Minimally invasive distal pancreatectomy:International collaboration to improve surgical treatment of left-sided pancreatic neoplasms

In this thesis, international collaborative efforts have been made to investigate the feasibility, safety, and outcomes of minimally invasive distal pancreatectomy. The minimally invasive approach towards distal pancreatectomy is increasingly integrated into standard surgical treatment for left-sided benign and pre-malignant neoplasms. Spleen-preserving minimally invasive distal pancreatectomy has shown superior outcomes compared to an open approach in terms of technical outcomes such as splenic preservation rates and long-term sequalae of esophageal varices. Both Warshaw and Kimura techniques can be performed minimally invasive with low rates of splenic infarction requiring reinterventions. On the longer term, quality of life is comparable between minimally invasive and open distal pancreatectomy.The role of a minimally invasive approach to resectable pancreatic cancer has been debated because of the expectation of inferior oncological outcomes in the absence of randomized trials. This thesis reports a randomized trial performed in 35 centers from 12 countries, which showed that the minimally invasive approach is non-inferior to open distal pancreatectomy in this patient group and may be considered a safe alternative to an open approach. Considering the arguably high-complex nature of distal pancreatectomy, a step-wise approach is crucial for the implementation of such procedure. In the Netherlands, a safe and sustained implementation was observed after the completion of a nationwide training program and randomized trial. Approximately two-thirds of patients are currently operated on using a minimally invasive approach. For the further nationwide and worldwide implementation, dedicated training curricula and registration of outcomes in (inter)national registries is advised

Laparoscopic versus open extended radical left pancreatectomy for pancreatic ductal adenocarcinoma: an international propensity-score matched study

Background A radical left pancreatectomy in patients with pancreatic ductal adenocarcinoma (PDAC) may require extended, multivisceral resections. The role of a laparoscopic approach in extended radical left pancreatectomy (ERLP) is unclear since comparative studies are lacking. The aim of this study was to compare outcomes after laparoscopic vs open ERLP in patients with PDAC. Methods An international multicenter propensity-score matched study including patients who underwent either laparoscopic or open ERLP (L-ERLP; O-ERLP) for PDAC was performed (2007-2015). The ISGPS definition for extended resection was used. Primary outcomes were overall survival, margin negative rate (R0), and lymph node retrieval. Results Between 2007 and 2015, 320 patients underwent ERLP in 34 centers from 12 countries (65 L-ERLP vs. 255 O-ERLP). After propensity-score matching, 44 L-ERLP could be matched to 44 O-ERLP. In the matched cohort, the conversion rate in L-ERLP group was 35%. The L-ERLP R0 resection rate (matched cohort) was comparable to O-ERLP (67% vs 48%; P = 0.063) but the lymph node yield was lower for L-ERLP than O-ERLP (median 11 vs 19, P = 0.023). L-ERLP was associated with less delayed gastric emptying (0% vs 16%, P = 0.006) and shorter hospital stay (median 9 vs 13 days, P = 0.005), as compared to O-ERLP. Outcomes were comparable for additional organ resections, vascular resections (besides splenic vessels), Clavien-Dindo grade >= III complications, or 90-day mortality (2% vs 2%, P = 0.973). The median overall survival was comparable between both groups (19 vs 20 months, P = 0.571). Conversion did not worsen outcomes in L-ERLP. Conclusion The laparoscopic approach may be used safely in selected patients requiring ERLP for PDAC, since morbidity, mortality, and overall survival seem comparable, as compared to O-ERLP. L-ERLP is associated with a high conversion rate and reduced lymph node yield but also with less delayed gastric emptying and a shorter hospital stay, as compared to O-ERLP

Minimally invasive versus open distal pancreatectomy: an individual patient data meta-analysis of two randomized controlled trials

Background: Minimally invasive distal pancreatectomy (MIDP) has been suggested to reduce postoperative outcomes as compared to open distal pancreatectomy (ODP). Recently, the first randomized controlled trials (RCTs) comparing MIDP to ODP were published. This individual patient data meta-analysis compared outcomes after MIDP versus ODP combining data from both RCTs. Methods: A systematic literature search was performed to identify RCTs on MIDP vs. ODP, and individual patient data were harmonized. Primary endpoint was the rate of major (Clavien-Dindo ≥ III) complications. Sensitivity analyses were performed in high-risk subgroups. Results: A total of 166 patients from the LEOPARD and LAPOP RCTs were included. The rate of major complications was 21% after MIDP vs. 35% after ODP (adjusted odds ratio 0.54; p = 0.148). MIDP significantly reduced length of hospital stay (6 vs. 8 days, p = 0.036), and delayed gastric emptying (4% vs. 16%, p = 0.049), as compared to ODP. A trend towards higher rates of postoperative pancreatic fistula was observed after MIDP (36% vs. 28%, p = 0.067). Outcomes were comparable in high-risk subgroups. Conclusion: This individual patient data meta-analysis showed that MIDP, when performed by trained surgeons, may be regarded as the preferred approach for distal pancreatectomy. Outcomes are improved after MIDP as compared to ODP, without obvious downsides in high-risk subgroups

Development of biotissue training models for anastomotic suturing in pancreatic surgery

Background: Anastomotic suturing is the Achilles heel of pancreatic surgery. Especially in laparoscopic and robotically assisted surgery, the pancreatic anastomosis should first be trained outside the operating room. Realistic training models are therefore needed. Methods: Models of the pancreas, small bowel, stomach, bile duct, and a realistic training torso were developed for training of anastomoses in pancreatic surgery. Pancreas models with soft and hard tex-tures, small and large ducts were incrementally developed and evaluated. Experienced pancreatic sur-geons (n = 44) evaluated haptic realism, rigidity, fragility of tissues, and realism of suturing and knot tying. Results: In the iterative development process the pancreas models showed high haptic realism and highest realism in suturing (4.6 & PLUSMN; 0.7 and 4.9 & PLUSMN; 0.5 on 1-5 Likert scale, soft pancreas). The small bowel model showed highest haptic realism (4.8 & PLUSMN; 0.4) and optimal wall thickness (0.1 & PLUSMN; 0.4 on -2 to +2 Likert scale) and suturing behavior (0.1 & PLUSMN; 0.4). The bile duct models showed optimal wall thickness (0.3 & PLUSMN; 0.8 and 0.4 & PLUSMN; 0.8 on -2 to +2 Likert scale) and optimal tissue fragility (0 & PLUSMN; 0.9 and 0.3 & PLUSMN; 0.7). Conclusion: The biotissue training models showed high haptic realism and realistic suturing behavior. They are suitable for realistic training of anastomoses in pancreatic surgery which may improve patient outcomes.Surgical oncolog

A blood-based biomarker panel indicates IL-10 and IL-12/23p40 are jointly associated as predictors of β-amyloid load in an AD cohort

Alzheimer\u27s Disease (AD) is the most common form of dementia, characterised by extracellular amyloid deposition as plaques and intracellular neurofibrillary tangles of tau protein. As no current clinical test can diagnose individuals at risk of developing AD, the aim of this project is to evaluate a blood-based biomarker panel to identify individuals who carry this risk. We analysed the levels of 22 biomarkers in clinically classified healthy controls (HC), mild cognitive impairment (MCI) and Alzheimer\u27s participants from the well characterised Australian Imaging, Biomarker and Lifestyle (AIBL) study of aging. High levels of IL-10 and IL-12/23p40 were significantly associated with amyloid deposition in HC, suggesting that these two biomarkers might be used to detect at risk individuals. Additionally, other biomarkers (Eotaxin-3, Leptin, PYY) exhibited altered levels in AD participants possessing the APOE ϵ4 allele. This suggests that the physiology of some potential biomarkers may be altered in AD due to the APOE ϵ4 allele, a major risk factor for AD. Taken together, these data highlight several potential biomarkers that can be used in a blood-based panel to allow earlier identification of individuals at risk of developing AD and/or early stage AD for which current therapies may be more beneficial

Minimally invasive distal pancreatectomy: International collaboration to improve surgical treatment of left-sided pancreatic neoplasms

In this thesis, international collaborative efforts have been made to investigate the feasibility, safety, and outcomes of minimally invasive distal pancreatectomy. The minimally invasive approach towards distal pancreatectomy is increasingly integrated into standard surgical treatment for left-sided benign and pre-malignant neoplasms. Spleen-preserving minimally invasive distal pancreatectomy has shown superior outcomes compared to an open approach in terms of technical outcomes such as splenic preservation rates and long-term sequalae of esophageal varices. Both Warshaw and Kimura techniques can be performed minimally invasive with low rates of splenic infarction requiring reinterventions. On the longer term, quality of life is comparable between minimally invasive and open distal pancreatectomy. The role of a minimally invasive approach to resectable pancreatic cancer has been debated because of the expectation of inferior oncological outcomes in the absence of randomized trials. This thesis reports a randomized trial performed in 35 centers from 12 countries, which showed that the minimally invasive approach is non-inferior to open distal pancreatectomy in this patient group and may be considered a safe alternative to an open approach. Considering the arguably high-complex nature of distal pancreatectomy, a step-wise approach is crucial for the implementation of such procedure. In the Netherlands, a safe and sustained implementation was observed after the completion of a nationwide training program and randomized trial. Approximately two-thirds of patients are currently operated on using a minimally invasive approach. For the further nationwide and worldwide implementation, dedicated training curricula and registration of outcomes in (inter)national registries is advised

Minimally invasive distal pancreatectomy: International collaboration to improve surgical treatment of left-sided pancreatic neoplasms

In this thesis, international collaborative efforts have been made to investigate the feasibility, safety, and outcomes of minimally invasive distal pancreatectomy. The minimally invasive approach towards distal pancreatectomy is increasingly integrated into standard surgical treatment for left-sided benign and pre-malignant neoplasms. Spleen-preserving minimally invasive distal pancreatectomy has shown superior outcomes compared to an open approach in terms of technical outcomes such as splenic preservation rates and long-term sequalae of esophageal varices. Both Warshaw and Kimura techniques can be performed minimally invasive with low rates of splenic infarction requiring reinterventions. On the longer term, quality of life is comparable between minimally invasive and open distal pancreatectomy. The role of a minimally invasive approach to resectable pancreatic cancer has been debated because of the expectation of inferior oncological outcomes in the absence of randomized trials. This thesis reports a randomized trial performed in 35 centers from 12 countries, which showed that the minimally invasive approach is non-inferior to open distal pancreatectomy in this patient group and may be considered a safe alternative to an open approach. Considering the arguably high-complex nature of distal pancreatectomy, a step-wise approach is crucial for the implementation of such procedure. In the Netherlands, a safe and sustained implementation was observed after the completion of a nationwide training program and randomized trial. Approximately two-thirds of patients are currently operated on using a minimally invasive approach. For the further nationwide and worldwide implementation, dedicated training curricula and registration of outcomes in (inter)national registries is advised

Diploma approach for standardized pathology assessment of distal pancreatectomy specimens

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant cancers. A minority (20%) of PDACs are found in the pancreatic body and tail. Accurate pathology assessment of the pancreatic specimen is essential for providing prognostic information and it may guide further treatment strategies. The recent 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/ UICC) staging system for pancreatic tumors has incorporated significant changes to tumor (pT) stage, which is predominantly based on tumor size. This change emphasizes the importance of careful block selection. Owing to the greater prevalence of tumors in the head of the pancreas, efforts are made to standardize the assessment of pancreatoduodenectomy specimens. However, consensus regarding the macroscopic assessment of distal (i.e., left) pancreatectomy specimens is lacking. The DIPLOMA approach includes the standardized measurement of pancreas and other resected organs, inking of relevant surgical margins and anatomical surfaces without removing covering layers of fat, measurement of tumor size (for T-stage), together with assessment of splenic vessel involvement (and other organs if present). All relevant margins are assessed, and relevant blocks are selected to confirm these parameters microscopically. The current protocol describes a standardized approach to the macroscopic assessment of distal pancreatectomy specimens. This approach was developed during several meetings with pathologists and surgeons during the preparation phase for an international multicenter trial (DIPLOMA, ISRCTN44897265), which focuses on radicality of distal pancreatectomy for pancreatic ductal adenocarcinoma. This standardized approach can be instrumental in the design of studies and will uniform reporting on the outcomes of distal pancreatectomy. The described technique is used in the DIPLOMA trial for pancreatic ductal adenocarcinoma but may also be useful for other indications