Prognostic benefit of preoperative transarterial chemoembolization in upfront resectable large hepatocellular carcinoma: a multicentric propensity score based analysis of European high-volume centers.

BACKGROUND: Hepatocellular carcinoma (HCC) have a dismal prognosis and any effective neoadjuvant treatment has been validated to date. We aimed to investigate the role of neoadjuvant transarterial chemoembolization (TACE) in upfront resectable HCC larger than 5 cm. METHODS: This is a multicentric retrospective study comparing outcomes of large HCC undergoing TACE followed by surgery or liver resection alone before and after propensity-score matching (PSM). RESULTS: A total of 384 patients were included of whom 60 (15.6%) received TACE. This group did not differ from upfront resected cases neither in terms of disease-free survival (p = 0.246) nor in overall survival (p = 0.276). After PSM, TACE still did not influence long-term outcomes (p = 0.935 and p = 0.172, for DFS and OS respectively). In subgroup analysis, TACE improved OS only in HCC ≥10 cm (p = 0.045), with a borderline significance after portal vein embolization/ligation (p = 0.087) and in single HCC (p = 0.052). CONCLUSIONS: TACE should not be systematically performed in all resectable large HCC. Selected cases could however potentially benefit from this procedure, as patients with huge and single tumors or those necessitating of a PVE.

Spontaneous idiopathic liver hemorrhage: a systematic review of a rare entity.

BACKGROUND: Spontaneous idiopathic liver hemorrhage (SILH) is a rare life-threatening condition occurring without a clear and specific etiology. A systematic review was performed to provide guidelines for the perioperative management of patients affected by SILH. A case report was also included. METHODS: A systematic search of the last 24-year literature was conducted and the manuscript was structured following point-by-point the PRISMA guidelines. RESULTS: After an initial selection of 6995 titles, 15 articles were considered for the final qualitative analysis (n = 22 patients, including the present report). Conservative treatment was chosen in 12 cases (54.5%) with stable clinical conditions, while 9 patients (40.9%) required a primary operative approach for emergency presentation at diagnosis. Direct liver resection was the preferred surgical treatment (n = 6), mostly major hepatectomies (n = 4). Hepatic arterial embolization was performed as the primary operative approach in three patients, followed by emergency laparotomy during the same hospitalization because of rebleeding in one case. Contrast-enhanced CT scan was the gold standard for diagnosis (n = 19). CONCLUSIONS: Conservative treatment of SILH is mainly based on stable clinical conditions and may be considered even in case of a limited arterial blush found on imaging. The absence of underlying hepatic or systemic disorders seems to correlate with favorable outcomes and no mortality.

JAK1 promotes HDV replication and is a potential target for antiviral therapy.

BACKGROUND & AIMS: Chronic co-infection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. To date, no treatment induces efficient viral clearance, and a better characterization of virus-host interactions is required to develop new therapeutic strategies. METHODS: Using loss-of-function strategies, we validated the unexpected proviral activity of Janus kinase 1 (JAK1) - a key player in innate immunity - in the HDV life cycle and determined its mechanism of action on HDV through various functional analyses including co-immunoprecipitation assays. RESULTS: We confirmed the key role of JAK1 kinase activity in HDV infection. Moreover, our results suggest that JAK1 inhibition is associated with a modulation of ERK1/2 activation and S-HDAg phosphorylation, which is crucial for viral replication. Finally, we showed that FDA-approved JAK1-specific inhibitors are efficient antivirals in relevant in vitro models including primary human hepatocytes. CONCLUSIONS: Taken together, we uncovered JAK1 as a key host factor for HDV replication and a potential target for new antiviral treatment. IMPACT AND IMPLICATIONS: Chronic hepatitis D is the most aggressive form of chronic viral hepatitis. As no curative treatment is currently available, new therapeutic strategies based on host-targeting agents are urgently needed. Here, using loss-of-function strategies, we uncover an unexpected interaction between JAK1, a major player in the innate antiviral response, and HDV infection. We demonstrated that JAK1 kinase activity is crucial for both the phosphorylation of the delta antigen and the replication of the virus. By demonstrating the antiviral potential of several FDA-approved JAK1 inhibitors, our results could pave the way for the development of innovative therapeutic strategies to tackle this global health threat.

Inflammation-related prognostic markers in resected hepatocellular carcinoma.

Hepatocellular carcinoma is usually detected late and therapeutic options are unsatisfactory. Despite marked progress in patient care, HCC remains among the deadliest cancers world-wide. While surgical resection remains a key option for early-stage HCC, the 5-year survival rates after surgical resection are limited. One reason for limited outcomes is the lack of reliable prognostic biomarkers to predict HCC recurrence. HCC prognosis has been shown to correlate with different systemic and pathological markers which are associated with patient survival and HCC recurrence. Liver inflammatory processes offer a large variety of systemic and pathological markers which may be exploited to improve the reliability of prognosis and decision making of liver surgeons and hepatologists. The following review aims to dissect the potential tools, targets and prognostic meaning of inflammatory markers in patients with resectable HCC. We analyze changes in circulant cellular populations and assess inflammatory biomarkers as a surrogate of impaired outcomes and provide an overview on predictive gene expression signatures including inflammatory transcriptional patterns, which are representative of poor survival in these patients.

Combining Radiofrequency Ablation with Hepatic Resection for Liver-Only Colorectal Metastases: A Propensity-Score Based Analysis of Long-Term Outcomes.

BACKGROUND: Combining liver resection (LR) with radiofrequency ablation (RFA) is nowadays an accepted option for treating colorectal liver metastases (CRLMs), but the number of lesions ablated is regularly described as a recurrence risk factor. In this study, we report our experience and determine the impact of RFA on long-term outcomes. METHOD: This is a retrospective study including patients undergoing LR with or without RFA for CRLM. All variables influencing disease-free survival (DFS) and disease-specific survival (DSS) were examined through a Cox regression analysis before and after propensity-score matching (PSM). RESULTS: Among the 128 patients included, 71 (55.5%) underwent LR alone and 57 (44.5%) underwent LR+RFA. With univariate analysis, LR+RFA showed a significantly worse DFS than LR alone (p = 0.028), which was not confirmed after PSM (p = 0.064). Thermal ablation did not influence DSS before or after matching (p = 0.282 and p = 0.189). When analyzing the subgroups of patients according to number of RFAs performed, no difference in long-term outcomes was observed (after PSM: p = 0.192 for DFS and p = 0.624 for DSS). Analysis of site of recurrence revealed that neither performing an RFA (p = 0.893) nor the number of lesions ablated (p = 0.093, p = 0.550, and p = 0.087 for 1, 2, and ≥ 2 RFAs) were associated with an increased risk of liver-only relapse. DISCUSSION: In the setting of a parenchymal sparing strategy, combining RFA with LR is safe in terms of oncological outcomes. Tumor burden, rather than RFA performed, independently influences risk of recurrence and patient survival.

Surgical Models of Liver Regeneration in Pigs: A Practical Review of the Literature for Researchers.

The remarkable capacity of regeneration of the liver is well known, although the involved mechanisms are far from being understood. Furthermore, limits concerning the residual functional mass of the liver remain critical in both fields of hepatic resection and transplantation. The aim of the present study was to review the surgical experiments regarding liver regeneration in pigs to promote experimental methodological standardization. The Pubmed, Medline, Scopus, and Cochrane Library databases were searched. Studies evaluating liver regeneration through surgical experiments performed on pigs were included. A total of 139 titles were screened, and 41 articles were included in the study, with 689 pigs in total. A total of 29 studies (71% of all) had a survival design, with an average study duration of 13 days. Overall, 36 studies (88%) considered partial hepatectomy, of which four were an associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Remnant liver volume ranged from 10% to 60%. Only 2 studies considered a hepatotoxic pre-treatment, while 25 studies evaluated additional liver procedures, such as stem cell application, ischemia/reperfusion injury, portal vein modulation, liver scaffold application, bio-artificial, and pharmacological liver treatment. Only nine authors analysed how cytokines and growth factors changed in response to liver resection. The most used imaging system to evaluate liver volume was CT-scan volumetry, even if performed only by nine authors. The pig represents one of the best animal models for the study of liver regeneration. However, it remains a mostly unexplored field due to the lack of experiments reproducing the chronic pathological aspects of the liver and the heterogeneity of existing studies.

Hyperspectral Imaging in Major Hepatectomies: Preliminary Results from the Ex-Machyna Trial.

Ischemia-reperfusion injury during major hepatic resections is associated with high rates of post-operative complications and liver failure. Real-time intra-operative detection of liver dysfunction could provide great insight into clinical outcomes. In the present study, we demonstrate the intra-operative application of a novel optical technology, hyperspectral imaging (HSI), to predict short-term post-operative outcomes after major hepatectomy. We considered fifteen consecutive patients undergoing major hepatic resection for malignant liver lesions from January 2020 to June 2021. HSI measures included tissue water index (TWI), organ hemoglobin index (OHI), tissue oxygenation (StO2%), and near infrared (NIR). Pre-operative, intra-operative, and post-operative serum and clinical outcomes were collected. NIR values were higher in unhealthy liver tissue (p = 0.003). StO2% negatively correlated with post-operative serum ALT values (r = -0.602), while ΔStO2% positively correlated with ALP (r = 0.594). TWI significantly correlated with post-operative reintervention and OHI with post-operative sepsis and liver failure. In conclusion, the HSI imaging system is accurate and precise in translating from pre-clinical to human studies in this first clinical trial. HSI indices are related to serum and outcome metrics. Further experimental and clinical studies are necessary to determine clinical value of this technology.

A Single-center Prospective Observational Study Investigating the Accuracy of Preoperative Diagnostic Procedures in the Assessment of Lymph Node Metastases in Nonfunctioning Pancreatic Neuroendocrine Tumors.

OBJECTIVE: To determine the accuracy of preoperative imaging, including contrast-enhanced computed tomography (CE-CT), endoscopic ultrasound (EUS), and 68 Gallium-DOTATOC positron emission tomography ( 68 Ga-DOTATOC PET), in identifying nodal metastases (N+) in sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). BACKGROUND: An accurate preoperative identification of N+ in NF-PanNETs is critical for surgical planning. The accuracy of different imaging techniques in detecting lymph node (LN) metastases in NF-PanNETs has been poorly investigated. METHODS: All consecutive patients undergoing surgery for sporadic NF-PanNETs (2018-2021) were enrolled in a prospective study (DETECTYON; NCT03918759). The accuracy of preoperative imaging techniques in detecting N+ was assessed through sensitivity, specificity positive and negative predictive values. RESULTS: Overall, 100 patients with NF-PanNETs underwent CE-CT, EUS, and 68 Ga-DOTATOC PET before pancreatic resection. LN metastases were found in 42 cases (42%). Sensitivity, specificity, positive predictive value, and negative predictive value of different imaging techniques were 26%, 95%, 79%, 64% for CE-CT, 19%, 98%, 89%, 63% for EUS, and 12%, 95%, 63%, 60% for 68 Ga-DOTATOC PET, respectively. Radiologic tumor size >4 cm and the presence of radiologic N+ at ≥1 imaging were independent predictors of N+ at pathology. The identification of N+ at ≥1 imaging technique was associated with a higher number of positive LNs compared with negative imaging (4 vs 2) ( P =0.012). CONCLUSIONS: CE-CT, EUS, and 68 Ga-DOTATOC PET are poorly sensitive in predicting nodal status in NF-PanNETs despite a high specificity.

Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation.

Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis-induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention.

Improving diagnostic accuracy and appropriate indications for surgery in pancreatic cystic neoplasms: the role of EUS.

BACKGROUND AND AIMS: Pancreatic cystic neoplasms (PCNs) represent a difficult preoperative diagnosis despite improvements in imaging. In this study, we compared preoperative and final pathologic diagnosis in a large cohort of resected PCNs, evaluating diagnostic accuracy with a specific focus on the value of EUS. METHODS: A retrospective analysis of patients undergoing resection between 2009 and 2019 for presumed PCNs was performed. Preoperative workup was reviewed by analyzing the role of imaging and EUS. Patients with a benign histology who did not show absolute indication were categorized as "delayable surgery." RESULTS: Of 585 patients who were retrospectively analyzed, in 108 (18.5%) final histology did not confirm preoperative diagnosis. EUS was associated with a lower rate of incorrect diagnosis (16%; P = .03), but the risk of overtreatment was similar regardless of instrumental diagnostic path (33/131 vs 68/328, P = .298). Dilatation of the main pancreatic duct and cytologic sampling were the only variables independently associated with a correct diagnosis (P < .001 and P = .041, respectively). Based on clinical presentation and final histology, pancreatic resection could have been spared or delayed in 101 of 459 patients (22%), and this was influenced by age (odds ratio [OR], .97; P = .002), cyst larger than 30 mm (OR, 1.89; P = .005), and type of operation (OR, 3.46 [P < .001] and 3.18 [P = .023] for distal pancreatectomies and other resections, respectively). CONCLUSIONS: The overall risk of unnecessary immediate surgery for PCNs is about 22% in a high-volume referral center. EUS with cytologic sampling is a useful procedure in the diagnostic management of PCNs, improving their diagnostic accuracy.

Augmented Reality and Image-Guided Robotic Liver Surgery.

Artificial intelligence makes surgical resection easier and safer, and, at the same time, can improve oncological results. The robotic system fits perfectly with these more or less diffused technologies, and it seems that this benefit is mutual. In liver surgery, robotic systems help surgeons to localize tumors and improve surgical results with well-defined preoperative planning or increased intraoperative detection. Furthermore, they can balance the absence of tactile feedback and help recognize intrahepatic biliary or vascular structures during parenchymal transection. Some of these systems are well known and are already widely diffused in open and laparoscopic hepatectomies, such as indocyanine green fluorescence or ultrasound-guided resections, whereas other tools, such as Augmented Reality, are far from being standardized because of the high complexity and elevated costs. In this paper, we review all the experiences in the literature on the use of artificial intelligence systems in robotic liver resections, describing all their practical applications and their weaknesses.

Resection and Reconstruction of a Replaced Common Hepatic Artery and Portal Vein During Pancreaticoduodenectomy.

The efficacy of FOLFIRINOX chemotherapy gave renewed interest for surgery in case of locally advanced pancreatic ductal adenocarcinoma. Consistent series of pancreatectomy with arterial and venous resection have been reported recently and that described acceptable short and long-term outcomes in selected patients operated by high volume institutions by dedicated surgical team. In a didactical video we showed our approach for resecting a locally advanced pancreatic ductal adenocarcinoma involving both the splenomesentericoportal venous confluence and a replaced common hepatic artery arising from the superior mesenteric artery (SMA). A large dorsal pancreatic artery arising from the SMA is used for the arterial reconstruction in this particular case. The approach used entails extensive bowel mobilization, mesenteric approach to the coelio-mesenteric vessels and arterial divestment making feasible arterial and venous resection with reconstruction without graft interposition.

R Status is a Relevant Prognostic Factor for Recurrence and Survival After Pancreatic Head Resection for Ductal Adenocarcinoma.

BACKGROUND: The prognostic role of resection margins in pancreatic ductal adenocarcinoma (PDAC) is debated. This study aimed to investigate the impact that global and individual resection margin status after pancreatic head resection for PDAC has on disease-free survival (DFS) and disease-specific survival (DSS). METHODS: Surgical specimens of pancreaticoduodenectomy/total pancreatectomy performed for PDAC were examined with a standardized protocol. Surgical margin status (biliary, pancreatic neck, duodenal, anterior and posterior pancreatic, superior mesenteric vein groove and superior mesenteric artery margins) was classified as the presence of malignant cells (1) directly at the inked surface (R1 direct), (2) within less than 1 mm (R1 ≤ 1 mm), or (3) with a distance greater than 1 mm (R0). Patients with a positive neck margin at the final histology were excluded from the study. RESULTS: Of the 362 patients included in the study, 179 patients (49.4 %) had an R0 resection, 123 patients (34 %) had an R1 ≤ 1 mm resection, and 60 patients (16.6 %) had an R1 direct resection. The independent predictors of DFS were R1 direct resection (hazard ratio [HR], 1.49), R1 ≤ 1 mm resection (HR, 1.38), involvement of one margin (HR, 1.36), and involvement of two margins or more (HR, 1.55). When surgical margins were analyzed separately, only R1 ≤ 1 mm superior mesenteric vein margin (HR, 1.58) and R1 direct posterior margin (HR, 1.69) were independently associated with DFS. CONCLUSIONS: Positive R status is an independent predictor of DFS (R1 direct and R1 ≤ 1 mm definitions) and of DSS (R1 direct). The presence of multiple positive margins is a risk factor for cancer recurrence and poor survival. Different surgical margins could have different prognostic roles.