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Mancikova V.,Hereditary Endocrine Cancer Group | Inglada-Perez L.,Hereditary Endocrine Cancer Group | Inglada-Perez L.,Center for Biomedical Research on Rare Diseases | Curras-Freixes M.,Hereditary Endocrine Cancer Group | And 16 more authors.
Thyroid | Year: 2014

Background: Tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical results in medullary thyroid carcinoma (MTC) patients. However, the considerable variability in patient response to treatment with TKIs remains largely unexplained. There is evidence that it could be due, at least in part, to alterations in genes associated with the disease via their effect on the expression of TKI targets. The objective of this study was to evaluate the influence of RAS mutations on the expression levels in MTC tumors of eight key TKI target proteins. Methods: We assessed by immunohistochemistry the expression of EGFR, KIT, MET, PDGFRB, VEGF, VEGFR1, VEGFR2, and VEGFR3 in a series of 84 primary MTC tumors that had previously been molecularly characterized, including 14 RAS-positive, 18 RETM918T-positive, and 24 RET C634-positive tumors, as well as 15 wild-type tumors with no mutations in the RET or RAS genes. Results: In contrast to RET-positive tumors, RAS-positive tumors expressed neither PDGFRB nor MET (p=0.0060 and 0.047, respectively). Similarly, fewer RAS-positive than RET-related tumors expressed VEGFR3 (p=0.00062). Finally, wild-type tumors expressed VEGF more often than both RAS- and RET-positive tumors (p=0.0082 and 0.011, respectively). Conclusions: This is the first study identifying that the expression of TKI targets differs according to the presence of RAS mutations in MTC. This information could potentially be used to select the most beneficial TKI treatment for these patients. © Copyright 2014, Mary Ann Liebert, Inc. 2014.

Martinez N.,Hospital Marques de Valdecilla IFIMAV | Almaraz C.,Hospital Marques de Valdecilla IFIMAV | Vaque J.P.,Hospital Marques de Valdecilla IFIMAV | Varela I.,Institute Biomedicina Y Biotecnologia Of Cantabria | And 24 more authors.
Leukemia | Year: 2014

Splenic marginal zone lymphoma (SMZL) is a B-cell neoplasm whose molecular pathogenesis remains fundamentally unexplained, requiring more precise diagnostic markers. Previous molecular studies have revealed 7q loss and mutations of nuclear factor κB (NF-κB), B-cell receptor (BCR) and Notch signalling genes. We performed whole-exome sequencing in a series of SMZL cases. Results confirmed that SMZL is an entity distinct from other low-grade B-cell lymphomas, and identified mutations in multiple genes involved in marginal zone development, and others involved in NF-κB, BCR, chromatin remodelling and the cytoskeleton. © 2014 Macmillan Publishers Limited.

Chua T.C.,University of New South Wales | Moran B.J.,Basingstoke and North Hampshire National Health Service Foundation Trust | Sugarbaker P.H.,Washington Cancer Institute | Levine E.A.,Wake forest University | And 17 more authors.
Journal of Clinical Oncology | Year: 2012

Purpose: Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. Patients and Methods: A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. Results: Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P = .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P = .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P = .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P = .001), debulking surgery (CCR 2 or 3; P = .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P = .001) were independent predictors of a poorer overall survival. Conclusion: The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes. © 2012 by American Society of Clinical Oncology.

Cascon A.,Hereditary Endocrine Cancer Group | Cascon A.,Research Center Biomedica En Red Of Enfermedades Raras | Comino-Mendez I.,Hereditary Endocrine Cancer Group | Curras-Freixes M.,Hereditary Endocrine Cancer Group | And 31 more authors.
Journal of the National Cancer Institute | Year: 2015

Disruption of the Krebs cycle is a hallmark of cancer. IDH1 and IDH2 mutations are found in many neoplasms, and germline alterations in SDH genes and FH predispose to pheochromocytoma/paraganglioma and other cancers. We describe a paraganglioma family carrying a germline mutation in MDH2, which encodes a Krebs cycle enzyme. Whole-exome sequencing was applied to tumor DNA obtained from a man age 55 years diagnosed with multiple malignant paragangliomas. Data were analyzed with the two-sided Student's t and Mann-Whitney U tests with Bonferroni correction for multiple comparisons. Between six-and 14-fold lower levels of MDH2 expression were observed in MDH2-mutated tumors compared with control patients. Knockdown (KD) of MDH2 in HeLa cells by shRNA triggered the accumulation of both malate (mean ± SD: wild-type [WT] = 1±0.18; KD = 2.24±0.17, P =. 043) and fumarate (WT = 1±0.06; KD = 2.6±0.25, P =. 033), which was reversed by transient introduction of WT MDH2 cDNA. Segregation of the mutation with disease and absence of MDH2 in mutated tumors revealed MDH2 as a novel pheochromocytoma/paraganglioma susceptibility gene. © 2015 © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Fernandez-Fernandez M.M.,Henares University Hospital | Fernandez-Fernandez M.M.,Hospital Universitario del Henares | Gonzalez L.M.-J.,Anderson Cancer Center Madrid | Calvo C.R.,VITHAS Nuestra Senora de America Hospital | And 3 more authors.
European Archives of Oto-Rhino-Laryngology | Year: 2015

The minimally invasive total laryngectomy avoids a wide surgical field and so it has the potential benefit of reducing the local morbidity, especially on radiated patients. This approach has been previously described on a robotic basis, the transoral robotic total laryngectomy (TORS-TL). We have designed a minimally invasive approach for total laryngectomy (TL) using the transoral ultrasonic surgery technique (TOUSS). TOUSS is a transoral, endoscopic, non-robotic approach for laryngeal and pharyngeal tumors, based on the ultrasonic scalpel as a resection tool. Two patients with a laryngeal squamous cell carcinoma with indication for total laryngectomy were surgically treated: one primary TL for a subglottic carcinoma and one salvage TL with partial pharyngectomy for a local relapse after chemoradiotherapy of a glottic carcinoma. The tumors were completely removed with free surgical margin in both patients. The functional recovery was satisfactory in terms of swallowing and speech (a tracheoesophageal puncture and voice prosthesis placement were done in the same procedure). No intraoperative complications were observed. The patient with previous chemoradiotherapy had a pharyngocutaneous fistula which closed spontaneously without additional surgery. We have demonstrated that transoral endoscopic approach to the larynx and pharynx is feasible without a robotic platform. TOUSS-TL can easily spread the transoral endoscopic philosophy as well as the benefits of a minimally invasive way to remove the entire larynx. Further research will show the advantages in terms of complications and functional outcomes. © 2015 The Author(s)

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