PurposeThe aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as... Show morePurposeThe aim of this study was to investigate the biodistribution of (super-)selective trans-arterial radioembolization (TARE) with holmium-166 microspheres (166Ho-MS), when administered as adjuvant therapy after RFA of HCC 2-5 cm. The objective was to establish a treatment volume absorbed dose that results in an absorbed dose of >= 120 Gy on the hyperemic zone around the ablation necrosis (i.e., target volume).MethodsIn this multicenter, prospective dose-escalation study in BCLC early stage HCC patients with lesions 2-5 cm, RFA was followed by (super-)selective infusion of 166Ho-MS on day 5-10 after RFA. Dose distribution within the treatment volume was based on SPECT-CT. Cohorts of up to 10 patients were treated with an incremental dose (60 Gy, 90 Gy, 120 Gy) of 166Ho-MS to the treatment volume. The primary endpoint was to obtain a target volume dose of >= 120 Gy in 9/10 patients within a cohort.ResultsTwelve patients were treated (male 10; median age, 66.5 years (IQR, [64.3-71.7])) with a median tumor diameter of 2.7 cm (IQR, [2.1-4.0]). At a treatment volume absorbed dose of 90 Gy, the primary endpoint was met with a median absorbed target volume dose of 138 Gy (IQR, [127-145]). No local recurrences were found within 1-year follow-up.ConclusionAdjuvant (super-)selective infusion of 166Ho-MS after RFA for the treatment of HCC can be administered safely at a dose of 90 Gy to the treatment volume while reaching a dose of >= 120 Gy to the target volume and may be a favorable adjuvant therapy for HCC lesions 2-5 cm.Trial registrationClinicaltrials.gov NCT03437382. (registered: 19-02-2018) Show less
BackgroundDetermining the resectability of pancreatic cancer with vascular involvement on preoperative computed tomography imaging remains challenging, especially following preoperative... Show moreBackgroundDetermining the resectability of pancreatic cancer with vascular involvement on preoperative computed tomography imaging remains challenging, especially following preoperative chemotherapy and chemoradiotherapy. Intraoperative ultrasound (IOUS) may provide real-time additional information, but prospective multicenter series confirming its value are lacking. Patients and MethodsThis prospective multicenter study included patients undergoing surgical exploration for pancreatic cancer with vascular involvement. All patients underwent IOUS at the start of explorative laparotomy. Primary outcomes were resectability status as defined by the National Comprehensive Cancer Network and the extent of vascular involvement. ResultsOverall, 85 patients were included, of whom 74 (87%) were post preoperative chemotherapy, and mostly following FOLFIRINOX regimen (n = 57; 76%). On the basis of preoperative imaging, 34 (40%) patients were staged as resectable (RPC), 32 (38%) borderline resectable (BRPC), and 19 (22%) locally advanced pancreatic cancer (LAPC). IOUS changed the resectability status in 32/85 (38%) patients (p < 0.001), including 8/19 (42%) patients with LAPC who were downstaged (4 to BRPC, 4 to RPC), and 22/32 (69%) patients with BRPC who were downstaged to RPC. Among patients with presumed superior mesenteric artery (SMA) involvement, 20/28 (71%) had no SMA involvement on IOUS. In 15 of these 20 patients a pancreatic resection was performed, all with R0 SMA margin. ConclusionIOUS during surgical exploration for pancreatic cancer and vascular involvement downstaged the resectability status in over one-third of patients, which could facilitate progress during surgical exploration. This finding should be confirmed by larger studies, including detailed pathology assessment. Show less
Introduction Benign liver tumours and cysts (BLTCs) comprise a heterogeneous group of cystic and solid lesions, including hepatic haemangioma, focal nodular hyperplasia and hepatocellular adenoma.... Show moreIntroduction Benign liver tumours and cysts (BLTCs) comprise a heterogeneous group of cystic and solid lesions, including hepatic haemangioma, focal nodular hyperplasia and hepatocellular adenoma. Some BLTCs, for example, (large) hepatocellular adenoma, are at risk of complications. Incidence of malignant degeneration or haemorrhage is low in most other BLTCs. Nevertheless, the diagnosis BLTC may carry a substantial burden and patients may be symptomatic, necessitating treatment. The indications for interventions remain matter of debate. The primary study aim is to investigate patient-reported outcomes (PROs) of patients with BLTCs, with special regards to the influence of invasive treatment as compared with the natural course of the disease.Methods and analysis A nationwide observational cohort study of patients with BLTC will be performed between October 2021 and October 2026, the minimal follow-up will be 2years. During surveillance, a questionnaire regarding symptoms and their impact will be sent to participants on a biannual basis and more often in case of invasive intervention. The questionnaire was previously developed based on PROs considered relevant to patients with BLTCs and their caregivers. Most questionnaires will be administered by computerised adaptive testing through the Patient-Reported Outcomes Measurement Information System. Data, such as treatment outcomes, will be extracted from electronic patient files. Multivariable analysis will be performed to identify patient and tumour characteristics associated with significant improvement in PROs or a complicated postoperative course. Ethics and dissemination The study was assessed by the Medical Ethics Committee of the University Medical Center Groningen and the Amsterdam UMC. Local consultants will provide information and informed consent will be asked of all patients. Results will be published in a peer-reviewed journal. Show less
Stroes, C.I.; Schokker, S.; Khurshed, M.; Woude, S.O. van der; Mathot, R.A.A.; Slingerland, M.; ... ; Laarhoven, H.W.M. van 2022
Purpose: Regorafenib monotherapy, a multikinase inhibitor of angiogenesis, tumor microenvironment, and tumorigenesis, showed promising results in gastric cancer. We aimed to assess the tolerability... Show morePurpose: Regorafenib monotherapy, a multikinase inhibitor of angiogenesis, tumor microenvironment, and tumorigenesis, showed promising results in gastric cancer. We aimed to assess the tolerability of regorafenib and paclitaxel in patients with advanced esophagogastric cancer (EGC) refractory to first-line treatment, and explore potential biomarkers. Methods: Patients received paclitaxel (80 mg/m(2)) on days 1, 8, and 15 of a 28-day cycle and regorafenib (80/120/160 mg) on days 1-21 in the dose-escalation cohort, and the maximum-tolerated dose (MTD) in the dose-expansion cohort. Exploratory, overall survival (OS) and progression-free survival (PFS) were compared to a propensity-score matched cohort receiving standard second-/third-line systemic treatment. Paclitaxel pharmacokinetics were assessed using samples from day 1 (D1) and day 15 (D15). We performed enzyme-linked immunosorbent assay measurements of galectin-1, RNA sequencing, and shallow whole-genome sequencing of metastatic tumor biopsies for biomarker analyses. Results: In the dose-escalation cohort (n = 14), the MTD of regorafenib was 120 mg. In all, 34 patients were enrolled in the dose-expansion cohort. Most common toxicities (all grades; grade >= 3) were fatigue (79%; 4%) and sensory neuropathy (63%; 4%). Best responses achieved were partial response (28%) and stable disease (54%). Median OS and PFS were 7.8 and 4.2 months, respectively (median follow-up: 7.8 months). OS (p = 0.08) and PFS (p = 0.81) were not significantly improved compared to the matched cohort. Paclitaxel concentrations were significantly increased with regorafenib (D15) compared with paclitaxel only (D1; p < 0.05); no associations were observed with toxicity or efficacy. An increase in circulating galectin-1 compared to baseline was associated with shorter OS (p < 0.01). Enrichment of angiogenesis-related gene expression was observed in short survivors measured by RNA sequencing. Chromosome 19q13.12-q13.2 amplification was associated with shorter OS (p = 0.02) and PFS (p = 0.02). Conclusion: Treatment with regorafenib and paclitaxel is tolerable and shows promising efficacy in advanced EGC refractory to first-line treatment. Galectin-1 and chromosome 19q13.12-q13.2 amplification could serve as negative predictive biomarkers for treatment response. Show less
Purpose To investigate the biodistribution of holmium-166 microspheres (Ho-166-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to... Show morePurpose To investigate the biodistribution of holmium-166 microspheres (Ho-166-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to establish a perfused liver administration dose that results in a tumoricidal dose of holmium-166 on the hyperaemic zone around the ablation necrosis (i.e. target volume). Materials and Methods This is a multicentre, prospective, dose-escalation study in HCC patients with a solitary lesion 2-5 cm, or a maximum of 3 lesions of <= 3 cm each. The day after RFA patients undergo angiography and cone-beam CT (CBCT) with (super)selective infusion of technetium-99 m labelled microalbumin aggregates (Tc-99m-MAA). The perfused liver volume is segmented from the CBCT and Ho-166-MS is administered to this treatment volume 5-10 days later. The dose of holmium-166 is escalated in a maximum of 3 patient cohorts (60 Gy, 90 Gy and 120 Gy) until the endpoint is reached. SPECT/CT is used to determine the biodistribution of holmium-166. The endpoint is met when a dose of >= 120 Gy has been reached on the target volume in 9/10 patients of a cohort. Secondary endpoints include toxicity, local recurrence, disease-free and overall survival. Discussion This study aims to find the optimal administration dose of adjuvant radioembolization with Ho-166-MS after RFA. Ultimately, the goal is to bring the efficacy of thermal ablation up to par with surgical resection for early-stage HCC patients. Show less
Purpose To investigate the biodistribution of holmium166 microspheres (166Ho-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to... Show morePurpose To investigate the biodistribution of holmium166 microspheres (166Ho-MS) when administered after radiofrequency ablation (RFA) of early-stage hepatocellular carcinoma (HCC). The aim is to establish a perfused liver administration dose that results in a tumoricidal dose of holmium-166 on the hyperaemic zone around the ablation necrosis (i.e. target volume). Materials and Methods This is a multicentre, prospective, dose-escalation study in HCC patients with a solitary lesion 2–5 cm, or a maximum of 3 lesions of B 3 cm each. The day after RFA patients undergo angiography and conebeam CT (CBCT) with (super)selective infusion of technetium-99 m labelled microalbumin aggregates (99mTcMAA). The perfused liver volume is segmented from the CBCT and 166Ho-MS is administered to this treatment volume 5–10 days later. The dose of holmium-166 is escalated in a maximum of 3 patient cohorts (60 Gy, 90 Gy and 120 Gy) until the endpoint is reached. SPECT/CT is used to determine the biodistribution of holmium-166. The endpoint is met when a dose of C 120 Gy has been reached on the target volume in 9/10 patients of a cohort. Secondary endpoints include toxicity, local recurrence, disease-free and overall survival. Discussion This study aims to find the optimal administration dose of adjuvant radioembolization with 166Ho-MS after RFA. Ultimately, the goal is to bring the efficacy of thermal ablation up to par with surgical resection for earlystage HCC patients. Show less
Smits, F.J.; Henry, A.C.; Besselink, M.G.; Busch, O.R.; Eijck, C.H. van; Arntz, M.; ... ; Dutch Pancreatic Cancer Group 2022
Background: Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk... Show moreBackground: Early recognition and management of postoperative complications, before they become clinically relevant, can improve postoperative outcomes for patients, especially for high-risk procedures such as pancreatic resection. Methods: We did an open-label, nationwide, stepped-wedge cluster-randomised trial that included all patients having pancreatic resection during a 22-month period in the Netherlands. In this trial design, all 17 centres that did pancreatic surgery were randomly allocated for the timing of the crossover from usual care (the control group) to treatment given in accordance with a multimodal, multidisciplinary algorithm for the early recognition and minimally invasive management of postoperative complications (the intervention group). Randomisation was done by an independent statistician using a computer-generated scheme, stratified to ensure that low-medium-volume centres alternated with high-volume centres. Patients and investigators were not masked to treatment. A smartphone app was designed that incorporated the algorithm and included the daily evaluation of clinical and biochemical markers. The algorithm determined when to do abdominal CT, radiological drainage, start antibiotic treatment, and remove abdominal drains. After crossover, clinicians were trained in how to use the algorithm during a 4-week wash-in period; analyses comparing outcomes between the control group and the intervention group included all patients other than those having pancreatic resection during this wash-in period. The primary outcome was a composite of bleeding that required invasive intervention, organ failure, and 90-day mortality, and was assessed by a masked adjudication committee. This trial was registered in the Netherlands Trial Register, NL6671. Findings: From Jan 8, 2018, to Nov 9, 2019, all 1805 patients who had pancreatic resection in the Netherlands were eligible for and included in this study. 57 patients who underwent resection during the wash-in phase were excluded from the primary analysis. 1748 patients (885 receiving usual care and 863 receiving algorithm-centred care) were included. The primary outcome occurred in fewer patients in the algorithm-centred care group than in the usual care group (73 [8%] of 863 patients vs 124 [14%] of 885 patients; adjusted risk ratio [RR] 0middot48, 95% CI 0middot38-0middot61; p<0middot0001). Among patients treated according to the algorithm, compared with patients who received usual care there was a decrease in bleeding that required intervention (47 [5%] patients vs 51 [6%] patients; RR 0middot65, 0middot42-0middot99; p=0middot046), organ failure (39 [5%] patients vs 92 [10%] patients; 0middot35, 0middot20-0middot60; p=0middot0001), and 90-day mortality (23 [3%] patients vs 44 [5%] patients; 0middot42, 0middot19-0middot92; p=0middot029). Interpretation: The algorithm for the early recognition and minimally invasive management of complications after pancreatic resection considerably improved clinical outcomes compared with usual care. This difference included an approximate 50% reduction in mortality at 90 days. Show less
Purpose The primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of < 10% in patients with hepatocellular carcinoma undergoing thermal... Show morePurpose The primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of < 10% in patients with hepatocellular carcinoma undergoing thermal ablation. Secondary objectives are to analyze the correlation between ablation margins and local recurrence and to assess efficacy.Materials and Methods This study is a prospective, multicenter, non-experimental, non-comparative, open-label study. Patients > 18 years with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma (or B with a maximum of two lesions < 5 cm each) are eligible. Patients will undergo dual-phase contrast-enhanced computed tomography directly before and after ablation. Ablation margins will be quantitatively assessed using co-registration software, blinding assessors (i.e. two experienced radiologists) for outcome. Presence and location of recurrence are evaluated independently on follow-up scans by two other experienced radiologists, blinded for the quantitative margin analysis. A sample size of 189 tumors (similar to 145 patients) is required to show with 80% power that the risk of local recurrence is confidently below 10%. A two-sided binomial z-test will be used to test the null hypothesis that the local recurrence rate is >= 10% for patients with a minimal ablation margin >= 2 mm. Logistic regression will be used to find the relationship between minimal ablation margins and local recurrence. Kaplan-Meier estimates are used to assess local and overall recurrence, disease-free and overall survival.Discussion It is expected that this study will result in a clear understanding of the correlation between ablation margins and local recurrence. Using co-registration software in future patients undergoing ablation for hepatocellular carcinoma may improve intraprocedural evaluation of technical success. Show less
PurposeThe primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of < 10% in patients with hepatocellular carcinoma undergoing thermal ablation.... Show morePurposeThe primary objective is to determine the minimal ablation margin required to achieve a local recurrence rate of < 10% in patients with hepatocellular carcinoma undergoing thermal ablation. Secondary objectives are to analyze the correlation between ablation margins and local recurrence and to assess efficacy.Materials and MethodsThis study is a prospective, multicenter, non-experimental, non-comparative, open-label study. Patients > 18 years with Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma (or B with a maximum of two lesions < 5 cm each) are eligible. Patients will undergo dual-phase contrast-enhanced computed tomography directly before and after ablation. Ablation margins will be quantitatively assessed using co-registration software, blinding assessors (i.e. two experienced radiologists) for outcome. Presence and location of recurrence are evaluated independently on follow-up scans by two other experienced radiologists, blinded for the quantitative margin analysis. A sample size of 189 tumors (~ 145 patients) is required to show with 80% power that the risk of local recurrence is confidently below 10%. A two-sided binomial z-test will be used to test the null hypothesis that the local recurrence rate is ≥ 10% for patients with a minimal ablation margin ≥ 2 mm. Logistic regression will be used to find the relationship between minimal ablation margins and local recurrence. Kaplan–Meier estimates are used to assess local and overall recurrence, disease-free and overall survival.DiscussionIt is expected that this study will result in a clear understanding of the correlation between ablation margins and local recurrence. Using co-registration software in future patients undergoing ablation for hepatocellular carcinoma may improve intraprocedural evaluation of technical success. Show less
Simple Summary: Hepatocellular carcinoma (HCC) is one of the deadliest forms of cancer. Selective internal radiation therapy (SIRT) is one of the therapeutic options for treatment of advanced HCC.... Show moreSimple Summary: Hepatocellular carcinoma (HCC) is one of the deadliest forms of cancer. Selective internal radiation therapy (SIRT) is one of the therapeutic options for treatment of advanced HCC. Studies show that SIRT has a high objective response rate, but lack of survival benefit when compared to different treatment modalities. We hypothesized that this is due to potential damage in healthy liver parenchyma as a side-effect of SIRT, resulting in functional changes to the liver. This can ultimately result in liver decompensation and potentially death. The aim of this retrospective study was to assess long-term liver-related complications after SIRT in patients with HCC. We analyzed patients who underwent SIRT and found that liver decompensation occurred more often after SIRT when compared to sorafenib. However, careful patient selection may result in a survival benefit after SIRT when compared to other treatments. The ABLI score may be a valuable prognostic score for selecting patients.Selective internal radiation therapy (SIRT) is used as a treatment for hepatocellular carcinoma (HCC). The aim of this study was to assess long-term liver-related complications of SIRT in patients who had not developed radioembolization-induced liver disease (REILD). The primary outcome was the percentage of patients without REILD that developed Child-Pugh (CP) & GE; B7 liver decompensation after SIRT. The secondary outcomes were overall survival (OS) and tumor response. These data were compared with a matched cohort of patients treated with sorafenib. Eighty-five patients were included, of whom 16 developed REILD. Of the remaining 69 patients, 38 developed liver decompensation CP & GE; B7. The median OS was 18 months. In patients without REILD, the median OS in patients with CP & GE; B7 was significantly shorter compared to those without CP & GE; B7; 16 vs. 31 months. In the case-matched analysis, the median OS was significantly longer in SIRT-treated patients; 16 vs. 8 months in sorafenib. Liver decompensation CP & GE; B7 occurred significantly more in SIRT when compared to sorafenib; 62% vs. 27%. The ALBI score was an independent predictor of liver decompensation (OR 0.07) and OS (HR 2.83). After SIRT, liver decompensation CP & GE; B7 often developed as a late complication in HCC patients and was associated with a shorter OS. The ALBI score was predictive of CP & GE; B7 liver decompensation and the OS, and this may be a valuable marker for patient selection for SIRT. Show less
Background: The combination treatment regimen of thermal ablation (TA) and transarterial chemoembolization (TACE) has gained a place in treatment of hepatocellular carcinoma (HCC) lesions > 3 cm... Show moreBackground: The combination treatment regimen of thermal ablation (TA) and transarterial chemoembolization (TACE) has gained a place in treatment of hepatocellular carcinoma (HCC) lesions > 3 cm unsuitable for surgery. Despite a high heterogeneity in the currently used treatment protocols, the pooled results of combined treatments seem to outperform those of TA or TACE alone. TACE preceding TA has been studied extensively, while results of the reverse treatment sequence are lacking. In this retrospective cohort study we compared the two treatment sequences. Patients and methods: 38 patients (median age: 68.5 yrs (range 40-84), male: 34, liver cirrhosis: 33, early stage HCC: 21, intermediate stage HCC: 17) were included in two tertiary referral centers, of whom 27 were treated with TA and adjuvant TACE (TA + TACE). The other 11 patients received TA with neoadjuvant TACE (TACE + TA). Overall survival (OS), time to progression (TTP) and local tumor progression (LTP) free survival were determined for the entire cohort and compared between the two treatment sequences. Results: The median OS of all patients was 52.7 months and the median time to LTP was 11.5 months (censored for liver transplantation). No differences were found with respect to OS between the two treatment sequences. Median time to LTP for TACE + TA was 23.6 months and 8.1 months for TA + TACE (p = 0.19). Discussion: No statistical differences were found for OS, TTP and time to LTP between patients treated with TA combined with neoadjuvant or adjuvant TACE. Show less
Elfrink, A.K.E.; Nieuwenhuizen, S.; Tol, M.P. van den; Burgmans, M.C.; Prevoo, W.; Coolsen, M.M.E.; ... ; Dutch Hepato Bili 2021
Background: Combining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital... Show moreBackground: Combining resection and thermal ablation can improve short-term postoperative outcomes in patients with colorectal liver metastases (CRLM). This study assessed nationwide hospital variation and short-term postoperative outcomes after combined resection and ablation.Methods: In this population-based study, all CRLM patients who underwent resection in the Netherlands between 2014 and 2018 were included. After propensity score matching for age, ASA-score, Charlson-score, diameter of largest CRLM, number of CRLM and earlier resection, postoperative outcomes were compared. Postoperative complicated course (PCC) was defined as discharge after 14 days or a major complication or death within 30 days of surgery.Results: Of 4639 included patients, 3697 (80%) underwent resection and 942 (20%) resection and ablation. Unadjusted percentage of patients who underwent resection and ablation per hospital ranged between 4 and 44%. Hospital variation persisted after case-mix correction. After matching, 734 patients remained in each group. Hospital stay (median 6 vs. 7 days, p = 0.011), PCC (11% vs. 14.7%, p = 0.043) and 30-day mortality (0.7% vs. 2.3%, p = 0.018) were lower in the resection and ablation group. Differences faded in multivariable logistic regression due to inclusion of major hepatectomy.Conclusion: Significant hospital variation was observed in the Netherlands. Short-term postoperative outcomes were better after combined resection and ablation, attributed to avoiding complications associated with major hepatectomy. Show less
BACKGROUNDPreoperative biliary drainage in patients with presumed resectable perihilar cholangiocarcinoma (PHC) is hypothesized to promote the occurrence of seeding metastases. Seeding metastases... Show moreBACKGROUNDPreoperative biliary drainage in patients with presumed resectable perihilar cholangiocarcinoma (PHC) is hypothesized to promote the occurrence of seeding metastases. Seeding metastases can occur at the surgical scars or at the site of postoperative drains, and in case of percutaneous biliary drainage, at the catheter port-site. To prevent seeding metastases after resection, we routinely treated PHC patients with preoperative radiotherapy (RT) for over 25 years until January 2018.AIMTo investigate the incidence of seeding metastases following resection of PHC.METHODSAll patients who underwent resection for pathology proven PHC between January 2000 and March 2019 were included in this retrospective study. Between 2000-January 2018, patients received preoperative RT (3 x 3.5 Gray). RT was omitted in patients treated after January 2018.RESULTSA total of 171 patients underwent resection for PHC between January 2000 and March 2019. Of 171 patients undergoing resection, 111 patients (65%) were treated with preoperative RT. Intraoperative bile cytology showed no difference in the presence of viable tumor cells in bile of patients undergoing preoperative RT or not. Overall, two patients (1.2%) with seeding metastases were identified, both in the laparotomy scar and both after preoperative RT (one patient with endoscopic and the other with percutaneous and endoscopic biliary drainage).CONCLUSIONThe incidence of seeding metastases in patients with resected PHC in our series was low (1.2%). This low incidence and the inability of providing evidence that preoperative low-dose RT prevents seeding metastases, has led us to discontinue preoperative RT in patients with resectable PHC in our center. Show less
BackgroundPancreatic resection is a major abdominal operation with 50% risk of postoperative complications. A common complication is pancreatic fistula, which may have severe clinical consequences... Show moreBackgroundPancreatic 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.MethodsThis 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 22months, 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 90days after pancreatic resection.DiscussionIt 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 registrationNetherlands Trial Register: NL 6671. Registered on 16 December 2017. Show less
Introduction Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post... Show moreIntroduction Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%-54%) and often severe complication. A prophylactic strategy is lacking.Methods and analysis The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium.Ethics and dissemination This study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal. Show less
