VENANCIO AVANCINI FERREIRA ALVES
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina - Líder
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/14 - Laboratório de Investigação em Patologia Hepática, Hospital das Clínicas, Faculdade de Medicina - Líder
15 resultados
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- Time to Recurrence as a Prognostic Factor in Parathyroid Carcinoma(2023) MAGNABOSCO, Felipe Ferraz; BRESCIA, Marilia D'Elboux Guimaraes; NASCIMENTO JUNIOR, Climerio Pereira; MASSONI NETO, Ledo Mazzei; ARAP, Sergio Samir; CASTRO JUNIOR, Gilberto de; LEDESMA, Felipe Lourenco; ALVES, Venancio Avancini Ferreira; KOWALSKI, Luiz Paulo; MARTIN, Regina Matsunaga; MONTENEGRO, Fabio Luiz de MenezesBackground Parathyroid carcinoma (PC) is a rare and challenging disease without clearly understood prognostic factors. Adequate management can improve outcomes. Characteristics of patients treated for PC over time and factors affecting prognosis were analyzed. Methods Retrospective cohort study including surgically treated patients for PC between 2000 and 2021. If malignancy was suspected, free-margin resection was performed. Demographic, clinical, laboratory, surgical, pathological, and follow-up characteristics were assessed. Results Seventeen patients were included. Mean tumor size was 32.5 mm, with 64.7% staged as pT1/pT2. None had lymph node involvement at admission, and 2 had distant metastases. Parathyroidectomy with ipsilateral thyroidectomy was performed in 82.2%. Mean postoperative calcium levels were different between patients who developed recurrence vs those who did not (P = .03). Six patients (40%) had no recurrence during follow-up, 2 (13.3%) only regional, 3 (20%) only distant, and 4 (26.6%) both regional and distant. At 5 and 10 years, 79% and 56% of patients were alive, respectively. Median disease-free survival was 70 months. Neither Tumor, Nodule, Metastasis system nor largest tumor dimension (P = .29 and P = .74, respectively) were predictive of death. En bloc resection was not superior to other surgical modalities (P = .97). Time between initial treatment and development of recurrence negatively impacted overall survival rate at 36 months (P = .01). Conclusion Patients with PC can survive for decades and have indolent disease course. Free margins seem to be the most important factor in initial surgery. Recurrence was common (60%), but patients with disease recurrence within 36 months of initial surgery had a lower survival rate.
- Postmortem Brains from Subjects with Diabetes Mellitus Display Reduced GLUT4 Expression and Soma Area in Hippocampal Neurons: Potential Involvement of Inflammation(2023) YONAMINE, Caio Yogi; PASSARELLI, Marisa; SUEMOTO, Claudia Kimie; PASQUALUCCI, Carlos Augusto; JACOB-FILHO, Wilson; ALVES, Venancio Avancini Ferreira; MARIE, Suely Kazue Nagahashi; CORREA-GIANNELLA, Maria Lucia; BRITTO, Luiz Roberto; MACHADO, Ubiratan FabresDiabetes mellitus (DM) is an important risk factor for dementia, which is a common neurodegenerative disorder. DM is known to activate inflammation, oxidative stress, and advanced glycation end products (AGEs) generation, all capable of inducing neuronal dysfunctions, thus participating in the neurodegeneration progress. In that process, disturbed neuronal glucose supply plays a key role, which in hippocampal neurons is controlled by the insulin-sensitive glucose transporter type 4 (GLUT4). We investigated the expression of GLUT4, nuclear factor NF-kappa B subunit p65 [NFKB (p65)], carboxymethyllysine and synapsin1 (immunohistochemistry), and soma area in human postmortem hippocampal samples from control, obese, and obese+DM subjects (41 subjects). Moreover, in human SH-SY5Y neurons, tumor necrosis factor (TNF) and glycated albumin (GA) effects were investigated in GLUT4, synapsin-1 (SYN1), tyrosine hydroxylase (TH), synaptophysin (SYP) proteins, and respective genes; NFKB binding activity in the SLC2A4 promoter; effects of increased histone acetylation grade by histone deacetylase 3 (HDAC3) inhibition. Hippocampal neurons (CA4 area) of obese+DM subjects displayed reduced GLUT4 expression and neuronal soma area, associated with increased expression of NFKB (p65). Challenges with TNF and GA decreased the SLC2A4/GLUT4 expression in SH-SY5Y neurons. TNF decreased SYN1, TH, and SYP mRNAs and respective proteins, and increased NFKB binding activity in the SLC2A4 promoter. Inhibition of HDAC3 increased the SLC2A4 expression and the total neuronal content of CRE-binding proteins (CREB/ICER), and also counterbalanced the repressor effect of TNF upon these parameters. This study revealed reduced postmortem human hippocampal GLUT4 content and neuronal soma area accompanied by increased proinflammatory activity in the brains of DM subjects. In isolated human neurons, inflammatory activation by TNF reduced not only the SLC2A4/GLUT4 expression but also the expression of some genes related to neuronal function (SYN1, TH, SYP). These effects may be related to epigenetic regulations (H3Kac and H4Kac status) since they can be counterbalanced by inhibiting HDAC3. These results uncover the improvement in GLUT4 expression and/or the inhibition of HDAC3 as promising therapeutic targets to fight DM-related neurodegeneration.
- Early variation of inflammatory indexes refines prognostic prediction in patients with hepatocellular carcinoma under systemic treatment(2023) FONSECA, Leonardo G. Da; URATANI, Lucas Fernando; SOARES, Gabriella Fernandes; AMARAL, Paulo Siqueira Do; ALENCAR, Regiane Saraiva De Souza Melo; CHAGAS, Aline Lopes; ALVES, Venancio Avancini Ferreira; CARRILHO, Flair JosePrognostic 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.
- Liver elastography can predict degree of advanced fibrosis for autoimmune hepatitis in biochemical remission(2023) PARANAGUA-VEZOZZO, Denise Cerqueira; TERRABUIO, Debora Raquel Benedita; REINOSO-PEREIRA, Gleicy Luz; MOUTINHO, Renata; ONO, Suzane Kioko; SALAS, Veronica Walwyn; FRANCA, Joao Italo Dias; ALVES, Venancio Avancini Ferreira; CANCADO, Eduardo Luiz Rachid; CARRILHO, Flair JoseBackground and AimThe 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. MethodsThirty-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). ResultsOne 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). ConclusionTE 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.
- Main autopsyfindings of visceral involvement by fatal mpox in patients with AIDS: necrotising nodular pneumonia, nodular ulcerative colitis, and diffuse vasculopathy(2023) DUARTE-NETO, Amaro Nunes; GONCALVES, Ana Maria; ELIODORO, Raissa Heloisa de Araujo; MARTINS, Wilker Dias; CLARO, Ingra Morales; VALENCA, Ian Nunes; PAES, Vitor Ribeiro; TEIXEIRA, Ralcyon; SZTAJNBOK, Jaques; SILVA, Ivan Leonardo Avelino Franca e; LEITE, Luiz Antonio Ferreira; MALAQUE, Ceila Maria Sant'Ana; BORGES, Luciana Marques Sansao; GONZALEZ, Mario Peribanez; BARRA, Luiz Alberto Costa; PEREIRA JUNIOR, Luiz Carlos; MELLO, Claudia Figueiredo; QUEIROZ, Wladimir; ATOMYA, Angela Naomi; FERNEZLIAN, Sandra de Morais; ALVES, Venancio Avancini Ferreira; LEITE, Katia Ramos Moreira; FERREIRA, Cristiane Rubia; SALDIVA, Paulo Hilario Nascimento; MAUAD, Thais; SILVA, Luiz Fernando Ferraz da; FARIA, Nuno R.; CORREA, Maria Cassia Jacinto Mendes; SABINO, Ester Cerdeira; SOTTO, Mirian Nacagami; DOLHNIKOFF, Marisa
- Understanding yellow fever-associated myocardial injury: an autopsy study(2023) GIUGNI, Fernando Rabioglio; DEMARCHIAIELLO, Vera; FARIA, Caroline Silverio; POUR, Shahab Zaki; CUNHA, Marielton dos Passos; GIUGNI, Melina Valdo; PINESI, Henrique Trombini; LEDESMA, Felipe Lourenco; MORAIS, Carolina Esteves; HO, Yeh-Li; SZTAJNBOK, Jaques; FERNEZLIAN, Sandra de Morais; SILVA, Luiz Fernando Ferraz da; MAUAD, Thais; ALVES, Venancio Avancini Ferreira; SALDIVA, Paulo Hilario do Nascimento; ANTONANGELO, Leila; DOLHNIKOFF, Marisa; DUARTE-NETO, Amaro NunesBackground Yellow fever (YF) is a viral hemorrhagic fever, endemic in parts of South America and Africa. There is scarce evidence about the pathogenesis of the myocardial injury. The objective of this study is to evaluate the cardiac pathology in fatal cases of YF.Methods This retrospective autopsy study included cases from the Sao Paulo (Brazil) epidemic of 2017-2019. We reviewed medical records and performed cardiac tissue histopathological evaluation, electron microscopy, immunohistochemical assays, RT-qPCR for YF virus (YFV)-RNA, and proteomics analysis on inflammatory and endothelial biomarkers.Findings Seventy-three confirmed YF cases with a median age of 48 (34-60) years were included. We observed myocardial fibrosis in 68 (93.2%) patients; cardiomyocyte hypertrophy in 68 (93.2%); endothelial alterations in 67 (91.8%); fiber necrosis in 50 (68.5%); viral myocarditis in 9 (12.3%); and secondary myocarditis in 5 (6.8%). Four out of five patients with 17DD vaccine-associated viscerotropic disease presented with myocarditis. The cardiac conduction system showed edema, hemorrhages and endothelial fibrinoid necrosis. Immunohistochemistry detected CD68-positive inflammatory interstitial cells and YFV antigens in endothelial and inflammatory cells. YFV-RNA was detected positive in 95.7% of the cardiac samples. The proteomics analysis demonstrated that YF patients had higher levels of multiple inflammatory and endothelial biomarkers in comparison to cardiovascular controls, and higher levels of interferon gamma-induced protein 10 (IP-10) in comparison to sepsis (p = 0.01) and cardiovascular controls (p < 0.001) in Dunn test.Interpretation Myocardial injury is frequent in severe YF, due to multifactorial mechanisms, including direct YFV-mediated damage, endothelial cell injury, and inflammatory response, with a possible prominent role for IP-10.
- Treatment Outcomes in Patients with Advanced Fibrolamellar Hepatocellular Carcinoma Under Systemic Treatment: Analysis of Clinical Characteristics, Management, and Radiomics(2023) FONSECA, Leonardo Da; YAMAMOTO, Victor Junji; CUNHA, Mateus Trinconi; TORRE, Giovanna Sawaya; ARAUJO, Raphael L. C.; FONSECA, Gilton Marques; CHEN, Andre Tsin Chih; CHAGAS, Aline Lopes; HERMAN, Paulo; ALVES, Venancio Avancini Ferreira; CARRILHO, Flair JosePurpose: 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.
- Adjuvant Vaccination with Allogenic Dendritic Cells Significantly Prolongs Overall Survival in High-Grade Gliomas: Results of a Phase II Trial(2023) LEPSKI, Guilherme; BERGAMI-SANTOS, Patricia C. C.; PINHO, Mariana P. P.; CHAUCA-TORRES, Nadia E. E.; EVANGELISTA, Gabriela C. M.; TEIXEIRA, Sarah F. F.; FLATOW, Elizabeth; OLIVEIRA, Jaqueline V. V. de; FOGOLIN, Carla; PERES, Nataly; AREVALO, Analia; ALVES, Venancio A. F.; BARBUTO, Jose A. M.Simple Summary Among all intracranial tumors, 31.5% are malignant, and among those, glioblastomas account for 47%. Recently, our group reported the case of a patient with glioblastoma who underwent vaccination based on dendritic cells and experienced near-complete tumor remission. Here we report the results of a phase I/II prospective, non-controlled clinical trial with 37 patients harboring glioblastoma or grade 4 astrocytomas. Patients received monthly intradermal injections of allogenic dendritic cell vaccinations. The survival curves of the vaccinated populations were compared with patients from the GDC (Genomics Data Commons) database, which revealed that overall survival was 75% greater in the vaccinated glioblastoma group (16 to 28 months, hazard ratio 0.53) and 200% greater in the vaccinated astrocytoma grade 4 group (20 to 60 months, hazard ratio 0.18). Furthermore, seven patients remain alive to this day. We believe that the data reported here can foster the continued improvement of treatment protocols based on cellular immunotherapy. Immunotherapy for cancer treatment has gained increased attention in recent years. Recently, our group reported the case of a patient with glioblastoma who underwent vaccination based on dendritic cells and experienced a strong Th1 immune response together with near-complete tumor remission. Here we report the results of a phase I/II prospective, non-controlled clinical trial with 37 patients harboring glioblastoma or grade 4 astrocytomas. At the time of first recurrence after surgery, patients began receiving monthly intradermal injections of allogenic DC-autologous tumor cell hybridomas. Overall survival, quality of life, and immunological profiles were assessed prospectively. Compared with patients in the Genomic Data Commons data bank, overall survival for vaccinated patients with glioblastoma was 27.6 +/- 2.4 months (vs. 16.3 +/- 0.7, log-rank p < 0.001, hazard ratio 0.53, 95%CI 0.36-0.78, p < 0.01), and it was 59.5 +/- 15.9 for vaccinated astrocytoma grade 4 patients (vs. 19.8 +/- 2.5, log-rank p < 0.05, hazard ratio 0.18, 95%CI 0.05-0.62, p < 0.01). Furthermore, seven vaccinated patients (two IDH-1-mutated and five wild type) remain alive at the time of this report (overall survival 47.9 months, SD 21.1, range: 25.4-78.6 months since diagnosis; and 34.2 months since recurrence, range: 17.8 to 40.7, SD 21.3). We believe that the data reported here can foster the improvement of treatment protocols for high-grade gliomas based on cellular immunotherapy.
- Phylogeographic patterns of the yellow fever virus around the metropolitan region of Sao Paulo, Brazil, 2016-2019(2022) CUNHA, Marielton dos Passos; DUARTE-NETO, Amaro Nunes; POUR, Shahab Zaki; PEREIRA, Barbara Brito de Souza; HO, Yeh-Li; PERONDI, Beatriz; SZTAJNBOK, Jaques; ALVES, Venancio Avancini Ferreira; SILVA, Luiz Fernando Ferraz da; DOLHNIKOFF, Marisa; SALDIVA, Paulo Hilario Nascimento; ZANOTTO, Paolo Marinho de AndradeFrom 2016 to 2019, the largest outbreak caused by the Yellow Fever virus (YFV) in the 21(st) century in the Americas occurred in southeastern Brazil. A sylvatic cycle of transmission was reported near densely populated areas, such as the large metropolitan area of the city of Sao Paulo. Here, we describe the origin, spread, and movement of the YFV throughout the state of Sao Paulo. Whole-genome sequences were obtained from tissues of two patients who died due to severe yellow fever, during 2018-2019. Molecular analysis indicated that all analyzed tissues were positive for YFV RNA, with the liver being the organ with the highest amount of viral RNA. Sequence analysis indicates that genomes belonged to the South American genotype I and were grouped in the epidemic clade II, which includes sequences from the states of Goias, Minas Gerais, and Sao Paulo of previous years. The analysis of viral dispersion indicates that the outbreak originated in Goias at the end of 2014 and reached the state of Sao Paulo through the state of Minas Gerais after 2016. When the virus reached near the urban area, it spread towards both the east and south regions of the state, not establishing an urban transmission cycle in the metropolitan region of Sao Paulo. The virus that moved towards the east met with YFV coming from the south of the state of Rio de Janeiro, and the YFV that was carried to the south reached the Brazilian states located in the south region of the country.
- African genetic ancestry is associated with lower frequency of PNPLA3 G allele in non-alcoholic fatty liver in an admixed population(2022) CAVALCANTE, Lourianne Nascimento; PORTO, Jun; MAZO, Daniel; LONGATTO-FILHO, Adhemar; STEFANO, Jose Tadeu; LYRA, Andre Castro; CARRILHO, Flair Jose; REIS, Rui Manuel; ALVES, Venancio A. F.; SANYAL, Arun J.; OLIVEIRA, Claudia P.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 Ances-try 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 transplanta-tion. 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) genotyp-ing were performed by RT-PCR. Genetic ancestry was determined using 46 insertion-deletion AIM; a<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), Amerin-dian (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.(c) 2022 Published by Elsevier Espana, S.L.U. on behalf of Fundacion Clinica Medica Sur, A.C. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)