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1.
J Clin Oncol ; 37(28): 2571-2580, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390276

RESUMO

PURPOSE: Somatostatin analogs (SSAs) are recommended for the first-line treatment of most patients with well-differentiated, gastroenteropancreatic (GEP) neuroendocrine tumors; however, benefit from treatment is heterogeneous. The aim of the current study was to develop and validate a progression-free survival (PFS) prediction model in SSA-treated patients. PATIENTS AND METHODS: We extracted data from the Spanish Group of Neuroendocrine and Endocrine Tumors Registry (R-GETNE). Patient eligibility criteria included GEP primary, Ki-67 of 20% or less, and first-line SSA monotherapy for advanced disease. An accelerated failure time model was developed to predict PFS, which was represented as a nomogram and an online calculator. The nomogram was externally validated in an independent series of consecutive eligible patients (The Christie NHS Foundation Trust, Manchester, United Kingdom). RESULTS: We recruited 535 patients (R-GETNE, n = 438; Manchester, n = 97). Median PFS and overall survival in the derivation cohort were 28.7 (95% CI, 23.8 to 31.1) and 85.9 months (95% CI, 71.5 to 96.7 months), respectively. Nine covariates significantly associated with PFS were primary tumor location, Ki-67 percentage, neutrophil-to-lymphocyte ratio, alkaline phosphatase, extent of liver involvement, presence of bone and peritoneal metastases, documented progression status, and the presence of symptoms when initiating SSA. The GETNE-TRASGU (Treated With Analog of Somatostatin in Gastroenteropancreatic and Unknown Primary NETs) model demonstrated suitable calibration, as well as fair discrimination ability with a C-index value of 0.714 (95% CI, 0.680 to 0.747) and 0.732 (95% CI, 0.658 to 0.806) in the derivation and validation series, respectively. CONCLUSION: The GETNE-TRASGU evidence-based prognostic tool stratifies patients with GEP neuroendocrine tumors receiving SSA treatment according to their estimated PFS. This nomogram may be useful when stratifying patients with neuroendocrine tumors in future trials. Furthermore, it could be a valuable tool for making treatment decisions in daily clinical practice.

2.
Artigo em Inglês | MEDLINE | ID: mdl-30675318

RESUMO

Background: Approximately 5 to 10% of all cancers are caused by inherited germline mutations, many of which are associated with different Hereditary Cancer Syndromes (HCS). In the context of the Program of Hereditary Cancer of the Valencia Community, individuals belonging to specific HCS and their families receive genetic counselling and genetic testing according to internationally established guidelines. The current diagnostic approach is based on sequencing a few high-risk genes related to each HCS; however, this method is time-consuming, expensive and does not achieve a confirmatory genetic diagnosis in many cases. This study aims to test the level of improvement offered by a Next Generation Sequencing (NGS) gene-panel compared to the standard approach in a diagnostic reference laboratory setting. Methods: A multi-gene NGS panel was used to test a total of 91 probands, previously classified as non-informative by analysing the high-risk genes defined in our guidelines. Results: Nineteen deleterious mutations were detected in 16% of patients, some mutations were found in already-tested high-risk genes (BRCA1, BRCA2, MSH2) and others in non-prevalent genes (RAD51D, PALB2, ATM, TP53, MUTYH, BRIP1). Conclusions: Overall, our findings reclassify several index cases into different HCS, and change the mutational status of 14 cases from non-informative to gene mutation carriers. In conclusion, we highlight the necessity of incorporating validated multi-gene NGS panels into the HCSs diagnostic routine to increase the performance of genetic diagnosis.

3.
Sci Rep ; 8(1): 15759, 2018 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-30361482

RESUMO

Here, we analyse changes throughout time in the isotopic niche of the Franciscana dolphin (Pontoporia blainvillei), the South American fur seal (Arctocephalus australis) and the South American sea lion (Otaria flavescens) from the Río de la Plata estuary and adjacent Atlantic Ocean to test the hypothesis that fishing may modify the diet of small-gape predators by reducing the average size of prey. The overall evidence, from stable isotope and stomach contents analyses, reveals major changes in resource partitioning between the three predators considered, mainly because of an increased access of Franciscana dolphins to juvenile demersal fishes. These results are consistent with the changes in the length distribution of demersal fish species resulting from fishing and suggest that Franciscana dolphin has been the most benefited species of the three marine mammal species considered because of its intermediate mouth gape. In conclusion, the impact of fishing on marine mammals goes beyond the simple reduction in prey biomass and is highly dependent on the mouth gape of the species involved.


Assuntos
Organismos Aquáticos/fisiologia , Pesqueiros , Cadeia Alimentar , Boca/fisiologia , Comportamento Predatório/fisiologia , Animais , Teorema de Bayes , Isótopos de Carbono/metabolismo , Golfinhos/fisiologia , Feminino , Otárias/fisiologia , Geografia , Marcação por Isótopo , Modelos Lineares , Masculino , Isótopos de Nitrogênio/metabolismo , Leões-Marinhos/fisiologia
4.
Biol Lett ; 14(5)2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29743263

RESUMO

The thermal response of maximum growth rate in morphology-based functional groups (MBFG) of freshwater phytoplankton is analysed. Contrasting an exponential Boltzmann-Arrhenius with a unimodal model, three main features were evaluated: (i) the activation energy of the rise (Er), (ii) the presence of a break in the thermal response and (iii) the activation energy of the fall (Ef). The whole dataset (N = 563) showed an exponential increase (Er ∼ 0.5), a break around 24°C and no temperature dependence after the breakpoint (Ef = 0). Contrasting thermal responses among MBFG were found. All groups showed positive activation energy (Er > 0), four showed no evidence of decline in growth rate (temperature range = 0-35°C) and two presented a breakpoint followed by a sharp decrease in growth rate. Our results evidenced systematic differences between MBFG in the thermal response and a coherent response significantly related to morphological traits other than size (i.e. within MBFG). These results provide relevant information for water quality modelling and climate change predictions.


Assuntos
Fitoplâncton/crescimento & desenvolvimento , Fitoplâncton/metabolismo , Temperatura Ambiente , Água Doce , Fitoplâncton/classificação
5.
Sci Total Environ ; 631-632: 169-179, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29524894

RESUMO

Environmental sustainability of South American rainfed agroecosystems is of current concern. In this work, we evaluate the occurrence of multiple pesticide residues in muscle tissue of wild fish species from two large rivers in South America (Uruguay and Negro Rivers). Two sampling campaigns (representing summer and winter crops) were performed during 2015 targeting a wide biodiversity of fish species used for human consumption (ranging from migratory to non-migratory and from detritivorous to top-predators). Three different localities associated to rainfed agriculture were assessed, two of them enclosed to a RAMSAR site (National Park "Esteros de Farrapos e Islas del Rio Uruguay"). Pesticide residues occurred in muscle tissue of 143 from 149 sampled fishes (96%). Thirty different pesticides were detected at concentrations from <1 to 194µgkg-1. Incidence of pesticides in fish were tightly related to: i) features of the contaminant: (Kow, environmental persistence and mobility) and ii) intensity of use of particular pesticides and land dedicated to rainfed agriculture. Trifloxystrobin, metolachlor and pyraclostrobin showed the highest rates of occurrence. Of great concern is that strobirulins have highest toxicity to fish from those detected compounds. From the pattern of pesticides occurring for non-migratory fish species it was possible to trend important spatial differences related to the intensity of rainfed agriculture. Results suggest a regular exposition of aquatic wild biota to sublethal concentrations of multiple semi-polar pesticides.


Assuntos
Monitoramento Ambiental , Peixes/metabolismo , Resíduos de Praguicidas/metabolismo , Poluentes Químicos da Água/análise , Agricultura , Animais , Ecossistema , Resíduos de Praguicidas/análise , Praguicidas/análise , Praguicidas/metabolismo , Chuva , Rios/química , América do Sul , Poluentes Químicos da Água/metabolismo
6.
Oncologist ; 23(4): 422-432, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29330208

RESUMO

BACKGROUND: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki-67 cutoff values in GEP-NENs. SUBJECTS, MATERIALS, AND METHODS: A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors [well differentiated]) or NECs (neuroendocrine carcinomas [poorly differentiated]), and by Ki-67 index as G1 (Ki-67 <2%), G2 (Ki-67 3%-20%), or G3 (Ki-67 >20%). Patients were stratified into five cohorts: NET-G1, NET-G2, NET-G3, NEC-G2, and NEC-G3. RESULTS: Five-year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5-year survival: 81% [Ki-67 3%-5%], 72% [Ki-67 6%-10%], 52% [Ki-67 11%-20%]) and G3 NENs (5-year survival: 35% [Ki-67 21%-50%], 22% [Ki-67 51%-100%]). Five-year survival was significantly greater for NET-G2 versus NEC-G2 (75.5% vs. 58.2%) and NET-G3 versus NEC-G3 (43.7% vs. 25.4%). CONCLUSION: Substantial clinical heterogeneity is observed within G2 and G3 GEP-NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index. IMPLICATIONS FOR PRACTICE: Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real-world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.


Assuntos
Carcinoma Neuroendócrino/classificação , Carcinoma Neuroendócrino/patologia , Neoplasias Intestinais/classificação , Neoplasias Intestinais/patologia , Tumores Neuroendócrinos/classificação , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/classificação , Neoplasias Pancreáticas/patologia , Sistema de Registros/estatística & dados numéricos , Neoplasias Gástricas/classificação , Neoplasias Gástricas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/mortalidade , Diferenciação Celular , Criança , Feminino , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/mortalidade , Antígeno Ki-67/metabolismo , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Tumores Neuroendócrinos/metabolismo , Tumores Neuroendócrinos/mortalidade , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Espanha , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Taxa de Sobrevida , Organização Mundial da Saúde , Adulto Jovem
7.
Oncotarget ; 9(97): 36894-36905, 2018 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-30651923

RESUMO

Several circulating biomarkers and single nucleotide polymorphisms (SNPs) have been correlated with efficacy and tolerability to antiangiogenic agents. These associations remain unexplored in well-differentiated, metastatic pancreatic neuroendocrine tumors treated with the multitargeted tyrosine kinase inhibitor sunitinib. We have assessed the effect on tumor response at 6 months, overall survival, progression-free survival and safety of 14 SNPs, and 6 soluble proteins. Forty-three patients were recruited. Two SNPs in the vascular endothelial growth factor receptor 3 (VEGFR-3) gene predicted lower overall survival: rs307826 with hazard ratio (HR) 3.67 (confidence interval [CI] 95%, 1.35-10.00) and rs307821 with HR 3.84 (CI 95%, 1.47-10.0). Interleukin-6 was associated with increased mortality: HR 1.06 (CI 95%, 1.01-1.12), and osteopontin was associated with shorter PFS: HR 1.087 (1.01-1.16), independently of Ki-67. Furthermore, levels of osteopontin remained higher at the end of the study in patients considered non-responders: 38.5 ng/mL vs. responders: 18.7 ng/mL, p-value=0.039. Dynamic upward variations were also observed with respect to IL-8 levels in sunitinib-refractory individuals: 28.5 pg/mL at baseline vs. 38.3 pg/mL at 3 months, p-value=0.024. In conclusion, two VEGFR-3 SNPs as well as various serum biomarkers were associated with diverse clinical outcomes in patients with well-differentiated pancreatic neuroendocrine tumors treated with sunitinib.

8.
Harmful Algae ; 70: 23-36, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-29169566

RESUMO

The Microcystis aeruginosa complex (MAC) clusters cosmopolitan and conspicuous harmful bloom-forming cyanobacteria able to produce cyanotoxins. It is hypothesized that low temperatures and brackish salinities are the main barriers to MAC proliferation. Here, patterns at multiple levels of organization irrespective of taxonomic identity (i.e. a trait-based approach) were analyzed. MAC responses from the intracellular (e.g. respiratory activity) to the ecosystem level (e.g. blooms) were evaluated in wide environmental gradients. Experimental results on buoyancy and respiratory activity in response to increased salinity (0-35) and a literature review of maximum growth rates under different temperatures and salinities were combined with field sampling from headwaters (800km upstream) to the marine end of the Rio de la Plata estuary (Uruguay-South America). Salinity and temperature were the major variables affecting MAC responses. Experimentally, freshwater MAC cells remained active for 24h in brackish waters (salinity=15) while colonies increased their flotation velocity. At the population level, maximum growth rate decreased with salinity and presented a unimodal exponential response with temperature, showing an optimum at 27.5°C and a rapid decrease thereafter. At the community and ecosystem levels, MAC occurred from fresh to marine waters (salinity 30) with a sustained relative increase of large mucilaginous colonies biovolume with respect to individual cells. Similarly, total biomass and, specific and morphological richness decreased with salinity while blooms were only detected in freshwater both at high (33°C) and low (11°C) temperatures. In brackish waters, large mucilaginous colonies presented advantages under osmotic restrictive conditions. These traits values have also been associated with higher toxicity potential. This suggest salinity or low temperatures would not represent effective barriers for the survival and transport of potentially toxic MAC under likely near future scenarios of increasing human impacts (i.e. eutrophication, dam construction and climate change).


Assuntos
Microcystis/crescimento & desenvolvimento , Rios/química , Mudança Climática , Ecossistema , Estuários , Salinidade , Água do Mar/química , Temperatura Ambiente
9.
J Gene Med ; 19(4)2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28306219

RESUMO

BACKGROUND: We identified a new and a recurrent POLD1 mutation associated with predisposition to colorectal cancer (CRC). We characterized the molecular and clinical nature of the potential POLD1 founder mutation in families from Valencia (Spain). METHODS: Clinical and molecular data were collected from four independent families known to have a POLD1 Leu474Pro mutation. To establish its founder effect, haplotype construction was performed using 14 flanking POLD1 polymorphic markers. We calculated penetrance estimates and clinical expressivity, globally and stratified by age and sex. RESULTS: We included 32 individuals from the four families: 20 carriers and 12 noncarriers. A common haplotype was identified in these families in a region comprising 2,995 Mb, confirming L474P as the first founder POLD1 mutation identified. Thirteen tumors diagnosed in 10 POLD1 carriers: eight CRC, three endometrial and two other tumors were considered. The median age of cancer onset for POLD1 mutation carriers was 48 years. The observed penetrance was 50% and the cumulative risk at age of 50 years was 30%. CONCLUSIONS: The findings of the present study contribute to a better understanding of CRC genetics in the Spanish population. The clinical phenotype for this mutation is similar to that in Lynch syndrome. Future studies using next generation sequencing with large gene panels for any hereditary cancer condition will offer the possibility of detecting POLE/POLD1 mutations in unsuspected clinical situations, demonstrating a more real and unbiased picture of the associated phenotype.


Assuntos
DNA Polimerase III/genética , Grupo com Ancestrais do Continente Europeu/genética , Efeito Fundador , Genética Populacional , Mutação de Sentido Incorreto , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/epidemiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Feminino , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Haplótipos , Heterozigoto , Humanos , Masculino , Repetições de Microssatélites , Pessoa de Meia-Idade , Penetrância , Fenótipo , Polimorfismo de Nucleotídeo Único , Vigilância da População , Espanha , Adulto Jovem
10.
Harmful Algae ; 62: 73-83, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28118894

RESUMO

Bloom-forming species belonging to Microcystis aeruginosa complex (MAC) are the most commonly reported worldwide. MAC blooms are composed by toxic and non-toxic genotypes and the environmental conditions favouring the dominance of toxic genotypes are still a matter of debate among the scientific community. In this study, we evaluated the distribution of toxic MAC genotypes along a seasonal cycle and over an environmental gradient spanning 800km, from a eutrophic freshwater reservoir in Río Uruguay to marine water in the outer limit of Río de la Plata. Abundance of four mcy genes, mcyB, mcyD, mcyE and mcyJ was determined by qPCR and used as a proxy of abundance of toxic MAC genotypes. All the mcy genes were detected through the seasonal cycle at all sampling sites, being systematically higher in the freshwater reservoir and decreasing towards the marine site. The highest toxic genotype abundance was found during the austral summer months. According to generalized linear regressions and random forest models, temperature and conductivity were the most relevant explanatory variables. This suggests that although toxic MAC genotypes grow optimally in freshwater, they are also able to tolerate the high-salinity and low temperature conditions found in estuarine and marine waters. This ability to resist harsh conditions impose a health risk and a management challenge. To our knowledge, this is the first report addressing several mcy genes in a broad gradient that includes a wide array of different environmental conditions.


Assuntos
Proteínas de Bactérias/análise , Toxinas Bacterianas/análise , Genótipo , Proliferação Nociva de Algas , Microcistinas/análise , Microcystis/fisiologia , Meio Ambiente , Água Doce/microbiologia , Microcystis/genética , Fitoplâncton , Dinâmica Populacional , Reação em Cadeia da Polimerase em Tempo Real , Estações do Ano , Água do Mar/microbiologia , Uruguai
11.
BMC Cancer ; 16(1): 858, 2016 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-27821081

RESUMO

BACKGROUND: There are clinical situations (CS) in which the use of somatostatin analogs (SSAs) in patients with neuroendocrine tumors (NET) is controversial due to lack of evidence. A Delphi study was conducted to develop common treatment guidelines for these CS, based on clinical practice and expert opinion of Spanish oncologists. METHODS: A scientific committee identified 5 CS with a common core (c-c) [non-functioning NET, not susceptible of surgery/locoregional therapy, Ki67 < 10 % (except for CS5: >10 %), ECOG ≤ 2], and controversy regarding use of SSAs, and prepared a Delphi questionnaire of 48 treatment statements. Statements were rated on a 1 (completely disagree) to 9 (completely agree) scale. Responses were grouped by tertiles: 1-3: Disagreement, 4-6: Neutral, 7-9: Agreement. Consensus was reached when the responses of ≥2/3 participants were located in the same tertile as the median value of all reported responses for that statement. RESULTS: Sixty five (81.2 %) of 80 invited oncologists with experience in the management of NETs answered a first round of the questionnaire and 57 (87.7 %) of those 65 answered a second round (mean age 43.5 years; 53.8 % women; median time of experience 9 years). Consensus was obtained in 42 (36 agreement and 6 disagreement) of the 48 statements (87.5 %). Regarding CS1 (Enteropancreatic NET, c-c, non-progressive in the last 3-6 months), overall, SSA treatment is recommended (a wait and see approach is anecdotal and reserved for fragile patients or with low tumor load or ki-67 < 2 %); CS2 (Pancreatic NET, c-c), overall, SSA monotherapy is recommended, except when high tumor load or tumor progression exists, where combination therapy would be considered; CS3 [Gastroenteropancreatic (GEP)-NET, c-c, in treatment with anti-proliferative dose of SSA and progressing], overall, SSA maintenance is recommended at the time of progression, with or without adding molecular targeted drugs; CS4 (GEP-NET, c-c, and negative octreoscan®), SSA in monotherapy is only considered in low-risk patients (low tumor load and Ki-67 < 5 %); CS5 [GEP-NET, c-c (ki67 > 10 %), and positive octreoscan®], monotherapy with SSA is mainly considered in patients with comorbidities. CONCLUSION: Several recommendations regarding use of SSAs in controversial NET CS were reached in consensus and might be considered as treatment guideline.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Intestinais/tratamento farmacológico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Gerenciamento Clínico , Prova Pericial , Feminino , Humanos , Neoplasias Intestinais/diagnóstico , Masculino , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Gástricas/diagnóstico , Inquéritos e Questionários
12.
Biol Lett ; 12(5)2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27220860

RESUMO

In this study, we focused on the exceptionally large mammals inhabiting the Americas during the Quaternary period and the paramount role of body size in species ecology. We evaluated two main features of Pleistocene food webs: the relationship between body size and (i) trophic position and (ii) vulnerability to predation. Despite the large range of species sizes, we found a hump-shaped relationship between trophic position and body size. We also found a negative trend in species vulnerability similar to that observed in modern faunas. The largest species lived near the boundary of energetic constraints, such that any shift in resource availability could drive these species to extinction. Our results reinforce several features of megafauna ecology: (i) the negative relationship between trophic position and body size implies that large-sized species were particularly vulnerable to changes in energetic support; (ii) living close to energetic imbalance could favour the incorporation of additional energy sources, for example, a transition from a herbivorous to a scavenging diet in the largest species (e.g. Megatherium) and (iii) the interactions and structure of Quaternary megafauna communities were shaped by similar forces to those shaping modern fauna communities.


Assuntos
Tamanho Corporal , Cadeia Alimentar , Mamíferos/fisiologia , Animais , Fósseis , Comportamento Predatório
13.
Am J Cancer Res ; 5(7): 2330-43, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26328265

RESUMO

This study aims to identify the profile of immunohistochemical (IHC) parameters, copy number aberrations (CNAs) and epigenetic alterations [promoter methylation (PM) and miR expression] related to hereditary (H) and triple negative (TN) breast cancer (BC). This profile could be of relevance for guiding tumor response to treatment with targeting therapy. The study comprises 278 formalin fixed paraffin-embedded BCs divided into two groups: H group, including 88 hereditary BC (HBC) and 190 non hereditary (NHBC), and TN group, containing 79 TNBC and 187 non TNBC (NTNBC). We assessed IHC parameters (Ki67, ER, PR, HER2, CK5/6, CK18 and Cadherin-E), CNA of 20 BC related genes, and PM of 24 tumor suppressor genes employing MLPA/MS-MLPA (MRC Holland, Amsterdam). MiR-4417, miR-423-3p, miR-590-5p and miR-187-3p expression was assessed by quantitative RT-PCR (Applied Biosystems). Binary logistic regression was applied to select the parameters that better differentiate the HBC or TN groups. For HBC we found that, ER expression, ERBB2 CNA and PM in RASSF1 and TIMP3 were associated with NHBC whereas; MYC and AURKA CNA were linked to HBC. For TNBC, we found that CDC6 CNA, GSTP1 and RASSF1 PM and miR-423-3p hyperexpression were characteristic of NTNBC, while MYC aberrations, BRCA1 hypermethylation and miR-590-5p and miR-4417 hyperexpression were more indicative of TNBC. The selected markers allow establishing BC subtypes, which are characterized by showing similar etiopathogenetic mechanisms, some of them being molecular targets for known drugs or possible molecular targets. These results could be the basis to implement a personalized therapy.

14.
BMC Cancer ; 15: 495, 2015 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-26138480

RESUMO

BACKGROUND: Based on the mechanism of action, combining somatostatin analogues (SSAs) with mTOR inhibitors or antiangiogenic agents may provide synergistic effects for the treatment of patients with neuroendocrine tumours (NETs). Herein, we investigate the use of these treatment combinations in clinical practice. METHODS: This retrospective cross-sectional analysis of patients with NETs treated with the SSA lanreotide and targeted therapies at 35 Spanish hospitals evaluated the efficacy and safety of lanreotide treatment combinations in clinical practice. The data of 159 treatment combinations with lanreotide in 133 patients was retrospectively collected. RESULTS: Of the 133 patients, with a median age of 59.4 (16-83) years, 70 (52.6%) patients were male, 64 (48.1%) had pancreatic NET, 23 (17.3%) had ECOG PS ≥ 2, 41 (30.8%) had functioning tumours, 63 (47.7%) underwent surgery of the primary tumour, 45 (33.8%) had received prior chemotherapy, and 115 (86.5%) had received prior SSAs. 115 patients received 1 lanreotide treatment combination and 18 patients received between 2 and 5 combinations. Lanreotide was mainly administered in combination with everolimus (73 combinations) or sunitinib (61 combinations). The probability of being progression-free was 78.5% (6 months), 68.6% (12 months) and 57.0% (18 months) for patients who only received everolimus plus lanreotide (n = 57) and 89.3% (6 months), 73.0% (12 months), and 67.4% (18 months) for patients who only received sunitinib and lanreotide (n = 50). In patients who only received everolimus plus lanreotide the median time-to-progression from the initiation of lanreotide combination treatment was 25.8 months (95% CI, 11.3, 40.3) and it had not yet been reached among the subgroup of patients only receiving sunitinib plus lanreotide. The safety profile of the combination treatment was comparable to that of the targeted agent alone. CONCLUSIONS: The combination of lanreotide and targeted therapies, mainly everolimus and sunitinib, is widely used in clinical practice without unexpected toxicities and suggests efficacy that should be explored in randomized prospective clinical trials.


Assuntos
Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Peptídeos Cíclicos/efeitos adversos , Peptídeos Cíclicos/uso terapêutico , Somatostatina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Estudos Transversais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Peptídeos Cíclicos/administração & dosagem , Estudos Retrospectivos , Somatostatina/administração & dosagem , Somatostatina/efeitos adversos , Somatostatina/uso terapêutico , Adulto Jovem
15.
Fam Cancer ; 14(4): 505-13, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26026974

RESUMO

Male breast cancer (MBC) is a rare disease that represents <1% of all breast cancers (BCs). We analyze the results of a multicenter study performed in Spanish familial MBC including family history of hereditary breast and ovarian cancer syndrome (HBOCS) and clinicopathological features. We also study the relationship between BRCA1/BRCA2 mutational status in male relatives affected with cancer (MAC) and, family history and tumor types. The study included 312 men index cases with family history of HBOCS and 61 MAC BRCA1/2 mutation-carriers. Family history, histological grade (HG), clinicopathological and immunohistochemistry data were collected. BRCA1/2 mutation analyses were performed by direct sequencing or screening methods and the large rearrangements by multiplex ligation dependent probe amplification. We found 49 mutation-carriers (15.7%), 95.9% with BRCA2 mutations. BRCA2 mutation-carriers were associated with families with at least one MBC and one BC in female (type II; p = 0.05). Strong association were found between the presence of pathogenic mutations in MBCs and the advanced HG (p = 0.003). c.658_659delTG, c.2808_2811delACAA, c.6275_6276delTT and c.9026_9030delATCAT were the most prevalent mutations. In 61 MAC we found 20 mutations in BRCA1 and 41 in BRCA2. For MAC we show that mutational status was differentially associated with family history (p = 0.018) and tumor type, being BRCA2 mutations linked with BC and prostatic cancer (p = 0.018). MBC caused by BRCA1/2 mutations define two types of MBCs. The most frequent caused by BRCA2 mutation linked to type II families and the rarest one attributed to BRCA1 mutation. Tumor associated with MAC suggest that only BRCA2 mutations have to do with a specific type of cancer (BC and prostatic cancer); but the linkage to tumors is questionable for BRCA1 mutations .


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama Masculina/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Neoplasias Ovarianas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama Masculina/epidemiologia , Neoplasias da Mama Masculina/patologia , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Feminino , Seguimentos , Testes Genéticos/métodos , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/patologia , Prognóstico , Espanha/epidemiologia , Síndrome , Adulto Jovem
16.
Tumori ; 101(5): 517-23, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26045120

RESUMO

BACKGROUND: Adjuvant chemoradiotherapy (CRT) improves relapse-free (RFS) and overall survival (OS) in patients with resected gastric cancer. However, difficulties in standardizing an optimal surgical approach and a perceived higher toxicity compared with the perioperative approach have limited its widespread application in Europe. The aim of our study was to assess toxicity and long-term outcomes of adjuvant CRT at our institution. METHODS: A retrospective review (September 2001-January 2012) was completed of patients with resected gastric cancer who received adjuvant CRT (Macdonald regimen). Adverse events and completion rates, RFS and OS were estimated. Univariate and multivariate analyses of prognostic factors for OS were performed. RESULTS: Eighty-seven patients were included. Most had diffuse (52%) and locally advanced tumors (stage III-IV; 66.7%). D2 lymphadenectomy was performed in 80.5%. The most frequent grade 3-4 toxicities were gastrointestinal (28%) and stomatitis (20%), with 78.2% completing treatment. With a median follow-up of 115 months, 58.5% had relapsed, most of them distantly. Median RFS and OS were 9 and 24 months, respectively. Univariate analysis showed that performance status, stage and lymph node burden were significant factors for OS. In the multivariate study, only stage and lymph node burden remained as independent OS predictors. CONCLUSIONS: Our implementation of the Macdonald regimen achieved worse outcomes than those reported in the INT-0116 trial. The rate of distant relapse remains unacceptably high. Higher rate of positive lymph nodes and of diffuse tumors could explain some differences. The use of perioperative chemotherapy, especially in patients with a poorer prognosis, might improve these results.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia Adjuvante , Gastrectomia , Linfonodos/patologia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Adulto , Idoso , Esquema de Medicação , Europa (Continente) , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Gastrectomia/métodos , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Excisão de Linfonodo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
17.
Am J Cancer Res ; 5(1): 375-85, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25628946

RESUMO

This study investigates the relationship of promoter methylation in tumor suppressor genes with copy-number aberrations (CNA) and with tumor markers in breast cancer (BCs). The study includes 98 formalin fixed paraffin-embedded BCs in which promoter methylation of 24 tumour suppressor genes were assessed by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA), CNA of 20 BC related genes by MLPA and ER, PR, HER2, CK5/6, CK18, EGFR, Cadherin-E, P53, Ki-67 and PARP expression by immunohistochemistry (IHC). Cluster analysis classed BCs in two groups according to promoter methylation percentage: the highly-methylated group (16 BCs), containing mostly hyper-methylated genes, and the sparsely-methylated group (82 BCs) with hypo-methylated genes. ATM, CDKN2A, VHL, CHFR and CDKN2B showed the greatest differences in the mean methylation percentage between these groups. We found no relationship of the IHC parameters or pathological features with methylation status, except for Catherin-E (p = 0.008). However the highly methylated BCs showed higher CNA proportion than the sparsely methylated BCs (p < 0.001, OR = 1.62; IC 95% [1.26, 2.07]). CDC6, MAPT, MED1, PRMD14 and AURKA showed the major differences in the CNA percentage between the two groups, exceeding the 22%. Methylation in RASSF1, CASP8, DAPK1 and GSTP1 conferred the highest probability of harboring CNA. Our results show a new link between promoter methylation and CNA giving support to the importance of methylation events to establish new BCs subtypes. Our findings may be also of relevance in personalized therapy assessment, which could benefit the hyper methylated BC patients group.

18.
Case Rep Oncol ; 7(2): 591-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-25298765

RESUMO

BACKGROUND: Cardiac metastases from papillary thyroid carcinoma are very uncommon. Their incidence is rising due to improvements in survival and diagnosis; nevertheless, our patient is the fourth case reported up to date. There are no clinical trials available in this scenario. Therefore, treatment choice is made based on clinical experience and case reports; notably, the largest case report series was prior to the approval for using tyrosine-kinase inhibitors in thyroid cancer. PATIENT: A 73-year-old lady had dedifferentiated papillary thyroid cancer with ongoing sorafenib. After 9 months on this treatment, she presented with dyspnea and heart failure. Differential diagnosis included infection, progression of disease and cardiotoxicity. After a comprehensive assessment (echocardiography, computed tomography, PET, magnetic resonance), we found progression of lung disease, and the appearance of heart metastases. RESULTS: After recovering from the basal status, she started on second-line treatment with sunitinib, which was well-tolerated. She achieved stable disease with a decrease in tumor marker levels. CONCLUSIONS: We should include cardiac metastases in the differential diagnosis of heart failure in cancer patients. Magnetic resonance imaging is the gold standard for assessment. Sorafenib is the mainstay of the first-line therapy in metastatic thyroid cancer, achieving long-term disease control with good tolerance. Sunitinib could be a safe second-line treatment option (not cardiotoxicity related) with promising results. Therefore, our report presents a sequence of treatment with tyrosine-kinase inhibitors in metastatic thyroid carcinoma with an encouraging outcome, which deserves further investigation.

19.
Eur J Cancer ; 50(13): 2241-50, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24953332

RESUMO

BACKGROUND AND AIMS: Individuals with tumours showing mismatch repair (MMR) deficiency not linked to germline mutations or somatic methylation of MMR genes have been recently referred as having 'Lynch-like syndrome' (LLS). The genetic basis of these LLS cases is unknown. MUTYH-associated polyposis patients show some phenotypic similarities to Lynch syndrome patients. The aim of this study was to investigate the prevalence of germline MUTYH mutations in a large series of LLS patients. METHODS: Two hundred and twenty-five probands fulfilling LLS criteria were included in this study. Screening of MUTYH recurrent mutations, whole coding sequencing and a large rearrangement analysis were undertaken. Age, sex, clinical, pathological and molecular characteristics of tumours including KRAS mutations were assessed. RESULTS: We found a prevalence of 3.1% of MAP syndrome in the whole series of LLS (7/225) and 3.9% when only cases fulfilling clinical criteria were considered (7/178). Patients with MUTYH biallelic mutations had more adenomas than monoallelic (P=0.02) and wildtype patients (P<0.0001). Six out of nine analysed tumours from six biallelic MUTYH carriers harboured KRAS-p.G12C mutation. This mutation was found to be associated with biallelic MUTYH germline mutation when compared with reported series of unselected colorectal cancer cohorts (P<0.0001). CONCLUSIONS: A proportion of unexplained LLS cases is caused by biallelic MUTYH mutations. The obtained results further justify the inclusion of MUTYH in the diagnostic strategy for Lynch syndrome-suspected patients.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , DNA Glicosilases/genética , Mutação em Linhagem Germinativa , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Proteínas ras/genética
20.
Hum Mol Genet ; 23(13): 3506-12, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24501277

RESUMO

Germline mutations in DNA polymerase ɛ (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onset CRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in a mismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays. POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.


Assuntos
Polipose Adenomatosa do Colo/genética , Neoplasias Colorretais/genética , DNA Polimerase III/genética , DNA Polimerase II/genética , Mutação em Linhagem Germinativa/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Ligação a Poli-ADP-Ribose
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