Treatment Outcomes in Patients with Advanced Fibrolamellar Hepatocellular Carcinoma Under Systemic Treatment: Analysis of Clinical Characteristics, Management, and Radiomics.

Purpose: Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare primary liver malignancy often diagnosed at advanced stages. While there are limited data on the efficacy of specific agents, we aim to report outcomes of patients treated with systemic therapies and explore prognostic factors. Patients and Methods: Medical records of patients treated between 2010 and 2022 were reviewed. Treatments were defined after multidisciplinary assessment. Descriptive statistics were used for baseline demographics. Time-to-event outcomes were estimated using the Kaplan-Meier method, compared by log-rank and adjusted by a regression model. Radiomic features (including size, shape, and texture) of the primary lesion were extracted and dimensionality reduced. An unsupervised Gaussian Mixture Model (GMM) clustering was performed, and survival was compared between clusters. Results: We identified 23 patients: 12 males, with a median age of 23.6 years. At diagnosis, 82.6% had metastases, most frequently to the lungs (39.1%), lymph nodes (39.1%), and peritoneum (21.7%). Patients received a median of three lines (1-8) of treatment, including different regimens. Sorafenib (39.1%), capecitabine (30.4%), and capecitabine/interferon (13%) were the most used first-line regimens. The median time-to-failure was 3.8 months (95% CI: 3.2-8.7). Capecitabine + interferon (42.1%) and platinum combinations (39.1%) were the most used second-line regimens, with a time-to-failure of 3.5 months (95% CI: 1.5-11.6). Median overall survival was 26.7 months (95% CI: 15.1-40.4). A high baseline neutrophil-to-lymphocyte ratio (NLR) was associated with worse survival (p=0.02). Radiomic features identified three clusters, with one cluster (n=6) having better survival (40.4 vs 22.6 months, p=0.039). Tumor sphericity in the arterial phase was the most relevant characteristic associated with a better prognosis (accuracy=0.93). Conclusion: FLHCC has unique features compared to conventional HCC, including young onset, gender balance, and absence of hepatopathy. Systemic therapies can provide encouraging survival, but lack of uniformity precludes defining a preferable regimen. Radiomics and NLR were suggested to correlate with prognosis and warrant further validation.

P53 and VEGF are promising biomarkers for sorafenib efficacy in an experimental model of NASH-related HCC.

The efficacy of systemic therapy for hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is poorly understood. In this study we evaluated the effects of sorafenib based on the expression of molecular markers related to major hepatocarcinogenesis pathways and angiogenesis in a NASH-related HCC model. Forty male rats were submitted to NASH-HCC induction through the combination of a high-fat and choline deficient diet and diethylnitrosamine (100 mg/L) administration in the drinking water for 13 and 16 weeks. After the induction period, the rats received daily gavage administration of saline solution (control) or Sorafenib (5 mg/kg/day) for 3 weeks. Thereafter, the animals were euthanized and samples from liver nodules were collected for histopathological analysis and immunohistochemical assessment of HEP-PAR-1, glutamine-synthetase, VEGF, survivin, ß-catenin and p53. A semi-quantitative score was used for VEGF, survivin and ß-catenin analysis. For p53, the percentage of positive cells was determined. Results were processed by Wilcoxon's test or Student's t-test. Both protocols efficiently induced HCC, most of them being moderately to poorly differentiated. Sorafenib-treated animals showed a decreased expression of VEGF and p53 in HCCs generated at 13 weeks when compared to control animals (p = 0.03; p = 0.04, respectively). No significant difference in ß-catenin and survivin were observed. There was a significant decrease in VEGF and p53 expression when comparing the two control groups (13 vs. 16 weeks, p < 0.01). p53 and VEGF are promising biomarkers for assessment of efficacy of Sorafenib, whereas survivin and ß-catenin were not found useful. Decreased immunohistochemical expression of p53 and VEGF in the 16 week control group may indicate a different metabolic status of HCC.

Brazilian Landscape of Hepatocellular Carcinoma.

The incidence of hepatocellular carcinoma (HCC) is expected to increase in the coming years, and strategies to mitigate the burden of this disease are needed in different regions. Geographic variations in epidemiology and risk factors, such as viral hepatitis and metabolic disease, pose challenges in adopting programs for early detection programs and management of patients with HCC. Brazil, like other countries, has high economic and social inequality, with heterogeneous access to health care. Viral hepatitis is the main risk factor but there is growing awareness of fatty liver disease. Risk factor monitoring and screening programs are unmet priorities because patients are often diagnosed at later stages. Advances in the management of patients with HCC have been made in recent years, including new tools for selecting patients for liver transplantation, sophisticated surgical techniques, and new systemic agents. High-volume academic centers often achieve favorable results through the adoption and application of established treatments, but this is not a reality in most regions of Brazil, because of disparities in wealth and resources. As HCC management requires a coordinated and multidisciplinary team, the role of local referral centers in decentralizing access to treatments and promoting health education in different regions should be encouraged and supported.

Liver elastography can predict degree of advanced fibrosis for autoimmune hepatitis in biochemical remission.

Background and Aim: The aim was to analyze the concordance of liver stiffness measurement (LSM) either by transient elastography (TE) or ARFI with liver biopsy in autoimmune hepatitis (AIH) patients with biochemical remission and to identify those with histological remission. Liver biopsy is still the golden standard for AIH diagnosis. However, it is an invasive procedure and these patients, most of the time, require many biopsies, so it would be valuable to search for noninvasive method that could select all these patients and keep under observation. Methods: Thirty-three patients with AIH were submitted for liver biopsy to evaluate histological remission after at least 18 months of normal aminotransferases. The efficiency of LSM and fibrosis stages was tested by a receiver operating characteristic curve analysis (AUROC). Results: One patient (3%) was F0, 6 (18.2%) were F1, 8 (24.2%) were F2, 10 (30.3%) were F3, and 8 (24.2%) were F4, according to METAVIR. Thirteen of thirty-three (39.4%) patients did not achieve histological remission. AUROC for F4 stage was 0.83 (IC: 0.76-0.99) for TE and 0.78 (IC: 0.65-0.95) for ARFI. Optimal LSM cutoff values were 12.3 kPa (Se = 87.5%, Sp = 88%) for TE and 1.65 m/s (Se = 87.5%, Sp = 76%) for ARFI. The tests were unable to differentiate patients with histological activity from those in histological remission (P < 0.05). Conclusion: TE and ARFI accurately identify liver fibrosis by METAVIR score in AIH patients with biochemical remission. No cutoff value was detected to indicate whether the patient achieved histological remission.

BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR SYSTEMIC TREATMENT OF HEPATOCELLULAR CARCINOMA.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

Early variation of inflammatory indexes refines prognostic prediction in patients with hepatocellular carcinoma under systemic treatment.

Prognostic markers in advanced hepatocellular carcinoma (HCC) are relevant for clinical decisions. Variations in inflammatory indexes, such as neutrophil-to-lymphocyte ratio (NLR) or platelet-to-lymphocyte ratio (PLR), may correlate with outcomes. In the present study, it was aimed to assess the prognostic role of inflammation indexes in patients with HCC and the evolutionary behavior of these variables within the first month of treatment in a cohort of patients treated with sorafenib from 2009-2021. Subgroups were divided based on the median of each variable ('low' or 'high)'. Survival was estimated using the Kaplan-Meier method. Hazard Ratio (HR) with 95% confidence interval (CI) were estimated using Cox regression models. A total of 373 patients were included, most Child-Pugh-A (83.1%) and BCLC-C (74%). Child-Pugh-A (P=0.011), performance status 0 (P<0.001), no ascites (P<0.001) and NLR<2.6 (P<0.001) were independently associated with improved survival. Baseline PLR was not correlated with survival (P=0.137). Patients who maintained low NLR at baseline and at 1 month (reference subgroup) had improved survival (18.6 months, 95% CI:15.4-22.0) compared with the subgroup that maintained high NLR at baseline and at 1 month (4.2 months, 95% CI:3.6-5.9), with HR: 3.80 (95% CI: 2.89-4.96). The subgroup with low NLR at baseline and high NLR at 1 month had a worse prognosis compared with the reference group (HR:1.4, 95% CI: 1.1-2.0), whereas the subgroup with high NLR at baseline and low at 1 month had similar outcome (HR:1.2, 95% CI: 0.8-1.6). It was concluded that evolutionary variation of NLR has a prognostic role in HCC patients under systemic therapy. This finding suggested that systemic inflammation and early modulation of the immune environment during treatment may correlate with outcomes.

AFP score and metroticket 2.0 perform similarly and could be used in a "within-ALL" clinical decision tool.

Background & Aims: Two recently developed composite models, the alpha-fetoprotein (AFP) score and Metroticket 2.0, could be used to select patients with hepatocellular carcinoma (HCC) who are candidates for liver transplantation (LT). The aim of this study was to compare the predictive performance of both models and to evaluate the net risk reclassification of post-LT recurrence between them using each model's original thresholds. Methods: This multicenter cohort study included 2,444 adult patients who underwent LT for HCC in 47 centers from Europe and Latin America. A competing risk regression analysis estimating sub-distribution hazard ratios (SHRs) and 95% CIs for recurrence was used (Fine and Gray method). Harrell's adapted c-statistics were estimated. The net reclassification index for recurrence was compared based on each model's original thresholds. Results: During a median follow-up of 3.8 years, there were 310 recurrences and 496 competing events (20.3%). Both models predicted recurrence, HCC survival and survival better than Milan criteria (p <0.0001). At last tumor reassessment before LT, c-statistics did not significantly differ between the two composite models, either as original or threshold versions, for recurrence (0.72 vs. 0.68; p = 0.06), HCC survival, and overall survival after LT. We observed predictive gaps and overlaps between the model's thresholds, and no significant gain on reclassification. Patients meeting both models ("within-ALL") at last tumor reassessment presented the lowest 5-year cumulative incidence of HCC recurrence (7.7%; 95% CI 5.1-11.5) and higher 5-year post-LT survival (70.0%; 95% CI 64.9-74.6). Conclusions: In this multicenter cohort, Metroticket 2.0 and the AFP score demonstrated a similar ability to predict HCC recurrence post-LT. The combination of these composite models might be a promising clinical approach. Impact and implications: Composite models were recently proposed for the selection of liver transplant (LT) candidates among individuals with hepatocellular carcinoma (HCC). We found that both the AFP score and Metroticket 2.0 predicted post-LT HCC recurrence and survival better than Milan criteria; the Metroticket 2.0 did not result in better reclassification for transplant selection compared to the AFP score, with predictive gaps and overlaps between the two models; patients who met low-risk thresholds for both models had the lowest 5-year recurrence rate. We propose prospectively testing the combination of both models, to further optimize the LT selection process for candidates with HCC.

Atualização das Recomendações da Sociedade Brasileira de Hepatologia para o Tratamento Sistêmico do Carcinoma Hepatocelular / Brazilian society of hepatology updated recommendations for systemic treatment of hepatocellular carcinoma

ABSTRACT Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2020 the updated recommendations for the diagnosis and treatment of HCC. Since then, new data have emerged in the literature, including new drugs approved for the systemic treatment of HCC that were not available at the time. The SBH board conducted an online single-topic meeting to discuss and review the recommendations on the systemic treatment of HCC. The invited experts were asked to conduct a systematic review of the literature on each topic related to systemic treatment and to present the summary data and recommendations during the meeting. All panelists gathered together for discussion of the topics and elaboration of the updated recommendations. The present document is the final version of the reviewed manuscript containing the recommendations of SBH and its aim is to assist healthcare professionals, policy-makers, and planners in Brazil and Latin America with systemic treatment decision-making of patients with HCC.

RESUMO O carcinoma hepatocelular (CHC) é uma das principais causas de mortalidade relacionada a câncer no Brasil e no mundo. A Sociedade Brasileira de Hepatologia (SBH) publicou em 2020 a atualização das recomendações da SBH para o diagnóstico e tratamento do CHC. Desde então, novas evidências científicas sobre o tratamento sistêmico do CHC foram relatadas na literatura médica, incluindo novos medicamentos aprovados que não estavam disponíveis na época do último consenso, levando a diretoria da SBH a promover uma reunião monotemática on-line para discutir e rever as recomendações sobre o tratamento sistêmico do CHC. Um grupo de experts foi convidado para realizar uma revisão sistemática da literatura e apresentar uma atualização, baseada em evidências científicas, sobre cada tópico relacionado ao tratamento sistêmico e a apresentar os dados e recomendações resumidas durante a reunião. Todos os painelistas se reuniram para discutir os tópicos e elaborar as recomendações atualizadas. O presente documento é a versão final do manuscrito revisado, contendo as recomendações da SBH, e seu objetivo é auxiliar os profissionais de saúde, formuladores de políticas e planejadores no Brasil e na América Latina na tomada de decisões sobre o tratamento sistêmico de pacientes com CHC.

Impaired anti-HBV vaccine response in non-cirrhotic chronic HCV is not overcome by double dose regimen: randomized control trial.

INTRODUCTION AND OBJECTIVES: Some studies suggest chronic HCV infection diminishes responses to the anti-HBV vaccine. We evaluated the efficacy of double versus standard dose HBV vaccination among HCV patients without cirrhosis. PATIENTS AND METHODS: 141 adults with untreated chronic HCV were randomized to HBV vaccination with double dose (40µg) or standard dose (20µg) at 0, 1 and 6 months; 70 healthy HCV-negative patients given standard dose served as controls. Vaccine response was defined by anti-HBs ≥10 mIU/mL. RESULTS: 128 patients (60 double, 68 standard doses) completed the study. Patients were of median age 52 years, 61% female, 60% fibrosis <2 of 4, and 76% genotype 1 with median 6-log 10 IU/mL HCV RNA. Overall seroprotection rate was 76.7% (95% CI: 65-87) in the 40µg versus 73.5% (95% CI: 63-84) in the 20µg dose HCV-positive groups (p =0.68) and 91.2% (95%CI:84-99) in HCV-negative controls (p =0.011 and 0.003, respectively). In multivariate logistic regression, vaccine dose (double vs. standard dose) was not associated with vaccine response (OR=0.63, p =0.33). Of 32 HCV-infected patients who were non-responders to 3- doses, 25 received the fourth dose of vaccine. The fourth dose seroconversion rate for the 40µg and 20µg groups were 45.5% and 21.4%, respectively. CONCLUSIONS: In HCV-infected patients without cirrhosis, impaired responses to HBV vaccination cannot be overcome by the use of double dose HBV vaccination, but adding a fourth dose of vaccine for non-responders may be an effective strategy. Other adjuvant measures are needed to enhance seroconversion rates in these patients. TRIAL REGISTER: U 1111-1264-2343 (www.ensaiosclinicos.gov.br).

Contrast phase recognition in liver computer tomography using deep learning.

Hepatocellular carcinoma (HCC) has become the 4th leading cause of cancer-related deaths, with high social, economical and health implications. Imaging techniques such as multiphase computed tomography (CT) have been successfully used for diagnosis of liver tumors such as HCC in a feasible and accurate way and its interpretation relies mainly on comparing the appearance of the lesions in the different contrast phases of the exam. Recently, some researchers have been dedicated to the development of tools based on machine learning (ML) algorithms, especially by deep learning techniques, to improve the diagnosis of liver lesions in imaging exams. However, the lack of standardization in the naming of the CT contrast phases in the DICOM metadata is a problem for real-life deployment of machine learning tools. Therefore, it is important to correctly identify the exam phase based only on the image and not on the exam metadata, which is unreliable. Motivated by this problem, we successfully created an annotation platform and implemented a convolutional neural network (CNN) to automatically identify the CT scan phases in the HCFMUSP database in the city of São Paulo, Brazil. We improved this algorithm with hyperparameter tuning and evaluated it with cross validation methods. Comparing its predictions with the radiologists annotation, it achieved an accuracy of 94.6%, 98% and 100% in the testing dataset for the slice, volume and exam evaluation, respectively.

NAFLD in Polycystic Ovary Syndrome: Association with PNPLA3 and Metabolic Features.

Background: The aim of this study was to determine the frequency of the rs738409 polymorphism in the patatin-like phospholipase domain containing 3 (PNPLA3) gene in patients with polycystic ovary syndrome (PCOS) and its impact on nonalcoholic fatty liver disease (NAFLD) risk and severity. We also evaluated other risk factors associated with NAFLD and advanced fibrosis. Methods: This was a cross-sectional study involving 163 patients with PCOS at a tertiary center. Genotyping for the PNPLA3 polymorphism was undertaken using a TaqMan assay. The degree of fibrosis was defined by transient elastography. Results: The prevalence of NAFLD was 72.4%, and the polymorphism was heterozygous in 41.7% and homozygous in 8% of patients. Homeostasis model assessment of insulin resistance ≥ 2.5 was the main factor associated with the risk of developing NAFLD (OR = 4.313, p = 0.022), and its effect was amplified by the polymorphism (OR = 12.198, p = 0.017). Age > 32 years also conferred a higher risk for NAFLD. HDL values ≥ 50 mg/dL conferred protection against the outcome. Metabolic syndrome (OR = 13.030, p = 0.020) and AST > 32 U/L (OR = 9.039, p = 0.009) were independent risk factors for advanced fibrosis. Conclusions: In women with PCOS, metabolic characteristics are more relevant than PNPLA3 polymorphism regarding the risk for NAFLD and its advanced forms, but these factors can act synergistically, increasing disease risk.

Hepatocellular carcinoma (HCC) in patients with Non-Alcoholic Fatty Liver Disease (NAFLD): screening, treatment and survival analysis in a Brazilian series.

OBJECTIVE: The aim of the present study was to evaluate the clinical features, Hepatocellular Carcinoma (HCC) screening, treatment modalities, and Overall Survival (OS) in a series of Non-Alcoholic Fatty Liver Disease-Related Hepatocellular Carcinoma (NAFLD-HCC) Brazilian patients. METHODS: This was a cross-sectional study at the Instituto do Cancer do Estado de São Paulo, at the Faculdade de Medicina da Universidade de São Paulo with the approval of the local research ethics committee. NAFLD patients with HCC diagnosed, from May 2010 to May 2019, were included. RESULTS: A total of 131 patients were included. Risk factors for NAFLD were present in 94.7% of the patients. Only 29% of patients were in the HCC screening program before diagnosis. HCC treatment was performed in 84.7% of patients. Cumulative survival at the end of the first year was 72%, second-year 52%, and fifth-year 32%. HCC screening before diagnosis was not significantly associated with higher cumulative survival. The independent factors associated with shorter general survival were BCLC C-D, p < 0.001, and the size of the largest nodule > 42 mm, p = 0.039. CONCLUSIONS: Although the efficacy of screening in our population regarding overall survival was hampered due to the sample size (29% had screening), BCLC stages C‒D and the size of the largest nodule larger than 42 mm were identified as independent factors of worse prognosis.

Synbiotic Supplementation Modulates Gut Microbiota, Regulates ß-Catenin Expression and Prevents Weight Gain in ob/ob Mice: Preliminary Findings.

BACKGROUND: Obesity is one of the main health problems in the world today, and dysbiosis seems to be one of the factors involved. The aim of this study was to examine the impact of synbiotic supplementation on obesity and the microbiota in ob/ob mice. Twenty animals were divided into four groups: obese treated (OT), obese control (OC), lean treated (LT) and lean control (LC). All animals received a standard diet for 8 weeks. The treated groups received a synbiotic (Simbioflora-Invictus Farmanutrição Ltd., Sao Paulo, Brazil) in water, while the nontreated groups received only water. After 8 weeks, all animals were sacrificed, and gut tissue and stool samples were collected for mRNA isolation and microbiota analysis, respectively. ß-Catenin, occludin, cadherin and zonulin in the gut tissue were analyzed via RT-qPCR. Microbiome DNA was extracted from stool samples and sequenced using an Ion PGM Torrent platform. RESULTS: Synbiotic supplementation reduced body weight gain in the OT group compared with the OC group (p = 0.0398) and was associated with an increase in Enterobacteriaceae (p = 0.005) and a decrease in Cyanobacteria (p = 0.047), Clostridiaceae (p = 0.026), Turicibacterales (p = 0.005) and Coprococcus (p = 0.047). On the other hand, a significant reduction in Sutterella (p = 0.009) and Turicibacter (p = 0.005) bacteria was observed in the LT group compared to the LC group. Alpha and beta diversities were different among all treated groups. ß-Catenin gene expression was significantly decreased in the gut tissue of the OT group (p ≤ 0.0001) compared to the other groups. No changes were observed in occludin, cadherin or zonulin gene expression in the gut tissue. CONCLUSIONS: Synbiotic supplementation prevents excessive weight gain, modulates the gut microbiota, and reduces ß-catenin expression in ob/ob mice.

Association between Metabolic Disorders and Cholangiocarcinoma: Impact of a Postulated Risk Factor with Rising Incidence.

Introduction and objectives: The incidence of cholangiocarcinoma (CCA) has been increasing globally. Although a concomitant increase in the incidence of metabolic disorders might suggest a causal relationship, the data are scarce. We aimed to describe the prevalence of metabolic disorders in patients with CCA and report the clinical features and outcomes. Patients and Methods: Retrospective study including patients with CCA. Patients were divided into: (1) past history of diabetes or/and overweight/obesity ("metabolic disorder group") and (2) without any of these features ("non-metabolic-disorder group"). A Cox regression model was used to determine the prognostic factors. Results: 122 patients were included. In total, 36 (29.5%) had overweight/obesity, 24 (19.7%) had diabetes, and 8 (6.6%) had both. A total of 29 (23.8%) patients had resectable disease and received upfront surgery. A total of 104 (85.2%) received chemotherapy for advanced/recurrent disease. The overall survival of the cohort was 14.3 months (95% CI: 10.1−17.3). ECOG-PS 0 (p < 0.0001), resectable disease (p = 0.018) and absence of vascular invasion (p = 0.048) were independently associated with better prognosis. The "metabolic disorder group" (n = 52) had a median survival of 15.5 months (95% CI 10.9−33.9) vs. 11.5 months (95% CI 8.4−16.5) in the "non-metabolic-disorder group" (n = 70) (HR: 1.10; 95% CI 0.62−1.94). Patients with resectable disease in the "metabolic group" had longer survival than patients in the "non-metabolic group" (43.4 months (95% CI 33.9-NR) vs. 21.8 months (95% CI 8.6−26.9); HR = 0.12, 95% CI 0.03−0.59). Conclusion: Metabolic disorders are frequent among CCA patients. Underlying metabolic comorbidities may be associated with prognosis in resectable CCA. There is a need to explore the mechanism that drives CCA carcinogenesis in a metabolic background.

HIGH VALUES OF LIVER STIFFNESS PLAY AN IMPORTANT ROLE IN STRATIFYING THE RISK OF HEPATOCELLULAR CARCINOMA IN CIRRHOTIC HEPATITIS C PATIENTS.

BACKGROUND: Evaluate the role of liver stiffness measurement (LSM) by transient elastography (TE) as a risk factor for hepatocellular carcinoma (HCC) occurrence in a prospective cohort of Brazilian hepatitis C virus (HCV) patients with cirrhosis. METHODS: A cohort of 99 consecutive HCV patients was included between 2011 and 2016 with baseline LSM ≥12 kilopascals (kPa). Baseline variables were evaluated and HCC occurrence was documented. Kaplan-Meier methods with a log-rank test and the use of cox univariate and multivariate analysis assessed the association between variables and clinical results. RESULTS: The mean age was 57.8±10.6 years. In a follow-up over a mean of 3.3 years, 20 (20.2%) patients developed HCC. In univariate logistic regression analysis, variables associated with HCC occurrence were: lower platelet count (P=0.0446), higher serum alpha-fetoprotein (P=0.0041) and bilirubin (P=0.0008) values, higher Model for End-Stage Liver Disease (MELD) score (P=0.0068) and higher LSM (P=0.0354). LSM evaluated by TE was independently associated with HCC development, and the best cut-off value for higher HCC risk was >21.1 kPa (HR: 5.548; 95%CI: 1.244-24.766; P=0.025). CONCLUSION: A high value of liver stiffness relates substantially to an increased risk for HCC occurrence in Brazilian patients with cirrhosis due to HCV.

Two decades of liver resection with a multidisciplinary approach in a single institution: What has changed? Analysis of 1409 cases.

OBJECTIVES: To evaluate results of patients undergoing liver resection in a single center over the past two decades with a particular look at Colorectal Liver Metastasis (CRLM) and Hepatocellular Carcinoma (HCC). METHOD: Patients were divided into two eras, from 2000 to 2010 (Era 1) and 2011 to 2020 (Era 2). The most frequent diagnosis was CRLM and HCC, with 738 (52.4%) and 227 (16.1%) cases respectively. An evaluation of all liver resection cases and a subgroup analysis of both CRLM and HCC were performed. Preoperative and per operative variables and long-term outcomes were evaluated. RESULTS: 1409 liver resections were performed. In Era 2 the authors observed higher BMI, more: minimally invasive surgeries, Pringle maneuvers, and minor liver resections; and less transfusion, less ICU necessity, and shorter length of hospital stay. Severe complications were observed in 14.7% of patients, and 90-day mortality was 4.2%. Morbidity and mortality between eras were not different. From 738 CRLM resections, in Era 2 there were significantly more patients submitted to neoadjuvant chemotherapy, bilateral metastases, and smaller sizes with significantly less transfusion, the necessity of ICU, and shorter length of hospital stay. More pedicle clamping, minimally invasive surgeries, and minor resections were also observed. From 227 HCC resections, in Era 2 significantly more minimally invasive surgeries, fewer transfusions, less necessity of ICU, and shorter length of hospital stay were observed. OS was not different between eras for CRLM and HCC. CONCLUSIONS: Surgical resection in a multidisciplinary environment remains the cornerstone for the curative treatment of primary and metastatic liver tumors.

African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population.

INTRODUCTION AND OBJECTIVES: PNPLA3 (rs738409) and TM6SF2 (rs58542926) variants, interindividual and ethnic differences may be risk factors for non-alcoholic fatty liver disease (NAFLD). The PNPLA3 G allele is associated with worse NAFLD evolution in Hispanics and Caucasians. TM6SF2 is associated with hypertriglyceridemia, NAFLD, and cardiovascular disease. We aimed to evaluate the association between genetic ancestry by Ancestry Informative Markers (AIM), PNPLA3 and TM6SF2 polymorphisms in patients with biopsy-proven NAFLD in an admixed population. METHODS: We included adults with biopsy-proven NAFLD and excluded patients with the presence of other chronic liver disease, alcohol intake >100g/week, HIV, drug-induced fatty liver disease, or liver transplantation. We classified NAFLD using the Non-Alcoholic Steatohepatitis Clinical Research Network (NASH-CRN) histological scoring system. The PNPLA3 (rs738409 c.444C>G) and TM6SF2 (rs58542926 c.449C>T) genotyping were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; α<0.05 was considered significant. RESULTS: A total of 248 patients with NAFLD were enrolled [34 with simple steatosis (NAFL); 214 with NASH]. Overall, we detected a greater European ancestry contribution (0.645), followed by African (0.173), Amerindian (0.095), and East Asian (0.087) ancestry contribution, without differences between NAFL and NASH patients. However, we found a higher African genetic ancestry contribution among patients with NAFL who had the PNPLA3 C/C genotype than those with the G allele (0.216 ± 0.205 versus 0.105 ± 0.101, respectively; p=0.047). Ancestry contributions did not differ among TM6SF2 genotypes. CONCLUSION: Among NAFL patients, greater African genetic ancestry was associated to a lower frequency of the PNPLA3 G allele, demonstrating a possible NASH ancestry-related protective factor.

Altos valores de rigidez hepática desempenham um papel importante na estratificação do risco de carcinoma hepatocelular em pacientes cirróticos com vírus C / High values of liver stiffness play an important role in stratifying the risk of hepatocellular carcinoma in cirrhotic hepatitis c patients

ABSTRACT Background: Evaluate the role of liver stiffness measurement (LSM) by transient elastography (TE) as a risk factor for hepatocellular carcinoma (HCC) occurrence in a prospective cohort of Brazilian hepatitis C virus (HCV) patients with cirrhosis. Methods: A cohort of 99 consecutive HCV patients was included between 2011 and 2016 with baseline LSM ≥12 kilopascals (kPa). Baseline variables were evaluated and HCC occurrence was documented. Kaplan-Meier methods with a log-rank test and the use of cox univariate and multivariate analysis assessed the association between variables and clinical results. Results: The mean age was 57.8±10.6 years. In a follow-up over a mean of 3.3 years, 20 (20.2%) patients developed HCC. In univariate logistic regression analysis, variables associated with HCC occurrence were: lower platelet count (P=0.0446), higher serum alpha-fetoprotein (P=0.0041) and bilirubin (P=0.0008) values, higher Model for End-Stage Liver Disease (MELD) score (P=0.0068) and higher LSM (P=0.0354). LSM evaluated by TE was independently associated with HCC development, and the best cut-off value for higher HCC risk was >21.1 kPa (HR: 5.548; 95%CI: 1.244-24.766; P=0.025). Conclusion: A high value of liver stiffness relates substantially to an increased risk for HCC occurrence in Brazilian patients with cirrhosis due to HCV.

RESUMO Contexto: O carcinoma hepatocelular (CHC) é o tumor maligno hepático mais comum, e a cirrose é o principal fator de risco para o seu desenvolvimento. Objetivo: Avaliar o papel da medição da rigidez hepática por elastografia transitória (ET) como fator de risco para ocorrência de CHC em uma coorte prospectiva de pacientes brasileiros com cirrose por vírus da hepatite C (VHC). Métodos: Um total de 99 pacientes com VHC e medida de rigidez hepática ≥12 kilopascals (kPa) foram incluídos consecutivamente, entre 2011 e 2016. As variáveis do baseline foram avaliadas e a ocorrência de CHC foi documentada. Os testes de Kaplan-Meier e log-rank, além das análises uni e multivariadas de Cox avaliaram a associação entre as variáveis e os resultados clínicos. Resultados: A média de idade foi de 57,8±10,6 anos. Vinte (20,2%) pacientes desenvolveram CHC, num período médio de seguimento de 3,3 anos. Na análise de regressão logística univariada, as variáveis associadas à ocorrência de CHC foram: contagem de plaquetas mais baixa (P=0,0446), valores séricos mais elevados de alfa-fetoproteína (P=0,0041) e de bilirrubina (P=0,0008), maior pontuação do escore MELD (P=0,0068) e valores mais altos de rigidez hepática por ET (P=0,0354). A medição da rigidez hepática por ET foi independentemente associada ao desenvolvimento de CHC, e o melhor valor de corte para maior risco de CHC foi >21,1kPa (HR: 5,548; IC95%: 1,244-24,766; P=0,025). Conclusão: Um alto valor de rigidez hepática está relacionado substancialmente a um risco aumentado de ocorrência de CHC em pacientes brasileiros com cirrose por HCV.

Hepatitis B Virus Infection among Japanese Immigrants and Descendants: The Need to Strengthen Preventive and Control Measures.

This cross-sectional study aimed to investigate the prevalence and risk factors of Hepatitis B virus infection among Japanese immigrants and their descendants from São Paulo (SP), and to verify the occurrence of occult hepatitis B and coinfection with HCV, Delta, and HTLV. All samples (n = 2.127) were tested for HBV serological markers by electrochemiluminescence. HBsAg and/or total anti-HBc positive samples were tested for HBV DNA by real-time PCR, and genotyped by sequencing using the Sanger methodology. The prevalence rate of HBV exposure was 13.4% (CI 95%: 11.9-14.9%), and 22 (1.1%) were HBsAg positive. A high rate of susceptibility to HBV infection was found (67.4%; CI 95%: 65.4-69.4%). In contrast, only 19.2% (CI 95%: 17.6-20.9%) presented a serological profile analogous to that elicited by Hepatitis B vaccination. HBV isolates (n = 8) were classified as genotypes HBV/B1 (62.5%), HBV/C2 (12.5%), HBV/F1b (12.5%), and HBV/A1 (12.5%). Hepatitis B vaccination strategies and educational measures to control this infection should be considered.

Updating the Phylodynamics of Yellow Fever Virus 2016-2019 Brazilian Outbreak With New 2018 and 2019 São Paulo Genomes.

The recent outbreak of yellow fever (YF) in São Paulo during 2016-2019 has been one of the most severe in the last decades, spreading to areas with low vaccine coverage. The aim of this study was to assess the genetic diversity of the yellow fever virus (YFV) from São Paulo 2016-2019 outbreak, integrating the available genomic data with new genomes from patients from the Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP). Using phylodynamics, we proposed the existence of new IE subclades, described their sequence signatures, and determined their locations and time of origin. Plasma or urine samples from acute severe YF cases (n = 56) with polymerase chain reaction (PCR) positive to YFV were submitted to viral genome amplification using 12 sets of primers. Thirty-nine amplified genomes were subsequently sequenced using next-generation sequencing (NGS). These 39 sequences, together with all the complete genomes publicly available, were aligned and used to determine nucleotide/amino acids substitutions and perform phylogenetic and phylodynamic analysis. All YFV genomes generated in this study belonged to the genotype South American I subgroup E. Twenty-one non-synonymous substitutions were identified among the new generated genomes. We analyzed two major clades of the genotypes IE, IE1, and IE2 and proposed the existence of subclades based on their sequence signatures. Also, we described the location and time of origin of these subclades. Overall, our findings provide an overview of YFV genomic characterization and phylodynamics of the 2016-2019 outbreak contributing to future virological and epidemiological studies.