Radiological diagnosis of hepatocellular carcinoma does not preclude biopsy before treatment.

Background & Aims: The diagnosis of hepatocellular carcinoma (HCC) in patients with cirrhosis relies on non-invasive criteria based on international guidelines. The advent of systemic therapies warrants reconsideration of the role of biopsy specimens in the diagnosis of HCC. Accordingly, we investigated the diagnostic performance of the LI-RADS 2018 and the AASLD 2011 criteria. Methods: Consecutive patients with cirrhosis who underwent a biopsy for suspected HCC between 2015 and 2020 were included. The available imaging studies (computed tomography and/or magnetic resonance imaging) were blindly reviewed by two independent radiologists. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were assessed for LI-RADS, AASLD, and biopsies. Results: In total, 167 patients underwent both available biopsy and imaging. Of the 137 relevant biopsies, 114 patients had HCC (83.2%), 12 (9%) had non-HCC malignant lesions, and 11 (8%) had benign nodules. The PPV and NPV of the biopsies were 100% and 62%, respectively; 30 biopsies were non-contributive. The PPV and NPV of the LI-RADS categories were 89% and 32.8% for LR-5 and 85.5% and 54.5% for LR-4 + 5 + TIV, respectively. The PPV and NPV of the 2011 AASLD criteria were 93.2% and 35.6%, respectively. The interobserver kappa (k = 0.380) for the LR-5 categories was reasonable. Of 100 LR-5 nodules, 11 were misclassified, in particular one case was a colorectal metastasis, and two cases were cholangiocarcinomas, of which nine were identified through biopsy, whereas six were correctly classified according to LI-RADS (LR-M or LR-TIV). Fifty percent of macrotrabecular HCC and 48.4% of poorly differentiated HCC (Edmonson 3 and 4) were not classified as LR-5. Conclusions: LI-RADS 2018 did not outperform the AASLD 2011 score as a non-invasive diagnosis of HCC. Tumor biopsy allowed restoration of an accurate diagnosis in 11% of LR-5 cases. A combined radiological and histological diagnosis should be considered mandatory for good treatment assessment. Impact and Implications: Although biopsy is not required for hepatocellular carcinoma diagnosis when the LI-RADS criteria are met according to current guidelines, our study underscores the limits of radiology and the need for biopsy when hepatocellular carcinoma is suspected. Histological findings could change therapeutics of liver tumors even if only for a small proportion of patients. Histological proof of the type of cancer is a standard in oncology.

PD1 and TIM3 Expression is Associated with Very Early Hepatocellular Carcinoma Recurrence After Percutaneous Thermal Ablation.

Purpose: Percutaneous thermal ablation (PTA) is a cornerstone in the management of early-stage hepatocellular carcinoma (HCC). However, intrahepatic distant recurrence (IDR) occurs in the majority of patients after PTA. The aim of this study was to evaluate the immune signature associated with very early IDR. Patients and Methods: Thirty-one patients (26 men, 5 women; mean age:72.4 ± 8.6; age range:57-86 years) who underwent PTA for HCC were included in this study. After PTA for HCC, patients were followed and later divided into two groups: a "very early recurrence" group in case of IDR within 12 months after PTA, and a "prolonged recurrence-free" group in case of no recurrence before 12 months of follow-up. Freshly harvested intratumoral and nontumoral liver tissues and peripheral blood were obtained before PTA and explored by multiparametric flow cytometry. Results: The frequency of PD1+CD4+ T cells was higher in the early recurrence group than in the prolonged recurrence-free group in the peripheral blood (24.3%, IQR: 22.3-36.5 vs 14.0%, IQR: 11.5-16.4, p<0.0001), in the nontumoral liver (37.9%, IQR: 36.0-50.0 vs 22.5%, IQR: 18.0-29.9, p=0.0004), and in the tumor (37.6%, IQR: 32.3-39.3 vs 24.0%, IQR: 20.0-30.3, p=0.0137). Similarly, the frequency of TIM+CD8+ T cells was higher in the very early recurrence group in the peripheral blood (p=0.0021), non-tumoral liver (p=0.0012), and tumor (p=0.0239). Conclusion: The expression of immune checkpoint molecules, such as PD1 and TIM3 on T cells identified HCC patients at risk of very early IDR after PTA who would likely benefit from adjuvant immunotherapy. Thus, our study contributes to a better understanding of the potential association of PTA with adjuvant immunotherapies.

Endovascular Lymphatic Decompression via Thoracic Duct Stent Placement for Refractory Ascites in Patients with Cirrhosis: A Pilot Study.

PURPOSE: To evaluate the technical and clinical success of endovascular lymphatic decompression via thoracic duct (TD) stent placement in patients with cirrhosis with refractory ascites. MATERIALS AND METHODS: Nine patients (6 men and 3 women; median age, 66 [interquartile range {IQR}, 65-68] years; range, 62-78 years) who underwent TD stent placement for refractory ascites with contraindications for liver transplantation and transjugular intrahepatic portosystemic shunt creation were included in this retrospective study. TD stent placement was performed under local anesthesia using retrograde access from the venous system. Self-expanding stents from 5 to 8 mm in diameter were used and extended into the subclavian vein by approximately 1 cm. Technical (correct positioning of the stent) and clinical success (no more requirement of paracentesis) were evaluated. In addition, the safety of the procedure and TD pressure evolution were evaluated. RESULTS: The technical success rate was 100%, and 3 (33%) patients reported clinical success. Five (56%) patients reported 7 minor adverse events (Grade I), among which 2 TD perforations were induced by stent angioplasty, with no clinical manifestation or treatment required. The median TD pressure decreased from 19 mm Hg (IQR, 11-24 mm Hg) at the beginning of the procedure to 6 mm Hg (IQR, 5-11 mm Hg) after TD stent placement. The median survival time after the procedure was 7.1 months. CONCLUSIONS: Endovascular lymphatic decompression via TD stent placement is feasible and safe and was effective on ascites in some patients with cirrhosis with refractory ascites.

Evolution of Thoracic Duct Congestion after Portal Decompression by TIPS in Cirrhotic Patients.

PURPOSE: To evaluate the thoracic duct (TD) diameter on CT scan in a population of cirrhotic patients before and after relief of portal hypertension by transjugular intrahepatic portosystemic shunt (TIPS) insertion. To evaluate the association between the initial TD diameters and the cirrhosis severity, the morphological signs of portal hypertension and the clinical success of TIPS. METHODS: This retrospective monocentric study included 54 cirrhotic patients who underwent TIPS insertion between 2010 and 2020. Measurements of the TD were performed in CT scan at two distinct points: at the cisterna chyli (CC) and at the terminal TD near the lymphovenous junction. RESULTS: The mean diameter of the TD was 6.4 mm (± 2.9) at the CC and 6.9 mm (± 1.9) near the lymphovenous junction. After TIPS, the mean diameter decreased to 5.1 (± 2.1) at the CC (p < 0.001) and to 4.3 (± 1.5) at the terminal TD (p = 0.001). The initial TD diameter was associated with the presence of voluminous venous collaterals (p = 0.04 at CC and p = 0.04 junction). The initial terminal TD diameter was weakly associated with the largest axis of the spleen (r = 0.126, p = 0.03) and moderately associated with the azygos vein diameter (r = 0.511, p = 0.001). Initial TD diameter was not associated with Child-Pugh score (r = 0.276, p = 0.08 and r = 0.169, p = 0.7) or with clinical success of TIPS on ascites (p = 0.33 and 0.60) or on bleeding (p = 0.13 and 0.99). CONCLUSION: The diameter of the TD decreases after TIPS, but its initial diameter does not seem to be predictive of the clinical success of TIPS.

Safety and Efficacy of Transarterial Chemoembolization in Elderly Patients with Intermediate Hepatocellular Carcinoma.

(1) Introduction: Transarterial chemoembolization (TACE) is the most widely used treatment for intermediate hepatocellular carcinoma (HCC), with limited data available in elderly patients. This study compares the safety and efficacy of TACE for HCC in elderly patients (≥70 years) versus younger patients (<70 years). (2) Materials and Methods: Patients treated by a first TACE for HCC at Grenoble-Alpes University Hospital from January 2012 to March 2017 were included. The primary objective was to compare the safety and predictive factors of serious adverse events between groups using univariate and multivariate analyses. Secondary objectives included tumor response and survival analyses. (3) Results: 271 patients were included: 88 elderly and 183 under 70 years. A total of 20.5% of elderly patients experienced serious adverse events versus 21.3% of patients under 70 (p = 0.87). The predictive factors of serious adverse events were Child−Pugh ≥ B7 (p < 0.0001), ECOG ≥ 1 (p = 0.0019), and MELD ≥ 9 (p = 0.0415). The serious adverse event rate was not increased with age (p = 0.87). The objective tumor response rate was 89.5% in elderly versus 78.7% in younger patients (p = 0.03). (4) Conclusion: This study showed similar safety profiles of the first TACE between elderly and younger patients, with comparable efficacy outcomes, suggesting that advanced age should not constitute a limitation in itself in treatment decision-making.

Liver Transplantation for Hepatocellular Carcinoma: A Real-Life Comparison of Milan Criteria and AFP Model.

PURPOSE: To compare the agreement for the criteria on the explant and the results of liver transplantation (LT) before and after adoption of the AFP (α-fetoprotein) model. METHODS: 523 patients consecutively listed in five French centers were reviewed to compare results of the Milan criteria period (MilanCP, n = 199) (before 2013) and the AFP score period (AFPscP, n = 324) (after 2013). (NCT03156582). RESULTS: During AFPscP, there was a significantly longer waiting time on the list (12.3 vs. 7.7 months, p < 0.001) and higher rate of bridging therapies (84 vs. 75%, p = 0.012) compared to the MilanCP. Dropout rate was slightly higher in the AFPscP (31 vs. 24%, p = 0.073). No difference was found in the histological AFP score between groups (p = 0.838) with a global agreement in 88% of patients. Post-LT recurrence was 9.2% in MilanCP vs. 13.2% in AFPscP (p = 0.239) and predictive factors were AFP > 2 on the last imaging, downstaging policy and salvage transplantation. Post-LT survival was similar (83 vs. 87% after 2 years, p = 0.100), but after propensity score analysis, the post-listing overall survival (OS) was worse in the AFPscP (HR 1.45, p = 0.045). CONCLUSIONS: Agreement for the AFP model on explant analysis (≤2) did not significantly change. AFP score > 2 was the major prognostic factor for recurrence. Graft allocation policy has a major impact on prognosis, with a post-listing OS significantly decreased, probably due to the increase in waiting time, increase in bridging therapies, downstaging policy and salvage transplantation.

Mu-opioid receptors and dietary protein stimulate a gut-brain neural circuitry limiting food intake.

Intestinal gluconeogenesis is involved in the control of food intake. We show that mu-opioid receptors (MORs) present in nerves in the portal vein walls respond to peptides to regulate a gut-brain neural circuit that controls intestinal gluconeogenesis and satiety. In vitro, peptides and protein digests behave as MOR antagonists in competition experiments. In vivo, they stimulate MOR-dependent induction of intestinal gluconeogenesis via activation of brain areas receiving inputs from gastrointestinal ascending nerves. MOR-knockout mice do not carry out intestinal gluconeogenesis in response to peptides and are insensitive to the satiety effect induced by protein-enriched diets. Portal infusions of MOR modulators have no effect on food intake in mice deficient for intestinal gluconeogenesis. Thus, the regulation of portal MORs by peptides triggering signals to and from the brain to induce intestinal gluconeogenesis are links in the satiety phenomenon associated with alimentary protein assimilation.