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2.
Ann Oncol ; 30(1): 115-123, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30423024

RESUMO

Background: Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed. Patients and methods: Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes. Results: Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P < 0.027] and are frequently polyclonal in ctDNA assays. Assessment of paired specimens shows that NF1 alterations arise in the setting of acquired resistance. An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4-hydroxy tamoxifen. Our study further identified a significant increase in tumor mutational burden (TMB) in mILCs relative to breast ILCs or metastatic IDCs (8.9% >20 mutations/mb; P < 0.001). Most TMB-high mILCs harbor an APOBEC trinucleotide signature (14/16; 88%). Conclusions: This study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibitor. Moreover, for an independent subset of mILC, TMB was elevated relative to breast ILC, suggesting possible benefit from immune checkpoint inhibitors.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/secundário , Resistencia a Medicamentos Antineoplásicos/genética , Neurofibromina 1/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
3.
Ann Oncol ; 29(4): 872-880, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29360925

RESUMO

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptor alfa de Estrogênio/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Metástase Neoplásica , Proteínas Recombinantes de Fusão/genética
4.
CPT Pharmacometrics Syst Pharmacol ; 5(4): 211-221, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-27104090

RESUMO

We previously investigated novel therapies for pediatric ependymoma and found 5-fluorouracil (5-FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation approach. Results from our preclinical PK-PD model suggested tumor concentrations exceeded the 1-hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK-PD model to children. To select a 5-FU dosage for our clinical trial in children with ependymoma, we simulated various 5-FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5-FU administration. We developed a pediatric population PK model of bolus 5-FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1-hour target exposure for antitumor effect.


Assuntos
Ependimoma/tratamento farmacológico , Fluoruracila/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/sangue , Antimetabólitos Antineoplásicos/farmacocinética , Proteínas Sanguíneas/metabolismo , Criança , Pré-Escolar , Simulação por Computador , Cálculos da Dosagem de Medicamento , Ependimoma/sangue , Ependimoma/metabolismo , Fluoruracila/sangue , Fluoruracila/farmacocinética , Humanos , Camundongos , Modelos Biológicos , Dinâmica não Linear , Ligação Proteica , Distribuição Aleatória
5.
J Postgrad Med ; 60(4): 357-61, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25370541

RESUMO

BACKGROUND: There is a lack of a psychometrically robust bariatric-specific health-related quality of life (HRQOL) tool. AIM: A single centre, prospective study to develop and validate a new bariatric-specific 81-item self-report HRQOL instrument called the Bariatric and Obesity-Specific Survey (BOSS). MATERIALS AND METHODS: Data were collected from 236 participants. Of these 83 patients were under consideration for bariatric surgery (Group 1) 68 patients had undergone a bariatric procedure (Group 2) and 85 normal healthy participants (Group 3). At baseline, participants were asked to complete the Short Form Health survey (SF-36), Hospital Anxiety and Depression (HADS) scale, Moorehead-Ardelt Quality of life Questionnaire (M-A QoLQ II), and a demographic data sheet. Two weeks following the completion of these five questionnaires, participants were asked to complete BOSS once more along with a feedback sheet. RESULTS: Exploratory factor analysis revealed a multidimensional instrument consisting of 42 items distributed over six domains that addressed various HRQOL aspects and dimensions pertinent to bariatric surgery, and relevant to morbidly obese patients. Further psychometric analysis showed that BOSS has adequate internal consistency reliability (Cronbach α = 0.970), test re-test reliability (ICC = 0.926), construct validity, criterion validity, face validity and acceptability. CONCLUSION: BOSS thus appears to be a valid and reliable multidimensional instrument that provides a clinically useful and relevant measure to assess HRQOL in patients undergoing bariatric surgery.


Assuntos
Cirurgia Bariátrica/psicologia , Obesidade Mórbida/cirurgia , Psicometria/instrumentação , Qualidade de Vida/psicologia , Inquéritos e Questionários , Adulto , Análise Fatorial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/psicologia , Período Pós-Operatório , Estudos Prospectivos , Reprodutibilidade dos Testes , Adulto Jovem
6.
Matrix Biol ; 32(5): 277-87, 2013 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-23369837

RESUMO

Chronic kidney disease (CKD) is characterised by the pathological accumulation of extracellular matrix (ECM) proteins leading to progressive kidney scarring via glomerular and tubular basement membrane expansion. Increased ECM synthesis and deposition, coupled with reduced ECM breakdown contribute to the elevated ECM level in CKD. Previous pre-clinical studies have demonstrated that increased plasmin activity has a beneficial effect in the protein overload model of CKD. As plasmin activation is downregulated by the action of the thrombin activated fibrinolytic inhibitor (TAFI), we tested the hypothesis that inhibition of TAFI might increase plasmin activity and reduce ECM accumulation in an in vitro model of glucose induced ECM expansion. Treatment of NRK52E tubular epithelial cells with increasing concentrations of glucose resulted in a 40% increase in TAFI activity, a 38% reduction in plasmin activity and a subsequent increase in ECM accumulation. In this model system, application of the previously reported TAFI inhibitor UK-396082 [(2S)-5-amino-2-[(1-n-propyl-1H-imidazol-4-yl)methyl]pentanoic acid] caused a reduction in TAFI activity, increased plasmin activity and induced a parallel decrease in ECM levels. In contrast, RNAi knockdown of plasmin resulted in an increase in ECM levels. The data presented here indicate that high glucose induces TAFI activity, inhibiting plasmin activation which results in elevated ECM levels in tubular epithelial cells. The results support the hypothesis that UK-396082 is able to reduce TAFI activity, normalising plasmin activity and preventing excess ECM accumulation suggesting that TAFI inhibition may have potential as an anti-scarring strategy in CKD.


Assuntos
Aminoácidos/farmacologia , Carboxipeptidase B2/genética , Inibidores Enzimáticos/farmacologia , Células Epiteliais/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Imidazóis/farmacologia , Túbulos Renais Proximais/efeitos dos fármacos , Animais , Carboxipeptidase B2/antagonistas & inibidores , Carboxipeptidase B2/metabolismo , Linhagem Celular , Células Epiteliais/enzimologia , Células Epiteliais/patologia , Matriz Extracelular/enzimologia , Matriz Extracelular/patologia , Fibrinolisina/antagonistas & inibidores , Fibrinolisina/genética , Fibrinolisina/metabolismo , Fibrinólise/efeitos dos fármacos , Fibrinólise/genética , Expressão Gênica/efeitos dos fármacos , Glucose/efeitos adversos , Humanos , Túbulos Renais Proximais/enzimologia , Túbulos Renais Proximais/patologia , Modelos Biológicos , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Ratos , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/enzimologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/patologia , Trombina/genética , Trombina/metabolismo
7.
Br J Pharmacol ; 153(7): 1344-52, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18204490

RESUMO

Despite progression in anticancer drug development and improvements in the clinical utilization of therapies, current treatment regimes are still dependent upon the use of systemic antiproliferative cytotoxic agents. Although these agents are unquestionably potent, their efficacy is limited by toxicity towards 'normal' cells and a lack of tumour selective targeting, resulting in a therapeutic index which is modest at best. Consequently, the development of more tumour selective cancer treatments, with better discrimination between tumour and normal cells is unequivocally an important goal for cancer drug discovery. One such strategy is to exploit the tumour phenotype as a mechanism for tumour-selective delivery of potent therapeutics. An exciting approach in this area is to develop anticancer therapeutics as prodrugs, which are non-toxic until activated by enzymes localized specifically in the tumour. Enzymes suitable for tumour-activated prodrug development must have increased activity in the tumour relative to non-diseased tissue and an ability to activate the prodrug to its active form. One class of enzyme satisfying these criteria are the tumour endoproteases, particularly the serine- and metallo-proteases. These proteolytic enzymes are essential for tumour angiogenesis, invasion and metastasis, the major defining features of malignancy. This review describes the concept behind development of tumour-endoprotease activated prodrugs and discusses the various studies to date that have demonstrated the huge potential of this approach for improvement of cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Antineoplásicos/química , Desenho de Fármacos , Endopeptidases/metabolismo , Humanos , Neoplasias/fisiopatologia , Pró-Fármacos/farmacologia
8.
Eur J Cancer ; 43(11): 1764-71, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17600697

RESUMO

Improved understanding of the involvement of matrix metalloproteinases (MMPs), including membrane-type MMPs (MT-MMPs), in human tumours has potential diagnostic, prognostic and therapeutic implications. We assessed the relationship between MT-MMP expression and clinicopathological parameters in human non-small cell lung cancer (NSCLC) and histologically normal lung tissue by quantitative Real Time PCR (qRT-PCR). All MT-MMPs (MMPs 14-17, 24 and 25) were detected by qRT-PCR with significantly higher MMP-14, -15 and -17 expression observed in tumour relative to normal lung specimens. MMP-16 was undetectable in normal lung but expressed in 8% tumours. MMP-15 demonstrated significant overexpression in adenocarcinomas relative to squamous cell carcinomas and normal lung tissue. MMP-14 mRNA expression strongly correlated to MMP-14 proteolytic activity in preclinical tumour models, indicating that qRT-PCR may predict MMP-14 activity levels in NSCLC. These data suggest that MMP-14, -15 and -17 may be good markers of disease, or therapeutic targets for treatment of human NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/enzimologia , Metaloproteinases da Matriz/metabolismo , Proteínas de Neoplasias/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Metaloproteinase 14 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo , RNA Neoplásico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Transplante Heterólogo
9.
BMJ ; 319(7219): 1241-7, 1999 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-10550090

RESUMO

OBJECTIVE: To compare the use and effect of a computer based information system for cancer patients that is personalised using each patient's medical record with a system providing only general information and with information provided in booklets. DESIGN: Randomised trial with three groups. Data collected at start of radiotherapy, one week later (when information provided), three weeks later, and three months later. PARTICIPANTS: 525 patients started radical radiotherapy; 438 completed follow up. INTERVENTIONS: Two groups were offered information via computer (personalised or general information, or both) with open access to computer thereafter; the third group was offered a selection of information booklets. OUTCOMES: Patients' views and preferences, use of computer and information, and psychological status; doctors' perceptions; cost of interventions. RESULTS: More patients offered the personalised information said that they had learnt something new, thought the information was relevant, used the computer again, and showed their computer printouts to others. There were no major differences in doctors' perceptions of patients. More of the general computer group were anxious at three months. With an electronic patient record system, in the long run the personalised information system would cost no more than the general system. Full access to booklets cost twice as much as the general system. CONCLUSIONS: Patients preferred computer systems that provided information from their medical records to systems that just provided general information. This has implications for the design and implementation of electronic patient record systems and reliance on general sources of patient information.


Assuntos
Bases de Dados como Assunto/estatística & dados numéricos , Neoplasias/terapia , Educação de Pacientes como Assunto/métodos , Atitude Frente aos Computadores , Computadores/economia , Custos e Análise de Custo , Coleta de Dados , Bases de Dados como Assunto/economia , Humanos , Informática Médica/economia , Satisfação do Paciente
11.
Br J Oral Maxillofac Surg ; 33(1): 9-14, 1995 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-7718535

RESUMO

61 orthognathic surgery patients were studied (39% male, 61% female). It confirms that the group of patients we see in the West of Scotland are well adjusted psychologically and that the majority seek orthognathic surgery for aesthetic reasons. The degree of satisfaction is high (87%). Dissatisfaction is not related to sex, age or procedure. Patients who were dissatisfied tend to have higher neuroticism scores on the Eysenck Personality Inventory and those patients who had had unreal expectations of post surgical pain, numbness and swelling, were likely to express dissatisfaction with the outcome in the early stages. Several patients initially expressed some dissatisfaction with the outcome after 3 months then went on to increase their score and by 12 months became satisfied with the procedure. The authors outline the importance of adequate patient preparation prior to surgery and the use of printed literature is recommended.


Assuntos
Anormalidades Maxilomandibulares/psicologia , Anormalidades Maxilomandibulares/cirurgia , Satisfação do Paciente , Cirurgia Bucal/psicologia , Adolescente , Adulto , Imagem Corporal , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Neuróticos/psicologia , Procedimentos Cirúrgicos Ortognáticos , Osteotomia/psicologia , Avaliação de Resultados em Cuidados de Saúde , Educação de Pacientes como Assunto , Inventário de Personalidade , Autoimagem , Inquéritos e Questionários
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