Development of HepatIA: A computed tomography annotation platform and database for artificial intelligence training in hepatocellular carcinoma detection at a Brazilian tertiary teaching hospital.

BACKGROUND: Hepatocellular carcinoma (HCC) is a prevalent tumor with high mortality rates. Computed tomography (CT) is crucial in the non-invasive diagnosis of HCC. Recent advancements in artificial intelligence (AI) have shown significant potential in medical imaging analysis. However, developing these AI algorithms is hindered by the scarcity of comprehensive, publicly available liver imaging datasets. OBJECTIVES: This study aims to detail the tools, data organization, and database structuring used in creating HepatIA, a medical imaging annotation platform and database at a Brazilian tertiary teaching hospital. HepatIA supports liver disease AI research at the institution. MATERIAL AND METHODS: The authors collected baseline characteristics and CT scans of 656 patients from 2008 to 2021. The database, designed using PostgreSQL and implemented with Django and Vue.js, includes 692 CT volumes from a four-phase abdominal CT protocol. Radiologists made segmentation annotations using the OHIF medical image viewer, incorporating MONAI Label for pre-annotation segmentation models. The annotation process included detailed descriptions of liver morphology and nodule characteristics. RESULTS: The HepatIA database currently includes healthy individuals and those with liver diseases such as HCC and cirrhosis. The database dashboard facilitates user interaction with intuitive plots and histograms. Key patient demographics include 64% males and an average age of 56.89 years. The database supports various filters for detailed searches, enhancing research capabilities. CONCLUSION: A comprehensive data structure was successfully created and integrated with the IT systems of a teaching hospital, enabling research on deep learning algorithms applied to abdominal CT scans for investigating hepatic lesions such as HCC.

[Thorns in hands, think in spiny keratoderma]. / Espinas en manos, piense en queratodermia espinosa.

Spiny keratoderma is a rare dermatological manifestation that occurs sporadically or hereditarily. These are millimetric hyperkeratotic lesions on the palms and/or soles, usually asymptomatic. Histopathologically, they consist of well-defined columns of parakeratosis on a thinned stratum corneum. Sporadic cases can be associated with chronic diseases or neoplasms. We present a case of palmar spiny keratoderma in a man in the seventh decade of life with cirrhosis due to primary sclerosing cholangitis, and hepatocellular carcinoma. He had remission of the skin lesions two months after performing a liver transplant. This behavior favors the interpretation of spiny keratoderma as a paraneoplastic manifestation of hepatocellular carcinoma. We have not found previous reports of spiny keratoderma from Argentina. We review the literature on this entity.

La queratodermia espinosa palmar es una manifestación dermatológica infrecuente que se presenta de forma esporádica o hereditaria. Se trata de lesiones hiperqueratósicas milimétricas en palmas y/o plantas, habitualmente asintomáticas. Histopatológicamente consisten en columnas de paraqueratosis bien delimitadas sobre un estrato córneo adelgazado. Los casos esporádicos se pueden asociar a enfermedades crónicas o neoplasias. Presentamos un caso de queratodermia espinosa palmar en un hombre en la séptima década de la vida con cirrosis secundaria a colangitis esclerosante primaria y hepatocarcinoma. Presentó remisión de las lesiones cutáneas a los dos meses de realizarse un trasplante hepático. Este comportamiento favorece la interpretación de la queratodermia espinosa como manifestación paraneoplásica del hepatocarcinoma. No hemos encontrado informes previos de queratodermia espinosa en Argentina. Realizamos una revisión de la literatura sobre esta entidad.

Cost-effectiveness of radiofrequency ablation versus percutaneous ethanol injection for early hepatocellular carcinoma in a resource-poor setting: a randomized trial.

OBJECTIVE: This study assessed the cost-effectiveness of radiofrequency ablation compared with percutaneous ethanol injection in patients with early hepatocellular carcinoma in relation to the objective response rate and costs related to the procedure. METHODS: This was a prospective single-center randomized trial. The primary outcome was cost-effectiveness. Secondary outcomes were the complete response rate according to the modified response evaluation criteria in solid tumors 60 days after randomization and the complication rate within 180 60 days. RESULTS: Fifty patients were placed into the following groups: percutaneous ethanol injection (n=23) and radiofrequency ablation (n=27). Fifty-four nodules were randomized (mean follow-up: 205.37 days). The estimated mean hospital cost was US$ 1854.11 and US$ 2770.96 for the Radiofrequency Ablation and Percutaneous Ethanol Injection Groups, respectively. The incremental cost-effectiveness ratio was US$ -2674.59, which is advantageous for radiofrequency ablation. After 60 d, 28 of 29 nodules in the Radiofrequency Ablation Group achieved complete response versus 12 of 22 in the Percutaneous Ethanol Injection Group (RD, 42.01 [95%CI= 20.55-63.24]; p<0.001). Only four early complications were observed among patients treated by percutaneous ethanol injection (p<0.05). Late complications occurred in two and one patient(s) in the Radiofrequency Ablation and Percutaneous Ethanol Injection Groups (p>0.05), respectively. CONCLUSION: Radiofrequency ablation was more cost-effective and achieved higher complete response and lower complication rates than the Percutaneous Ethanol Injection Group within this cohort. REGISTRY OF CLINICAL TRIALS: NCT06450613.

Intriguing hepatoprotective effects of sucrose on hepatocellular carcinoma pathogenesis.

Chronic liver disease is closely linked to dietary intake factors, such as high consumption of simple carbohydrates including sucrose. In this study, the influence of sucrose on the development of hepatocellular carcinoma (HCC), the most common primary liver malignancy, was explored. Using the hepatocarcinogen diethylnitrosamine (DEN) to induce HCC in the rat, we co-administered sucrose with DEN. The co-administration significantly modified body, liver and pancreas weight, as well as, serum fatty acids and triglycerides. DEN caused liver structural alteration, fibrosis, and tumor formation; surprisingly, co-administration with sucrose restored hepatic lipids, improved liver architecture, and reduced fibrosis and tumor development. Sucrose intake negatively regulated tumor markers and cell proliferation, and reduced the expression of genes associated with lipid metabolism and oxidative stress response. These findings highlight a hepatoprotective effect of sucrose during DEN-induced hepatocarcinogenesis, underlining an intriguing role of high sucrose consumption during HCC development and providing new insights as well as possible pathways of cellular protection under sucrose intake on hepatocarcinogenesis.

Alpha lipoic acid diminishes migration and invasion in hepatocellular carcinoma cells through an AMPK-p53 axis.

Hepatocellular carcinoma (HCC) associated with viral or metabolic liver diseases is a growing cancer without effective therapy. AMPK is downregulated in HCC and its activation diminishes tumor growth. Alpha lipoic acid (ALA), an indirect AMPK activator that inhibits hepatic steatosis, shows antitumor effects in different cancers. We aimed to study its putative action in liver-cancer derived cell lines through AMPK signaling. We performed cytometric studies for apoptosis and cell cycle, and 2D and 3D migration analysis in HepG2/C3A and Hep3B cells. ALA led to significant inhibition of cell migration/invasion only in HepG2/C3A cells. We showed that these effects depended on AMPK, and ALA also increased the levels and nuclear compartmentalization of the AMPK target p53. The anti-invasive effect of ALA was abrogated in stable-silenced (shTP53) versus isogenic-TP53 HepG2/C3A cells. Furthermore, ALA inhibited epithelial-mesenchymal transition (EMT) in control HepG2/C3A but not in shTP53 nor in Hep3B cells. Besides, we spotted that in patients from the HCC-TCGA dataset some EMT genes showed different expression patterns or survival depending on TP53. ALA emerges as a potent activator of AMPK-p53 axis in HCC cells, and it decreases migration/invasion by reducing EMT which could mitigate the disease in wild-type TP53 patients.

Diagnostic value of serum inflammatory markers in predicting early refractoriness of transarterial chemoembolization in patients with Barcelona Clinic Liver Cancer Stage 0, A, and B hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is an established therapeutic strategy for intermediate stage Barcelona Clinic Liver Cancer (BCLC) hepatocellular carcinoma (HCC). However, patients who are early refractory to TACE may not benefit from repeated TACE treatment. Our primary objective was to assess the diagnostic value of inflammatory markers in identifying early TACE refractory for patients with early (BCLC 0 and A) or intermediate (BCLC B) stage HCC. We retrospectively reviewed the HCC patients who underwent TACE as the initial treatment in two hospitals. Patients with early TACE refractoriness had significantly poorer median overall survival (OS) (16 vs 40 months, P<0.001) and progression-free survival (PFS) (7 vs 23 months, P<0.001) compared to TACE non-refractory patients. In the multivariate regression analysis, tumor size (P<0.001), bilobular invasion (P=0.007), high aspartate aminotransferase-to-platelet ratio index (APRI) (P=0.007), and high alpha fetoprotein (AFP) level (P=0.035) were independent risk factors for early TACE refractoriness. The predictive model showcasing these factors exhibited high ability proficiency, with an area under curve (AUC) of 0.833 (95%CI=0.774-0.892) in the training cohort, 0.750 (95%CI: 0.640-0.861) in the internal-validation cohort, and 0.733 (95%CI: 0.594-0.872) in the external-validation cohort. Calibration curve analysis revealed good agreement between the actual and predicted probabilities of early TACE refractoriness. Our preliminary study estimated the potential value of inflammatory markers in predicting early TACE refractoriness and provides a predictive model to assist in identifying patients who may not benefit from repeat TACE treatment.

Hedgehog components are overexpressed in a series of liver cancer cases.

Liver cancers, including hepatocellular carcinoma (HCC), are the sixth most common cancer and the third leading cause of cancer-related death worldwide, representing a global public health problem. This study evaluated nine patients with HCC. Six of the cases involved hepatic explants, and three involved hepatic segmentectomy for tumor resection. Eight out of nine tumors were HCC, with one being a combined hepatocellular-cholangiocarcinoma tumor. Conventional markers of hepatocellular differentiation (Hep Par-1, arginase, pCEA, and glutamine synthetase) were positive in all patients, while markers of hepatic precursor cells (CK19, CK7, EpCAM, and CD56) were negative in most patients, and when positive, they were detected in small, isolated foci. Based on in silico analysis of HCC tumors from The Cancer Genome Atlas database, we found that Hedgehog (HH) pathway components (GLI1, GLI2, GLI3 and GAS1) have high connectivity values (module membership > 0.7) and are strongly correlated with each other and with other genes in biologically relevant modules for HCC. We further validated this finding by analyzing the gene expression of HH components (PTCH1, GLI1, GLI2 and GLI3) in our samples through qPCR, as well as by immunohistochemical analysis. Additionally, we conducted a chemosensitivity analysis using primary HCC cultures treated with a panel of 18 drugs that affect the HH pathway and/or HCC. Most HCC samples were sensitive to sunitinib. Our results offer a comprehensive view of the molecular landscape of HCC, highlighting the significance of the HH pathway and providing insight into focused treatments for HCC.

Hepatitis B virus X protein differentially regulates the angiogenesis of Hepatocellular Carcinoma through p53-VEGF axis according to glucose levels.

INTRODUCTION AND OBJECTIVES: Blood glucose fluctuates severely in the diabetes (DM) and tumor microenvironment. Our previous works have found Hepatitis B virus X protein (HBx) differentially regulated metastasis and apoptosis of hepatoma cells depending on glucose concentration. We here aimed to explore whether HBx played dual roles in the angiogenesis of hepatocellular carcinoma varying on different glucose levels. MATERIALS AND METHODS: We collected conditioned medium from HBx-overexpressing cells cultured with two solubilities of glucose, and then applied to EA.hy926 cells. Alternatively, a co-culture cell system was established with hepatoma cells and EA.hy926 cells. We analyzed the angiogenesis of EA.hy926 cells with CCK8, wound-healing, transwell-migartion and tube formation experiment. ELISA was conducted to detect the secretion levels of angiogenesis-related factors. siRNAs were used to detect the P53-VEGF axis. RESULTS: HBx expressed in hepatoma cells suppressed VEGF secretion, and subsequently inhibited the proliferation, migration and tube formation of EA.hy926 cells in a high glucose condition, while attenuating these in the lower glucose condition. Furthermore, the p53-VEGF axis was required for the dual role of HBx in angiogenesis. Additionally, HBx mainly regulated the nuclear p53. CONCLUSIONS: These data suggest that the dual roles of HBx confer hepatoma cells to remain in a glucose-rich environment and escape from the glucose-low milieu through tumor vessels, promoting liver tumor progression overall. We exclusively revealed the dual role of HBx on the angiogenesis of liver tumors, which may shed new light on the mechanism and management strategy of HBV- and DM-related hepatocellular carcinoma.

IL-6/STAT3 signaling pathway induces prostate apoptosis response protein-4(PAR-4) to stimulate malignant behaviors of hepatocellular carcinoma cells.

INTRODUCTION AND OBJECTIVES: Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells. MATERIALS AND METHODS: TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model. RESULTS: Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model. CONCLUSIONS: PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.

Development of machine learning-based personalized predictive models for risk evaluation of hepatocellular carcinoma in hepatitis B virus-related cirrhosis patients with low levels of serum alpha-fetoprotein.

INTRODUCTION AND OBJECTIVES: The increasing incidence of hepatocellular carcinoma (HCC) in China is an urgent issue, necessitating early diagnosis and treatment. This study aimed to develop personalized predictive models by combining machine learning (ML) technology with a demographic, medical history, and noninvasive biomarker data. These models can enhance the decision-making capabilities of physicians for HCC in hepatitis B virus (HBV)-related cirrhosis patients with low serum alpha-fetoprotein (AFP) levels. PATIENTS AND METHODS: A total of 6,980 patients treated between January 2012 and December 2018 were included. Pre-treatment laboratory tests and clinical data were obtained. The significant risk factors for HCC were identified, and the relative risk of each variable affecting its diagnosis was calculated using ML and univariate regression analysis. The data set was then randomly partitioned into validation (20 %) and training sets (80 %) to develop the ML models. RESULTS: Twelve independent risk factors for HCC were identified using Gaussian naïve Bayes, extreme gradient boosting (XGBoost), random forest, and least absolute shrinkage and selection operation regression models. Multivariate analysis revealed that male sex, age >60 years, alkaline phosphate >150 U/L, AFP >25 ng/mL, carcinoembryonic antigen >5 ng/mL, and fibrinogen >4 g/L were the risk factors, whereas hypertension, calcium <2.25 mmol/L, potassium ≤3.5 mmol/L, direct bilirubin >6.8 µmol/L, hemoglobin <110 g/L, and glutamic-pyruvic transaminase >40 U/L were the protective factors in HCC patients. Based on these factors, a nomogram was constructed, showing an area under the curve (AUC) of 0.746 (sensitivity = 0.710, specificity=0.646), which was significantly higher than AFP AUC of 0.658 (sensitivity = 0.462, specificity=0.766). Compared with several ML algorithms, the XGBoost model had an AUC of 0.832 (sensitivity = 0.745, specificity=0.766) and an independent validation AUC of 0.829 (sensitivity = 0.766, specificity = 0.737), making it the top-performing model in both sets. The external validation results have proven the accuracy of the XGBoost model. CONCLUSIONS: The proposed XGBoost demonstrated a promising ability for individualized prediction of HCC in HBV-related cirrhosis patients with low-level AFP.

CircROBO1 knockdown improves the radiosensitivity of hepatocellular carcinoma by regulating RAD21.

INTRODUCTION AND OBJECTIVES: Radioresistance is a common problem in the treatment of many cancers, including hepatocellular carcinoma (HCC). Previous studies have shown that circROBO1 is highly expressed in HCC tissues and acts as a cancer promoter to accelerate the malignant progression of HCC. However, the role and mechanism of circROBO1 in HCC radioresistance remain unclear. MATERIALS AND METHODS: CircROBO1, microRNA (miR)-136-5p and RAD21 expression levels were analyzed by quantitative real-time PCR. Cell function and radioresistance were evaluated by colony formation assay, cell counting kit 8 assay, EdU assay and flow cytometry. Protein expression was determined using western blot analysis. RNA interaction was analyzed by dual-luciferase reporter assay and RNA pull-down assay. In vivo experiments were performed by constructing mice xenograft models. RESULTS: CircROBO1 was highly expressed in HCC, and its knockdown inhibited HCC cell proliferation and promoted apoptosis to enhance cell radiosensitivity. On the mechanism, circROBO1 could serve as miR-136-5p sponge to positively regulate RAD21. MiR-136-5p inhibitor or RAD21 overexpression reversed the regulation of circROBO1 knockdown on the radiosensitivity of HCC cells. Also, circROBO1 interference improved the radiosensitivity of HCC tumors in vivo. CONCLUSIONS: CircROBO1 might be a promising target for treating HCC radioresistance.

Genomic instabilities in hepatocellular carcinoma: biomarkers and application in immunotherapies.

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. For patients with advanced HCC, liver function decompensation often occurs, which leads to poor tolerance to chemotherapies and other aggressive treatments. Therefore, it remains critical to develop effective therapeutic strategies for HCC. Etiological factors for HCC are complex and multifaceted, including hepatitis virus infection, alcohol, drug abuse, chronic metabolic abnormalities, and others. Thus, HCC has been categorized as a "genomically unstable" cancer due to the typical manifestation of chromosome breakage and aneuploidy, and oxidative DNA damage. In recent years, immunotherapy has provided a new option for cancer treatments, and the degree of genomic instability positively correlates with immunotherapy efficacies. This article reviews the endogenous and exogenous causes that affect the genomic stability of liver cells; it also updates the current biomarkers and their detection methods for genomic instabilities and relevant applications in cancer immunotherapies. Including genomic instability biomarkers in consideration of cancer treatment options shall increase the patients' well-being.

Limited utility of routine bone scintigraphy in the staging of patients with hepatocellular carcinoma: A cross-sectional study.

INTRODUCTION AND OBJECTIVES: The most widely used staging system for hepatocellular carcinoma (HCC) is the Barcelona Liver Clinic Cancer (BCLC) system, which considers tumor burden, performance status, and liver function. Tumor burden is assessed with cross sectional imaging of the abdomen and chest, controversy surrounds the routine use of bone scintigraphy (BS) for detecting extrahepatic metastases. This study evaluated the role of BS in staging HCC in Mexican patients. PATIENTS AND METHODS: Retrospective cross-sectional study of all adults with HCC at a Mexican referral center from 2000 to 2018. Staging included abdominal computed tomography (CT) or magnetic resonance imaging, chest CT, and BS. The main outcome was the impact of BS on staging and/or therapy plans. RESULTS: Among 238 patients, 2 with fibrolamellar variant and 44 with incomplete data were excluded. Median age was 66 years, 84 % had cirrhosis, and the predominant etiology was hepatitis C virus (43 %). BCLC stages were distributed as follows: A (14 %), B (7 %), C (68 %), and D (11 %). Extrahepatic disease was present in 18 %; only 8 % patients had a positive BS. Among the positive cases, 4 were true positives, but they did not alter staging or therapy plans. CONCLUSIONS: Routine BS in HCC staging demonstrated low yield, with a notable rate of false positives. Considering the implications of extrahepatic disease, BS may be justified for liver transplant candidates outside conventional criteria. Our study highlights the limited role of BS in early-stage HCC and advocates for a more selective utilization.

Efficacy and safety of palliative treatment in patients with autoimmune liver disease-associated hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease. MATERIALS AND METHODS: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability. RESULTS: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7). CONCLUSIONS: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials.

First Detection of Hepatitis B Virus Subgenotype A5, and Characterization of Occult Infection and Hepatocellular Carcinoma-Related Mutations in Latin American and African Immigrants in Brazil.

This study aims to characterize the molecular profile of the hepatitis B virus (HBV) among socially vulnerable immigrants residing in Brazil to investigate the introduction of uncommon HBV strains into the country. Serum samples from 102 immigrants with positive serology for the HBV core antibody (anti-HBc) were tested for the presence of HBV DNA by PCR assays. Among these, 24 were also positive for the HBV surface antigen (HBsAg). The full or partial genome was sequenced to determine genotype by phylogenetic analysis. Participants were from Haiti (79.4%), Guinea-Bissau (11.8%), Venezuela (7.8%), and Colombia (1%). Of the 21 HBV DNA-positive samples, subgenotypes A1 (52.4%), A5 (28.6%), E (9.5%), F2 (4.8%), and F3 (4.8%) were identified. Among the 78 HBsAg-negative participants, four were positive for HBV DNA, resulting in an occult HBV infection rate of 5.1%. Phylogenetic analysis suggested that most strains were likely introduced to Brazil by migration. Importantly, 80% of A5 sequences had the A1762T/G1764A double mutation, linked to an increased risk of hepatocellular carcinoma development. In conclusion, this study is the first report of HBV subgenotype A5 in Brazil, shedding new light on the diversity of HBV strains circulating in the country. Understanding the genetic diversity of HBV in immigrant communities can lead to better prevention and control strategies, benefiting both immigrants and wider society.

[Impact of hepatic resection in the treatment of hepatocellular carcinoma]. / Impacto de la resección hepática en el tratamiento del hepatocarcinoma.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related deaths worldwide. Hepatic resection is the treatment of choice for non-cirrhotic patients, while in cirrhotic individuals, the choice depends on tumor stage and liver function. METHODS: In this retrospective study conducted at Hospital El Cruce between 2015 and 2022, patients with HCC undergoing hepatic resection, both cirrhotic and non-cirrhotic, were evaluated. Morbidity, mortality, recurrence rate, and survival were analyzed. RESULTS: A total of 262 hepatectomies were performed, with 44 for HCC treatment. Among them, 35 were minor hepatectomies, and 9 were major hepatectomies (noncirrhotic patients). The majority were males (77%) with an average age of 58.5 years. Twenty-nine patients had cirrhosis, with hepatitis C (HCV) being the main cause in 48%, HCV with alcohol as a cofactor (21%), and alcohol alone (17%). Morbidity was 47.7%, with predominance of minor complications. Disease recurrence occurred in 59% of patients, and associated factors included tumor size and elevated AFP levels. Survival was better in cirrhotic patients compared to non-cirrhotic ones. DISCUSSION: Results tion 5837 Hepatic resection is an effective option for treating HCC in well-selected cirrhotic and non-cirrhotic patients, with encouraging results in terms of survival and disease control. Additionally, close surveillance for early recurrence detection and timely interventions is suggested.

Introducción: El carcinoma hepatocelular (HCC) es el cáncer primario más común del hígado y la tercera causa principal de muerte por cáncer en todo el mundo. La resección hepática es el tratamiento de elección para pacientes no cirróticos, mientras que, en cirróticos, la elección depende del estadio tumoral y la función hepática. Métodos: En este estudio retrospectivo realizado en el Hospital El Cruce entre 2015 y 2022, se evaluaron pacientes con HCC sometidos a resección hepática, tanto cirróticos como no cirróticos. Se analizó la morbimortalidad, la tasa de recurrencia y la sobrevida. Resultados: Se realizaron 262 hepatectomías, 44 fueron para tratamiento del HCC, de las cuales 35 fueron hepatectomías menores, y 9 hepatectomías mayores (no cirróticos). La mayoría eran hombres (77%) con una edad promedio de 58.5 años. Hubo 29 pacientes con cirrosis, siendo la hepatitis C (HCV) la causa principal en un 48%, HCV con alcohol como cofactor (21%) y alcohol (17%). La morbilidad fue del 47.7%, con complicaciones menores predominantes. La recurrencia de enfermedad ocurrió en el 59% de los pacientes, y los factores asociados incluyeron tamaño tumoral y niveles elevados de Alfafetoproteína. La supervivencia fue mejor en pacientes cirróticos en comparación con no cirróticos. Conclusión: La resección hepática es una opción efectiva para el tratamiento del HCC en pacientes bien seleccionados cirróticos y no cirróticos, con resultados alentadores en términos de supervivencia y control de la enfermedad. Además, se sugiere una vigilancia cercana para detectar recurrencias tempranas y proporcionar tratamientos oportunos.

Phase Angle but Not Psoas Muscle Predicts Nutritional Risk and Prognosis in Males with Hepatocellular Carcinoma.

Despite those with hepatocellular carcinoma (HCC) being at increased risk of malnutrition, there is a notable absence of practical approaches for nutritional assessment in clinical practice. We investigated the usefulness of phase angle (PhA) and Total Psoas Area Index (TPAI) for indicating nutritional risk and HCC prognosis. Weight, height, body mass index (BMI), adductor pollicis muscle thickness (APMT), and handgrip strength (HGS) were assessed. The Nutritional Risk Index (NRI) was calculated. Body composition was assessed using bioimpedance spectroscopy and magnetic resonance imaging. The Child-Turcotte-Pugh (CTP) score and Barcelona-Clinic Liver Cancer (BCLC) classification determined the prognosis. Fifty-one males with HCC were enrolled (CTP C = 11.8%). PhA showed a moderate positive correlation with APMT (r = 0.450; p < 0.001) and HGS (r = 0.418; p = 0.002) and a weak positive correlation with TPAI (r = 0.332; p = 0.021). PhA had a strong positive correlation with NRI (r = 0.614; p < 0.001). Mean PhA values were significantly different according to disease severity (CTP C p = 0.001, and BCLC D p = 0.053). TPAI had no significant correlation with HGS, CTP, or BCLC. PhA was a superior approach for predicting nutritional risk and prognosis in HCC than TPAI. Lower PhA is associated with disease progression, lower muscle mass and function, greater severity of nutritional risk, and increased mortality in HCC.

Modified mesenchymal stromal cells by in vitro transcribed mRNA: a therapeutic strategy for hepatocellular carcinoma.

BACKGROUND: Mesenchymal stromal cells (MSCs) tropism for tumours allows their use as carriers of antitumoural factors and in vitro transcribed mRNA (IVT mRNA) is a promising tool for effective transient expression without insertional mutagenesis risk. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with antitumor properties by stimulating the specific immune response. The aim of this work was to generate modified MSCs by IVT mRNA transfection to overexpress GM-CSF and determine their therapeutic effect alone or in combination with doxorubicin (Dox) in a murine model of hepatocellular carcinoma (HCC). METHODS: DsRed or GM-CSF IVT mRNAs were generated from a cDNA template designed with specific primers followed by reverse transcription. Lipofectamine was used to transfect MSCs with DsRed (MSC/DsRed) or GM-CSF IVT mRNA (MSC/GM-CSF). Gene expression and cell surface markers were determined by flow cytometry. GM-CSF secretion was determined by ELISA. For in vitro experiments, the J774 macrophage line and bone marrow monocytes from mice were used to test GM-CSF function. An HCC model was developed by subcutaneous inoculation (s.c.) of Hepa129 cells into C3H/HeN mice. After s.c. injection of MSC/GM-CSF, Dox, or their combination, tumour size and mouse survival were evaluated. Tumour samples were collected for mRNA analysis and flow cytometry. RESULTS: DsRed expression by MSCs was observed from 2 h to 15 days after IVT mRNA transfection. Tumour growth remained unaltered after the administration of DsRed-expressing MSCs in a murine model of HCC and MSCs expressing GM-CSF maintained their phenotypic characteristic and migration capability. GM-CSF secreted by modified MSCs induced the differentiation of murine monocytes to dendritic cells and promoted a proinflammatory phenotype in the J774 macrophage cell line. In vivo, MSC/GM-CSF in combination with Dox strongly reduced HCC tumour growth in C3H/HeN mice and extended mouse survival in comparison with individual treatments. In addition, the tumours in the MSC/GM-CSF + Dox treated group exhibited elevated expression of proinflammatory genes and increased infiltration of CD8 + T cells and macrophages. CONCLUSIONS: Our results showed that IVT mRNA transfection is a suitable strategy for obtaining modified MSCs for therapeutic purposes. MSC/GM-CSF in combination with low doses of Dox led to a synergistic effect by increasing the proinflammatory tumour microenvironment, enhancing the antitumoural response in HCC.

A novel role of AIM2 inflammasome-mediated pyroptosis in radiofrequency ablation of hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: The absence of melanoma 2 (AIM2) protein triggers the activation of the inflammasome cascade. It is unclear whether AIM2 plays a role in hepatocellular carcinoma (HCC) and radiofrequency ablation (RFA), which uses radiofrequency waves to treat tumors. In this study, we investigated if RFA could induce pyroptosis, also called cell inflammatory necrosis, in HCC through AIM2-inflammasome signaling in vivo and in vitro. MATERIALS AND METHODS: BALB/c nude mice were used to generate HepG2 or SMMC-7721 cell-derived tumor xenografts. HCC cells with knockdown or overexpression of AIM2 were created using short hairpin RNA (shRNA) and expression vector transfection, respectively, for functional and mechanistic studies. Downstream effects were examined using flow cytometry, qRT-PCR, ELISAs, and other molecular assays. RESULTS: RFA significantly suppressed tumor growth in HCC cell xenografts. Flow cytometry analysis revealed that RFA could induce pyroptosis. Furthermore, AIM2, NLRP3, caspase-1, γ-H2AX, and DNA-PKc had significantly greater expression levels in liver tissues from mice treated with RFA compared with those of the controls. Additionally, interleukin (IL)-1ß and IL-18 expression levels were significantly higher in the HCC cell-derived xenograft mice treated with RFA compared with those without RFA. Notably, a significantly greater effect was achieved in the RFA complete ablation group versus the partial ablation group. Knockdown or overexpression of AIM2 in HCC cells demonstrated that AIM2 exerted a role in RFA-induced pyroptosis. CONCLUSIONS: RFA can suppress HCC tumor growth by inducing pyroptosis via AIM2. Therefore, therapeutically intervening with AIM2-mediated inflammasome signaling may help improve RFA treatment outcomes for HCC patients.