Banff 2022 Liver Group Meeting report: Monitoring long-term allograft health.

The Banff Working Group on Liver Allograft Pathology met in September 2022. Participants included hepatologists, surgeons, pathologists, immunologists, and histocompatibility specialists. Presentations and discussions focused on the evaluation of long-term allograft health, including noninvasive and tissue monitoring, immunosuppression optimization, and long-term structural changes. Potential revision of the rejection classification scheme to better accommodate and communicate late T cell-mediated rejection patterns and related structural changes, such as nodular regenerative hyperplasia, were discussed. Improved stratification of long-term maintenance immunosuppression to match the heterogeneity of patient settings will be central to improving long-term patient survival. Such personalized therapeutics are in turn contingent on a better understanding and monitoring of allograft status within a rational decision-making approach, likely to be facilitated in implementation with emerging decision-support tools. Proposed revisions to rejection classification emerging from the meeting include the incorporation of interface hepatitis and fibrosis staging. These will be opened to online testing, modified accordingly, and subject to consensus discussion leading up to the next Banff conference.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Transcriptomic characterization of cancer-testis antigens identifies MAGEA3 as a driver of tumor progression in hepatocellular carcinoma.

Cancer testis antigens (CTAs) are an extensive gene family with a unique expression pattern restricted to germ cells, but aberrantly reactivated in cancer tissues. Studies indicate that the expression (or re-expression) of CTAs within the MAGE-A family is common in hepatocellular carcinoma (HCC). However, no systematic characterization has yet been reported. The aim of this study is to perform a comprehensive profile of CTA de-regulation in HCC and experimentally evaluate the role of MAGEA3 as a driver of HCC progression. The transcriptomic analysis of 44 multi-regionally sampled HCCs from 12 patients identified high intra-tumor heterogeneity of CTAs. In addition, a subset of CTAs was significantly overexpressed in histologically poorly differentiated regions. Further analysis of CTAs in larger patient cohorts revealed high CTA expression related to worse overall survival and several other markers of poor prognosis. Functional analysis of MAGEA3 was performed in human HCC cell lines by gene silencing and in a genetic mouse model by overexpression of MAGEA3 in the liver. Knockdown of MAGEA3 decreased cell proliferation, colony formation and increased apoptosis. MAGEA3 overexpression was associated with more aggressive tumors in vivo. In conclusion MAGEA3 enhances tumor progression and should be considered as a novel therapeutic target in HCC.

Novel microenvironment-based classification of intrahepatic cholangiocarcinoma with therapeutic implications.

OBJECTIVE: The diversity of the tumour microenvironment (TME) of intrahepatic cholangiocarcinoma (iCCA) has not been comprehensively assessed. We aimed to generate a novel molecular iCCA classifier that incorporates elements of the stroma, tumour and immune microenvironment ('STIM' classification). DESIGN: We applied virtual deconvolution to transcriptomic data from ~900 iCCAs, enabling us to devise a novel classification by selecting for the most relevant TME components. Murine models were generated through hydrodynamic tail vein injection and compared with the human disease. RESULTS: iCCA is composed of five robust STIM classes encompassing both inflamed (35%) and non-inflamed profiles (65%). The inflamed classes, named immune classical (~10%) and inflammatory stroma (~25%), differ in oncogenic pathways and extent of desmoplasia, with the inflammatory stroma showing T cell exhaustion, abundant stroma and KRAS mutations (p<0.001). Analysis of cell-cell interactions highlights cancer-associated fibroblast subtypes as potential mediators of immune evasion. Among the non-inflamed classes, the desert-like class (~20%) harbours the lowest immune infiltration with abundant regulatory T cells (p<0.001), whereas the hepatic stem-like class (~35%) is enriched in 'M2-like' macrophages, mutations in IDH1/2 and BAP1, and FGFR2 fusions. The remaining class (tumour classical: ~10%) is defined by cell cycle pathways and poor prognosis. Comparative analysis unveils high similarity between a KRAS/p19 murine model and the inflammatory stroma class (p=0.02). The KRAS-SOS inhibitor, BI3406, sensitises a KRAS-mutant iCCA murine model to anti-PD1 therapy. CONCLUSIONS: We describe a comprehensive TME-based stratification of iCCA. Cross-species analysis establishes murine models that align closely to human iCCA for the preclinical testing of combination strategies.

Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.

OBJECTIVE: We previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy. DESIGN: We performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients. RESULTS: Our integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-ßcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes. CONCLUSION: We have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.

Lymphoepithelioma-like neoplasm of the biliary tract with 'probable low malignant potential'.

AIMS: Lymphoepithelioma-like carcinomas (LELCs) are uncommon epithelial cancers characteristically showing two distinct components consisting of malignant epithelial cells and prominent dense lymphoid infiltrate. Hepatic LELCs consist of two types, the lymphoepithelioma-like hepatocellular carcinoma and lymphoepithelioma-like cholangiocarcinoma (LEL-CCA), with the latter being strongly associated with Epstein-Barr virus (EBV). METHODS AND RESULTS: We present a series of three cases of intrahepatic biliary EBV-associated LEL tumours in which the biliary epithelial component showed a distinctly benign appearance, instead of the usual malignant epithelial features of a typical CCA or EBV-associated LEL-CCA. In the lesions, the biliary epithelium showed interconnecting glands or cords of cells. All had a very low proliferation (Ki-67) index. Immunohistochemistry for IDH1 and TP53 performed on two cases was negative and molecular tests for EGFR and KRAS gene mutations performed on one were negative. Prognosis was very good in all three cases, with patients alive with no evidence of disease 24-62 months after surgery. Intriguingly, all three cases had co-infection of HBV and EBV. These cases are also discussed in the context of the 63 cases of LEL-CCA available in the literature, with a focus on epidemiology, clinicopathological features and potential research interests. CONCLUSIONS: Based on the distinct clinicopathological features and unique survival benefits, we believe these tumours represent the benign end of the spectrum of EBV-associated lymphoepithelial biliary carcinomas. Whether these tumours require a revision of the current nomenclature to 'lymphoepithelioma-like neoplasm of the biliary tract with probable low malignant potential' will require more detailed analysis with larger case-series.

MR elastography outperforms shear wave elastography for the diagnosis of clinically significant portal hypertension.

OBJECTIVES: Portal hypertension (PH) is associated with complications such as ascites and esophageal varices and is typically diagnosed through invasive hepatic venous pressure gradient (HVPG) measurement, which is not widely available. In this study, we aim to assess the diagnostic performance of 2D/3D MR elastography (MRE) and shear wave elastography (SWE) measures of liver and spleen stiffness (LS and SS) and spleen volume, to noninvasively diagnose clinically significant portal hypertension (CSPH) using HVPG measurement as the reference. METHODS: In this prospective study, patients with liver disease underwent 2D/3D MRE and SWE of the liver and spleen, as well as HVPG measurement. The correlation between MRE/SWE measures of LS/SS and spleen volume with HVPG was assessed. ROC analysis was used to determine the utility of MRE, SWE, and spleen volume for diagnosing CSPH. RESULTS: Thirty-six patients (M/F 22/14, mean age 55 ± 14 years) were included. Of the evaluated parameters, 3D MRE SS had the strongest correlation with HVPG (r = 0.686, p < 0.001), followed by 2D MRE SS (r = 0.476, p = 0.004). 3D MRE SS displayed the best performance for diagnosis of CSPH (AUC = 0.911) followed by 2D MRE SS (AUC = 0.845) and 3D MRE LS (AUC = 0.804). SWE SS showed poor performance for diagnosis of CSPH (AUC = 0.583) while spleen volume was a fair predictor (AUC = 0.738). 3D MRE SS was significantly superior to SWE LS/SS (p ≤ 0.021) for the diagnosis of CSPH. CONCLUSION: SS measured with 3D MRE outperforms SWE for the diagnosis of CSPH. SS appears to be a useful biomarker for assessing PH severity. These results need further validation. KEY POINTS: • Spleen stiffness measured with 2D and 3D MR elastography correlates significantly with hepatic venous pressure gradient measurement. • Spleen stiffness measured with 3D MR elastography demonstrates excellent performance for the diagnosis of clinically significant portal hypertension (AUC 0.911). • Spleen stiffness measured with 3D MR elastography outperforms liver and spleen stiffness measured with shear wave elastography for diagnosis of clinically significant portal hypertension.

Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis.

BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. METHODS: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. RESULTS: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/TGF-ß proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. CONCLUSIONS: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. LAY SUMMARY: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.

Morphology of tumor and nontumor tissue in liver resection specimens for hepatocellular carcinoma following nivolumab therapy.

Nivolumab is an immune checkpoint inhibitor (ICI) approved for treatment of many cancers, including hepatocellular carcinoma (HCC). Liver injury is a known complication in patients treated with nivolumab for nonliver tumors. To date, the morphologic changes to tumor and nontumor liver have not been well-characterized in HCC patients. We identified 20 patients who underwent partial hepatectomy or liver transplantation after receiving nivolumab for HCC. Demographics, laboratory values, and imaging results were obtained from medical records. All available slides from resection specimens were evaluated for tumor necrosis, tumor-infiltrating lymphocytes (TILs), and features of liver injury. Patients in the study included 16 males and 4 females with median age of 56 years. The underlying liver disease was HBV in 10, HCV in 6, and unknown/other in 4. Twelve patients were treated with nivolumab in the neoadjuvant setting, whereas eight were treated with nivolumab, usually along with other therapies, before undergoing liver transplantation. On review of resection specimens, three patients (all from the neoadjuvant group) demonstrated marked treatment response attributable to nivolumab. TILs were present in 17/20 cases. One case that showed treatment response in the neoadjuvant group demonstrated non-necrotizing granulomas and prominent bile duct intraepithelial lymphocytes (IELs) in the nontumor liver. One case from the transplant group showed bile duct damage and prominent ductular reaction after long-term nivolumab therapy (32 doses). Our findings indicate that nivolumab is effective in a subset of patients, including in the neoadjuvant setting. Granulomas and bile duct IELs are rare findings in cases treated with nivolumab but, when seen, may indicate potential response to therapy. Bile duct damage and ductular reaction may be manifestations of long-term nivolumab therapy. Future prospective and longitudinal studies with pretreatment tumor biopsies may help identify patients apt to respond to ICI therapy and further characterize patterns of ICI-related liver injury.

Noninvasive diagnosis of portal hypertension using gadoxetate DCE-MRI of the liver and spleen.

OBJECTIVES: To assess the performance of gadoxetate dynamic contrast-enhanced (DCE) MRI of the liver and spleen for noninvasive diagnosis of portal hypertension (PH). METHODS: Thirty-five patients (M/F 22/13, mean age 55 years) with chronic liver disease who underwent hepatic venous pressure gradient (HVPG) measurements were prospectively enrolled in this IRB-approved study. All patients underwent multiparametric MRI including gadoxetate DCE-MRI acquisition. Model-based and model-free DCE-MRI analyses were performed. The correlation between DCE-MRI parameters and HVPG was assessed. ROC analysis was employed to determine the diagnostic performance of DCE-MRI parameters alone and in combination for prediction of PH and clinically significant (CS)PH (HVPG > 5 and ≥ 10 mmHg, respectively). RESULTS: Mean HVPG was 7.0 ± 5.0 mmHg (range 0-18 mmHg). Twenty-one (60%) patients had PH, of whom 9 had CSPH. Modeled liver uptake fraction fi and uptake rate ki and model-free parameters liver upslope and uptake were all significantly negatively correlated with HVPG (r range - 0.490 to - 0.398, p value range 0.003-0.018), while spleen interstitial fraction ve was significantly positively correlated with HVPG (r = 0.336, p = 0.048). For PH diagnosis, liver ki showed the best diagnostic performance with an AUC, sensitivity, and specificity of 0.74 (confidence interval (CI) 0.57-0.91), 71.4%, and 78.6%. The combination of liver ki and spleen ve was selected as the best classifier for diagnosis of CSPH with an AUC, sensitivity, and specificity of 0.87 (CI 0.75-0.99), 100%, and 73.1%. CONCLUSIONS: Our results demonstrate the potential utility of hepatocyte uptake parameters and spleen interstitial fraction obtained with gadoxetate DCE-MRI for the diagnosis of PH and CSPH. KEY POINTS: • Liver uptake and spleen interstitial fraction estimates from gadoxetate DCE-MRI are significantly correlated with portal pressure measurements. • Liver uptake rate shows good diagnostic performance for the diagnosis of portal hypertension. • The combination of liver uptake rate with spleen interstitial fraction exhibits excellent diagnostic performance for the diagnosis of clinically significant portal hypertension.

Robust cellular reprogramming occurs spontaneously during liver regeneration.

Cellular reprogramming-the ability to interconvert distinct cell types with defined factors-is transforming the field of regenerative medicine. However, this phenomenon has rarely been observed in vivo without exogenous factors. Here, we report that activation of Notch, a signaling pathway that mediates lineage segregation during liver development, is sufficient to reprogram hepatocytes into biliary epithelial cells (BECs). Moreover, using lineage tracing, we show that hepatocytes undergo widespread hepatocyte-to-BEC reprogramming following injuries that provoke a biliary response, a process requiring Notch. These results provide direct evidence that mammalian regeneration prompts extensive and dramatic changes in cellular identity under injury conditions.

Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Cholangiocarcinoma (CCA), a deadly malignancy of the bile ducts, can be classified based on its anatomical location into either intrahepatic (iCCA) or extrahepatic (eCCA), each with different pathogenesis and clinical management. There is limited understanding of the molecular landscape of eCCA and no targeted therapy with clinical efficacy has been approved. We aimed to provide a molecular classification of eCCA and identify potential targets for molecular therapies. METHODS: An integrative genomic analysis of an international multicenter cohort of 189 eCCA cases was conducted. Genomic analysis included whole-genome expression, targeted DNA-sequencing and immunohistochemistry. Molecular findings were validated in an external set of 181 biliary tract tumors from the ICGC. RESULTS: KRAS (36.7%), TP53 (34.7%), ARID1A (14%) and SMAD4 (10.7%) were the most prevalent mutations, with ∼25% of tumors having a putative actionable genomic alteration according to OncoKB. Transcriptome-based unsupervised clustering helped us define 4 molecular classes of eCCA. Tumors classified within the Metabolic class (19%) showed a hepatocyte-like phenotype with activation of the transcription factor HNF4A and enrichment in gene signatures related to bile acid metabolism. The Proliferation class (23%), more common in patients with distal CCA, was characterized by enrichment of MYC targets, ERBB2 mutations/amplifications and activation of mTOR signaling. The Mesenchymal class (47%) was defined by signatures of epithelial-mesenchymal transition, aberrant TGFß signaling and poor overall survival. Finally, tumors in the Immune class (11%) had a higher lymphocyte infiltration, overexpression of PD-1/PD-L1 and molecular features associated with a better response to immune checkpoint inhibitors. CONCLUSION: An integrative molecular characterization identified distinct subclasses of eCCA. Genomic traits of each class provide the rationale for exploring patient stratification and novel therapeutic approaches. LAY SUMMARY: Targeted therapies have not been approved for the treatment of extrahepatic cholangiocarcinoma. We performed a multi-platform molecular characterization of this tumor in a cohort of 189 patients. These analyses revealed 4 novel transcriptome-based molecular classes of extrahepatic cholangiocarcinoma and identified ∼25% of tumors with actionable genomic alterations, which has potential prognostic and therapeutic implications.

Malignant transformation of liver fatty acid binding protein-deficient hepatocellular adenomas: histopathologic spectrum of a rare phenomenon.

The molecular classification of hepatocellular adenomas highlights a distinctive genotype-phenotype correlation. Malignant transformation is an exceptionally rare complication of hepatocyte nuclear factor 1α (HNF1A)-inactivated hepatocellular adenomas. This subtype is characterized by loss of liver fatty acid binding protein immunoexpression. In this study, we characterized the histopathologic spectrum of 13 liver fatty acid binding protein-deficient hepatocellular adenoma cases showing malignant transformation from multiple centers. Clinicopathologic characteristics of these patients were evaluated. Stains for reticulin, liver fatty acid binding protein, beta-catenin and glutamine synthetase were applied to these lesions. Moreover, the findings were compared to patients with ß-catenin mutated hepatocellular adenoma. Liver fatty acid binding protein-deficient hepatocellular adenomas with borderline features/carcinoma were seen predominantly in females (77%) with an average age of 46 ± 18 years and multiple lesions (77%; five patients with adenomatosis). Meanwhile, ß-catenin mutated hepatocellular adenoma patients with malignant transformation were predominantly male (67%, p = 0.018) with single lesion (86%, p = 0.0009). The largest liver fatty acid binding protein-deficient hepatocellular adenoma nodule in each patient ranged from 4 to 15.5 cm. Loss of liver fatty acid binding protein by immunohistochemistry was noted in all adenoma and borderline/carcinoma components. Features of malignant transformation were pseudoglandular architecture (85%), cytologic atypia (85%), architectural atypia (100%) and lack of steatosis (100%). Other findings included myxoid change (39%), peliosis (46%) and sinusoidal dilatation (46%). Molecular studies confirmed somatic inactivation of HNF1A in 3 cases and absence of TERT promotor and exon 3 CTNNB1 mutations in five cases. To summarize, liver fatty acid binding protein-deficient hepatocellular adenoma with malignant transformation is most frequently seen in female patients with multiple lesions. Most of these lesions demonstrate pseudoglandular architecture, cytologic and architectural atypia, with lack of steatosis. The natural history of these lesions is relatively benign with the exception of disease recurrence in 1 patient.

Aberrant von Willebrand factor expression of sinusoidal endothelial cells and quiescence of hepatic stellate cells in nodular regenerative hyperplasia and obliterative portal venopathy.

AIMS: Nodular regenerative hyperplasia (NRH) and obliterative portal venopathy (OPV), entities that comprise idiopathic non-cirrhotic portal hypertension (INCPH), are under-recognised diseases of uncertain aetiology and the diagnosis can be easily missed on liver biopsy. The expression of CD34 and von Willebrand factor (vWF) in liver sinusoidal endothelial cells (LSEC) and alpha-smooth muscle actin (ASMA) in hepatic stellate cells (HSCs) is unknown in NRH and OPV. We sought to investigate the pathogenesis and potential immunomarkers that might aid in making the diagnosis of NRH and OPV. METHODS AND RESULTS: Immunohistochemical (IHC) staining for CD34, vWF and ASMA was performed in clinically and histologically well-characterised NRH (n = 15) and OPV (n = 47) liver specimens. Among the 47 OPV cases, 37 (78.7%) had concurrent features of NRH. CD34 positive staining was mainly confined to small vessels in the portal tracts and LSECs in periportal areas, a finding similar to that in non-NRH/OPV livers. However, expression of vWF in LSECs was positive in the compressed sinusoids of NRH and in a patchy or geographic pattern, particularly prominent in the perivenular areas and dilated sinusoids of OPV cases. HSCs were negative for ASMA in all NRH and OPV cases. CONCLUSION: Our findings indicate that NRH may be a subtle but common concurrent morphological feature in OPV. The aberrant expression of vWF in LSECs suggests that endothelial injury may play a role in the pathogenesis, which may thus aid in the recognition and diagnosis of NRH and OPV, particularly when confronted with otherwise apparent normal liver histology on needle biopsy.

Splenic T1ρ as a noninvasive biomarker for portal hypertension.

BACKGROUND: There is a need for noninvasive methods for the diagnosis and monitoring of portal hypertension (PH). PURPOSE: To 1) assess the correlation of liver and spleen T1 and T1ρ measurements with portal pressures in patients with chronic liver disease, and 2) to compare the diagnostic performance of the relaxation parameters with radiological assessment of PH. STUDY TYPE: Prospective. SUBJECTS: Twenty-five patients (M/F 16/9, mean age 56 years, range 21-78 years) undergoing portal pressure (hepatic venous pressure gradient [HVPG]) measurements. FIELD STRENGTH/SEQUENCE: 1.5T abdominal MRI scan, including T1ρ and T1 mapping. ASSESSMENT: Liver and spleen T1ρ and T1 , radiological PH score, and (normalized) spleen length were evaluated. STATISTICAL TESTS: Spearman correlation of all MRI parameters with HVPG was assessed. The diagnostic performance of the assessed parameters for prediction of PH (HVPG ≥5 mmHg) and clinically significant PH (CSPH, HVPG ≥10 mmHg) was determined by receiver operating characteristic (ROC) analysis. RESULTS: The mean HVPG measurement was 7.8 ± 5.3 mmHg (PH, n = 18 [72%] including CSPH, n = 9 [36%]). PH score, (normalized) spleen length and spleen T1ρ significantly correlated with HVPG, with the strongest correlation found for spleen T1ρ (r = 0.613, P = 0.001). Spleen T1ρ was the only parameter that showed significant diagnostic performance for assessment of PH (area under the curve [AUC] 0.817, P = 0.015) and CSPH (AUC = 0.778, P = 0.024). Normalized spleen length also showed significant diagnostic performance for prediction of CSPH, with a slightly lower AUC (= 0.764, P = 0.031). The radiological PH score, T1ρ and T1 of the liver and T1 of the spleen, did not show significant diagnostic performance for assessment of CSPH (P > 0.075). DATA CONCLUSION: Spleen T1ρ showed a significant correlation with portal pressure and showed improved diagnostic performance for prediction of CSPH compared to radiological assessment. These initial results need confirmation in a larger cohort. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;52:787-794.

Hepatocellular carcinoma detection in liver cirrhosis: diagnostic performance of contrast-enhanced CT vs. MRI with extracellular contrast vs. gadoxetic acid.

OBJECTIVES: To evaluate the diagnostic performance of contrast-enhanced CT vs. MRI with extracellular contrast agents (EC-MRI) vs. MRI with gadoxetic acid (EOB-MRI) for HCC detection in patients with liver cirrhosis using liver explant as the reference. The additional value of hepatobiliary phase (HBP) post Gadoxetic acid was also assessed. METHODS: Two-hundred seventy-seven consecutive patients who underwent liver transplantation over a 9 year period and imaging within 90 days of were retrospectively included. Imaging consisted in CT (n = 100), EC-MRI (n = 77) and EOB-MRI (n = 100), the latter subdivided into dynamic EOB-MRI and full EOB-MRI (dynamic+HBP). Three radiologists retrospectively categorized lesions ≥ 1 cm using the LI-RADSv2017 algorithm. Dynamic EOB-MRI was re-evaluated with the addition of HBP. Results were correlated with explant pathology. RESULTS: Pathology demonstrated 265 HCCs (mean size 2.1 ± 1.4 cm) in 177 patients. Per-patient sensitivities were 86.3% for CT, 89.5% for EC-MRI, 92.8% for dynamic EOB-MRI and 95.2% for full EOB-MRI (pooled reader data), with a significant difference between CT and dynamic/full EOB-MRI (p = 0.032/0.002), and between EC-MRI and full EOB-MRI (p = 0.047). Per-lesion sensitivities for CT, EC-MRI, dynamic EOB-MRI and full EOB-MRI were 59.5%,78.5%,69.7% and 76.8%, respectively, with a significant difference between MRI groups and CT (p-range:0.001-0.04), and no difference between EC-MRI and dynamic EOB-MRI (p = 0.949). For HCCs 1-1.9 cm, sensitivities were 34.4%, 64.6%, 57.3% and 67.3%, respectively, with all MRI groups significantly superior to CT (p ≤ 0.01) and full EOB-MRI superior to dynamic EOB-MRI (p = 0.002). CONCLUSIONS: EOB-MRI outperforms CT and EC-MRI for per-patient HCC detection sensitivity, and is equivalent to EC-MRI for per-lesion sensitivity. MRI methods outperform CT for detection of HCCs 1-1.9 cm. KEY POINTS: • MRI is superior to CT for HCC detection in patients with liver cirrhosis. • EOB-MRI outperforms CT and MRI using extracellular contrast agents (EC-MRI) for per-patient HCC detection sensitivity, and is equivalent to EC-MRI for per-lesion sensitivity. • The addition of hepatobiliary phase images improves HCC detection when using gadoxetic acid.

MRI radiomics features predict immuno-oncological characteristics of hepatocellular carcinoma.

OBJECTIVE: To assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC). METHODS: This retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months. RESULTS: Qualitative (r = - 0.41-0.40, p < 0.042) and quantitative (r = - 0.52-0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41-0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = - 0.48-0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76-0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098-0929). CONCLUSIONS: MRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation. KEY POINTS: • MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma. • Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.

Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial.

OBJECTIVE: Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN: Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS: BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION: In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER: NCT00692770.

Combination of Gene Expression Signature and Model for End-Stage Liver Disease Score Predicts Survival of Patients With Severe Alcoholic Hepatitis.

BACKGROUND & AIMS: Patients with severe alcoholic hepatitis (AH) have a high risk of death within 90 days. Corticosteroids, which can cause severe adverse events, are the only treatment that increases short-term survival. It is a challenge to predict outcomes of patients with severe AH. Therefore, we developed a scoring system to predict patient survival, integrating baseline molecular and clinical variables. METHODS: We obtained fixed liver biopsy samples from 71 consecutive patients diagnosed with severe AH and treated with corticosteroids from July 2006 through December 2013 in Brussels, Belgium (derivation cohort). Gene expression patterns were analyzed by microarrays and clinical data were collected for 180 days. We identified gene expression signatures and clinical data that are associated with survival without liver transplantation at 90 and 180 days after initiation of corticosteroid therapy. Findings were validated using liver biopsies from 48 consecutive patients with severe AH treated with corticosteroids, collected from March 2010 through February 2015 at hospitals in Belgium and Switzerland (validation cohort 1) and in liver biopsies from 20 patients (9 received corticosteroid treatment), collected from January 2012 through May 2015 in the United States (validation cohort 2). RESULTS: We integrated data on expression patterns of 123 genes and the model for end-stage liver disease (MELD) scores to assign patients to groups with poor survival (29% survived 90 days and 26% survived 180 days) and good survival (76% survived 90 days and 65% survived 180 days) (P < .001) in the derivation cohort. We named this assignment system the gene signature-MELD (gs-MELD) score. In validation cohort 1, the gs-MELD score discriminated patients with poor survival (43% survived 90 days) from those with good survival (96% survived 90 days) (P < .001). The gs-MELD score also discriminated between patients with a poor survival at 180 days (34% survived) and a good survival at 180 days (84% survived) (P < .001). The time-dependent area under the receiver operator characteristic curve for the score was 0.86 (95% confidence interval 0.73-0.99) for survival at 90 days, and 0.83 (95% confidence interval 0.71-0.96) for survival at 180 days. This score outperformed other clinical models to predict survival of patients with severe AH in validation cohort 1. In validation cohort 2, the gs-MELD discriminated patients with a poor survival at 90 days (12% survived) from those with a good survival at 90 days (100%) (P < .001). CONCLUSIONS: We integrated data on baseline liver gene expression pattern and the MELD score to create the gs-MELD scoring system, which identifies patients with severe AH, treated or not with corticosteroids, most and least likely to survive for 90 and 180 days.

cHCC-CCA: Consensus terminology for primary liver carcinomas with both hepatocytic and cholangiocytic differentation.

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, because of a lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This article represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. CONCLUSION: It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin (H&E); immunostains are supportive, but not essential for diagnosis. (Hepatology 2018;68:113-126).