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
35 resultados
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conferenceObject Integrative Molecular Profiling of Non-Alcoholic Steatohepatitis-Related Hepatocellular Carcinoma(2018) TORRECILLA, Sara; PINYOL, Roser; WEI-QIANG, Leow; WANG, Huan; MOEINI, Agrin; MONTIRONI, Carla; BASSAGANYAS, Laia; ANDREU-OLLER, Carmen; OLIVEIRA, Claudia P. M. S.; ALVES, Venancio A. F.; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; BOFFETTA, Paolo; DUFOUR, Jean-Francois; THUNG, Swan N.; UZILOV, Andrew; CARRILHO, Flair Jose; CHANG, Charissa Y.; SIA, Daniela; LLOVET, Josep M.- Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features (NIFTP): Achieving Better Agreement By Refining Diagnostic Criteria(2018) ALVES, Venancio A. F.; KAKUDO, Kennichi; LIVOLSI, Virginia; LLOYD, Ricardo V.; NIKIFOROV, Yuri E.; NOSE, Vania; PAPOTTI, Mauro; THOMPSON, Lester D. R.
- A phenotypical map of disseminated hepatocellular carcinoma suggests clonal constraints in metastatic sites(2019) MARTINS-FILHO, Sebastiao N.; ALVES, Venancio A. F.; WAKAMATSU, Alda; MAEDA, Miho; CRAIG, Amanda J.; ASSATO, Aline K.; VILLACORTA-MARTIN, Carlos; D'AVOLA, Delia; LABGAA, Ismail; CARRILHO, Flair J.; THUNG, Swan N.; VILLANUEVA, AugustoAims Access to tissue in patients with hepatocellular carcinoma (HCC) is limited compared to other malignancies, particularly at advanced stages. This has precluded a thorough characterisation of molecular drivers of HCC dissemination, particularly in relation to distant metastases. Biomarker assessment is restricted to early stages, and paired primary-metastatic comparisons between samples from the same patient are difficult. Methods and results We report the evaluation of 88 patients with HCC who underwent autopsy, including multiregional sampling of primary and metastatic sites totalling 230 nodules analysed. The study included morphological assessment, immunohistochemistry and mutation status of the TERT promoter, the most frequently mutated gene in HCC. We confirm a strong predilection of HCC for lung dissemination, including subclinical micrometastases (unrecognised during imaging and macroscopic examinations) in 30% of patients with disseminated disease. Size of dominant tumour nodule; multinodularity; macrovascular invasion; high histological, nuclear and architectural grades; and cellular crowding were associated with the presence of extrahepatic metastasis. Among the immunohistochemistry markers tested, metastatic nodules had significantly higher K19 and EpCAM expression than primary liver tumours. Morphological and immunohistochemical features showed that metastatic HCC could be traced back to the primary tumour, sometimes to a specific hepatic nodule. Conclusions This study suggests limited heterogeneity in metastatic sites compared to primary tumour sites.
- Rebmab200, a Humanized Monoclonal Antibody Targeting the Sodium Phosphate Transporter NaPi2b Displays Strong Immune Mediated Cytotoxicity against Cancer: A Novel Reagent for Targeted Antibody Therapy of Cancer(2013) SANTOS, Mariana Lopes dos; YEDA, Fernanda Perez; TSURUTA, Lilian Rumi; HORTA, Bruno Brasil; PIMENTA JR., Alecio A.; DEGAKI, Theri Leica; SOARES, Ibere C.; TUMA, Maria Carolina; OKAMOTO, Oswaldo Keith; ALVES, Venancio A. F.; OLD, Lloyd J.; RITTER, Gerd; MORO, Ana MariaNaPi2b, a sodium-dependent phosphate transporter, is highly expressed in ovarian carcinomas and is recognized by the murine monoclonal antibody MX35. The antibody had shown excellent targeting to ovarian cancer in several early phase clinical trials but being murine the antibody's full therapeutic potential could not be explored. To overcome this impediment we developed a humanized antibody version named Rebmab200, expressed in human PER.C6 (R) cells and cloned by limiting dilution. In order to select a clone with high therapeutic potential clones were characterized using a series of physicochemical assays, flow cytometry, real-time surface plasmon resonance, glycosylation analyses, immunohistochemistry, antibody-dependent cell-mediated cytotoxicity, complement-dependent-cytotoxicity assays and quantitative PCR. Comparative analyses of Rebmab200 and MX35 monoclonal antibodies demonstrated that the two antibodies had similar specificity for NaPi2b by flow cytometry with a panel of 30 cell lines and maintained similar kinetic parameters. Robust and high producer cell clones potentially suitable for use in manufacturing were obtained. Rebmab200 antibodies were assessed by immunohistochemistry using a large panel of tissues including human carcinomas of ovarian, lung, kidney and breast origin. An assessment of its binding towards 33 normal human organs was performed as well. Rebmab200 showed selected strong reactivity with the tested tumor types but little or no reactivity with the normal tissues tested confirming its potential for targeted therapeutics strategies. The remarkable cytotoxicity shown by Rebmab200 in OVCAR-3 cells is a significant addition to the traits of stability and productivity displayed by the top clones of Rebmab200. Antibody-dependent cell-mediated toxicity functionality was confirmed in repeated assays using cancer cell lines derived from ovary, kidney and lung as targets. To explore use of this antibody in clinical trials, GMP production of Rebmab200 has been initiated. As the next step of development, Phase I clinical trials are now planned for translation of Rebmab200 into the clinic.
- Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis(2021) PINYOL, Roser; TORRECILLA, Sara; WANG, Huan; MONTIRONI, Carla; PIQUE-GILI, Marta; TORRES-MARTIN, Miguel; WEI-QIANG, Leow; WILLOUGHBY, Catherine E.; RAMADORI, Pierluigi; ANDREU-OLLER, Carmen; TAIK, Patricia; LEE, Youngmin A.; MOEINI, Agrin; PEIX, Judit; FAURE-DUPUY, Suzanne; RIEDL, Tobias; SCHUEHLE, Svenja; OLIVEIRA, Claudia P.; ALVES, Venancio A.; BOFFETTA, Paolo; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; DUFOUR, Jean-Francois; THUNG, Swan N.; REEVES, Helen L.; CARRILHO, Flair J.; CHANG, Charissa; V, Andrew Uzilov; HEIKENWALDER, Mathias; SANYAL, Arun; FRIEDMAN, Scott L.; SIA, Daniela; LLOVET, Josep M.Background and Aims: Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) is increasing globally, but its molecular features are not well defined. We aimed to identify unique molecular traits characterising NASH-HCC compared to other HCC aetiologies. Methods: We collected 80 NASH-HCC and 125 NASH samples from 5 institutions. Expression array (n = 53 NASH-HCC; n = 74 NASH) and whole exome sequencing (n = 52 NASH-HCC) data were compared to HCCs of other aetiologies (n = 184). Three NASH-HCC mouse models were analysed by RNA-seq/expression-array (n = 20). Activin A receptor type 2A (ACVR2A) was silenced in HCC cells and proliferation assessed by colorimetric and colony formation assays. Results: Mutational profiling of NASH-HCC tumours revealed TERT promoter (56%), CTNNB1 (28%), TP53 (18%) and ACVR2A (10%) as the most frequently mutated genes. ACVR2A mutation rates were higher in NASH-HCC than in other HCC aetiologies (10% vs. 3%, p <0.05). In vitro, ACVR2A silencing prompted a significant increase in cell proliferation in HCC cells. We identified a novel mutational signature (MutSig-NASH-HCC) significantly associated with NASH-HCC (16% vs. 2% in viral/alcohol-HCC, p = 0.03). Tumour mutational burden was higher in non-cirrhotic than in cirrhotic NASH-HCCs (1.45 vs. 0.94 mutations/megabase; p <0.0017). Compared to other aetiologies of HCC, NASH-HCCs were enriched in bile and fatty acid signalling, oxidative stress and inflammation, and presented a higher fraction of Wnt/ TGF-beta proliferation subclass tumours (42% vs. 26%, p = 0.01) and a lower prevalence of the CTNNB1 subclass. Compared to other aetiologies, NASH-HCC showed a significantly higher prevalence of an immunosuppressive cancer field. In 3 murine models of NASH-HCC, key features of human NASH-HCC were preserved. Conclusions: NASH-HCCs display unique molecular features including higher rates of ACVR2A mutations and the presence of a newly identified mutational signature. Lay summary: The prevalence of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH) is increasing globally, but its molecular traits are not well characterised. In this study, we uncovered higher rates of ACVR2A mutations (10%) - a potential tumour suppressor - and the presence of a novel mutational signature that characterises NASH-related HCC.
- Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma A Paradigm Shift to Reduce Overtreatment of Indolent Tumors(2016) NIKIFOROV, Yuri E.; SEETHALA, Raja R.; TALLINI, Giovanni; BALOCH, Zubair W.; BASOLO, Fulvio; THOMPSON, Lester D. R.; BARLETTA, Justine A.; WENIG, Bruce M.; GHUZLAN, Abir Al; KAKUDO, Kennichi; GIORDANO, Thomas J.; ALVES, Venancio A.; KHANAFSHAR, Elham; ASA, Sylvia L.; EL-NAGGAR, Adel K.; GOODING, William E.; HODAK, Steven P.; LLOYD, Ricardo V.; MAYTAL, Guy; METE, Ozgur; NIKIFOROVA, Marina N.; NOSE, Vania; PAPOTTI, Mauro; POLLER, David N.; SADOW, Peter M.; TISCHLER, Arthur S.; TUTTLE, Michael; WALL, Kathryn B.; LIVOLSI, Virginia A.; RANDOLPH, Gregory W.; GHOSSEIN, Ronald A.IMPORTANCE Although growing evidence points to highly indolent behavior of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), most patients with EFVPTC are treated as having conventional thyroid cancer. OBJECTIVE To evaluate clinical outcomes, refine diagnostic criteria, and develop a nomenclature that appropriately reflects the biological and clinical characteristics of EFVPTC. DESIGN, SETTING, AND PARTICIPANTS International, multidisciplinary, retrospective study of patients with thyroid nodules diagnosed as EFVPTC, including 109 patients with noninvasive EFVPTC observed for 10 to 26 years and 101 patients with invasive EFVPTC observed for 1 to 18 years. Review of digitized histologic slides collected at 13 sites in 5 countries by 24 thyroid pathologists from 7 countries. A series of teleconferences and a face-to-face conference were used to establish consensus diagnostic criteria and develop new nomenclature. MAIN OUTCOMES AND MEASURES Frequency of adverse outcomes, including death from disease, distant or locoregional metastases, and structural or biochemical recurrence, in patients with noninvasive and invasive EFVPTC diagnosed on the basis of a set of reproducible histopathologic criteria. RESULTS Consensus diagnostic criteria for EFVPTC were developed by 24 thyroid pathologists. All of the 109 patients with noninvasive EFVPTC (67 treated with only lobectomy, none received radioactive iodine ablation) were alive with no evidence of disease at final follow-up (median [range], 13 [10-26] years). An adverse event was seen in 12 of 101 (12%) of the cases of invasive EFVPTC, including 5 patients developing distant metastases, 2 of whom died of disease. Based on the outcome information for noninvasive EFVPTC, the name ""noninvasive follicular thyroid neoplasm with papillary-like nuclear features"" (NIFTP) was adopted. A simplified diagnostic nuclear scoring scheme was developed and validated, yielding a sensitivity of 98.6%(95% CI, 96.3%-99.4%), specificity of 90.1% (95% CI, 86.0%-93.1%), and overall classification accuracy of 94.3%(95% CI, 92.1%-96.0%) for NIFTP. CONCLUSIONS AND RELEVANCE Thyroid tumors currently diagnosed as noninvasive EFVPTC have a very low risk of adverse outcome and should be termed NIFTP. This reclassification will affect a large population of patients worldwide and result in a significant reduction in psychological and clinical consequences associated with the diagnosis of cancer.
- Prognostic significance of poorly differentiated clusters and tumor budding in colorectal liver metastases(2018) FONSECA, Gilton M.; MELLO, Evandro S. de; FARAJ, Sheila F.; KRUGER, Jaime A. P.; COELHO, Fabricio F.; JEISMANN, Vagner B.; LUPINACCI, Renato M.; CECCONELLO, Ivan; ALVES, Venancio A. F.; PAWLIK, Timothy M.; HERMAN, PauloBackgroundHistomorphological features have been described as prognostic factors after resection of colorectal liver metastases (CLM). The objectives of this study were to assess the prognostic significance of tumor budding (TB) and poorly differentiated clusters (PDC) among CLM, and their association with other prognostic factors. MethodsWe evaluated 229 patients who underwent a first resection of CLM. Slides stained by HE were assessed for TB, PDC, tumor border pattern, peritumoral pseudocapsule, peritumoral, and intratumoral inflammatory infiltrate. Lymphatic and portal invasion were evaluated through D2-40 and CD34 antibody. ResultsFactors independently associated with poor overall survival were nodules>4 (P=0.002), presence of PDC G3 (P=0.007), portal invasion (P=0.005), and absence of tumor pseudocapsule (P=0.006). Factors independently associated with disease-free survival included number of nodules>4 (P<0.001), presence of PDC G3 (P=0.005), infiltrative border (P=0.031), portal invasion (P=0.006), and absent/mild peritumoral inflammatory infiltrate (P=0.002). PDC and TB were also associated with histological factors, as portal invasion (TB), peritumoral inflammatory infiltration (PDC), infiltrative border, and absence of tumor pseudocapsule (TB and PDC). ConclusionsThis is the first study demonstrating PDC as a prognostic factor in CLM. TB was also a prognostic factor, but it was not an independent predictor of survival.
- Distinctive molecular traits of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis(2019) TORRECILLA, Sara; PINYOL, Roser; WANG, Huan; MONTIRONI, Carla; ANDREU-OLLER, Carmen; LEOW, Wei Qiang; MOEINI, Agrin; OLIVEIRA, Claudia; ALVES, Venancio Avancini Ferreira; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; BOFFETTA, Paolo; DUFOUR, Jean-Francois; THUNG, Swan N.; UZILOV, Andrew; CARRILHO, Flair Jose; CHANG, Charissa; SIA, Daniela; LLOVET, Josep M.
conferenceObject MOLECULAR AND MUTATIONAL LANDSCAPE OF HEPATOCELLULAR CARCINOMA (HCC) RELATED TO NONALCOHOLIC STEATOHEPATITIS (NASH)(2020) PIQUE-GILI, Marta; PINYOL, Roser; TORRECILLA, Sara; WANG, Huan; MONTIRONI, Carla; RAMADORI, Pierluigi; WILLOUGHBY, Catherine E.; ANDREU-OLLER, Carmen; TORRES-MARTIN, Miguel; LEOW, Wei-Qiang; MOEINI, Agrin; TAIK, Patricia; GALLOFRE, Judit Peix; OLIVEIRA, Claudia P. M. S.; ALVES, Venancio A. F.; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; BOFFETTA, Paolo; DUFOUR, Jean-Francois; THUNG, Swan N.; REEVES, Helen; UZILOV, Andrew; CARRILHO, Flair J.; CHANG, Charissa Y.; HEIKENWAELDER, Mathias; SANYAL, Arun J.; FRIEDMAN, Scott L.; SIA, Daniela; LLOVET, Josep M.- Molecular characterisation of hepatocellular carcinoma in patients with non-alcoholic steatohepatitis (vol 75, pg 865, 2021)(2021) PINYOL, Roser; TORRECILLA, Sara; WANG, Huan; MONTIRONI, Carla; PIQUE-GILI, Marta; TORRES-MARTIN, Miguel; WEI-QIANG, Leow; WILLOUGHBY, Catherine E.; RAMADORI, Pierluigi; ANDREU-OLLER, Carmen; TAIK, Patricia; LEE, Youngmin A.; MOEINI, Agrin; PEIX, Judit; FAURE-DUPUY, Suzanne; RIEDL, Tobias; SCHUEHLE, Svenja; OLIVEIRA, Claudia P.; ALVES, Venancio A.; BOFFETTA, Paolo; LACHENMAYER, Anja; ROESSLER, Stephanie; MINGUEZ, Beatriz; SCHIRMACHER, Peter; DUFOUR, Jean-Francois; THUNG, Swan N.; REEVES, Helen L.; CARRILHO, Flair J.; CHANG, Charissa; UZILOV, Andrew V.; HEIKENWALDER, Mathias; SANYAL, Arun; FRIEDMAN, Scott L.; SIA, Daniela; LLOVET, Josep M.