Adjuvant holmium-166 radioembolization after radiofrequency ablation in early-stage hepatocellular carcinoma patients: a dose-finding study (HORA EST HCC trial).

PURPOSE: The 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). METHODS: In 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. RESULTS: Twelve 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. CONCLUSION: Adjuvant (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 REGISTRATION: Clinicaltrials.gov NCT03437382 . (registered: 19-02-2018).

Diagnosis and treatment of patients with suspected mucinous cystic neoplasms of the liver: a retrospective cohort study.

PURPOSE: Mucinous cystic neoplasms of the liver (MCN-L) are hepatic cysts with a low malignant potential. The recent European Association for the Study of the Liver (EASL) guidelines provide guidance on the imaging features and surgical management of MCN-L, yet are hampered by a lack of studies adhering to the revised World Health Organization (WHO) criteria. This study attempted to validate the new 2022 EASL-guidelines in a retrospective cohort study of patients who underwent surgery for suspected MCN-L. METHODS: Patients undergoing surgery for suspected MCN-L in a single center between 2010 and 2020 were included. Imaging features were assessed according to the EASL guidelines and were compared to final pathological diagnoses, according to the WHO criteria. RESULTS: In total, 35 patients were included. In three patients, there were no worrisome imaging features, yet final pathological diagnosis showed MCN-L. Contrarily, six patients with worrisome imaging features did not have MCN-L. Five patients were diagnosed with MCN-L on final pathology. The sensitivity of the EASL-guidelines for the diagnosis of MCN-L was 40% (95%CI: 5.3-85%) and the specificity was 80% (95% CI: 61-92%). CONCLUSION: Although the new EASL-guidelines provide some guidance, they could not reliably distinguish MCN-L from other cysts in our series. Thus, preoperative diagnosis of MCN-L remains challenging and we should be careful in selecting surgical strategies based on these criteria.

Evaluation of ear, nose, and throat-screening in liver transplantation candidates: A retrospective cohort study.

BACKGROUND: Patients with end-stage liver disease can be treated with a liver transplantation (LT). Before listing, candidates are subjected to a screening procedure according to the EASL Clinical Practice Guidelines for LT. In our hospital, this includes an ear, nose, and throat (ENT) examination, directed towards the identification of (asymptomatic) infections and head and neck malignancies. METHODS: We retrospectively reviewed all ENT screening examinations in LT candidates from 2007 to 2022. The screening consisted of a visit to the ENT outpatient clinic combined with sinus radiography. RESULTS: ENT screening was performed in 1099 patients. Sixty-one cases were identified, either diagnosed with an infection (n = 58, almost exclusively sinusitis) or a neoplasm (n = 3, of which two malignancies). With binary logistic regression, we could not identify significant risk factors for diagnosing sinusitis. 711 patients underwent LT. After LT, two patients developed a novel malignancy of the head and neck area, while 14 patients were diagnosed with sinusitis, two of the latter already showed opacification on sinus radiography during screening. Despite immunosuppressive drugs, no complicated sinusitis was observed. CONCLUSION: Sinusitis or a neoplasm was diagnosed in almost 6% in a large cohort of LT candidates. Although almost a third of sinusitis patients were not treated accordingly, we did not observe any complicated sinusitis after LT. A more conservative approach to sinusitis may therefore be justified in LT candidates, especially in asymptomatic cases. At our institution, we aim to refer only those patients with specific ENT complaints .

Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity.

BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. METHODS: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. RESULTS: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). CONCLUSION: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. TRIAL REGISTRATION: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

Relief of symptoms and quality of life after conservative versus surgical treatment of benign liver tumors (CONSULT): a retrospective propensity score matched study.

BACKGROUND: Surgery can be considered for selected patients with benign liver tumours (BLT). The aim of this study was to compare symptoms and quality of life (QoL) after conservative and surgical management of BLT. METHODS: In this dual-site cross-sectional retrospective study, adult patients with BLT diagnosed between 2000 and 2019 completed EORTC QLQ-C30 questionnaires on current symptoms and symptoms at diagnosis. Summary scores (SumScores) and QoL scores at follow-up were compared between surgically and conservatively treated patients by matched t-tests. Propensity score matching attempted to reduce confounding. Higher scores indicate less symptoms and higher QoL. RESULTS: Fifty surgically (22.6%) and 171 (77.4%) conservatively treated patients were included at median 95 (IQR:66-120) and 91 (IQR:52-129) months, respectively. Most surgically treated patients reported stable, improved or disappeared symptoms (87%) and would undergo surgery again (94%). After propensity score matching, surgical patients had higher SumScores (mean difference 9.2, 95%CI:1.0-17.4, p = 0.028) but not higher QoL scores (p = 0.331) at follow-up than conservatively treated counterparts (31 patients in both groups). DISCUSSION: Patients who had undergone surgery often reported they would undergo surgery again. Moreover, they had less symptoms than conservatively managed patients while they were propensity score matched on relevant variables, including baseline symptoms.

Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease.

Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.

Decompensation as initial presentation in patients with liver cirrhosis is associated with an increased risk of future decompensation and mortality.

BACKGROUND AND AIMS: The clinical course of patients with liver cirrhosis and adherence to hepatocellular carcinoma (HCC) screening guidelines are not well studied in the Netherlands. We investigated this and potential risk factors for decompensation and transplant-free survival (TFS) in a large regional cohort. METHODS: We performed a retrospective cohort study of patients with confirmed liver cirrhosis in Amsterdam, the Netherlands. Clinical parameters, decompensation events, development of HCC, and medication use were extracted from medical records. RESULTS: In total, 681 hospitalized and outpatients were included. Mortality risk was increased by: age (aHR 1.07, p < 0.01), smoking (aHR 1.83, p < 0.01), decompensated initial presentation (aHR 1.43, p = 0.04) and increased MELD (aHR 1.07, p < 0.01). PPI use tended to increase mortality risk (aHR 1.35, p = 0.05). The risk of future decompensation was increased with increased age (aHR 1.02, p < 0.01), decompensated initial presentation (aHR 1.37, p = 0.03) and alcohol misuse as etiology (aHR 1.34, p = 0.04). Adequately screened patients for HCC had a longer TFS compared to patients who were not (48 vs 22 months), p < 0.01). CONCLUSIONS: In patients with cirrhosis, decompensation at initial presentation was associated with an increased risk of future decompensation and mortality. Alcoholic cirrhosis was associated with an increased risk of future decompensation. Adequate HCC surveillance was associated with markedly better survival.

Development of a set of patient reported outcome measures for patients with benign liver tumours and cysts: patient focus groups and systematic review.

BACKGROUND: Patient reported outcome measures (PROMs) may be useful for patients with benign liver tumours and cysts (BLTC) to evaluate the impact of treatment and/or guide shared decision making. Yet, a set of PROMs relevant to patients with BLTC is currently unavailable. In this study, we selected a PROMs set for patients with BLTC. METHODS: Potentially relevant patient reported outcomes (PROs) were selected by psychologist-researchers based on keywords used or suggested by participants of two virtual focus groups meetings consisting of thirteen female BLTC patients with a median age of 50 years. Subsequently, patients were asked to report their most relevant PROs. PROMs identified by systematic literature review and computerized adaptive tests (CATs) in the Patient-Reported Outcomes Measurement Information System (PROMIS) were considered in selecting the final PROMs set to assess relevant outcomes. RESULTS: The most important PROs were: insecurity/anxiety (11/12 patients), pain (9/12 patients), fatigue (8/12 patients), and limitations in daily life (5/12 patients). The literature review included 23 studies, which used various generic and disease-specific PROMs, often not measuring (all) relevant PROs. The final selected PROMs set included numerical rating scales for pain, two questions on overall health and quality of life and four PROMIS CATs. CONCLUSIONS: A PROMs set generically and efficiently measuring outcomes relevant for patients with BLTC was developed and may be used in future research and clinical practice.

Study Protocol: Adjuvant Holmium-166 Radioembolization After Radiofrequency Ablation in Early-Stage Hepatocellular Carcinoma Patients-A Dose-Finding Study (HORA EST HCC Trial).

PURPOSE: To investigate the biodistribution of holmium-166 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 ≤ 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 (99mTc-MAA). 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 ≥ 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 early-stage HCC patients. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03437382.

Quantified integrated hepatitis B virus is related to viral activity in patients with chronic hepatitis B.

BACKGROUND AND AIMS: HBV can integrate in the host genome of the hepatocyte and recent findings suggest that integrated HBV contributes to the persistent production of viral proteins. Here, we quantified the levels of integrated HBV in patients with chronic hepatitis B (CHB) and analyzed the relation between HBV integration, virological activity (plasma HBV DNA and HBsAg levels), and clinical outcomes. APPROACH AND RESULTS: We developed and validated a multistep Arthrobacter luteus (Alu)-PCR that specifically amplifies integrated HBV and RT-Alu-PCR detecting mRNA transcripts derived from integrated HBV. Pretreatment liver biopsy samples and baseline characteristics of 124 patients with CHB either treated for 48 weeks with pegylated interferon plus adefovir or tenofovir or receiving no treatment were available for analysis. Integrated HBV sequences containing open reading frame S and X (but not C) and S and X mRNA transcripts derived from integrated HBV could be detected and quantified in liver biopsies. Integrated HBV levels correlated with HBV DNA, HBsAg, alanine aminotransferase plasma levels, and the liver histology activity index but not to levels of intrahepatic covalently closed circular DNA (cccDNA), plasma pregenomic RNA, or hepatitis B core-related antigen. Multivariable logistic regression analysis showed that lower baseline HBV integration levels were independently associated with HBsAg loss (functional cure) within 5 years follow-up. CONCLUSIONS: Integrated HBV levels are strongly correlated with surrogate markers for virological activity but not to cccDNA levels and are predictive for HBsAg loss. Our data suggest that integrated HBV is closely related to HBV replication and may therefore be an important tool in the evaluation and development of treatment modalities aiming to cure CHB.

Real-life data on the impact of successful downstaging in patients with hepatocellular carcinoma: A Dutch Multicenter Study.

Patients 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.

Study protocol for a multicentre nationwide prospective cohort study to investigate the natural course and clinical outcome in benign liver tumours and cysts in the Netherlands: the BELIVER study.

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. 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 2 years. 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. STUDY REGISTRATION: NL8231-10 December 2019; Netherlands Trial Register.

Liver Decompensation as Late Complication in HCC Patients with Long-Term Response following Selective Internal Radiation Therapy.

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) ≥ 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 ≥ B7. The median OS was 18 months. In patients without REILD, the median OS in patients with CP ≥ B7 was significantly shorter compared to those without CP ≥ 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 ≥ 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 ≥ B7 often developed as a late complication in HCC patients and was associated with a shorter OS. The ALBI score was predictive of CP ≥ B7 liver decompensation and the OS, and this may be a valuable marker for patient selection for SIRT.

Hepatocellular adenoma in men: A nationwide assessment of pathology and correlation with clinical course.

BACKGROUND & AIMS: Hepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course. METHODS: Dutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death. RESULTS: A total of 66 patients from 26 centres fulfilling the inclusion criteria with a mean (±SD) age of 45.0 ± 21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow-up of 9.6 years, tumour-related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (P = .031). Four B-catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision. CONCLUSIONS: Expert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well-differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines.

TIGIT and PD1 Co-blockade Restores ex vivo Functions of Human Tumor-Infiltrating CD8+ T Cells in Hepatocellular Carcinoma.

BACKGROUND & AIMS: TIGIT is a co-inhibitory receptor, and its suitability as a target for cancer immunotherapy in HCC is unknown. PD1 blockade is clinically effective in about 20% of advanced HCC patients. Here we aim to determine whether co-blockade of TIGIT/PD1 has added value to restore functionality of HCC tumor-infiltrating T cells (TILs). METHODS: Mononuclear leukocytes were isolated from tumors, paired tumor-free liver tissues (TFL) and peripheral blood of HCC patients, and used for flow cytometric phenotyping and functional assays. CD3/CD28 T-cell stimulation and antigen-specific assays were used to study the ex vivo effects of TIGIT/PD1 single or dual blockade on T-cell functions. RESULTS: TIGIT was enriched, whereas its co-stimulatory counterpart CD226 was down-regulated on PD1high CD8+ TILs. PD1high TIGIT+ CD8+ TILs co-expressed exhaustion markers TIM3 and LAG3 and demonstrated higher TOX expression. Furthermore, this subset showed decreased capacity to produce IFN-γ and TNF-α. Expression of TIGIT-ligand CD155 was up-regulated on tumor cells compared with hepatocytes in TFL. Whereas single PD1 blockade preferentially enhanced ex vivo functions of CD8+ TILs from tumors with PD1high CD8+ TILs (high PD1 expressers), co-blockade of TIGIT and PD1 improved proliferation and cytokine production of CD8+ TILs from tumors enriched for PD1int CD8+ TILs (low PD1 expressers). Importantly, ex vivo co-blockade of TIGIT/PD1 improved proliferation, cytokine production, and cytotoxicity of CD8+ TILs compared with single PD1 blockade. CONCLUSIONS: Ex vivo, co-blockade of TIGIT/PD1 improves functionality of CD8+ TILs that do not respond to single PD1 blockade. Therefore co-blockade of TIGIT/PD1 could be a promising immune therapeutic strategy for HCC patients.

The utility of 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT/CT for selective internal radiation therapy in hepatocellular carcinoma.

BACKGROUND: Studies assessing the impact of selective internal radiation therapy (SIRT) on the regional liver function in patients with hepatocellular carcinoma (HCC) are sparse. This study assessed the changes in total and regional liver function using hepatobiliary scintigraphy (HBS) and investigated the utility of HBS to predict post-SIRT liver dysfunction. METHODS: Patients treated with SIRT for HCC between 2011 and 2019, underwent Tc-mebrofenin HBS with single-photon emission computed tomography/computed tomography (SPECT/CT) before and 6 weeks after SIRT. The corrected mebrofenin uptake rate (cMUR) and corresponding volume was measured in the total liver, and in treated and nontreated liver regions. Patients with and without post-SIRT liver dysfunction were compared. RESULTS: A total of 29 patients, all Child-Pugh-A and mostly intermediate (72%) stage HCC were included in this study. Due to SIRT, the cMURtotal declined from 5.8 to 4.5%/min/m (P < 0.001). Twenty-two patients underwent a lobar SIRT, which induced a decline in cMUR (2.9-1.7%/min/m, P < 0.001) and volume (1228-1101, P = 0.002) of the treated liver region, without a change in cMUR (2.4-2.0%/min/m, P = 0.808) or volume (632-644 mL, P = 0.661) of the contralateral nontreated lobe. There were no significant pre-SIRT differences in total or regional cMUR or volume between patients with and without post-SIRT liver dysfunction. CONCLUSION: In patients treated with SIRT for HCC, HBS accurately identified changes in total and regional liver function and may have a complementary role to personalize lobar or selective SIRT. In this pilot study, there were no pre-SIRT differences in cMUR or volume to aid in predicting post-SIRT liver dysfunction.

The value of sorafenib trough levels in patients with advanced hepatocellular carcinoma - a substudy of the SORAMIC trial.

Background: Sorafenib for advanced hepatocellular carcinoma (HCC) is dose adjusted by toxicity. Preliminary studies have suggested an association between plasma concentrations of sorafenib and its main metabolite (M2) and clinical outcomes. This study aimed to validate these findings and establish target values for sorafenib trough concentrations.Methods: Patients with advanced HCC were prospectively recruited within a multicenter phase II study (SORAMIC). Patients with blood samples available at trough level were included for this pharmacokinetic (PK) substudy. Trough plasma concentrations of sorafenib and its main metabolite (M2) were associated with sorafenib-related toxicity and overall survival (OS).Results: Seventy-four patients were included with a median OS of 19.7 months (95% CI 16.1-23.3). Patients received sorafenib for a median of 51 weeks (IQR 27-62) and blood samples were drawn after a median of 25 weeks (IQR 10-42). Patients had a median trough concentration of 3217 ng/ml (IQR 2166-4526) and 360 ng/ml (IQR 190-593) with coefficients of variation of 65% and 146% for sorafenib and M2, respectively. Patients who experienced severe sorafenib-related toxicity received a lower average daily dose (551 vs 730 mg/day, p = .003), but showed no significant differences in sorafenib (3298 vs 2915 ng/ml, p = .442) or M2 trough levels (428 vs 283 ng/ml, p = .159). Trough levels of sorafenib or M2 showed no significant association with OS.Conclusions: In patients with advanced HCC treated with sorafenib, the administered dose, trough levels of sorafenib or M2, and clinical outcomes were poorly correlated. Toxicity-adjusted dosing remains the standard for sorafenib treatment.

Improved survival prediction and comparison of prognostic models for patients with hepatocellular carcinoma treated with sorafenib.

BACKGROUND: The 'Prediction Of Survival in Advanced Sorafenib-treated HCC' (PROSASH) model addressed the heterogeneous survival of patients with hepatocellular carcinoma (HCC) treated with sorafenib in clinical trials but requires validation in daily clinical practice. This study aimed to validate, compare and optimize this model for survival prediction. METHODS: Patients treated with sorafenib for HCC at five tertiary European centres were retrospectively staged according to the PROSASH model. In addition, the optimized PROSASH-II model was developed using the data of four centres (training set) and tested in an independent dataset. These models for overall survival (OS) were then compared with existing prognostic models. RESULTS: The PROSASH model was validated in 445 patients, showing clear differences between the four risk groups (OS 16.9-4.6 months). A total of 920 patients (n = 615 in training set, n = 305 in validation set) were available to develop PROSASH-II. This optimized model incorporated fewer and less subjective parameters: the serum albumin, bilirubin and alpha-foetoprotein, and macrovascular invasion, extrahepatic spread and largest tumour size on imaging. Both PROSASH and PROSASH-II showed improved discrimination (C-index 0.62 and 0.63, respectively) compared with existing prognostic scores (C-index ≤0.59). CONCLUSIONS: In HCC patients treated with sorafenib, individualized prediction of survival and risk group stratification using baseline prognostic and predictive parameters with the PROSASH model was validated. The refined PROSASH-II model performed at least as good with fewer and more objective parameters. PROSASH-II can be used as a tool for tailored treatment of HCC in daily practice and to define pre-planned subgroups for future studies.

Body Composition Is an Independent Predictor of Outcome in Patients with Hepatocellular Carcinoma Treated with Sorafenib.

BACKGROUND: Previous studies have suggested body composition as a predictor of sorafenib toxicity and outcome in patients with advanced hepatocellular carcinoma (HCC). Large studies on the impact of body composition parameters in European HCC patients are lacking. Our aim was to validate the prognostic value of body composition parameters in Dutch patients with HCC treated with sorafenib. PATIENTS AND METHODS: A retrospective analysis was performed in a cohort of HCC patients treated with sorafenib at two Dutch tertiary referral centers between 2007 and 2016. Body composition (adipose and skeletal muscle tissue) was measured at baseline by computed tomography (CT). Low skeletal muscle mass (SMM) and density were defined using published cut-offs. Body composition parameters were correlated with overall survival (OS), time to progression, response rate, and toxicity. RESULTS: A total of 278 patients were included, mostly Child-Pugh class A (85%) and Barcelona Clinic Liver Cancer (BCLC) stage C (73%), with a median OS of 9.5 months (95% CI 8.1-11.0). Patients with combined low SMM and low total adipose tissue index (TATI) (n = 68, 25%) had a poor median OS (5.8, 95% CI 4.8-6.8) compared with other patients (11.7, 95% CI 9.4-14.0). Combined low SMM and low TATI remained an independent predictor of OS (HR 1.56, 95% CI 1.15-2.11, p = 0.004) after adjusting for known prognostic factors. There was no association between body composition and sorafenib toxicity. CONCLUSIONS: In Dutch HCC patients treated with sorafenib, the combined presence of low SMM and low TATI was associated with impaired survival, independent of known prognostic factors. CT assessment of body composition may provide additional prognostic information prior to sorafenib treatment.