A single digital droplet PCR assay to detect multiple KIT exon 11 mutations in tumor and plasma from patients with gastrointestinal stromal tumors

__Background:__ Gastrointestinal stromal tumors (GISTs) are characterized by oncogenic KIT mutations that cluster in two exon 11 hotspots. The aim of this study was to develop a single, sensitive, quantitative digital droplet PCR (ddPCR) assay for the detection of common exon 11 mutations in both GIST tumor tissue and in circulating tumor DNA (ctDNA) isolated from GIST patients' plasma. __Methods:__ A ddPCR assay was designed using two probes that cover both hotspots. Available archival FFPE tumor tissue from 27 consecutive patients with known KIT exon 11 mutations and 9 randomly selected patients without exon 11 mutations were tested. Plasma samples were prospectively collected in a multicenter bio-databank from December 2014. ctDNA was analyzed of 22 patients with an exon 11 mutation and a baseline plasma sample. __Results:__ The ddPCR assay detected the exon 11 mutation in 21 of 22 tumors with exon 11 mutations covered by the assay. Mutations in ctDNA were detected at baseline in 13 of 14 metastasized patien

Outcome of pancreatic surgery during the first 6 years of a mandatory audit within the Dutch Pancreatic Cancer Group

Objective:To describe outcome after pancreatic surgery in the first 6 years of a mandatory nationwide audit. Background:Within the Dutch Pancreatic Cancer Group, efforts have been made to improve outcome after pancreatic surgery. These include collaborative projects, clinical auditing, and implementation of an algorithm for early recognition and management of postoperative complications. However, nationwide changes in outcome over time have not yet been described. Methods:This nationwide cohort study included consecutive patients after pancreatoduodenectomy (PD) and distal pancreatectomy from the mandatory Dutch Pancreatic Cancer Audit (January 2014-December 2019). Patient, tumor, and treatment characteristics were compared between 3 time periods (2014-2015, 2016-2017, and 2018-2019). Short-term surgical outcome was investigated using multilevel multivariable logistic regression analyses. Primary endpoints were failure to rescue (FTR) and in-hospital mortality. Results:Overall, 5345 patients were included, of whom 4227 after PD and 1118 after distal pancreatectomy. After PD, FTR improved from 13% to 7.4% [odds ratio (OR) 0.64, 95% confidence interval (CI) 0.50-0.80, P75 years (18%-22%, P=0.006), American Society of Anesthesiologists score & GE;3 (19%-31%, P<0.001) and Charlson comorbidity score & GE;2 (24%-34%, P<0.001). The rates of textbook outcome (57%-55%, P=0.283) and major complications remained stable (31%-33%, P=0.207), whereas complication-related intensive care admission decreased (13%-9%, P=0.002). After distal pancreatectomy, improvements in FTR from 8.8% to 5.9% (OR 0.65, 95% CI 0.30-1.37, P=0.253) and in-hospital mortality from 1.6% to 1.3% (OR 0.88, 95% CI 0.45-1.72, P=0.711) were not statistically significant. Conclusions:During the first 6 years of a nationwide audit, in-hospital mortality and FTR after PD improved despite operating on more high-risk patients. Several collaborative efforts may have contributed to these improvements.Surgical oncolog

The feasibility, proficiency, and mastery learning curves in 635 robotic pancreatoduodenectomies following a multicenter training program: "Standing on the Shoulders of Giants"

Objective: To assess the feasibility, proficiency, and mastery learning curves for robotic pancreatoduodenectomy (RPD) in "second-generation" RPD centers following a multicenter training program adhering to the IDEAL framework.Background: The long learning curves for RPD reported from "pioneering" expert centers may discourage centers interested in starting an RPD program. However, the feasibility, proficiency, and mastery learning curves may be shorter in "second-generation" centers that participated in dedicated RPD training programs, although data are lacking. We report on the learning curves for RPD in "second-generation" centers trained in a dedicated nationwide program.Methods: Post hoc analysis of all consecutive patients undergoing RPD in 7 centers that participated in the LAELAPS-3 training program, each with a minimum annual volume of 50 pancreatoduodenectomies, using the mandatory Dutch Pancreatic Cancer Audit (March 2016-December 2021). Cumulative sum analysis determined cutoffs for the 3 learning curves: operative time for the feasibility (1) risk-adjusted major complication (Clavien-Dindo grade >= III) for the proficiency, (2) and textbook outcome for the mastery, (3) learning curve. Outcomes before and after the cutoffs were compared for the proficiency and mastery learning curves. A survey was used to assess changes in practice and the most valued "lessons learned."Results: Overall, 635 RPD were performed by 17 trained surgeons, with a conversion rate of 6.6% (n=42). The median annual volume of RPD per center was 22.56.8. From 2016 to 2021, the nationwide annual use of RPD increased from 0% to 23% whereas the use of laparoscopic pancreatoduodenectomy decreased from 15% to 0%. The rate of major complications was 36.9% (n=234), surgical site infection 6.3% (n=40), postoperative pancreatic fistula (grade B/C) 26.9% (n=171), and 30-day/in-hospital mortality 3.5% (n=22). Cutoffs for the feasibility, proficiency, and mastery learning curves were reached at 15, 62, and 84 RPD. Major morbidity and 30-day/in-hospital mortality did not differ significantly before and after the cutoffs for the proficiency and mastery learning curves. Previous experience in laparoscopic pancreatoduodenectomy shortened the feasibility (-12 RPDs, -44%), proficiency (-32 RPDs, -34%), and mastery phase learning curve (-34 RPDs, -23%), but did not improve clinical outcome.Conclusions: The feasibility, proficiency, and mastery learning curves for RPD at 15, 62, and 84 procedures in "second-generation" centers after a multicenter training program were considerably shorter than previously reported from "pioneering" expert centers. The learning curve cutoffs and prior laparoscopic experience did not impact major morbidity and mortality. These findings demonstrate the safety and value of a nationwide training program for RPD in centers with sufficient volume.Surgical oncolog

The Dutch pancreatic cancer project: Improving outcome in pancreatic surgery

Pancreatic surgery is complex and carries a high risk of complications. This thesis entitled “The Dutch Pancreatic Cancer Project: improving outcome in pancreatic surgery”, aims to identify factors adding to the improvement of clinical outcome of patients after pancreatic surgery, first by focusing on the reduction of complications (Part I) and secondly by identifying leads to improve survival (Part II). In part I of this thesis, the leakage of pancreatic fluid after pancreatic surgery, i.e. postoperative pancreatic fistula (POPF, i.e. grade B/C), was addressed as the most feared complication in pancreatic surgery. Furthermore, the need for preventive measures was emphasized. In pancreatic cancer patients who received preoperative chemoradiotherapy, the rate of POPF was significantly lower compared to patients after immediate surgery (i.e., without preoperative therapy) after pancreatoduodenectomy. Changes in acinar cell function and pancreatic texture caused by radiotherapy may play a role in this declined risk of POPF. However, preoperative chemoradiotherapy is only indicated for patients undergoing PD for patients with pancreatic cancer, while this thesis concluded that patients with periampullary tumors have a much higher risk of developing POPF. It was hypothesized that a single dose of preoperative radiotherapy targeting the intended site of the pancreatic anastomosis induces local fibrosis of the pancreatic tissue, potentially reducing the risk of pancreatic fistula after pancreatoduodenectomy in patients at high risk of POPF. The FIBROPANC study protocol was presented, in which the safety and feasibility of this hypothesis will be investigated. Additionally, it was concluded that several national efforts have resulted in a significant decrease in in-hospital mortality and an improvement in failure to rescue after pancreatoduodenectomy in the Netherlands. In part II of this thesis, a unified variable list for reporting patient characteristics and outcome measures in randomized trials in patients with pancreatic cancer was presented, enabling better comparison between trials. It was also concluded that the basal-like molecular subtype of pancreatic carcinoma is associated with poor survival after pancreatic resection. In addition, involvement of the para-aortic lymph node station 16b1 is also associated with poor survival in patients with pancreatic or periampullary carcinoma. The role of direct resection in these groups was discussed

The Dutch pancreatic cancer project: Improving outcome in pancreatic surgery

Pancreatic surgery is complex and carries a high risk of complications. This thesis entitled “The Dutch Pancreatic Cancer Project: improving outcome in pancreatic surgery”, aims to identify factors adding to the improvement of clinical outcome of patients after pancreatic surgery, first by focusing on the reduction of complications (Part I) and secondly by identifying leads to improve survival (Part II). In part I of this thesis, the leakage of pancreatic fluid after pancreatic surgery, i.e. postoperative pancreatic fistula (POPF, i.e. grade B/C), was addressed as the most feared complication in pancreatic surgery. Furthermore, the need for preventive measures was emphasized. In pancreatic cancer patients who received preoperative chemoradiotherapy, the rate of POPF was significantly lower compared to patients after immediate surgery (i.e., without preoperative therapy) after pancreatoduodenectomy. Changes in acinar cell function and pancreatic texture caused by radiotherapy may play a role in this declined risk of POPF. However, preoperative chemoradiotherapy is only indicated for patients undergoing PD for patients with pancreatic cancer, while this thesis concluded that patients with periampullary tumors have a much higher risk of developing POPF. It was hypothesized that a single dose of preoperative radiotherapy targeting the intended site of the pancreatic anastomosis induces local fibrosis of the pancreatic tissue, potentially reducing the risk of pancreatic fistula after pancreatoduodenectomy in patients at high risk of POPF. The FIBROPANC study protocol was presented, in which the safety and feasibility of this hypothesis will be investigated. Additionally, it was concluded that several national efforts have resulted in a significant decrease in in-hospital mortality and an improvement in failure to rescue after pancreatoduodenectomy in the Netherlands. In part II of this thesis, a unified variable list for reporting patient characteristics and outcome measures in randomized trials in patients with pancreatic cancer was presented, enabling better comparison between trials. It was also concluded that the basal-like molecular subtype of pancreatic carcinoma is associated with poor survival after pancreatic resection. In addition, involvement of the para-aortic lymph node station 16b1 is also associated with poor survival in patients with pancreatic or periampullary carcinoma. The role of direct resection in these groups was discussed

Occult gastrointestinal bleeding due to a Dieulafoy lesion in the terminal ileum

A 50-year-old man awaiting liver transplantation for primary sclerosing cholangitis developed iron-deficiency anaemia. Repeated occult gastrointestinal bleeding led to an increasing need for blood transfusions. After multiple oesophagogastroduodenoscopies and colonoscopies, videocapsule endoscopy finally demonstrated a polyp-like lesion in the terminal ileum. The lesion had not been detected despite two attempts (oral and anal) at double-balloon enteroscopy and even a peroperative enteroscopy. Only during a second laparotomy, again involving peroperative enteroscopy, a small red lesion was detected and resected 80 cm proximal to the ileocecal valve (Bauhin's valve). Histology revealed a Dieulafoy lesion. Four months later, after normalisation and stabilisation of his haemoglobin level, the patient received a successful liver transplant. If the cause of occult gastrointestinal bleeding in a patient remains unclear despite regular endoscopic procedures, new techniques like videocapsule endoscopy and double-balloon enteroscopy may contribute to identifying the cause. This may lead to an exceptional finding such as a Dieulafoy lesion in the distal ileu