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1. Immunological and molecular features of the tumor microenvironment of long-term survivors of ovarian cancer

Author

Nelson, Brad H, Hamilton, Phineas T, Phung, Minh Tung, Milne, Katy, Harris, Bronwyn, Thornton, Shelby, Stevens, Donald LI, Kalaria, Shreena, Singh, Karanvir, Laumont, Céline M, Moss, Elena, Alimujiang, Aliya, Meagher, Nicola S, Bolithon, Adelyn, Fereday, Sian, Kennedy, Catherine J, Hendley, Joy, Ariyaratne, Dinuka, Alsop, Kathryn, Traficante, Nadia, Goode, Ellen L, Karnezis, Anthony N, Shen, Hui, Richardson, Jean, Deurloo, Cindy McKinnon, Chase, Anne, Grout, Bronwyn, Doherty, Jennifer A, Harris, Holly R, Cushing-Haugen, Kara L, Anglesio, Michael S, Heinze, Karolin, Huntsman, David, Talhouk, Aline, Hanley, Gillian E, Alsop, Jennifer, Jimenez-Linan, Mercedes, Pharoah, Paul DP, Boros, Jessica, Brand, Alison H, Harnett, Paul R, Sharma, Raghwa, Hecht, Jonathan L, Sasamoto, Naoko, Terry, Kathryn L, Karlan, Beth Y, Lester, Jenny, Carney, Michael E, Goodman, Marc T, Hernandez, Brenda Y, Wilkens, Lynne R, Behrens, Sabine, Fortner, Renée Turzanski, Fasching, Peter A, Bisinotto, Christiani, dos Reis, Francisco José Candido, Ghatage, Prafull, Köbel, Martin, Elishaev, Esther, Modugno, Francesmary, Cook, Linda S, Le, Nhu D, Gentry-Maharaj, Aleksandra, Menon, Usha, García, María J, Rodriguez-Antona, Cristina, Farrington, Kyo M, Kelemen, Linda E, Kommoss, Stefan, Staebler, Annette, Garsed, Dale W, Brenton, James D, Piskorz, Anna M, Bowtell, David DL, DeFazio, Anna, Ramus, Susan J, Pike, Malcolm C, and Pearce, Celeste Leigh

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Cancer, Women's Health, Ovarian Cancer, Rare Diseases, Orphan Drug, Humans, Female, Tumor Microenvironment, Ovarian Neoplasms, Cancer Survivors, Middle Aged, Aged, CD8-Positive T-Lymphocytes, Neoplasm Proteins, Adult, Cellular immune response, Epidemiology, Oncology, Medical and Health Sciences, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

BACKGROUNDDespite an overall poor prognosis, about 15% of patients with advanced-stage tubo-ovarian high-grade serous carcinoma (HGSC) survive 10 or more years after standard treatment.METHODSWe evaluated the tumor microenvironment of this exceptional, understudied group using a large international cohort enriched for long-term survivors (LTS; 10+ years; n = 374) compared with mid-term (MTS; 5-7.99 years; n = 433) and short-term survivors (STS; 2-4.99 years; n = 416). Primary tumor samples were immunostained and scored for intraepithelial and intrastromal densities of 10 immune-cell subsets (including T cells, B cells, plasma cells, myeloid cells, PD-1+ cells, and PD-L1+ cells) and epithelial content.RESULTSPositive associations with LTS compared with STS were seen for 9 of 10 immune-cell subsets. In particular, the combination of intraepithelial CD8+ T cells and intrastromal B cells showed near 5-fold increased odds of LTS compared with STS. All of these associations were stronger in tumors with high epithelial content and/or the C4/Differentiated molecular subtype, despite immune-cell densities generally being higher in tumors with low epithelial content and/or the C2/Immunoreactive molecular subtype.CONCLUSIONThe tumor microenvironment of HGSC LTS is distinguished by the intersection of T and B cell coinfiltration, high epithelial content, and C4/differentiated molecular subtype, features which may inspire new approaches to immunotherapy.FUNDINGOvarian Cancer Research Program (OCRP) of the Congressionally Directed Medical Research Program (CDMRP), U.S. Department of Defense (DOD); American Cancer Society; BC Cancer Foundation; Canada's Networks of Centres of Excellence; Canadian Cancer Society; Canadian Institutes of Health Research; Cancer Councils of New South Wales, Victoria, Queensland, South Australia, and Tasmania, Cancer Foundation of Western Australia; Cancer Institute NSW; Cancer Research UK; Deutsche Forschungsgesellschaft; ELAN Funds of the University of Erlangen-Nuremberg; Fred C. and Katherine B. Andersen Foundation; Genome BC; German Cancer Research Center; German Federal Ministry of Education and Research, Programme of Clinical Biomedical Research; Instituto de Salud Carlos III; Mayo Foundation; Minnesota Ovarian Cancer Alliance; Ministerio de Economía y Competitividad; Medical Research Council (MRC); National Center for Advancing Translational Sciences; National Health and Medical Research Council of Australia (NHMRC); Ovarian Cancer Australia; Peter MacCallum Foundation; Sydney West Translational Cancer Research Centre; Terry Fox Research Institute; The Eve Appeal (The Oak Foundation); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge; University of Pittsburgh School of Medicine; U.S. National Cancer Institute of the National Institutes of Health; VGH & UBC Hospital Foundation; Victorian Cancer Agency.

Published
2024

3. p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study

Author

Köbel, Martin, Kang, Eun‐Young, Weir, Ashley, Rambau, Peter F, Lee, Cheng‐Han, Nelson, Gregg S, Ghatage, Prafull, Meagher, Nicola S, Riggan, Marjorie J, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Bisinotto, Christiani, Boisen, Michelle, Boros, Jessica, Brand, Alison H, Brooks‐Wilson, Angela, Carney, Michael E, Coulson, Penny, Courtney‐Brooks, Madeleine, Cushing‐Haugen, Kara L, Cybulski, Cezary, Deen, Suha, El‐Bahrawy, Mona A, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Group, AOCS, Fischer, Anna, Gayther, Simon A, Barquin‐Garcia, Arantzazu, Gentry‐Maharaj, Aleksandra, Gilks, C Blake, Gronwald, Helena, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartkopf, Andreas D, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Huang, Yajue, Jakubowska, Anna, Jimenez‐Linan, Mercedes, Jones, Michael E, Kennedy, Catherine J, Kluz, Tomasz, Koziak, Jennifer M, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Longacre, Teri A, Lycke, Maria, Mateoiu, Constantina, McCauley, Bryan M, McGuire, Valerie, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Paz‐Ares, Luis, Ramón y Cajal, Teresa, Rothstein, Joseph H, Ruebner, Matthias, Schoemaker, Minouk J, Shah, Mitul, Sharma, Raghwa, Sherman, Mark E, Shvetsov, Yurii B, Singh, Naveena, Steed, Helen, Storr, Sarah J, Talhouk, Aline, Traficante, Nadia, Wang, Chen, Whittemore, Alice S, Widschwendter, Martin, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, dos Reis, Francisco J Candido, Campbell, Ian, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, Fortner, Renée T, García, María J, Goodman, Marc T, Goode, Ellen L, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kelemen, Linda E, Kommoss, Stefan, Le, Nhu D, and Martin, Stewart G

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Women's Health, Rare Diseases, Ovarian Cancer, Cancer, Clinical Research, 2.1 Biological and endogenous factors, Humans, Female, Tumor Suppressor Protein p53, Ovarian Neoplasms, Carcinoma, Ovarian Epithelial, Carcinoma, Endometrioid, ovarian cancer, high-grade serous carcinoma, endometrioid, clear cell, TP53, p53, prognosis, AOCS Group, Clinical sciences
Abstract

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

Published
2023

4. Increased FOXJ1 protein expression is associated with improved overall survival in high-grade serous ovarian carcinoma: an Ovarian Tumor Tissue Analysis Consortium Study

Author

Weir, Ashley, Kang, Eun-Young, Meagher, Nicola S, Nelson, Gregg S, Ghatage, Prafull, Lee, Cheng-Han, Riggan, Marjorie J, Gentry-Maharaj, Aleksandra, Ryan, Andy, Singh, Naveena, Widschwendter, Martin, Alsop, Jennifer, Anglesio, Michael S, Beckmann, Matthias W, Berger, Jessica, Bisinotto, Christiani, Boros, Jessica, Brand, Alison H, Brenton, James D, Brooks-Wilson, Angela, Carney, Michael E, Cunningham, Julie M, Cushing-Haugen, Kara L, Cybulski, Cezary, Elishaev, Esther, Erber, Ramona, Fereday, Sian, Fischer, Anna, Paz-Ares, Luis, Gayarre, Javier, Gilks, Blake C, Grube, Marcel, Harnett, Paul R, Harris, Holly R, Hartmann, Arndt, Hein, Alexander, Hendley, Joy, Hernandez, Brenda Y, Heublein, Sabine, Huang, Yajue, Huzarski, Tomasz, Jakubowska, Anna, Jimenez-Linan, Mercedes, Kennedy, Catherine J, Kommoss, Felix KF, Koziak, Jennifer M, Kraemer, Bernhard, Le, Nhu D, Lesnock, Jaime, Lester, Jenny, Lubiński, Jan, Menkiszak, Janusz, Ney, Britta, Olawaiye, Alexander, Orsulic, Sandra, Osorio, Ana, Robles-Díaz, Luis, Ruebner, Matthias, Shah, Mitul, Sharma, Raghwa, Shvetsov, Yurii B, Steed, Helen, Talhouk, Aline, Taylor, Sarah E, Traficante, Nadia, Vierkant, Robert A, Wang, Chen, Wilkens, Lynne R, Winham, Stacey J, Benitez, Javier, Berchuck, Andrew, Bowtell, David D, Candido dos Reis, Francisco J, Cook, Linda S, DeFazio, Anna, Doherty, Jennifer A, Fasching, Peter A, García, María J, Goode, Ellen L, Goodman, Marc T, Gronwald, Jacek, Huntsman, David G, Karlan, Beth Y, Kommoss, Stefan, Modugno, Francesmary, Schildkraut, Joellen M, Sinn, Hans-Peter, Staebler, Annette, Kelemen, Linda E, Ford, Caroline E, Menon, Usha, Pharoah, Paul DP, Köbel, Martin, and Ramus, Susan J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Rare Diseases, Cancer, Women's Health, Ovarian Cancer, Genetics, 2.1 Biological and endogenous factors, Humans, Female, Ovarian Neoplasms, Prognosis, Survival Analysis, RNA, Messenger, Cystadenocarcinoma, Serous, Biomarkers, Tumor, Forkhead Transcription Factors, AOCs group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

BackgroundRecently, we showed a >60% difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC.MethodsTwo prognostic genes, FOXJ1 and GMNN, were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort (n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis.ResultsConsistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with >50% expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67-0.91, p 35% GMNN expression showed a trend for better outcomes, though this was not significant.ConclusionWe provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.

Published
2023

5. Profiling the immune landscape in mucinous ovarian carcinoma.

Author

Meagher, Nicola, Hamilton, Phineas, Milne, Katy, Thornton, Shelby, Harris, Bronwyn, Weir, Ashley, Alsop, Jennifer, Bisinoto, Christiani, Brenton, James, Brooks-Wilson, Angela, Chiu, Derek, Cushing-Haugen, Kara, Fereday, Sian, Garsed, Dale, Gayther, Simon, Gentry-Maharaj, Aleksandra, Gilks, Blake, Jimenez-Linan, Mercedes, Kennedy, Catherine, Le, Nhu, Piskorz, Anna, Riggan, Marjorie, Shah, Mitul, Singh, Naveena, Talhouk, Aline, Widschwendter, Martin, Bowtell, David, Candido Dos Reis, Francisco, Cook, Linda, Fortner, Renée, García, María, Harris, Holly, Huntsman, David, Köbel, Martin, Menon, Usha, Pharoah, Paul, Doherty, Jennifer, Anglesio, Michael, Pike, Malcolm, Pearce, Celeste, Friedlander, Michael, DeFazio, Anna, Nelson, Brad, Ramus, Susan, and Karnezis, Anthony

Subjects
Immune infiltrate, Mucinous ovarian carcinoma, Rare histotype, Humans, Female, B7-H1 Antigen, Carcinoma, Ovarian Epithelial, Ovarian Neoplasms, CD8-Positive T-Lymphocytes, Forkhead Transcription Factors, Lymphocytes, Tumor-Infiltrating, Tumor Microenvironment
Abstract

OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically cold, suggesting they may have limited response to current immunotherapies.

Published
2023

7. MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma

Author

Kang, Eun Young, Millstein, Joshua, Popovic, Gordana, Meagher, Nicola S, Bolithon, Adelyn, Talhouk, Aline, Chiu, Derek S, Anglesio, Michael S, Leung, Betty, Tang, Katrina, Lambie, Neil, Pavanello, Marina, Da-anoy, Annalyn, Lambrechts, Diether, Loverix, Liselore, Olbrecht, Siel, Bisinotto, Christiani, Garcia-Donas, Jesus, Ruiz-Llorente, Sergio, Yagüe-Fernandez, Monica, Edwards, Robert P, Elishaev, Esther, Olawaiye, Alexander, Taylor, Sarah, Ataseven, Beyhan, du Bois, Andreas, Harter, Philipp, Lester, Jenny, Høgdall, Claus K, Armasu, Sebastian M, Huang, Yajue, Vierkant, Robert A, Wang, Chen, Winham, Stacey J, Heublein, Sabine, Kommoss, Felix KF, Cramer, Daniel W, Sasamoto, Naoko, van-Wagensveld, Lilian, Lycke, Maria, Mateoiu, Constantina, Joseph, Janine, Pike, Malcolm C, Odunsi, Kunle, Tseng, Chiu-Chen, Pearce, Celeste L, Bilic, Sanela, Conrads, Thomas P, Hartmann, Arndt, Hein, Alexander, Jones, Michael E, Leung, Yee, Beckmann, Matthias W, Ruebner, Matthias, Schoemaker, Minouk J, Terry, Kathryn L, El-Bahrawy, Mona A, Coulson, Penny, Etter, John L, LaVigne-Mager, Katherine, Andress, Juergen, Grube, Marcel, Fischer, Anna, Neudeck, Nina, Robertson, Greg, Farrell, Rhonda, Barlow, Ellen, Quinn, Carmel, Hettiaratchi, Anusha, Casablanca, Yovanni, Erber, Ramona, Stewart, Colin JR, Tan, Adeline, Yu, Yu, Boros, Jessica, Brand, Alison H, Harnett, Paul R, Kennedy, Catherine J, Nevins, Nikilyn, Morgan, Terry, Fasching, Peter A, Vergote, Ignace, Swerdlow, Anthony J, Candido dos Reis, Francisco J, Maxwell, G Larry, Neuhausen, Susan L, Barquin-Garcia, Arantzazu, Modugno, Francesmary, Moysich, Kirsten B, Crowe, Philip J, Hirasawa, Akira, Heitz, Florian, Karlan, Beth Y, Goode, Ellen L, Sinn, Peter, Horlings, Hugo M, Høgdall, Estrid, Sundfeldt, Karin, Kommoss, Stefan, and Staebler, Annette

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Women's Health, Infectious Diseases, Rare Diseases, HIV/AIDS, Genetics, Sexually Transmitted Infections, 5.1 Pharmaceuticals, 2.1 Biological and endogenous factors, Biomarkers, Tumor, Cell Proliferation, Cystadenocarcinoma, Serous, Female, Humans, Ki-67 Antigen, Minichromosome Maintenance Complex Component 3, Ovarian Neoplasms, RNA, Messenger, Survival Rate, High-grade serous carcinoma, Proliferation, MCM3, Clinical Sciences, Pathology, Clinical sciences
Abstract

Tubo-ovarian high-grade serous carcinomas (HGSC) are highly proliferative neoplasms that generally respond well to platinum/taxane chemotherapy. We recently identified minichromosome maintenance complex component 3 (MCM3), which is involved in the initiation of DNA replication and proliferation, as a favorable prognostic marker in HGSC. Our objective was to further validate whether MCM3 mRNA expression and possibly MCM3 protein levels are associated with survival in patients with HGSC. MCM3 mRNA expression was measured using NanoString expression profiling on formalin-fixed and paraffin-embedded tissue (N = 2355 HGSC) and MCM3 protein expression was assessed by immunohistochemistry (N = 522 HGSC) and compared with Ki-67. Kaplan-Meier curves and the Cox proportional hazards model were used to estimate associations with survival. Among chemotherapy-naïve HGSC, higher MCM3 mRNA expression (one standard deviation increase in the score) was associated with longer overall survival (HR = 0.87, 95% CI 0.81-0.92, p

Published
2022

11. Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium.

Author

Martins, Filipe Correia, Couturier, Dominique-Laurent, Paterson, Anna, Karnezis, Anthony N, Chow, Christine, Nazeran, Tayyebeh M, Odunsi, Adekunle, Gentry-Maharaj, Aleksandra, Vrvilo, Aleksandra, Hein, Alexander, Talhouk, Aline, Osorio, Ana, Hartkopf, Andreas D, Brooks-Wilson, Angela, DeFazio, Anna, Fischer, Anna, Hartmann, Arndt, Hernandez, Brenda Y, McCauley, Bryan M, Karpinskyj, Chloe, de Sousa, Christiani B, Høgdall, Claus, Tiezzi, Daniel G, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Keeney, Gary, Nelson, Gregg, Steed, Helen, Song, Honglin, Luk, Hugh, Benitez, Javier, Alsop, Jennifer, Koziak, Jennifer M, Lester, Jenny, Rothstein, Joseph H, de Andrade, Jurandyr M, Lundvall, Lene, Paz-Ares, Luis, Robles-Díaz, Luis, Wilkens, Lynne R, Garcia, Maria J, Intermaggio, Maria P, Alcaraz, Marie-Lyne, Brett, Mary A, Beckmann, Matthias W, Jimenez-Linan, Mercedes, Anglesio, Michael, Carney, Michael E, Schneider, Michael, Traficante, Nadia, Pejovic, Nadja, Singh, Naveena, Le, Nhu, Sinn, Peter, Ghatage, Prafull, Erber, Ramona, Edwards, Robert, Vierkant, Robert, Ness, Roberta B, Leung, Samuel, Orsulic, Sandra, Brucker, Sara Y, Kaufmann, Scott H, Fereday, Sian, Gayther, Simon, Winham, Stacey J, Kommoss, Stefan, Pejovic, Tanja, Longacre, Teri A, McGuire, Valerie, Rhenius, Valerie, Sieh, Weiva, Shvetsov, Yurii B, Whittemore, Alice S, Staebler, Annette, Karlan, Beth Y, Rodriguez-Antona, Cristina, Bowtell, David D, Goode, Ellen L, Høgdall, Estrid, Candido Dos Reis, Francisco J, Gronwald, Jacek, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, Fasching, Peter A, Crawford, Robin, Deen, Suha, Menon, Usha, Huntsman, David G, Köbel, Martin, Ramus, Susan J, Pharoah, Paul DP, and Brenton, James D

Subjects
Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

BackgroundPTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.MethodsTumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran-Mantel-Haenszel tests.ResultsDownregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65-0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value

Published
2020

12. Comparative polyphasic characterization of Weissella strains isolated from beaked whale and rainbow trout (Oncorhynchus mykiss): confirmation of Weissella ceti sp. nov. and description of the novel Weissella tructae sp. nov. isolated from farmed rainbow trout

Author

Pereira, Felipe Luiz, Dorella, Fernanda Alves, Castrejón-Nájera, Jésica, Reis, Francisco Yan Tavares, Ortega, César, Irgang, Rute, Echeverría-Bugueño, Macarena, Avendaño-Herrera, Ruben, and Figueiredo, Henrique César Pereira

Published
2022
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14. Hérnia diafragmática congênita: uma breve revisão da literatura

Author

Aragão, José Aderval, primary, Mota, Matheus Jhonnata Santos, additional, Moreno, Victor Petersen Dantas, additional, Aragão, Iapunira Catarina Sant’Anna, additional, Aragão, Felipe Matheus Sant’Anna, additional, Lourenço, Bárbara Costa, additional, Feitosa, Vera Lúcia Correa, additional, and Reis, Francisco Prado, additional

Published
2023
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15. Endometrial carcinosarcoma

Author

Bogani, Giorgio, Ray-Coquard, Isabelle, Concin, Nicole, Ngoi, Natalie Yan Li, Morice, Philippe, Caruso, Giuseppe, Enomoto, Takayuki, Takehara, Kazuhiro, Denys, Hannelore, Lorusso, Domenica, Coleman, Robert, Vaughan, Michelle M, Takano, Masashi, Provencher, Diane Michele, Sagae, Satoru, Wimberger, Pauline, Póka, Robert, Segev, Yakir, Kim, Se Ik, Kim, Jae-Weon, Candido dos Reis, Francisco Jose, Ramirez, Pedro T, Mariani, Andrea, Leitao, Mario, Makker, Vicky, Abu-Rustum, Nadeem R, Vergote, Ignace, Zannoni, Gianfranco, Tan, David, McCormack, Mary, Paolini, Biagio, Bini, Marta, Raspagliesi, Francesco, Benedetti Panici, Pierluigi, Di Donato, Violante, Muzii, Ludovico, Colombo, Nicoletta, Pignata, Sandro, Scambia, Giovanni, and Monk, Bradley J

Published
2023
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18. Profiling the immune landscape in mucinous ovarian carcinoma

Author

Meagher, Nicola S., Hamilton, Phineas, Milne, Katy, Thornton, Shelby, Harris, Bronwyn, Weir, Ashley, Alsop, Jennifer, Bisinoto, Christiani, Brenton, James D., Brooks-Wilson, Angela, Chiu, Derek S., Cushing-Haugen, Kara L., Fereday, Sian, Garsed, Dale W., Gayther, Simon A., Gentry-Maharaj, Aleksandra, Gilks, Blake, Jimenez-Linan, Mercedes, Kennedy, Catherine J., Le, Nhu D., Piskorz, Anna M., Riggan, Marjorie J., Shah, Mitul, Singh, Naveena, Talhouk, Aline, Widschwendter, Martin, Bowtell, David D.L., Candido dos Reis, Francisco J., Cook, Linda S., Fortner, Renée T., García, María J., Harris, Holly R., Huntsman, David G., Karnezis, Anthony N., Köbel, Martin, Menon, Usha, Pharoah, Paul D.P., Doherty, Jennifer A., Anglesio, Michael S., Pike, Malcolm C., Pearce, Celeste Leigh, Friedlander, Michael L., DeFazio, Anna, Nelson, Brad H., and Ramus, Susan J.

Published
2023
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20. Clinical research in ovarian cancer: consensus recommendations from the Gynecologic Cancer InterGroup

Author

Mahner, Sven, Reuss, Alexander, du Bois, Andreas, Grimm, Christoph, Marth, Christian, Berger, Regina, Concin, Nicole, Chang, Ting-Chang, Ochiai, Kazunori, Gebski, Val, Davis, Alison, Beale, Philip, Vergote, Ignace, Kridelka, Frédéric, Denys, Hannelore, Vandecaveye, Vincent, Candido dos Reis, Francisco Jose, Del Pilar Estevez Diz, Maria, Stuart, Gavin, MacKay, Helen, Carey, Mark, Cibula, David, Dundr (path), Pavel, Dorigo, Oliver, Berek, Jonathan, O'Donnell, Dearbhaile, Saadeh, Abu, Boere, Ingrid, Lok, Christianne, Coronado, Pluvio, Ottevanger, Nelleke, Tan, David SP, Ng, Joseph, Gonzalez Martin, Antonio, Oaknin, Ana, Poveda, Andres, Perez Fidalgo, Alejandro, Rauh-Hain, Alejandro, Lu, Karen, López-Zavala, Carlos, Gómez-García, Eva María, Ray-Coquard, Isabelle, Paoletti, Xavier, Kurtz, Jean-Emmanuel, Joly, Florence, Votan, Bénédicte, Bookman, Michael, Moore, Kathleen, Arend, Rebecca, Fujiwara, Keiichi, Fujiwara, Hiroyuki, Hasegawa, Kosei, Bruchim, Ilan, Tsoref, Dalia, Oda, Katsutoshi, Okamoto, Aikou, Enomoto, Takayuki, Michel, Dayana, Kim, Hee-Seung, Lee, Jung-Yun, Mukhopadhyay, Asima, Katsaros, Dionyssios, Colombo, Nicoletta, Pignata, Sandro, Lorusso, Domenica, Scambia, Giovanni, Kohn, Elise, Lee, Jung-Min, McNeish, Iain, Nicum, Shibani, Farrelly, Laura, Sehouli, Jalid, Keller, Maren, Braicu, Elena, Bjørge, Line, Mirza, Mansoor Raza, Auranen, Annika, Welch, Stephen, Oza, Amit M, Heinzelmann, Viola, Gourley, Charlie, Roxburgh, Patricia, Herrington, C Simon, Glasspool, Ros, Zang, Rongyu, Zhu, Jianqing, Gonzalez-Martin, Antonio, Kohn, Elise C, Berek, Jonathan S, Tan, David S P, Stuart, Gavin C E, and Bookman, Michael A

Published
2022
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21. Susceptibility of Tambaqui (Colossoma macropomum) to Nile Tilapia-Derived Streptococcus agalactiae and Francisella orientalis.

Author

Reis, Francisco Yan Tavares, Rocha, Victória Pontes, Janampa-Sarmiento, Peter Charrie, Santos, Ágna Ferreira, Leibowitz, Márcia Pimenta, Luz, Ronald Kennedy, Pierezan, Felipe, Gallani, Sílvia Umeda, Tavares, Guilherme Campos, and Figueiredo, Henrique César Pereira

Subjects
TAMBAQUI, FRESHWATER fishes, STREPTOCOCCUS agalactiae, STREPTOCOCCAL diseases, DISEASE progression, NILE tilapia
Abstract

Nile tilapia (Oreochromis niloticus) and tambaqui (Colossoma macropomum) are the two most produced freshwater fishes in Brazil. This study investigated the potential pathogenicity of Streptococcus agalactiae and Francisella orientalis, previously isolated from diseased Nile tilapia, to tambaqui. Experimental infection trials were conducted in juvenile tambaqui at a dose of approximately 107 CFU fish−1, assessing clinical signs, mortality, bacterial recovery, and histopathological changes. Results demonstrated that S. agalactiae exhibited high pathogenicity to tambaqui, causing rapid disease progression, high mortality (83.33%) within 48 h post-infection, and severe lesions in multiple organs, under the experimental conditions. In contrast, F. orientalis infection did not result in mortality or clinical signs, despite bacterial recovery and granulomatous inflammation observed in the tissues. This study highlights the need to consider the potential impact of these pathogens in tambaqui farming. [ABSTRACT FROM AUTHOR]

Published
2024
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22. Quality of Life of People with Motor Disabilities, Involved or not in Parasports.

Author

Andrade Dantas, Karollyni Bastos, Gastélum-Cuadras, Gabriel, García Fernández, David Arnoldo, Prado Reis, Francisco, Pinho Morais, Raissa, and Martin Dantas, Estélio Henrique

Subjects
QUALITY of life, DATA distribution, PEOPLE with disabilities, CONTINUOUS distributions, PARASOCIAL relationships, DISABILITIES
Abstract

Copyright of Retos: Nuevas Perspectivas de Educación Física, Deporte y Recreación is the property of Federacion Espanola de Asociaciones de Docentes de Educacion Fisica and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2024

23. Clear cell carcinoma of the endometrium

Author

Bogani, Giorgio, Ray-Coquard, Isabelle, Concin, Nicole, Ngoi, Natalie Y.L., Morice, Philippe, Enomoto, Takayuki, Takehara, Kazuhiro, Denys, Hannelore, Lorusso, Domenica, Coleman, Robert, Vaughan, Michelle M., Takano, Masashi, Provencher, Diane, Sagae, Satoru, Wimberger, Pauline, Póka, Robert, Segev, Yakir, Kim, Se Ik, Kim, Jae-Weon, Candido dos Reis, Francisco J., Mariani, Andrea, Leitao, Mario M., Jr, Makker, Viky, Rustum, Nadeem Abu, Vergote, Ignace, Zannoni, Gian Franco, Tan, David S.P., McCormack, Mary, Bini, Marta, Lopez, Salvatore, Raspagliesi, Francesco, Panici, Pierluigi Benedetti, di Donato, Violante, Muzii, Ludovico, Colombo, Nicoletta, Scambia, Giovanni, Pignata, Sandro, and Monk, Bradley J.

Published
2022
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24. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis consortium study.

Author

Rambau, Peter F, Vierkant, Robert A, Intermaggio, Maria P, Kelemen, Linda E, Goodman, Marc T, Herpel, Esther, Pharoah, Paul D, Kommoss, Stefan, Jimenez-Linan, Mercedes, Karlan, Beth Y, Gentry-Maharaj, Aleksandra, Menon, Usha, Polo, Susanna Hernando, Candido Dos Reis, Francisco J, Doherty, Jennifer Anne, Gayther, Simon A, Sharma, Raghwa, Larson, Melissa C, Harnett, Paul R, Hatfield, Emma, de Andrade, Jurandyr M, Nelson, Gregg S, Steed, Helen, Schildkraut, Joellen M, Carney, Micheal E, Høgdall, Estrid, Whittemore, Alice S, Widschwendter, Martin, Kennedy, Catherine J, Wang, Frances, Wang, Qin, Wang, Chen, Armasu, Sebastian M, Daley, Frances, Coulson, Penny, Jones, Micheal E, Anglesio, Micheal S, Chow, Christine, de Fazio, Anna, García-Closas, Montserrat, Brucker, Sara Y, Cybulski, Cezary, Harris, Holly R, Hartkopf, Andreas D, Huzarski, Tomasz, Jensen, Allan, Lubiński, Jan, Oszurek, Oleg, Benitez, Javier, Mina, Fady, Staebler, Annette, Taran, Florin Andrei, Pasternak, Jana, Talhouk, Aline, Rossing, Mary Anne, Hendley, Joy, AOCS Group, Edwards, Robert P, Fereday, Sian, Modugno, Francesmary, Ness, Roberta B, Sieh, Weiva, El-Bahrawy, Mona A, Winham, Stacey J, Lester, Jenny, Kjaer, Susanne K, Gronwald, Jacek, Sinn, Peter, Fasching, Peter A, Chang-Claude, Jenny, Moysich, Kirsten B, Bowtell, David D, Hernandez, Brenda Y, Luk, Hugh, Behrens, Sabine, Shah, Mitul, Jung, Audrey, Ghatage, Prafull, Alsop, Jennifer, Alsop, Kathryn, García-Donas, Jesús, Thompson, Pamela J, Swerdlow, Anthony J, Karpinskyj, Chloe, Cazorla-Jiménez, Alicia, García, María J, Deen, Susha, Wilkens, Lynne R, Palacios, José, Berchuck, Andrew, Koziak, Jennifer M, Brenton, James D, Cook, Linda S, Goode, Ellen L, Huntsman, David G, Ramus, Susan J, and Köbel, Martin

Subjects
AOCS Group, Ovary, Humans, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Ovarian Neoplasms, Prognosis, Immunohistochemistry, Survival Rate, Adult, Aged, Middle Aged, Female, Cyclin-Dependent Kinase Inhibitor p16, RT-QPCR, immunocytochemistry, ovary, Adenocarcinoma, Mucinous, Cystadenocarcinoma, Serous, Cancer, Genetics, Ovarian Cancer, Rare Diseases, 2.1 Biological and endogenous factors
Abstract

We aimed to validate the prognostic association of p16 expression in ovarian high-grade serous carcinomas (HGSC) and to explore it in other ovarian carcinoma histotypes. p16 protein expression was assessed by clinical-grade immunohistochemistry in 6525 ovarian carcinomas including 4334 HGSC using tissue microarrays from 24 studies participating in the Ovarian Tumor Tissue Analysis consortium. p16 expression patterns were interpreted as abnormal (either overexpression referred to as block expression or absence) or normal (heterogeneous). CDKN2A (which encodes p16) mRNA expression was also analyzed in a subset (n = 2280) mostly representing HGSC (n = 2010). Association of p16 expression with overall survival (OS) was determined within histotypes as was CDKN2A expression for HGSC only. p16 block expression was most frequent in HGSC (56%) but neither protein nor mRNA expression was associated with OS. However, relative to heterogeneous expression, block expression was associated with shorter OS in endometriosis-associated carcinomas, clear cell [hazard ratio (HR): 2.02, 95% confidence (CI) 1.47-2.77, p < 0.001] and endometrioid (HR: 1.88, 95% CI 1.30-2.75, p = 0.004), while absence was associated with shorter OS in low-grade serous carcinomas (HR: 2.95, 95% CI 1.61-5.38, p = 0.001). Absence was most frequent in mucinous carcinoma (50%), and was not associated with OS in this histotype. The prognostic value of p16 expression is histotype-specific and pattern dependent. We provide definitive evidence against an association of p16 expression with survival in ovarian HGSC as previously suggested. Block expression of p16 in clear cell and endometrioid carcinoma should be further validated as a prognostic marker, and absence in low-grade serous carcinoma justifies CDK4 inhibition.

Published
2018

25. MyD88 and TLR4 Expression in Epithelial Ovarian Cancer.

Author

Block, Matthew S, Vierkant, Robert A, Rambau, Peter F, Winham, Stacey J, Wagner, Philipp, Traficante, Nadia, Tołoczko, Aleksandra, Tiezzi, Daniel G, Taran, Florin Andrei, Sinn, Peter, Sieh, Weiva, Sharma, Raghwa, Rothstein, Joseph H, Ramón Y Cajal, Teresa, Paz-Ares, Luis, Oszurek, Oleg, Orsulic, Sandra, Ness, Roberta B, Nelson, Gregg, Modugno, Francesmary, Menkiszak, Janusz, McGuire, Valerie, McCauley, Bryan M, Mack, Marie, Lubiński, Jan, Longacre, Teri A, Li, Zheng, Lester, Jenny, Kennedy, Catherine J, Kalli, Kimberly R, Jung, Audrey Y, Johnatty, Sharon E, Jimenez-Linan, Mercedes, Jensen, Allan, Intermaggio, Maria P, Hung, Jillian, Herpel, Esther, Hernandez, Brenda Y, Hartkopf, Andreas D, Harnett, Paul R, Ghatage, Prafull, García-Bueno, José M, Gao, Bo, Fereday, Sian, Eilber, Ursula, Edwards, Robert P, de Sousa, Christiani B, de Andrade, Jurandyr M, Chudecka-Głaz, Anita, Chenevix-Trench, Georgia, Cazorla, Alicia, Brucker, Sara Y, Australian Ovarian Cancer Study Group, Alsop, Jennifer, Whittemore, Alice S, Steed, Helen, Staebler, Annette, Moysich, Kirsten B, Menon, Usha, Koziak, Jennifer M, Kommoss, Stefan, Kjaer, Susanne K, Kelemen, Linda E, Karlan, Beth Y, Huntsman, David G, Høgdall, Estrid, Gronwald, Jacek, Goodman, Marc T, Gilks, Blake, García, María José, Fasching, Peter A, de Fazio, Anna, Deen, Suha, Chang-Claude, Jenny, Candido Dos Reis, Francisco J, Campbell, Ian G, Brenton, James D, Bowtell, David D, Benítez, Javier, Pharoah, Paul DP, Köbel, Martin, Ramus, Susan J, and Goode, Ellen L

Subjects
Australian Ovarian Cancer Study Group, Humans, Ovarian Neoplasms, Tissue Array Analysis, Immunohistochemistry, Survival Analysis, Adult, Aged, Middle Aged, Female, Toll-Like Receptor 4, Myeloid Differentiation Factor 88, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Biomarkers, Tumor, Carcinoma, Ovarian Epithelial, Medical and Health Sciences
Abstract

ObjectiveTo evaluate myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 (TLR4) expression in relation to clinical features of epithelial ovarian cancer, histologic subtypes, and overall survival.Patients and methodsWe conducted centralized immunohistochemical staining, semi-quantitative scoring, and survival analysis in 5263 patients participating in the Ovarian Tumor Tissue Analysis consortium. Patients were diagnosed between January 1, 1978, and December 31, 2014, including 2865 high-grade serous ovarian carcinomas (HGSOCs), with more than 12,000 person-years of follow-up time. Tissue microarrays were stained for MyD88 and TLR4, and staining intensity was classified using a 2-tiered system for each marker (weak vs strong).ResultsExpression of MyD88 and TLR4 was similar in all histotypes except clear cell ovarian cancer, which showed reduced expression compared with other histotypes (P

Published
2018

28. Multiple Wormian Bones in the Lambdoid Suture: A Report of Rare Occurrence

Author

Aragão, José Aderval, primary, De Oliveira, Roberto Ferreira, additional, De Sousa Silva, Smilly Oliveira, additional, Riffel, Lucas Inacio, additional, Sant’Anna Aragão, Iapunira Catarina, additional, Sant’Anna Aragão, Felipe Matheus, additional, Borges, Giulianna da Rocha, additional, Reis, Francisco Prado, additional, and Mendonça, Deise Maria Furtado de, additional

Published
2024
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32. Uterine serous carcinoma

Author

Bogani, Giorgio, Ray-Coquard, Isabelle, Concin, Nicole, Ngoi, Natalie Y.L., Morice, Philippe, Enomoto, Takayuki, Takehara, Kazuhiro, Denys, Hannelore, Nout, Remi A., Lorusso, Domenica, Vaughan, Michelle M., Bini, Marta, Takano, Masashi, Provencher, Diane, Indini, Alice, Sagae, Satoru, Wimberger, Pauline, Póka, Robert, Segev, Yakir, Kim, Se Ik, Candido dos Reis, Francisco J., Lopez, Salvatore, Mariani, Andrea, Leitao, Mario M., Jr, Raspagliesi, Francesco, Panici, Pieluigi Benedetti, Di Donato, Violante, Muzii, Ludovico, Colombo, Nicoletta, Scambia, Giovanni, Pignata, Sandro, and Monk, Bradley J.

Published
2021
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34. Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer

Author

Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas D, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Eilber, Ursula, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, deFazio, Anna, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, dos Reis, Francisco J Candido, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, and Ramus, Susan J

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Immunology, Women's Health, Ovarian Cancer, Cancer, Clinical Research, Rare Diseases, BRCA2 Protein, CD8 Antigens, Carcinoma, Ovarian Epithelial, Cohort Studies, Cystadenocarcinoma, Serous, Female, Humans, Lymphocytes, Tumor-Infiltrating, Middle Aged, Mutation, Neoplasm Grading, Ovarian Neoplasms, Prospective Studies, Survival Analysis, Treatment Outcome, Ovarian Tumor Tissue Analysis (OTTA) Consortium, Public Health and Health Services, Oncology and carcinogenesis
Abstract

ImportanceCytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.ObjectiveTo define the prognostic role of CD8+ TILs in epithelial ovarian cancer.Design, setting, and participantsThis was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.ExposuresFollowing immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Main outcomes and measuresOverall survival time.ResultsThe final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.Conclusions and relevanceThis study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Published
2017

35. Dose-Response Association of CD8+ Tumor-Infiltrating Lymphocytes and Survival Time in High-Grade Serous Ovarian Cancer.

Author

Ovarian Tumor Tissue Analysis (OTTA) Consortium, Goode, Ellen L, Block, Matthew S, Kalli, Kimberly R, Vierkant, Robert A, Chen, Wenqian, Fogarty, Zachary C, Gentry-Maharaj, Aleksandra, Tołoczko, Aleksandra, Hein, Alexander, Bouligny, Aliecia L, Jensen, Allan, Osorio, Ana, Hartkopf, Andreas, Ryan, Andy, Chudecka-Głaz, Anita, Magliocco, Anthony M, Hartmann, Arndt, Jung, Audrey Y, Gao, Bo, Hernandez, Brenda Y, Fridley, Brooke L, McCauley, Bryan M, Kennedy, Catherine J, Wang, Chen, Karpinskyj, Chloe, de Sousa, Christiani B, Tiezzi, Daniel G, Wachter, David L, Herpel, Esther, Taran, Florin Andrei, Modugno, Francesmary, Nelson, Gregg, Lubiński, Jan, Menkiszak, Janusz, Alsop, Jennifer, Lester, Jenny, García-Donas, Jesús, Nation, Jill, Hung, Jillian, Palacios, José, Rothstein, Joseph H, Kelley, Joseph L, de Andrade, Jurandyr M, Robles-Díaz, Luis, Intermaggio, Maria P, Widschwendter, Martin, Beckmann, Matthias W, Ruebner, Matthias, Jimenez-Linan, Mercedes, Singh, Naveena, Oszurek, Oleg, Harnett, Paul R, Rambau, Peter F, Sinn, Peter, Wagner, Philipp, Ghatage, Prafull, Sharma, Raghwa, Edwards, Robert P, Ness, Roberta B, Orsulic, Sandra, Brucker, Sara Y, Johnatty, Sharon E, Longacre, Teri A, Ursula, Eilber, McGuire, Valerie, Sieh, Weiva, Natanzon, Yanina, Li, Zheng, Whittemore, Alice S, Anna, deFazio, Staebler, Annette, Karlan, Beth Y, Gilks, Blake, Bowtell, David D, Høgdall, Estrid, Candido dos Reis, Francisco J, Steed, Helen, Campbell, Ian G, Gronwald, Jacek, Benítez, Javier, Koziak, Jennifer M, Chang-Claude, Jenny, Moysich, Kirsten B, Kelemen, Linda E, Cook, Linda S, Goodman, Marc T, García, María José, Fasching, Peter A, Kommoss, Stefan, Deen, Suha, Kjaer, Susanne K, Menon, Usha, Brenton, James D, Pharoah, Paul DP, Chenevix-Trench, Georgia, Huntsman, David G, Winham, Stacey J, Köbel, Martin, and Ramus, Susan J

Subjects
Ovarian Tumor Tissue Analysis (OTTA) Consortium, Lymphocytes, Tumor-Infiltrating, Humans, Cystadenocarcinoma, Serous, Ovarian Neoplasms, BRCA2 Protein, Treatment Outcome, Survival Analysis, Cohort Studies, Prospective Studies, Mutation, Middle Aged, Female, Neoplasm Grading, CD8 Antigens, Carcinoma, Ovarian Epithelial, Lymphocytes, Tumor-Infiltrating, Cystadenocarcinoma, Serous, Carcinoma, Ovarian Epithelial, Cancer, Prevention, Ovarian Cancer, Rare Diseases, Vaccine Related, Clinical Research, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

ImportanceCytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) participate in immune control of epithelial ovarian cancer; however, little is known about prognostic patterns of CD8+ TILs by histotype and in relation to other clinical factors.ObjectiveTo define the prognostic role of CD8+ TILs in epithelial ovarian cancer.Design, setting, and participantsThis was a multicenter observational, prospective survival cohort study of the Ovarian Tumor Tissue Analysis Consortium. More than 5500 patients, including 3196 with high-grade serous ovarian carcinomas (HGSOCs), were followed prospectively for over 24 650 person-years.ExposuresFollowing immunohistochemical analysis, CD8+ TILs were identified within the epithelial components of tumor islets. Patients were grouped based on the estimated number of CD8+ TILs per high-powered field: negative (none), low (1-2), moderate (3-19), and high (≥20). CD8+ TILs in a subset of patients were also assessed in a quantitative, uncategorized manner, and the functional form of associations with survival was assessed using penalized B-splines.Main outcomes and measuresOverall survival time.ResultsThe final sample included 5577 women; mean age at diagnosis was 58.4 years (median, 58.2 years). Among the 5 major invasive histotypes, HGSOCs showed the most infiltration. CD8+ TILs in HGSOCs were significantly associated with longer overall survival; median survival was 2.8 years for patients with no CD8+ TILs and 3.0 years, 3.8 years, and 5.1 years for patients with low, moderate, or high levels of CD8+ TILs, respectively (P value for trend = 4.2 × 10−16). A survival benefit was also observed among women with endometrioid and mucinous carcinomas, but not for those with the other histotypes. Among HGSOCs, CD8+ TILs were favorable regardless of extent of residual disease following cytoreduction, known standard treatment, and germline BRCA1 pathogenic mutation, but were not prognostic for BRCA2 mutation carriers. Evaluation of uncategorized CD8+ TIL counts showed a near-log-linear functional form.Conclusions and relevanceThis study demonstrates the histotype-specific nature of immune infiltration and provides definitive evidence for a dose-response relationship between CD8+ TILs and HGSOC survival. That the extent of infiltration is prognostic, not merely its presence or absence, suggests that understanding factors that drive infiltration will be the key to unraveling outcome heterogeneity in this cancer.

Published
2017

36. Extensive CFTR sequencing through NGS in Brazilian individuals with cystic fibrosis: unravelling regional discrepancies in the country

Author

Antunes, Mara Lícia Machado, Andries, Lilian Cristina Ferreira, de Castro, Virginia Auxiliadora Freitas, Adde, Fabíola Villac, Perez, Maria Fernanda Botelho Hernandez, Dantas, Vera Maria, Monte, Luciana de Freitas Velloso, Goya, Adriana, Rached, Samia, Costa, Lusmaia Damaceno Camargo, Prado, Lorenna Junqueira Almeida, Guimarães, Elizabet Vilar, de Carvalho Fernandez Fonseca, Ana Cristina, Nishi, Marina Pires, Riedi, Carlos Antônio, Filho, Nelson Augusto Rosario, Canan, Mariane Gonçalves Martynychen, Fernandes, Maria Inez Machado, Augustin, Albin Eugenio, Garcia, Rosângela Villela, da Silva Zembrzuski, Maria Margarete, de Oliveira, Kátia Izabel, Hoffmann, Anneliese, Ricachinevsky, Cláudio, de Tarso Roth Dalcin, Paulo, Ziegler, Bruna, de Souza Paiva Borgli, Daniela, Ferrao, Daniele Menezes Torres, da Silva, Elizabeth Passos Simoes, Santana, Maria Angelica, de Sousa, Maria Amenaide Carvalho Alves, de Castro e Silva, Claudia, Filho, Evalto Monte de Araujo, Veras, Tiago Neves, Neto, Noberto Ludwig, Cutolo, Luiz Roberto Agea, Vergara, Alberto Andrade, Melo, Suzana Fonseca Oliveira, Moreira, Maria do Espírito Santo Almeida, Melotti, Roberta de Cássia Nunes Cruz, Malini, Fernanda Barbosa dos Santos, de Fuccio, Marcelo Bicalho, Pessoa, Bruno Porto, Esposito, Concetta, Kussek, Paulo Cesar, Foletto, Glaunir Maria, Pinto, Leonardo Araujo, Epifanio, Matias, Rodrigues, Marcelo Tadday, Duarte, Marta Cristina, Meneses, Daniela Gois, de Carvalho Martins, Valéria, Valente, Sônia Elenita Lopes, de Azevedo Ferreira, Arlan, Cartaxo, Constantino Giovanni Braga, Haidar, Denise Maria Costa, Firmida, Mônica de Cássia, de Castro, Marcos César Santos, de Souza, Edna Lucia Santos, Mota, Lais Ribeiro, de Negreiros Moura, Katharina Vidal, Rodrigues, Joaquim Carlos, Nakaie, Cleyde Myriam Aversa, Folescu, Tânia Wrobel, Sad, Izabela, de Britto, Murilo Carlos Amorim, Castelletti, Carlos Henrique Medeiros, Gonçalves, Cláudia Mello, Muramatu, Lucia, Fischer, Gilberto Bueno, Ferrari, Giesela Fleischer, Tostes, Luciana Oliveira Silvano, Bertuzzo, Carmen Silvia, Marson, Fernando Augusto de Lima, Chiba, Sonia Mayumi, De Sillos, Marcela Duarte, da Silva Filho, Luiz Vicente Ribeiro Ferreira, Maróstica, Paulo José Cauduro, Athanazio, Rodrigo Abensur, Reis, Francisco José Caldeira, Damaceno, Neiva, Paes, Angela Tavares, Hira, Adilson Yuuji, Schlesinger, David, Kok, Fernando, and Amaral, Margarida D.

Published
2021
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37. O USO DE DELTA-9-HIDROCANNABINOL (THC) E CANNABIDIOL (CBD) NO TRATAMENTO DA DOENÇA DE ALZHEIMER: UMA REVISÃO INTEGRATIVA

Author

Aragão, José Aderval, primary, Marassi, Pedro Henrique Adário, additional, Lourenço, Bárbara Costa, additional, Oliveira, Ana Clara Rodrigues, additional, Pizano, Anna Karoline da Rocha, additional, Sant’anna Aragão, Marina Elizabeth Cavalcanti de, additional, Sant’Anna Aragão, Iapunira Catarina, additional, Sant’Anna Aragão, Felipe Matheus, additional, and Reis, Francisco Prado, additional

Published
2022
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38. MÚSCULO PSOAS MENOR: RELATO DE CASO E ANÁLISE MORFOMÉTRICA

Author

Aragão, José Aderval, primary, Melo, Danilo Menezes de, additional, Gama Filho, João Marlus Costa da, additional, Guerra, Danilo Ribeiro, additional, Sant’Anna Aragão, Felipe Matheus, additional, Sant’Anna Aragão, Iapunira Catarina, additional, Cardoso, Paôla, additional, Lourenço, Bárbara Costa, additional, Sant’anna Aragão, Marina Elizabeth Cavalcanti de, additional, and Reis, Francisco Prado, additional

Published
2022
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39. MÚSCULO PALMAR CURTO EM FETO HUMANO: RELATO DE CASO E IMPLICAÇÕES CLÍNICAS

Author

Aragão, José Aderval, primary, Chagas, Lucas Rosário, additional, Pereira, Renata Fontes, additional, Fortes, Luís Henrique Santos, additional, Nascimento, Marcelo Diaz, additional, Souza, Gladson Gomes de, additional, Sant’Anna Aragão, Felipe Matheus, additional, Sant’Anna Aragão, Iapunira Catarina, additional, Sant’anna Aragão, Marina Elizabeth Cavalcanti de, additional, and Reis, Francisco Prado, additional

Published
2022
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42. MÚSCULO PECTORALIS QUARTUS EM FETO HUMANO: RELATO DE CASO

Author

Aragão, José Aderval, primary, Campos, Wallace Brener Santana, additional, Santos, Asaf Ramos dos, additional, Fortes, Luís Henrique Santos, additional, Nascimento, Marcelo Diaz, additional, Souza, Gladson Gomes de, additional, Aragão, Marina Elizabeth Cavalcanti de Sant’anna, additional, and Reis, Francisco Prado, additional

Published
2022
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43. TRIPLA VARIAÇÃO DO MÚSCULO FLEXOR SUPERFICIAL DOS DEDOS

Author

Sousa, Hugo Alves de, primary, Godoy, José Roberto Pimenta de, additional, Silva, Rogério Wagner da, additional, Regattieri, Neysa Aparecida Tinoco, additional, Nogueira, Bruno Rabelo, additional, Silva, Felipe Teixeira da, additional, Ribeiro, Asaph Lucas Cunha, additional, Carvalho, Phellip de, additional, Pereira, Ronaldo Sergio Santana, additional, and Reis, Francisco Prado, additional

Published
2022
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44. LOBO PIRAMIDAL DA GLÂNDULA TIREOIDE EM FETOS HUMANOS: RELATO DE CASOS E REVISÃO DA LITERATURA

Author

Aragão, José Aderval, primary, Gomes, Rafael Dantas, additional, Cruz, Joás Alves da, additional, Fortes, Luís Henrique, additional, Nascimento, Marcelo Diaz, additional, Souza, Gladson Gomes de, additional, Sant’Anna Aragão, Iapunira Catarina, additional, Sant’Anna Aragão, Felipe Matheus, additional, Sant’anna Aragão, Marina Elizabeth Cavalcanti de, additional, and Reis, Francisco Prado, additional

Published
2022
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46. URETER DUPLO: RELATO DE CASO E REVISÃO DA LITERATURA

Author

Aragão, José Aderval, primary, Franca, Joyce Nunes Felix, additional, Sant’Anna Aragão, Felipe Matheus, additional, Sant’Anna Aragão, Iapunira Catarina, additional, Sant’anna Aragão, Marina Elizabeth Cavalcanti de, additional, Barros, Lucimario de Carvalho, additional, Fortes, Luís Henrique Santos, additional, Nascimento, Marcelo Diaz, additional, Souza, Gladson Gomes de, additional, and Reis, Francisco Prado, additional

Published
2022
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47. ARTÉRIAS RENAIS POLARES: RELATO DE CASOS

Author

Aragão, José Aderval, primary, Menezes, Marcelo Antônio Silva, additional, Andrade, Milena Santana de, additional, Fortes, Luís Henrique Santos, additional, Nascimento, Marcelo Diaz, additional, Souza, Gladson Gomes de, additional, and Reis, Francisco Prado, additional

Published
2022
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48. MÚSCULO EXTENSOR RADIAL ACESSÓRIO DO CARPO: RELATO DE CASO E REVISÃO DA LITERATURA

Author

Aragão, José Aderval, primary, Correia, Victoria Mirella dos Santos, additional, Andrade, Jonatas Santos, additional, Sant’Anna Aragão, Felipe Matheus, additional, Sant’Anna Aragão, Iapunira Catarina, additional, Belém, Ana Beatriz Tavares Cunha, additional, Cardoso, Paôla, additional, Lourenço, Bárbara Costa, additional, Sant’anna Aragão, Marina Elizabeth Cavalcanti de, additional, and Reis, Francisco Prado, additional

Published
2022
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