RESUMO
BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.
Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Resultado do TratamentoRESUMO
Chemotherapy remains the mainstay of treatment for advanced pancreatic ductal adenocarcinoma (pda). Two randomized trials have demonstrated superiority of the combination regimens folfirinox (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) and gemcitabine plus nab-paclitaxel over gemcitabine monotherapy as a first-line treatment in adequately fit subjects. Selected pda patients progressing to first-line therapy can receive secondline treatment with moderate clinical benefit. Nevertheless, the optimal algorithm and the role of combination therapy in second-line are still unclear. Published second-line pda clinical trials enrolled patients progressing to gemcitabine-based therapies in use before the approval of nab-paclitaxel and folfirinox. The evolving scenario in second-line may affect the choice of the first-line treatment. For example, nanoliposomal irinotecan plus 5-fluouracil and leucovorin is a novel second-line option which will be suitable only for patients progressing to gemcitabine-based therapy. Therefore, clinical judgement and appropriate patient selection remain key elements in treatment decision. In this review, we aim to illustrate currently available options and define a possible algorithm to guide treatment choice. Future clinical trials taking into account sequential treatment as a new paradigm in pda will help define a standard algorithm.
RESUMO
Mesenchymal stromal cells possess immunosuppressive properties that might be used for the therapy of inflammatory diseases of various geneses. The effects of mesenchymal stromal cells depend on their lifetime in the recipient tissues. During heterologous transplantation, mesenchymal stromal cells are eliminated by NK cells. We studied NK cell formation in mixed cultures of Wharton's jelly mesenchymal stromal cells and peripheral blood lymphocytes from an autologous donor. Lymphocytes were activated by a mitogen or IL-2. The lifetime of mesenchymal stromal cells was estimated by MTT test. Cytotoxic activity and phenotype of NK cells were evaluated by flow cytometry. It was found that activation of NK cells depended on IL-2 and was registered on day 2 of incubation with IL-2. In cultures with mitogen-activated lymphocytes, cytotoxicity was observed after 5-6 days. Cytotoxicity of NK correlated with significant decrease in CD16+ and increase in CD56+ NK and with reduction of mesenchymal stromal cell viability. Thus, the main mechanism of elimination of mesenchymal stromal cells is cytotoxicity of NK cells that depended on IL-2 production.
Assuntos
Interleucina-2/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Células-Tronco Mesenquimais/efeitos dos fármacos , Fito-Hemaglutininas/farmacologia , Antígeno CD56/genética , Antígeno CD56/imunologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Sangue Fetal/citologia , Sangue Fetal/imunologia , Feto , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Expressão Gênica , Humanos , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/imunologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Receptores de IgG/genética , Receptores de IgG/imunologia , Geleia de Wharton/citologia , Geleia de Wharton/imunologiaRESUMO
BACKGROUND: Little contemporary data are available regarding Australian patterns of care in adult medulloblastoma. It is unclear whether treatment, extrapolated from paediatric protocols despite known differences between the two groups, results in comparable efficacy. AIM: To perform a retrospective review of patterns of care in adult medulloblastoma, especially with respect to adjuvant chemotherapy, in Australian patients. METHODS: All medulloblastoma patients aged 15 years or older at two neuro-oncology institutions were identified from January 1995-May 2011. Patients with supratentorial or peripheral tumours were excluded. Standardised data were extracted from each institution regarding symptoms, disease staging, treatments received, toxicities and survival outcomes. RESULTS: Seventeen eligible patients were identified. Median age was 37 years (range 20-67 years). All had good performance status (Eastern Cooperative Oncology Group 0-1). There were 11 standard-risk de novo patients, three high-risk de novo patients and three patients with recurrent disease. Median overall survival (OS) had not been reached for standard-risk patients with median follow up of 58 months. The median OS for high-risk de novo patients was 21 months, while the median OS was 15 months for patients with recurrent disease. Treatment was well tolerated, with haematological toxicities being most common. CONCLUSIONS: Combined modality therapy (surgery followed by postoperative radiotherapy and adjuvant chemotherapy) was well tolerated and associated with good outcomes in standard-risk de novo patients. High-risk and recurrent disease patients do extremely poorly regardless of treatment and better treatment strategies are needed in these patients.
Assuntos
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Meduloblastoma/diagnóstico , Meduloblastoma/terapia , Adulto , Idoso , Neoplasias Encefálicas/mortalidade , Quimioterapia Adjuvante/métodos , Estudos de Coortes , Terapia Combinada/métodos , Feminino , Seguimentos , Humanos , Masculino , Meduloblastoma/mortalidade , Pessoa de Meia-Idade , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Adulto JovemRESUMO
Phylogenetic analysis of the haemagglutinin (HA) gene shows that the influenza A(H1N1)2009 viruses collected in Hong Kong clustered in two main branches characterised by the E391E and E391K amino acids. The main branch E391K evolved in two sub-branches with N142D and S202T mutations that first appeared in March and July 2010, respectively, with the latter becoming the predominant strain. These genetic variants that emerged display similar antigenic characteristics.Concurrent with genetic surveillance, laboratories should continue monitoring the circulating viruses antigenically.
Assuntos
Evolução Biológica , Evolução Molecular , Variação Genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H1N1/genética , Influenza Humana/genética , Anticorpos Antivirais/genética , Genes Virais , Glicoproteínas de Hemaglutininação de Vírus da Influenza/análise , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Hong Kong , Humanos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H1N1/isolamento & purificação , Vacinas contra Influenza/genética , Influenza Humana/epidemiologia , Influenza Humana/imunologia , Mutação , Neuraminidase/análise , Neuraminidase/genética , Filogenia , RNA Viral/genética , Análise de Sequência de DNARESUMO
Centromeric instability is characterized by dynamic formation of centromeric breaks, deletions, isochromosomes and translocations, which are commonly observed in cancer. So far, however, the mechanisms of centromeric instability in cancer cells are still poorly understood. In this study, we tested the hypothesis that G(2) checkpoint defect promotes centromeric instability. Our observations from multiple approaches consistently support this hypothesis. We found that overexpression of cyclin B1, one of the pivotal genes driving G(2) to M phase transition, impaired G(2) checkpoint and promoted the formation of centromeric aberrations in telomerase-immortalized cell lines. Conversely, centromeric instability in cancer cells was ameliorated through reinforcement of G(2) checkpoint by cyclin B1 knockdown. Remarkably, treatment with KU55933 for only 2.5 h, which abrogated G(2) checkpoint, was sufficient to produce centromeric aberrations. Moreover, centromeric aberrations constituted the major form of structural abnormalities in G(2) checkpoint-defective ataxia telangiectasia cells. Statistical analysis showed that the frequencies of centromeric aberrations in G(2) checkpoint-defective cells were always significantly overrepresented compared with random assumption. As there are multiple pathways leading to G(2) checkpoint defect, our finding offers a broad explanation for the common occurrence of centromeric aberrations in cancer cells.
Assuntos
Centrômero/metabolismo , Instabilidade Cromossômica/genética , Ciclina B1/metabolismo , Fase G2/genética , Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia , Estudos de Casos e Controles , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Divisão Celular/efeitos dos fármacos , Divisão Celular/genética , Divisão Celular/efeitos da radiação , Linhagem Celular , Linhagem Celular Transformada , Linhagem Celular Tumoral , Centrômero/efeitos dos fármacos , Ciclina B1/genética , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Raios gama , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Índice Mitótico , Morfolinas/farmacologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Pironas/farmacologia , Telomerase/genética , Translocação Genética/genética , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: Brain natriuretic peptide (BNP) may help general practitioners (GPs) to "rule-out" heart failure (HF) and reduce referral burden on specialist assessment clinics. AIMS: To determine the diagnostic value of BNP in HF referrals by GPs to a specialist unit. METHODS: From 2003 to 2007, 327 GP referrals were made to a HF new patient diagnostic clinic (NDC) with a provisional diagnosis of HF. The NDC provides rapid assessment of potential HF patients and ensures appropriate therapy and follow-up for those with a confirmed diagnosis. HF diagnosis was confirmed by the Framingham criteria. RESULTS: HF was present in 39% of cases referred (mean age 75 +/- 10 years, 49% male). The inclusion of BNP as a "rule-out" test with a cut-off value of 100 pg/mL would have reduced the number of patients originally referred to the NDC by 175. However, this would have resulted in delayed diagnosis and treatment of 20 (16%) "false-negative" patients. CONCLUSIONS: Availability of BNP to GPs would improve referral patterns but with high risk of delayed diagnosis. The data underline the need for a shared-care approach to the new diagnosis of HF.
Assuntos
Insuficiência Cardíaca/diagnóstico , Peptídeo Natriurético Encefálico/sangue , Idoso , Biomarcadores/sangue , Distribuição de Qui-Quadrado , Comorbidade , Ecocardiografia , Feminino , Insuficiência Cardíaca/sangue , Humanos , Masculino , Valor Preditivo dos Testes , Encaminhamento e Consulta/estatística & dados numéricos , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
Renal artery stenosis is a common cause (1-6%) of secondary hypertension. Renal artery stenting has recently been employed as an adjunct to antihypertensive medication. We evaluated 92 patients who underwent renal angiography of whom 30 were stented. There was a reduction (p < 0.01) in blood pressure immediately post renal artery stenting--systolic BP from 157 +/- 20 to 140 +/- 21 mmHg and diastolic BP from 81 +/- 13 to 72 +/- 12 mmHg was sustained at 6 months follow up (148 +/- 20/76 +/- 12 mmHg) in the outpatients' clinic. The amount of antihypertensive medication did not differ post stenting--2.7 +/- 1.2 pre vs 2.7 +/- 1.2 drugs post procedure. Renal artery stenting did not provide a 'cure' for any patient with atherosclerotic renovascular hypertension and until the results of randomized studies are known we believe use should be restricted.
Assuntos
Implante de Prótese Vascular , Hipertensão Renovascular/cirurgia , Avaliação de Resultados em Cuidados de Saúde , Obstrução da Artéria Renal/cirurgia , Stents , Idoso , Pressão Sanguínea , Progressão da Doença , Feminino , Hospitalização , Humanos , Hipertensão Renovascular/etiologia , Irlanda , Masculino , Pessoa de Meia-Idade , Artéria Renal/patologia , Artéria Renal/cirurgia , Obstrução da Artéria Renal/complicaçõesRESUMO
Screening of strains producing a stable form of L-lactate cytochrome c oxidoreductase (flavocytochrome b2, FC b2) was carried out among 14 yeast species. Enzyme activity was detected in polyacrylamide gel after the electrophoresis of cell-free extracts. The FC b2 of Hansenula polymorpha, Rhodotorula pilimanae, and Kluyveromyces lactis are characterized by high thermostability; in particular, the FC b2 of H. polymorpha retains its activity and tetrameric structure even after heating at 60 degrees C for 10 min. Constitutive synthesis of FC b2 was observed in H. polymorpha grown on either glucose, ethanol, or glycerol. L-Lactate induces de novo synthesis of FC b2, as proved by the use of cycloheximide, an inhibitor of protein synthesis.
Assuntos
Proteínas Fúngicas/biossíntese , Regulação Enzimológica da Expressão Gênica/fisiologia , Regulação Fúngica da Expressão Gênica/fisiologia , L-Lactato Desidrogenase (Citocromo)/biossíntese , Saccharomycetales/enzimologia , Saccharomycetales/crescimento & desenvolvimentoRESUMO
BACKGROUND: Multiple reports have described associations between occupational inhalant exposure and lung disease. Previous occupational lung disease investigations have studied populations consisting of both smokers and nonsmokers. Smoking complicates interpretation of toxicant exposure-response relationships. The objective of this study was to determine whether, among never-smokers, occupational exposure to gases, dusts, or fumes is associated with a history of respiratory disorders and pulmonary function test defined obstructive lung disease. METHODS: We performed a retrospective analysis of 517 never-smoker patients who underwent pulmonary function testing in our clinical laboratory between 1986 and 1999. We calculated the relative risks of developing adverse respiratory health outcomes given a history of exposure to occupational inhalants. RESULTS: Compared with persons with a negative occupational exposure history, exposed persons had an increased risk of reporting a history of bronchitis [relative risk (RR), 1.59; 95% confidence interval (CI), 1.20-2.12], recurrent lung infections (RR, 2.09; 95% CI, 1.14-3.82), and bronchodilator use (RR, 1.61; 95% CI, 1.26-2.06). There was also a statistically significant association between a history of inhalant exposure and the finding of an obstructive ventilatory defect on pulmonary function testing (RR, 1.79; 95% CI, 1.12-2.85). A history of inhalant exposure was not associated with self-reported asthma (RR, 1.08; 95% CI, 0.83-1.41). The population attributable risk estimates for respiratory disorders due to inhalant exposure were: bronchitis, 23.6%; recurrent lung infection, 36.3%; bronchodilator use, 24.3%; and obstructive lung disease, 29.6%. CONCLUSIONS: Occupational inhalant exposure is a strong risk factor for lung disease in this population of never smokers. A significant burden of respiratory disease in this population may be attributable to occupational inhalant exposure.
Assuntos
Exposição por Inalação/efeitos adversos , Doenças Profissionais/etiologia , Exposição Ocupacional/efeitos adversos , Doenças Respiratórias/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Doenças Respiratórias/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Fumar , Inquéritos e QuestionáriosRESUMO
In this study, we investigated the effect of pressure on protein structure and stability at high temperature. Thermoinactivation experiments at 5 and 500 atm were performed using the wild-type (WT) enzyme and two single mutants (D167T and T138E) of the glutamate dehydrogenase (GDH) from the hyperthermophile Thermococcus litoralis. All three GDHs were stabilized, although to different degrees, by the application of 500 atm. Interestingly, the degree of pressure stabilization correlated with GDH stability as well as the magnitude of electrostatic repulsion created by residues at positions 138 and 167. Thermoinactivation experiments also were performed in the presence of trehalose. Addition of the sugar stabilized all three GDHs; the degree of sugar-induced thermostabilization followed the same order as pressure stabilization. Previous studies suggested a mechanism whereby the enzyme adopts a more compact and rigid structure and volume fluctuations away from the native state are diminished under pressure. The present results on the three GDHs allowed us to further confirm and refine the proposed mechanism for pressure-induced thermostabilization. In particular, we propose that pressure stabilizes against thermoinactivation by shifting the equilibrium between conformational substates of the GDH hexamer, thus inhibiting irreversible aggregation.
Assuntos
Glutamato Desidrogenase/química , Glutamato Desidrogenase/metabolismo , Temperatura Alta , Thermococcus/enzimologia , Estabilidade Enzimática , Cinética , Modelos Moleculares , Pressão , Estrutura Quaternária de Proteína , Trealose/metabolismoAssuntos
Fibrose Cística/complicações , Doenças dos Seios Paranasais/etiologia , Sinusite/etiologia , Adolescente , Adulto , Criança , Proteção da Criança , Pré-Escolar , Fibrose Cística/diagnóstico por imagem , Fibrose Cística/terapia , Humanos , Doenças dos Seios Paranasais/diagnóstico por imagem , Doenças dos Seios Paranasais/terapia , Radiografia , Sinusite/diagnóstico por imagem , Sinusite/terapiaRESUMO
BACKGROUND/PURPOSE: The T-tube ileostomy was first used at Texas Children's Hospital in 1959. The purpose of this study is to update the experience since the initial report of this technique in 1981. METHODS: A database of 448 patients with cystic fibrosis (CF) seen in the authors' institution was used to identify 83 patients (18.5%) who presented with meconium ileus. The clinic and hospital charts of these patients were reviewed retrospectively to identify patients who had undergone placement of a T-tube ileostomy. RESULTS: Surgery was performed in 60 of 83 patients for complications of meconium ileus or failure to evacuate the meconium after a contrast enema. Of these patients, 21 of 60 (35%) underwent placement of a T-tube ileostomy. An additional 8 patients were identified who underwent placement of a T-tube ileostomy but were not included in the CF database, for a total of 29 patients who have been treated with T-tube ileostomy since 1959 at Texas Children's Hospital. Five patients were excluded from analysis because of insufficient data or misdiagnosis. One of the 24 patients in the series died of complications of prematurity. A total of 20 of 23 patients had resolution of their meconium ileus after T-tube irrigation with n-acetylcysteine or pancreatic enzymes. Three patients required additional surgery to relieve persistent bowel obstruction. All patients had the T-tube removed within the first 8 weeks after surgery. Two patients required subsequent repair of an incisional hernia. There were otherwise no complications of this procedure, with an average follow-up of 11.5 years. CONCLUSION: In patients with uncomplicated meconium ileus unrelieved by contrast enema, the T-tube ileostomy is an effective and safe treatment.
Assuntos
Fibrose Cística/complicações , Ileostomia/métodos , Obstrução Intestinal/cirurgia , Humanos , Recém-Nascido , Obstrução Intestinal/etiologia , MecônioRESUMO
The authors describe a young woman who developed severe toxemia during pregnancy, requiring emergency lower segment cesarian section at 27 weeks of gestation. Postpartum angiography showed a discrete stenotic lesion of the abdominal aorta proximal to the origin of the renal artery. Angioplasty was performed, followed by the insertion of a wall stent at the site of the stenosis. Her hypertension control improved dramatically after the stenting. This is, so far, the first reported case using a wall stent following angioplasty to relieve abdominal aortic stenosis due to Takayasu's arteritis.
Assuntos
Angioplastia com Balão , Doenças da Aorta/terapia , Complicações Cardiovasculares na Gravidez/terapia , Stents , Arterite de Takayasu/complicações , Adulto , Aorta Abdominal , Doenças da Aorta/etiologia , Feminino , Humanos , Gravidez , Arterite de Takayasu/diagnósticoRESUMO
We describe our experience with the ChoiCE PT (Boston Scientific Corporation, MN) guidewire, which resulted in perforation of the distal coronary artery in two instances. This newly introduced guidewire differs from earlier guidewires in its ability to cross lesions in tortuous arteries. However, when it buckles deep in the coronary artery, perforation can easily result. While the ChoiCE PT guidewire is a useful addition to our armamentarium in interventional procedures, it should be treated with care.
Assuntos
Angioplastia Coronária com Balão/instrumentação , Tamponamento Cardíaco/etiologia , Doença das Coronárias/terapia , Vasos Coronários/lesões , Idoso , Tamponamento Cardíaco/diagnóstico por imagem , Angiografia Coronária , Doença das Coronárias/diagnóstico por imagem , Desenho de Equipamento , Falha de Equipamento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Stents , Propriedades de SuperfícieRESUMO
The transforming growth factor-beta (TGF-beta) family of regulatory growth factors can reversibly arrest cell division in the G1 phase of the cell cycle. Previously, TGF-beta3 was shown to protect epithelial cells and hematopoietic cells from cytotoxic damage in vitro and in vivo, and to reduce the severity and duration of oral mucositis induced by 5-fluorouracil (5-FU) in vivo. In the present study, we tested whether TGF-beta3 can protect epithelial cells from a range of chemotherapy drugs with differing mechanisms of action, using the CCL64 cell line as a model system. We report that preincubation of cells with TGF-beta3 for 24 hr resulted in enhanced clonogenicity following exposure to vinblastine, vincristine, etoposide, taxol, ara-C, methotrexate, or 5-FU. Protection was measured in colony-forming assays, which demonstrated that the protected cells could re-enter the cell cycle and undergo multiple rounds of cell division. At high cytotoxic drug concentrations, absolute colony counts were increased for the cultures prearrested by TGF-beta3, as compared with the proliferating control cultures. The effects of TGF-beta3 were reduced for cisplatin and doxorubicin, drugs that are toxic to cells throughout the cell cycle. Thus, TGF-beta3 can effectively reduce the cytotoxicity of anticancer drugs that act predominantly in S or M phase of the cell cycle.