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Background: To study the feasibility of hepatobiliary scintigraphy (HBS) to improve selection and planning of patients with hepatocellular carcinoma (HCC) treated with holmium-166 (166Ho)-microspheres radioembolization. Results: Thirty-one patients with HCC were included and treated with 166Ho- radioembolization as part of a prospective phase 2 study. Twenty-seven patients were eligible for analysis, 67% had a cirrhotic liver morphology on imaging, 70% had multifocal disease and 51% had bilobar disease. None of the patients had clinical signs of liver decompensation (Child Pugh ≤ B7, median MELD 9 or ALBI − 2.55). Global and regional hepatic function was based on manual delineation of HBS using 200 MBq 99mTc-mebrofenine, acquired during screening and approximately three months after 166Ho-radioembolization, referred to as liver clearance rate (LCR). In line with LCR at baseline, a significant correlation was found between LCR and lab results, including bilirubin, albumin, ALT, MELD-score, and ALBI-score (p < 0.05) during follow-up. HBS showed a significant decrease in median LCR (-16%; p = 0.0017) and volume (-17%; p = 0.0027) in the treated liver, without a significant increase in the non-treated liver. Median relative change in overall LCR in non-cirrhotics was 0% (range − 23–33%), in cirrhotics − 10% (range − 40 − 19%; p = 0.40). Conclusion: HBS showed that hepatic function and volume significantly decreased in parts of the liver treated with 166Ho-microspheres radioembolization in patients with HCC. Cirrhotic patients do not seem to have the capacity to increase hepatic function in the treated part of the liver. Trial registration: Registry name: Clinicaltrials.gov. Trial number: NCT03379844. Date of registration: 21 November 2017. Trial URL: https://clinicaltrials.gov/study/NCT03379844?cond=hcc&term=hepar primary&rank=1#study-overview. [ABSTRACT FROM AUTHOR]

Distinguishing malignant from benign liver lesions based on magnetic resonance imaging (MRI) is an important but often challenging task, especially in noncirrhotic livers. We developed and externally validated a radiomics model to quantitatively assess T2-weighted MRI to distinguish the most common malignant and benign primary solid liver lesions in noncirrhotic livers. Data sets were retrospectively collected from three tertiary referral centers (A, B, and C) between 2002 and 2018. Patients with malignant (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) and benign (hepatocellular adenoma and focal nodular hyperplasia) lesions were included. A radiomics model based on T2-weighted MRI was developed in data set A using a combination of machine learning approaches. The model was internally evaluated on data set A through cross-validation, externally validated on data sets B and C, and compared to visual scoring of two experienced abdominal radiologists on data set C. The overall data set included 486 patients (A: 187, B: 98, and C: 201). The radiomics model had a mean area under the curve (AUC) of 0.78 upon internal validation on data set A and a similar AUC in external validation (B: 0.74 and C: 0.76). In data set C, the two radiologists showed moderate agreement (Cohen's κ: 0.61) and achieved AUCs of 0.86 and 0.82. Our T2-weighted MRI radiomics model shows potential for distinguishing malignant from benign primary solid liver lesions. External validation indicated that the model is generalizable despite substantial MRI acquisition protocol differences. Pending further optimization and generalization, this model may aid radiologists in improving the diagnostic workup of patients with liver lesions. [ABSTRACT FROM AUTHOR]

Many prognostic models for Hepatocellular Carcinoma (HCC) have been developed to inform patients and doctors about individual prognosis. Previous reviews of these models were qualitative and did not assess performance at external validation. We assessed the performance of prognostic models for HCC and set a benchmark for biomarker studies. All externally validated models predicting survival for patients with resected HCC were systematically reviewed. After selection, we extracted descriptive statistics and aggregated c-indices using meta-analysis. Thirty-eight validated prognostic models were included. Models used on average 7 (IQR:4–9) prognostic factors. Tumor size, tumor number, and vascular invasion were almost always included. Alpha-fetoprotein (AFP) was commonly incorporated since 2007. Recently, the more subjective items ascites and encephalopathy have been dropped. Eight established models performed poor to moderate at external validation, with a pooled C-index below 0.7; including the Barcelona Clinic Liver Cancer (BCLC) system, the American Joint Committee on Cancer (AJCC) 7th edition, the Cancer of the Liver Italian (CLIP) Program, and the Japan Integrated Staging (JIS) score. Out of 24 prognostic models predicting OS, only 6 (25%) had good performance at external validation with pooled C-indices above 0.7; the Li-post (0.77), Li-OS (0.74), Yang-pre (0.74), Yang-post (0.76), Shanghai-score (0.70), and Wang-nomogram (0.71). Models improved over time, but overall performance and study quality remained low. Six validated prognostic models demonstrated good performance for predicting survival after resection of HCC. These models can guide patients and doctors and are a benchmark for future models incorporating novel biomarkers. [ABSTRACT FROM AUTHOR]

No curative treatment options are available for advanced hepatocellular carcinoma (HCC). Anti‐PD1 antibody therapy can induce tumor regression in 20% of advanced HCC patients, demonstrating that co‐inhibitory immune checkpoint blockade has therapeutic potential for this type of cancer. However, whether agonistic targeting of co‐stimulatory receptors might be able to stimulate anti‐tumor immunity in HCC is as yet unknown. We investigated whether agonistic targeting of the co‐stimulatory receptor GITR could reinvigorate ex vivo functional responses of tumor‐infiltrating lymphocytes (TIL) freshly isolated from resected tumors of HCC patients. In addition, we compared GITR expression between TIL and paired samples of leukocytes isolated from blood and tumor‐free liver tissues, and studied the effects of combined GITR and PD1 targeting on ex vivo TIL responses. In all three tissue compartments, CD4+FoxP3+ regulatory T cells (Treg) showed higher GITR−expression than effector T‐cell subsets. The highest expression of GITR was found on CD4+FoxP3hiCD45RA− activated Treg in tumors. Recombinant GITR‐ligand as well as a humanized agonistic anti‐GITR antibody enhanced ex vivo proliferative responses of CD4+ and CD8+ TIL to tumor antigens presented by mRNA‐transfected autologous B‐cell blasts, and also reinforced proliferation, IFN‐γ secretion and granzyme B production in stimulations of TIL with CD3/CD28 antibodies. Combining GITR ligation with anti‐PD1 antibody nivolumab further enhanced tumor antigen‐specific responses of TIL in some, but not all, HCC patients, compared to either single treatment. In conclusion, agonistic targeting of GITR can enhance functionality of HCC TIL, and may therefore be a promising strategy for single or combinatorial immunotherapy in HCC. What's new? Therapeutic antibodies that block interaction of the T cell co‐inhibitory receptor PD1 can unleash pre‐existing anti‐cancer T cell responses in hepatocellular carcinoma (HCC). However, whether agonistic targeting of co‐stimulatory receptors could stimulate anti‐tumor immunity remains unknown. This study is the first to show that agonistic targeting of the co‐stimulatory receptor GITR can reinforce the functionality of tumor‐infiltrating T cells isolated from human tumors. Combined targeting of PD1 and GITR exerts additive stimulatory effects on ex vivo functionality of tumor‐infiltrating T cells from HCC patients. Targeting of GITR thus emerges as a promising strategy for single or combinatorial immunotherapy in HCC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) may be diagnosed in the absence of cirrhosis. However, little is known about prognostic factors for the survival of HCC patients with a non-cirrhotic liver in the absence of well-established risk factors. Method: Survival rates and risk factors for survival and recurrence were analysed in all patients diagnosed between 2000 and 2010 with HCC in a non-cirrhotic liver and in the absence of well-established risk factors. Results: Ninety-four patients were analysed. Treatment with curative intent consisted of surgical resection in 43 patients (46%) and radiofrequency ablation in 4 patients (4%). In patients treated with curative intent and alive 30 days after treatment (n = 40), 1- and 5-year overall survival rates were 95 and 51%, respectively. Patients with a high preoperative α-fetoprotein (AFP) serum level, the presence of microvascular invasion in the resected specimen, a complicated postoperative course and a major resection, due to a greater tumour volume, had a significantly worse outcome and a higher recurrence rate. In multivariate analysis, a high AFP serum level at presentation was significantly associated with recurrence and a worse survival. Conclusion: HCC presenting in a non-cirrhotic liver in the absence of well-established risk factors has a poor prognosis. Increased AFP serum levels are significantly associated with clinical outcome. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: To explore the potential use of magnetic resonance imaging (MRI) in predicting the outcome for patients with hepatocellular carcinoma (HCC), imaging characteristics were correlated with pathological findings and clinical outcome. Materials and Methods: With permission from the Ethical Board, clinical data and tissues of resected HCC patients were collected, including the preoperative MRI. The role of MRI characteristics on recurrence and survival were evaluated with univariate and multivariate analyses. Results: Between January 2000 and December 2008, 87 patients with 104 HCCs were operated on. Microvascular invasion was present in 55 lesions (53%). HCC was characterized as well differentiated in 15 lesions (14%), as moderate in 50 lesions (48%), and as poorly differentiated in 34 lesions (33%). Due to preoperative treatment in five lesions (5%) no vital tumor was left. In 85 lesions (88%) washout of contrast was noted. Of the 87 patients, 28 (32%) with 37 lesions developed HCC recurrence; these patients had microvascular invasion significantly more often and a moderate or poorly differentiated tumor ( P < 0.001 and P = 0.025, respectively). MRI more often showed washout when HCC was moderately or poorly differentiated ( P < 0.001) or microvascular invasion was present ( P = 0.032). Conclusion: Differentiation grade and microvascular invasion are significantly associated with the presence of washout demonstrated on dynamic contrast-enhanced MRI. J. Magn. Reson. Imaging 2012;36:641-647. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Summary: Patients with hepatocellular carcinoma (HCC) are characterized by a weak T-cell response to their tumor, and chronic carriers of hepatitis B virus or hepatitis C virus have a poor T-cell response against the virus. These inadequate T-cell responses may be due to insufficient activation of the T cells by dendritic cells (DCs). Because lymph nodes (LNs) are the primary site of antigen-specific T-cell activation, we hypothesized that hepatic LNs of patients with HCC and/or chronic viral hepatitis might have aberrant compositions of their DC populations. To address this hypothesis, we enumerated mature myeloid DCs (MDCs) and plasmacytoid DCs (PDCs) in hepatic LNs by quantitative immunohistochemistry. Patients with HCC and chronic viral hepatitis and patients with chronic viral hepatitis without HCC were compared with patients with liver inflammation of nonviral etiology and with organ donors with healthy livers. The numbers of PDCs and mature MDCs in hepatic LNs of patients with chronic viral hepatitis did not differ from those of patients with liver inflammation of nonviral etiology nor from individuals with healthy livers. However, hepatic LNs of patients with HBV or HCV infection complicated by HCC showed a 1.5-fold reduction in numbers of mature MDCs and a 4-fold increase in numbers of PDCs in their T-cell areas compared with those of patients with viral hepatitis only (P < .01). In conclusion, patients with HCC have an aberrant composition of the DC population in their hepatic LNs. This may be one of the causes of the inadequate T-cell response against HCC in these patients. [Copyright &y& Elsevier]

Microvascular invasion (MVI) is an established prognosticator in hepatocellular carcinoma (HCC). Histopathological growth patterns (HGPs) classify the invasive margin of hepatic tumors, with superior survival observed for the desmoplastic HGP. Our aim was to investigate non-cirrhotic HCC in light of MVI and the HGP. A retrospective cohort study was performed in resected non-cirrhotic HCC. MVI was assessed prospectively. The HGP was determined retrospectively, blinded, and according to guidelines. Overall and disease-free survival (OS, DFS) were evaluated by Kaplan–Meier and multivariable Cox regression. The HGP was determined in 155 eligible patients, 55 (35%) featured a desmoplastic HGP. MVI was observed in 92 (59%) and was uncorrelated with HGP (64% vs 57%, p = 0.42). On multivariable analysis, non-desmoplastic and MVI-positive were associated with an adjusted HR [95%CI] of 1.61 [0.98–2.65] and 3.22 [1.89–5.51] for OS, and 1.59 [1.05–2.41] and 2.30 [1.52–3.50] for DFS. Effect modification for OS existed between HGP and MVI (p < 0.01). Non-desmoplastic MVI-positive patients had a 5-year OS of 36% (HR: 5.21 [2.68–10.12]), compared to 60% for desmoplastic regardless of MVI (HR: 2.12 [1.08–4.18]), and 86% in non-desmoplastic MVI-negative. HCCs in non-cirrhotic livers display HGPs which may be of prognostic importance, especially when combined with MVI. [ABSTRACT FROM AUTHOR]

Background & Aims Effectiveness of surveillance for hepatocellular carcinoma is controversial. We here explore its effects in “real life” clinical practice. Methods Patients with hepatocellular carcinoma diagnosed in the period 2005–2012 in five Dutch academic centers were evaluated. Surveillance was defined as ⩾2 screening tests during three preceding years and at least one radiologic imaging test within 18 months before diagnosis. Results 295 (27%) of 1074 cases underwent surveillance. Median time interval between last negative radiologic imaging and hepatocellular carcinoma diagnosis was 7.5 months. In the surveillance group, cirrhosis (97% vs . 60%, p <0.001) and viral hepatitis were more frequent, and non-alcoholic fatty liver disease or absence of risk factors less frequent. In case of surveillance, tumor size was significantly smaller (2.7 vs . 6.0 cm), with lower alpha–fetoprotein levels (16 vs . 44 μg/L), earlier tumor stage (BCLC 0 and A combined: 61% vs . 21%) and resection/transplantation (34% vs . 25%) or radiofrequency ablation (23% vs . 7%) more often applied, with significantly higher 1-, 3-, and 5-year survival rates. Survival benefit by surveillance remained significant after adjustment for lead-time bias based on assumed tumor doubling time of 90 days, but not with doubling time of ⩾120 days. In multivariate analysis, surveillance was an independent predictor for mortality (for interval ⩽9 respectively >9 months: adjusted HRs 0.51 and 0.50, 95% confidence intervals: 0.39–0.67 and 0.37–0.69). Conclusions Surveillance for hepatocellular carcinoma was associated with smaller tumor size, earlier tumor stage, with an impact on therapeutic strategy and was an independent predictor of survival. [ABSTRACT FROM AUTHOR]

Abstract: Background: Patients with hepatocellular carcinoma (HCC) undergo extensive staging investigations when being assessed for surgical resection. The aim of this study was to assess the use and yield of baseline bone scintigraphy in patients with HCC necessitating high-risk surgical resection. Material and methods: All patients diagnosed with HCC between 2000 and 2010 within a tertiary referral center were reviewed. Recurrence and survival rates were compared between patients with and without bone scintigraphy in their preoperative work-up. Results: A total of 366 patients were diagnosed with resectable HCC. In the work-up for resection 137 HCC patients (41%) underwent bone scintigraphy, which showed bone metastases in 3 (2%). There was no significant difference in long-term survival between patients with and without bone scintigraphy. None of the patients with a positive bone scintigraphy died due to skeletal bone metastases. Only one patient had an indication for bone scintigraphy based on clinical suspicion. Two patients were found to have asymptomatic skeletal metastases prior to surgery. Symptomatic skeletal metastases were identified at an estimated cost of €27,008 per case. Conclusions: Clinically unsuspicious bone lesions turned out to be metastases in two patients, with an estimated cost of €27,008 per case. Recurrence rate and disease-free and overall survival showed no significant difference between patients with and without preoperative baseline bone scintigraphy. There is no justification for routine preoperative bone scintigraphy to detect asymptomatic skeletal metastases in patients with resectable HCC. [Copyright &y& Elsevier]

Background & Aims: A molecular and pathological classification system for hepatocellular adenomas (HCA) was recently introduced and four major subgroups were identified. We aimed to validate this adenoma classification system and to determine the clinical relevance of the subtypes for surgical management. Methods: Paraffin fixed liver tissue slides and resection specimens of patients radiologically diagnosed as HCA were retrieved from the department of pathology. Immunostainings included liver-fatty acid binding protein (L-FABP), serum amyloid A (SAA), C-reactive protein (CRP), glutamine synthetase (GS) and β-catenin. Results: From 2000 to 2010, 58 cases (71 lesions) were surgically resected. Fourteen lesions were diagnosed as focal nodular hyperplasia with a characteristic map-like staining pattern of GS. Inflammatory HCA expressing CRP and SAA was documented in 36 of 57 adenomas (63%). Three of these inflammatory adenomas were also β-catenin positive as well as GS positive and only one was CRP and SAA and GS positive. We identified eleven L-FABP-negative HCA (19%) and four β-catenin positive HCA (7%), without expression of CRP and SAA and with normal L-FABP staining, one of which was also GS positive. Six HCA were unclassifiable (11%). In three patients multiple adenomas of different subtypes were found. Conclusions: Morphology and additional immunohistochemical markers can discriminate between different types of HCA in>90% of cases and this classification, including the identification of β-catenin positive adenomas may have important implications in the decision for surveillance or treatment. Interpretation of nuclear staining for β-catenin can be difficult due to uneven staining distribution or focal nuclear staining and additional molecular biology may be required. [ABSTRACT FROM AUTHOR]