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.

Arsenic may be a carcinogenic determinant of a subset of gallbladder cancer: A pilot study.

Gallbladder cancer (GBC) is one of the deadliest malignancy and treatment options are deplorably limited. Better strategies of prevention are urgently needed but knowledge on risk factors remains scarce. Recent data suggested that arsenic (As) may be involved in GBC carcinogenesis but the question remains debated. To date, there are no data on As measurement in GBC samples. This pilot study aimed to measure As concentrations in tissue samples from patients with GBC compared to non-cancerous gallbladder (NCGB). Included patients underwent cholecystectomy at Hospital Clinico Universidad de Chile, Santiago in Chile, a country with high As exposure, between 2001 and 2020. Tissue samples were preserved in formalin-fixed, paraffin-embedded blocks. Selected samples were retrieved, processed and submitted to inductively coupled plasma mass spectrometry (ICP-MS) to determine As concentrations. A total of 77 patients were included, including 35 GBC and 42 NCGB. The two groups were comparable, except for age (68 vs. 49 years, p < 0.001). Measured in 11 GBC and 38 NCGB, total As was detected in 5 GBC (14%) compared to 0 NCGB samples (p < 0.001). GBC group also showed higher median values of As compared to NCGB (p < 0.001). This pilot study provided a proof-of-concept to measure As concentrations in gallbladder samples and showed higher level of As in GBC samples compared to NCGB, paving the way for future studies aiming to investigate the impact of As on GBC, which may contribute to the prevention of this deadly disease.

Carcinogenic effect of arsenic in digestive cancers: a systematic review.

BACKGROUND: The carcinogenic effect of arsenic (As) has been documented in lung, bladder and skin cancers but remains unclear for digestive cancers, although metabolic pathways of As and recent data suggest that it may be an important determinant in these malignancies as well. OBJECTIVE: This study aimed to systematically review the available literature investigating the potential association between As and digestive cancers. METHODS: An extensive search was conducted in Medline Ovid SP, Cochrane, PubMed, Embase.com, Cochrane Library Wiley, Web of Science and Google Scholar. Studies providing original data in humans, with As measurement and analysis of association with digestive cancers including esogastric cancers (esophagus and stomach), hepato-pancreatico-biliary (HPB) cancers (including biliary tract, liver and pancreas) and colorectal cancers were eligible. RESULTS: A total of 35 studies were identified, 17 ecological, 13 case-control and 5 cohort studies. Associations between As and digestive cancers were reported for both risks of incidence and cancer-related mortality. Overall, 43% (3/7) and 48% (10/21) studies highlighted an association between As and the incidence or the mortality of digestive cancers, respectively. CONCLUSIONS: A substantial proportion of studies exploring the potential link between As and digestive cancers suggested an association, particularly in HPB malignancies. These findings emphasize the need to further investigate this topic with dedicated and high-quality studies, as it may have an important impact, including for prevention strategies.

Functional, biological, and radiological evaluation of the pancreaticojejunal anastomosis 1 year after pancreatoduodenectomy: a prospective study.

PURPOSE: This prospective study aimed to analyze the functional, biological, and radiological aspects of the pancreatic anastomosis 1 year after pancreatoduodenectomy (PD). METHODS: From 2016 to 2019, patients with PD indication were screened. Questionnaires about pancreas insufficiency, fecal elastase tests, and magnetic resonance imaging (MRI) were performed before and 1 year after PD. RESULTS: Twenty patients were prospectively included. The only difference between pre- and postoperative questionnaires was constipation (less frequent 1 year after PD). Median pre- and postoperative fecal elastase levels were 96 µg/g (IQR 15-196, normal value > 200) and 15 µg/g (IQR 15-26, p = 0.042). There were no significant differences in terms of main pancreatic duct (MPD) size (4, IQR 3-5 vs. 4 mm, IQR 3-5, p = 0.892), border regularity, stenosis, visibility, image improvement, and secondary pancreatic duct dilation before and after secretin injection. All patients but one (2 refused and 2 were lost to follow-up, 15/16, 94%) had a patent pancreaticojejunal anastomosis on 1-year MRI. CONCLUSION: Although median 1-year fecal elastase was significantly lower than preoperatively, suggesting that exocrine secretion was altered, the anatomical outcome as assessed by MRI was excellent showing high patency rate (15/16, 94%) at 1 year. This emphasizes the difference between anatomy and function.

[Novelties on the management of alveolar echinococcosis]. / Nouveautés dans la prise en charge de l'échinococcose alvéolaire.

Alveolar echinococcosis is an endemic parasitosis in Switzerland. This pathology mainly infects the liver and develops similarly as a malignant tumor with its ability to spread into the hepatic parenchyma and its capacity of developing distant lesions via hematogenous dissemination. Treatment is based on complete surgical resection coupled with albendazole treatment. Recently, ex vivo liver resections with auto-transplantation have been shown to be feasible in case of end-stage alveolar echinococcosis. Moreover, new biomarkers such as programmed death-ligand 1 (PD-L1), a protein with immunomodulation property, have shown their potential impact on the treatment and follow-up of patients with alveolar echinococcosis.

L'échinococcose alvéolaire est une parasitose endémique en Suisse. Cette pathologie touche principalement le foie et se développe telle une tumeur maligne, par sa propension à envahir le parenchyme hépatique et par sa capacité à développer des lésions à distance par voie hématogène. Le traitement repose sur une exérèse chirurgicale complète couplée à un traitement d'albendazole. Récemment, des techniques de résection hépatique ex vivo avec auto-transplantation ont montré leur faisabilité en cas d'échinococcose alvéolaire avancée. De plus, de nouveaux marqueurs, comme le programmed death-ligand 1 (PD-L1), protéine jouant un rôle dans l'immunomodulation, ont montré leur potentiel impact pour le traitement et le suivi des patients atteints d'échinococcose alvéolaire.

Basic Science with Preclinical Models to Investigate and Develop Liquid Biopsy: What Are the Available Data and Is It a Fruitful Approach?

The molecular analysis of circulating analytes (circulating tumor-DNA (ctDNA), -cells (CTCs) and -RNA (ctRNA)/exosomes) deriving from solid tumors and detected in the bloodstream-referred as liquid biopsy-has emerged as one of the most promising concepts in cancer management. Compelling data have evidenced its pivotal contribution and unique polyvalence through multiple applications. These data essentially derived from translational research. Therewith, data on liquid biopsy in basic research with preclinical models are scarce, a concerning lack that has been widely acknowledged in the field. This report aimed to comprehensively review the available data on the topic, for each analyte. Only 17, 17 and 2 studies in basic research investigated ctDNA, CTCs and ctRNA/exosomes, respectively. Albeit rare, these studies displayed noteworthy relevance, demonstrating the capacity to investigate questions related to the biology underlying analytes release that could not be explored via translational research with human samples. Translational, clinical and technological sectors of liquid biopsy may benefit from basic research and should take note of some important findings generated by these studies. Overall, results underscored the need to intensify the efforts to conduct future studies on liquid biopsy in basic research with new preclinical models.

Unannotated small RNA clusters associated with circulating extracellular vesicles detect early stage liver cancer.

OBJECTIVE: Surveillance tools for early cancer detection are suboptimal, including hepatocellular carcinoma (HCC), and biomarkers are urgently needed. Extracellular vesicles (EVs) have gained increasing scientific interest due to their involvement in tumour initiation and metastasis; however, most extracellular RNA (exRNA) blood-based biomarker studies are limited to annotated genomic regions. DESIGN: EVs were isolated with differential ultracentrifugation and integrated nanoscale deterministic lateral displacement arrays (nanoDLD) and quality assessed by electron microscopy, immunoblotting, nanoparticle tracking and deconvolution analysis. Genome-wide sequencing of the largely unexplored small exRNA landscape, including unannotated transcripts, identified and reproducibly quantified small RNA clusters (smRCs). Their key genomic features were delineated across biospecimens and EV isolation techniques in prostate cancer and HCC. Three independent exRNA cancer datasets with a total of 479 samples from 375 patients, including longitudinal samples, were used for this study. RESULTS: ExRNA smRCs were dominated by uncharacterised, unannotated small RNA with a consensus sequence of 20 nt. An unannotated 3-smRC signature was significantly overexpressed in plasma exRNA of patients with HCC (p<0.01, n=157). An independent validation in a phase 2 biomarker case-control study revealed 86% sensitivity and 91% specificity for the detection of early HCC from controls at risk (n=209) (area under the receiver operating curve (AUC): 0.87). The 3-smRC signature was independent of alpha-fetoprotein (p<0.0001) and a composite model yielded an increased AUC of 0.93. CONCLUSION: These findings directly lead to the prospect of a minimally invasive, blood-only, operator-independent clinical tool for HCC surveillance, thus highlighting the potential of unannotated smRCs for biomarker research in cancer.

Early postoperative decrease of albumin is an independent predictor of major complications after oncological esophagectomy: A multicenter study.

BACKGROUND AND OBJECTIVES: Serum albumin perioperative decrease (∆Alb) may reflect the magnitude of the physiological stress induced by surgery. Studies highlighted its value to predict adverse postoperative outcomes, but data in esophageal surgery are scant. This study aimed to investigate the role of ∆Alb to predict major complications after esophagectomy for cancer. METHODS: Multicenter retrospective study conducted in five high-volume centers, including consecutive patients undergoing an esophagectomy for cancer between 2006 and 2017. Patients were randomly assigned to a training (n = 696) and a validation (n = 350) cohort. Albumin decrease was calculated on postoperative day 1 and defined as ΔAlb. The primary endpoint was major complications according to Clavien classification. RESULTS: In the training cohort, esophagectomy induced a rapid drop of albumin. Cut-off of ΔAlb was established at 11 g/L and allowed to distinguish patients with adverse outcomes. On multivariable analysis, ΔAlb was identified as an independent predictor of major complications (OR, 1.06; 95% CI, 1.01-1.11; p = .014). Higher BMI and laparoscopy were associated with lower ΔAlb. Analysis of the validation cohort provided consistent findings. CONCLUSIONS: ΔAlb appeared as a promising biomarker after oncological esophagectomy, allowing prediction of potential adverse outcomes.

Predictors of complications after liver surgery: a systematic review of the literature.

BACKGROUND: Numerous potential predictors of adverse outcomes have been reported but their performance and utilization in practice seem heterogenous. This study aimed to systematically review the literature on the role and value of predictors of complications after hepatectomy. METHODS: A systematic review following the PRISMA guidelines was performed. Studies on liver transplant were excluded. Only studies assessing overall or major complications were included. RESULTS: A total of 10'965 abstracts were screened. After application of exclusion criteria, 72 articles including 68'480 patients were included. A total of 72 markers with 48 pre-, 9 intra- and 15 postoperative factors were identified as predictors of complications. Preoperative and intraoperative predictive markers retrieved several times with the highest odds ratios (OR) were ASA score (OR range: 1.3-7.5, significant in 8 studies) and intraoperative need for red blood cell transfusion (OR range: 1.2-17.1, significant in 24 studies), respectively. CONCLUSION: Numerous markers have been described to predict the complication risk after hepatectomy. Because of their intrinsic characteristics, most markers such as ASA score and need for red blood cell transfusion are of limited clinical interest. There is a clear need to identify new biomarkers and to develop scores that could easily be implemented in clinical practice.

Prognostic value of positive histological margins in patients with pancreatic head ductal adenocarcinoma and lymph node involvement: an international multicentric study.

BACKGROUND: Resection margin status and lymph node (LN) involvement are known prognostic factors for patients who undergo pancreatoduodenectomy for pancreatic ductal adenocarcinoma (PDAC). This study aimed to compare overall survival (OS) and disease-free survival (DFS) by resection margin status in patients with PDAC and LN involvement. METHODS: A retrospective international multicentric study was performed including four Western centers. Multivariable Cox analysis was performed to identify prognostic factors of OS and DFS. Median OS and DFS were calculated using Kaplan-Meier curves and compared using log-rank tests. RESULTS: A cohort of 814 PDAC patients with pancreatoduodenectomy were analyzed. A total of 651 patients had LN involvement (80%). On multivariable analysis R1 resection was not an independent factor of worse OS and DFS in patients with LN involvement (HR 1.1, p = 0.565; HR 1.2, p = 0.174). Only tumor size, grade, and adjuvant chemotherapy were associated with OS and DFS. Median OS and DFS were similar between patients with R0 and R1 resections (23 vs. 20 months, p = 0.196; 15 vs. 14 months, p = 0.080). CONCLUSION: Resection status was not identified as predictor of OS or DFS in PDAC patients with LN involvement. Extensive surgery to achieve R0 resection in such patients might not influence the disease course.

[Preoperative liver venous deprivation]. / Embolisation portale et sus-hépatique combinée avant hépatectomie ma.

Some hepato-biliary cancers require major liver resections. Post hepatectomy liver failure is a complication that occurs when the remnant liver cannot maintain its synthetic and excretory functions. To overcome this issue, portal vein embolization has been developed to induce future remnant liver hypertrophy preoperatively. However, up to 20% of patients cannot proceed to the hepatectomy due to insufficient hypertrophy or tumor progression in the interval between the embolization and the planned surgery. Liver venous deprivation (LVD) is a technique that combine ipsilateral portal and hepatic vein embolization. With this technique, the hypertrophy seems to be faster and more important, with low complications rate and no mortality associated with the procedure.

Certains cancers hépatobiliaires nécessitent des résections hépatiques majeures. L'insuffisance hépatocellulaire est une complication postopératoire avec un risque de mortalité qui survient lorsque le foie restant ne peut maintenir ses fonctions de synthèse et d'excrétion. L'embolisation de la veine porte a été développée pour induire une hypertrophie du futur foie restant en préopératoire afin d'éviter cette complication. Cependant, 20 % des patients ne peuvent pas bénéficier de l'hépatectomie en raison d'une hypertrophie insuffisante ou d'une progression de la maladie oncologique dans l'intervalle entre l'embolisation et la chirurgie. L'embolisation portale et sus-hépatique combinée est une technique qui consiste à combiner durant le même geste l'embolisation de la veine porte et de la veine sus-hépatique ipsilatérale. Par cette technique, l'hypertrophie semble alors plus rapide et importante, avec peu de complications et aucune mortalité en lien avec la procédure.

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.

Impact of ERAS compliance on the delay between surgery and adjuvant chemotherapy in hepatobiliary and pancreatic malignancies.

BACKGROUND: Multidisciplinary approach with adjuvant chemotherapy is the key element to provide optimal outcomes in pancreas and liver malignancies. However, post-operative complications may increase the interval between surgery and chemotherapy with negative oncologic effects. HYPOTHESIS AND STUDY AIM: The aim of the study was to analyse whether compliance to Enhanced Recovery After Surgery (ERAS) pathway was associated with decreased interval to adjuvant chemotherapy. METHODS: Retrospective analysis of all consecutive ERAS patients with surgery for hepatobiliary or pancreatic malignancies at the University Hospital of Lausanne between 2012 and 2016. Multivariate analysis was performed to assess the impact of ERAS compliance on time to chemotherapy. RESULTS: A total of 133 patients with adjuvant chemotherapy were included (n = 44 liver and n = 89 pancreatic cancer). Median compliance to ERAS was 61% (IQR 55-67) for the study population, and median delay to chemotherapy was 49 days (IQR 39-61). Overall, compliance ≥ 67% to ERAS induced a significant reduction in the interval between surgery and chemotherapy for young patients (< 65 years old) with or without severe comorbidities (reduction of 22 and 10 days, respectively). High compliance in young ASA3 patients with liver colorectal metastases was associated with an increase of 481 days of DFS. CONCLUSIONS: ERAS compliance ≥ 67% tends to be associated with a reduction in the delay to adjuvant chemotherapy for young patients with hepatobiliary and pancreatic malignancies. More prospective studies with strict adhesion to the ERAS protocol are needed to confirm these results.

Acute kidney injury after liver surgery: does postoperative urine output correlate with postoperative serum creatinine?

BACKGROUND: Acute kidney injury (AKI) after hepatectomy occurs in around 10% of cases. AKI is often defined based only on postoperative serum creatinine increase. This study aimed to assess if postoperative urine output (UO) correlated with serum creatinine after hepatectomy. METHODS: All consecutive hepatectomy patients (2010-2016) were assessed. AKI was defined according to KDIGO criteria: serum creatinine increase ≥26.5 µmol/l, creatinine increase ≥1.5x baseline creatinine, or postoperative oliguria. Oliguria was defined as daily mean UO <0.5 mL/kg/h. AKI was subdivided into creatinine-based or oliguria-based AKI according to the defining criterion. RESULTS: Out of 285 patients, AKI was observed in 79 cases (28%). Creatinine-based AKI occurred in 25 patients (9%) and oliguria-based only AKI in 54 patients (19%). Ten patients fulfilled both criteria (4%). Postoperative UO correlated poorly with postoperative serum creatinine level in both whole cohort (rho = -0.34, p <0.001) and AKI subgroup (rho = -0.189, p = 0.124). No association was found between postoperative oliguria and postoperative serum creatinine increase (HR = 0.5, 95%CI: 0.2-1.9, p = 0.341). On multivariable analysis, operation duration >360 minutes was the only predictor of creatinine increase (HR = 3.6, 95%CI: 1.1-11.4, p = 0.032). CONCLUSION: Postoperative UO showed poor correlation with postoperative serum creatinine both in all patients and AKI patients. Surgery duration >360 minutes appeared as the only independent predictor of postoperative serum creatinine increase.

Impact of postoperative weight gain on complications after liver surgery.

BACKGROUND: Recent data has suggested that excessive perioperative weight gain may be associated with adverse outcomes after abdominal surgery, but this observation remains unexplored following liver surgery. The present study aimed to investigate the predictive value of perioperative weight fluctuation in predicting complications after liver surgery. METHODS: Retrospective monocentric analysis of consecutive patients undergoing liver surgery between 2010 and 2016. Patients without available perioperative weight were excluded. Test variable was postoperative weight change (ΔWeight) measured on day 2 (POD2). Primary outcome was postoperative major morbidity according to Clavien classification (grades III-IV). Secondary outcomes were overall complications, Comprehensive Complication Index (CCI) and length of hospital stay (LoS). Area under the receiver operating characteristic curve (AUROC) and logistic regression with multivariable analysis were performed. RESULTS: A total of 181 patients met the inclusion criteria. Major and overall postoperative complications were reported in 25 (14%) and 87 (48%) patients, respectively. On POD2, median ΔWeight was 2.6 Kg (IQR: 1.1-4.0). Patients with major complications showed increased ΔWeight of 4.2 Kg (IQR: 2.7-5.7), compared to 2.3 Kg (IQR: 0.9-3.7) in patients without major complications (p < 0.001). AUROC of ΔWeight for major complications was 0.74, determining an optimal cut-off of 3.5 Kg, which yielded a negative predictive value of 94%. Multivariable analysis identified ΔWeight ≥3.5 Kg as independent predictor of major complications (OR, 4.73; 95% CI, 1.51-14.80; p = 0.008). CONCLUSION: ΔWeight ≥3.5 Kg was independently associated with major complications after liver surgery. Perioperative fluctuation of weight appears as an important predictor of adverse outcomes after liver surgery.

A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites.

AIMS: Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary-metastatic comparisons between samples from the same patient are difficult. METHODS AND RESULTS: We report the evaluation of 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological assessment, immunohistochemistry and mutation status of the TERT promoter, the most frequently mutated gene in HCC. We confirm a strong predilection of HCC for lung dissemination, including subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher K19 and EpCAM expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule. CONCLUSIONS: This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.

Feasibility and safety of liver transplantation or resection after transarterial radioembolization with Yttrium-90 for unresectable hepatocellular carcinoma.

BACKGROUND: The benefit of transarterial radioembolization (TARE) in patients with unresectable hepatocellular carcinoma (HCC) is increasingly evidenced. However, data on outcome of liver transplantation or resection after TARE remain scarce. This study aimed to assess the safety and feasibility of surgery after TARE in patients with unresectable HCC. METHODS: Patients exclusively undergoing TARE followed by either orthotopic liver transplantation (OLT) or liver resection (LR) for HCC between 2012 and 2016 were included. Primary outcomes were postoperative morbidity and mortality. Secondary outcomes were overall survival (OS) and response to TARE. RESULTS: Among 349 patients with HCC treated with TARE, 32 (9%) underwent either OLT (n = 22) or LR (n = 10), which represent the study cohort. In this group, TARE induced decreased viable nodules (p < 0.001), an efficient downsizing (p < 0.001) as well as a significant downstaging based on BCLC classification (p < 0.001). Overall, major complications and mortality after surgery occurred in 5 (16%) and 1 (3%) patients, respectively. For the whole study cohort, OS was 47 months while survival rates at 1-, 3- and 5-years reached 97%, 86% and 86%, respectively. DISCUSSION: Liver surgery after TARE is feasible and safe. This strategy allows to offer a curative treatment in a subset of patients with unresectable HCC.