Cost-effectiveness of pancreas surveillance: The CDKN2A-p16-Leiden cohort.

BACKGROUND: CDKN2A-p16-Leiden mutation carriers have a high lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC), with very poor survival. Surveillance may improve prognosis. OBJECTIVE: To assess the cost-effectiveness of surveillance, as compared to no surveillance. METHODS: In 2000, a surveillance program was initiated at Leiden University Medical Center with annual MRI and optional endoscopic ultrasound. Data were collected on the resection rate of screen-detected tumors and on survival. The Kaplan-Meier method and a parametric cure model were used to analyze and compare survival. Based on the surveillance and survival data from the screening program, a state-transition model was constructed to estimate lifelong outcomes. RESULTS: A total of 347 mutation carriers participated in the surveillance program. PDAC was detected in 31 patients (8.9%) and the tumor could be resected in 22 patients (71.0%). Long-term cure among patients with resected PDAC was estimated at 47.1% (p < 0.001). The surveillance program was estimated to reduce mortality from PDAC by 12.1% and increase average life expectancy by 2.10 years. Lifelong costs increased by €13,900 per patient, with a cost-utility ratio of €14,000 per quality-adjusted life year gained. For annual surveillance to have an acceptable cost-effectiveness in other settings, lifetime PDAC risk needs to be 10% or higher. CONCLUSION: The tumor could be resected in most patients with a screen-detected PDAC. These patients had considerably better survival and as a result annual surveillance was found to be cost-effective.

Resection of the Portal-Superior Mesenteric Vein in Pancreatic Cancer: Pathological Assessment and Recurrence Patterns.

OBJECTIVES: The portal vein (PV)-superior mesenteric vein (SMV) margin is the most affected margin in pancreatic cancer. This study investigates the association between venous resection, tumor invasion in the resected PV-SMV, recurrence patterns, and overall survival (OS). METHODS: This multicenter cohort study included patients who underwent pancreatoduodenectomy for pancreatic cancer (2010-2017). In addition, a systematic literature search was performed. RESULTS: In total, 531 patients were included, of which 149 (28%) underwent venous resection of whom 53% had tumor invasion in the resected PV-SMV. Patients with venous resection had a significant higher rate of R1 margins (69% vs 37%) and had more often multiple R1 margins (43% vs 16%). Patient with venous resection had a significant shorter time to locoregional recurrence and a shorter OS (15 vs 19 months). At multivariable analyses, venous resection and tumor invasion in the resected PV-SMV were not predictive for time to recurrence and OS. The literature overview showed that pathological assessment of the resected PV-SMV is not adequately standardized. CONCLUSIONS: Only half of patients with venous resection had pathology confirmed tumor invasion in the resected PV-SMV, and both are not independently associated with time to recurrence and OS. The pathological assessment of the resected PV-SMV needs to be standardized.

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

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.

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

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 vivo 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 in vivo were reported as having a tumor-positive margin. Lesions that showcased no protruding rim in the wound bed in vivo 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 in vivo 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).

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.

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.

Minimally invasive versus open distal pancreatectomy (LEOPARD): study protocol for a randomized controlled trial.

BACKGROUND: Observational cohort studies have suggested that minimally invasive distal pancreatectomy (MIDP) is associated with better short-term outcomes compared with open distal pancreatectomy (ODP), such as less intraoperative blood loss, lower morbidity, shorter length of hospital stay, and reduced total costs. Confounding by indication has probably influenced these findings, given that case-matched studies failed to confirm the superiority of MIDP. This accentuates the need for multicenter randomized controlled trials, which are currently lacking. We hypothesize that time to functional recovery is shorter after MIDP compared with ODP even in an enhanced recovery setting. METHODS: LEOPARD is a randomized controlled, parallel-group, patient-blinded, multicenter, superiority trial in all 17 centers of the Dutch Pancreatic Cancer Group. A total of 102 patients with symptomatic benign, premalignant or malignant disease will be randomly allocated to undergo MIDP or ODP in an enhanced recovery setting. The primary outcome is time (days) to functional recovery, defined as all of the following: independently mobile at the preoperative level, sufficient pain control with oral medication alone, ability to maintain sufficient (i.e. >50%) daily required caloric intake, no intravenous fluid administration and no signs of infection. Secondary outcomes are operative and postoperative outcomes, including clinically relevant complications, mortality, quality of life and costs. DISCUSSION: The LEOPARD trial is designed to investigate whether MIDP reduces the time to functional recovery compared with ODP in an enhanced recovery setting. TRIAL REGISTRATION: Dutch Trial Register, NTR5188 . Registered on 9 April 2015.

Multimodal treatment of perianal fistulas in Crohn's disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial.

BACKGROUND: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. METHODS/DESIGN: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. DISCUSSION: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. TRIAL REGISTRATION: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).