Open, laparoscopic liver resection and percutaneous thermal ablation in elderly patients with hepatocellular carcinoma: outcomes and therapeutic strategy.

BACKGROUND: Liver resection and percutaneous thermal ablation (PTA) are considered curative option for hepatocellular carcinoma (HCC). This study aims to compare short- and long-term outcomes between open liver resection (OLR), laparoscopic liver resection (LLR), and PTA in elderly patients with single HCC and to define a liver map for therapeutic strategy according to HCC location and size. METHODS: A multicenter retrospective study was conducted in 10 European Hospital Center, including 239 consecutive liver resection (OLR and LLR) and PTA in elderly patients ≥ 70 years old with single HCC ≤ 30 mm. Perioperative data and long-term oncological outcomes were collected and compared between groups before and after propensity score matching. RESULTS: A total of 239 patients were enrolled, distributed as follows: 61 in the ORL group, 88 in the LLR group, and 90 in the PTA group. The hospital stay was longer in OLR and LLR groups compared to the PTA group (6, 5 and 3 days, respectively, p < 0.05). Morbidity was lower in the PTA group compared to the OLR group (11 vs. 26%, respectively, p < 0.05). Overall survival (OS) at 5 years was significantly higher in the OLR and LLR groups compared to the PTA group (82, 81, and 34%, respectively, p < 0.001). Disease-free survival (DFS) at 5 years was also significantly higher in the ORL and LLR groups compared to the PTA group (66, 50 and 20%, respectively, p < 0.001). These results were also confirmed after a propensity score matching analysis between surgery group (OLR and LLR) and the PTA group. PTA was the most used treatment for subcapsular and deep HCC not in contact with vascular structures compared to OLR and LLR. CONCLUSION: PTA in elderly patients ensures a shorter hospital stay and lower morbidity but worst survival compared to liver resection.

Targeting the liver clock improves fibrosis by restoring TGF-ß signaling.

BACKGROUND & AIMS: Liver fibrosis is the major driver of hepatocellular carcinoma and liver disease-related death. Approved antifibrotic therapies are absent and compounds in development have limited efficacy. Increased TGF-ß signaling drives collagen deposition by hepatic stellate cells (HSCs)/myofibroblasts. Here, we aimed to dissect the role of the circadian clock (CC) in controlling TGF-ß signaling and liver fibrosis. METHODS: Using CC-mutant mice, enriched HSCs and myofibroblasts obtained from healthy and fibrotic mice in different CC phases and loss-of-function studies in human hepatocytes and myofibroblasts, we investigated the relationship between CC and TGF-ß signaling. We explored hepatocyte-myofibroblast communication through bioinformatic analyses of single-nuclei transcriptomes and performed validation in cell-based models. Using mouse models for MASH (metabolic dysfunction-associated steatohepatitis)-related fibrosis and spheroids from patients with liver disease, we performed proof-of-concept studies to validate pharmacological targetability and clinical translatability. RESULTS: We discovered that the CC oscillator temporally gates TGF-ß signaling and this regulation is broken in fibrosis. We demonstrate that HSCs and myofibroblasts contain a functional CC with rhythmic expression of numerous genes, including fibrogenic genes. Perturbation studies in hepatocytes and myofibroblasts revealed a reciprocal relationship between TGF-ß activation and CC perturbation, which was confirmed in patient-derived ex vivo and in vivo models. Pharmacological modulation of CC-TGF-ß signaling inhibited fibrosis in mouse models in vivo as well as in patient-derived liver spheroids. CONCLUSION: The CC regulates TGF-ß signaling, and the breakdown of this control is associated with liver fibrosis in patients. Pharmacological proof-of-concept studies across different models have uncovered the CC as a novel therapeutic target for liver fibrosis - a growing unmet medical need. IMPACT AND IMPLICATIONS: Liver fibrosis due to metabolic diseases is a global health challenge. Many liver functions are rhythmic throughout the day, being controlled by the circadian clock (CC). Here we demonstrate that regulation of the CC is perturbed upon chronic liver injury and this perturbation contributes to fibrotic disease. By showing that a compound targeting the CC improves liver fibrosis in patient-derived models, this study provides a novel therapeutic candidate strategy to treat fibrosis in patients. Additional studies will be needed for clinical translation. Since the findings uncover a previously undiscovered profibrotic mechanism and therapeutic target, the study is of interest for scientists investigating liver disease, clinical hepatologists and drug developers.

Surgical optomics: hyperspectral imaging and deep learning towards precision intraoperative automatic tissue recognition-results from the EX-MACHYNA trial.

BACKGROUND: Hyperspectral imaging (HSI), combined with machine learning, can help to identify characteristic tissue signatures enabling automatic tissue recognition during surgery. This study aims to develop the first HSI-based automatic abdominal tissue recognition with human data in a prospective bi-center setting. METHODS: Data were collected from patients undergoing elective open abdominal surgery at two international tertiary referral hospitals from September 2020 to June 2021. HS images were captured at various time points throughout the surgical procedure. Resulting RGB images were annotated with 13 distinct organ labels. Convolutional Neural Networks (CNNs) were employed for the analysis, with both external and internal validation settings utilized. RESULTS: A total of 169 patients were included, 73 (43.2%) from Strasbourg and 96 (56.8%) from Verona. The internal validation within centers combined patients from both centers into a single cohort, randomly allocated to the training (127 patients, 75.1%, 585 images) and test sets (42 patients, 24.9%, 181 images). This validation setting showed the best performance. The highest true positive rate was achieved for the skin (100%) and the liver (97%). Misclassifications included tissues with a similar embryological origin (omentum and mesentery: 32%) or with overlaying boundaries (liver and hepatic ligament: 22%). The median DICE score for ten tissue classes exceeded 80%. CONCLUSION: To improve automatic surgical scene segmentation and to drive clinical translation, multicenter accurate HSI datasets are essential, but further work is needed to quantify the clinical value of HSI. HSI might be included in a new omics science, namely surgical optomics, which uses light to extract quantifiable tissue features during surgery.

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.

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.

Dynamic surgical anatomy using 3D reconstruction technology in complex hepato-biliary surgery with vascular involvement. Results from an international multicentric survey.

INTRODUCTION: Three-dimensional liver modeling can lead to substantial changes in choosing the type and extension of liver resection. This study aimed to explore whether 3D reconstruction helps to better understand the relationship between liver tumors and neighboring vascular structures compared to standard 2D CT scan images. METHODS: Contrast-enhanced CT scan images of 11 patients suffering from primary and secondary hepatic tumors were selected. Twenty-three experienced HBP surgeons participated to the survey. A standardized questionnaire outlining 16 different vascular structures (items) having a potential relationship with the tumor was provided. Intraoperative and histopathological findings were used as the reference standard. The proper hypothesis was that 3D accuracy is greater than 2D. As a secondary endpoint, inter-raters' agreement was explored. RESULTS: The mean difference between 3D and 2D, was 2.6 points (SE: 0.40; 95 % CI: 1.7-3.5; p < 0.0001). After sensitivity analysis, the results favored 3D visualization as well (mean difference 1.7 points; SE: 0.32; 95 % CI: 1.0-2.5; p = 0.0004). The inter-raters' agreement was moderate for both methods (2D: W = 0.45; 3D: W = 0.44). CONCLUSION: 3D reconstruction may give a significant contribution to better understanding liver vascular anatomy and the precise relationship between the tumor and the neighboring structures.

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.

Left-sided portal hypertension: Update and proposition of management algorithm.

Left-sided or segmental portal hypertension (SPHT) is a rare entity, most often associated with pancreatic disease or antecedent pancreatic surgery. The starting point is splenic vein obstruction secondary to local inflammation or, less often, extrinsic compression. SPHT leads to splenomegaly and development of collateral porto-systemic venous circulation. SPHT should be suspected in patients with pancreatic history who present with episodic upper gastrointestinal bleeding and splenomegaly with normal liver function tests. The most common clinical presentation is major upper gastrointestinal bleeding secondary to rupture of esophageal and/or gastric varices. At the present time, there are no management recommendations for SPHT, particularly when the patient is asymptomatic. In patients with upper gastro-intestinal bleeding, hemostasis can be obtained either by medical or interventional means according to patient status and available resources. For symptomatic patients, splenectomy is the reference treatment. Recently, less invasive, radiologic procedures, such as splenic artery embolization, have been developed as an alternative to surgery. Additionally, sonography-guided endoscopic hemostasis can also be envisioned, leading to the diagnosis and treatment of the lesion by elastic band ligation or by glue injection into the varices during the same procedure. The goal of this article is to describe the pathophysiological mechanisms behind SPHT and its clinical manifestations and treatment, based on a review of the literature. Because of the absence of recommendations for the management of SPHT, we propose a decisional algorithm for the management of SPHT based on the literature.

Liver ischemia-reperfusion injury: From trigger loading to shot firing.

An ischemia-reperfusion injury (IRI) results from a prolonged ischemic insult followed by the restoration of blood perfusion, being a common cause of morbidity and mortality, especially in liver transplantation. At the maximum of the potential damage, IRI is characterized by 2 main phases. The first is the ischemic phase, where the hypoxia and vascular stasis induces cell damage and the accumulation of damage-associated molecular patterns and cytokines. The second is the reperfusion phase, where the local sterile inflammatory response driven by innate immunity leads to a massive cell death and impaired liver functionality. The ischemic time becomes crucial in patients with underlying pathophysiological conditions. It is possible to compare this process to a shooting gun, where the loading trigger is the ischemia period and the firing shot is the reperfusion phase. In this optic, this article aims at reviewing the main ischemic events following the phases of the surgical timeline, considering the consequent reperfusion damage.

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.

Impact of body mass index in elderly patients treated with laparoscopic liver resection for hepatocellular carcinoma.

BACKGROUND: The impact of obesity on surgical outcomes in elderly patients candidate for liver surgery is still debated. AIM: To evaluate the impact of high body mass index (BMI) on perioperative and oncological outcome in elderly patients (> 70 years old) treated with laparoscopic liver resection for hepatocellular carcinoma (HCC). METHODS: Retrospective multicenter study including 224 elderly patients (> 70 years old) operated by laparoscopy for HCC (196 with a BMI < 30 and 28 with BMI ≥ 30), observed from January 2009 to January 2019. RESULTS: After propensity score matching, patients in two groups presented comparable results, in terms of operative time (median range: 200 min vs 205 min, P = 0.7 respectively in non-obese and obese patients), complications rate (22% vs 26%, P = 1.0), length of hospital stay (median range: 4.5 d vs 6.0 d, P = 0.1). There are no significant differences in terms of short- and long-term postoperative results. CONCLUSION: The present study showed that BMI did not impact perioperative and oncologic outcomes in elderly patients treated by laparoscopic resection for HCC.

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.

Paradigm shift: should preoperative 3D reconstruction models become mandatory before hepatectomy for hepatocellular carcinoma (HCC)? Results of a multicenter prospective trial.

BACKGROUND: A preoperative surgical strategy before hepatectomy for hepatocellular carcinoma is fundamental to minimize postoperative morbidity and mortality and to reach the best oncologic outcomes. Preoperative 3D reconstruction models may help to better choose the type of procedure to perform and possibly change the initially established plan based on conventional 2D imaging. METHODS: A non-randomized multicenter prospective trial with 136 patients presenting with a resectable hepatocellular carcinoma who underwent open or minimally invasive liver resection. Measurement was based on the modification rate analysis between conventional 2D imaging (named "Plan A") and 3D model analysis ("Plan B"), and from Plan B to the final procedure performed (named "Plan C"). RESULTS: The modification rate from Plan B to Plan C (18%) was less frequent than the modification from Plan A to Plan B (35%) (OR = 0.32 [0.15; 0.64]). Concerning secondary objectives, resection margins were underestimated in Plan B as compared to Plan C (-3.10 mm [-5.04; -1.15]). CONCLUSION: Preoperative 3D imaging is associated with a better prediction of the performed surgical procedure for liver resections in HCC, as compared to classical 2D imaging.

Liver resection versus radiofrequency ablation in octogenarian patients for hepatocellular carcinoma: a propensity score multicenter analysis.

BACKGROUND: Liver resection (LR) and radiofrequency ablation (RFA) are considered curative options for hepatocellular carcinoma (HCC). The aim of this study was to compare outcomes after LR and RFA in octogenarian patients with HCC. MATERIALS AND METHODS: This multicenter retrospective study included 102 elderly patients (> 80 years old) treated between January 2009 and January 2019, who underwent LR or RFA for HCC (65 and 37 with, respectively). RESULTS: After Propensity Score Matching, the postoperative course of LR was burdened by a higher rate of complications than RFA group (64% vs 14%, respectively, p: 0.001). The LR group had also significantly longer operative time (207 ± 85 min vs 33 ± 49 min, p < 0.001) and postoperative hospital stays than the RFA group (7 d vs 2 d, p = 0.019). Overall survival at 1-, 2-, and 3-year were 86%, 86%, and 70% for the LR group and 82%, 64%, and 52% for the RFA group (p = 0.380). Disease-free survival at 1-, 2-, and 3-year were 89%, 74%, and 56% for the LR group, and 51%, 40%, and 40% for the RFA group (p = 0.037). CONCLUSION: Despite a higher rate of Dindo-Clavien I-II post-operative complications, a longer operative time and length of hospital stay, LR in octogenarian patients can provide comparable 90d mortality than RFA and better long-term outcomes.

Treatment of HCC with claudin-1-specific antibodies suppresses carcinogenic signaling and reprograms the tumor microenvironment.

BACKGROUND & AIMS: Despite recent approvals, the response to treatment and prognosis of patients with advanced hepatocellular carcinoma (HCC) remain poor. Claudin-1 (CLDN1) is a membrane protein that is expressed at tight junctions, but it can also be exposed non-junctionally, such as on the basolateral membrane of the human hepatocyte. While CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 and its role as a therapeutic target in HCC remains unexplored. METHODS: Using humanized monoclonal antibodies (mAbs) specifically targeting the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as a therapeutic target for HCC. RESULTS: Targeting non-junctional CLDN1 markedly suppressed tumor growth and invasion in cell line-based models of HCC and patient-derived 3D ex vivo models. Moreover, the robust effect on tumor growth was confirmed in vivo in a large series of cell line-derived xenograft and patient-derived xenograft mouse models. Mechanistic studies, including single-cell RNA sequencing of multicellular patient HCC tumorspheres, suggested that CLDN1 regulates tumor stemness, metabolism, oncogenic signaling and perturbs the tumor immune microenvironment. CONCLUSIONS: Our results provide the rationale for targeting CLDN1 in HCC and pave the way for the clinical development of CLDN1-specific mAbs for the treatment of advanced HCC. IMPACT AND IMPLICATIONS: Hepatocellular carcinoma (HCC) is associated with high mortality and unsatisfactory treatment options. Herein, we identified the cell surface protein Claudin-1 as a treatment target for advanced HCC. Monoclonal antibodies targeting Claudin-1 inhibit tumor growth in patient-derived ex vivo and in vivo models by modulating signaling, cell stemness and the tumor immune microenvironment. Given the differentiated mechanism of action, the identification of Claudin-1 as a novel therapeutic target for HCC provides an opportunity to break the plateau of limited treatment response. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of advanced HCC. It is therefore of key impact for physicians, scientists and drug developers in the field of liver cancer and gastrointestinal oncology.

Peri-operative score for elderly patients with resectable hepatocellular carcinoma.

BACKGROUND: Liver resection is the mainstay for a curative treatment for patients with resectable hepatocellular carcinoma (HCC), also in elderly population. Despite this, the evaluation of patient condition, liver function and extent of disease remains a demanding process with the aim to reduce postoperative morbidity and mortality. AIM: To identify new perioperative risk factors that could be associated with higher 90- and 180-d mortality in elderly patients eligible for liver resection for HCC considering traditional perioperative risk scores and to develop a risk score. METHODS: A multicentric, retrospective study was performed by reviewing the medical records of patients aged 70 years or older who electively underwent liver resection for HCC; several independent variables correlated with death from all causes at 90 and 180 d were studied. The coefficients of Cox regression proportional-hazards model for six-month mortality were rounded to the nearest integer to assign risk factors' weights and derive the scoring algorithm. RESULTS: Multivariate analysis found variables (American Society of Anesthesiology score, high rate of comorbidities, Mayo end stage liver disease score and size of biggest lesion) that had independent correlations with increased 90- and 180-d mortality. A clinical risk score was developed with survival profiles. CONCLUSION: This score can aid in stratifying this population in order to assess who can benefit from surgical treatment in terms of postoperative mortality.