Long-Term Overall Survival After Selective Internal Radiation Therapy for Locally Advanced Hepatocellular Carcinomas: Updated Analysis of DOSISPHERE-01 Trial.

Interim analysis of the DOSISPHERE-01 study demonstrated a strong improvement in response and overall survival (OS) on using 90Y-loaded glass microspheres with personalized dosimetry compared with standard dosimetry in patients with nonoperable locally advanced hepatocellular carcinoma. This report sought to provide a long-term analysis of OS. Methods: In this phase II study (ClinicalTrials.gov identifier NCT02582034), treatment was randomly assigned (1:1) with the goal to deliver either at least 205 Gy (if possible >250-300 Gy) to the index lesion in the personalized dosimetry approach (PDA) or 120 ± 20 Gy to the treated volume in the standard dosimetry approach (SDA). The 3-mo response of the index lesion was the primary endpoint, with OS being one of the secondary endpoints. This report is a post hoc long-term analysis of OS. Results: Overall, 60 hepatocellular carcinoma patients with at least 1 lesion larger than 7 cm and more than 30% of hepatic reserve were randomized (intent-to-treat population: PDA, n = 31; SDA, n = 29), with 56 actually treated (modified intent-to-treat population: n = 28 in each arm). The median follow-up for long-term analysis was 65.8 mo (range, 2.1-73.1 mo). Median OS was 24.8 mo and 10.7 mo (hazard ratio [HR], 0.51; 95% CI, 0.29-0.9; P = 0.02) for PDA and SDA, respectively, in the modified intent-to-treat population. Median OS was 22.9 mo for patients with a tumor dose of at least 205 Gy, versus 10.3 mo for those with a tumor dose of less than 205 Gy (HR, 0.42; 95% CI, 0.22-0.81; P = 0.0095), and was 22.9 mo for patients with a perfused liver dose of 150 Gy or higher, versus 10.3 mo for those with a perfused liver dose of less than 150 Gy (HR, 0.42; 95% CI, 0.23-0.75; P = 0.0033). Lastly, median OS was not reached in patients who were secondarily resected (n = 11, 10 in the PDA group and 1 in the SDA group), versus 10.8 mo in those without secondary resection (n = 45) (HR, 0.17; 95% CI, 0.065-0.43; P = 0.0002). Only resected patients displayed favorable long-term OS rates, meaning an OS of more than 50% at 5 y. Conclusion: After longer follow-up, personalized dosimetry sustained a meaningful improvement in OS, which was dramatically improved for patients who were accurately downstaged toward resection, including most portal vein thrombosis patients.

First report of Acinetobacter pittii acute community-acquired pneumonia in an immunocompetent patient in France following a heat wave.

BACKGROUND: In recent years, Acinetobacter baumannii-calcoaceticus complex (ABC) infections have attracted attention, mainly because of the impact of carbapenem-resistant isolates in hospital-acquired infections. However, acute community-acquired ABC infections are not uncommon in warm and humid countries, where they are responsible for community-acquired infections with specific clinical features. To date, such infection has not been reported in France. CASE PRESENTATION: We report the case of a 55-year-old non-immunocompromised patient living in France with no known risk factors for community-acquired ABC infections who presented pneumonia with bloodstream infection due to wild-type A. pittii. The outcome was favorable after 7 days of antibiotic treatment with cefepime. We confirmed bacterial identification with whole-genome sequencing, and we examined the A. pitii core-genome phylogeny for genomic clusters. CONCLUSIONS: This situation is uncommon in Europe and occurred after a heat wave in France with temperatures above 38 °C. Herein, we discuss the possibility that this pneumonia may be emerging in the current context of global warming.

Atezolizumab and bevacizumab for non-resectable or metastatic combined hepatocellular-cholangiocarcinoma: A multicentric retrospective study.

BACKGROUNDS: The efficacy of atezolizumab/bevacizumab has never been reported in patients with metastatic/unresectable combined hepatocellular-cholangiocarcinoma (cHCC-CCA). PATIENTS AND METHODS: We retrospectively included patients with a histological diagnosis of unresectable/metastatic cHCC-CCA and treated with atezolizumab/bevacizumab (2020-2022) in 7 centers. Clinical and radiological features were collected at the beginning of atezolizumab/bevacizumab. We reported the radiological response using RECIST criteria, overall survival (OS) and progression-free survival (PFS). RESULTS: Sixteen patients with cHCC-CCA were included and were predominantly male (75%) with advanced fibrosis/cirrhosis (69%). Nine patients received atezolizumab/bevacizumab as a first-line systemic treatment, 5 as a second line, 1 as a third line and 1 as a fifth line. Severe digestive bleeding occurred in 2 patients. Among the 9 patients treated in the first line, 4 experienced radiological progression, 3 partial response and 1 had stable disease. Patients treated with atezolizumab/bevacizumab in the first line had a median OS of 13 months and a median PFS of 3 months. Among the 7 patients receiving atezolizumab/bevacizumab as a second line or more, 4 patients harbored a stable disease, 2 a partial response, and 1 a progressive disease. CONCLUSIONS: The combination of atezolizumab and bevacizumab showed signs of anti-tumor efficacy in patients with unresectable/metastatic cHCC-CCA.

Herpes Simplex Virus Hepatitis in Patients Requiring Intensive Care Unit Admission: A Retrospective, Multicenter, Observational Study.

The clinical features and short-term prognosis of patients admitted to the intensive care unit for herpes hepatitis are lacking. Of 33 patients admitted between 2006 and 2022, 22 were immunocompromised, 4 were pregnant women, and 23 died. Sixteen patients developed a hemophagocytic syndrome. Acyclovir was initiated a median (interquartile range) of 1 (0-3) day after admission.

Unresectable hepatocellular carcinoma at dawn of immunotherapy era: real-world data from the French prospective CHIEF cohort.

BACKGROUND AND OBJECTIVES: Hepatocellular carcinoma epidemiological data are limited in France. The Epidemio Liver Immunotherapy Tecentriq outcome research (ELITor) retrospective study, based on real-world data from the Carcinome HépatocellulaIrE en France (CHIEF) French cohort of hepatocellular carcinoma patients, aimed to get insight into the treatment patterns, the sociodemographic, clinical, biological, and etiological characteristics, and the quality of life of patients with unresectable hepatocellular carcinoma. METHODS AND RESULTS: Between 1 September 2019 and 4 December 2020, 367 patients from the CHIEF cohort received at least one locoregional (52.8%) chemoembolization or radioembolization or systemic treatment (88.3%) and were selected for ELITor. Most patients had a Barcelona Clinic Liver Cancer (BCLC) C (93.2%) hepatocellular carcinoma stage and were affected by cirrhosis (67.7%). Alcohol was confirmed as the main etiology both as a single etiology (29.1%) and in association with other risk factors (26.9%), mainly metabolic disorders (16.2%).Tyrosine-kinase inhibitors, mainly sorafenib, were the most administered systemic treatments in first line. Patients who received at least one combination of atezolizumab and bevacizumab during the study period ( N  = 53) had a better performance status and less portal hypertension frequency than the overall population and more hepatitis B virus infection and fewer metabolic disorders as single etiology. Overall, the global health score before treatment (62.3 ±â€…21.9) was in line with that of reference cancer patients and worsened in 51.9% of the cases after first-line palliative-intent treatment. CONCLUSION: This study provided real-life data on advanced hepatocellular carcinoma characteristics and treatment patterns and described the first patients to receive the atezolizumab-bevacizumab combination before it became the new standard of care for advanced hepatocellular carcinoma.

Beyond atezolizumab plus bevacizumab in patients with advanced hepatocellular carcinoma: overall efficacy and safety of tyrosine kinase inhibitors in a real-world setting.

Background: In patients with advanced hepatocellular carcinoma (HCC) progressing after atezolizumab and bevacizumab, the optimal therapeutic sequence is still unclear and no second-line agent has proven its efficacy. Objectives: The aim of this retrospective multicenter real-world cohort study was to provide an evaluation of the efficacy and safety of the use of second-line tyrosine kinase inhibitors (TKIs) in this population. Methods: All patients with advanced HCC, treated in first-line setting by atezolizumab-bevacizumab, and who received at least one dose of treatment with TKI were included in this study. All the data were retrospectively collected from medical records. The primary outcome was progression-free survival (PFS). Secondary outcomes were overall survival (OS), overall global survival (OGS), and safety. A total of 82 patients were included in this study. Results: Patients were assigned to the regorafenib group (n = 29, 35.4%) or other TKI (sorafenib n = 41, lenvatinib n = 8, or cabozantinib n = 4) group (n = 53). PFS was not significantly different between the two groups [2.6 versus 2.8 months, HR 1.07 (95% CI: 0.61-1.86), p = 0.818]. Median PFS rates were 2.6, 4.4, and 2.8 months in sorafenib-, lenvatinib-, and cabozantinib group, respectively. OS was statistically different between the regorafenib group and other TKI group [15.8 versus 7.0 months, HR 0.40 (95% CI: 0.20-0.79), p = 0.023]. When adjusting on confounding factors, there was still a difference in OS favoring the regorafenib group (adjusted hazard ratio 0.35, p = 0.019). OGS of patients who received regorafenib was improved compared to other TKI [18.6 versus 15.0 months, HR 0.42 (95% CI: 0.22-0.84), p = 0.036]. Twenty percent of patients had grade 3 and none had grade 4 or 5 adverse events. In patients who experienced disease progression and fit for a third-line treatment, 80% and 50% received cabozantinib in regorafenib group and other TKI group, respectively. Conclusion: Efficacy of any TKI in the second-line setting was not affected by atezolizumab-bevacizumab treatment as first-line therapy. The safety profile in the second-line setting was consistent with the results shown in pivotal studies. PFS rates of patients were similar, regardless of TKI type. Regorafenib was associated with better OS and OGS rates compared to other TKI. These data need to be confirmed in prospective comparative studies.

Anterior Versus Classical Approach During Right Hepatectomy for Hepatocellular Carcinoma: Inverse Propensity Score Weighted Analysis.

BACKGROUND: Eastern data highlight the oncological benefits of the anterior approach (AA) during right hepatectomy (RH) for hepatocellular carcinoma (HCC). However, to our knowledge, previous western data on this topic are scarce. In this study, the oncological outcomes of AA and classical approach (CA) during RH for HCC were compared. METHODS: A retrospective inverse propensity score-weighted fashion (IPTW) case-control study was performed in two French hepatobiliary surgery departments. Overall survival (OS), disease-free survival (DFS), and early recurrence rate (within 2 years after surgery) were analyzed. RESULTS: Survival analysis was performed for 114 patients (CA group,60 patients; AA group, 54 patients). Before IPTW adjustment, the 3-year DFS rates were 29.4% (AA group) and 44% (CA group), respectively. No significant differences were found in DFS (HR = 1.1, 95%CI:0.62-1.9, p = 0.77) and OS (HR = 1.2, 95%CI:0.54-2.6, p = 0.66). After IPTW, DFS and OS analyses showed no differences between the two groups (p = 0.77 and p = 0.46, respectively). Early recurrence rates were similar before and after IPTW. Satellite nodules were the only significant independent risk factor for recurrence. CONCLUSION: AA and CA did not result in significant differences in DFS, OS, or early recurrence after right hepatectomy for HCC before and after IPTW.

Impact of COVID-19 on the management of hepatocellular carcinoma in a high-prevalence area: What's new 12 months later?

INTRODUCTION AND OBJECTIVES: The lockdown policy introduced in 2020 to minimize the spread of the COVID-19 pandemic, significantly affected the management and care of patients affected by hepatocellular carcinoma (HCC). The aim of this follow-up study was to determine the 12 months impact of the COVID-19 pandemic on the cohort of patients affected by HCC during the lockdown, within six French academic referral centers in the metropolitan area of Paris. MATERIALS AND METHODS: We performed a 12 months follow-up of the cross-sectional study cohort included in 2020 on the management of patients affected by HCC during the first six weeks of the COVID-19 pandemic (exposed), compared to the same period in 2019 (unexposed). Overall survival were compared between the groups. Predictors of mortality were analysed with Cox regression. RESULTS: From the initial cohort, 575 patients were included (n = 263 Exposed_COVID, n = 312 Unexposed_COVID). Overall and disease free survival at 12 months were 59.9 ± 3.2% vs 74.3 ± 2.5% (p<0.001) and 40.2 ± 3.5% vs 63.5 ± 3.1% (p<0.001) according to the period of exposure (Exposed_COVID vs Unexposed_COVID, respectively). Adjusted Cox regression revealed that the period of exposure (Exposed_COVID HR: 1.79, 95%CI (1.36, 2.35) p<0.001) and BCLC stage B, C and D (BCLC B HR: 1.82, 95%CI (1.07, 3.08) p = 0.027 - BCLC C HR: 1.96, 95%CI (1.14, 3.38) p = 0.015 - BCLC D HR: 3.21, 95%CI (1.76, 5.85) p<0.001) were predictors of death. CONCLUSIONS: Disruption of routine healthcare services because of the pandemic translated to reduced 1 year overall and disease-free survival among patients affected by HCC, in the metropolitan area of Paris, France.

MRI features associated with HCC histologic subtypes: a western American and European bicenter study.

OBJECTIVES: To evaluate if preoperative MRI can predict the most frequent HCC subtypes in North American and European patients treated with surgical resection. METHODS: A total of 119 HCCs in 97 patients were included in the North American group and 191 HCCs in 176 patients were included in the European group. Lesion subtyping was based on morphologic features and immuno-histopathological analysis. Two radiologists reviewed preoperative MRI and evaluated the presence of imaging features including LI-RADS major and ancillary features to identify clinical, biologic, and imaging features associated with the main HCC subtypes. RESULTS: Sixty-four percent of HCCs were conventional. The most frequent subtypes were macrotrabecular-massive (MTM-15%) and steatohepatitic (13%). Necrosis (OR = 3.32; 95% CI: 1.39, 7.89; p = .0064) and observation size (OR = 1.011; 95% CI: 1.0022, 1.019; p = .014) were independent predictors of MTM-HCC. Fat in mass (OR = 15.07; 95% CI: 6.57, 34.57; p < .0001), tumor size (OR = 0.97; 95% CI: 0.96, 0.99; p = .0037), and absence of chronic HCV infection (OR = 0.24; 95% CI: 0.084, 0.67; p = .0068) were independent predictors of steatohepatitic HCC. Independent predictors of conventional HCCs were viral C hepatitis (OR = 3.20; 95% CI: 1.62, 6.34; p = .0008), absence of fat (OR = 0.25; 95% CI: 0.12, 0.52; p = .0002), absence of tumor in vein (OR = 0.34; 95% CI: 0.13, 0.84; p = .020), and higher tumor-to-liver ADC ratio (OR = 1.96; 95% CI: 1.14, 3.35; p = .014) CONCLUSION: MRI is useful in predicting the most frequent HCC subtypes even in cohorts with different distributions of liver disease etiologies and tumor subtypes which might have future treatment and management implications. KEY POINTS: • Representation of both liver disease etiologies and HCC subtypes differed between the North American and European cohorts of patients. • Retrospective two-center study showed that liver MRI is useful in predicting the most frequent HCC subtypes.

Body weight changes and duration of estrogen exposure modulate the evolution of hepatocellular adenomas after contraception discontinuation.

BACKGROUND AND AIMS: The natural history of hepatocellular adenomas (HCAs) remains to be better described, especially in nonresected patients. We aim to identify the predictive factors of HCA evolution after estrogen-based contraception discontinuation. APPROACH AND RESULTS: We retrospectively included patients with a histological diagnosis of HCA from three centers. Clinical, radiological, and pathological data were collected to identify predictive factors of radiological evolution per Response Evaluation Criteria in Solid Tumors, version 1.1, and occurrence of complications (bleeding, malignant transformation). We built a score using variables that modulate estrogen levels: body mass index and duration of estrogen-based contraception. An external cohort was used to validate this score. 183 patients were included in the cohort, including 161 women (89%) using estrogen-based contraception for a median of 12 years. Thirty percent of patients had at least one HNF1A -inactivated HCA, 45.5% at least one inflammatory HCA, and 11% at least one HCA with activation of ß-catenin (bHCA). Twenty-one symptomatic bleedings (11%) and eleven malignant transformations (6%) occurred. Ages < 37 years old ( p = 0.004) and HCA > 5 cm at imaging were independently associated with symptomatic bleeding ( p = 0.003), whereas a bHCA was associated with malignant transformation ( p < 0.001). After a median follow-up of 5 years, radiological regression was observed in 31%, stabilization in 47%, and progression in 22% of patients. Weight loss was associated with regression ( p < 0.0001) and weight gain with progression ( p = 0.02). The estrogen exposure score predicted radiological regression (odds ratio, 2.33; confidence interval 95%, 1.29-4.19; p = 0.005) with a linear relationship between the rate of estrogen exposure and the probability of regression. This result was confirmed in an external cohort of 72 female patients ( p = 0.003). CONCLUSION: Weight variation is strongly associated with radiological evolution after oral contraception discontinuation. A score of estrogen exposure, easily assessable in clinical practice at diagnosis, predicts regression of HCA.

Educational interventions to integrate surgical staff within medical units during the COVID-19 pandemic: EDUCOVID survey.

BACKGROUND: The SARS-CoV-2 (COVID-19) pandemic required a rapid surge of healthcare capacity to face a growing number of critically ill patients. For this reason, a support reserve of physicians, including surgeons, were required to be reassigned to offer support. OBJECTIVE: To realize a survey on the educational programs deployed (face-to-face or e-learning focusing on infective area, basic gestures, COVID clinical management and intensive care medicine), and their impact on behavior change (Kirkpatrick 3) of the target population of surgeons, measured on a five modalities Likert scale. DESIGN: Cross-sectional online e-survey (NCT04732858) within surgeons from the Assistance Publique - Hôpitaux de Paris network, metropolitan area of Paris, France. RESULTS: Cross-sectional e-Survey: among 382 surgeons invited, 37 (9.7%) participated. The effectiveness of the educational interventions on behavior changes was rated within the highest region of the Likert scale by 15% (n = 3) and 22% (n = 6) for 'e-learning' and 'face-to-face' delivery modes, respectively. CONCLUSIONS: Despite the low response rate, this survey suggests an overall low impact on behaviour change among responders affiliated to a surgical discipline.

Systemic Treatments with Tyrosine Kinase Inhibitor and Platinum-Based Chemotherapy in Patients with Unresectable or Metastatic Hepatocholangiocarcinoma.

Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37-1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43-1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23-3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31-9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08-4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27-3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44-3.49, p = 0.67). Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.

Macrotrabecular-Massive Hepatocellular Carcinoma: Light and Shadow in Current Knowledge.

The subject of this narrative review is macrotrabecular-massive hepatocellular carcinoma (MTM-HCC). Despite their rarity, these tumours are of general interest because of their epidemiological and clinical features and for representing a distinct model of the interaction between the angiogenetic system and neoplastic cells. The MTM-HCC subtype is associated with various adverse biological and pathological parameters (the Alfa-foetoprotein (AFP) serum level, tumour size, vascular invasion, and satellite nodules) and is a key determinant of patient prognosis, with a strong and independent predictive value for early and overall tumour recurrence. Gene expression profiling has demonstrated that angiogenesis activation is a hallmark feature of MTM-HCC, with overexpression of both angiopoietin 2 (ANGPT2) and vascular endothelial growth factor A (VEGFA).

Liver resection for single large hepatocellular carcinoma: a prognostic factors study.

INTRODUCTION AND OBJECTIVES: Liver resection is the only curative therapeutic option for large hepatocellular carcinoma (> 5 cm), but survival is worse than in smaller tumours, mostly due to the high recurrence rate. There is currently no proper tool for stratifying relapse risk. Herein, we investigated prognostic factors before hepatectomy in patients with a single large hepatocellular carcinoma (HCC). MATERIAL AND METHODS: We retrospectively identified 119 patients who underwent liver resection for a single large HCC in 2 tertiary academic French centres and collected pre- and post-operative clinical, biological and radiological features. The primary outcome was overall survival at five years. Secondary outcomes were recurrence-free survival at five years and prognostic factors for recurrence. RESULTS: A total of 84% of the patients were male, and the median age was 66 years old (IQR 58-74). Thirty-nine (33%) had Child-Pugh A cirrhosis, and the mean Model for End-Stage Liver Disease (MELD) score was 6 (6-6). The aetiology of liver disease was predominantly alcohol-related (48%), followed by nonalcoholic steatohepatitis (22%), hepatitis B (18%) and hepatitis C (10%). The mean tumour size was 70 mm (55-110). The median overall survival was 72.5 months (IC 95%: 56.2-88.7), and the five-year overall survival was 55.1 ± 5.5%. The median recurrence-free survival was 26.6 months (95% CI: 16.0-37.1), and the five-year recurrence-free survival rate was 37.8 ± 5%. In multivariate analysis, preoperative prognostic factors for recurrence were baseline alpha-fetoprotein (AFP) > 7 ng/mL (p<0.001), portal veinous invasion (p=0.003) and cirrhosis (p=0.020). Using these factors, we created a simple recurrence-risk scoring system that classified three groups with distinct disease-free survival medians (p<0.001): no risk factors (65 months), 1 risk factor (36 months), and ≥2 risk factors (8.9 months). CONCLUSION: Liver resection is the only curative option for large HCC, and we confirmed that survival could be acceptable in experienced centres. Recurrence is the primary issue of surgery, and we proposed a simple preoperative score to help identify patients with the most worrisome prognosis and possible candidates for combined therapy.

Impact of Extended Use of Ablation Techniques in Cirrhotic Patients with Hepatocellular Carcinoma: A Cost-Effectiveness Analysis.

BACKGROUND: To evaluate the cost-effectiveness of the extended use of ablation for the treatment of hepatocellular carcinoma (HCC) with cirrhosis in an expert ablation center when compared to the non-extended use of ablation in equivalent tertiary care centers. METHODS: Consecutive cirrhotic patients with non-metastatic HCC, no prior treatment, and referred to three tertiary care centers between 2012 and 2016 were retrospectively identified. The Bondy group, including all of the patients treated at Jean Verdier Hospital, where the extended use of ablation is routinely performed, was compared to the standard of care (SOC) group, including all of the patients treated at the Beaujon and Mondor Hospitals, using propensity score matching. A cost-effectiveness analysis was carried out from the perspective of French health insurance using a Markov model on a lifetime horizon. RESULTS: 532 patients were matched. The Bondy group led to incremental discounted lifetime effects of 0.8 life-years gained (LYG) (95% confidence interval: 0.4, 1.3) and a decrease in lifetime costs of EUR 7288 (USD 8016) (95% confidence interval: EUR 5730 [USD 6303], EUR 10,620 [USD 11,682]) per patient, compared with the SOC group, resulting in a dominant mean incremental cost-effectiveness ratio (ICER). A compliance with the Barcelona Clinic Liver Classification (BCLC) guidelines for earlier stage contributed to the greater part of the ICER. CONCLUSION: The extended use of ablation in cirrhotic patients with HCC was more effective and less expensive than the non-extended use of the ablation strategy.

Fat in mass in primary liver lesions: are usual MRI diagnostic criteria of both malignant and benign liver lesions still applicable?

PURPOSE: To evaluate the accuracy of the usual MRI diagnostic patterns of primary liver lesions applied to the diagnosis of pathologically proven fat-containing liver lesions. MATERIALS AND METHODS: This monocentric IRB approved retrospective study included all patients with pathologically proven focal liver lesions and documented intra-tumoral fat on pathology and who underwent preoperative liver MRI for characterization. Both liver morphology and usual lesion MRI features were analyzed and their distribution correlated to the final pathological result (Khi-2 or Fisher exact tests, Student t-test or Mann-Whitney U test, as appropriate). The Sensitivity (Se) and Specificity (Sp) of MRI patterns known to be associated to both Hepatocellular Carcinoma (HCC), Focal Nodular Hyperplasia (FNH), and Hepatocellular Adenoma (HCA) subtypes were evaluated. RESULTS: Between March 2014 and November 2021, 66 lesions were included, corresponding to: 26 HCC, 32 HCA, 6 FNH and 2 hepatic angiomyolipoma (HAML). All lesions developed on a dysmorphic liver were HCC. A non-rim arterial phase hyperenhancement with a washout and an enhancing capsule had a 98% specificity for HCC diagnosis; A homogeneous dropout of signal on the opposed phase had a sensitivity of 92% and a specificity of 89% for the diagnosis of HNF1alpha inactivated subtype of HCA (HHCA). The FNH pattern was specific at 100% for the diagnosis of FNH with a 40% Se. Finally, the accuracy of inflammatory hepatocellular adenoma (IHCA) pattern had a low 60% Se but a high 89% Sp for IHCA diagnosis. CONCLUSION: Known MRI patterns remain reliable for the accurate diagnosis of primary liver tumors on MRI even in fat-containing lesions.

Bi-allelic hydroxymethylbilane synthase inactivation defines a homogenous clinico-molecular subtype of hepatocellular carcinoma.

BACKGROUND & AIMS: Acute intermittent porphyria (AIP), caused by heterozygous germline mutations of the heme synthesis pathway enzyme HMBS (hydroxymethylbilane synthase), confers a high risk of hepatocellular carcinoma (HCC) development. Yet, the role of HMBS in liver tumorigenesis remains unclear. METHODS: Herein, we explore HMBS alterations in a large series of 758 HCC cases, including 4 patients with AIP. We quantify the impact of HMBS mutations on heme biosynthesis pathway intermediates and we investigate the molecular and clinical features of HMBS-mutated tumors. RESULTS: We identify recurrent bi-allelic HMBS inactivation, both in patients with AIP acquiring a second somatic HMBS mutation and in sporadic HCC with 2 somatic hits. HMBS alterations are enriched in truncating mutations, in particular in splice regions, leading to abnormal transcript structures. Bi-allelic HMBS inactivation results in a massive accumulation of its toxic substrate porphobilinogen and synergizes with CTNNB1-activating mutations, leading to the development of well-differentiated tumors with a transcriptomic signature of Wnt/ß-catenin pathway activation and a DNA methylation signature related to ageing. HMBS-inactivated HCC mostly affects females, in the absence of fibrosis and classical HCC risk factors. CONCLUSIONS: These data identify HMBS as a tumor suppressor gene whose bi-allelic inactivation defines a homogenous clinical and molecular HCC subtype. LAY SUMMARY: Heme (the precursor to hemoglobin, which plays a key role in oxygen transport around the body) synthesis occurs in the liver and involves several enzymes including hydroxymethylbilane synthase (HMBS). HMBS mutations cause acute intermittent porphyria, a disease caused by the accumulation of toxic porphyrin precursors. Herein, we show that HMBS inactivation is also involved in the development of liver cancers with distinct clinical and molecular characteristics.

Artificial intelligence predicts immune and inflammatory gene signatures directly from hepatocellular carcinoma histology.

BACKGROUND & AIMS: Patients with hepatocellular carcinoma (HCC) displaying overexpression of immune gene signatures are likely to be more sensitive to immunotherapy, however, the use of such signatures in clinical settings remains challenging. We thus aimed, using artificial intelligence (AI) on whole-slide digital histological images, to develop models able to predict the activation of 6 immune gene signatures. METHODS: AI models were trained and validated in 2 different series of patients with HCC treated by surgical resection. Gene expression was investigated using RNA sequencing or NanoString technology. Three deep learning approaches were investigated: patch-based, classic MIL and CLAM. Pathological reviewing of the most predictive tissue areas was performed for all gene signatures. RESULTS: The CLAM model showed the best overall performance in the discovery series. Its best-fold areas under the receiver operating characteristic curves (AUCs) for the prediction of tumors with upregulation of the immune gene signatures ranged from 0.78 to 0.91. The different models generalized well in the validation dataset with AUCs ranging from 0.81 to 0.92. Pathological analysis of highly predictive tissue areas showed enrichment in lymphocytes, plasma cells, and neutrophils. CONCLUSION: We have developed and validated AI-based pathology models able to predict the activation of several immune and inflammatory gene signatures. Our approach also provides insights into the morphological features that impact the model predictions. This proof-of-concept study shows that AI-based pathology could represent a novel type of biomarker that will ease the translation of our biological knowledge of HCC into clinical practice. LAY SUMMARY: Immune and inflammatory gene signatures may be associated with increased sensitivity to immunotherapy in patients with advanced hepatocellular carcinoma. In the present study, the use of artificial intelligence-based pathology enabled us to predict the activation of these signatures directly from histology.

Immune Profiling of Combined Hepatocellular- Cholangiocarcinoma Reveals Distinct Subtypes and Activation of Gene Signatures Predictive of Response to Immunotherapy.

PURPOSE: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare malignancy associated with an overall poor prognosis. We aimed to investigate the immune profile of cHCC-CCA and determine its impact on disease outcome. EXPERIMENTAL DESIGN: We performed a multicenter study of 96 patients with cHCC-CCA. Gene expression profile was analyzed using nCounter PanCancer IO 360 Panel. Densities of main immune cells subsets were quantified from digital slides of IHC stainings. Genetic alterations were investigated using targeted next-generation sequencing. RESULTS: Two main immune subtypes of cHCC-CCA were identified by clustering analysis: an "immune-high" (IH) subtype (57% of the cases) and an "immune-low" (IL) subtype (43% of the cases). Tumors classified as IH showed overexpression of genes related to immune cells recruitment, adaptive and innate immunity, antigen presentation, cytotoxicity, immune suppression, and inflammation (P < 0.0001). IH cHCC-CCAs also displayed activation of gene signatures recently shown to be associated with response to immunotherapy in patients with HCC. Quantification of immunostainings confirmed that IH tumors were also characterized by higher densities of immune cells. Immune subtypes were not associated with any genetic alterations. Finally, multivariate analysis showed that the IH subtype was an independent predictor of improved overall survival. CONCLUSIONS: We have identified a subgroup of cHCC-CCA that displays features of an ongoing intratumor immune response, along with an activation of gene signatures predictive of response to immunotherapy in HCC. This tumor subclass is associated with an improved clinical outcome. These findings suggest that a subset of patients with cHCC-CCA may benefit from immunomodulating therapeutic approaches.