgium.

Worldwide shortage of standard brain dead donors (DBD) has revived the use of kidneys donated after circulatory death (DCD). We reviewed the Belgian DCD kidney transplant (KT) experience since its reintroduction in 2000. Risk factors for delayed graft function (DGF) were identified using multivariate analysis. Five-year patient/graft survival was assessed using Kaplan-Meier curves. The evolution of the kidney donor type and the impact of DCDs on the total KT activity in Belgium were compared with the Netherlands. Between 2000 and 2009, 287 DCD KT were performed. Primary nonfunction occurred in 1% and DGF in 31%. Five-year patient and death-censored graft survival were 93% and 95%, respectively. In multivariate analysis, cold storage (versus machine perfusion), cold ischemic time, and histidine-tryptophan-ketoglutarate solution were independent risk factors for the development of DGF. Despite an increased number of DCD donations and transplantations, the total number of deceased KT did not increase significantly. This could suggest a shift from DBDs to DCDs. To increase KT activity, Belgium should further expand controlled DCD programs while simultaneously improve the identification of all potential DBDs and avoid their referral for donation as DCDs before brain death occurs. Furthermore, living donation remains underused.
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http://dx.doi.org/10.1111/j.1432-2277.2012.01510.xDOI Listing
August 2012

Tacrolimus-related polyneuropathy: case report and review of the literature.

Clin Neurol Neurosurg 2008 Mar 4;110(3):291-4. Epub 2007 Dec 4.

Department of Critical Care Medicine, University Hospital of Antwerp, University of Antwerp, Wilrijkstraat 10, B 2650 Edegem, Belgium.

Patients, in particular recipients of orthotopic liver transplants, receiving the immunosuppressant tacrolimus (FK-506), are at risk for developing central neurotoxic adverse events. We report the occurrence of a tacrolimus-induced peripheral neurotoxic event, i.e. pure motor axonal polyneuropathy of the lower limbs in a 44-year-old woman, 9 days after combined orthotopic liver and pancreas transplantation. She was treated for 5 days with intravenous immunoglobulins. Partial recovery followed over months to years. An overview of all 11 reported FK506-associated polyneuropathies is given.
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http://dx.doi.org/10.1016/j.clineuro.2007.10.014DOI Listing
March 2008