Background Robotic surgery may improve surgical performance during minimally invasive pancreatoduodenectomy as compared to 3D- and 2D-laparoscopy but comparative studies are lacking. This study... Show moreBackground Robotic surgery may improve surgical performance during minimally invasive pancreatoduodenectomy as compared to 3D- and 2D-laparoscopy but comparative studies are lacking. This study assessed the impact of robotic surgery versus 3D- and 2D-laparoscopy on surgical performance and operative time using a standardized biotissue model for pancreatico- and hepatico-jejunostomy using pooled data from two randomized controlled crossover trials (RCTs). Methods Pooled analysis of data from two RCTs with 60 participants (36 surgeons, 24 residents) from 11 countries (December 2017-July 2019) was conducted. Each included participant completed two pancreatico- and two hepatico-jejunostomies in biotissue using 3D-robotic surgery, 3D-laparoscopy, or 2D-laparoscopy. Primary outcomes were the objective structured assessment of technical skills (OSATS: 12-60) rating, scored by observers blinded for 3D/2D and the operative time required to complete both anastomoses. Sensitivity analysis excluded participants with excess experience compared to others. Results A total of 220 anastomoses were completed (robotic 80, 3D-laparoscopy 70, 2D-laparoscopy 70). Participants in the robotic group had less surgical experience [median 1 (0-2) versus 6 years (4-12), p < 0.001], as compared to the laparoscopic group. Robotic surgery resulted in higher OSATS ratings (50, 43, 39 points, p = .021 and p < .001) and shorter operative time (56.5, 65.0, 81.5 min, p = .055 and p < .001), as compared to 3D- and 2D-laparoscopy, respectively, which remained in the sensitivity analysis. Conclusion In a pooled analysis of two RCTs in a biotissue model, robotic surgery resulted in better surgical performance scores and shorter operative time for biotissue pancreatic and biliary anastomoses, as compared to 3D- and 2D-laparoscopy. Show less
Acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic cancer are three distinct pancreatic diseases with different prognoses and treatment options. However, it may be difficult to... Show moreAcute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic cancer are three distinct pancreatic diseases with different prognoses and treatment options. However, it may be difficult to differentiate between benign and malignant disease. AP may be a first symptom of pancreatic cancer, particularly in patients between the ages of 56 and 75 with presumed idiopathic AP who had a concomitant diagnosis of new-onset diabetes mellitus or patients who present with CP at diagnosis of AP. In these patients, additional imaging is warranted, preferably by endoscopic ultrasonography. CP may lead to pancreatic cancer through oncogenic mutations, mostly in patients with hereditary CP, and in patients in whom risk factors for pancreatic cancer (e.g., nicotine and alcohol abuse) are also present. Patients with PRSS1-mediated CP and patients with a history of autosomal dominant hereditary CP without known genetic mutations may be considered for surveillance for pancreatic cancer. Pancreatic inflammation may mimic pancreatic cancer by appearing as a focal mass-forming lesion on imaging. Differentiation between the above mentioned benign and malignant disease may be facilitated by specific features like the duct-penetrating sign and the duct-to-parenchyma ratio. Research efforts are aimed towards developing a superior discriminant between pancreatitis and pancreatic cancer in the form of imaging modalities or biomarkers. This may aid clinicians in timely diagnosing pancreatic cancer in a potentially curable stage. Show less
Balak, J.R.A.; Juksar, J.; Carlotti, F.; Nigro, A. lo; Koning, E.J.P. de 2019
Purpose of Review Novel 3D organoid culture techniques have enabled long-term expansion of pancreatic tissue. This review comprehensively summarizes and evaluates the applications of primary tissue... Show morePurpose of Review Novel 3D organoid culture techniques have enabled long-term expansion of pancreatic tissue. This review comprehensively summarizes and evaluates the applications of primary tissue-derived pancreatic organoids in regenerative studies, disease modelling, and personalized medicine.Recent Findings Organoids derived from human fetal and adult pancreatic tissue have been used to study pancreas development and repair. Generated adult human pancreatic organoids harbor the capacity for clonal expansion and endocrine cell formation. In addition, organoids have been generated from human pancreatic ductal adenocarcinoma in order to study tumor behavior and assess drug responses.Summary Pancreatic organoids constitute an important translational bridge between in vitro and in vivo models, enhancing our understanding of pancreatic cell biology. Current applications for pancreatic organoid technology include studies on tissue regeneration, disease modelling, and drug screening. Show less
Damen, M.; Leeuwen, M. van; Webb, A.; Klomp, D.; Castro, C.A. de 2019
Objective To determine T-1 and T-2 relaxation times of healthy pancreas parenchyma at 7 T using a multi-transmit system. Materials and methods Twenty-six healthy subjects were scanned with a 7 T MR... Show moreObjective To determine T-1 and T-2 relaxation times of healthy pancreas parenchyma at 7 T using a multi-transmit system. Materials and methods Twenty-six healthy subjects were scanned with a 7 T MR system using eight parallel transceiver antennas, each with two additional receive loops. A Look-Locker sequence was used to obtain images for T-1 determination, while T-2 was obtained from spin-echo images and magnetic resonance spectroscopy measurements with different echo times. T-1 and T-2 times were calculated using a mono-exponential fit of the average magnitude signal from a region of interest in the pancreas and were tested for correlation with age. Results The age range of the included subjects was 21-72 years. Average T-1 and T-2 relaxation times in healthy pancreas were 896 +/- 149 ms, and 26.7 +/- 5.3 ms, respectively. No correlation with age was found. Conclusion T-1 and T-2 relaxation times of the healthy pancreas were reported for 7 T, which can be used for image acquisition optimization. No significant correlations were found between age and T-1 or T-2 relaxation times of the pancreas. Considering their low standard deviation and no observable age dependence, these values may be used as a baseline to study potentially pancreatic tissue affected by disease. Show less
Diabetes mellitus is amongst the leading causes of morbidity and mortality worldwide. Insulin-producing pancreatic β-cells are central in establishing adequate glucose regulation and loss of... Show moreDiabetes mellitus is amongst the leading causes of morbidity and mortality worldwide. Insulin-producing pancreatic β-cells are central in establishing adequate glucose regulation and loss of functional β-cells results in the development of diabetes. Although it was previously thought that fully differentiated cells cannot change phenotype, murine studies recently indicated that mature β-cells can change identity into other islet cells under conditions of (metabolic) stress.We present a novel agarose based microwell culture system that can be used for aggregate formation of human or rodent islet cells. We show that this platform provides reproducible results to study aggregation of primary human islet cells. Using this culture system together with β-cell specific lineage tracing, we find that mature human β-cells can spontaneously lose their identity and convert into glucagon-containing α-cells. We then used human pancreatic tissue from donors with T2DM and matched controls to explore loss of β-cell identity in T2DM. We report that cells indicative of loss of β-cell identity are found more frequently in tissue samples from donors with a history of T2DM. Finally, we show that Pax4 and GLP-1 receptor agonists can partially prevent loss of identity β-cell in our ex vivo model. Show less
In chapter 2, the pancreas was used as a paradigm to study human organ development and assess the quality of our fetal material. In a descriptive, histochemical study, we investigated how blood... Show moreIn chapter 2, the pancreas was used as a paradigm to study human organ development and assess the quality of our fetal material. In a descriptive, histochemical study, we investigated how blood and lymphatic vascular networks develop and their association with basement membranes and smooth muscle cells between gestational weeks 9 and 22 (W9 and W22). In Chapter 3, 4 and 5, we analyzed a total of 21 fetal organs and maternal endometrium at three time points (W9, W18 and W22) at the transcriptional and epigenetic level, thereby, providing an atlas of human organ development. The rare fetal material also allowed us to investigate the presence of an epigenetic memory from the cell of origin in induced pluripotent stem cells (iPSCs). We generated isogenic iPSC lines from six fetal organs (brain, skin, kidney, muscle, lung and pancreas) in chapter 5. The six iPSC lines had very similar DNA methylation profiles, however, we showed that the two clones derived from the brain harbored 18 hypermethylated and 6 hypomethylated CpGs also found in the fetal brain and we demonstrated that the brain-iPSC clones appeared to have a differentiation bias towards neural derivatives when comparing neural differentiation of the brain- and skin-iPSC clones. Show less
Gurp, L. van; Loomans, C.J.M.; Krieken, P.P. van; Dharmadhikari, G.; Jansen, E.; Ringnalda, F.C.A.S.; ... ; Koning, E.J.P. de 2016
Insulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via... Show moreInsulin-producing pancreatic _-cells are essential to maintain blood glucose levels within a narrow range. _-cells can adapt to an increased insulin demand by enhancing insulin secretion via increased _-cell function and/or increased _-cell mass. Inadequate _-cell adaptation leads to hyperglycemia and eventually diabetes mellitus. Therefore, it is critical to understand how the _-cell mass is regulated. We investigated _- and _-cell adaptation in response to different metabolic changes. We found that _-cell adaptation in response to insulin resistance in mice, rats, and deceased organ donors was regionally heterogeneous throughout the pancreas. We also observed that the glucagon-producing _-cell mass adapts to metabolic changes, resulting in the maintenance of the _- to _-cell ratio. Furthermore, we show that treatment of normoglycemic mice with a glucagon-like-peptide-1 receptor agonist improved _-cell function and that this is associated with a decrease in _-cell mass in order to maintain normoglycemia. In mice fed a high-fat, low-carbohydrate ketogenic diet beta-cell adaptation failed, resulting in symptoms that are associated with diabetes in humans. Finally, we developed three high-throughput culture platforms for human islets to assess _-cell function that can be used in future studies to identify novel mechanisms involved in _- and _-cell adaptation. Show less
Pancreas transplantation and islet of Langerhans transplantation are potential solutions to treat patients with type 1 diabetes. However, pancreas grafts are scarce and there is a shortage of donor... Show morePancreas transplantation and islet of Langerhans transplantation are potential solutions to treat patients with type 1 diabetes. However, pancreas grafts are scarce and there is a shortage of donor pancreata relative to the number of patients needing a transplant. The aim of this thesis was to further optimize pancreas graft survival in pancreas transplantation and to optimize islet isolation outcomes in islet of Langerhans transplantation, leading to better use of available organs. The focus in pancreas transplantation should be on optimizing recipients to improve graft survival and on improving quality of pancreata procured by centers not performing pancreas transplantation (for example, by training procurement surgeons to optimize pancreas procurement, thereby increasing the number of transplantable organs. In islets transplantation, it is recommended that the reporting of donor, pancreas and isolation factors should become more standardized, which would enable us to determine more accurately which factors are important predictors for islet isolation outcome. Furthermore, if more biomedical factors (e.g. the presence of hyperemic islets) would be reported in addition to the other factors, we would be able to assess the independent effect of these biomedical factors for islet isolation outcome and eventually the effect on islet transplantation in the clinical setting. Show less
Clinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) varies strikingly, both in terms of symptoms and outcome. An understanding of the basic biology unique to GEP-NETs is... Show moreClinical behaviour of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) varies strikingly, both in terms of symptoms and outcome. An understanding of the basic biology unique to GEP-NETs is necessary for optimum management of patients with these complex tumors. Although markers for GEP-NETs exist, sensitive and specific markers that predict tumor growth and behaviour are lacking. The general purpose of the studies described in this thesis was to investigate the epidemiology, diagnosis and pathogenesis of GEP-NETs in The Netherlands, to reveal insights in the pathological mechanisms contributing to the development and progression of these tumors. Not only worldwide but also in The Netherlands, the incidence of these tumors is increasing. The diverse studies contribute to a better understanding of the role of angiogenesis, neuropeptides and matrix metallo-proteinases in neuroendocrine tumors of the digestive tract and pancreas. Additional studies and further research will possible lead to new diagnostic and therapeutic implications of endoglin, bombesin and MMPs in patients with gastroenteropancreatic neuroendocrine tumors. Show less
![Transluminal endoscopic step-up approach versus minimally invasive surgical step-up approach in patients with infected necrotising pancreatitis (TENSION trial): design and rationale of a randomised controlled multicenter trial [ISRCTN09186711]](/sites/all/modules/custom/islandora_solr_search/images/defaultimg.png?solr_nav%5Bid%5D=b691bbdd874d1a886799&solr_nav%5Bpage%5D=0&solr_nav%5Boffset%5D=10)
