Prophylactic abdominal drainage after distal pancreatectomy (PANDORINA): an international, multicentre, open-label, randomised controlled, non-inferiority trial.

BACKGROUND: Prophylactic passive abdominal drainage is standard practice after distal pancreatectomy. This approach aims to mitigate the consequences of postoperative pancreatic fistula (POPF) but its added value, especially in patients at low risk of POPF, is currently being debated. We aimed to assess the non-inferiority of a no-drain policy in patients after distal pancreatectomy. METHODS: In this international, multicentre, open-label, randomised controlled, non-inferiority trial, we recruited patients aged 18 years or older undergoing open or minimally invasive elective distal pancreatectomy for all indications in 12 centres in the Netherlands and Italy. We excluded patients with an American Society of Anesthesiology (ASA) physical status of 4-5 or WHO performance status of 3-4, added by amendment following the death of a patient with ASA 4 due to a pre-existing cardiac condition. Patients were randomly assigned (1:1) intraoperatively by permuted blocks (size four to eight) to either no drain or prophylactic passive drain placement, stratified by annual centre volume (<40 or ≥40 distal pancreatectomies) and low risk or high risk of grade B or C POPF. High-risk was defined as a pancreatic duct of more than 3 mm in diameter, a pancreatic thickness at the neck of more than 19 mm, or both, based on the Distal Pancreatectomy Fistula Risk Score. Other patients were considered low-risk. The primary outcome was the rate of major morbidity (Clavien-Dindo score ≥III), and the most relevant secondary outcome was grade B or C POPF, grading per the International Study Group for Pancreatic Surgery. Outcomes were assessed up to 90 days postoperatively and analysed in the intention-to-treat population and per-protocol population, which only included patients who received the allocated treatment. A prespecified non-inferiority margin of 8% was compared with the upper limit of the two-sided 95% CI (Wald) of unadjusted risk difference to assess non-inferiority. This trial is closed and registered in the Netherlands Trial Registry, NL9116. FINDINGS: Between Oct 3, 2020, and April 28, 2023, 376 patients were screened for eligibility and 282 patients were randomly assigned to the no-drain group (n=138; 75 [54%] women and 63 [46%] men) or the drain group (n=144; 73 [51%] women and 71 [49%] men). Seven patients in the no-drain group received a drain intraoperatively; consequently, the per-protocol population included 131 patients in the no-drain group and 144 patients in the drain group. The rate of major morbidity was non-inferior in the no-drain group compared with the drain group in the intention-to-treat analysis (21 [15%] vs 29 [20%]; risk difference -4·9 percentage points [95% CI -13·8 to 4·0]; pnon-inferiority=0·0022) and the per-protocol analysis (21 [16%] vs 29 [20%]; risk difference -4·1 percentage points [-13·2 to 5·0]; pnon-inferiority=0·0045). Grade B or C POPF was observed in 16 (12%) patients in the no-drain group and in 39 (27%) patients in the drain group (risk difference -15·5 percentage points [95% CI -24·5 to -6·5]; pnon-inferiority<0·0001) in the intention-to-treat analysis. Three patients in the no-drain group died within 90 days; the cause of death in two was not considered related to the trial. The third death was a patient with an ASA score of 4 who died after sepsis and a watershed cerebral infarction at second admission, leading to multiple organ failure. No patients in the drain group died within 90 days. INTERPRETATION: A no-drain policy is safe in terms of major morbidity and reduced the detection of grade B or C POPF, and should be the new standard approach in eligible patients undergoing distal pancreatectomy. FUNDING: Ethicon UK (Johnson & Johnson Medical, Edinburgh, UK).

Nationwide use and Outcome of Minimally Invasive Distal Pancreatectomy in IDEAL Stage IV following a Training Program and Randomized Trial.

OBJECTIVE: To assess the nationwide long-term uptake and outcomes of minimally invasive distal pancreatectomy (MIDP) after a nationwide training program and randomized trial. BACKGROUND: Two randomized trials demonstrated the superiority of MIDP over open distal pancreatectomy (ODP) in terms of functional recovery and hospital stay. Data on implementation of MIDP on a nationwide level are lacking. METHODS: Nationwide audit-based study including consecutive patients after MIDP and ODP in 16 centers in the Dutch Pancreatic Cancer Audit (2014 to 2021). The cohort was divided into three periods: early implementation, during the LEOPARD randomized trial, and late implementation. Primary endpoints were MIDP implementation rate and textbook outcome. RESULTS: Overall, 1496 patients were included with 848 MIDP (56.5%) and 648 ODP (43.5%). From the early to the late implementation period, the use of MIDP increased from 48.6% to 63.0% and of robotic MIDP from 5.5% to 29.7% ( P <0.001). The overall use of MIDP (45% to 75%) and robotic MIDP (1% to 84%) varied widely between centers ( P <0.001). In the late implementation period, 5/16 centers performed >75% of procedures as MIDP. After MIDP, in-hospital mortality and textbook outcome remained stable over time. In the late implementation period, ODP was more often performed in ASA score III-IV (24.9% vs. 35.7%, P =0.001), pancreatic cancer (24.2% vs. 45.9%, P <0.001), vascular involvement (4.6% vs. 21.9%, P <0.001), and multivisceral involvement (10.5% vs. 25.3%, P <0.001). After MIDP, shorter hospital stay (median 7 vs. 8 d, P <0.001) and less blood loss (median 150 vs. 500 mL, P <0.001), but more grade B/C postoperative pancreatic fistula (24.4% vs. 17.2%, P =0.008) occurred as compared to ODP. CONCLUSION: A sustained nationwide implementation of MIDP after a successful training program and randomized trial was obtained with satisfactory outcomes. Future studies should assess the considerable variation in the use of MIDP between centers and, especially, robotic MIDP.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

OBJECTIVE: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. BACKGROUND: PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. METHODS: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. RESULTS: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. DISCUSSIONS: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

Long-term yield of pancreatic cancer surveillance in high-risk individuals.

OBJECTIVE: We aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals. DESIGN: From 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit. RESULTS: 366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1-32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001). CONCLUSION: The diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

The Impact of Neoadjuvant Treatment on Survival in Patients Undergoing Pancreatoduodenectomy With Concomitant Portomesenteric Venous Resection: An International Multicenter Analysis.

OBJECTIVE: The aim of this study was to evaluate whether neoadjuvant therapy (NAT) critically influenced microscopically complete resection (R0) rates and long-term outcomes for patients with pancreatic ductal adenocarcinoma who underwent pancreatoduodenectomy (PD) with portomesenteric vein resection (PVR) from a diverse, world-wide group of high-volume centers. SUMMARY OF BACKGROUND DATA: Limited size studies suggest that NAT improves R0 rates and overall survival compared to upfront surgery in R/BR-PDAC patients. METHODS: This multicenter study analyzed consecutive patients with R/BR-PDAC who underwent PD with PVR in 23 high-volume centers from 2009 to 2018. RESULTS: Data from 1192 patients with PD and PVR were collected and analyzed. The median age was 68 [interquartile range (IQR) 60-73] years and 52% were males. Some 186 (15.6%) and 131 (10.9%) patients received neoadjuvant chemotherapy (NAC) alone and neoadjuvant chemoradiotherapy, respectively. The R0/R1/R2 rates were 57%, 39.3%, and 3.2% in patients who received NAT compared to 46.6%, 49.9%, and 3.5% in patients who did not, respectively (P =0.004). The 1-, 3-, and 5-year OS in patients receiving NAT was 79%, 41%, and 29%, while for those that did not it was 73%, 29%, and 18%, respectively (P <0.001). Multivariable analysis showed no administration of NAT, high tumor grade, lymphovascular invasion, R1/R2 resection, no adjuvant chemotherapy, occurrence of Clavien-Dindo grade 3 or higher postoperative complications within 90 days, preoperative diabetes mellitus, male sex and portal vein involvement were negative independent predictive factors for OS. CONCLUSION: Patients with PDAC of the pancreatic head expected to undergo venous reconstruction should routinely be considered for NAT.

Eligibility for Liver Transplantation in Patients with Perihilar Cholangiocarcinoma.

BACKGROUND: Liver transplantation (LT) has been performed in a select group of patients presenting with unresectable or primary sclerosing cholangitis (PSC)-associated perihilar cholangiocarcinoma (pCCA) in the Mayo Clinic with a reported 5-year overall survival (OS) of 53% on intention-to-treat analysis. The objective of this study was to estimate eligibility for LT in a cohort of pCCA patients in two tertiary referral centers. METHODS: Patients diagnosed with pCCA between 2002 and 2014 were included from two tertiary referral centers in the Netherlands. The selection criteria used by the Mayo Clinic were retrospectively applied to determine the proportion of patients that would have been eligible for LT. RESULTS: A total of 732 consecutive patients with pCCA were identified, of whom 24 (4%) had PSC-associated pCCA. Overall, 154 patients had resectable disease on imaging and 335 patients were ineligible for LT because of lymph node or distant metastases. An age limit of 70 years led to the exclusion of 50 patients who would otherwise be eligible for LT. After applying the Mayo Clinic criteria, only 34 patients (5%) were potentially eligible for LT. Median survival from diagnosis for these 34 patients was 13 months (95% CI 3-23). CONCLUSION: Only 5% of all patients presenting with pCCA were potentially eligible for LT under the Mayo criteria. Without transplantation, a median OS of about 1 year was observed.

Added value of 3D-vision during robotic pancreatoduodenectomy anastomoses in biotissue (LAEBOT 3D2D): a randomized controlled cross-over trial.

BACKGROUND: We tested the added value of 3D-vision on procedure time and surgical performance during robotic pancreatoduodenectomy anastomoses in biotissue. Robotic surgery has the advantage of articulating instruments and 3D-vision. Consensus is lacking on the added value of 3D-vision during laparoscopic surgery. Given the improved dexterity with robotic surgery, the added value of 3D-vision may be even less with robotic surgery. METHODS: In this experimental randomized controlled cross-over trial, 20 surgeons and surgical residents from 5 countries performed robotic pancreaticojejunostomy and hepaticojejunostomy anastomoses in a biotissue organ model using the da Vinci® system and were randomized to start with either 3D- or 2D-vision. Primary endpoint was the time required to complete both anastomoses. Secondary endpoint was the objective structured assessment of technical skill (OSATS; range 12-60) rating; scored by two observers blinded to 3D/2D. RESULTS: Robotic 3D-vision reduced the combined operative time from 78.1 to 57.3 min (24.6% reduction, p < 0.001; 20.8 min reduction, 95% confidence intervals 12.8-28.8 min). This reduction was consistent for both anastomoses and between surgeons and residents, p < 0.001. Robotic 3D-vision improved OSATS performance by 6.1 points (20.8% improvement, p = 0.003) compared to 2D (39.4 to 45.1 points, ± 5.5). CONCLUSION: 3D-vision has a considerable added value during robotic pancreatoduodenectomy anastomoses in biotissue in both time reduction and improved surgical performance as compared to 2D-vision.

Defining Benchmark Outcomes for Pancreatoduodenectomy With Portomesenteric Venous Resection.

OBJECTIVE: The aim of this study was to establish clinically relevant outcome benchmark values using criteria for pancreatoduodenectomy (PD) with portomesenteric venous resection (PVR) from a low-risk cohort managed in high-volume centers. SUMMARY BACKGROUND DATA: PD with PVR is regarded as the standard of care in patients with cancer involvement of the portomesenteric venous axis. There are, however, no benchmark outcome indicators for this population which hampers comparisons of patients undergoing PD with and without PVR resection. METHODS: This multicenter study analyzed patients undergoing PD with any type of PVR in 23 high-volume centers from 2009 to 2018. Nineteen outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers (NCT04053998). RESULTS: Out of 1462 patients with PD and PVR, 840 (58%) formed the benchmark cohort, with a mean age was 64 (SD11) years, 413 (49%) were females. Benchmark cutoffs, among others, were calculated as follows: Clinically relevant pancreatic fistula rate (International Study Group of Pancreatic Surgery): ≤14%; in-hospital mortality rate: ≤4%; major complication rate Grade≥3 and the CCI up to 6 months postoperatively: ≤36% and ≤26, respectively; portal vein thrombosis rate: ≤14% and 5-year survival for patients with pancreatic ductal adenocarcinoma: ≥9%. CONCLUSION: These novel benchmark cutoffs targeting surgical performance, morbidity, mortality, and oncological parameters show relatively inferior results in patients undergoing vascular resection because of involvement of the portomesenteric venous axis. These benchmark values however can be used to conclusively assess the results of different centers or surgeons operating on this high-risk group.

Staging Laparoscopy in Patients with Intrahepatic Cholangiocarcinoma: Is It Still Useful?

BACKGROUND: The role of staging laparoscopy in patients with intrahepatic cholangiocarcinoma remains unclear. Despite extensive preoperative imaging, approximately 25% of patients are deemed unresectable at laparotomy due to metastasized disease. The aim of this study was to evaluate the frequency of unresectable disease found at staging laparoscopy and to identify predictors for detecting metastasized intrahepatic cholangiocarcinoma. METHODS: We retrospectively collected records of all patients with intrahepatic cholangiocarcinoma, presenting at our institution from 2008 to 2017. Staging laparoscopy was performed on the suspicion of distant metastases and on indication in larger tumors. The yield and sensitivity of staging laparoscopy was calculated. Reasons for unresectability at staging laparoscopy or laparotomy were recorded. RESULTS: Among a total of 80 patients with potentially resectable intrahepatic cholangiocarcinoma, 35 patients underwent staging laparoscopy on the suspicion of distant metastases. Unresectable disease was found at staging laparoscopy in 15 patients. Reasons for unresectability were liver metastasis (n = 6), peritoneal metastasis (n = 4), severe cirrhosis (n = 2), locally advanced tumor with satellite lesions (n = 1), and distant lymph node metastasis (n = 2). Considering optimal preoperative imaging, the true yield of staging laparoscopy was 20% (7/35). Two patients did not undergo laparotomy due to progression after staging laparoscopy. Of the remaining 18 patients who underwent laparotomy, 6 patients (30%) had unresectable disease, mostly because of distant metastasis (n = 4). CONCLUSIONS: The role of staging laparoscopy to detect unresectable intrahepatic cholangiocarcinoma is highly dependent on the quality of preoperative imaging. Currently, no accurate selection criteria on imaging exist to select patients with intrahepatic cholangiocarcinoma who potentially benefit from staging laparoscopy.

Added value of 3D-vision during laparoscopic biotissue pancreatico- and hepaticojejunostomy (LAELAPS 3D2D): an international randomized cross-over trial.

BACKGROUND: It is currently unclear what the added value is of 3D-laparoscopy during pancreatic and biliary surgery. 3D-laparoscopy could improve procedure time and/or surgical performance, for instance in demanding anastomoses such as pancreatico- and hepaticojejunostomy. The impact of 3D-laparoscopy could be negligible in more experienced surgeons. METHODS: We conducted a randomized controlled cross-over trial including 20 expert laparoscopic surgeons and 20 surgical residents from 9 countries (Argentina, Estonia, Israel, Italy, the Netherlands, South Africa, Spain, UK, USA). All participants performed a pancreaticojejunostomy (PJ) and a hepaticojejunostomy (HJ) using 3D- and 2D-laparoscopy on biotissue organ models according to the Pittsburgh method. Primary endpoint was the time required to complete both anastomoses. Secondary endpoint was the objective structured assessment of technical skill (OSATS; range 12-60) rating. Observers were blinded for 3D/2D and expertise. RESULTS: A total of 40 participants completed 144 PJs and HJs. 3D-laparoscopy reduced the operative time with 15.5 min (95%CI 10.2-24.5 min), from 81.0 to 64.4 min, p = 0.001. This reduction was observed for both experts and residents (13.0 vs 22.2 min, intergroup significance p = 0.354). The OSATS improved with 5.1 points, SD ± 6.3, with 3D-laparoscopy, p = 0.001. This improvement was observed for both experts and residents (4.6 vs 5.6 points, p = 0.519). Of all participants, 37/39 participants stated to prefer 3D laparoscopy whereas 14/39 reported side effects. Minor side effects were reported by 10/39 participants whereas 2/39 participants reported severe side effects (both severe eye strain). CONCLUSION: 3D-laparoscopy, as compared to 2D-laparoscopy, reduced the operative time and improved surgical performance for PJ and HJ anastomoses in both experts and residents with mostly minor side effects.

Learning climate positively influences residents' work-related well-being.

An optimal learning climate is crucial for the quality of residency training and may also improve residents' well-being and empathy. We investigated the associations of learning climate with residents' work-related well-being. A multicenter questionnaire study was performed among 271 surgery and gynaecology residents in 21 training programs from September 2012 to February 2013. Residents were asked to complete work-related well-being measurements: work engagement (Utrecht Work Engagement Scale), job and specialty satisfaction (measures from Physician Worklife Study), and physician empathy (Jefferson Scale of Physician Empathy). The Dutch Residency Educational Climate Test was used to evaluate learning climate. Multivariate adjusted linear regression analyses were used to estimate associations of learning climate with work-related well-being measures. Well-being measures were completed by 144 residents (53.1%). Learning climate was evaluated by 193 residents, yielding 9.2 evaluations per training program on average. Overall learning climate score was positively associated with work engagement [regression coefficient b = 0.58; 95% confidence interval (CI) 0.18-0.98; p = 0.004] and job satisfaction (b = 0.80; 95% CI 0.48-1.13; p < 0.001). No associations were found between learning climate and empathy and specialty satisfaction. Residents' work engagement and job satisfaction are positively related to the learning climate and may be further enhanced by improved learning climates of training programs.

A preoperative prognostic model to predict surgical success in patients with perihilar cholangiocarcinoma.

BACKGROUND: Patients with resectable perihilar cholangiocarcinoma (PHC) on imaging have a substantial risk of metastatic or locally advanced disease, incomplete (R1) resection, and 90-day mortality. Our aim was to develop a preoperative prognostic model to predict surgical success, defined as a complete (R0) resection without 90-day mortality, in patients with resectable PHC on imaging. STUDY DESIGN: Patients with PHC who underwent exploratory laparotomy in three tertiary referral centers were identified. Multivariable logistic regression was performed to identify preoperatively available prognostic factors. A prognostic model was developed using data from two European centers and validated in one American center. RESULTS: In total, 671 patients with PHC underwent exploratory laparotomy. In the derivation cohort, surgical success was achieved in 102 of 331 patients (30.8%). No resection was performed in 176 patients (53.2%) because of metastatic or locally advanced disease. Of the 155 patients (46.8%) who underwent a resection, 38 (24.5%) had an R1-resection. Of the remaining 117 (35.3%), 15 (12.8%) had 90-day mortality. Independent poor prognostic factors for surgical success were identified, and a preoperative prognostic model was developed with a concordance index of 0.71. External validation showed good concordance (0.70). CONCLUSION: Surgical success was achieved in only 30% of patients with PHC undergoing exploratory laparotomy and could be predicted by age, cholangitis, hepatic artery involvement, lymph node metastases, and Blumgart stage.

Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial.

BACKGROUND: In patients with resectable perihilar cholangiocarcinoma, biliary drainage is recommended to treat obstructive jaundice and optimise the clinical condition before liver resection. Little evidence exists on the preferred initial method of biliary drainage. We therefore investigated the incidence of severe drainage-related complications of endoscopic biliary drainage or percutaneous transhepatic biliary drainage in patients with potentially resectable perihilar cholangiocarcinoma. METHODS: We did a multicentre, randomised controlled trial at four academic centres in the Netherlands. Patients who were aged at least 18 years with potentially resectable perihilar cholangiocarcinoma requiring major liver resection, and biliary obstruction of the future liver remnant (defined as a bilirubin concentration of >50 µmol/L [2·9 mg/dL]), were randomly assigned (1:1) to receive endoscopic biliary drainage or percutaneous transhepatic biliary drainage through the use of computer-generated allocation. Randomisation, done by the trial coordinator, was stratified for previous (attempted) biliary drainage, the extent of bile duct involvement, and enrolling centre. Patients were enrolled by clinicians of the participating centres. The primary outcome was the number of severe complications between randomisation and surgery in the intention-to-treat population. The trial was registered at the Netherlands National Trial Register, number NTR4243. FINDINGS: From Sept 26, 2013, to April 29, 2016, 261 patients were screened for participation, and 54 eligible patients were randomly assigned to endoscopic biliary drainage (n=27) or percutaneous transhepatic biliary drainage (n=27). The study was prematurely closed because of higher mortality in the percutaneous transhepatic biliary drainage group (11 [41%] of 27 patients) than in the endoscopic biliary drainage group (three [11%] of 27 patients; relative risk 3·67, 95% CI 1·15-11·69; p=0·03). Three of the 11 deaths among patients in the percutaneous transhepatic biliary drainage group occurred before surgery. The proportion of patients with severe preoperative drainage-related complications was similar between the groups (17 [63%] patients in the percutaneous transhepatic biliary drainage group vs 18 [67%] in the endoscopic biliary drainage group; relative risk 0·94, 95% CI 0·64-1·40). 16 (59%) patients in the percutaneous transhepatic biliary drainage group and ten (37%) patients in the endoscopic biliary drainage group developed preoperative cholangitis (p=0·1). 15 (56%) patients required additional percutaneous transhepatic biliary drainage after endoscopic biliary drainage, whereas only one (4%) patient required endoscopic biliary drainage after percutaneous transhepatic biliary drainage. INTERPRETATION: The study was prematurely stopped because of higher all-cause mortality in the percutaneous transhepatic biliary drainage group. Post-drainage complications were similar between groups, but the data should be interpreted with caution because of the small sample size. The results call for further prospective studies and reconsideration of indications and strategy towards biliary drainage in this complex disease. FUNDING: Dutch Cancer Foundation.

Variation in hospital mortality after pancreatoduodenectomy is related to failure to rescue rather than major complications: a nationwide audit.

BACKGROUND: In the mandatory nationwide Dutch Pancreatic Cancer Audit, rates of major complications and Failure to Rescue (FTR) after pancreatoduodenectomy between low- and high-mortality hospitals are compared, and independent predictors for FTR investigated. METHODS: Patients undergoing pancreatoduodenectomy in 2014 and 2015 in The Netherlands were included. Hospitals were divided into quartiles based on mortality rates. The rate of major complications (Clavien-Dindo ≥3) and death after a major complication (FTR) were compared between these quartiles. Independent predictors for FTR were identified by multivariable logistic regression analysis. RESULTS: Out of 1.342 patients, 391 (29%) developed a major complication and in-hospital mortality was 4.2%. FTR occurred in 56 (14.3%) patients. Mortality was 0.9% in the first hospital quartile (4 hospitals, 327 patients) and 8.1% in the fourth quartile (5 hospitals, 310 patients). The rate of major complications increased by 40% (25.7% vs 35.2%) between the first and fourth hospital quartile, whereas the FTR rate increased by 560% (3.6% vs 22.9%). Independent predictors of FTR were male sex (OR = 2.1, 95%CI 1.2-3.9), age >75 years (OR = 4.3, 1.8-10.2), BMI ≥30 (OR = 2.9, 1.3-6.6), histopathological diagnosis of periampullary cancer (OR = 2.0, 1.1-3.7), and hospital volume <30 (OR = 3.9, 1.6-9.6). CONCLUSIONS: Variations in mortality between hospitals after pancreatoduodenectomy were explained mainly by differences in FTR, rather than the incidence of major complications.

Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share a consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639, rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous = 1.19, 95% CI 1.02-1.38, p = 0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous = 0.51, 95% CI 0.39-0.67, p = 1.10 × 10-6 ) and MORC4-rs 12837024 (ORhomozygous = 2.07 (1.55-2.77, ptrend = 0.7 × 10-11 ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639, rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants.

The prognostic value of portal vein and hepatic artery involvement in patients with perihilar cholangiocarcinoma.

BACKGROUND: Although several classifications of perihilar cholangiocarcinoma (PHC) include vascular involvement, its prognostic value has not been investigated. Our aim was to assess the prognostic value of unilateral and main/bilateral involvement of the portal vein (PV) and hepatic artery (HA) on imaging in patients with PHC. METHODS: All patients with PHC between 2002 and 2014 were included regardless of stage or management. Vascular involvement was defined as apparent tumor contact of at least 180° to the PV or HA on imaging. Kaplan-Meier method with log-rank test was used to compare overall survival (OS) between groups. Cox regression was used for multivariable analysis. RESULTS: In total, 674 patients were included with a median OS of 12.2 (95% CI 10.6-13.7) months. Patients with unilateral PV involvement had a median OS of 13.3 (11.0-15.7) months, compared with 14.7 (11.7-17.6) in patients without PV involvement (p = 0.12). Patients with main/bilateral PV involvement had an inferior median OS of 8.0 (5.4-10.7, p < 0.001) months. Median OS for patients with unilateral HA involvement was 10.6 (9.3-12.0) months compared with 16.9 (13.2-20.5) in patients without HA involvement (p < 0.001). Patients with main/bilateral HA involvement had an inferior median OS of 6.9 (3.3-10.5, p < 0.001). Independent poor prognostic factors included unilateral and main/bilateral HA involvement, but not PV involvement. CONCLUSION: Both unilateral and main HA involvement are independent poor prognostic factors for OS in patients presenting with PHC, whereas PV involvement is not.

Ablation with irreversible electroporation in patients with advanced perihilar cholangiocarcinoma (ALPACA): a multicentre phase I/II feasibility study protocol.

INTRODUCTION: The majority of patients with perihilar cholangiocarcinoma (PHC) has locally advanced disease or distant lymph node metastases on presentation or exploratory laparotomy, which makes them not eligible for resection. As the prognosis of patients with locally advanced PHC or lymph node metastases in the palliative setting is significantly better compared with patients with organ metastases, ablative therapies may be beneficial. Unfortunately, current ablative options are limited. Photodynamic therapy causes skin phototoxicity and thermal ablative methods, such as stereotactic body radiation therapy and radiofrequency ablation, which are affected by a heat/cold-sink effect when tumours are located close to vascular structures, such as the liver hilum. These limitations may be overcome by irreversible electroporation (IRE), a relatively new ablative method that is currently being studied in several other soft tissue tumours, such as hepatic and pancreatic tumours. METHODS AND ANALYSIS: In this multicentre phase I/II safety and feasibility study, 20 patients with unresectable PHC due to vascular or distant lymph node involvement will undergo IRE. Ten patients who present with unresectable PHC will undergo CT-guided percutaneous IRE, whereas ultrasound-guided IRE will be performed in 10 patients with unresectable tumours detected at exploratory laparotomy. The primary outcome is the total number of clinically relevant complications (Common Terminology Criteria for Adverse Events, score of≥3) within 90 days. Secondary outcomes include quality of life, tumour response, metal stent patency and survival. Follow-up will be 2 years. ETHICS AND DISSEMINATION: The protocol has been approved by the local ethics committees. Data and results will be submitted to a peer-reviewed journal. CONCLUSION: The Ablation with irreversible eLectroportation in Patients with Advanced perihilar CholangiocarcinomA (ALPACA) study is designed to assess the feasibility of IRE for advanced PHC. The main purpose is to inform whether a follow-up trial to evaluate safety and effectiveness in a larger cohort would be feasible.

Future remnant liver function as predictive factor for the hypertrophy response after portal vein embolization.

BACKGROUND: Preoperative portal vein embolization is widely used to increase the future remnant liver. Identification of nonresponders to portal vein embolization is essential because these patients may benefit from associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), which induces a more powerful hypertrophy response. 99mTc-mebrofenin hepatobiliary scintigraphy is a quantitative method for assessment of future remnant liver function with a calculated cutoff value for the prediction of postoperative liver failure. The aim of this study was to analyze future remnant liver function before portal vein embolization to predict sufficient functional hypertrophy response after portal vein embolization. METHODS: Sixty-three patients who underwent preoperative portal vein embolization and computed tomography imaging were included. Hepatobiliary scintigraphy was performed to determine pre-portal vein embolization and post-portal vein embolization future remnant liver function. Receiver operator characteristic analysis of pre-portal vein embolization future remnant liver function was performed to identify patients who would meet the post-portal vein embolization cutoff value for sufficient function (ie, 2.7%/min/m2). RESULTS: Mean pre-portal vein embolization future remnant liver function was 1.80% ± 0.45%/min/m2 and increased to 2.89% ± 0.97%/min/m2 post-portal vein embolization. Receiver operator characteristic analysis in 33 patients who did not receive chemotherapy revealed that a pre-portal vein embolization future remnant liver function of ≥1.72%/min/m2 was able to identify patients who would meet the safe future remnant liver function cutoff value 3 weeks after portal vein embolization (area under the curve = 0.820). The predictive value was less pronounced in 30 patients treated with neoadjuvant chemotherapy (area under the curve = 0.618). A total of 45 of 63 patients underwent liver resection, of whom 5 of 45 developed postoperative liver failure; 4 of 5 patients had a post-portal vein embolization future remnant liver function below the cutoff value for safe resection. CONCLUSION: When selecting patients for portal vein embolization, future remnant liver function assessed with hepatobiliary scintigraphy can be used as a predictor of insufficient functional hypertrophy after portal vein embolization, especially in nonchemotherapy patients. These patients are potential candidates for ALPPS.