Background: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical... Show moreBackground: Management of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA), is multidisciplinary and subject to practice variation. We aimed to evaluate variation in clinical management of FNH and HCA in Europe.Methods: We distributed an online survey (November 2021-March 2022) among 294 European experts. The survey included questions on local practice and included eight clinical vignettes. The clinical vignettes focused on FNH or HCA management in the setting of sex, lifestyle modifi-cation, and pregnancy.Results: The response rate was 32% and respondents included surgeons (38%), gastroenterolo-gists/hepatologists (25%), radiologists (32%), and pathologists (1.6%) from ten European coun-tries. We observed practice variation with regard to lifestyle modification and imaging follow-up in patients with FNH, and with regard to the management of HCA >5 cm before and during pregnancy. Finally, the management of HCA >5 cm after lifestyle modification deviated from EASL guideline recommendations.Conclusion: Our survey illustrates variability in FNH and HCA management in Europe. Several areas were identified for future research and guideline recommendations, including FNH follow-up and the management of HCA >5 cm. We propose the organization of Delphi consensus meet-ings to prioritize areas of research and update current guidelines to optimize management for all patients with benign liver tumors.(c) 2023 Published by Elsevier Masson SAS. Show less
The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a... Show moreThe aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade >= 3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2)) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%-59.9%) vs. 43.7%, 95% CI: 32.8%-52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1 +/- 15 vs. 67.6 +/- 16 mL/min/1.73 m(2), p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade >= 3 at 36 months compared to normal-dose extended-release TAC. Show less
The aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in... Show moreThe aim of this study was to investigate whether the combination of low-dose sirolimus (SRL) and low-dose extended-release tacrolimus (TAC) compared to normal-dose extended-release TAC results in a difference in the renal function and comparable rates of rejection, graft and patient survival at 36 months after transplantation. This study was an open-label, multicenter randomized, controlled trial. Patients were randomized to once-daily normal-dose extended-release TAC (control group) or once-daily combination therapy of SRL and low-dose extended-release TAC (interventional group). The primary endpoint was the cumulative incidence of chronic kidney disease (CKD) defined as grade ≥3 (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2) at 36 months after transplantation. In total, 196 patients were included. CKD at 36 months was not different between the control and interventional group (50.8%, 95% CI: 39.7%–59.9%) vs. 43.7%, 95% CI: 32.8%–52.8%). Only at 6 months after transplantation, the eGFR was higher in the interventional group compared to the control group (mean eGFR 73.1±15 vs. 67.6±16 mL/min/1.73 m2, p=0.02) in the intention-to-treat population. No differences in the secondary endpoints and the number of serious adverse events were found between the groups. Once daily low-dose SRL combined with low-dose extended-release TAC does ultimately not provide less CKD grade ≥3 at 36 months compared to normal-dose extended-release TAC. Show less
Hepatocellular adenomas (HCAs) are benign liver tumors associated with bleeding or malignant transformation. Data on the indication for surgery are scarce. We analyzed indications and outcome of... Show moreHepatocellular adenomas (HCAs) are benign liver tumors associated with bleeding or malignant transformation. Data on the indication for surgery are scarce. We analyzed indications and outcome of patients operated for HCAs < 50 mm compared to HCAs >= 50 mm. Changes in final postoperative diagnosis were assessed. We performed a retrospective study that included patients who underwent resection for (suspected) HCAs in the Netherlands from 2014 to 2019. Indication for resection was analyzed and stratified for small (<50 mm) and large (>= 50 mm) tumors. Logistic regression analysis was performed on factors influencing change in tumor diagnosis. Out of 222 patients who underwent surgery, 44 (20%) patients had a tumor <50 mm. Median age was 46 (interquartile range [IQR], 33-56) years in patients with small tumors and 37 (IQR, 31-46) years in patients with large tumors (p = 0.016). Patients with small tumors were more frequently men (21% vs. 5%, p = 0.002). Main indications for resection in patients with small tumors were suspicion of (pre)malignancy (55%), (previous) bleeding (14%), and male sex (11%). Patients with large tumors received operations because of tumor size >50 mm (52%), suspicion of (pre)malignancy (28%), and (previous) bleeding (5.1%). No difference was observed in HCA-subtype distribution between small and large tumors. Ninety-six (43%) patients had a postoperative change in diagnosis. Independent risk factors for change in diagnosis were tumor size <50 mm (adjusted odds ratio [aOR], 3.4; p < 0.01), male sex (aOR, 3.7; p = 0.03), and lack of hepatobiliary contrast-enhanced magnetic resonance imaging (CE-MRI) (aOR, 1.8; p = 0.04). Resection for small (suspected) HCAs was mainly indicated by suspicion of (pre)malignancy, whereas for large (suspected) HCAs, tumor size was the most prevalent indication. Male sex, tumor size <50 mm, and lack of hepatobiliary CE-MRI were independent risk factors for postoperative change in tumor diagnosis. Show less
Objectives: To investigate the accrual proportion and patients' reasons for not participating in the PREOPANC trial on neoadjuvant chemoradiotherapy versus immediate surgery in resectable and... Show moreObjectives: To investigate the accrual proportion and patients' reasons for not participating in the PREOPANC trial on neoadjuvant chemoradiotherapy versus immediate surgery in resectable and borderline resectable pancreatic cancer, and to compare these patients' outcomes with those of patients who had been randomized in the trial. Summary of Background Data: The external validity of multicenter randomized trials in cancer treatment has been criticized for suboptimal non-representative inclusion. In trials, it is unclear how outcomes compare between randomized and nonrandomized patients. Methods: At 8 of 16 participant centers, this multicenter observational study identified validation patients, who had been eligible but not randomized during recruitment for the PREOPANC trial. We assessed the accrual proportion, investigated their most common reasons for not participating in the trial, and compared resection rates, radical (R0) resection rates, and overall survival between the validation patients and PREOPANC patients, who had been randomized in the trial to immediate surgery. Results: In total, 455 patients had been eligible during the recruitment period, 151 of whom (33%) had been randomized. Fifty-five percent of the 304 validation patients had refused to participate. Median overall survival in the validation group was 15.2 months, against 15.5 months in the PREOPANC group (P = 1.00). The respective resection rates (76% vs 73%) and R0 resection rates (51% vs 46%) did not differ between the groups. Conclusions: The PREOPANC trial included a reasonable percentage of 33% of eligible patients. In terms of the outcomes survival, resection rate, and R0 resection rate, this appeared to be a representative group. 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
Background: The aim of this study was to determine pancreatic surgery specific short- and long-term complications of pediatric, adolescent and young adult (PAYA) patients who underwent pancreatic... Show moreBackground: The aim of this study was to determine pancreatic surgery specific short- and long-term complications of pediatric, adolescent and young adult (PAYA) patients who underwent pancreatic resection, as compared to a comparator cohort of adults. Methods: A nationwide retrospective cohort study was performed in PAYA patients who underwent pancreatic resection between 2007 and 2016. PAYA was defined as all patients 40 years at time of surgery. Pancreatic surgery-specific complications were assessed according to international definitions and textbook outcome was determined. Results: A total of 230 patients were included in the PAYA cohort (112 distal pancreatectomies, 99 pancreatoduodenectomies), and 2526 patients in the comparator cohort. For pancreatoduodenectomy, severe morbidity (29.3% vs. 28.6%; P = 0.881), in-hospital mortality (1% vs. 4%; P = 0.179) and textbook outcome (62% vs. 58%; P = 0.572) were comparable between the PAYA and the comparator cohort. These outcomes were also similar for distal pancreatectomy. After pancreatoduodenectomy, new-onset diabetes mellitus (8% vs. 16%) and exocrine pancreatic insufficiency (27% vs. 73%) were lower in the PAYA cohort when compared to adult literature. Conclusion: Pancreatic surgery-specific complications were comparable with patients 40 years. Development of endocrine and exocrine insufficiency in PAYA patients who underwent pancreatoduodenectomy, however, was substantially lower compared to adult literature. Show less
Objective: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the... Show moreObjective: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial).Summary and Background Data: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov:NCT00355862), the effect of sirolimus on the recurrence of HCC after LTwas investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data.Patients and Methods: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence.Results: Sirolimus use for >= 3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) >= 10 ng/mL and having used sirolimus for >= 3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49- 0.59, P = 0.0079- 0.0245).Conclusions: mTOR-inhibitor treatment with sirolimus for >= 3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients.Clinical Trial Registration: EudraCT: 2005-005362-36 Clinicaltrials.gov: NCT00355862. Show less
Objective: Evaluation of the trends in incidence, diagnostics, treatment and survival of patients with hepatocellular carcinoma (HCC) in the Netherlands.Method: Data regarding incidence,... Show moreObjective: Evaluation of the trends in incidence, diagnostics, treatment and survival of patients with hepatocellular carcinoma (HCC) in the Netherlands.Method: Data regarding incidence, diagnostics, primary treatment and survival of patients with HCC in the period 2009-2016 were obtained from the Netherlands Cancer Registry. Trends in incidence, diagnostics, various treatment modalities (except liver transplantation, due to inaccurate data) and regional treatment preferences were analysed. Survival was evaluated using Kaplan-Meier curves and multivariable Cox proportional hazard regression modelling.Results: In the period of 2009-2016, 3838 patients were diagnosed with HCC. A distinct decrease in the percentage of patients who underwent tumour biopsy was observed (from 51% in 2009-2010 to 42% in 2015-2016). Percentage of patients who underwent cancer treatment increased markedly (from 49% in 2009-2010 to 57% in 2015-2016), mainly because of an increasing use of resection and ablation. The number of hospitals where resections were performed or sorafenib treatment prescribed decreased slightly. The number of hospitals sporadically (<1 ablation per year) performing ablations increased. There were significant differences between regions in the application of resection, ablation and transarterial chemoembolisation /radioembolisation (p < 0.05 after 'case mix'-correction). One-, 3 and 5-year survival of patients with HCC significantly improved in the studied period. Receiving cancer treatment was associated with increased survival, whereas increasing age and an advanced tumour stage were both associated with decreased survival.Conclusion: From 2009 to 2016, patients with hepatocellular carcinoma more often received cancer treatment and their survival improved. There were significant differences in types of treatment between various regions. (C) 2020 Elsevier Ltd. All rights reserved. Show less
Nieuwenhuizen, S.; Puijk, R.S.; Bemd, B. van den; Aldrighetti, L.; Arntz, M.; Boezem, P.B. van den; ... ; Meijerink, M.R. 2020
The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We... Show moreThe guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG <= 2, ASA <= 3 and Charlson comorbidity index <= 8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies. Show less
Background The optimal treatment sequence for patients with rectal cancer and synchronous liver metastases remains unclear. The aim of this study was to evaluate the feasibility and effectiveness... Show moreBackground The optimal treatment sequence for patients with rectal cancer and synchronous liver metastases remains unclear. The aim of this study was to evaluate the feasibility and effectiveness of short-course pelvic radiotherapy (5 x 5 Gy) followed by systemic therapy and local treatment of all tumour sites in patients with potentially curable stage IV rectal cancer in daily practice.Methods This was a retrospective study performed in eight tertiary referral centres in the Netherlands. Patients aged 18 years or above with rectal cancer and potentially resectable liver +/- extrahepatic metastases, treated between 2010 and 2015, were eligible. Main outcomes included full completion of treatment schedule, symptom control and survival.Results In total, 169 patients were included with a median follow-up of 49 center dot 5 (95 pr cent c.i. 43 center dot 6 to 55 center dot 6) months. The completion rate for the entire treatment schedule was 65 center dot 7 per cent. Three-year progression-free survival and overall survival (OS) rates were 24 center dot 2 (95 per cent c.i. 16 center dot 6 to 31 center dot 6) and 48 center dot 8 (40 center dot 4 to 57 center dot 2) per cent respectively. Median OS of patients who responded well and completed the treatment schedule was 51 center dot 5 months, compared with 15 center dot 1 months for patients who did not complete the treatment (P < 0 center dot 001). Adequate symptom control of the primary tumour was achieved in 87 center dot 0 per cent of all patients.Conclusion Multimodal treatment is palliative in most patients, and associated with good survival rates in those able to complete the schedule. Show less
