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BACKGROUND: Providing patients with access to health information that can be obtained outside of an office visit is an important part of education, yet little is known about the effectiveness of outreach modalities to connect older adults to online educational tools. The objective was to identify the effectiveness and cost of outreach modalities providing online information about advance care planning (ACP) for older adults. METHODS: Six different outreach modalities were utilized to connect patients to online educational tools (ACP video decision aids). Participants were 13,582 patients aged 65 and older of 185 primary care providers with appointments over a 30-month period within a large health system in the greater New York City area. Main outcome measures were number of online video views and costs per outreach for each modality. KEY RESULTS: There were 1150 video views for 21,407 remote outreach events. Text messages, sent to the largest volume of patients (8869), had the highest outcome rate (9.6%) and were the most economical ($0.09). Characterization of phone calls demonstrated 21.7% engagement in the topic of ACP but resulted in minimal video views (<1%) and incurred the highest cost per outreach ($2.88). In-office handouts had negligible results (<1%). CONCLUSIONS: Text was the most cost-effective modality to connect older adults to an online educational tool in this pragmatic trial, though overall efficacy of all modalities was low.
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Planejamento Antecipado de Cuidados , Telecomunicações , Idoso , Humanos , Cidade de Nova Iorque , Atenção Primária à SaúdeAssuntos
Neoplasias do Endométrio , Instabilidade de Microssatélites , Anticorpos Monoclonais Humanizados , Reparo de Erro de Pareamento de DNA/genética , Neoplasias do Endométrio/tratamento farmacológico , Neoplasias do Endométrio/genética , Feminino , Humanos , Repetições de Microssatélites , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genéticaAssuntos
Anti-Inflamatórios/uso terapêutico , Doenças do Sistema Nervoso Central/tratamento farmacológico , Infliximab/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Sarcoidose/tratamento farmacológico , Doenças do Sistema Nervoso Central/diagnóstico por imagem , Doenças do Sistema Nervoso Central/fisiopatologia , Fluordesoxiglucose F18/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos/administração & dosagem , Sarcoidose/diagnóstico por imagem , Sarcoidose/fisiopatologia , Resultado do TratamentoRESUMO
PURPOSE OF INVESTIGATION: A retrospective study to evaluate six cycles of cisplatin 40 mg/m2 on day 1 and ifosfamide 1,200 mg/m2 daily on days 1 to 4 with Mesna every four weeks as first line treatment for 29 patients with a diagnosis of uterine carcinosarcoma. MATERIALS AND METHODS: A total of 23 of 29 patients received high dose rate intracavitary vaginal cuff brachytherapy (VCBT) with two fractions of seven Gy each. Median age was 65 years (range 40-82); 13 (44.8%) had Stage I disease, three (10.3%) had Stage II, eight (27.6%) had Stage III, and five (17.2%) patients had Stage IV disease. RESULTS: Most common toxicities were anemia grade 1 (35%)/grade 2 (45%), and neutropenia grade 3 (17%)/grade 4 (6.9%). Eleven dose modifications, four treatment discontinuations, and one patient withdrawal occurred. At a median follow up of 45 months (range 9 to 144), Progression free survival (PFS) was 20% and overall survival (OS) was 40% for Stage IV, PFS 75% and OS 62.5% for Stage III, compared to a PFS 75% and OS 72.2% for Stages I-II. Median OS for the entire group was 12.43 years (95% CI 3.69 to inf); for Stage I-III 12.4 years (6.1 to inf), and for Stage IV 15.6 months (95% CI 9.4 to inf). CONCLUSIONS: Cisplatin and ifosfamide chemotherapy with VCBT was well tolerated and has promising activity in uterine carcinosarcoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Braquiterapia/métodos , Carcinossarcoma/terapia , Neoplasias Uterinas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/induzido quimicamente , Carcinossarcoma/patologia , Quimiorradioterapia , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Ifosfamida/administração & dosagem , Mesna/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/induzido quimicamente , Substâncias Protetoras/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias Uterinas/patologiaRESUMO
OBJECTIVE: To identify variables with a preoperative computed tomography scan that influence survival of cats undergoing surgical removal of a primary lung tumour. A secondary objective was to determine whether histologic type and or grade of feline pulmonary tumours affects long term survival. METHODS: Medical records were retrospectively reviewed for cats with preoperative computed tomography scans and surgical resection of primary lung tumours. Pulmonary carcinomas were reviewed for histologic diagnosis using two different approaches, histologic grade as well as major histologic pattern. RESULTS: Median survival time of all (n = 28) cats was 156 days. Median survival time for cats with lymph node enlargement was 65 days versus 498 days for cats without lymph node enlargement on preoperative computed tomography scan. Median survival time for cats with preoperative pleural effusion was 2 · 5 days versus 467 days for cats without pleural effusion. Cats with low or intermediate grade tumours had a median survival time of 730 days versus 105 days for cats with high grade tumours. CLINICAL SIGNIFICANCE: Cats with preoperative lymph node enlargement and pleural effusion have shorter survival times than cats without.
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Doenças do Gato/diagnóstico por imagem , Neoplasias Pulmonares/veterinária , Tomografia Computadorizada por Raios X/veterinária , Animais , Doenças do Gato/mortalidade , Doenças do Gato/patologia , Doenças do Gato/cirurgia , Gatos , Feminino , Pulmão/diagnóstico por imagem , Pulmão/patologia , Pulmão/cirurgia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Estudos Retrospectivos , Análise de SobrevidaRESUMO
BACKGROUND: Uterine serous carcinomas (USCs) are an aggressive form of uterine cancer that may rely on HER2/neu amplification as a driver of proliferation. The objective of this paper is to assess the sensitivity of USC cell lines with and without HER2/neu gene amplification to afatinib, an irreversible ErbB tyrosine kinase inhibitor, and to test the efficacy of afatinib in the treatment of HER2-amplified USC xenografts. METHODS: Eight of fifteen primary USC cell lines (four with HER2 amplification and four without) demonstrating similar in vitro growth rates were treated with scalar concentrations of afatinib. Effects on cell growth, signalling and cell cycle distribution were determined by flow cytometry assays. Mice harbouring xenografts of HER2/neu-amplified USC were treated with afatinib by gavage to determine the effect on tumour growth and overall survival. RESULTS: Primary chemotherapy-resistant USC cell lines harbouring HER2/neu gene amplification were exquisitely sensitive to afatinib exposure (mean ± s.e.m. IC50=0.0056 ± 0.0006 µM) and significantly more sensitive than HER2/neu-non-amplified USC cell lines (mean ± s.e.m. IC50=0.563 ± 0.092 µM, P<0.0001). Afatinib exposure resulted in abrogation of cell survival, inhibition of HER2/neu autophosphorylation and S6 transcription factor phosphorylation in HER2/neu overexpressing USC and inhibited the growth of HER2-amplified tumour xenografts improving overall survival (P=0.0017). CONCLUSIONS: Afatinib may be highly effective against HER2/neu-amplified chemotherapy-resistant USC. The investigation of afatinib in patients harbouring HER2/neu-amplified USC is warranted.
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Cistadenocarcinoma Seroso/tratamento farmacológico , Neoplasias do Endométrio/tratamento farmacológico , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Neoplasias Uterinas/tratamento farmacológico , Adulto , Afatinib , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Técnicas Imunoenzimáticas , Hibridização in Situ Fluorescente , Técnicas In Vitro , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Fosforilação/efeitos dos fármacos , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Células Tumorais Cultivadas , Neoplasias Uterinas/metabolismo , Neoplasias Uterinas/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
INTRODUCTION: Treating therapy-resistant patients with inherited arrhythmia syndromes can be difficult and left cardiac sympathetic denervation (LCSD) might be a viable alternative treatment option. We provide an overview of the indications and outcomes of LCSD in patients with inherited arrhythmia syndromes in the only tertiary referral centre in the Netherlands where LCSD is conducted in these patients. METHODS: This was a retrospective study, including all patients with inherited arrhythmia syndromes who underwent LCSD in our institution between 2005 and 2013. LCSD involved ablation of the lower part of the left stellate ganglion and the first four thoracic ganglia. RESULTS: Seventeen patients, 12 long-QT syndrome (LQTS) patients (71 %) and 5 catecholaminergic polymorphic ventricular tachycardia (CPVT) patients (29 %), underwent LCSD. Most patients (94 %) were referred because of therapy-refractory cardiac events. In 87 % the annual cardiac event rate decreased. However, after 2 years the probability of complete cardiac event-free survival was 59 % in LQTS and 60 % in CPVT patients. Two patients (12 %) had major non-reversible LCSD-related complications: one patient suffered from a Harlequin face post-procedure and one severely affected LQT8 patient died the day after LCSD due to complications secondary to an arrhythmic storm during the procedure. CONCLUSION: LSCD for inherited arrhythmia syndromes, which is applied on a relatively small scale in the Netherlands, reduced the cardiac event rate in 87 % of the high-risk patients who had therapy-refractory cardiac events, while the rate of major complications was low. Therefore, LSCD seems a viable treatment for patients with inherited arrhythmia syndromes without other options for therapy.
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Under certain circumstances, the placement of arterial catheters can be difficult. In these instances, a form of guidance is preferred to avoid repeated insertions of the arterial catheter. Ultrasonic guidance is generally used in these instances, but the equipment required is expensive and cumbersome. This study produced an arterial catheter that is guided by the impedance of biological tissue encountered between the patient's skin and the lumen of the artery, with the aim of producing a cheaper and manageable alternative to ultrasonic guidance. Additionally, this study has inspected the impedance of human tissue in order to determine whether or not a sufficient and discernable difference between the impedance of the different tissue types could be identified and thus be used to guide an arterial catheter based on said impedance differences. The results indicate that the difference between subcutaneous tissue, fat tissue and skeletal muscle tissue are not clear enough to make accurate discrimination between tissue types. However, the study shows a clear difference between the impedance of arterial blood and the aforementioned tissue, allowing for the device to determine when accurate placement has been achieved. From the results obtained in the studies, the discrimination between blood and other intermediary tissue can be made with 99,4% confidence.
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Cateteres de Demora , Impedância Elétrica/uso terapêutico , Animais , Eletrodos , Desenho de Equipamento , Humanos , Técnicas In Vitro , Sus scrofaRESUMO
BACKGROUND: We studied the genetic fingerprints of ovarian cancer and validated the potential of Mammaglobin b (SCGB2A1), one of the top differentially expressed genes found in our analysis, as a novel ovarian tumour rejection antigen. METHODS: We profiled 70 ovarian carcinomas including 24 serous (OSPC), 15 clear-cell (CC), 24 endometrioid (EAC) and 7 poorly differentiated tumours, and 14 normal human ovarian surface epithelial (HOSE) control cell lines using the Human HG-U133 Plus 2.0 chip (Affymetrix). Quantitative real-time PCR and immunohistochemistry staining techniques were used to validate microarray data at RNA and protein levels for SCGB2A1. Full-length human-recombinant SCGB2A1 was used to pulse monocyte-derived dendritic cells (DCs) to stimulate autologous SCGB2A1-specific cytotoxic T-lymphocyte (CTL) responses against chemo-naive and chemo-resistant autologous ovarian tumours. RESULTS: Gene expression profiling identified SCGB2A1 as a top differentially expressed gene in all histological ovarian cancer types tested. The CD8+ CTL populations generated against SCGB2A1 were able to consistently induce lysis of autologous primary (chemo-naive) and metastatic/recurrent (chemo-resistant) target tumour cells expressing SCGB2A1, whereas autologous HLA-identical noncancerous cells were not lysed. Cytotoxicity against autologous tumour cells was significantly inhibited by anti-HLA-class I (W6/32) monoclonal antibody. Intracellular cytokine expression measured by flow cytometry showed a striking type 1 cytokine profile (i.e., high IFN-γ secretion) in SCGB2A1-specific CTLs. CONCLUSION: SCGB2A1 is a top differentially expressed gene in all major histological types of ovarian cancers and may represent a novel and attractive target for the immunotherapy of patients harbouring recurrent disease resistant to chemotherapy.
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Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Mamoglobina B/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Neoplasias/genética , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Mamoglobina B/genética , Análise em Microsséries , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/terapia , Transcriptoma , Estudos de Validação como AssuntoRESUMO
BACKGROUND: This open-label, multicentre, phase 2 trial evaluated the efficacy and tolerability of the mammalian target of rapamycin inhibitor ridaforolimus in women with advanced endometrial cancer. METHODS: Women with measurable recurrent or persistent endometrial cancer and documented disease progression were treated with ridaforolimus 12.5 mg intravenously once daily for 5 consecutive days every 2 weeks in a 4-week cycle. The primary end point was clinical benefit response, defined as an objective response or prolonged stable disease of 16 weeks or more. RESULTS: In all, 45 patients were treated with single-agent ridaforolimus. Clinical benefit was achieved by 13 patients (29%), including 5 (11%) with confirmed partial responses and 8 (18%) with prolonged stable disease. All patients with clinical benefit response received ridaforolimus for more than 4 months. In this heavily pretreated population, the 6-month progression-free survival was 18%. Ridaforolimus was generally well tolerated: adverse events were predictable and manageable, consistent with prior studies in other malignancies. Overall, the most common adverse events were diarrhoea (58%) and mouth sores (56%); most common grade 3 or higher adverse events were anaemia (27%) and hyperglycaemia (11%). CONCLUSION: Single-agent ridaforolimus has antitumor activity and acceptable tolerability in advanced endometrial cancer patients. Further clinical evaluation of ridaforolimus is warranted.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias do Endométrio/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Retratamento , Sirolimo/administração & dosagem , Sirolimo/efeitos adversos , Sirolimo/uso terapêuticoRESUMO
Measuring the states of cell signaling pathways in tumor samples promises to advance the understanding of oncogenesis and identify response biomarkers. Here, we describe the use of Reverse Phase Protein Arrays (RPPAs or RPLAs) to profile signaling proteins in 56 breast cancers and matched normal tissue. In RPPAs, hundreds to thousands of lysates are arrayed in dense regular grids and each grid is probed with a different antibody (100 in the current work, of which 71 yielded strong signals with breast tissue). Although RPPA technology is quite widely used, measuring changes in phosphorylation reflective of protein activation remains challenging. Using repeat deposition and well-validated antibodies, we show that diverse patterns of phosphorylation can be monitored in tumor samples and changes mapped onto signaling networks in a coherent fashion. The patterns are consistent with biomarker-based classification of breast cancers and known mechanisms of oncogenesis. We explore in detail one tumor-associated pattern that involves changes in the abundance of the Axl receptor tyrosine kinase (RTK) and phosphorylation of the cMet RTK. Both cMet and Axl have been implicated in breast cancer, or in resistance to anticancer drugs, but the two RTKs are not known to be linked functionally. Protein depletion and overexpression studies in a 'triple-negative' breast cell line reveal cross talk between Axl and cMet involving Axl-mediated modification of cMet, a requirement for cMet in efficient and timely signal transduction by the Axl ligand Gas6 and the potential for the two receptors to interact physically. These findings have potential therapeutic implications, as they imply that bi-specific receptor inhibitors (for example, ATP-competitive small-kinase inhibitors such as GSK1363089, BMS-777607 or MP470) may be more efficacious than the mono-specific therapeutic antibodies currently in development (for example, Onartuzumab).
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Neoplasias da Mama/metabolismo , Análise Serial de Proteínas/métodos , Transdução de Sinais/fisiologia , Análise por Conglomerados , Feminino , Humanos , Proteômica/métodos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor Tirosina Quinase AxlRESUMO
A significant series of experimental and clinical studies have demonstrated the close association between reduced vagal reflexes (baroreflex sensitivity, BRS) and increased sudden and non-sudden cardiovascular mortality. Subsequently, evidence was provided that, also among chronic heart failure (HF) patients, depressed BRS is associated with a poorer outcome. At the same time, the encouraging results with experimental and clinical attempts to increase cardiac vagal activity led to a few experimental studies with vagal stimulation (VS) in different models for HF. We first performed a pilot study for VS in HF patients, and then in 2011 we reported the results of a small size multicentre clinical trial. The 6-month and 1-year results are encouraging for feasibility, safety and appear to have a favourable clinical effect. An ongoing large clinical trial will provide a definitive assessment of the efficacy and usefulness of chronic VS in HF patients.
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BACKGROUND: We evaluated the expression of CD46, CD55 and CD59 membrane-bound complement-regulatory proteins (mCRPs) in primary uterine serous carcinoma (USC) and the ability of small interfering RNA (siRNA) against these mCRPs to sensitise USC to complement-dependent cytotoxicity (CDC) and antibody (trastuzumab)-dependent cellular cytotoxicity (ADCC) in vitro. METHODS: Membrane-bound complement-regulatory proteins expression was evaluated using real-time PCR (RT-PCR) and flow cytometry, whereas Her2/neu expression and c-erbB2 gene amplification were assessed using immunohistochemistry, flow cytometry and fluorescent in-situ hybridisation. The biological effect of siRNA-mediated knockdown of mCRPs on HER2/neu-overexpressing USC cell lines was evaluated in CDC and ADCC 4-h chromium-release assays. RESULTS: High expression of mCRPs was found in USC cell lines when compared with normal endometrial cells (P<0.05). RT-PCR and FACS analyses demonstrated that anti-mCRP siRNAs were effective in reducing CD46, CD55 and CD59 expression on USC (P<0.05). Baseline complement-dependent cytotoxicity (CDC) against USC cell lines was low (mean ± s.e.m.=6.8 ± 0.9%) but significantly increased upon CD55 and CD59 knockdown (11.6 ± 0.8% and 10.7 ± 0.9%, respectively, P<0.05). Importantly, in the absence of complement, both CD55 and CD59, but not CD46, knockdowns significantly augmented ADCC against USC overexpressing Her2/neu. CONCLUSION: Uterine serous carcinoma express high levels of the mCRPs CD46, CD55 and CD59. Small interfering RNA inhibition of CD55 and CD59, but not CD46, sensitises USC to both CDC and ADCC in vitro, and if specifically targeted to tumour cells, may significantly increase trastuzumab-mediated therapeutic effect in vivo.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos , Antígenos CD55/metabolismo , Antígenos CD59/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias do Colo do Útero/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/metabolismo , Antígenos CD55/química , Antígenos CD55/genética , Antígenos CD59/química , Antígenos CD59/genética , Ativação do Complemento , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/imunologia , Citotoxicidade Imunológica , Regulação para Baixo , Feminino , Citometria de Fluxo , Humanos , Hibridização in Situ Fluorescente , Proteína Cofatora de Membrana/genética , Proteína Cofatora de Membrana/metabolismo , Pessoa de Meia-Idade , Prognóstico , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/genética , Trastuzumab , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/imunologiaRESUMO
Germline variants in the 3' untranslated region (3'UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3'UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09-2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31-7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3'UTR lesions, and that direct targeting may be a viable future treatment approach.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Regiões 3' não Traduzidas/genética , Idoso , Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/metabolismo , Carboplatina/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Análise Multivariada , Mutação , Neoplasias Epiteliais e Glandulares/genética , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Prognóstico , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas p21(ras) , Interferência de RNA , Resultado do Tratamento , Proteínas ras/metabolismoRESUMO
BACKGROUND: We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro. METHODS: Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays. RESULTS: Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01). CONCLUSION: FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Genes erbB-2 , Neoplasias Uterinas/metabolismo , Idoso , Idoso de 80 Anos ou mais , Citotoxicidade Celular Dependente de Anticorpos , Meios de Cultivo Condicionados , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunoterapia , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Trastuzumab , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/terapiaRESUMO
The La protein is an essential RNA-binding protein implicated in different aspects of RNA metabolism. Herein, we report that small interfering (siRNA)-mediated La depletion reduces cell proliferation of different cell lines concomitant with a reduction in cyclin D1 (CCND1) protein. To exclude off-target effects we demonstrate that exogenous La expression in La-depleted cells restores cell proliferation and CCND1 protein levels. In contrast, proliferation of immortalized CCND1 knockout cells is not affected by La depletion, supporting a functional coherence between La, CCND1 and proliferation. Furthermore, we document by reversible in vivo crosslinking and ribonucleoprotein (RNP) immunoprecipitation an association of the La protein with CCND1 messengerRNA and that CCND1 internal ribosome entry site (IRES)-dependent translation is modulated by La protein level within the cell. In addition, we show elevated La protein expression in cervical cancer tissue and its correlation with aberrant CCND1 protein levels in cervical tumor tissue lysates. In conclusion, this study establishes a role of La in cell proliferation and CCND1 expression and demonstrates for the first time an overexpression of the RNA-binding protein La in solid tumors.
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Autoantígenos/metabolismo , Carcinoma de Células Escamosas/metabolismo , Ciclina D1/biossíntese , Ribonucleoproteínas/metabolismo , Neoplasias do Colo do Útero/metabolismo , Autoantígenos/genética , Western Blotting , Carcinoma de Células Escamosas/genética , Proliferação de Células , Separação Celular , Feminino , Citometria de Fluxo , Expressão Gênica , Técnicas de Inativação de Genes , Células HeLa , Humanos , Imuno-Histoquímica , Imunoprecipitação , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ribonucleoproteínas/genética , Análise Serial de Tecidos , Neoplasias do Colo do Útero/genética , Antígeno SS-BRESUMO
BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immuno-conjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF. METHODS: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3+ levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h (51)Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50-100 IU ml(-1)). RESULTS: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; P<0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing+/-s.d., 65.6+/-3.7%, range 57.5-77.0%, P<0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC. CONCLUSION: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell lines overexpressing TF. The hI-con1 may represent a novel therapeutic agent for the treatment of patients harbouring advanced, recurrent and/or metastatic USPC refractory to standard treatment modalities.
Assuntos
Carcinoma Papilar/terapia , Fator VII/uso terapêutico , Imunoterapia , Proteínas Recombinantes de Fusão/uso terapêutico , Neoplasias Uterinas/terapia , Carcinoma Papilar/imunologia , Carcinoma Papilar/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Imuno-Histoquímica , Células Matadoras Naturais/imunologia , Reação em Cadeia da Polimerase , Neoplasias Uterinas/imunologia , Neoplasias Uterinas/patologiaRESUMO
Authors evaluated a set of 1182 patients who underwent a surgery for thyroid disease at two workplaces--1st Surgery Clinic of L. Pasteur Teaching Hospital of Kosice and ENT Department of East-Slovak Oncology Institute, a. s. of Kosice during 5 year period from the point of view of Medullary Thyroid Carcinoma. Of the given number, 9 suffered a confirmed diagnosis of Medullary Thyroid Carcinoma. Incidence and treatment results conform to available publications. The most important elements for successful treatment are considered the early diagnosis and sufficient surgical treatment. The early diagnosis is in hands of GPs and endocrinologists and is the most important regarding the success of treatment. It is useful to direct the surgical treatment into Centres where--regarding rare occurrence, seriousness of disease and specific treatment--the optimum result may be achieved.
Assuntos
Neoplasias da Glândula Tireoide , Adulto , Idoso , Carcinoma Medular/diagnóstico , Carcinoma Medular/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/cirurgiaRESUMO
BACKGROUND: A high proportion of women consulting for depression have a history of childhood abuse and trauma. AIM: To compare the efficacy and costs associated with a treatment that enquires directly into childhood trauma and understands present interpersonal difficulties as a compulsion to repeat the traumatic past, versus the usual treatment, in women with severe depression and childhood trauma. MATERIAL AND METHODS: Eighty seven women with depression and prior history of early trauma that sought help at the Mental Health Unit of the Hospital de Curicó were studied. Forty four were randomly assigned to the experimental treatment, and 43 to the usual management. Patients were evaluated using the Hamilton Depression Scale, the Outcome Questionnaire (OQ 45.2) and an expenditures sheet at baseline, three and six months. An intention to treat analysis and a simple cost-analysis were performed. RESULTS: Hamilton and OQ 45.2 scores improved in both treatment groups, with significantly better results achieved in the experimental patients. The direct overall costs of experimental and control treatments were CLP 8,628,587 and 9,688,240, respectively. The main contributors to costs in both arms were medications (26.5%), followed by the number of psychiatric consultations (19.2%) in the experimental group and by hospitalizations (25.4%) in the control group. The costs per patient recovered in experimental and control groups were CLP 616,328 and 1,973,649, respectively. CONCLUSIONS: The proposed model resulted more effective for the treatment of this group of women.