BackgroundGuidelines recommend standard pre-operative cardiac screening in all liver transplantation (LT) recipients, despite the relatively low prevalence of obstructive coronary artery disease.... Show moreBackgroundGuidelines recommend standard pre-operative cardiac screening in all liver transplantation (LT) recipients, despite the relatively low prevalence of obstructive coronary artery disease. Most LT recipients often have non-gated computed tomography (CT) performed of the chest and abdomen. This study evaluated the ability of coronary artery calcification (CAC) assessment on consecutively available scans, to identify a selection of low-risk patients, in whom further cardiac imaging can be safely withheld.MethodsLT recipients with prior non-gated CT chest-abdomen were included. CAC was visually scored on a semi-quantitative ordinal scale. Stress myocardial perfusion, coronary CT angiography (CCTA) and invasive coronary angiography (ICA) were used as golden standard. The sensitivity and specificity of CAC to exclude and predict obstructive CAD were assessed. In addition, peri- and postoperative mortality and cardiac events were analyzed.Results149 LT recipients (ranged 31–71 years) were included. In 75% of patients, no CAC and mild CAC could rule out obstructive CAD on CCTA and ICA with 100% certainty. The threshold of mild CAC had a sensitivity of 100% for both CCTA and ICA and a specificity of 91% and 68%, respectively. None of the patients with no or mild calcifications experienced peri- and post-operative cardiac events or died of cardiac causes.ConclusionVisual evaluation of CAC on prior non-gated CT can accurately and safely exclude obstructive CAD in LT recipients. Incorporation of these already available data can optimize cardiac screening, by safely withholding or correctly allocating dedicated cardiac imaging in LT recipients. Thereby, reducing patients' test burden and save health care expenses. Show less
Broekhoven, A.G.C.; Ostyn, T.; Melkebeke, L. van; Verspaget, H.W.; Merwe, S. van der; Verbeek, J.; ... ; Nevens, F. 2024
ObjectivesAlcoholic hepatitis (AH) is a frequent precipitating event for the development of acute-on-chronic liver failure (ACLF), a syndrome characterised by organ failures due to immune... Show moreObjectivesAlcoholic hepatitis (AH) is a frequent precipitating event for the development of acute-on-chronic liver failure (ACLF), a syndrome characterised by organ failures due to immune dysfunction. The histological features of this complication are not well characterized. We investigated whether ACLF has specific histological characteristics.MethodsProspective cohort study in consecutive adult patients admitted between 03-2008 and 04-2021 to a tertiary referral centre with suspected AH. Diagnosis of AH was based on clinical presentation and confirmed by transjugular liver biopsy. All biopsies were assessed by a dedicated liver pathologist, blinded for clinical data and outcome. Diagnosis of ACLF was based on EASL-CLIF criteria. Histological and clinical characteristics of patients with and without ACLF at baseline were compared.Results184 patients with biopsy-proven AH were enrolled. Median time from hospital admission to transjugular biopsy was 4.5 days (IQR 2-8). At baseline, ACLF was present in 73 patients (39.7%). Out of the 110 patients without ACLF at baseline, 30 (27.3%) developed ACLF within 28 days (median 7.5 days (IQR 2-20)). At baseline, ductular bilirubinostasis (DB) was the only histological feature significantly more frequently present in patients with ACLF compared to patients without ACLF (50.7% vs. 30.6%, p = 0.003). No clear association between histological features and the development of ACLF later on could be demonstrated.ConclusionsIn this well-defined cohort of patients with biopsy-proven AH, DB was associated with the presence of ACLF. This finding fits with the pathophysiology of this syndrome, which is characterized by systemic inflammation and an increased risk of infections. Show less
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
Purpose: The primary objective of this study was to determine the feasibility of ablation margin quantification using a standardized scanning protocol during thermal ablation (TA) of hepatocellular... Show morePurpose: The primary objective of this study was to determine the feasibility of ablation margin quantification using a standardized scanning protocol during thermal ablation (TA) of hepatocellular carcinoma (HCC), and a rigid registration algorithm. Secondary objectives were to determine the inter- and intra-observer variability of tumor segmentation and quantification of the minimal ablation margin (MAM). Materials and methods: Twenty patients who underwent thermal ablation for HCC were included. There were thirteen men and seven women with a mean age of 67.1 +/- 10.8 (standard deviation [SD]) years (age range: 49.1-81.1 years). All patients underwent contrast-enhanced computed tomography examination under general anesthesia directly before and after TA, with preoxygenated breath hold. Contrast-enhanced computed tomography examinations were analyzed by radiologists using rigid registration software. Registration was deemed feasible when accurate rigid co-registration could be obtained. Inter- and intra-observer rates of tumor segmentation and MAM quantification were calculated. MAM values were correlated with local tumor progression (LTP) after one year of follow-up. Results: Co-registration of pre- and post-ablation images was feasible in 16 out of 20 patients (80%) and 26 out of 31 tumors (84%). Mean Dice similarity coefficient for inter- and intra-observer variability of tumor segmentation were 0.815 and 0.830, respectively. Mean MAM was 0.63 +/- 3.589 (SD) mm (range: -6.26 -6.65 mm). LTP occurred in four out of 20 patients (20%). The mean MAM value for patients who developed LTP was -4.00 mm, as compared to 0.727 mm for patients who did not develop LTP. Conclusion: Ablation margin quantification is feasible using a standardized contrast-enhanced computed tomography protocol. Interpretation of MAM was hampered by the occurrence of tissue shrinkage during TA. Further validation in a larger cohort should lead to meaningful cut-off values for technical success of TA. (c) 2023 The Author(s). Published by Elsevier Masson SAS on behalf of Societe francaise de radiologie. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Show less
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further... Show moreThe prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further testing. However, liver enzymes within the normal range do not exclude the presence of MASLD. We examined the prevalence of MASLD in a middle-aged population with overweight and normal liver enzymes. In addition, we examined the accuracy of 4 sets of noninvasive proxies for MASLD.We included 1017 participants from the Netherlands epidemiology of obesity cohort study with body mass index ≥25 kg/m2 and liver enzymes (asparate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase) within normal range. The diagnostic accuracy of biomarker scores (fatty liver index, liver fat score [LFS], STEATO-ELSA, and hepatic steatosis index) was determined against elevated hepatic triglyceride content measured by 1proton magnetic resonance spectroscopy.Participants (mean age 56 years, 49% women), had a median body mass index of 29.6 kg/m2 and a median hepatic triglyceride content of 4.4%. MASLD was present in 42% of participants and was more common in men than women, with respectively 47% and 36% being affected. The LFS showed the highest accuracy with an area under the curve of 0.72. We identified metabolic syndrome as the prime predictor for MASLD with an odds ratio of 2.95 (95% confidence interval 2.20–3.98).The prevalence of MASLD in middle-aged men and women with overweight and liver enzymes within the normal range is over 40%. LFS showed the highest accuracy to detect MASLD, but, overall, biomarker scores performed relatively poor. The presence of metabolic syndrome was the prime predictor of MASLD. Show less
Alblas, G.; Lamb, H.J.; Rosendaal, F.R.; Hoek, B. van; Coenraad, M.J.; Mutsert, R. de 2023
Background and aim: Non-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content >= 5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination... Show moreBackground and aim: Non-alcoholic fatty liver disease (NAFLD) is defined as a liver fat content >= 5.56%. It is of clinical interest to know the prevalence of NAFLD in people with a combination of metabolic risk factors. We aimed to examine the prevalence of NAFLD, including groups with metabolic risk factors.Methods and results: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity (NEO) study, liver fat content was assessed using proton magnetic resonance spectroscopy (H-MRS). Participants with excessive alcohol consumption or missing values were excluded, leaving a total of 1570 participants for the analyses. Mean (SD) age of the population was 55 years, BMI 25.9 (4.0) kg/m(2) and 46% were men. The prevalence of NAFLD was 27% (95% CI 24-30). The prevalence of NAFLD was increased in participants with hypertriglyceridemia (57%, 52-63), obesity (62%, 58-66) and diabetes (69%, 61-77). The prevalence of NAFLD was highest in those with diabetes and obesity (79%, 71-87), obesity and hypertriglyceridemia (81%, 76-86) and with diabetes and hypertriglyceridemia (86%, 77-95). NAFLD was also present in 12% (8-16) of participants without overweight.Conclusions: The prevalence of NAFLD in a middle-aged population in the Netherlands in 2010 was 27%. The prevalence of NAFLD is particularly increased in individuals with diabetes, obesity, and hypertriglyceridemia. This information may help clinicians and general practitioners in the risk stratification of their patients in daily practice.(c) 2023 The Author(s). Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
This narrative review addresses the definition of acute-on-chronic liver failure, a condition associated with high short-term mortality in patients with chronic liver disease and/or cirrhosis. We... Show moreThis narrative review addresses the definition of acute-on-chronic liver failure, a condition associated with high short-term mortality in patients with chronic liver disease and/or cirrhosis. We provide two major points of view: the East and the West perspective. Both definitions vary regarding the underlying patient population and organ failure(s) definition. Nevertheless, all the definitions have their clinical utility: from the core concept of having the "liver" as a conditio sine qua non, the syndrome cannot exist (Asian Pacific Association for the Study of the Liver); a data-driven, robust definition (European Association for the Study of the Liver); a bedside tool that can quickly identify patients at high risk of dying (North American Consortium for the Study of End-stage Liver Disease [NACSELD]). In each section, we provide the overall definitions, the criteria of organ failure(s), and some epidemiological data illustrating how these apply in each area of the world. Show less
Melkebeke, L. van; Broekhoven, A.G.C.; Ostyn, T.; Korf, H.; Coenraad, M.J.; Vangoitsenhoven, R.; ... ; Verbeek, J. 2023
Purpose: Patients with prior bariatric surgery (BS) are at risk to develop alcohol use disorder (AUD) and alcohol-related liver disease (ALD). Severe alcoholic hepatitis (sAH) is one of the most... Show morePurpose: Patients with prior bariatric surgery (BS) are at risk to develop alcohol use disorder (AUD) and alcohol-related liver disease (ALD). Severe alcoholic hepatitis (sAH) is one of the most severe manifestations of ALD with a 28-day mortality of 20-50%. The impact of prior BS on patients presenting with sAH was assessed. Methods: From 01/2008 to 04/2021, consecutive patients admitted to a tertiary referral center with biopsy-proven sAH were included in a database. Results: One hundred fifty-eight sAH patients of which 28 patients had a history of BS (BS group) were identified. Of this BS group, 24 patients underwent a Roux-en-Y gastric bypass (RYGB), 3 a biliopancreatic diversion, 1 an adjustable gastric band, and no patients a sleeve gastrectomy. The proportion of patients with BS increased threefold over time during the study period. Patients in the BS group were significantly younger at diagnosis of sAH (44.3 years vs 52.4 years), were more frequently female, and had a higher body mass index and a higher grade of steatosis on liver biopsy. The correlation between BS and a younger age at diagnosis remained significant in a multivariate regression analysis. There were no differences in disease severity between both groups. Furthermore, there were no differences in corticosteroid response, 28-day, 90-day, or 1-year survival. Conclusion: Prior BS is independently associated with a younger age of presentation with sAH, but is not independently associated with a different disease severity or outcome. These findings support the need for early detection of AUD in patients who underwent BS, in particular RYGB. Show less
This letter to the editor responds to comments from Rizzo et al on recently reported results of a phase II study of dovitinib therapy for hepatocellular carcinoma.
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
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
Broekhoven, A.G.C.; Fiocco, M.; Sprengers, D.; Takkenberg, R.B.; Meer, S. van; Erpecum, K.J. van; ... ; Coenraad, M.J. 2022
Patients with Barcelona Clinic Liver Cancer intermediate stage hepatocellular carcinoma (HCC) theoretically are an excellent group to consider downstaging using locoregional therapy (LRT) since... Show morePatients with Barcelona Clinic Liver Cancer intermediate stage hepatocellular carcinoma (HCC) theoretically are an excellent group to consider downstaging using locoregional therapy (LRT) since they do not have extrahepatic spread or vascular invasion. Once successful, this can change the treatment strategy from palliative to curative intention. Although downstaging therapy is suggested in guidelines, it is still not widely accepted. Moreover, studies on downstaging are mainly performed in high-incidence HCC countries. Therefore, our aim was to gain insight in therapeutic strategies in patients with intermediate stage HCC and their impact on intention-to-treat survival in a real-life setting in a low-incidence HCC country.We retrospectively analyzed data from the national Dutch HCC registry. From this database, consisting of 1409 patients with a diagnosis of HCC between 2005-2013 in 5 Dutch tertiary referral centers, we identified 165 patients with intermediate stage HCC. Out of these patients, 63 (38%) were not offered LRT, whereas 102 (62%) did receive LRT. Subsequently, 50 (49%) of the 102 patients who received LRT were successfully downstaged. Eleven patients (22% of successfully downstaged patients) eventually underwent liver transplantation. Cox regression analysis showed that a lower MELD score, an AFP value <100 ng/ml, successful downstaging and liver transplantation (all <= p = 0.01) were positively associated to overall survival.In conclusion, our results demonstrate that LRT is not routinely offered to intermediate stage HCC patients in the Netherlands. Nevertheless, we showed that patients with intermediate stage HCC who are successfully downstaged have a survival benefit compared to those who were not. Show less
Broekhoven, A.G.C.; Fiocco, M.; Sprengers, D.; Takkenberg, R.B.; Meer, S. van; Erpecum, K.J. van; ... ; Coenraad, M.J. 2022
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
Objective: Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody... Show moreObjective: Immunosuppressive agents are known to interfere with T and/or B lymphocytes, which are required to mount an adequate serologic response. Therefore, we aim to investigate the antibody response to SARS-CoV-2 in liver transplant (LT) recipients after COVID-19. Design: Prospective multicentre case-control study, analysing antibodies against the nucleocapsid protein, spike (S) protein of SARS-CoV-2 and their neutralising activity in LT recipients with confirmed SARS-CoV-2 infection (COVID-19-LT) compared with immunocompetent patients (COVID-19-immunocompetent) and LT recipients without COVID-19 symptoms (non-COVID-19-LT). Results: Overall, 35 LT recipients were included in the COVID-19-LT cohort. 35 and 70 subjects fulfilling the matching criteria were assigned to the COVID-19-immunocompetent and non-COVID-19-LT cohorts, respectively. We showed that LT recipients, despite immunosuppression and less symptoms, mounted a detectable antinucleocapsid antibody titre in 80% of the cases, although significantly lower compared with the COVID-19-immunocompetent cohort (3.73 vs 7.36 index level, p<0.001). When analysing anti-S antibody response, no difference in positivity rate was found between the COVID-19-LT and COVID-19-immunocompetent cohorts (97.1% vs 100%, p=0.314). Functional antibody testing showed neutralising activity in 82.9% of LT recipients (vs 100% in COVID-19-immunocompetent cohort, p=0.024). Conclusions: Our findings suggest that the humoral response of LT recipients is only slightly lower than expected, compared with COVID-19 immunocompetent controls. Testing for anti-S antibodies alone can lead to an overestimation of the neutralising ability in LT recipients. Altogether, routine antibody testing against separate SARS-CoV-2 antigens and functional testing show that the far majority of LT patients are capable of mounting an adequate antibody response with neutralising ability. Show less
Background & aims: Acute-on-chronic liver failure (ACLF) is usually associated with a precipitating event and results in the failure of other organ systems and high short-term mortality.... Show moreBackground & aims: Acute-on-chronic liver failure (ACLF) is usually associated with a precipitating event and results in the failure of other organ systems and high short-term mortality. Current prediction models fail to adequately estimate prognosis and need for liver transplantation (LT) in ACLF. This study develops and validates a dynamic prediction model for patients with ACLF that uses both longitudinal and survival data.Methods: Adult patients on the UNOS waitlist for LT between 11.01.2016-31.12.2019 were included. Repeated model for end-stage liver disease-sodium (MELD-Na) measurements were jointly modelled with Cox survival analysis to develop the ACLF joint model (ACLF-JM). Model validation was carried out using separate testing data with area under curve (AUC) and prediction errors. An online ACLF-JM tool was created for clinical application.Results: In total, 30,533 patients were included. ACLF grade 1 to 3 was present in 16.4%, 10.4% and 6.2% of patients, respectively. The ACLF-JM predicted survival significantly (p <0.001) better than the MELD-Na score, both at baseline and during follow-up. For 28- and 90-day predictions, ACLF-JM AUCs ranged between 0.840-0.871 and 0.833-875, respectively. Compared to MELD-Na, AUCs and prediction errors were improved by 23.1%-62.0% and 5%-37.6% respectively. Also, the ACLF-JM could have prioritized patients with relatively low MELD-Na scores but with a 4-fold higher rate of waiting list mortality.Conclusions: The ACLF-JM dynamically predicts outcome based on current and past disease severity. Prediction performance is excellent over time, even in patients with ACLF-3. Therefore, the ACLF-JM could be used as a clinical tool in the evaluation of prognosis and treatment in patients with ACLF.Lay summary: Acute-on-chronic liver failure (ACLF) progresses rapidly and often leads to death. Liver transplantation is used as a treatment and the sickest patients are treated first. In this study, we develop a model that predicts survival in ACLF and we show that the newly developed model performs better than the currently used model for ranking patients on the liver transplant waiting list. (C) 2021 The Author(s). Published by Elsevier B.V. Show less
Karkampouna, S.; Helm, D. van der; Scarpa, M.; Hoek, B. van; Verspaget, H.W.; Goumans, M.J.; ... ; Julio, M.K.D. 2021
Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO... Show moreOncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (alpha SMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4), were evaluated for CRIPTO expression and fibrotic markers. CRIPTO was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for CRIPTO and fibrotic markers in three models of heart injury following myocardial infarction, pressure overload, and ex vivo induced fibrosis. Patients with end-stage liver cirrhosis showed elevated CRIPTO levels in plasma, which decreased 1 year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of CRIPTO in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. CRIPTO expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, CRIPTO-positive cells were observed in damaged liver areas around the central vein, which preceded the expression of alpha SMA-positive stellate cells, i.e., mediators of fibrosis. In the chronic mouse models, the fibrosis and CRIPTO expression were still present after 11 weeks, whereas in the acute model the liver regenerated and the fibrosis and CRIPTO expression resolved. In vivo overexpression of CRIPTO in this model led to an increase in fibrotic markers, while blockage of CRIPTO secreted function inhibited the extent of fibrotic areas and marker expression (alpha SMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. CRIPTO expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction CRIPTO is upregulated initially in cardiac interstitial cells, followed by expression in alpha SMA-positive myofibroblasts throughout the infarct area. After the scar formation, CRIPTO expression decreased concomitantly with the alpha SMA expression. Temporal expression of CRIPTO in alpha SMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis.Furthermore, CRIPTO expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Our results are indicative for a functional role of CRIPTO in the induction of fibrogenesis as well as a potential target in the antifibrotic treatments and stimulation of tissue regeneration. 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
