MARCELO LUIZ BALANCIN
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- Comprehensive analysis of immune, extracellular matrices and pathogens profile in lung granulomatosis of unexplained etiology(2018) SOUZA, Paola da Costa; DONDO, Patricia Suemi; SOUZA, Gabriela; LOPES, Deborah; MOSCARDI, Marcel; MARTINHO, Vinicius de Miranda; LOURENCO, Rodolfo Daniel de Mattos; PRIETO, Tabatha; BALANCIN, Marcelo Luiz; ASSATO, Aline Kawassaki; TEODORO, Walcy Rosolia; RODRIGUES, Silvia; LIMA, Mariana; CASTELLANO, Maria Vera; COLETTA, Ester; PARRA, Edwin Roger; CAPELOZZI, Vera LuizaThis study analyzed the type 1 and type 2 T helper (Th1/Th2) cytokines (including interleukins), immune cellular, matrix profile, and pathogens in granulomas with unexplained etiology compared to those with infectious and noninfectious etiology. Surgical lung biopsies from 108 patients were retrospectively reviewed. Histochemistry, immunohistochemistry, immunofluorescence, morphometry and polymerase chain reaction were used, respectively, to evaluate total collagen and elastin fibers, collagen I and III, immune cells, cytokines, matrix metalloproteinase-9, myofibroblasts, and multiple usual and unusual pathogens. No relevant polymerase chain reaction expression was found in unexplained granulomas. A significant difference was found between the absolute number of eosinophils, macrophages, and lymphocytes within granulomas compared to uninvolved lung tissue. Granulomas with unexplained etiology (UEG) presented increased number of eosinophils and high expression of interleukins (ILs) IL-4/IL-5 and transforming growth factor-beta. In sarcoidosis, CD4/CD8 cell number was significantly higher within and outside granulomas, respectively; the opposite was detected in hypersensitivity pneumonitis. Again, a significant difference was found between the high number of myofibroblasts and matrix metalloproteinase-9 in UEG, hypersensitivity pneumonitis, and sarcoidosis compared to granulomas of tuberculosis. Granulomas of paracoccidioisis exhibited increased type I collagen and elastic fibers. Th1 immune cellular profile was similar among granulomas with unexplained, infectious, and noninfectious etiology. In contrast, modulation of Th2 and matrix remodeling was associated with more fibroelastogenesis and scarring of lung tissue in UEG compared to infectious and noninfectious. We concluded that IL-4/IL-5 and transforming growth factor-beta might be used as surrogate markers of early fibrosis, reducing the need for genotyping, and promise therapeutic target in unexplained granulomas.
- Histomorphometric evaluation of the Ki-67 proliferation rate and CD34 microvascular and D2-40 lymphovascular densities drives the pulmonary typical carcinoid outcome(2018) VILHENA, Alyne Fonseca de; PEREIRA, Joao Carlos das Neves; PARRA, Edwin Roger; BALANCIN, Marcelo Luiz; AB'SABER, Alexandre; MARTINS, Vanessa; FARHAT, Cecilia; ABRANTES, Marcelo Militao; CAMPOS, Jose Ribas Milanez de; TEDDE, Miguel Lia; TAKAGAKI, Teresa; CAPELOZZI, Vera LuizaKi-67 has shown promise as a prognostic factor in pulmonary carcinoids. In this study, we sought to validate the importance of Ki-67 and study the relationships between Ki-67 and other stromal biomarkers of vascular density. We examined Ki-67, CD34, and D2-40 in tumor tissues from 128 patients with surgically excised typical carcinoid of the lung. We used immunohistochemistry and morphometry to evaluate the amount of tumor staining for cellular proliferation (Ki-67), microvascular density (CD34-MVD), and D2-40 lymphovascular density. The main outcome was overall survival, considered as life expectancy until death from metastasis. Specimens from patients with central tumors showed high CD34-MVD (P = .01), which was also significantly associated with a compromised surgical margin, lymph node metastasis, and clinical stage Ib. Equally significant was high D2-40 lymphovascular density in central specimens with a compromised surgical margin and lymph node metastasis. A high Ki-67 proliferation rate was significantly associated with tumors from patients with clinical stage IIb, IIIa, and IV disease. Multivariate Cox model analysis demonstrated that tumor location and stage, surgical margin, tumor size, and N stage were significantly related to survival time (P < .05). Quantitative staining of the tumor for Ki-67 and CD34-MVD served as prognostic factors (P < .05), which were more relevant than the surgical and pathological stage. Ki-67 greater than 5% and CD34-MVD greater than 7% staining comprise a subset of patients with higher death hazard; this outcome may harbor evidence for further prospective studies of target therapy after surgical resection.
- Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group(2020) AMGAD, Mohamed; STOVGAARD, Elisabeth Specht; BALSLEV, Eva; THAGAARD, Jeppe; CHEN, Weijie; DUDGEON, Sarah; SHARMA, Ashish; KERNER, Jennifer K.; DENKERT, Carsten; YUAN, Yinyin; ABDULJABBAR, Khalid; WIENERT, Stephan; SAVAS, Peter; VOORWERK, Leonie; BECK, Andrew H.; MADABHUSHI, Anant; HARTMAN, Johan; SEBASTIAN, Manu M.; HORLINGS, Hugo M.; HUDECEK, Jan; CIOMPI, Francesco; MOORE, David A.; SINGH, Rajendra; ROBLIN, Elvire; BALANCIN, Marcelo Luiz; MATHIEU, Marie-Christine; LENNERZ, Jochen K.; KIRTANI, Pawan; CHEN, I-Chun; BRAYBROOKE, Jeremy P.; PRUNERI, Giancarlo; DEMARIA, Sandra; ADAMS, Sylvia; SCHNITT, Stuart J.; LAKHANI, Sunil R.; ROJO, Federico; COMERMA, Laura; BADVE, Sunil S.; KHOJASTEH, Mehrnoush; SYMMANS, W. Fraser; SOTIRIOU, Christos; GONZALEZ-ERICSSON, Paula; POGUE-GEILE, Katherine L.; KIM, Rim S.; RIMM, David L.; VIALE, Giuseppe; HEWITT, Stephen M.; BARTLETT, John M. S.; PENAULT-LLORCA, Frederique; GOEL, Shom; LIEN, Huang-Chun; LOIBL, Sibylle; KOS, Zuzana; LOI, Sherene; HANNA, Matthew G.; MICHIELS, Stefan; KOK, Marleen; NIELSEN, Torsten O.; LAZAR, Alexander J.; BAGO-HORVATH, Zsuzsanna; KOOREMAN, Loes F. S.; LAAK, Jeroen A. W. M. van der; SALTZ, Joel; GALLAS, Brandon D.; KURKURE, Uday; BARNES, Michael; SALGADO, Roberto; COOPER, Lee A. D.Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.
- The path to a better biomarker: application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice(2020) I, Paula Gonzalez-Ericsson; STOVGAARD, Elisabeth S.; SUA, Luz F.; REISENBICHLER, Emily; KOS, Zuzana; CARTER, Jodi M.; MICHIELS, Stefan; QUESNE, John Le; NIELSEN, Torsten O.; LAENKHOLM, Anne-Vibeke; FOX, Stephen B.; ADAM, Julien; BARTLETT, John M. S.; RIMM, David L.; QUINN, Cecily; PEETERS, Dieter; V, Maria Dieci; VINCENT-SALOMON, Anne; CREE, Ian; I, Akira Hida; BALKO, Justin M.; HAYNES, Harry R.; FRAHM, Isabel; ACOSTA-HAAB, Gabriela; BALANCIN, Marcelo; BELLOLIO, Enrique; YANG, Wentao; KIRTANI, Pawan; SUGIE, Tomoharu; EHINGER, Anna; CASTANEDA, Carlos A.; KOK, Marleen; MCARTHUR, Heather; SIZIOPIKOU, Kalliopi; BADVE, Sunil; FINEBERG, Susan; GOWN, Allen; VIALE, Giuseppe; SCHNITT, Stuart J.; PRUNERI, Giancarlo; PENAULT-LLORCA, Frederique; HEWITT, Stephen; THOMPSON, E. Aubrey; ALLISON, Kimberly H.; SYMMANS, William F.; BELLIZZI, Andrew M.; BROGI, Edi; MOORE, David A.; LARSIMONT, Denis; DILLON, Deborah A.; LAZAR, Alexander; LIEN, Huangchun; GOETZ, Matthew P.; BROECKX, Glenn; BAIRI, Khalid El; HARBECK, Nadia; CIMINO-MATHEWS, Ashley; SOTIRIOU, Christos; ADAMS, Sylvia; LIU, Shi-Wei; LOIBL, Sibylle; CHEN, I-Chun; LAKHANI, Sunil R.; JUCO, Jonathan W.; DENKERT, Carsten; BLACKLEY, Elizabeth F.; DEMARIA, Sandra; LEON-FERRE, Roberto; GLUZ, Oleg; ZARDAVAS, Dimitrios; EMANCIPATOR, Kenneth; ELY, Scott; LOI, Sherene; SALGADO, Roberto; SANDERS, MelindaImmune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying >= 1% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin-stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. (c) 2020 Pathological Society of Great Britain and Ireland.
- COVID-19 bimodal clinical and pathological phenotypes(2022) BATAH, Sabrina S.; BENATTI, Maira N.; SIYUAN, Li; TELINI, Wagner M.; BARBOZA, Jamile O.; MENEZES, Marcelo B.; NADAI, Tales R.; SA, Keyla S. G.; VASWANI, Chirag M.; GUPTA, Sahil; ZAMBONI, Dario S.; WADA, Danilo T.; CALADO, Rodrigo T.; OLIVEIRA, Rene D. R.; LOUZADA-JUNIOR, Paulo; AUXILIADORA-MARTINS, Maria; VERAS, Flavio P.; CUNHA, Larissa D.; CUNHA, Thiago M.; LUPPINO-ASSAD, Rodrigo; BALANCIN, Marcelo L.; MORAIS, Sirlei S.; MARTINS, Ronaldo B.; ARRUDA, Eurico; CHAHUD, Fernando; SANTOS, Marcel Koenigkam; CETLIN, Andrea A.; CUNHA, Fernando Q.; SANTOS, Claudia dos; CAPELOZZI, Vera L.; FUKUOKA, Junya; ACHCAR, Rosane Duarte; FABRO, Alexandre T.
conferenceObject Adrenal Cystic Lesions of Lymphatic Origin: A Clinical and Pathological Study of 6 New Cases and Systematic Literature Review(2020) MARQUES-PIUBELLI, Mario; POMA-GONZALEZ, Eloiza; BALANCIN, Marcelo; GONCALVES, Victor; BOTELHO, Maria Luiza; FRAGOSO, Maria; ZERBINI, Maria- The Immunological Landscape of M1 and M2 Macrophages and Their Spatial Distribution in Patients with Malignant Pleural Mesothelioma(2023) LABERIANO-FERNANDEZ, Caddie; BALDAVIRA, Camila Machado; MACHADO-RUGOLO, Juliana; TAMEGNON, Auriole; PANDURENGAN, Renganayaki Krishna; AB'SABER, Alexandre Muxfeldt; BALANCIN, Marcelo Luiz; TAKAGAKI, Teresa Yae; NAGAI, Maria Aparecida; CAPELOZZI, Vera Luiza; PARRA, Edwin RogerSimple Summary Identifying biomarkers to guide immunotherapy regimens remains an unmet clinical need in malignant pleural mesothelioma. A potential source of such markers is tumor-associated macrophages (TAMs), which contribute to the immunosuppressive microenvironment of mesothelioma. By examining distinct subsets of pleural macrophages to identify their gene signatures and protein expression, we found that TAMs preferentially contribute to M2a and M2b phenotypes, and M2a, M2b, and M2c more specifically contributed to immune tolerance. CD206, ARG1, CD274, CD163, and MRP8-14 are potential therapeutic targets in this disease.Abstract Background: Several tumor-associated macrophages (TAMs) have shown promise as prognosticators in cancer. Our aim was to validate the importance of TAMs in malignant pleural mesothelioma (MPM) using a two-stage design. Methods: We explored The Cancer Genome Atlas (TCGA-MESO) to select immune-relevant macrophage genes in MPM, including M1/M2 markers, as a discovery cohort. This computational cohort was used to create a multiplex immunofluorescence panel. Moreover, a cohort of 68 samples of MPM in paraffin blocks was used to validate the macrophage phenotypes and the co-localization and spatial distribution of these immune cells within the TME and the stromal or tumor compartments. Results: The discovery cohort revealed six immune-relevant macrophage genes (CD68, CD86, CD163, CD206, ARG1, CD274), and complementary genes were differentially expressed by M1 and M2 phenotypes with distinct roles in the tumor microenvironment and were associated with the prognosis. In addition, immune-suppressed MPMs with increased enrichment of CD68, CD86, and CD163 genes and high densities of M2 macrophages expressing CD163 and CD206 proteins were associated with worse overall survival (OS). Interestingly, below-median distances from malignant cells to specific M2a and M2c macrophages were associated with worse OS, suggesting an M2 macrophage-driven suppressive component in these tumors. Conclusions: The interactions between TAMs in situ and, particularly, CD206+ macrophages are highly relevant to patient outcomes. High-resolution technology is important for identifying the roles of macrophage populations in tissue specimens and identifying potential therapeutic candidates in MPM.
- Incorporation of TILs in daily breast cancer care: how much evidence can we bear?(2022) LAENKHOLM, Anne-Vibeke; CALLAGY, Grace; BALANCIN, Marcelo; BARTLETT, John M. S.; SOTIRIOU, Christos; MARCHIO, Caterina; KOK, Marleen; ANJOS, Carlos Henrique Dos; SALGADO, RobertoOne of the most important developments in the breast cancer field has been an improved understanding of prognostic and predictive biomarkers, of which TILs are increasingly gaining importance. The evaluation of TILs by light microscopy on a H&E-stained section is workable in a daily practice setting. Reproducibility of reporting TILs is good, but heterogeneity is a cause of variation. TILs provide clinicians with important prognostic information for patients with TNBC, as early-stage TNBC with high TILs have > 98% 5-year survival and TILs predict benefit to immunotherapy. Importantly, while TILs do not have level of evidence IA, TILs should be used as a prognostic factor with caution and with other accepted prognostic variables, such as tumour size and lymph node status, to inform clinicians and patients on their treatment options. A framework on how to use the TILs in daily practice is proposed, including a co-assessment with PD-L1 for its predictive role to immunotherapy.
conferenceObject Adrenal Cystic Lesions of Lymphatic Origin: A Clinical and Pathological Study of 6 New Cases and Systematic Literature Review(2020) MARQUES-PIUBELLI, Mario; POMA-GONZALEZ, Eloiza; BALANCIN, Marcelo; GONCALVES, Victor; BOTELHO, Maria Luiza; FRAGOSO, Maria; ZERBINI, Maria- The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group(2021) BAIRI, Khalid El; HAYNES, Harry R.; BLACKLEY, Elizabeth; FINEBERG, Susan; SHEAR, Jeffrey; TURNER, Sophia; FREITAS, Juliana Ribeiro de; SUR, Daniel; AMENDOLA, Luis Claudio; GHARIB, Masoumeh; KALLALA, Amine; ARUN, Indu; AZMOUDEH-ARDALAN, Farid; FUJIMOTO, Luciana; SUA, Luz F.; LIU, Shi-Wei; LIEN, Huang-Chun; KIRTANI, Pawan; BALANCIN, Marcelo; ATTAR, Hicham El; GULERIA, Prerna; YANG, Wenxian; SHASH, Emad; CHEN, I-Chun; BAUTISTA, Veronica; MOURA, Jose Fernando Do Prado; RAPOPORT, Bernardo L.; CASTANEDA, Carlos; SPENGLER, Eunice; ACOSTA-HAAB, Gabriela; FRAHM, Isabel; SANCHEZ, Joselyn; CASTILLO, Miluska; BOUCHMAA, Najat; ZIN, Reena R. Md; SHUI, Ruohong; ONYUMA, Timothy; YANG, Wentao; HUSAIN, Zaheed; WILLARD-GALLO, Karen; COOSEMANS, An; PEREZ, Edith A.; PROVENZANO, Elena; ERICSSON, Paula Gonzalez; RICHARDET, Eduardo; MEHROTRA, Ravi; SARANCONE, Sandra; EHINGER, Anna; RIMM, David L.; BARTLETT, John M. S.; VIALE, Giuseppe; DENKERT, Carsten; HIDA, Akira I.; SOTIRIOU, Christos; LOIBL, Sibylle; HEWITT, Stephen M.; BADVE, Sunil; SYMMANS, William Fraser; KIM, Rim S.; PRUNERI, Giancarlo; GOEL, Shom; FRANCIS, Prudence A.; INURRIGARRO, Gloria; YAMAGUCHI, Rin; GARCIA-RIVELLO, Hernan; HORLINGS, Hugo; AFQIR, Said; SALGADO, Roberto; ADAMS, Sylvia; KOK, Marleen; DIECI, Maria Vittoria; MICHIELS, Stefan; DEMARIA, Sandra; LOI, ShereneThe advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.