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495 results on '"Tumores"'

1. Neoadjuvant Radio-chemotherapy Safety Pilot Study in Patients With Glioblastoma (GLINERA)

Author: Asociación de Afectados Por Tumores Cerebrales en España (ASATE) and Juan Antonio Barcia Albacar, Professor
Published: 2024

2. Platinum-Cetuximab Combined With Docetaxel or With 5FU in Patients With Recurrent/Metastatic HNSCC (TPExtreme)

Author: Grupo Español de Tratamiento de Tumores de Cabeza y Cuello and AIO-Studien-gGmbH
Published: 2022

3. Head and Neck cancERs International cOviD-19 collabOraTion

Author: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Grupo Español de Tratamiento de Tumores de Cabeza y Cuello, National Cancer Centre, Singapore, Emory University, University of Toronto, University of Birmingham, The University of Queensland, and Amanda Psyrri, Associate Professor of Medical Oncology
Published: 2022

4. Prospective Evaluation of Patients With Uterine Cervical Cancer in Brazilian Health Institutions - The EVITA I Study

Author: EVA - Grupo Brasileiro de Tumores Ginecológicos and Roche Pharma AG
Published: 2021

5. Celecoxib Combined With Fluorouracil and Leucovorin in Treating Patients With Resected Stage III Adenocarcinoma (Cancer) of the Colon

Author: Dutch Colorectal Cancer Group (DCCG), Arbeitsgemeinschaft fur Internistische Onkologie, Onkologie, Egyptian Foundation For Cancer Research, EORTC GI Group (EORTC 40023), Federation Francophone de Cancerologie Digestive, GCCD-APIO - Grupo Cooperativo do Cancro Digestivo da Associação Portuguesa de Investigação, Oncológica, Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente, GOCCI - Gruppo Oncologico Chirurgico Cooperativo Italiano, GOIRC - Gruppo Oncologico Italiano di Ricerca Clinica, SG - Scandinavian Group, and TTD - Grupo Español para el Tratamiento de Tumores Digestivos
Published: 2015

6. High-Dose Fluorouracil With or Without Leucovorin Compared With Standard Fluorouracil Plus Leucovorin Following Surgery in Treating Patients With Stage III Colon Cancer

Author: European Organisation for Research and Treatment of Cancer - EORTC, Federation Francophone de Cancerologie Digestive, and Grupo Espanol Tratamiento Tumores Digestivos
Published: 2013

7. Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin

Author: Grupo Español de Tumores Neuroendocrinos y Endocrinos, Capdevila, Jaume, Hernando, J., Teulé, Alex, López, C., García-Carbonero, Rocío, Benavent, Marta, Custodio, A., García-Álvarez, Alejandro, Cubillo, A., Alonso, V., Carmona-Bayonas, Alberto, Alonso-Gordoa, T., Crespo, Guillermo, Jiménez-Fonseca, Paula, Blanco, M., Viudez, A., Casta, A. La, Sevilla, I., Segura, A., Llanos, M., Landolfi, Stefania, Nuciforo, Paolo, Manzano, J. L., Grupo Español de Tumores Neuroendocrinos y Endocrinos, Capdevila, Jaume, Hernando, J., Teulé, Alex, López, C., García-Carbonero, Rocío, Benavent, Marta, Custodio, A., García-Álvarez, Alejandro, Cubillo, A., Alonso, V., Carmona-Bayonas, Alberto, Alonso-Gordoa, T., Crespo, Guillermo, Jiménez-Fonseca, Paula, Blanco, M., Viudez, A., Casta, A. La, Sevilla, I., Segura, A., Llanos, M., Landolfi, Stefania, Nuciforo, Paolo, and Manzano, J. L.
Abstract: Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.
Published: 2023

8. Sequential chemotherapy regimen of induction with panitumumab and paclitaxel followed by radiotherapy and panitumumab in patients with locally advanced head and neck cancer unfit for platinum derivatives. The phase II, PANTERA/TTCC-2010-06 study

Author: J. Lambea Sorrosal, Grupo Español de Tratamiento de Tumores de Cabeza y Cuello, B. Cirauqui Cirauqui, A Lozano Borbalas, L. C. Iglesias Docampo, José A. Caballero, J Marruecos Querol, J M Ponce Ortega, M. Taberna Sanz, M. Plana Serrahima, I. Planas Toledano, E Ortega Izquierdo, Javier Martinez-Trufero, J C Adansa, I. Pajares Bernad, R. Mesia Nin, and Jordi Rubió-Casadevall
Subjects: 0301 basic medicine, Cisplatin, Cancer Research, medicine.medical_specialty, business.industry, medicine.medical_treatment, Head and neck cancer, Induction chemotherapy, General Medicine, medicine.disease, Gastroenterology, Radiation therapy, 03 medical and health sciences, Regimen, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Internal medicine, Concomitant, medicine, Clinical endpoint, Panitumumab, business, medicine.drug
Abstract: Sequential treatment of Panitumumab (Pb) plus Paclitaxel (Px) as induction treatment (IT) followed by concurrent bioradiotherapy (Bio–RT) with Pb may be an alternative for locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) in patients ineligible for high-dose cisplatin therapy. Phase II, single-arm, multicentre study, with two-stage design, in patients ≥ 18 years with stage III–IVa–b LA-SCCHN unfit for platinum. Patients received Px + Pb (9 weeks) as IT followed by Bio–RT + Pb. Primary endpoint: overall response rate (ORR) after IT, defined as: more than 70% of patients achieving complete response (CR) or partial response (PR) to IT. Secondary end-points: progression-free survival, organ preservation rate, safety profile. Study ended prematurely (51 patients) due to slow recruitment. ORR: 66.7% (95% CI: 53.7–79.6), 8 (15.7%) CR and 26 (51.0%) PR. 39 patients (76%) completed radiotherapy (RT). Pb and/or Px-related adverse events (AEs) grade 3–4: 56.9% during IT and 63.4% during the concomitant phase, of which most common were skin toxicity (33.3%). Five deaths occurred during treatment, two of them (3.9%) were Pb and/or Px-related. Although underpowered, ORR was higher than the pre-specified boundary for considering the treatment active. Although Px + Pb as IT provides some benefit, the safety profile is worse than expected. To consider Pb + Px as IT as an alternative for platinum-unsuitable LA-SCCHN, further research/investigation would be needed.
Published: 2021
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9. Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease

Author: Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), Grupo Español de Tumores Neuroendocrinos y Endocrinos, Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Herrera-Martínez, Aura D. [0000-0003-1437-9878], Castaño, Justo P. [0000-0002-3145-7287], Luque, Raúl M. [0000-0002-7585-1913], Moreno-Moreno, Paloma, Ibáñez-Costa, Alejandro, Venegas Moreno, Eva, Fuentes-Fayos, Antonio C., Alhambra-Expósito, María R., Fajardo-Montañana, Carmen, García-Martínez, Araceli, Dios Fuentes, Elena, Vázquez-Borrego, Mari C., Remón-Ruiz, Pablo, Cámara, Rosa, Lamas, Cristina, Padillo-Cuenca, José Carlos, Solivera, Juan, Cano González, David A., Gahete, Manuel D., Herrera-Martínez, Aura D., Picó-Alfonso, Antonio Miguel, Soto-Moreno, Alfonso, Gálvez-Moreno, María Ángeles, Castaño, Justo P., Luque, Raúl M., Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), Grupo Español de Tumores Neuroendocrinos y Endocrinos, Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Herrera-Martínez, Aura D. [0000-0003-1437-9878], Castaño, Justo P. [0000-0002-3145-7287], Luque, Raúl M. [0000-0002-7585-1913], Moreno-Moreno, Paloma, Ibáñez-Costa, Alejandro, Venegas Moreno, Eva, Fuentes-Fayos, Antonio C., Alhambra-Expósito, María R., Fajardo-Montañana, Carmen, García-Martínez, Araceli, Dios Fuentes, Elena, Vázquez-Borrego, Mari C., Remón-Ruiz, Pablo, Cámara, Rosa, Lamas, Cristina, Padillo-Cuenca, José Carlos, Solivera, Juan, Cano González, David A., Gahete, Manuel D., Herrera-Martínez, Aura D., Picó-Alfonso, Antonio Miguel, Soto-Moreno, Alfonso, Gálvez-Moreno, María Ángeles, Castaño, Justo P., and Luque, Raúl M.
Abstract: [Context] Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse., [Objectives] This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas., [Methods] A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years’ follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery., [Results] Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P < .001)., [Conclusion] This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas.
Published: 2022

10. Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial

Author: Grupo de Tratamiento de los Tumores Digestivos (España), Sanofi, Tabernero, Josep [0000-0002-2495-8139], Aranda, Enrique [0000-0002-5471-2842], Élez, Elena, Gómez-España, María Auxiliadora, Grávalos, Cristina, García-Alfonso, Pilar, Ortiz-Morales, María José, Losa, Ferrán, Alés Díaz, Inmaculada, Graña, Begoña, Toledano Fonseca, Marta, Valladares-Ayerbes, Manuel, Polo, Eduardo, Salgado, Mercedes, Martínez de Castro, Eva, Safont, María José, Salud, Antonieta, Ruiz-Casado, Ana, Tabernero, Josep, Riesco-Martínez, María del Carmen, Rodríguez-Ariza, Antonio, Aranda, Enrique, Grupo de Tratamiento de los Tumores Digestivos (España), Sanofi, Tabernero, Josep [0000-0002-2495-8139], Aranda, Enrique [0000-0002-5471-2842], Élez, Elena, Gómez-España, María Auxiliadora, Grávalos, Cristina, García-Alfonso, Pilar, Ortiz-Morales, María José, Losa, Ferrán, Alés Díaz, Inmaculada, Graña, Begoña, Toledano Fonseca, Marta, Valladares-Ayerbes, Manuel, Polo, Eduardo, Salgado, Mercedes, Martínez de Castro, Eva, Safont, María José, Salud, Antonieta, Ruiz-Casado, Ana, Tabernero, Josep, Riesco-Martínez, María del Carmen, Rodríguez-Ariza, Antonio, and Aranda, Enrique
Abstract: [Background] Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE)., [Methods] Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed., [Results] In total, 101 patients were followed for a median of 12 (6–17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels., [Conclusions] This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.
Published: 2022

11. Epigenetic and post-transcriptional regulation of somatostatin receptor subtype 5 (SST5 ) in pituitary and pancreatic neuroendocrine tumors

Author: Junta de Andalucía, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), EMBO, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Fundación Eugenio Rodríguez Pascual, Medical Research Council (UK), Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Ibáñez-Costa, Alejandro [0000-0003-4649-0095], Gahete, Manuel D. [0000-0002-4578-2179], Castaño, Justo P. [0000-0002-3145-7287], Pedraza-Arévalo, Sergio, Ibáñez-Costa, Alejandro, Blázquez-Encinas, Ricardo, Branco, Miguel R., Vázquez-Borrego, Mari C., Herrera-Martínez, Aura D., Venegas Moreno, Eva, Serrano-Blanch, Raquel, Arjona-Sánchez, Álvaro, Gálvez-Moreno, María Ángeles, Korbonits, Marta, Soto-Moreno, Alfonso, Gahete, Manuel D., Charalambous, Marika, Luque, Raúl M., Castaño, Justo P., Junta de Andalucía, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), EMBO, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Fundación Eugenio Rodríguez Pascual, Medical Research Council (UK), Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Ibáñez-Costa, Alejandro [0000-0003-4649-0095], Gahete, Manuel D. [0000-0002-4578-2179], Castaño, Justo P. [0000-0002-3145-7287], Pedraza-Arévalo, Sergio, Ibáñez-Costa, Alejandro, Blázquez-Encinas, Ricardo, Branco, Miguel R., Vázquez-Borrego, Mari C., Herrera-Martínez, Aura D., Venegas Moreno, Eva, Serrano-Blanch, Raquel, Arjona-Sánchez, Álvaro, Gálvez-Moreno, María Ángeles, Korbonits, Marta, Soto-Moreno, Alfonso, Gahete, Manuel D., Charalambous, Marika, Luque, Raúl M., and Castaño, Justo P.
Abstract: Somatostatin receptor subtype 5 (SST5 ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response.
Published: 2022

12. Sunitinib and Evofosfamide (TH-302) in Systemic Treatment-Naïve Patients with Grade 1/2 Metastatic Pancreatic Neuroendocrine Tumors: The GETNE-1408 Trial

Author: Grupo Español de Tumores Neuroendocrinos y Endocrinos, Grande, Enrique, Rodríguez-Antona, Cristina, López, Carlos, Alonso Gordoa, Teresa, Benavent, Marta, Capdevila, Jaume, Teulé, Alex, Custodio, Ana, Sevilla, Isabel, Hernando Cubero, Jorge, Gajate, Pablo, Molina-Cerrillo, Javier, Díez, Juan José, Santos, María, Lanillos, Javier, García-Carbonero, Rocío, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Grande, Enrique, Rodríguez-Antona, Cristina, López, Carlos, Alonso Gordoa, Teresa, Benavent, Marta, Capdevila, Jaume, Teulé, Alex, Custodio, Ana, Sevilla, Isabel, Hernando Cubero, Jorge, Gajate, Pablo, Molina-Cerrillo, Javier, Díez, Juan José, Santos, María, Lanillos, Javier, and García-Carbonero, Rocío
Abstract: [Background] Sunitinib (SUN)-induced hypoxia within the tumor could promote the activation of the prodrug evofosfamide (EVO), locally releasing the cytotoxic DNA alkylator bromo-isophosphoramide mustard. SUNEVO, a phase II, open-label, single-arm trial, investigated the potential synergy of SUN plus EVO in advanced progressive pancreatic neuroendocrine tumors (panNETs)., [Methods] Systemic treatment-naïve patients with advanced or metastatic, unresectable, grade 1/2 panNETs with a Ki67 ≤20%, received EVO 340 mg/m2 on days 8, 15, and 22 every 4 weeks and sunitinib 37.5 mg/day continuously. The primary endpoint was objective response rate, measured every 8 weeks by RECIST version 1.1., [Results] From 2015 to 2018, 17 patients were enrolled. The median age was 62.4 years, 47% had a Ki67 >10%, and 70.6% had liver metastasis. Patients received a median of five and four cycles of SUN and EVO, respectively. After a median follow-up of 15.7 months, 17.6% of patients achieved a complete (n = 1) or partial response (n = 2), and 11 patients had stable disease (64.7%). The median progression-free survival was 10.4 months (95% confidence interval, 2.6–18.0). Treatment-related adverse events (grade ≥3) were observed in 64.7% of the patients, the most frequent being neutropenia (35.3%), fatigue (17.6%), and thrombopenia (11.8%). Treatment discontinuation due to toxicity was reported in 88.2% of the patients. No correlation was found between treatment response and DAXX, ATRX, MEN1, SETD2, and PTEN gene mutations., [Conclusion] SUN plus EVO had a negative toxicity profile that should be taken into account for further clinical research in advanced panNETs. The combination showed moderate activity in terms of treatment response that did not correlate with somatic mutations. (Clinical trial identification number: NCT02402062), [Implications for Practice] Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in pancreatic neuroendocrine tumors (panNETs), reaching a median objective response rate of 17.6% and median progression-free survival of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs' resistance to antiangiogenic agents with other therapies with a safer profile.
Published: 2021

13. Jejunum/ ileum Neuroendocrine Tumours: results of a multicentric retrospective study

Author: José Manuel Lopes, Ana Cristina Sanches, Gustavo Rocha, Isabel Fernandes, Grupo Estudos Tumores Neuroendocrinos, Ana Luisa Catarino, Ana Paula Santos, Bernardo Dias Pereira, John Preto, Maria João Bugalho, Juan Mellidez, Isabel Claro, Fernando Rodrigues, and Ana Paula da Silva Marques
Subjects: Jejunum, medicine.medical_specialty, medicine.anatomical_structure, business.industry, Internal medicine, General surgery, medicine, Ileum, Retrospective cohort study, business, Gastroenterology
Published: 2017
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14. Prospective validation of a lymphocyte infiltration prognostic test in stage III colon cancer patients treated with adjuvant FOLFOX.

Author: UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (MGD) Service d'oncologie médicale, UCL - (SLuc) Unité d'oncologie médicale, Emile, Jean-François, Julié, Catherine, Le Malicot, Karine, Lepage, Come, Tabernero, Josep, Mini, Enrico, Folprecht, Gunnar, Van Laethem, Jean-Luc, Dimet, Stéphanie, Boulagnon-Rombi, Camille, Allard, Marc-Antoine, Penault-Llorca, Frédérique, Bennouna, Jaafar, Laurent-Puig, Pierre, Taieb, Julien, PETACC8 Study Investigators, Austrian Breast and Colorectal cancer Study Group (ABCSG), Belgian Group of Digestive Oncology (BGDO), Lone Nørgård Petersen, Fédération Francophone de Cancérologie Digestive (FFCD), Fédération Nationale des Centres de Lutte Contre le Cancer (UNICANCER), Fédération Nationale des Centres de Lutte Contre le Cancer Association Européenne de Recherche en Oncologie (AERO), Arbeitsgemeinschaft Internistische Onkologie (AIO), Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD), Gruppo Oncologico dell'Italia Meridionale (GOIM), Istituto Oncologico Romagnolo (IOR), Gruppo Cooperativo Chirurgico Italiano (GOCCI), Gruppo Oncologico Nord Ovest (GONO), Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), Gruppo Cooperativo do Cancro Digestivo da Associação Portuguesa de Investigação Oncológica (GCCD, APIO), Grupo Español para el Tratamiento de los Tumores Digestivos (TTD), John Allen Bridgewater, Kerger, Joseph, Humblet, Yves, UCL - SSS/IREC/MIRO - Pôle d'imagerie moléculaire, radiothérapie et oncologie, UCL - (MGD) Service d'oncologie médicale, UCL - (SLuc) Unité d'oncologie médicale, Emile, Jean-François, Julié, Catherine, Le Malicot, Karine, Lepage, Come, Tabernero, Josep, Mini, Enrico, Folprecht, Gunnar, Van Laethem, Jean-Luc, Dimet, Stéphanie, Boulagnon-Rombi, Camille, Allard, Marc-Antoine, Penault-Llorca, Frédérique, Bennouna, Jaafar, Laurent-Puig, Pierre, Taieb, Julien, PETACC8 Study Investigators, Austrian Breast and Colorectal cancer Study Group (ABCSG), Belgian Group of Digestive Oncology (BGDO), Lone Nørgård Petersen, Fédération Francophone de Cancérologie Digestive (FFCD), Fédération Nationale des Centres de Lutte Contre le Cancer (UNICANCER), Fédération Nationale des Centres de Lutte Contre le Cancer Association Européenne de Recherche en Oncologie (AERO), Arbeitsgemeinschaft Internistische Onkologie (AIO), Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD), Gruppo Oncologico dell'Italia Meridionale (GOIM), Istituto Oncologico Romagnolo (IOR), Gruppo Cooperativo Chirurgico Italiano (GOCCI), Gruppo Oncologico Nord Ovest (GONO), Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC), Gruppo Cooperativo do Cancro Digestivo da Associação Portuguesa de Investigação Oncológica (GCCD, APIO), Grupo Español para el Tratamiento de los Tumores Digestivos (TTD), John Allen Bridgewater, Kerger, Joseph, and Humblet, Yves
Abstract: BACKGROUND: The prognostic value of lymphocyte infiltration (LI) of colorectal carcinoma (CC) has been demonstrated by several groups. However, no validated test is currently available for clinical practice. We previously described an automated and reproducible method for testing LI and aimed to validate it for clinical use. PATIENTS AND METHODS: According to National Institutes of Health criteria, we designed a prospective validation of this biomarker in patients included in the PETACC8 phase III study. Primary objective was to compare percentage of patients alive and without recurrence at 2 years in patients with high versus low LI (#NCT02364024). Associations of LI with patient recurrence and survival were analysed, and multivariable models were adjusted for treatment and relevant factors. Automated testing of LI was performed on virtual slides without access to clinical data. RESULTS: Among the 1220 CC patients enrolled, LI was high, low and not evaluable in 241 (19.8%), 790 (64.8%) and 189 (15.5%), respectively. Primary objective was met with a 2-year recurrence rate of 14.4% versus 21.1% in patients with high and low LI, respectively (p = 0.02). Patients with high LI also had better disease free survival (DFS) and overall survival (OS). Tumour stage, grade, RAS status and BRAF status were with LI the only prognostic markers in multivariable analysis for OS. Subgroup analyses revealed that high LI had better DFS and OS in mismatch repair (MMR) proficient patients, and in patients without RAS mutation, but not in MMR deficient and RAS mutated patients. CONCLUSION: Although this is the first validation with high level of evidence (IIB) of the prognostic value of a LI test in colon cancers, it still needs to be confirmed in independent series of colon cancer patients.
Published: 2017

15. Hiperaldosteronismo primário: resultados do primeiro estudo multicêntrico português realizado pelo Grupo de Estudos de Tumores da Supra-Renal

Author: Fernandes, V, Silva, T, Martins, D, Gonçalves, D, Almeida, R, Monteiro, AM, Neves, C, Simões, H, Marques, P, Serra, F, Pereira, ML, and Grupo de Estudos de Tumores da Supra-Renal
Subjects: Aldosterona, Hiperaldosteronismo
Abstract: Introduction: Primary Aldosteronism (PA) is the most prevalent cause of secondary hypertension. Nevertheless, there is no portuguese multicenter study characterizing PA patients. Aims: To characterize the clinical presentation, diagnostic workup, treatment and follow-up of patients with confirmed PA. Methods: Retrospective multicenter study of PA patients followed in 9 portuguese hospitals. Results: Sixty-three cases were selected with a mean age of diagnosis of 52.1 ± 13.1 years, 9.9 years after the diagnosis of hypertension. At presentation, 37 cases (60.7%) had hypertension, 11 (22.9%) had resistant hypertension and 20 (32.8%) of patients had hipokalemia (mean 3.2 mmol/L). Baseline laboratory showed a mean serum aldosterone of 33.4ng/dL, plasmatic renin activity (PRA) of 0.2ng/mL/h with an aldosterone/PRA ratio of 97.1. Confirmatory testing was performed with saline infusion in 55 patients (positive in 84.4%) and captopril test in 14 (positive in 85.7%). Imaging showed adenomas in 55 cases, hyperplasia in 2 and bilateral cases in 8. Arterial venous sampling (AVS) was performed in 9 patients (14,5%) and was conclusive in 1. Iodocholesterol scintigraphy was done in 14 cases (22%) with unilateral fixation in 9 and no fixation in 4. Patients were treated with laparoscopic adrenalectomy in 28 cases (58.3%) and mineralocorticoid receptor antagonists in 20 cases (41.7%). The surgical treated group had less duration of hypertension (8 versus 14 years, p = 0.002), higher prevalence of anti-hypertensive drugs at presentation (100 versus 75% p = 0.009) and bigger tumour size (1.8 versus 1.5 cm, p = 0.022). During follow-up there was a trend towards a greater proportion of patients with no hypertension improvement in the medical treatment group (29.4% versus 7.4%, p = 0.089). Conclusion: This is the first Portuguese PA multicenter study. It suggests that PA remains an under- -diagnosed condition with a significant delay in diagnosis. Surgical treated patients had a more aggressive disease and showed a trend towards better hypertension control.
Published: 2016

16. Jejunum/ ileum Neuroendocrine Tumours: results of a multicentric retrospective study

Author: Marques, Ana Paula, primary, Santos, Ana Paula, additional, Claro, Isabel, additional, Sanches, Ana Cristina, additional, Fernandes, Isabel, additional, Lopes, Jose Manuel, additional, Preto, John, additional, Rodrigues, Fernando, additional, Catarino, Ana Luisa, additional, Mellidez, Juan, additional, Pereira, Bernardo, additional, Rocha, Gustavo, additional, Bugalho, Maria Joao, additional, and Neuroendocrinos, Grupo Estudos Tumores, additional
Published: 2017
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17. Health-related quality of life in well-differentiated metastatic gastroenteropancreatic neuroendocrine tumors

Author: Novartis, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Jiménez-Fonseca, Paula, Carmona-Bayonas, Alberto, Martín-Pérez, E., Crespo, Guillermo, Serrano, R., Llanos, Marta, Villabona, C., García-Carbonero, Rocío, Aller-Pardo, Javier, Capdevila, Jaume, Grande, Enrique, Novartis, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Jiménez-Fonseca, Paula, Carmona-Bayonas, Alberto, Martín-Pérez, E., Crespo, Guillermo, Serrano, R., Llanos, Marta, Villabona, C., García-Carbonero, Rocío, Aller-Pardo, Javier, Capdevila, Jaume, and Grande, Enrique
Abstract: © 2015, Springer Science+Business Media New York. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms capable of producing hormones. The development of new treatments has improved progression-free survival, albeit with increased toxicity. Health-related quality of life (HRQoL) has become an important endpoint in clinical research to evaluate patients’ well-being in such a contradictory scenario. In this review, we examine key reported outcomes across clinical studies exploring HRQoL in patients with GEP-NETs. We have conducted a review of the literature using PubMed, The Cochrane Library, EMBASE, and Google Scholar. Selection criteria for articles were (1) publication in English between 1995 and 2014, (2) patients with GEP-NET, and (3) analysis of HRQoL, including mental health and psychological symptoms. Forty-nine studies met the inclusion criteria (31 clinical trials, 14 observational studies, and 4 developments of NET-specific HRQoL instruments). The scope and nature of the literature was diverse with 27 instruments used to measure aspects of HRQoL. EORTC QLQ-C30 was the most frequently used, in 38 of the 49 studies. Standardized measures revealed that in spite of generally good HRQoL, GEP-NET patients have specific psychological and physical complaints. The clinical benefit of somatostatin analogs and sunitinib has been clearly supported by HRQoL assessment. Improvement in HRQoL scores or symptom relief over time was also reported in 14 trials of peptide receptor radionuclide therapy, however the absence of randomized studies obviate definitive conclusions. We have also identified several unanswered questions that should be addressed in further research concerning chemotherapy, everolimus, surgery, local ablative therapies, and chemoembolization. Future research should incorporate GEP-NET-specific HRQoL instruments into phase III trials. This review may help both clinicians and researchers to select the most appropriate tools to assess ch
Published: 2015

18. Effectiveness of gemcitabine and capecitabine in advanced colorectal cancer patients: A retrospective analysis

Author: Ana Fernandez-Montes, Ana Medina, Carlos Romero Reinoso, Guillermo Quintero, Mónica Jorge, M. Salgado, Maria Luz Pellon, Margarita Reboredo, and Asociacion Grupo Gallego de Investigacion en Tumores Digestivos
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, Gemcitabine, Advanced colorectal cancer, Capecitabine, Internal medicine, Retrospective analysis, Medicine, In patient, business, medicine.drug
Abstract: 649 Background: In ASCO2004, Y. Fernandez et al. showed their experience in gemcitabine/capecitabine use in patients with metastatic advanced colorectal cancer (ACRC), with previous progression or contraindicated standar treatment, with encouraging results. This study was design to evaluate the efficacy and safety of this combination in these patients, in our area. Methods: This is an observational, multicentric and retrospective study performed in metastatic colorectal cancer patients refractory to treatment. The study treatment was to evaluate the gemcitabine/capecitabine (gemcitabine 1000 mg/m2, day 1+ capecitabine 1250 mg/m2/12hours, days 1-7, every 15 days) until progression or unacceptable toxicity. The principal endpoint was the best overall response rate achieved during the study period. Secondary endpoints were Progresión Free Survival (PFS), Overall Survival (OS) and safety profile. Results: Of 45 patients recruited a total of 39 patients were evaluated. Median age was 66(37-78) and 69.2 were male. 86.8% of the patients were ECOG PS 1. Mean time from diagnostic was 2.7±2.4 years. Primary tumor was: colon 73.7%, rectum 23.7% and both 2.6%. Adjuvant therapy was received in 34.3% of the patients. Metastatic locations were: liver 82.1%, lung 64.1% and lymph nodes 25.6%. Previous treatment lines received: two 48.7%, three 23.1%, four 17.9%, five 7.7% and six 2.6%. The mean of cycles were 6.4±6 and mean time of treatment was 3.3±2.8 months. Best response during treatment period was partial response 2.9%, stable disease 17.6% and progression 79.4%. OS was 7.32 months and median PFS was 3.02 months. Most frequent toxicities grade 3 experienced: Palmar plantar erythrodysesthesia 5.1%, neutropenia 5.1%, asthenia 2.6%, dyspnea 2.6% and hiperbilirrubinemia 2.6%. No grade 4 toxicities were reported. Conclusions: Despite of the adequate safety profile of the gemcitabine/capecitabine combination, our study does not confirm the efficacy figures reported by others authors. New agents or combinations should be investigated in the treatment of this patient subgroup.
Published: 2012
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19. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study.

Author: Martín-Richard, Marta, Massutí, Bartomeu, Pineda, Eva, Alfonso, Vicente, Marmol, Maribel, Castellano, Daniel, Fonseca, Emilio, Galán, Antonio, Llanos, Marta, Sala, Maria Angeles, Pericay, Carlos, Rivera, Fernando, Sastre, Javier, Segura, Ángel, Quindós, Maria, Maisonobe, Pascal, Alonso, Vicente, Segura, Angel, and TTD (Tumores del Tracto Digestivo) Study Group
Abstract: Background: Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs.Methods: This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist.Results: Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe.Conclusion: Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class.Trial Registration: ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18. [ABSTRACT FROM AUTHOR]
Published: 2013
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20. [The first Mexican consensus of endometrial cancer. Grupo de Investigación en Cáncer de Ovario y Tumores Ginecológicos de México]. | Primer consenso Mexicano de cancer de endometrio

Author: Ruvalcaba-Limón, E., David Cantu-de Leon, León-Rodríguez, E., Cortés-Esteban, P., Serrano-Olvera, A., Morales-Vásquez, F., Sosa-Sánchez, R., Poveda-Velasco, A., Crismatt-Zapata, A., Santillán-Gómez, A., Aguilar-Jiménez, C., Alanís-López, P., Alfaro-Ramírez, P., Alvarez-Avitia, M. A., Aranda-Flores, C. E., Arias-Ceballos, J. H., Arrieta-Rodríguez, O., Barragán-Curiel, E., Botello-Hernández, D., Brom-Valladares, R., Cabrera-Galeana, P. A., Cantón-Romero, J. C., Capdeville-García, D., Cárdenas-Sánchez, J., Castorena-Roji, G., Cepeda-López, F. R., Cervantes-Sánchez, G., Cetina-Pérez, L. C., Coronel-Martínez, J. A., Cortés-Cárdenas, S. A., Cruz-López, J. C., La Garza-Salazar, J. G., Díaz-Romero, C., Dueñas-González, A., Valle-Solís, A. E., Escudero-De Los Ríos, P., Flores-Alvarez, E., García-Matus, R., Gerson-Cwilich, R., González-Enciso, A., González-De-León, C., Guevara-Torres, A. G., Herbert-Núñez, G. S., Hernández-Hernández, C., Hernández-Hernández, D. M., Isla-Ortiz, D., Jesús-Sandoval, R., Jiménez-Cervantes, C., Kuri-Exsome, R., López-Obispo, J. L., Maffuz-Aziz, A., Martínez-Barrera, L. M., Medina-Castro, J. M., Montalvo-Esquivel, G., Mora-Aguilar, V. H., Morales-Palomares, M. A., Morán-Mendoza, A., Morgan-Villela, G., Mota-García, A., Muñoz-González, D. E., Murillo-Cruz, D. A., Novoa-Vargas, A., Ochoa-Carrillo, F. J., Oñate-Ocaña, L. F., Ortega-Rojo, A., Palacios-Martínez, A. G., Palomeque-López, A., Pérez-Montiel, M. D., Quijano-Castro, F., Rivera-Rivera, S., Rivera-Rubí, L. M., Robles-Flores, J. U., Rodríguez-Trejo, A., Salas-Gonzáles, E., Silva, J. A., Solorza-Luna, G., Souto-Del-Bosque, R., Tirado-Gómez, L. L., Torrescano-González, S., Torres-Lobatón, A., Trejo-Durán, E., Villavicencio-Valencia, V., Gallardo-Rincón, D., and Tumores Ginecologicos Mexico, Grupo Investigacion En Cancer Ovario Y.

21. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations

Author: [ 1 ] Harvard TH Chan Sch Publ Hlth, Boston, MA USA Show more [ 2 ] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel Show more [ 3 ] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel Show more [ 4 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany Show more [ 5 ] Univ Chicago, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 6 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China Show more [ 7 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary Show more [ 8 ] Univ Buenos Aires, CONICET, Fac Med, INBIOMED, Buenos Aires, DF, Argentina Show more [ 9 ] CEMIC, Dept Clin Chem, Med Direct, Buenos Aires, DF, Argentina [ 10 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia Show more [ 11 ] Odense Univ Hosp, Dept Clin Genet, Odense, Denmark Show more [ 12 ] City Hope Canc Ctr, Div Clin Canc Genom, Duarte, CA USA [ 13 ] Hong Kong Sanat & Hosp, Dept Pathol, Div Mol Pathol, Happy Valley, Hong Kong, Peoples R China [ 14 ] Dept Lab Med & Pathol, Rochester, MN USA Show more [ 15 ] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA Show more [ 16 ] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil Show more [ 17 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea Show more [ 18 ] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea Show more [ 19 ] Seoul Natl Univ, Canc Res Ctr, Seoul, South Korea Show more [ 20 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia Show more [ 21 ] Univ Pretoria, Dept Genet, Canc Genet Lab, Pretoria, South Africa Show more [ 22 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England Show more [ 23 ] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Brisbane, Qld, Australia [ 24 ] Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands [ 25 ] City Hope Clin Canc Genom Community Res Network, D, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute; Boston USA, The Susanne Levy Gertner Oncogenetics Unit; Institute of Human Genetics; Chaim Sheba Medical Center, Ramat Gan 52621, and the Sackler School of Medicine; Tel-Aviv University; Tel-Aviv Israel, Molecular Genetics of Breast Cancer; German Cancer Research Center (DKFZ); Heidelberg Germany, Center for Clinical Cancer Genetics and Global Health; University of Chicago; Chicago USA, The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center; Hong Kong Sanatorium and Hospital; Hong Kong China, Department of Molecular Genetics; National Institute of Oncology; Budapest Hungary, INBIOMED; Faculty of Medicine, University of Buenos Aires/CONICET and CEMIC, Department of Clinical Chemistry; Medical Direction; Buenos Aires Argentina, Cancer Research Initiatives Foundation; Sime Darby Medical Centre; Subang Jaya Malaysia, Department of Clinical Genetics; Odense University Hospital; Odense Denmark, Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty; University Hospital Cologne; Cologne Germany, Clinical Genetics Services; Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Division of Gynecologic Oncology; North Shore University Health System; University of Chicago; Evanston USA, All Wales Medical Genetics Services; University Hospital of Wales; Cardiff UK, Department of Gynecology; Vilnius University Hospital Santariskiu Clinics; Centre of Woman's Health and pathology; Vilnius Lithuania, Center for Genomic Medicine; Rigshospitalet; University of Copenhagen; Copenhagen Denmark, Clinical Cancer Genetics Program; Division of Human Genetics; Department of Internal Medicine; The Comprehensive Cancer Center; The Ohio State University; Columbus USA, Cancer Genetics Laboratory, Department of Genetics; University of Pretoria; South Africa, Department of Genetics and Pathology; Pomeranian Medical University; Szczecin Poland, Department of Medicine, Abramson Cancer Center; Perelman School of Medicine at the University of Pennsylvania; Philadelphia USA, Department of Internal Medicine; Division of Oncology; University of Kansas Medical Center; Westwood USA, North East Thames Regional Genetics Service; Great Ormond Street Hospital for Children NHS Trust; London UK, Genomics Center; Centre Hospitalier Universitaire de Québec Research Center and Laval University; Quebec City Canada, Dept of OB/GYN and Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Clinical Genetics; Aarhus University Hospital; Aarhus N Denmark, Division of Clinical Cancer Genomics; City of Hope Cancer Center; California USA, Medical Genetics Unit; University of London; St George's UK, Département Oncologie Génétique; Prévention et Dépistage; Institut Paoli-Calmettes; Marseille Medical School-AM University; Marseille France, Department of Breast Medical Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care; University of Cambridge; Cambridge UK, Department of Population Sciences; Beckman Research Institute of City of Hope; Duarte USA, Institute of Cell and Molecular Pathology; Hannover Medical School; Hannover Germany, Institute of Human Genetics; University Hospital Heidelberg; Heidelberg Germany, National Human Genome Research Institute; National Institutes of Health; Bethesda USA, Dept of OB/GYN, Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Genetics; Portuguese Oncology Institute of Porto (IPO Porto); Porto Portugal, Department of Epidemiology; Columbia University; New York USA, Genetic Counseling Unit; Hereditary Cancer Program; IDIBELL (Bellvitge Biomedical Research Institute); Catalan Institute of Oncology, CIBERONC; Gran Via de l'Hospitalet; Barcelona Spain, Department of Health Sciences Research; Mayo Clinic; Rochester USA, Genetics and Computational Biology Department; QIMR Berghofer Medical Research Institute; Brisbane Australia, Department of Medicine; Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Program in Cancer Genetics; Departments of Human Genetics and Oncology; McGill University; Montreal Canada, Immunology and Molecular Oncology Unit; Veneto Institute of Oncology IOV - IRCCS; Padua Italy, Division of Human Genetics; Departments of Internal Medicine and Cancer Biology and Genetics; Comprehensive Cancer Center; The Ohio State University; Columbus USA, Clinical Genetics Research Laboratory, Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Parkville Familial Cancer Centre; Royal Melbourne Hospital; Melbourne Australia, Department of Medical Oncology; Beth Israel Deaconess Medical Center; Massachusetts USA, Department of Clinical Genetics; Leiden University Medical Center; Leiden The Netherlands, Department of Genetics; University Medical Center; Groningen University; Groningen The Netherlands, Family Cancer Clinic; Netherlands Cancer Institute; Amsterdam The Netherlands, Department of Medical Genetics; University Medical Center; Utrecht The Netherlands, Center for Medical Genetics; Ghent University; Gent Belgium, Unit of Hereditary Cancer; Department of Epidemiology, Prevention and Special Functions; IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro; Genoa Italy, Institute of Human Genetics; Campus Virchov Klinikum; Berlin Germany, Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela; Spain, Departamento de Investigacion y de Tumores Mamarios del; Instituto Nacional de Cancerologia; Mexico City Mexico, Department of Oncology; Karolinska University Hospital; Stockholm Sweden, Institute of Genetic Medicine; Centre for Life; Newcastle Upon Tyne Hospitals NHS Trust; Newcastle upon Tyne UK, Oxford Regional Genetics Service; Churchill Hospital; Oxford UK, Department of Gynaecology and Obstetrics; University Hospital; Ulm Germany, Department of Clinical Genetics; Academic Medical Center; Amsterdam The Netherlands, Institute of Human Genetics; Regensburg University; Regensburg Germany, Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology); National Centre for Scientific Research “Demokritos”; Athens Greece, Unit of Medical Genetics, Department of Medical Oncology and Hematology; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT); Milan Italy, Institute of Oncology; Rivka Ziv Medical Center; Zefat Israel, Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Institute of Human Genetics; University Leipzig; Leipzig Germany, Center for Medical Genetics; North Shore University Health System; Evanston USA, Medical Director, Center for Medical Genetics, NorthShore University HealthSystem, Clinical Assistant Professor of Medicine; University of Chicago Pritzker School of Medicine; Evanston USA, City of Hope Clinical Cancer Genomics Community Research Network; Duarte USA, Yorkshire Regional Genetics Service; Chapel Allerton Hospital; Leeds UK, Department of Clinical Genetics; Helsinki University Hospital; Helsinki Finland, Hereditary Cancer Clinic; Prince of Wales Hospital; Randwick Australia, Lunenfeld-Tanenbaum Research Institute; Toronto Canada, Laboratory of Cell Biology, Department of Pathology, hus 9, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland and BMC (Biomedical Centre), Faculty of Medicine; University of Iceland; Reykjavik Iceland, Department of Gynaecology & Oncology; Medical University of Vienna; Austria, Department of Medical Oncology; Vall d'Hebron University Hospital; Barcelona Spain, Division of Cancer Prevention and Genetics; Istituto Europeo di Oncologia (IEO); Milan Italy, Department of Gynaecology and Obstetrics; University Hospital Düsseldorf, Heinrich-Heine University; Düsseldorf Germany, Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Madrid Spain, The Institute of Oncology; Chaim Sheba Medical Center; Ramat Gan Israel, UCSF Cancer Genetics and Prevention Program; San Francisco USA, Department of Clinical Genetics; Maastricht University Medical Center; Maastricht The Netherlands, Unité de Prévention et d'Epidémiologie Génétique; Centre Léon Bérard, 28 rue Laënnec; Lyon France, N.N. Petrov Institute of Oncology; St. Petersburg Russia, Department of Clinical Genetics; Royal Devon & Exeter Hospital; Exeter UK, Service de Génétique; Institut Curie, 26 rue d'Ulm; Paris France, Department of Medicine; Huntsman Cancer Institute; Salt Lake City USA, Molecular Oncology Laboratory; Hospital Clinico San Carlos; Instituto de Investigación Sanitaria San Carlos (IdISSC); Centro Investigación Biomédica en Red de Cáncer (CIBERONC); Madrid Spain, Institute of Human Genetics; University Hospital of Schleswig-Holstein; Kiel Germany, Section of Molecular Genetics, Dept. of Laboratory Medicine; University Hospital of Pisa; Pisa Italy, Research Division; Peter MacCallum Cancer Centre; Melbourne Australia, CRCHU de Quebec-oncologie, Centre des maladies du sein Deschênes-Fabia; Hôpital du Saint-Sacrement; Sainte-Foy Canada, Lombardi Comprehensive Cancer Center; Georgetown University; Washington USA, Departments of Pediatrics and Medicine; Columbia University; New York USA, Department of Clinical Genetics, Family Cancer Clinic; Erasmus University Medical Center; Rotterdam The Netherlands, Sheffield Clinical Genetics Service; Sheffield Children's Hospital; Sheffield UK, Department of Clinical Genetics; South Glasgow University Hospitals; Glasgow UK, Unité d'oncogénétique; ICO-Centre René Gauducheau; Saint Herblain France, Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area; Vall d'Hebron University Hospital; Barcelona Spain, Department of Gynaecology and Obstetrics; Ludwig-Maximilian University; Munich Germany, Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM; Universidad de Valladolid; Valladolid Spain, Institute of Human Genetics; University of Münster; Münster Germany, Nottingham Clinical Genetics Service; Nottingham University Hospitals NHS Trust; Nottingham UK, Oncogenetics Team; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; London UK, Department of Clinical Genetics; Lund University Hospital; Lund Sweden, Clinical Genetics; Guy's and St. Thomas’ NHS Foundation Trust; London UK, Department of Oncology, Rigshospitalet; Copenhagen University Hospital; Copenhagen Denmark, Institute for Medical Informatics, Statistics and Epidemiology; University of Leipzig; Leipzig Germany, Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar; Technical University; Munich Germany, Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences; University of Manchester, Central Manchester University Hospitals NHS Foundation Trust; Manchester UK, Centre de Lutte Contre le Cancer Georges François Leclerc, France and Genomic and Immunotherapy Medical Institute; Dijon University Hospital; Dijon France, Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology-Bellvitge Biomedical Research Institute); Barcelona Spain, Laboratoire de Génétique Chromosomique; Hôtel Dieu Centre Hospitalier; Chambéry France, Department of Cancer Epidemiology and Genetics; Masaryk Memorial Cancer Institute; Brno Czech Republic, Columbus Cancer Council, Ohio State University; Columbus USA, Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona); Catalan Institute of Oncology; Girona Spain, Oncogenetics Department; Barretos Cancer Hospital; Barretos Brazil, UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research; Jonsson Comprehensive Cancer Center; Los Angeles USA, Cancer Risk and Prevention Clinic; Dana-Farber Cancer Institute; Boston USA, Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics; University of Würzburg, Germany; Würzburg, Department of Clinical Genetics; Copenhagen Denmark, Service Régional Oncogénétique Poitou-Charentes; Centre Hospitalier; Niort France, Department of Molecular Medicine; University La Sapienza, and Istituto Pasteur - Fondazione Cenci-Bolognetti; Rome Italy, Bâtiment Cheney D; Centre Léon Bérard; Lyon France, Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital; Toronto Canada, Department of Pathology and Laboratory Medicine; University of Kansas Medical Center; Kansas City USA, Clinical Genetics Branch, DCEG, NCI; NIH; Bethesda USA, Parkville Familial Cancer Centre; Peter MacCallum Cancer Centre; Melbourne Australia, Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine; Vilnius University Hospital Santariskiu Clinics; Vilnius Lithuania, Department of Epidemiology, Cancer Prevention Institute of California; Fremont USA, Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles USA, Division of Molecular Pathology; Department of Pathology; Hong Kong Sanatorium & Hospital; Happy Valley Hong Kong, Department of Gynecology and Obstetrics; Medical Faculty and University Hospital Carl Gustav Carus; Dresden Germany, Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria; Australia and The Sir Peter MacCallum Department of Oncology University of Melbourne; Parkville Australia, Department of Surgery; Daerim St. Mary's Hospital; Seoul Korea, The Gyneco-Oncology Department; Chaim Sheba Medical Center; Ramat Gan Israel, Servicio de Genética-CIBERER U705; Hospital de la Santa Creu i Sant Pau; Barcelona Spain, The Feinstein Institute for Medical Research; Manhasset USA, Department of Laboratory Medicine and Pathology; and Health Sciences Research; Rochester USA, Department of Surgery; Soonchunhyang University and Seoul Hospital; Seoul Korea, Inserm U900, Institut Curie; PSL Research University; Paris France, Department of Oncology Radiumhemmet and Institution of Oncology and Patology; Karolinska University Hospital and Karolinska Institutet; Solna Sweden, Department of Health Sciences Research; Mayo Clinic; Scottsdale USA, Oncogénétique; Institut Bergonié; Bordeaux France, Clinical Genetics Branch, DCEG, NCI, NIH; Bethesda USA, Department of Gynecological Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Department of Dermatology; University of Utah School of Medicine; Salt Lake City USA, Centre Antoine Lacassagne; Nice France, Laboratorio de Genética Molecular, Servicio de Genética; Hospital Universitario Cruces, BioCruces Health Research Institute; Barakaldo Spain, Department of Surgery; National Institute of Oncology; Budapest Hungary, Department of Clinical Genetics; VU University Medical Center; Amsterdam The Netherlands, Department of Human Genetics; Radboud University Medical Center; Nijmegen The Netherlands, Vilnius university Santariskiu hospital; National Center of Pathology; Vilnius Lithuania, NRG Oncology; Statistics and Data Management Center; Roswell Park Cancer Institute; Buffalo USA, Department of Cancer Prevention and Control; Roswell Park Cancer Institute; Buffalo USA, Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto Canada, Department of Obstetrics and Gynecology; University of Helsinki and Helsinki University Hospital; HUS Finland, Cancer Genetics Service; Division of Medical Oncology; National Cancer Centre Singapore; Bukit Merah Singapore, Institute of Medical Genetics and Applied Genomics; University of Tuebingen; Tuebingen Germany, Molecular Oncology Research Center; Barretos Cancer Hospital; São Paulo Brazil, Cancer Genetics and Prevention Program; University of California San Francisco; San Francisco USA, Clinical Genetics Research Laboratory; Dept. of Medicine; Cancer Biology and Genetics; Memorial Sloan-Kettering Cancer Center; New York USA, Department of Clinical Genetics; Sahlgrenska University Hospital; Gothenburg Sweden, West Midlands Regional Genetics Service; Birmingham Women's Hospital Healthcare NHS Trust; Edgbaston UK, Human Genetics Group; Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Biomedical Network on Rare Diseases (CIBERER); Madrid Spain, Unit of Medical Genetics; Department of Biomedical; Experimental and Clinical Sciences; University of Florence; Florence Italy, Department of Medical Sciences; University of Turin; Turin Italy, Section of Molecular Diagnostics; Department of Biochemistry; Aalborg University Hospital; Aalborg Denmark, Department of Preventive Medicine; Seoul National University College of Medicine; Seoul Korea, IFOM; The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology; Milan Italy, Service de Génétique Clinique Chromosomique et Moléculaire; Hôpital Nord; St Etienne France, Unité d'Oncogénétique; CHU Arnaud de Villeneuve; Montpellier France, Unit of Molecular Bases of Genetic Risk and Genetic Testing; Department of Research; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Istituto Nazionale Tumori (INT); Milan Italy, School of Women's and Children's Health; UNSW; Sydney Australia, Department of Clinical Genetics; Karolinska University Hospital; Stockholm Sweden, Rebbeck, Timothy R., Friebel, Tara M., Friedman, Eitan, Hamann, Ute, Huo, Dezheng, Kwong, Ava, Olah, Edith, Olopade, Olufunmilayo I., Solano, Angela R., Teo, Soo-Hwang, Thomassen, Mads, Rashid, Muhammad Usman, Rhiem, Kerstin, Robson, Mark, Rodriguez, Gustavo C., Rogers, Mark T., Rudaitis, Vilius, Schmidt, Ane Y., Schmutzler, Rita Katharina, Senter, Leigha, van Rensburg, Elizabeth J., Gronwald, Jacek, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Simard, Jacques, Singer, Christian F., Skytte, Anne-Bine, Slavin, Thomas P., Snape, Katie, Sobol, Hagay, Southey, Melissa, Gutierrez-Barrera, Angelica, McGuffog, Lesley, Steele, Linda, Steinemann, Doris, Sukiennicki, Grzegorz, Sutter, Christian, Szabo, Csilla I., Tan, Yen Y., Teixeira, Manuel R., Terry, Mary Beth, Teulé, Alex, Hahnen, Eric, Thomas, Abigail, Parsons, Michael T., Thull, Darcy L., Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Topka, Sabine, Trainer, Alison H, Tung, Nadine, van Asperen, Christi J., Hauke, Jan, van der Hout, Annemieke H., van der Kolk, Lizet E., Leslie, Goska, van der Luijt, Rob B., Van Heetvelde, Mattias, Varesco, Liliana, Varon-Mateeva, Raymonda, Vega, Ana, Villarreal-Garza, Cynthia, von Wachenfeldt, Anna, Henderson, Alex, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Aalfs, Cora M., Weber, Bernhard H. F., Yannoukakos, Drakoulis, Yoon, Sook-Yee, Zanzottera, Cristina, Zidan, Jamal, Zorn, Kristin K., Hentschel, Julia, Hutten Selkirk, Christina G., Hulick, Peter J., Chenevix-Trench, Georgia, Spurdle, Amanda B., Abugattas, Julio, Antoniou, Antonis C., Nathanson, Katherine L., Adlard, Julian, Agata, Simona, Aittomäki, Kristiina, Hogervorst, Frans B.L., Andrews, Lesley, Andrulis, Irene L., Arason, Adalgeir, Arnold, Norbert, Arun, Banu K., Asseryanis, Ella, Auerbach, Leo, Azzollini, Jacopo, Balmaña, Judith, Barile, Monica, Honisch, Ellen, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berger, Andreas, Berger, Raanan, Blanco, Amie M., Blazer, Kathleen R., Blok, Marinus J., Bonadona, Valérie, Bonanni, Bernardo, Imyanitov, Evgeny N., Bradbury, Angela R., Brewer, Carole, Buecher, Bruno, Buys, Saundra S., Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Campbell, Ian, Caputo, Sandrine M., Chiquette, Jocelyne, Isaacs, Claudine, Chung, Wendy K., Claes, Kathleen B.M., Collée, J. Margriet, Cook, Jackie, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Pauw, Antoine, Delnatte, Capucine, Diez, Orland, Weitzel, Jeffrey N., Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M., Dorfling, Cecilia M., Velazquez, Carolina, Dworniczak, Bernd, Eason, Jacqueline, Easton, Douglas F., Eeles, Ros, Ehrencrona, Hans, Izatt, Louise, Ejlertsen, Bent, Engel, Christoph, Engert, Stefanie, Evans, D. Gareth, Faivre, Laurence, Feliubadaló, Lidia, Ferrer, Sandra Fert, Foretova, Lenka, Fowler, Jeffrey, Frost, Debra, Izquierdo, Angel, Galvão, Henrique C. R., Ganz, Patricia A., Garber, Judy, Gauthier-Villars, Marion, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Giraud, Sophie, Glendon, Gord, Jakubowska, Anna, Godwin, Andrew K., Greene, Mark H., James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M., Vijai, Joseph, Kaczmarek, Katarzyna, Karlan, Beth Y., Chan, TL, Kast, Karin, Investigators, KConFab, Kim, Sung-Won, Konstantopoulou, Irene, Korach, Jacob, Laitman, Yael, Lasa, Adriana, Lasset, Christine, Lázaro, Conxi, Lee, Annette, Couch, Fergus J., Lee, Min Hyuk, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Lindor, Noralane M., Longy, Michel, Loud, Jennifer T., Lu, Karen H., Lubinski, Jan, Machackova, Eva, Goldgar, David E., Manoukian, Siranoush, Mari, Véronique, Martínez-Bouzas, Cristina, Matrai, Zoltan, Mebirouk, Noura, Meijers-Heijboer, Hanne E.J., Meindl, Alfons, Mensenkamp, Arjen R., Mickys, Ugnius, Miller, Austin, Kruse, Torben A., Montagna, Marco, Moysich, Kirsten B., Mulligan, Anna Marie, Musinsky, Jacob, Neuhausen, Susan L., Nevanlinna, Heli, Ngeow, Joanne, Nguyen, Huu Phuc, Niederacher, Dieter, Nielsen, Henriette Roed, Palmero, Edenir Inêz, Nielsen, Finn Cilius, Nussbaum, Robert L., Offit, Kenneth, Öfverholm, Anna, Ong, Kai-ren, Osorio, Ana, Papi, Laura, Papp, Janos, Pasini, Barbara, Pedersen, Inge Sokilde, Park, Sue Kyung, Peixoto, Ana, Peruga, Nina, Peterlongo, Paolo, Pohl, Esther, Pradhan, Nisha, Prajzendanc, Karolina, Prieur, Fabienne, Pujol, Pascal, Radice, Paolo, Ramus, Susan J., Torres, Diana, Rantala, Johanna, [ 1 ] Harvard TH Chan Sch Publ Hlth, Boston, MA USA Show more [ 2 ] Chaim Sheba Med Ctr, Inst Human Genet, Susanne Levy Gertner Oncogenet Unit, IL-52621 Ramat Gan, Israel Show more [ 3 ] Tel Aviv Univ, Sackler Sch Med, Tel Aviv, Israel Show more [ 4 ] German Canc Res Ctr, Mol Genet Breast Canc, Heidelberg, Germany Show more [ 5 ] Univ Chicago, Ctr Clin Canc Genet & Global Hlth, Chicago, IL 60637 USA [ 6 ] Hong Kong Sanat & Hosp, Canc Genet Ctr, Hong Kong Hereditary Breast Canc Family Registry, Hong Kong, Hong Kong, Peoples R China Show more [ 7 ] Natl Inst Oncol, Dept Mol Genet, Budapest, Hungary Show more [ 8 ] Univ Buenos Aires, CONICET, Fac Med, INBIOMED, Buenos Aires, DF, Argentina Show more [ 9 ] CEMIC, Dept Clin Chem, Med Direct, Buenos Aires, DF, Argentina [ 10 ] Sime Darby Med Ctr, Canc Res Initiat Fdn, Subang Jaya, Malaysia Show more [ 11 ] Odense Univ Hosp, Dept Clin Genet, Odense, Denmark Show more [ 12 ] City Hope Canc Ctr, Div Clin Canc Genom, Duarte, CA USA [ 13 ] Hong Kong Sanat & Hosp, Dept Pathol, Div Mol Pathol, Happy Valley, Hong Kong, Peoples R China [ 14 ] Dept Lab Med & Pathol, Rochester, MN USA Show more [ 15 ] Univ Utah, Sch Med, Dept Dermatol, Salt Lake City, UT USA Show more [ 16 ] Barretos Canc Hosp, Mol Oncol Res Ctr, Sao Paulo, Brazil Show more [ 17 ] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea Show more [ 18 ] Seoul Natl Univ, Grad Sch, Dept Biomed Sci, Seoul, South Korea Show more [ 19 ] Seoul Natl Univ, Canc Res Ctr, Seoul, South Korea Show more [ 20 ] Pontificia Univ Javeriana, Inst Human Genet, Bogota, Colombia Show more [ 21 ] Univ Pretoria, Dept Genet, Canc Genet Lab, Pretoria, South Africa Show more [ 22 ] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England Show more [ 23 ] QIMR Berghofer Med Res Inst, Genet & Computat Biol Dept, Brisbane, Qld, Australia [ 24 ] Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands [ 25 ] City Hope Clin Canc Genom Community Res Network, D, Harvard TH Chan School of Public Health and Dana Farber Cancer Institute; Boston USA, The Susanne Levy Gertner Oncogenetics Unit; Institute of Human Genetics; Chaim Sheba Medical Center, Ramat Gan 52621, and the Sackler School of Medicine; Tel-Aviv University; Tel-Aviv Israel, Molecular Genetics of Breast Cancer; German Cancer Research Center (DKFZ); Heidelberg Germany, Center for Clinical Cancer Genetics and Global Health; University of Chicago; Chicago USA, The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center; Hong Kong Sanatorium and Hospital; Hong Kong China, Department of Molecular Genetics; National Institute of Oncology; Budapest Hungary, INBIOMED; Faculty of Medicine, University of Buenos Aires/CONICET and CEMIC, Department of Clinical Chemistry; Medical Direction; Buenos Aires Argentina, Cancer Research Initiatives Foundation; Sime Darby Medical Centre; Subang Jaya Malaysia, Department of Clinical Genetics; Odense University Hospital; Odense Denmark, Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty; University Hospital Cologne; Cologne Germany, Clinical Genetics Services; Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Division of Gynecologic Oncology; North Shore University Health System; University of Chicago; Evanston USA, All Wales Medical Genetics Services; University Hospital of Wales; Cardiff UK, Department of Gynecology; Vilnius University Hospital Santariskiu Clinics; Centre of Woman's Health and pathology; Vilnius Lithuania, Center for Genomic Medicine; Rigshospitalet; University of Copenhagen; Copenhagen Denmark, Clinical Cancer Genetics Program; Division of Human Genetics; Department of Internal Medicine; The Comprehensive Cancer Center; The Ohio State University; Columbus USA, Cancer Genetics Laboratory, Department of Genetics; University of Pretoria; South Africa, Department of Genetics and Pathology; Pomeranian Medical University; Szczecin Poland, Department of Medicine, Abramson Cancer Center; Perelman School of Medicine at the University of Pennsylvania; Philadelphia USA, Department of Internal Medicine; Division of Oncology; University of Kansas Medical Center; Westwood USA, North East Thames Regional Genetics Service; Great Ormond Street Hospital for Children NHS Trust; London UK, Genomics Center; Centre Hospitalier Universitaire de Québec Research Center and Laval University; Quebec City Canada, Dept of OB/GYN and Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Clinical Genetics; Aarhus University Hospital; Aarhus N Denmark, Division of Clinical Cancer Genomics; City of Hope Cancer Center; California USA, Medical Genetics Unit; University of London; St George's UK, Département Oncologie Génétique; Prévention et Dépistage; Institut Paoli-Calmettes; Marseille Medical School-AM University; Marseille France, Department of Breast Medical Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care; University of Cambridge; Cambridge UK, Department of Population Sciences; Beckman Research Institute of City of Hope; Duarte USA, Institute of Cell and Molecular Pathology; Hannover Medical School; Hannover Germany, Institute of Human Genetics; University Hospital Heidelberg; Heidelberg Germany, National Human Genome Research Institute; National Institutes of Health; Bethesda USA, Dept of OB/GYN, Comprehensive Cancer Center; Medical University of Vienna; Vienna Austria, Department of Genetics; Portuguese Oncology Institute of Porto (IPO Porto); Porto Portugal, Department of Epidemiology; Columbia University; New York USA, Genetic Counseling Unit; Hereditary Cancer Program; IDIBELL (Bellvitge Biomedical Research Institute); Catalan Institute of Oncology, CIBERONC; Gran Via de l'Hospitalet; Barcelona Spain, Department of Health Sciences Research; Mayo Clinic; Rochester USA, Genetics and Computational Biology Department; QIMR Berghofer Medical Research Institute; Brisbane Australia, Department of Medicine; Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Program in Cancer Genetics; Departments of Human Genetics and Oncology; McGill University; Montreal Canada, Immunology and Molecular Oncology Unit; Veneto Institute of Oncology IOV - IRCCS; Padua Italy, Division of Human Genetics; Departments of Internal Medicine and Cancer Biology and Genetics; Comprehensive Cancer Center; The Ohio State University; Columbus USA, Clinical Genetics Research Laboratory, Dept. of Medicine; Memorial Sloan-Kettering Cancer Center; New York USA, Parkville Familial Cancer Centre; Royal Melbourne Hospital; Melbourne Australia, Department of Medical Oncology; Beth Israel Deaconess Medical Center; Massachusetts USA, Department of Clinical Genetics; Leiden University Medical Center; Leiden The Netherlands, Department of Genetics; University Medical Center; Groningen University; Groningen The Netherlands, Family Cancer Clinic; Netherlands Cancer Institute; Amsterdam The Netherlands, Department of Medical Genetics; University Medical Center; Utrecht The Netherlands, Center for Medical Genetics; Ghent University; Gent Belgium, Unit of Hereditary Cancer; Department of Epidemiology, Prevention and Special Functions; IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) AOU San Martino - IST Istituto Nazionale per la Ricerca sul Cancro; Genoa Italy, Institute of Human Genetics; Campus Virchov Klinikum; Berlin Germany, Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela; Spain, Departamento de Investigacion y de Tumores Mamarios del; Instituto Nacional de Cancerologia; Mexico City Mexico, Department of Oncology; Karolinska University Hospital; Stockholm Sweden, Institute of Genetic Medicine; Centre for Life; Newcastle Upon Tyne Hospitals NHS Trust; Newcastle upon Tyne UK, Oxford Regional Genetics Service; Churchill Hospital; Oxford UK, Department of Gynaecology and Obstetrics; University Hospital; Ulm Germany, Department of Clinical Genetics; Academic Medical Center; Amsterdam The Netherlands, Institute of Human Genetics; Regensburg University; Regensburg Germany, Molecular Diagnostics Laboratory, INRASTES (Institute of Nuclear and Radiological Sciences and Technology); National Centre for Scientific Research “Demokritos”; Athens Greece, Unit of Medical Genetics, Department of Medical Oncology and Hematology; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Instituto Nazionale Tumori (INT); Milan Italy, Institute of Oncology; Rivka Ziv Medical Center; Zefat Israel, Magee-Womens Hospital; University of Pittsburgh School of Medicine; Pittsburgh USA, Institute of Human Genetics; University Leipzig; Leipzig Germany, Center for Medical Genetics; North Shore University Health System; Evanston USA, Medical Director, Center for Medical Genetics, NorthShore University HealthSystem, Clinical Assistant Professor of Medicine; University of Chicago Pritzker School of Medicine; Evanston USA, City of Hope Clinical Cancer Genomics Community Research Network; Duarte USA, Yorkshire Regional Genetics Service; Chapel Allerton Hospital; Leeds UK, Department of Clinical Genetics; Helsinki University Hospital; Helsinki Finland, Hereditary Cancer Clinic; Prince of Wales Hospital; Randwick Australia, Lunenfeld-Tanenbaum Research Institute; Toronto Canada, Laboratory of Cell Biology, Department of Pathology, hus 9, Landspitali-LSH v/Hringbraut, 101 Reykjavik, Iceland and BMC (Biomedical Centre), Faculty of Medicine; University of Iceland; Reykjavik Iceland, Department of Gynaecology & Oncology; Medical University of Vienna; Austria, Department of Medical Oncology; Vall d'Hebron University Hospital; Barcelona Spain, Division of Cancer Prevention and Genetics; Istituto Europeo di Oncologia (IEO); Milan Italy, Department of Gynaecology and Obstetrics; University Hospital Düsseldorf, Heinrich-Heine University; Düsseldorf Germany, Human Genetics Group and Genotyping Unit (CEGEN), Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Madrid Spain, The Institute of Oncology; Chaim Sheba Medical Center; Ramat Gan Israel, UCSF Cancer Genetics and Prevention Program; San Francisco USA, Department of Clinical Genetics; Maastricht University Medical Center; Maastricht The Netherlands, Unité de Prévention et d'Epidémiologie Génétique; Centre Léon Bérard, 28 rue Laënnec; Lyon France, N.N. Petrov Institute of Oncology; St. Petersburg Russia, Department of Clinical Genetics; Royal Devon & Exeter Hospital; Exeter UK, Service de Génétique; Institut Curie, 26 rue d'Ulm; Paris France, Department of Medicine; Huntsman Cancer Institute; Salt Lake City USA, Molecular Oncology Laboratory; Hospital Clinico San Carlos; Instituto de Investigación Sanitaria San Carlos (IdISSC); Centro Investigación Biomédica en Red de Cáncer (CIBERONC); Madrid Spain, Institute of Human Genetics; University Hospital of Schleswig-Holstein; Kiel Germany, Section of Molecular Genetics, Dept. of Laboratory Medicine; University Hospital of Pisa; Pisa Italy, Research Division; Peter MacCallum Cancer Centre; Melbourne Australia, CRCHU de Quebec-oncologie, Centre des maladies du sein Deschênes-Fabia; Hôpital du Saint-Sacrement; Sainte-Foy Canada, Lombardi Comprehensive Cancer Center; Georgetown University; Washington USA, Departments of Pediatrics and Medicine; Columbia University; New York USA, Department of Clinical Genetics, Family Cancer Clinic; Erasmus University Medical Center; Rotterdam The Netherlands, Sheffield Clinical Genetics Service; Sheffield Children's Hospital; Sheffield UK, Department of Clinical Genetics; South Glasgow University Hospitals; Glasgow UK, Unité d'oncogénétique; ICO-Centre René Gauducheau; Saint Herblain France, Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area; Vall d'Hebron University Hospital; Barcelona Spain, Department of Gynaecology and Obstetrics; Ludwig-Maximilian University; Munich Germany, Cáncer Hereditario, Instituto de Biología y Genética Molecular, IBGM; Universidad de Valladolid; Valladolid Spain, Institute of Human Genetics; University of Münster; Münster Germany, Nottingham Clinical Genetics Service; Nottingham University Hospitals NHS Trust; Nottingham UK, Oncogenetics Team; The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; London UK, Department of Clinical Genetics; Lund University Hospital; Lund Sweden, Clinical Genetics; Guy's and St. Thomas’ NHS Foundation Trust; London UK, Department of Oncology, Rigshospitalet; Copenhagen University Hospital; Copenhagen Denmark, Institute for Medical Informatics, Statistics and Epidemiology; University of Leipzig; Leipzig Germany, Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar; Technical University; Munich Germany, Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Sciences; University of Manchester, Central Manchester University Hospitals NHS Foundation Trust; Manchester UK, Centre de Lutte Contre le Cancer Georges François Leclerc, France and Genomic and Immunotherapy Medical Institute; Dijon University Hospital; Dijon France, Molecular Diagnostic Unit, Hereditary Cancer Program, ICO-IDIBELL (Catalan Institute of Oncology-Bellvitge Biomedical Research Institute); Barcelona Spain, Laboratoire de Génétique Chromosomique; Hôtel Dieu Centre Hospitalier; Chambéry France, Department of Cancer Epidemiology and Genetics; Masaryk Memorial Cancer Institute; Brno Czech Republic, Columbus Cancer Council, Ohio State University; Columbus USA, Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona); Catalan Institute of Oncology; Girona Spain, Oncogenetics Department; Barretos Cancer Hospital; Barretos Brazil, UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research; Jonsson Comprehensive Cancer Center; Los Angeles USA, Cancer Risk and Prevention Clinic; Dana-Farber Cancer Institute; Boston USA, Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics; University of Würzburg, Germany; Würzburg, Department of Clinical Genetics; Copenhagen Denmark, Service Régional Oncogénétique Poitou-Charentes; Centre Hospitalier; Niort France, Department of Molecular Medicine; University La Sapienza, and Istituto Pasteur - Fondazione Cenci-Bolognetti; Rome Italy, Bâtiment Cheney D; Centre Léon Bérard; Lyon France, Ontario Cancer Genetics Network: Lunenfeld-Tanenbaum Research Institute; Mount Sinai Hospital; Toronto Canada, Department of Pathology and Laboratory Medicine; University of Kansas Medical Center; Kansas City USA, Clinical Genetics Branch, DCEG, NCI; NIH; Bethesda USA, Parkville Familial Cancer Centre; Peter MacCallum Cancer Centre; Melbourne Australia, Hematology, oncology and transfusion medicine center, Dept. of Molecular and Regenerative Medicine; Vilnius University Hospital Santariskiu Clinics; Vilnius Lithuania, Department of Epidemiology, Cancer Prevention Institute of California; Fremont USA, Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute; Cedars-Sinai Medical Center; Los Angeles USA, Division of Molecular Pathology; Department of Pathology; Hong Kong Sanatorium & Hospital; Happy Valley Hong Kong, Department of Gynecology and Obstetrics; Medical Faculty and University Hospital Carl Gustav Carus; Dresden Germany, Research Department, Peter MacCallum Cancer Centre, Melbourne, Victoria; Australia and The Sir Peter MacCallum Department of Oncology University of Melbourne; Parkville Australia, Department of Surgery; Daerim St. Mary's Hospital; Seoul Korea, The Gyneco-Oncology Department; Chaim Sheba Medical Center; Ramat Gan Israel, Servicio de Genética-CIBERER U705; Hospital de la Santa Creu i Sant Pau; Barcelona Spain, The Feinstein Institute for Medical Research; Manhasset USA, Department of Laboratory Medicine and Pathology; and Health Sciences Research; Rochester USA, Department of Surgery; Soonchunhyang University and Seoul Hospital; Seoul Korea, Inserm U900, Institut Curie; PSL Research University; Paris France, Department of Oncology Radiumhemmet and Institution of Oncology and Patology; Karolinska University Hospital and Karolinska Institutet; Solna Sweden, Department of Health Sciences Research; Mayo Clinic; Scottsdale USA, Oncogénétique; Institut Bergonié; Bordeaux France, Clinical Genetics Branch, DCEG, NCI, NIH; Bethesda USA, Department of Gynecological Oncology and Clinical Cancer Genetics Program; University Of Texas MD Anderson Cancer Center; Houston USA, Department of Dermatology; University of Utah School of Medicine; Salt Lake City USA, Centre Antoine Lacassagne; Nice France, Laboratorio de Genética Molecular, Servicio de Genética; Hospital Universitario Cruces, BioCruces Health Research Institute; Barakaldo Spain, Department of Surgery; National Institute of Oncology; Budapest Hungary, Department of Clinical Genetics; VU University Medical Center; Amsterdam The Netherlands, Department of Human Genetics; Radboud University Medical Center; Nijmegen The Netherlands, Vilnius university Santariskiu hospital; National Center of Pathology; Vilnius Lithuania, NRG Oncology; Statistics and Data Management Center; Roswell Park Cancer Institute; Buffalo USA, Department of Cancer Prevention and Control; Roswell Park Cancer Institute; Buffalo USA, Department of Laboratory Medicine and Pathobiology; University of Toronto; Toronto Canada, Department of Obstetrics and Gynecology; University of Helsinki and Helsinki University Hospital; HUS Finland, Cancer Genetics Service; Division of Medical Oncology; National Cancer Centre Singapore; Bukit Merah Singapore, Institute of Medical Genetics and Applied Genomics; University of Tuebingen; Tuebingen Germany, Molecular Oncology Research Center; Barretos Cancer Hospital; São Paulo Brazil, Cancer Genetics and Prevention Program; University of California San Francisco; San Francisco USA, Clinical Genetics Research Laboratory; Dept. of Medicine; Cancer Biology and Genetics; Memorial Sloan-Kettering Cancer Center; New York USA, Department of Clinical Genetics; Sahlgrenska University Hospital; Gothenburg Sweden, West Midlands Regional Genetics Service; Birmingham Women's Hospital Healthcare NHS Trust; Edgbaston UK, Human Genetics Group; Human Cancer Genetics Programme; Spanish National Cancer Research Centre (CNIO); Biomedical Network on Rare Diseases (CIBERER); Madrid Spain, Unit of Medical Genetics; Department of Biomedical; Experimental and Clinical Sciences; University of Florence; Florence Italy, Department of Medical Sciences; University of Turin; Turin Italy, Section of Molecular Diagnostics; Department of Biochemistry; Aalborg University Hospital; Aalborg Denmark, Department of Preventive Medicine; Seoul National University College of Medicine; Seoul Korea, IFOM; The FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology; Milan Italy, Service de Génétique Clinique Chromosomique et Moléculaire; Hôpital Nord; St Etienne France, Unité d'Oncogénétique; CHU Arnaud de Villeneuve; Montpellier France, Unit of Molecular Bases of Genetic Risk and Genetic Testing; Department of Research; Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico), Istituto Nazionale Tumori (INT); Milan Italy, School of Women's and Children's Health; UNSW; Sydney Australia, Department of Clinical Genetics; Karolinska University Hospital; Stockholm Sweden, Rebbeck, Timothy R., Friebel, Tara M., Friedman, Eitan, Hamann, Ute, Huo, Dezheng, Kwong, Ava, Olah, Edith, Olopade, Olufunmilayo I., Solano, Angela R., Teo, Soo-Hwang, Thomassen, Mads, Rashid, Muhammad Usman, Rhiem, Kerstin, Robson, Mark, Rodriguez, Gustavo C., Rogers, Mark T., Rudaitis, Vilius, Schmidt, Ane Y., Schmutzler, Rita Katharina, Senter, Leigha, van Rensburg, Elizabeth J., Gronwald, Jacek, Shah, Payal D., Sharma, Priyanka, Side, Lucy E., Simard, Jacques, Singer, Christian F., Skytte, Anne-Bine, Slavin, Thomas P., Snape, Katie, Sobol, Hagay, Southey, Melissa, Gutierrez-Barrera, Angelica, McGuffog, Lesley, Steele, Linda, Steinemann, Doris, Sukiennicki, Grzegorz, Sutter, Christian, Szabo, Csilla I., Tan, Yen Y., Teixeira, Manuel R., Terry, Mary Beth, Teulé, Alex, Hahnen, Eric, Thomas, Abigail, Parsons, Michael T., Thull, Darcy L., Tischkowitz, Marc, Tognazzo, Silvia, Toland, Amanda Ewart, Topka, Sabine, Trainer, Alison H, Tung, Nadine, van Asperen, Christi J., Hauke, Jan, van der Hout, Annemieke H., van der Kolk, Lizet E., Leslie, Goska, van der Luijt, Rob B., Van Heetvelde, Mattias, Varesco, Liliana, Varon-Mateeva, Raymonda, Vega, Ana, Villarreal-Garza, Cynthia, von Wachenfeldt, Anna, Henderson, Alex, Walker, Lisa, Wang-Gohrke, Shan, Wappenschmidt, Barbara, Aalfs, Cora M., Weber, Bernhard H. F., Yannoukakos, Drakoulis, Yoon, Sook-Yee, Zanzottera, Cristina, Zidan, Jamal, Zorn, Kristin K., Hentschel, Julia, Hutten Selkirk, Christina G., Hulick, Peter J., Chenevix-Trench, Georgia, Spurdle, Amanda B., Abugattas, Julio, Antoniou, Antonis C., Nathanson, Katherine L., Adlard, Julian, Agata, Simona, Aittomäki, Kristiina, Hogervorst, Frans B.L., Andrews, Lesley, Andrulis, Irene L., Arason, Adalgeir, Arnold, Norbert, Arun, Banu K., Asseryanis, Ella, Auerbach, Leo, Azzollini, Jacopo, Balmaña, Judith, Barile, Monica, Honisch, Ellen, Barkardottir, Rosa B., Barrowdale, Daniel, Benitez, Javier, Berger, Andreas, Berger, Raanan, Blanco, Amie M., Blazer, Kathleen R., Blok, Marinus J., Bonadona, Valérie, Bonanni, Bernardo, Imyanitov, Evgeny N., Bradbury, Angela R., Brewer, Carole, Buecher, Bruno, Buys, Saundra S., Caldes, Trinidad, Caliebe, Almuth, Caligo, Maria A., Campbell, Ian, Caputo, Sandrine M., Chiquette, Jocelyne, Isaacs, Claudine, Chung, Wendy K., Claes, Kathleen B.M., Collée, J. Margriet, Cook, Jackie, Davidson, Rosemarie, de la Hoya, Miguel, De Leeneer, Kim, de Pauw, Antoine, Delnatte, Capucine, Diez, Orland, Weitzel, Jeffrey N., Ding, Yuan Chun, Ditsch, Nina, Domchek, Susan M., Dorfling, Cecilia M., Velazquez, Carolina, Dworniczak, Bernd, Eason, Jacqueline, Easton, Douglas F., Eeles, Ros, Ehrencrona, Hans, Izatt, Louise, Ejlertsen, Bent, Engel, Christoph, Engert, Stefanie, Evans, D. Gareth, Faivre, Laurence, Feliubadaló, Lidia, Ferrer, Sandra Fert, Foretova, Lenka, Fowler, Jeffrey, Frost, Debra, Izquierdo, Angel, Galvão, Henrique C. R., Ganz, Patricia A., Garber, Judy, Gauthier-Villars, Marion, Gehrig, Andrea, Gerdes, Anne-Marie, Gesta, Paul, Giannini, Giuseppe, Giraud, Sophie, Glendon, Gord, Jakubowska, Anna, Godwin, Andrew K., Greene, Mark H., James, Paul, Janavicius, Ramunas, Jensen, Uffe Birk, John, Esther M., Vijai, Joseph, Kaczmarek, Katarzyna, Karlan, Beth Y., Chan, TL, Kast, Karin, Investigators, KConFab, Kim, Sung-Won, Konstantopoulou, Irene, Korach, Jacob, Laitman, Yael, Lasa, Adriana, Lasset, Christine, Lázaro, Conxi, Lee, Annette, Couch, Fergus J., Lee, Min Hyuk, Lester, Jenny, Lesueur, Fabienne, Liljegren, Annelie, Lindor, Noralane M., Longy, Michel, Loud, Jennifer T., Lu, Karen H., Lubinski, Jan, Machackova, Eva, Goldgar, David E., Manoukian, Siranoush, Mari, Véronique, Martínez-Bouzas, Cristina, Matrai, Zoltan, Mebirouk, Noura, Meijers-Heijboer, Hanne E.J., Meindl, Alfons, Mensenkamp, Arjen R., Mickys, Ugnius, Miller, Austin, Kruse, Torben A., Montagna, Marco, Moysich, Kirsten B., Mulligan, Anna Marie, Musinsky, Jacob, Neuhausen, Susan L., Nevanlinna, Heli, Ngeow, Joanne, Nguyen, Huu Phuc, Niederacher, Dieter, Nielsen, Henriette Roed, Palmero, Edenir Inêz, Nielsen, Finn Cilius, Nussbaum, Robert L., Offit, Kenneth, Öfverholm, Anna, Ong, Kai-ren, Osorio, Ana, Papi, Laura, Papp, Janos, Pasini, Barbara, Pedersen, Inge Sokilde, Park, Sue Kyung, Peixoto, Ana, Peruga, Nina, Peterlongo, Paolo, Pohl, Esther, Pradhan, Nisha, Prajzendanc, Karolina, Prieur, Fabienne, Pujol, Pascal, Radice, Paolo, Ramus, Susan J., Torres, Diana, and Rantala, Johanna
Abstract: To access publisher's full text version of this article click on the hyperlink below, The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

22. Integrative Clinical, Radiological, and Molecular Analysis for Predicting Remission and Recurrence of Cushing Disease

Author: Paloma Moreno-Moreno, Alejandro Ibáñez-Costa, Eva Venegas-Moreno, Antonio C Fuentes-Fayos, María R Alhambra-Expósito, Carmen Fajardo-Montañana, Araceli García-Martínez, Elena Dios, Mari C Vázquez-Borrego, Pablo Remón-Ruiz, Rosa Cámara, Cristina Lamas, José Carlos Padillo-Cuenca, Juan Solivera, David A Cano, Manuel D Gahete, Aura D Herrera-Martínez, Antonio Picó, Alfonso Soto-Moreno, María Ángeles Gálvez-Moreno, Justo P Castaño, Raúl M Luque, Junta de Andalucía, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), Grupo Español de Tumores Neuroendocrinos y Endocrinos, Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Herrera-Martínez, Aura D., Castaño, Justo P., and Luque, Raúl M.
Subjects: Hydrocortisone, Remission, Cushing disease, Biochemical variables, Pituitary Diseases, Endocrinology, Diabetes and Metabolism, ACTH-secreting pituitary tumors, Remission Induction, Biochemistry (medical), Clinical Biochemistry, Molecular markers, Relapsed disease, Biochemistry, Treatment Outcome, Endocrinology, Predictive biomarkers, Recurrence, Pituitary Gland, Humans, Pituitary Neoplasms, Pituitary ACTH Hypersecretion, Retrospective Studies
Abstract: [Context] Adrenocorticotropin (ACTH)-secreting pituitary tumors (ACTHomas) are associated with severe comorbidities and increased mortality. Current treatments mainly focus on remission and prevention of persistent disease and recurrence. However, there are still no useful biomarkers to accurately predict the clinical outcome after surgery, long-term remission, or disease relapse., [Objectives] This work aimed to identify clinical, biochemical, and molecular markers for predicting long-term clinical outcome and remission in ACTHomas., [Methods] A retrospective multicenter study was performed with 60 ACTHomas patients diagnosed between 2004 and 2018 with at least 2 years’ follow-up. Clinical/biochemical variables were evaluated yearly. Molecular expression profile of the somatostatin/ghrelin/dopamine regulatory systems components and of key pituitary factors and proliferation markers were evaluated in tumor samples after the first surgery., [Results] Clinical variables including tumor size, time until diagnosis/first surgery, serum prolactin, and postsurgery cortisol levels were associated with tumor remission and relapsed disease. The molecular markers analyzed were distinctly expressed in ACTHomas, with some components (ie, SSTR1, CRHR1, and MKI67) showing instructive associations with recurrence and/or remission. Notably, an integrative model including selected clinical variables (tumor size/postsurgery serum cortisol), and molecular markers (SSTR1/CRHR1) can accurately predict the clinical evolution and remission of patients with ACTHomas, generating a receiver operating characteristic curve with an area under the curve of 1 (P, [Conclusion] This study demonstrates that the combination of a set of clinical and molecular biomarkers in ACTHomas is able to accurately predict the clinical evolution and remission of patients. Consequently, the postsurgery molecular profile represents a valuable tool for clinical evaluation and follow-up of patients with ACTHomas., This work was supported by the Junta de Andalucía (Nos. P20_00442, PEER-0048-2020, A-0006-2017, A-0055-2018, C-0015-2014, RC-0006-2018; postdoctoral grant DOC_01584, and BIO-0139); Ministry of Science and Innovation (Nos. PID2019-105564RB-I00 and PID2019-105201RB-I00); Instituto de Salud Carlos III, cofunded by the European Union (ERDF/ESF, “Investing in your future”; Nos. PI13/02043; PI16/00175, PI21/01012, and Sara Borrell programme CD19/00255); Spanish Ministry of Universities (predoctoral contract FPU16-05059); a GETNE2019 research grant; and CIBERobn. CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain.
Published: 2022
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23. Epigenetic and post‐transcriptional regulation of somatostatin receptor subtype 5 (SST5) in pituitary and pancreatic neuroendocrine tumors

Author: Alfonso Soto-Moreno, Miguel R. Branco, Marika Charalambous, Mari C Vázquez-Borrego, Eva Venegas-Moreno, Manuel D. Gahete, María A Gálvez-Moreno, Sergio Pedraza-Arevalo, Alejandro Ibáñez-Costa, Raquel Serrano-Blanch, Aura D. Herrera-Martínez, Álvaro Arjona-Sánchez, Raúl M. Luque, Justo P. Castaño, Ricardo Blazquez-Encinas, Márta Korbonits, Junta de Andalucía, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, European Commission, Ministerio de Educación, Cultura y Deporte (España), EMBO, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Fundación Eugenio Rodríguez Pascual, Medical Research Council (UK), Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (España), Ibáñez-Costa, Alejandro, Gahete, Manuel D., and Castaño, Justo P.
Subjects: Cancer Research, natural antisense transcript, Biology, pituitary, Epigenesis, Genetic, Genetics, Gene silencing, Humans, Pituitary Neoplasms, Epigenetics, Receptors, Somatostatin, pancreas, Post-transcriptional regulation, RC254-282, epigenetics, Somatostatin receptor, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, General Medicine, Methylation, DNA Methylation, Antisense RNA, Pancreatic Neoplasms, Neuroendocrine Tumors, SST5, Oncology, CpG site, DNA methylation, Cancer research, Molecular Medicine, neuroendocrine tumors
Abstract: Somatostatin receptor subtype 5 (SST5 ) is an emerging biomarker and actionable target in pituitary (PitNETs) and pancreatic (PanNETs) neuroendocrine tumors. Transcriptional and epigenetic regulation of SSTR5 gene expression and mRNA biogenesis is poorly understood. Recently, an overlapping natural antisense transcript, SSTR5-AS1, potentially regulating SSTR5 expression, was identified. We aimed to elucidate whether epigenetic processes contribute to the regulation of SSTR5 expression in PitNETs (somatotropinomas) and PanNETs. We analyzed the SSTR5/SSTR5-AS1 human locus in silico to identify CpG islands. SSTR5 and SSTR5-AS1 expression was assessed by quantitative real-time PCR (qPCR) in 27 somatotropinomas, 11 normal pituitaries (NPs), and 15 PanNETs/paired adjacent (control) samples. We evaluated methylation grade in four CpG islands in the SSTR5/SSTR5-AS1 genes. Results revealed that SSTR5 and SSTR5-AS1 were directly correlated in NP, somatotropinoma, and PanNET samples. Interestingly, selected CpG islands were differentially methylated in somatotropinomas compared with NPs. In PanNETs cell lines, SSTR5-AS1 silencing downregulated SSTR5 expression, altered aggressiveness features, and influenced pasireotide response. These results provide evidence that SSTR5 expression in PitNETs and PanNETs can be epigenetically regulated by the SSTR5-AS1 antisense transcript and, indirectly, by DNA methylation, which may thereby impact tumor behavior and treatment response., This research was funded by Junta de Andalucía (BIO-0139, P20_00442; PEER-0048-2020); Spanish Ministry of Economy (BFU2016-80360-R), Ministry of Science and Innovation (PID2019-105201RB-I00, PID2019-105564RB-I00); and ISCIII (PI16-00264, CD19/00255), co-funded with EU funds from FEDER Program. People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under project WHRI-ACADEMY, REA grant agreement n° 608765; MECD (FPU14/04290, FPU18/02275); EMBO (short term fellowship 6802); GETNE G2019 Research Grant; Fundación Eugenio Rodriguez Pascual (FERP2019); project grants from the UK Medical Research Council (MR/R022836/1; MR/L002345/1); and CIBERobn; CIBER Fisiopatología de la Obesidad y Nutriciín is an initiative of Instituto de Salud Carlos III.
Published: 2022

24. Avances en tumores del estroma gastrointestinal: ¿hacia dónde vamos?

Author: Juan A, Fernández-Hernández, Sonia, Cantín-Blázquez, Elena, García-Somacarrera, Evaristo, Varo-Pérez, José A, González-López, José M, Asencio-Pascual, Marta, Mendiola, César, Serrano, Eduardo, García-Granero, Vicente, Artigas-Raventós, Institut Català de la Salut, [Fernández-Hernández JA, Cantín-Blázquez S, García-Somacarrera E, Varo-Pérez E, González-López JA, Asencio-Pascual JM] Sección de Tumores Mesenquimales y Sarcomas, Asociación Española de Cirujanos, Madrid, Spain. [Serrano C] Sarcoma Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
Subjects: Other subheadings::Other subheadings::/antagonists & inhibitors [Other subheadings], Gastrointestinal Stromal Tumors, Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores], Aparell digestiu - Càncer - Cirurgia, Other subheadings::Other subheadings::/drug therapy [Other subheadings], Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Gastrointestinal Neoplasms [DISEASES], neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias gastrointestinales [ENFERMEDADES], Imatinib Mesylate, Sunitinib, Humans, enzimas y coenzimas::enzimas::transferasas::fosfotransferasas::fosfotransferasas (grupo alcohol aceptor)::proteína cinasas::proteína-tirosina cinasas [COMPUESTOS QUÍMICOS Y DROGAS], Surgery, Otros calificadores::Otros calificadores::/antagonistas & inhibidores [Otros calificadores], Enzymes and Coenzymes::Enzymes::Transferases::Phosphotransferases::Phosphotransferases (Alcohol Group Acceptor)::Protein Kinases::Protein-Tyrosine Kinases [CHEMICALS AND DRUGS], Gastrointestinal Neoplasms, Aparell digestiu - Càncer - Tractament, Proteïnes quinases - Inhibidors - Ús terapèutic
Abstract: Tumores del estroma gastrointestinal; Inhibidores de la tirosina cinasa; Laparoscopia Gastrointestinal stromal tumors; Tyrosine kinase inhibitors; Laparoscopy Tumors de l'estroma gastrointestinal; Inhibidors de la tirosina cinasa; Laparoscòpia Los tumores del estroma gastrointestinal (GIST) suponen el 1-2% de los tumores digestivos, siendo su localización más frecuente el estómago (55-60%) y el intestino delgado (30%). Los avances más importantes sucedidos en los últimos años se centran en cuatro áreas: biología molecular, abordaje quirúrgico laparoscópico, manejo técnico del GIST en localizaciones inusuales y tratamiento e integración de la cirugía en el manejo del GIST avanzado. Los avances en el conocimiento de la biología molecular del GIST han dado lugar a la progresiva identificación de nueva mutaciones oncogénicas que hacen del concepto wild type obsoleto. Estos avances han permitido el desarrollo de dos nuevos fármacos, avapritinib y ripretinib, lo que permite el tratamiento de pacientes con mutaciones resistentes a las tres líneas terapéuticas clásicas. El tratamiento quirúrgico del GIST se rige por unos principios técnicos bien establecidos que el abordaje laparoscópico debe cumplir, abordaje que queda limitado por dos factores clave: localización y tamaño. El GIST de localización infrecuente (esófago, duodeno o recto, o extradigestivo) supone un reto terapéutico. Estos pacientes deben ser manejados en un contexto multidisciplinario. La cirugía queda integrada en el manejo del GIST avanzado, considerándose como adyuvante a los inhibidores de la tirosina cinasa. Gastrointestinal Stromal Sarcomas (GIST) are mesenchymal neoplasms whose incidence accounts for 1-2% of digestive tumors, being located in the stomach (55-60%) and small intestine (30%). The advances in its knowledge and management succeeded in the last years have being spectacular. This review aims to summarize the most important of them for surgeons. We identified four areas of interest: molecular oncology, laparoscopic approach, management of GIST located at unusual locations, and management of advanced GIST. Advances in the field of molecular oncology lead to the discovery of new oncogenic mutations making the term Wil Type GIST obsolete. Moreover, these advances allow for the development of 2 new drugs: Avapritinib and Ripretinib, that added to the previous 3 commercially available drugs (imatinib, sunitinib and regorafenib) make possible the management of GIST with resistant mutations. The principles of the surgical management of primary GIST are well stablished which laparoscopic approach must accomplish. This approach is limited by 2 main factors: location and size. The diagnosis of GIST in unusual locations as esophagus, duodenum, rectum of out of the gastrointestinal tract (EGIST), implies an extraordinary therapeutic challenge, being imperative to manage them by surgeons and oncologist among others in the setting of a multidisciplinary team. The management of advanced/metastatic GIST has changed in a revolutionary fashion because surgery is now part of its treatment as adjuvant to tyrosine kinase inhibitors.
Published: 2022

25. Effect of aflibercept plus FOLFIRI and potential efficacy biomarkers in patients with metastatic colorectal cancer: the POLAF trial

Author: Elena Élez, María Auxiliadora Gómez-España, Cristina Grávalos, Pilar García-Alfonso, María José Ortiz-Morales, Ferrán Losa, Inmaculada Alés Díaz, Begoña Graña, Marta Toledano-Fonseca, Manuel Valladares-Ayerbes, Eduardo Polo, Mercedes Salgado, Eva Martínez de Castro, María José Safont, Antonieta Salud, Ana Ruiz-Casado, Josep Tabernero, María del Carmen Riesco, Antonio Rodriguez-Ariza, Enrique Aranda, Grupo de Tratamiento de los Tumores Digestivos, Sanofi, Tabernero, Josep, and Aranda, Enrique
Subjects: Vascular Endothelial Growth Factor A, Cancer Research, Recombinant Fusion Proteins, Leucovorin, Irinotecan, Colorectal cancer, Article, Combination drug therapy, Receptors, Vascular Endothelial Growth Factor, Oncology, Antineoplastic Combined Chemotherapy Protocols, Humans, Camptothecin, Fluorouracil, Colorectal Neoplasms, Biomarkers
Abstract: [Background] Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE)., [Methods] Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed., [Results] In total, 101 patients were followed for a median of 12 (6–17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was, [Conclusions] This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes., This work was supported by the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD) through an unrestricted grant provided by Sanofi (no grant number is applicable).
Published: 2021

26. Helpful Criteria When Implementing NGS Panels in Childhood Lymphoblastic Leukemia

Author: Rocío Benito, Montserrat Torrebadell, Antonio Jiménez-Velasco, Joaquín Sánchez, José María Fernández, Adrián Montaño, Eva Barragán, Margarita Ortega, Elena Esperanza-Cebollada, Marta Martín-Izquierdo, Nerea Vega-García, Jesús M. Hernández-Rivas, Joan Maynou, Marta Llop, Jesus M Hernández-Sánchez, Manuel Ramírez, Susana Riesco, Cristina Robledo, Alvaro Lassaletta, Mireia Camós, José Cervera, Clara Vicente-Garcés, Javier Alonso, Alfredo Minguela, José Luis Dapena, Susana Rives, Guerau Fernandez, Fundación Uno entre cien mil, Instituto de Salud Carlos III, Fundación Sonrisa de Alex & Todos somos Iván, Junta de Castilla y León, European Regional Development Fund (ERDF/FEDER), Generalitat Valenciana, Fundación AMPILE., Sociedad Española de Hematología y Hemoterapia, Fundación Científica AECC, [Vega-Garcia N, Esperanza-Cebollada E, Vicente-Garcés C] Hematology Laboratory, Hospital Sant Joan de Déu Barcelona, Passeig Sant Joan de Déu 2, 08950 Esplugues de Llobregat, Barcelona, Spain. Leukemia and other Pediatric Hemopathies, Developmental Tumors Biology Group, Institut de Recerca Hospital Sant Joan de Déu, Santa Rosa 39-57, 08950 Esplugues de Llobregat, Barcelona, Spain. [Benito R] IBSAL, IBMCC, CIC, Universidad de Salamanca-CSIC, 37008 Salamanca, Spain. [Llop M] Molecular Biology Unit, Hospital Universitario y Politécnico La Fe, 46026 Valencia, Spain. [Robledo C] Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Majadahonda, 28222 Madrid, Spain. [Ortega M] Servei d’Hematologia, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Universitat Autònoma de Barcelona, Bellaterra, Spain, Vall d'Hebron Barcelona Hospital Campus, Fundación Unoentrecienmil, Fundación la Sonrisa de Alex para la investigación y el tratamiento del sarcoma de Ewing, Junta de Castilla y León (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Generalitat Valenciana (España), Fundación AMPILE, Asociación Española Contra el Cáncer, and Asociación Todos somos Iván
Subjects: medicine.medical_specialty, Childhood acute lymphoblastic leukemia, Bioinformatics analysis, técnicas de investigación::técnicas genéticas::análisis de secuencias::análisis de secuencias de ADN [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Lymphoblastic Leukemia, Concordance, Medicine (miscellaneous), lcsh:Medicine, personas::Grupos de Edad::niño [DENOMINACIONES DE GRUPOS], Article, 03 medical and health sciences, 0302 clinical medicine, Daily practice, Medicine, Medical physics, Childhood Acute Lymphoblastic Leukemia, Daily routine, 030304 developmental biology, Seqüència de nucleòtids, 0303 health sciences, neoplasias::neoplasias por tipo histológico::leucemia::leucemia linfoide::leucemia-linfoma linfoblástico de células precursoras::leucemia-linfoma linfoblástico de células B precursoras [ENFERMEDADES], business.industry, lcsh:R, Cancer, Persons::Age Groups::Child [NAMED GROUPS], medicine.disease, Investigative Techniques::Genetic Techniques::Sequence Analysis::Sequence Analysis, DNA [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Clinical Practice, NGS-targeted panel, Leucèmia limfoblàstica, 030220 oncology & carcinogenesis, childhood acute lymphoblastic leukemia, Next-generation sequencing, next-generation sequencing, business, Infants, Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia, Lymphoid::Precursor Cell Lymphoblastic Leukemia-Lymphoma::Precursor B-Cell Lymphoblastic Leukemia-Lymphoma [DISEASES]
Abstract: The development of Next-Generation Sequencing (NGS) has provided useful diagnostic, prognostic, and therapeutic strategies for individualized management of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients. Consequently, NGS is rapidly being established in clinical practice. However, the technology’s complexity, bioinformatics analysis, and the different available options difficult a broad consensus between different laboratories in its daily routine introduction. This collaborative study among Spanish centers was aimed to assess the feasibility, pros, and cons of our customized panel and other commercial alternatives of NGS-targeted approaches. The custom panel was tested in three different sequencing centers. We used the same samples to assess other commercial panels (OncomineTM Childhood Cancer Research Assay, Archer®FusionPlex® ALL, and Human Comprehensive Cancer Panel GeneRead Panel v2®). Overall, the panels showed a good performance in different centers and platforms, but each NGS approach presented some issues, as well as pros and cons. Moreover, a previous consensus on the analysis and reporting following international guidelines would be preferable to improve the concordance in results among centers. Our study shows the challenges posed by NGS methodology and the need to consider several aspects of the chosen NGS-targeted approach and reach a consensus before implementing it in daily practice.
Published: 2020

27. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility

Author: Ana Patiño-García, Thomas G. P. Grunewald, David G. Cox, Lindsay M. Morton, Michelle Manning, Sandrine Grossetête-Lalami, Gaëlle Pierron, Nadège Corradini, Stephen J. Chanock, Kathleen Wyatt, Udo Kontny, Gregory T. Armstrong, Jean Michon, Sakina Zaidi, Didier Surdez, Wolfgang Hartmann, Heinrich Kovar, Olivier Delattre, Jennifer Kriebel, Nathalie Gaspar, Perrine Marec Bérard, Valérie Laurence, Casey L. Dagnall, Thomas Kirchner, Stéphanie Reynaud, Uta Dirksen, Nathaniel Rothman, Konstantin Strauch, Margaret A. Tucker, Lisa Mirabello, Smita Bhatia, Markus Metzler, Laurie Burdett, Neal D. Freedman, Rebeca Alba Rubio, Franck Tirode, Andreas E. Kulozik, Meredith Yeager, Kristine Jones, Javier Alonso, Stelly Ballet, Olivier Mirabeau, Eve Lapouble, Robert N. Hoover, Weiyin Zhou, Wendy M. Leisenring, Leslie L. Robison, Piero Picci, Javed Khan, Thomas Meitinger, Anna González-Neira, Eric Karlins, Mitchell J. Machiela, Unión Europea, TIRODE, Franck, Clinical Genetics Branch, Division of Cancer Epidemiology & Genetics, National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], German Cancer Consortium [Heidelberg] (DKTK), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unité de Génétique Somatique, Institut Curie [Paris], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Département d'Oncologie Médicale [Institut Curie, Paris], Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, Frederick National Laboratory for Cancer Research (FNLCR), Unité de Génétique Somatique [Institut Curie, Paris], Children’s Cancer Research Institute [Vienna, Austria], Département de cancérologie de l'enfant et de l'adolescent [Gustave Roussy], Institut Gustave Roussy (IGR), Division of Pediatric Hematology, Oncology and Stem Cell Transplantation [Aechen, Germany], Genotyping Unit (CeGen), Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Istituto Ortopedico Rizzoli [Bologna, Italy], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Center for Applied Medical Research [Plamplona] (CIMA), Universidad de Navarra [Pamplona] (UNAV), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Genetics Branch, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Department of Epidemiology and Cancer Control [Memphis, TN, USA], Cancer Prevention and Clinical Statistics Program [Seattle, WA, USA], Institute for Cancer Outcomes and Survivorship [Birmingham, AL, USA], University Children's Hospital of Heidelberg [Heidelberg, Germany], Research Unit of Molecular Biology [Neuherberg, Germany], Institute of Epidemiology [Neuherberg] (EPI), German Research Center for Environmental Health - Helmholtz Center München (GmbH), German Center for Diabetes Diseases [Neuherberg, Germany] (DZD), Institute of Human Genetics [Neuherberg] (IHG), Helmholtz Zentrum München = German Research Center for Environmental Health, Institute of Human Genetics [Munich, Germany], Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen = Uniklinikum Erlangen, Gerhard-Domagk-Institute of Pathology, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institute of Genetic Epidemiology [Neuherberg, Germany], Chair of Genetic Epidemiology [Munich, Germany] (IBE), Institute of Pathology [Munich, Germany], University Children's Hospital of Essen [Essen, Germany], This work was supported by the Intramural Research Program of the U.S. NationalCancer Institute and the Intramural Research Program of the American Cancer Society.This work was supported by grants from the Institut Curie, the Inserm, the LigueNationale Contre le Cancer (Equipe labellisée, Carte d’Identité des Tumeurs programand Recherche Epidémiologique 2009 program), the ANR-10-EQPX-03 from the AgenceNationale de la Recherche, the European PROVABES (ERA-649 NET TRANSCAN JTC2011), and ASSET (FP7-HEALTH-2010-259348) projects. This research was supportedby FP7 grant 'EURO EWING Consortium' No. 602856 and the following associations:Courir pour Mathieu, Dans les pas du Géant, Les Bagouzamanon, Enfants et Santé, M lavie avec Lisa, Lulu et les petites bouilles de lune, les Amis de Claire, l’Etoile de Martin andthe Société Française de lutte contre les Cancers et les leucémies de l’Enfant et del’adolescent. The laboratory of T. G. P. Grünewald is supported by grants from the‘Verein zur Förderung von Wissenschaft und Forschung an der Medizinischen Fakultätder LMU München (WiFoMed)’, by LMU Munich’s Institutional Strategy LMU excellentwithin the framework of the German Excellence Initiative, the ‘Mehr LEBEN für krebskranke Kinder—Bettina-Bräu-Stiftung’, the Walter Schulz Foundation, the WilhelmSander-Foundation (2016.167.1), and by the German Cancer Aid (DKH-111886 andDKH-70112257). D. Surdez is supported by SiRIC (Grant « INCa-DGOS-4654). Wethank the following clinicians for providing samples used in this study: C. Alenda, F.Almazán, D. Ansoborlo, L. Aymerich, L. Benboukbher, C. Beléndez, C. Berger, C. Bergeron, P. Biron, J.Y. Blay, E. Bompas, H. Bonnefoi, P. Boutard, B. Bui-Nguyen, D.Chauveaux, C. Calvo, A. Carboné, C. Clement, T. Contra, N. Corradini, A.S. Defachelles,V. Gandemer-Delignieres, A. Deville, A. Echevarria, J. Fayette, M. Fraga, D. Frappaz, J.L.Fuster, P. García-Miguel, J.C. Gentet, P. Kerbrat, V. Laithier, V. Laurence, P. Leblond, O.Lejars, R. López-Almaraz, B. López-Ibor, P. Lutz, J.F. Mallet, L. Mansuy, P. Marec Bérard,G. Margueritte, A. Marie Cardine, C. Melero, L. Mignot, F. Millot, O. Minckes, G.Margueritte, C. Mata, M.E. Mateos, M. Melo, C. Moscardó, M. Munzer, B. Narciso, A.Navajas, D. Orbach, C. Oudot, H. Pacquement, C. Paillard, Y. Perel, T. Philip, C. Piguet,M.I. Pintor, D. Plantaz, E. Plouvier, S. Ramirez-Del-Villar, I. Ray-Coquard, Y. Reguerre,M. Rios, P. Rohrlich, H. Rubie, A. Sastre, G. Schleiermacher, C. Schmitt, P. Schneider, L.Sierrasesumaga, C. Soler, N. Sirvent, S. Taque, E. Thebaud, A. Thyss, R. Tichit, J.J. Uriz, J.P. Vannier, F. Watelle-Pichon. This work was supported by the Instituto de SaludCarlos III (PI16CIII/00026) and the Asociación Pablo Ugarte, Fundación Sonrisa deAlex, ASION-La Hucha de Tomás, Sociedad Española de Hematología y OncologíaPediátricas. The Childhood Cancer Survivor Study is supported by the NationalCancer Institute (CA55727, G.T. Armstrong, Principal Investigator), with funding forgenotyping from the Intramural Research Program of the National Institutes ofHealth, National Cancer Institute. The KORA study was initiated and financed by theHelmholtz Zentrum München—German Research Center for Environmental Health,which is funded by the German Federal Ministry of Education and Research (BMBF) andby the State of Bavaria. Furthermore, KORA research was supported within the MunichCenter of Health Sciences (MC-Health), Ludwig-Maximilians-Universität, as part ofLMUinnovativ, Helmholtz-Zentrum München (HZM), University Hospital Erlangen [Germany], Westfälische Wilhelms-Universität Münster (WWU), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, Candidate gene, Oncogene Proteins, Fusion, Medizin, General Physics and Astronomy, Genome-wide association study, Cell Cycle Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Science, Genetics, Multidisciplinary, Nuclear Proteins, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Homeobox Protein Nkx-2.2, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Quality Control, Risk, Genotype, Science, European Continental Ancestry Group, Quantitative Trait Loci, Single-nucleotide polymorphism, Locus (genetics), [SDV.CAN]Life Sciences [q-bio]/Cancer, Sarcoma, Ewing, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, Article, White People, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Genetic Predisposition to Disease, Allele, Alleles, Cell Proliferation, Homeodomain Proteins, Proto-Oncogene Protein c-fli-1, Gene Expression Profiling, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, General Chemistry, Zebrafish Proteins, Pediatric cancer, 030104 developmental biology, Expression quantitative trait loci, lcsh:Q, RNA-Binding Protein EWS, Transcription Factors, Genome-Wide Association Study
Abstract: Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk., Ewing sarcoma (EWS) is a rare pediatric bone cancer typically involving the EWSR1-FLI1 fusion. Here the authors perform a genome-wide association study and report three new EWS risk loci that reside near GGAA repeat sequences, and identify candidate genes (RREB1 and KIZ) from eQTL analysis.
Published: 2018
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28. Integrated miRNA and mRNA expression profiling identifies novel targets and pathological mechanisms in autoimmune thyroid diseases

Author: Rebeca Martínez-Hernández, Francisco Sánchez-Madrid, Mónica Marazuela, Noa B. Martín-Cófreces, Ana Serrano-Somavilla, Ana M. Ramos-Leví, María Ujué González, Javier Casares-Arias, Miguel Sampedro-Núñez, Juan Carlos Triviño, Alberto Lens-Pardo, Lorena Torné, José Luis Muñoz de Nova, UAM. Departamento de Cirugía, UAM. Departamento de Medicina, Instituto de Investigación del Hospital de La Princesa (IP), Instituto de Salud Carlos III, Comunidad de Madrid, Grupo Español de Tumores Neuroendocrinos y Endocrinos, European Commission, Consejo Superior de Investigaciones Científicas (España), Comunidad de Madrid (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), and Ministerio de Economía, Industria y Competitividad (España)
Subjects: 0301 basic medicine, Male, Research paper, Graves' disease, Biopsy, lcsh:Medicine, Autoimmunity, Parkin, 0302 clinical medicine, Gene expression, Gene Regulatory Networks, lcsh:R5-920, Reverse Transcriptase Polymerase Chain Reaction, Cilium, Thyroid, General Medicine, Middle Aged, Immunohistochemistry, microRNAs, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Cytokines, Female, Inflammation Mediators, lcsh:Medicine (General), Adult, Medicina, mRNA, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Autoimmune Diseases, 03 medical and health sciences, Hashimoto's thyroiditis, Ciliogenesis, Next generation sequencing, microRNA, medicine, Humans, Genetic Predisposition to Disease, RNA, Messenger, Cilia, Genetic Association Studies, Gene Expression Profiling, lcsh:R, Computational Biology, medicine.disease, Thyroid Diseases, Gene expression profiling, Autoimmune thyroid disease, 030104 developmental biology, Cancer research, Graves’ disease, Biomarkers
Abstract: [Background] The mechanisms underlying autoimmune thyroid disease (AITD) remain elusive. Identification of such mechanisms would reveal novel and/or better therapeutic targets. Here, we use integrated analysis of miRNAs and mRNAs expression profiling to identify potential therapeutic targets involved in the mechanisms underlying AITD., [Methods] miRNA and mRNA from twenty fresh-frozen thyroid tissues (15 from AITD patients and 5 from healthy controls) were subjected to next-generation sequencing. An anti-correlated method revealed potential pathways and disease targets, including proteins involved in the formation of primary cilia. Thus, we examined the distribution and length of primary cilia in thyroid tissues from AITD and controls using immunofluorescence and scanning electron microscopy, and parsed cilia formation in thyroid cell lines in response to inflammatory stimuli in the presence of miRNA mimics., [Findings] We found that the expression of miR-21-5p, miR-146b-3p, miR-5571-3p and miR-6503-3p was anti-correlated with Enolase 4 (ENO4), in-turned planar cell polarity protein (INTU), kinesin family member 27 (KIF27), parkin co-regulated (PACRG) and serine/threonine kinase 36 (STK36) genes. Functional classification of these miRNA/mRNAs revealed that their differential expression was associated with cilia organization. We demonstrated that the number and length of primary cilia in thyroid tissues was significantly lower in AITD than in control (frequency of follicular ciliated cells in controls = 67.54% vs a mean of 22.74% and 21.61% in HT and GD respectively p = 0.0001, by one-way ANOVA test). In addition, pro-inflammatory cytokines (IFNγ and TNFα) and specific miRNA mimics for the newly identified target genes affected cilia appearance in thyroid cell lines., [Interpretation] Integrated miRNA/gene expression analysis has identified abnormal ciliogenesis as a novel susceptibility pathway that is involved in the pathogenesis of AITD. These results reflect that ciliogenesis plays a relevant role in AITD, and opens research pathways to design therapeutic targets in AITD., This work was supported by the following grants: Proyectos de Investigación en Salud (FIS) PIE13-0041 and PI16-02091 (funded by Instituto de Salud Carlos III), TIRONET2-CM, B2017/BMD-3724 (funded by Comunidad de Madrid), GETNE G1707 (funded by Grupo Español de Tumores Neuroendocrinos y Endocrinos) and cofinanced by FEDER funds to MM. We also acknowledge the service from the MiNa Laboratory at IMN, and funding from CM (project S2018/NMT-4291 TEC2SPACE), MINECO (project CSIC13-4E-1794) and EU (FEDER, FSE) to M.U.G. The funders had no role in study design, data collection, data analysis, interpretation or writing of the report.
Published: 2019

29. The second European interdisciplinary Ewing sarcoma research summit--A joint effort to deconstructing the multiple layers of a complex disease

Author: Nathan C. Sheffield, Andrei Zinovyev, Branka Radic Sarikas, Jeffrey A. Toretsky, Marc Ladanyi, Markus Metzler, Theodore Papamarkou, Guenther H. S. Richter, Enrique de Alava, Elizabeth S. Stewart, Patrick J. Grohar, Lee J. Helman, Beat W. Schäfer, Florencia Cidre-Aranaz, James F. Amatruda, Keri Schadler, Kimberly Stegmaier, Anang A. Shelat, Thomas G. P. Grunewald, Poul H. Sorensen, Paul S. Meltzer, Jaume Mora, Oscar M. Tirado, Takuro Nakamura, Joseph A. Ludwig, Olivier Delattre, Alejandro Sweet-Cordero, Uta Dirksen, Richard Moriggl, Peter J. Houghton, Claudia Rossig, Stephen L. Lessnick, Stefan Burdach, Karoly Szuhai, Elizabeth R. Lawlor, Kristiina Iljin, Franck Tirode, Wietske van der Ent, Françoise Rédini, Aykut Üren, Heinrich Kovar, Erika Brunet, Eberhard Korsching, Katia Scotlandi, Kalliopi Tsafou, Ewa Snaar-Jagalska, Unión Europea. Comisión Europea. 7 Programa Marco, Children’s Cancer Research Institute [Vienna, Austria], Department of Pediatrics [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Departments of Pediatrics, Molecular Biology and Internal Medicine [Dallas, TX, USA], University of Texas Southwestern Medical Center [Dallas], Structure et Instabilité des Génomes (STRING), Muséum national d'Histoire naturelle (MNHN)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Children’s Cancer Research Center and Department of Pediatrics [Munich, Germany], Technical University and Comprehensive Cancer Center Munich - CCCM [Germany]-Klinikum rechts der Isar [Munich, Germany], Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Laboratorio de Patología Molecular (USAL-CSIC), Centro de Investigación del Cáncer, Universitätsklinikum Münster [Munster, Germany], Unité de génétique et biologie des cancers (U830), Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institute of Biology [Leiden, The Netherlands], Leiden University, Center for Cancer and Cell Biology [Grand Rapids, MI, USA], Van Andel Institute [Grand Rapids]-Helen DeVos Children’s Hospital [Grand Rapids, MI, USA], Laboratory for Pediatric Sarcoma Biology [Munich, Germany], Ludwig-Maximilian-Universität München Pathologisches Institut [Germany], Center for Cancer Rearch [Bethesda, MA, USA], National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Greehey Children’s Cancer Research Institute [San Antonio, TX, USA], The University of Texas Health Science Center at Houston (UTHealth), VTT Technical Research Centre of Finland (VTT), Institute of Bioinformatics [Muenster, Germany], University of Münster, Department of Pathology and Human Oncology and Pathogenesis Program [New York, NY, USA], Memorial Sloane Kettering Cancer Center [New York], Department of Pediatrics and Department of Pathology [Ann Arbor, MI, USA], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Division of Pediatric Hematology/ Oncology/BMT [Columbus, OH, USA], Abigail Wexner Research Institute, Nationwide Children's Hospital-Nationwide Children's Hospital, Department of Sarcoma Medical Oncology [Houston, TX, USA], The University of Texas M.D. Anderson Cancer Center [Houston], Genetics Branch [Bethesda, MD, USA] (Center for Cancer Research), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen [Germany], Department of Pediatric Oncology [Barcelona, Spain], Hospital Sant Joan de Déu [Barcelona], Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria], Institute of Animal Breeding and Genetics [Vienna, Austria] (Department for Biomedical Sciences), University of Veterinary Medicine [Vienna] (Vetmeduni), Division of Carcinogenesis [Tokyo, Japan], The Cancer Institute [Tokyo, Japan]-Japanese Foundation for Cancer Research [Tokyo, Japan], School of Mathematics and Statistics [Glasgow, UK], University of Glasgow, Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Pediatrics Research [Houston, TX, USA], Department of Oncology and Children’s Research Center [Zurich, Switzerland], University Children’s Hospital Zurich, CRS Development of Biomolecular Therapies [Bologna, Italy] (Experimental Oncology Lab), University of Bologna-The Rizzoli Institute [Bologna, Italy], Department of Chemical Biology and Therapeutics [Memphis,TN, USA], St Jude Children's Research Hospital, Department of Molecular Oncology [British Columbia, Canada], British Columbia Cancer Research Centre [British Columbia, Canada], Department of Pediatric Oncology [Boston, MA, USA], Dana-Farber Cancer Institute [Boston], Department of Developmental Neurobiology [Memphis, TN, USA], Division of Hematology and Oncology [Stanford, CA, USA] (Department of Pediatrics), Stanford University, Department of Molecular Cell Biology [Leiden, The Netherlands], Leiden University Medical Center (LUMC), Molecular Oncology Laboratory [Barcelona, Spain] (Sarcoma Research Group), Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL)-L’Hospitalet de Llobregat [Barcelona, Spain], Department of Oncology [Washington, DC, USA], Georgetown University School of Medicine [Washington, DC USA], Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), The conference was supported by the European Union’s Seventh Framework Programme grants 261743 (ENCCA) and 259348 (ASSET)., European Project: 259348,EC:FP7:HEALTH,FP7-HEALTH-2010-two-stage,ASSET(2010), European Commission, Universiteit Leiden, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), University Hospital Erlangen = Uniklinikum Erlangen, Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), University of Bologna/Università di Bologna-The Rizzoli Institute [Bologna, Italy], Universiteit Leiden-Universiteit Leiden, Mines Paris - PSL (École nationale supérieure des mines de Paris), maurice, sandrine, and ASSET: Analysing and Striking the Sensitivities of Embryonal Tumours - ASSET - - EC:FP7:HEALTH2010-11-01 - 2016-04-30 - 259348 - VALID
Subjects: 0301 basic medicine, Oncogene Proteins, Fusion, Complex disease, Context (language use), [SDV.CAN]Life Sciences [q-bio]/Cancer, Bone Neoplasms, Computational biology, Disease, Review, Sarcoma, Ewing, Biology, Bioinformatics, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, SDG 3 - Good Health and Well-being, medicine, Humans, development, geography, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, therapy, Summit, geography.geographical_feature_category, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, epigenetics, Proto-Oncogene Protein c-fli-1, ta1182, Gene rearrangement, medicine.disease, ta3122, microenvironment, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Susceptibility locus, Identification (biology), Sarcoma, RNA-Binding Protein EWS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Ewing sarcoma, Signal Transduction
Abstract: Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second >European interdisciplinary Ewing sarcoma research summit> assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNAsequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intratumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits., The conference was supported by the European Union’s Seventh Framework Programme grants 261743(ENCCA) and 259348 (ASSET).
Published: 2016
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30. The first European interdisciplinary ewing sarcoma research summit

Author: Jozef Ban, Enrique de Alava, Pierre Åman, Stephen L. Lessnick, Dave N. T. Aryee, Stefan Burdach, Udo Kontny, Stephan Niedan, Jeffrey A. Toretsky, Simone Fulda, Lee J. Helman, Raphaela Schwentner, Selena Ventura, Angelika Eggert, Françoise Rédini, Antonio Llombart-Bosch, Markus Metzler, Poul H. Sorensen, Beat W. Schäfer, Heinrich Kovar, Argyro Fourtouna, Katia Scotlandi, Gunther Richter, Sue A. Burchill, Uta Dirksen, Olivier Delattre, Richard Moriggl, Elizabeth R. Lawlor, David Herrero-Martin, Javier Alonso, Martin S. Staege, Lucia T. Riedmann, Pancras C.W. Hogendoorn, Franck Tirode, Ruth Ladenstein, Claudia Rossig, Jenny Potratz, Children’s Cancer Research Institute [Vienna, Austria], Department of Pediatrics [Vienna, Austria], Medizinische Universität Wien = Medical University of Vienna, Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica [Madrid, Spain], Instituto de Salud Carlos III [Madrid] (ISC)- Instituto de Investigación en Enfermedades Raras (IIER), Sahlgrenska Academy at University of Gothenburg [Göteborg], Leeds Institute of Molecular Medicine, University of Leeds, Children’s Cancer Research Center and Department of Pediatrics [Munich, Germany], Technical University and Comprehensive Cancer Center Munich - CCCM [Germany]-Klinikum rechts der Isar [Munich, Germany], University Hospital of Salamanca, Unité de génétique et biologie des cancers (U830), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Universitätsklinikum Münster [Munster, Germany], Goethe-University, Goethe-Universität Frankfurt am Main, Center for Cancer Rearch [Bethesda, MA, USA], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Leiden University Medical Center (LUMC), University Children's Hospital [Freiburg, Germany], Department of Pediatrics and Department of Pathology [Ann Arbor, MI, USA], University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Department of Pathology [Ann Arbor, MI, USA] (Medical School), Huntsman Cancer Institute [Salt Lake City], University of Utah, University of Valencia, Pediatric Oncology and Hematology [Erlangen, Germany], University Hospital Erlangen [Germany], Ludwig Boltzmann Institute for Cancer Research [Vienna, Austria], Physiopathologie de la résorption osseuse et thérapie des tumeurs osseuses primitives, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Oncology and Children’s Research Center [Zurich, Switzerland], University Children’s Hospital Zurich, CRS Development of Biomolecular Therapies [Bologna, Italy] (Experimental Oncology Lab), University of Bologna-The Rizzoli Institute [Bologna, Italy], Department of Molecular Oncology [British Columbia, Canada], British Columbia Cancer Research Centre [British Columbia, Canada], Children's Cancer Research Center [Halle, Germany], Georgetown Lombardi Comprehensive Cancer Center, University Children's Hospital of Essen, Klinikum rechts der Isar [Munich, Germany]-Technical University and Comprehensive Cancer Center Munich - CCCM [Germany], TIRODE, Franck, Université Paris Descartes - Paris 5 (UPD5)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), University Hospital Erlangen = Uniklinikum Erlangen, University of Bologna/Università di Bologna-The Rizzoli Institute [Bologna, Italy], and Widemann, BC
Subjects: Epigenomics, Cancer Research, Alternative medicine, Medizin, ComputingMilieux_LEGALASPECTSOFCOMPUTING, Review Article, Bioinformatics, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, drug screen, 0302 clinical medicine, Drug screen, Cancer genomics, signalling, Sarcomagenesis, 0303 health sciences, sarcomagenesis, Summit, geography.geographical_feature_category, Opinion leadership, Genomics, Laboratory results, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Prognosis, animal models, 3. Good health, Animal models, Metastatic Ewing Sarcoma, Oncology, 030220 oncology & carcinogenesis, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Epigenetics, Sarcoma, Immunotherapy, Prioritization, medicine.medical_specialty, [SDV.CAN]Life Sciences [q-bio]/Cancer, lcsh:RC254-282, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, genomics, 030304 developmental biology, Medical education, geography, epigenetics, business.industry, biomarkers, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, medicine.disease, Clinical trial, prognosis, business, Biomarkers, Ewing sarcoma
Abstract: This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License.-- et al., The European Network for Cancer Research in Children and Adolescents (ENCCA) provides an interaction platform for stakeholders in research and care of children with cancer. Among ENCCA objectives is the establishment of biology-based prioritization mechanisms for the selection of innovative targets, drugs, and prognostic markers for validation in clinical trials. Specifically for sarcomas, there is a burning need for novel treatment options, since current chemotherapeutic treatment protocols have met their limits. This is most obvious for metastatic Ewing sarcoma (ES), where long term survival rates are still below 20%. Despite significant progress in our understanding of ES biology, clinical translation of promising laboratory results has not yet taken place due to fragmentation of research and lack of an institutionalized discussion forum. To fill this gap, ENCCA assembled 30 European expert scientists and five North American opinion leaders in December 2011 to exchange thoughts and discuss the state of the art in ES research and latest results from the bench, and to propose biological studies and novel promising therapeutics for the upcoming European EWING2008 and EWING2012 clinical trials.
Published: 2012
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31. Targeting DAX-1 in embryonic stem cells and cancer

Author: Javier Alonso, Enzo Lalli, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Unidad de Tumores Sólidos Infantiles – Unidad de Investigación Biomédica, and Instituto de Salud Carlos III [Madrid] (ISC)
Subjects: Oncogene Proteins, Fusion, Cellular differentiation, Clinical Biochemistry, MESH: Cell Cycle, MESH: Codon, Terminator, MESH: Reproduction, MESH: Genotype, 0302 clinical medicine, Neoplasms, Drug Discovery, MESH: Germ-Line Mutation, MESH: Animals, MESH: Neoplasms, MESH: Codon, Nonsense, MESH: Li-Fraumeni Syndrome, MESH: Tumor Suppressor Protein p53, MESH: Embryonic Stem Cells, MESH: DAX-1 Orphan Nuclear Receptor, MESH: Etoposide, MESH: Heterozygote, 0303 health sciences, MESH: Middle Aged, MESH: Proto-Oncogene Protein c-fli-1, Adrenal cortex, Reproduction, Cell Differentiation, 3. Good health, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Molecular Medicine, Stem cell, MESH: Cells, Cultured, Homeobox protein NANOG, MESH: Cell Differentiation, MESH: Pedigree, MESH: Antineoplastic Agents, Phytogenic, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, MESH: Phenotype, MESH: Cyclin-Dependent Kinase Inhibitor p21, 03 medical and health sciences, Cancer stem cell, MESH: Cell Proliferation, MESH: Polymorphism, Genetic, medicine, Animals, Humans, Transcription factor, Embryonic Stem Cells, 030304 developmental biology, Pharmacology, MESH: DNA Damage, MESH: Humans, DAX-1 Orphan Nuclear Receptor, Proto-Oncogene Protein c-fli-1, MESH: Apoptosis, MESH: Adult, Embryonic stem cell, MESH: Male, Nuclear receptor, MESH: Fibroblasts, Immunology, Adrenal Cortex, MESH: Adrenal Cortex, RNA-Binding Protein EWS, Neuroscience, MESH: Female, MESH: Oncogene Proteins, Fusion
Abstract: International audience; IMPORTANCE OF THE FIELD: DAX-1 (NR0B1) is an unusual orphan nuclear receptor whose function is essential for the development of the human adrenal cortex and onset of puberty. Recent data have implicated this transcription factor also in embryonic stem cell and cancer biology. AREAS COVERED IN THIS REVIEW: The role of DAX-1 in the regulation of development and function of the adrenal cortex, reproductive axis, embryonic stem cells and a few types of cancer. WHAT THE READER WILL GAIN: Here we review the past and present milestones in DAX-1 research and try to provide hints about the development and fields of application of DAX-1-targeted drugs in the future. TAKE HOME MESSAGE: The unusual structure and restricted expression pattern of DAX-1 may offer unique opportunities for drug discovery.
Published: 2010
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32. Concentraciones séricas de hormona de crecimiento en perras con tumores mamarios espontáneos antes y después de la mastectomía

Author: Corrada, Y., Goya, R.G., Gobello, C., Facultad de Veterinaria, and Tumores
Subjects: Hormonas del crecimiento, Mamas, 6 - Ciencias aplicadas::63 - Agricultura. Silvicultura. Zootecnia. Caza. Pesca::636 - Veterinaria. Explotación y cría de animales. Cría del ganado y de animales domésticos [CDU], Perras
Published: 2003

33. Comparative study of flare photometry in patients with choroidal malignant melanoma and choroidal nevus

Author: Clélia Maria Erwenne, Martha Motono Chojniak, Priscilla Luppi Ballalai, Universidade Federal de São Paulo (UNIFESP), and Hospital A C Camargo Departamento de Tumores Oculares
Subjects: medicine.medical_specialty, Nevi and melanomas, genetic structures, Fotometria, Fotometria/métodos, Choroid neoplasms, Barreira hemato-aquosa, law.invention, Ophthalmoscopy, Photometry, law, Ophthalmology, Mydriasis, medicine, Nevos e melanomas, Nevus, skin and connective tissue diseases, Melanoma, medicine.diagnostic_test, business.industry, Lasers, Neoplasias da coróide, General Medicine, Diagnóstico diferencial, medicine.disease, Dermatology, eye diseases, Choroidal nevus, Estudo comparativo, Blood-aqueous barrier, Lasers/uso diagnostico, Differential diagnosis, sense organs, Comparative study, medicine.symptom, business, Flare
Abstract: Introdução: Os tumores malignos intra-oculares estão associados com um aumento do flare na câmara anterior, causado por uma quebra na barreira hemato-aquosa, que pode ocorrer por vários mecanismos. Estudos utilizando a flarefotometria confirmam o aumento do flare em olhos com tumores intra-oculares malignos e benignos. Objetivo: Avaliar a flarefotometria como auxiliar no diagnóstico diferencial de melanoma maligno e nevo de coróide, comparando-se com olhos contralaterais normais. Métodos: Foram avaliados olhos com melanoma maligno e olhos com nevo de coróide diagnosticados por meio de oftalmoscopia indireta e/ou ultra-sonografia. Os olhos normais contralaterais foram utilizados como controles. A flarefotometria foi realizada em todos os pacientes, sob midríase bilateral, utilizando equipamento Laser Flare Meter (FC 500, Kowa). Foram aplicados os testes de Wilcoxon, Mann-Whitney, e Spearman para análise estatística. Resultados: A média da flarefotometria nos olhos com melanoma maligno de coróide foi 17,1 ph/ms e nos olhos normais contralaterais foi 4,06 ph/ms. Nos olhos com nevo de coróide o valor da flarefotometria foi 6,12 ph/ms e nos olhos contralaterais normais foi 4,47 ph/ms. O valor da flarefotometria foi maior nos olhos com melanoma maligno e nevo quando comparado com os olhos contralaterais normais (p
Published: 2002

34. Termoterapia transpupilar em melanoma maligno da coróide

Author: Clélia Maria Erwenne, Martha M. Motomo Chojniak, Fausto Uno, Tércio Guia, Universidade Federal de São Paulo (UNIFESP), Hospital A. C. Camargo, and Hospital A. C. Camargo Setor de Tumores
Subjects: Ophthalmology, Melanoma/terapia, Laser surgery, Hipertermia induzida, Neoplasias da coróide/terapia, Neoplasias da coróide, General Medicine, Cirurgia a laser, Choroid neoplasms, Induced hyperthermia, Hipertermia induzida/métodos, Melanoma
Abstract: Objetivo: Vários métodos vem sendo utilizados para o tratamento dos melanomas da coróide. A proposta deste trabalho preliminar é avaliar a eficácia da termoterapia transpupilar (TTT) como tratamento primário de melanomas da coróide pequenos. Métodos: Foi realizado um trabalho prospectivo e não-randomizado para avaliar os aspectos clínicos, resposta do tumor, complicações e resultados visuais de pacientes portadores de melanomas da coróide pequenos (até 4,0 mm de espessura e 12 mm de diâmetro basal) tratados por termoterapia transpupilar utilizando-se sucessivas aplicações de laser diodo contínuo de 810 nm. Resultados: Foram tratados 11 pacientes portadores de melanomas da coróide pequenos. O tumor era único e pigmentado em 100% dos casos. Crescimento documentado esteve presente em 5 pacientes (45,45%) previamente ao tratamento e fatores de risco para crescimento ou metástase estavam presentes em todos os pacientes. O tempo de seguimento destes pacientes a partir do tratamento foi em média de 5,72 meses (3 - 8 meses). Foram utilizadas 3 sessões de laser em 5 pacientes (45,45%) e 4 sessões em 6 pacientes (64,64%). As lesões apresentavam, por ocasião do diagnóstico, uma espessura média de 2,65 mm (1,85-3,86 mm), com maior diâmetro basal médio de 7,98 mm (4,2-11,33 mm). Após o tratamento, a espessura média foi de 1,83 mm (0,98-2,93 mm) e o maior diâmetro basal médio foi de 6,59 mm (3,81 mm -10,67 mm). Das lesões tratadas, 100% apresentaram diminuição da altura e do máximo diâmetro basal, tendo sido a diminuição média da espessura de 0,89 mm e do máximo diâmetro basal de 1,39 mm. A acuidade visual manteve-se inalterada em 5 casos (45,45%) e piorou após o tratamento em 6 casos (54,54%). Ocorreram complicações em 9 casos, tendo sido considerada complicação grave 1 caso de descolamento parcial da retina (9,09%); as outras complicações foram consideradas leves: pequenas hemorragias intra-retinianas em 7 pacientes (63,63%), vitreite associada a tênues membranas vítreas em 1 paciente (9,09%) e quemose associada a edema palpebral em 1 paciente (9,09%). Controle tumoral local com conservação do globo ocular foi observado durante este pequeno tempo de seguimento em 100% dos pacientes tratados. Por ocasião da última revisão, 100% dos pacientes estavam vivos e sem doença metastática. Conclusão: Este estudo preliminar sugere que a termoterapia transpupilar apresenta-se como um método efetivo e seguro para o tratamento de selecionados melanomas pequenos da coróide. Para melhor avaliação é necessário tempo de seguimento prolongado. Purpose: Several methods have been used for treatment of choroidal melanoma. The purpose of this preliminary paper is to evaluate the effectiveness of transpupillary thermo- therapy (TTT) as a primary treatment of small choroidal melanomas. Methods: This is a prospective nonrandomized study evaluating clinical aspects, tumor response, complications and visual outcome in patients presenting small choroidal melanomas (up to 4.0 mm thick and 12 mm base diameter) treated with TTT over 810 nm laser diode applications. Results: There were 11 patients treated with trans-pupillary thermotherapy, all of them presenting pig-mented small choroidal melanomas. Growth previous to treatment was documented in 5 patients and risk factors for growth or metastatic disease was present in all the patients. After treatment the patients were followed for 3 to 8 months (mean 5.7 months). Three laser sessions were used in 5 pa-tients and 4 sessions in 6 patients. The lesions presented at the beginning of the treatment a mean thickness of 2.7 mm, with a mean larger base diameter of 7.8 mm. All the lesions responded to treatment and presented decrease of thickness and base diameters. After transpupillary thermotherapy, the lesions' mean thickness was 1.8 mm and the mean larger base diameter was 6.7 mm. The mean reduction in thickness was 0.9 mm and the mean decrease in larger base diameter was 1.4 mm. The visual acuity remained unaffected in 5 cases and worsened after treatment in 6 cases. Nine patients presented compli- cations. A major complication occurred in a single patient who presented retinal detachment. Minor compli-cations were observed as follows: small retinal hemorrhages (7 patients), vitreous inflammation associated with tenuous vitreous membranes (1 patient) and conjunctiva and eyelid edema (1 patient). Local tumor control and conservation of the eyeball was accomplished in all the patients; they are all alive without evidence of metastatic disease in this initial follow-up period. Conclusion: This preliminary study suggests that the transpupillary thermotherapy is a promi-sing, effective and safe method for treatment of selected small choroidal melanomas. Further studies with longer follow-up period are necessary to better evaluate this treatment. Universidade Federal de São Paulo (UNIFESP) Departamento de Oftalmologia Setor de Ultra-som Hospital A. C. Camargo Universidade Federal de São Paulo (UNIFESP) Departamento de Oftalmologia Setor de Retina Hospital A. C. Camargo Setor de Tumores Universidade Federal de São Paulo (UNIFESP) UNIFESP, Depto. de Oftalmologia Setor de Ultra-som UNIFESP, Depto. de Oftalmologia Setor de Retina UNIFESP SciELO
Published: 2001

35. STAT3 Regulates the Redox Profile in MDA-MB-231 Breast Cancer Cells.

Author: Rodrigues JA, Pires BRB, de Amorim ISS, Siqueira PB, de Sousa Rodrigues MM, de Souza da Fonseca A, Panis C, and Mencalha AL
Subjects: Humans, Cell Line, Tumor, Female, Nitric Oxide metabolism, Tyrosine metabolism, Tyrosine analogs & derivatives, Transcription Factor RelA metabolism, Signal Transduction, STAT3 Transcription Factor metabolism, Oxidation-Reduction, Glutathione metabolism, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Reactive Oxygen Species metabolism, NF-E2-Related Factor 2 metabolism, NF-E2-Related Factor 2 genetics
Abstract: Unbalanced redox status and constitutive STAT3 activation are related to several aspects of tumor biology and poor prognosis, including metastasis and drug resistance. The triple-negative breast cancer (TNBC) is listed as the most aggressive and exhibits the worst prognosis among the breast cancer subtypes. Although the mechanism of reactive oxygen species (ROS) generation led to STAT3 activation is described, there is no data concerning the STAT3 influence on redox homeostasis in TNBC. To address the role of STAT3 signaling in redox balance, we inhibited STAT3 in TNBC cells and investigated its impact on total ROS levels, contents of hydroperoxides, nitric oxide (NO), and total glutathione (GSH), as well as the expression levels of 3-nitrotyrosine (3NT), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), and nuclear factor kappa B (NF-κB)/p65. Our results indicate that ROS levels depend on the STAT3 activation, while the hydroperoxide level remained unchanged, and NO and 3NT expression increased. Furthermore, GSH levels, Nrf2, and NF-κB/p65 protein levels are decreased in the STAT3-inhibited cells. Accordingly, TNBC patients' data from TCGA demonstrated that both STAT3 mRNA levels and STAT3 signature are correlated to NF-κB/p65 and Nrf2 signatures. Our findings implicate STAT3 in controlling redox balance and regulating redox-related genes' expression in triple-negative breast cancer., Competing Interests: Compliance with ethical standards Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Published: 2024
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36. Digital orthopaedic surgery: Benefits and challenges of extended reality and spatial computing.

Author: Pérez-Mañanes R and Calvo-Haro JA
Published: 2024
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37. Systematic literature review and meta-analysis of health state utility values in metastatic castration-resistant prostate cancer.

Author: Castro E, Figliuzzi R, Walsh S, Craigie S, Nazari J, Niyazov A, and Samjoo IA
Abstract: Despite being an important goal, the preservation of quality of life of patients with metastatic castration-resistant prostate cancer (mCRPC) is poorly characterized across lines of therapy. In this review, a systematic literature review and meta-analysis were conducted to synthesize EuroQoL 5-Dimension (EQ-5D) data among adult men with asymptomatic or mildly symptomatic mCRPC in both first line (1L) and second line and later (2L+) therapy. MEDLINE, Embase, and Cochrane CENTRAL were searched from inception to October 2022 using Ovid. Supplemental searches of other data sources were also conducted (PROSPERO registration: CRD42021283512). Meta-analyses were conducted to estimate pooled EQ-5D index utility values and EQ visual analog scale (VAS) scores in both 1L and 2L+. Various sensitivity analyses were also conducted. Forty-five unique publications met the inclusion criteria. In primary studies, baseline EQ-5D index utility values ranged from 0.7 to 0.9 in 1L and 0.63 to 0.7 in 2L+. Twelve trials and observational studies were feasible for inclusion in the meta-analysis. The pooled mean baseline EQ-5D index utility value was estimated as 0.79 (95% CI, 0.70-0.84) and 0.69 (95% CI, 0.67-0.71) for 1L (n = 7 studies) and 2L + (n = 4 studies), respectively. The pooled mean baseline EQ VAS score was estimated as 74.63 (95% CI, 70.97-78.29) and 65.82 (95% CI, 64.53-67.11) in 1L and 2L+, respectively. Limitations include hampered comparability between studies due to heterogeneity in study design and geographical regions. This study provides a comprehensive synthesis of EQ-5D data presently available in adults with mCRPC in both 1L and 2L + therapy., (© The Author(s) 2024. Published by Oxford University Press.)
Published: 2024
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38. Reduced expression of FOXE1 in differentiated thyroid cancer, the contribution of CPG methylation, and their clinical relevance.

Author: De Lima EU, Dos Santos FF, Da Silva IC, De Lima CRA, Frutuoso VS, Caso GF, De Oliveira PR, Bezerra AK, Cerutti JM, Tamura RE, Ramos HE, and de Rubio IGS
Subjects: Humans, Female, Middle Aged, Male, Adult, Cell Line, Tumor, Aged, Down-Regulation, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Clinical Relevance, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, DNA Methylation, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Thyroid Neoplasms metabolism, CpG Islands, Gene Expression Regulation, Neoplastic, Promoter Regions, Genetic
Abstract: Introduction: Forkhead box E1 ( FOXE1 ) is a transcription factor with a crucial role in thyroid morphogenesis and differentiation. Promoter hypermethylation downregulates FOXE1 expression in different tumor types; nevertheless, its expression and relationship with methylation status in differentiated thyroid cancer (DTC) remain unclear., Methods: A total of 33 pairs of matched samples of PTC tumors and non-tumors were included. Tumor cell cultures were treated with either 5-Aza-2'-deoxycytidine demethylating agent or dimethyl sulfoxide (DMSO). A real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to assess FOXE1 expression. The methylation status was quantified using bisulfite sequencing. A luciferase gene assay was used to determine CpG-island functionality. Gene expression and promoter methylation of FOXE1 and FOXE1-regulated genes were also analyzed with data from The Cancer Genome Atlas (TCGA) thyroid samples., Results: After demethylating treatment, increased FOXE1 mRNA was observed concomitantly with reduced promoter methylation of CpGisland2. A negative correlation between mRNA downregulation and an increased methylation level of CpGisland2 was observed in tumors. Diminished protein expression was also detected in some DTC cell lines and in some tumor samples, suggesting the involvement of post-transcriptional regulatory mechanisms. CPGisland2 was proved to be an enhancer. TCGA data analysis showed low FOXE1 mRNA expression in tumors with a negative correlation with methylation status and a positive correlation with the expression of most of its target genes. Reduced FOXE1 expression, accompanied by a high methylation level, was associated with PTC aggressiveness (tall cell variant, advanced extra thyroid extension, T4 American Joint Committee on Cancer (AJCC) classification), age at diagnosis (over 45 years old), and presence of a BRAFV600E mutation., Conclusion: FOXE1 mRNA was downregulated in DTC compared with non-tumors, followed by high CpGisland methylation. A coupling of low mRNA expression and high methylation status was related to characteristics of aggressiveness in DTC tumors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 De Lima, Dos Santos, Da Silva, De Lima, Frutuoso, Caso, De Oliveira, Bezerra, Cerutti, Tamura, Ramos and Rubio.)
Published: 2024
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39. Executive Summary of the Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR) Spanish Society of Emergency and Emergency Medicine (SEMES) and Spanish Society of Otolaryngology, Head and Neck Surgery (SEORL-CCC) Guideline for difficult airway management.

Author: Gómez-Ríos MÁ, Sastre JA, Onrubia-Fuertes X, López T, Abad-Gurumeta A, Casans-Frances R, Gómez-Ríos D, Garzón JC, Martínez-Pons V, Casalderrey-Rivas M, Fernández-Vaquero MÁ, Martínez-Hurtado E, Martín-Larrauri R, Reviriego-Agudo L, Gutierrez-Couto U, García-Fernández J, Serrano-Moraza A, Martín LJR, Leis CC, Ramírez SE, Orgeira JMF, Lima MJV, Mayo-Yáñez M, Parente-Arias P, Sistiaga-Suárez JA, Bernal-Sprekelsen M, and Charco-Mora P
Subjects: Humans, Adult, Intubation, Intratracheal, Emergency Medicine education, Societies, Medical, Airway Management methods, Airway Management standards
Abstract: The Airway section of the Spanish Society of Anesthesiology, Reanimation and Pain Therapy (SEDAR), Spanish Society of Emergency and Emergency Medicine (SEMES) and Spanish Society of Otolaryngology, Head and Neck Surgery (SEORL-CCC) present the Guidelines for the integral management of difficult airway in adult patients. This document provides recommendations based on current scientific evidence, theoretical-educational tools and implementation tools, mainly cognitive aids, applicable to the treatment of the airway in the field of anesthesiology, critical care, emergencies and prehospital medicine. Its principles are focused on the human factors, cognitive processes for decision-making in critical situations and optimization in the progression of the application of strategies to preserve adequate alveolar oxygenation in order to improve safety and quality of care., (Copyright © 2024 Sociedad Española de Otorrinolaringología y Cirugía de Cabeza y Cuello. Published by Elsevier España, S.L.U. All rights reserved.)
Published: 2024
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40. Cholecystectomy and digestive cancer in Chile: Complementary results from interrupted time series and aggregated data analyses.

Author: Gonzalez C, García-Pérez A, Nervi B, Munoz C, Morales E, Losada H, Merino-Pereira G, Rothhammer F, and Lorenzo Bermejo J
Subjects: Humans, Chile epidemiology, Female, Middle Aged, Male, Adult, Digestive System Neoplasms surgery, Digestive System Neoplasms mortality, Aged, Data Analysis, Cholecystectomy statistics & numerical data, Cholecystectomy methods, Interrupted Time Series Analysis, Gallbladder Neoplasms mortality, Gallbladder Neoplasms surgery, Gallbladder Neoplasms epidemiology
Abstract: Gallbladder cancer (GBC) mortality in Chile is among the highest worldwide. In 2006, the Chilean government launched a programme guaranteeing access to gallbladder surgery (cholecystectomy) for patients aged 35-49 years. We evaluated the impact of this programme on digestive cancer mortality. After conducting an interrupted time series analysis of hospitalisation and mortality data from 2002 to 2018 publicly available from the Chilean Department of Health Statistics and Information, we calculated the change in the proportion of individuals without gallbladder since 10 years. We then estimated age, gender, region, and calendar-year standardised mortality ratios (SMRs) as a function of the change in the proportion of individuals without gallbladder. The cholecystectomy rate increased by 45 operations per 100,000 persons per year (95%CI 19-72) after the introduction of the health programme. Each 1% increase in the proportion of individuals without gallbladder since 10 years was associated with a 0.73% decrease in GBC mortality (95% CI -1.05% to -0.38%), but the negative correlation was limited to women, southern Chile and age over 60. We also found decreasing mortality rates for extrahepatic bile duct, liver, oesophageal and stomach cancer with increasing proportions of individuals without gallbladder. To conclude, 12 years after its inception, the Chilean cholecystectomy programme has markedly and heterogeneously changed cholecystectomy rates. Results based on aggregate data indicate a negative correlation between the proportion of individuals without gallbladder and mortality due to gallbladder and other digestive cancers, which requires validation using individual-level longitudinal data to reduce the potential impact of ecological bias., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
Published: 2025
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41. Follicular cell-derived thyroid carcinomas harboring novel genetic BRAF NON-V600E mutations: real-world data obtained using a multigene panel.

Author: von Ammon JL, Machado GJR, da Matta RRC, Telles AC, Carrijo F, Dos Santos BAF, Brandão JCD, da Silva TM, Hecht F, Colozza-Gama GA, Tezzei JH, Cerutti JM, and Ramos HE
Subjects: Humans, Female, Male, Adult, Middle Aged, Cross-Sectional Studies, Aged, High-Throughput Nucleotide Sequencing methods, Young Adult, DNA Mutational Analysis methods, Proto-Oncogene Proteins B-raf genetics, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Mutation, Adenocarcinoma, Follicular genetics, Adenocarcinoma, Follicular pathology
Abstract: Objectives: To assess the molecular profile of follicular cell-derived thyroid carcinomas (FCDTCs) and correlate the identified mutations with the clinical and pathological features of the affected patients., Materials and Methods: Cross-sectional study of tumor samples from 100 adult patients diagnosed with FCDTC between 2010 and 2019. The patients' clinical and pathological data were collected. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumors using the ReliaPrep FFPE gDNA Miniprep System. Genotyping of target genomic regions ( KRAS, NRAS, BRAF, EGFR , and PIK3CA ) was performed using the AmpliSeq panel, while sequencing was performed on the iSeq 100 platform., Results: The patients' mean age was 39 years. In all, 82% of the tumors were classic papillary thyroid carcinomas. Overall, 54 (54%) tumor samples yielded satisfactory results on next-generation sequencing (NGS), of which 31 harbored mutations. BRAF gene mutations were the most frequent, with the BRAF V600E mutation present in 10 tumors. Seven tumors had BRAF NON-V600E mutations not previously described in FCDTCs (G464E, G464R, G466E, S467L, G469E, G596D, and the T599Ifs*10 deletion) but described in other types of cancer ( i.e. , skin/melanoma, lung, colorectal, and others). One tumor had a previously reported BRAF A598V mutation. EGFR gene mutations were found in 16 (29%) and KRAS or NRAS alterations in 8 (14%) of the 54 tumors analyzed., Conclusion: We described herein seven non-hotspot/novel variants in the BRAF gene, highlighting their potential role in expanding our understanding of FCDTC genetics., Competing Interests: Disclosure: no potential conflict of interest relevant to this article was reported.
Published: 2024
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42. Onco-Ontogeny of Squamous Cell Cancer of the First Pharyngeal Arch Derivatives.

Author: Sat-Muñoz D, Balderas-Peña LM, Gómez-Sánchez E, Martínez-Herrera BE, Trujillo-Hernández B, Quiroga-Morales LA, Salazar-Páramo M, Dávalos-Rodríguez IP, Nuño-Guzmán CM, Velázquez-Flores MC, Ochoa-Plascencia MR, Muciño-Hernández MI, Isiordia-Espinoza MA, Mireles-Ramírez MA, and Hernández-Salazar E
Subjects: Humans, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Squamous Cell Carcinoma of Head and Neck genetics, Squamous Cell Carcinoma of Head and Neck pathology, Squamous Cell Carcinoma of Head and Neck metabolism, Animals, Carcinogenesis genetics, Carcinogenesis pathology, Gene Expression Regulation, Neoplastic, Signal Transduction, Branchial Region metabolism, Branchial Region pathology
Abstract: Head and neck squamous cell carcinoma (H&NSCC) is an anatomic, biological, and genetic complex disease. It involves more than 1000 genes implied in its oncogenesis; for this review, we limit our search and description to the genes implied in the onco-ontogeny of the derivates from the first pharyngeal arch during embryo development. They can be grouped as transcription factors and signaling molecules (that act as growth factors that bind to receptors). Finally, we propose the term embryo-oncogenesis to refer to the activation, reactivation, and use of the genes involved in the embryo's development during the oncogenesis or malignant tumor invasion and metastasis events as part of an onco-ontogenic inverse process.
Published: 2024
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43. [Perceived stress in Mexican patients newly diagnosed with breast cancer].

Author: Neri-Flores V, Gálvez-Hernández CL, Riveros-Rosas A, Arce-Salinas CH, Acosta-Quiroz CO, and Del Río-Portilla F IY
Subjects: Humans, Female, Cross-Sectional Studies, Mexico, Middle Aged, Adult, Aged, Reproducibility of Results, Surveys and Questionnaires, Breast Neoplasms psychology, Breast Neoplasms diagnosis, Stress, Psychological etiology, Stress, Psychological diagnosis, Psychometrics
Abstract: Background: Cancer diagnosis has been described as a significant factor causing psychological stress, which may increase a vulnerability to develop psychological disorders, decrease quality of life levels and affect the response to cancer treatment., Objective: To validate the Newly Diagnosed Breast Cancer Stress Scale (NDBCSS) and to explore the differences concerning clinical and sociodemographic variables., Material and Methods: Cross-sectional study. Patients recently diagnosed with breast cancer on the day they received the definitive cancer diagnosis were invited to participate. The Perceived Stress Scale (PSS) and the NDBCSS were completed; the latter previously underwent a validation process into Spanish (reliability, content validity, structure -EFA- and convergent validity)., Results: 176 patients participated; their mean age was of 52.8 years. The scale obtained a content validity of 0.53 and reliability of 0.791; the EFA showed 2 factors explaining 42.31% of the variance. Stress levels were 23.05 (PSS) and 13.2 (NDBCSS). Concern about side effects, the progression of the illness and the lack of information were reported as the most critical stressors for these patients., Conclusions: The NDBCSS showed acceptable psychometric properties for its application in Mexican patients and probably for patients with similar personal characteristics and linguistic and cultural contexts. Based on the results, it is possible to design precise interventions addressed to the stressors they face, such as the impact of the disease and the treatment., (Licencia CC 4.0 (BY-NC-ND) © 2024 Revista Médica del Instituto Mexicano del Seguro Social.)
Published: 2024
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44. Pituitary stalk thickening in pediatric patients: an underrecognized diagnosis?

Author: Zepeda D, Guarda FJ, Okuma C, and Hernández MI
Subjects: Humans, Child, Male, Retrospective Studies, Adolescent, Female, Child, Preschool, Chile, Pituitary Diseases diagnosis, Magnetic Resonance Imaging, Pituitary Neoplasms diagnosis, Pituitary Neoplasms pathology, Pituitary Gland pathology, Pituitary Gland diagnostic imaging
Abstract: Objective: Pituitary stalk thickening (PST) is a rare condition in pediatric patients. Data on PST in Latin American pediatric populations are scarce. The aim of this study was to characterize a comprehensive cohort of pediatric patients diagnosed with PST in Chile between 2020 and 2022., Subjects and Methods: Retrospective review of medical records from 2020 to 2022 of patients under 18 years old diagnosed with PST, defined as a pituitary stalk width ≥ 3 mm at the pituitary insertion and/or ≥ 4 mm at the optic chiasm. A literature review was also performed to compare the identified cases with previously published ones., Results: Nine patients with PST were identified. Their mean age at diagnosis was 10.36 years (range 2.4-17 years). The patients' main manifestations were polydipsia and polyuria (100%) and poor growth (77.8%). Eight patients had germ cell tumors, while one patient had Langerhans cell histiocytosis. At the time of diagnosis, all patients had arginine vasopressin (AVP) deficiency, along with a deficiency in at least one anterior pituitary hormone. Germ cell tumor markers were negative in all patients. A biopsy-confirmed diagnosis was obtained in all cases. Four patients required a second biopsy. The frequency of PST due to germ cell tumors was four patients/year during the study period, which is twice the expected frequency in Chile., Conclusion: This study, characterizing the largest cohort of pediatric patients with PST in Latin America, found germ cell tumors to be the main etiology of this condition. It is important to focus diagnostic procedures on obtaining a correct diagnosis and promptly initiating appropriate treatment in patients with PST. Regional cooperation is essential for gathering data from larger cohorts to enhance our understanding of pediatric PST and improve patient outcomes., Competing Interests: Disclosure: no potential conflict of interest relevant to this article was reported.
Published: 2024
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45. Radical cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal sarcomatosis: Results from a reference center and considerations based on current evidence.

Author: Muñoz Casares FC, Padillo Ruiz FJ, González de Pedro C, Gómez Barbadillo J, Martín Broto J, Almoguera González F, Díaz Gómez D, Fernández-Hernández JÁ, González López JA, and Asencio Pascual JM
Subjects: Humans, Middle Aged, Female, Male, Adult, Aged, Young Adult, Adolescent, Combined Modality Therapy methods, Prospective Studies, Child, Cytoreduction Surgical Procedures methods, Peritoneal Neoplasms therapy, Peritoneal Neoplasms pathology, Peritoneal Neoplasms drug therapy, Hyperthermic Intraperitoneal Chemotherapy methods, Sarcoma therapy, Sarcoma surgery, Sarcoma pathology, Sarcoma drug therapy
Abstract: Introduction: Peritoneal sarcomatosis is a rare disease, with multiple histological origins and poor overall prognosis. The option of radical cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is controversial. The results of a surgical team experienced in these procedures are analyzed and discussed based on the available evidence., Methods: Study on a prospective database of patients with peritoneal sarcomatosis who underwent CRS and HIPEC, from 2016 to 2022, in a national reference center for sarcomas and peritoneal oncological surgery, who met the established inclusion/exclusion criteria., Results: 23 patients were included in the study, with a median age of 53 years (6-68). Recurrent/persistent clinical presentation predominated (78.3%). Visceral origin (including GIST and non-GIST peritoneal) accounted for 47.8% of patients, compared to 43.5% uterine and 8.7% retroperitoneal. The median PCI was 17 (3-36), with CC0 cytoreduction of 87%. Postoperative morbidity (Dindo Clavien III-IV) of 13%, with no postoperative mortality in the series. Overall survival and disease-free survival at 5 years were 64% and 34%, respectively. Histological grade was the most influential prognostic factor for survival., Conclusions: The results of the series, with low morbidity, support the benefit of radical peritoneal oncological surgery in patients with peritoneal sarcomatosis after adequate selection, as long as it is performed in high-volume centers, experienced surgeons and expert multidisciplinary teams. However, the role of HIPEC remains to be demonstrated and pending future studies., (Copyright © 2024 AEC. Published by Elsevier España, S.L.U. All rights reserved.)
Published: 2024
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46. The Expression Profiles of lncRNAs Are Associated with Neoadjuvant Chemotherapy Resistance in Locally Advanced, Luminal B-Type Breast Cancer.

Author: González-Woge M, Contreras-Espinosa L, García-Gordillo JA, Aguilar-Villanueva S, Bargallo-Rocha E, Cabrera-Galeana P, Vasquez-Mata T, Cervantes-López X, Vargas-Lías DS, Montiel-Manríquez R, Bautista-Hinojosa L, Rebollar-Vega R, Castro-Hernández C, Álvarez-Gómez RM, De La Rosa-Velázquez IA, Díaz-Chávez J, Jiménez-Trejo F, Arriaga-Canon C, and Herrera LA
Subjects: Humans, Female, Cell Line, Tumor, Gene Expression Profiling, GATA3 Transcription Factor genetics, GATA3 Transcription Factor metabolism, Transcriptome, RNA, Long Noncoding genetics, Breast Neoplasms genetics, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Breast Neoplasms metabolism, Drug Resistance, Neoplasm genetics, Neoadjuvant Therapy, Gene Expression Regulation, Neoplastic, Biomarkers, Tumor genetics
Abstract: lncRNAs are noncoding transcripts with tissue and cancer specificity. Particularly, in breast cancer, lncRNAs exhibit subtype-specific expression; they are particularly upregulated in luminal tumors. However, no gene signature-based laboratory tests have been developed for luminal breast cancer identification or the differential diagnosis of luminal tumors, since no luminal A- or B-specific genes have been identified. Particularly, luminal B patients are of clinical interest, since they have the most variable response to neoadjuvant treatment; thus, it is necessary to develop diagnostic and predictive biomarkers for these patients to optimize treatment decision-making and improve treatment quality. In this study, we analyzed the lncRNA expression profiles of breast cancer cell lines and patient tumor samples from RNA-Seq data to identify an lncRNA signature specific for luminal phenotypes. We identified an lncRNA signature consisting of LINC01016, GATA3-AS1, MAPT-IT1, and DSCAM-AS1 that exhibits luminal subtype-specific expression; among these lncRNAs, GATA3-AS1 is associated with the presence of residual disease (Wilcoxon test, p < 0.05), which is related to neoadjuvant chemotherapy resistance in luminal B breast cancer patients. Furthermore, analysis of GATA3-AS1 expression using RNA in situ hybridization (RNA ISH) demonstrated that this lncRNA is detectable in histological slides. Similar to estrogen receptors and Ki67, both commonly detected biomarkers, GATA3-AS1 proves to be a suitable predictive biomarker for clinical application in breast cancer laboratory tests.
Published: 2024
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47. Transcriptome of bone marrow-Derived stem cells reveals new inflammatory mediators related to increased survival in patients with multiple myeloma.

Author: Tagliari de Oliveira S, Binato R, Ellen Broto G, Tomie Takakura E, Navarro Gordan Ferreira Martins L, Abdelhay E, and Panis C
Subjects: Humans, Middle Aged, Male, Female, Aged, Oxidative Stress, Adult, Bone Marrow Cells metabolism, Survival Analysis, NF-kappa B metabolism, Inflammation metabolism, Inflammation genetics, Gene Expression Profiling, Hematopoietic Stem Cells metabolism, Tumor Necrosis Factor-alpha metabolism, Multiple Myeloma genetics, Multiple Myeloma mortality, Multiple Myeloma metabolism, Transcriptome genetics, Inflammation Mediators metabolism
Abstract: Although multiple myeloma (MM) is a neoplasm that leads affected individuals to death, little is known about why some patients survive much longer than others. In this context, we investigated the transcriptomic profile of bone marrow hematopoietic stem cells obtained from MM patients and compared the clinical outcomes of death and survival six months after bone marrow transplantation. The leukapheresis products of 39 patients with MM eligible for autologous transplantation were collected and analyzed. After extraction, the RNA was analyzed using the GeneChip Human Exon 1.0 Array method. The transcriptome profile was analyzed in silico, and the differentially expressed signaling pathways of interest were validated. The results showed a difference in the expression of inflammation-related genes, immune response processes, and the oxidative stress pathway. The in silico study also pointed out the involvement of the NFκB transcription factor in the possible modulation of these genes. We chose to validate molecules participating in these processes, including the cytokines TNF-α, IFN-γ, and TGF-β1; in addition, we measured the levels of oxidative stress mediators (pro-oxidant profile and the total antioxidant capacity). TNF-α levels were significantly reduced in patients who died and were over 50 years old at diagnosis, as well as in patients with plasmacytoma. Increased TNF-α was detected in patients with very high levels of β2-microglobulin. IFN-γ reduction was observed in patients with a complete response to treatment compared to those with a very good response. Patients with plasmacytoma who died also had an increased pro-oxidant profile. These data show the profile of inflammatory response markers that are altered in patients with MM who die quickly and serve as a basis for the development of future studies of markers to predict better survival in this disease., Competing Interests: Declaration of competing interest The study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), grant 305335/2021-9. The study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), grant 305335/2021-9., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
Published: 2024
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48. Identification of prognostic factors for survival in patients with metastatic gastric adenocarcinoma in a Mexican population.

Author: León AM, Hall WB, Lino LS, Salcedo RA, García JS, Miranda G, Hernández R, Herrera A, and Zepeda C
Subjects: Humans, Male, Female, Mexico epidemiology, Middle Aged, Prognosis, Aged, Adult, Aged, 80 and over, Retrospective Studies, Neutrophils, Neoplasm Metastasis, Lymphocytes pathology, Survival Rate, Stomach Neoplasms mortality, Stomach Neoplasms pathology, Stomach Neoplasms blood, Adenocarcinoma mortality, Adenocarcinoma secondary, Adenocarcinoma blood
Abstract: Introduction and Aims: Gastric adenocarcinoma is among the high-ranking tumors, with respect to frequency and mortality, worldwide. The inflammatory process and immune system activity are associated with oncologic control. Our aim was to identify whether the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and other variables are prognostic factors for survival in patients with metastatic gastric cancer in a Mexican population., Material and Methods: Patients diagnosed with metastatic gastric adenocarcinoma, hospitalized within the time frame of December 2011 to 2021, were analyzed. The NLR, PLR, and albumin and hemoglobin levels obtained from blood samples were calculated. Functional status (ECOG and Karnofsky), sex, histology, and the presence of signet ring cells were also considered possible prognostic factors. Each factor's prognostic value for overall survival was determined through univariate and multivariate analyses., Results: The study included 956 patients diagnosed with metastatic gastric cancer, of whom 494 (51.7%) were men and 462 (48.3%) were women. The main histologic finding was diffuse adenocarcinoma (n = 619, 64.7%), followed by intestinal adenocarcinoma (n = 293, 30.6%), and the presence of signet ring cells was found in 659 (68.9%) patients. Diagnostic laparoscopy was performed on 238 patients (24.9%) to confirm peritoneal carcinomatosis. The multivariate analysis showed that an NLR above 3.2 (HR 1.51, 95% CI 1.27-1.8; p < 0.001), albumin below 3.5 g/dl (HR 1.25, CI 1.06-1.47; p = 0.006), and an ECOG performance status of 2 or higher (HR 1.39, CI 1.10-1.76; p = 0.005) were independent factors that predicted a lower survival rate, whereas a Karnofsky score above 70% (HR 0.69, CI 0.53-0.91; p = 0.008) was associated with a better survival rate. Lastly, the PLR was not statistically significant in the multivariate analysis., Conclusions: The NLR, nutritional status assessed through albumin measurement, and functional status can act as independent prognostic survival factors in hospitalized Mexican patients diagnosed with metastatic gastric adenocarcinoma and be taken into account during therapeutic decision-making., (Copyright © 2023 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.)
Published: 2024
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49. Immune-Related Peripheral Neuropathy Associated with Immune Checkpoint Inhibitors: Case Report and Review of Literature.

Author: Bonilla CE and Ávila V
Abstract: Immune checkpoint inhibitors (ICIs) are a group of drugs that have improved outcomes for patients with various cancers. Generally considered safe and well tolerated, these drugs are occasionally linked to immune-mediated or immune-related adverse events. Among these, autoimmune neurological events are rare, displaying varying incidence rates across different studies. Peripheral neuropathy, although one of the more common neurological immune-related events, is at times underestimated. This case report highlights an adult patient diagnosed with metastatic intrahepatic cholangiocarcinoma. Initially, the patient underwent chemoimmunotherapy with gemcitabine, cisplatin, and durvalumab for eight cycles, achieving partial response without significant toxicity. Following this, the patient continued with maintenance monotherapy with durvalumab every 28 days. After completing six cycles of maintenance therapy, the patient suddenly experienced paresthesia and hypoesthesia in four limbs, accompanied by apraxia in the hands that was more pronounced on the right side. Additionally, the patient reported neuropathic pain in the right arm and encountered limitations in certain instrumental activities of daily living. Diagnostic studies, including laboratory and electrophysiological studies, combined with the clinical presentation, identified immune-related peripheral polyneuropathy. Durvalumab was suspended and prednisolone therapy was initiated, resulting in a rapid resolution of all neuropathic symptoms. In addition to the clinical case, this article reviews the literature on immunotherapy-associated peripheral neuropathy., Competing Interests: Dr. Carlos Bonilla reports serving on advisory boards for Amgen, Janssen, Bristol, Merck Serono, Pfizer, AstraZeneca, and Merck Sharp & Dohme; acting as an investigator in clinical trials from Bristol and Merck Sharp & Dohme; and receiving sponsorship to attend oncology meetings from Amgen, Merck Sharp & Dohme, and Merck Serono. Dr. Vaneza Avila has no conflicts of interest to declare., (Copyright © 2024 Carlos Eduardo Bonilla and Vaneza Ávila.)
Published: 2024
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50. A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma.

Author: Rey V, Tornín J, Alba-Linares JJ, Robledo C, Murillo D, Rodríguez A, Gallego B, Huergo C, Viera C, Braña A, Astudillo A, Heymann D, Szuhai K, Bovée JVMG, Fernández AF, Fraga MF, Alonso J, and Rodríguez R
Subjects: Humans, Animals, Mice, Precision Medicine, Isocitrate Dehydrogenase genetics, Mutation, Chondrosarcoma drug therapy, Chondrosarcoma genetics, Sarcoma, Bone Neoplasms genetics, Aminopyridines, Triazines
Abstract: Background: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth., Methods: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses)., Findings: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors., Interpretation: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas., Funding: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027)., Competing Interests: Declaration of interests The authors declare that they have no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Published: 2024
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