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1.
Ann Oncol ; 27(7): 1249-56, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27052654

RESUMO

BACKGROUND: Trastuzumab emtansine (T-DM1) exhibited enhanced antitumor activity when combined with docetaxel or pertuzumab in preclinical studies. This phase Ib/IIa study assessed the feasibility of T-DM1 + docetaxel in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and T-DM1 + docetaxel ± pertuzumab in patients with HER2-positive locally advanced breast cancer (LABC). PATIENTS AND METHODS: Phase Ib (part 1) explored dose escalation, with T-DM1 + docetaxel administered for greater than or equal to six cycles in patients with MBC. Phase Ib (part 2) began with the maximum tolerated dose (MTD) identified in part 1. Patients with LABC were administered less than or equal to six cycles of T-DM1 + docetaxel or T-DM1 + docetaxel + pertuzumab. Phase IIa explored the MTDs identified in phase Ib. RESULTS: Administered with T-DM1 (3.6 mg/kg), the docetaxel MTD was 60 mg/m(2) in MBC. In LABC, the MTD was 100 mg/m(2) docetaxel in combination with T-DM1 (3.6 mg/kg), given with granulocyte colony-stimulating factor (G-CSF). Administered with T-DM1 (3.6 mg/kg) + pertuzumab (840 mg, cycle 1; 420 mg, subsequent cycles), the docetaxel MTD in LABC was 75 mg/m(2) with G-CSF support. Neutropenia was the most common grade 3-4 adverse event (AE; MBC, 72% and LABC, 29%). In total, 48% (12/25) of MBC patients and 47% (34/73) of LABC patients experienced AEs requiring dose modification. In MBC (median prior systemic agents = 5), the objective response rate was 80.0% (20/25; 95% confidence interval [CI] 59.3-93.2) and the median progression-free survival was 13.8 months (range, 1.6-33.5). The pathologic complete response (ypT0/is, ypN0) rate in LABC was 60.3% (44/73; 95% CI 48.1-71.5). Pharmacokinetic analyses indicated a low risk of drug-drug interaction between T-DM1 and docetaxel. CONCLUSIONS: T-DM1 combined with docetaxel ± pertuzumab appeared efficacious in MBC or LABC; however, nearly half of patients experienced AEs requiring dose reductions with these T-DM1 combinations. CLINICALTRIALSGOV IDENTIFIER: NCT00934856.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Maitansina/análogos & derivados , Receptor ErbB-2/genética , Taxoides/administração & dosagem , Trastuzumab/administração & dosagem , Ado-Trastuzumab Emtansina , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Docetaxel , Feminino , Fator Estimulador de Colônias de Granulócitos/genética , Humanos , Maitansina/administração & dosagem , Maitansina/efeitos adversos , Maitansina/farmacocinética , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Taxoides/efeitos adversos , Taxoides/farmacocinética , Trastuzumab/efeitos adversos , Trastuzumab/farmacocinética
2.
Acta Virol ; 60(3): 260-70, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27640436

RESUMO

Rotavirus is the major cause of severe virus-associated gastroenteritis worldwide in children aged 5 and younger. Many children lose their lives annually due to this infection and the impact is particularly pronounced in developing countries. The mature rotavirus is a non-enveloped triple-layered nucleocapsid containing 11 double stranded RNA segments. Here a global view on the sequence and structure of the three main capsid proteins, VP2, VP6 and VP7 is shown by generating a consensus sequence for each of these rotavirus proteins, for each species obtained from published data of representative rotavirus genotypes from across the world and across species. Degree of conservation between species was represented on homology models for each of the proteins. VP7 shows the highest level of variation with 14-45 amino acids showing conservation of less than 60%. These changes are localised to the outer surface alluding to a possible mechanism in evading the immune system. The middle layer, VP6 shows lower variability with only 14-32 sites having lower than 70% conservation. The inner structural layer made up of VP2 showed the lowest variability with only 1-16 sites having less than 70% conservation across species. The results correlate with each protein's multiple structural roles in the infection cycle. Thus, although the nucleotide sequences vary due to the error-prone nature of replication and lack of proof reading, the corresponding amino acid sequence of VP2, 6 and 7 remain relatively conserved. Benefits of this knowledge about the conservation include the ability to target proteins at sites that cannot undergo mutational changes without influencing viral fitness; as well as possibility to study systems that are highly evolved for structure and function in order to determine how to generate and manipulate such systems for use in various biotechnological applications.


Assuntos
Proteínas do Capsídeo/metabolismo , Rotavirus/metabolismo , Sequência de Aminoácidos , Proteínas do Capsídeo/genética , Regulação Viral da Expressão Gênica/fisiologia , Modelos Moleculares , Dados de Sequência Molecular , Conformação Proteica , Rotavirus/genética
3.
J Autoimmun ; 59: 38-42, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25725581

RESUMO

Genetic variants in il2 and il2ra have been associated with autoimmune disease susceptibility in both genome-wide association studies (GWAS) in humans and in genetic linkage studies in experimental models of autoimmunity. Specifically, genetic variants resulting in a low IL-2 phenotype are susceptibility alleles while variants resulting in a high IL-2 phenotype are resistance alleles. The association of high IL-2 phenotypes with resistance has been attributed primarily to the T cell intrinsic promotion of regulatory T cell development, maintenance, and function; however, IL-2 can also act T cell intrinsically to dampen differentiation of pathogenic IL-17-producing Th17 cells. Here, we have uncovered a novel T cell extrinsic mechanism whereby IL-2 promotes both IFN-γ and IL-27 production from tissue resident macrophages which in turn dampen the differentiation of pathogenic Th17 cells.


Assuntos
Doenças Autoimunes/imunologia , Interleucina-2/metabolismo , Macrófagos/imunologia , Subpopulações de Linfócitos T/imunologia , Células Th17/imunologia , Animais , Doenças Autoimunes/genética , Diferenciação Celular , Células Cultivadas , Feminino , Predisposição Genética para Doença , Humanos , Interferon gama/metabolismo , Interleucina-2/genética , Interleucina-27/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Modelos Animais , Polimorfismo Genético
4.
Br J Cancer ; 110(3): 565-72, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24300977

RESUMO

BACKGROUND: Progesterone receptor (PR) expression assessment in early invasive breast cancer remains controversial. This study sought to re-evaluate PR expression as a potential therapeutic guide in early breast cancer; particularly in oestrogen receptor (ER)-positive, lymph node (LN)-negative disease. METHODS: A population cohort of 1074 patients presenting to a single Cancer Centre over 4 years (2000-2004) underwent surgery for primary invasive breast cancer with curative intent. Prospective data collection included patient demographics, pathology, ER and PR expression, HER2 status, adjuvant chemotherapy and endocrine therapy. Progesterone receptor expression was compared with (all causes) overall survival (OS), breast cancer-specific survival (BCSS) and disease-free survival (DFS). RESULTS: Overall survival was 71.0% and BCSS was 83.0% at median follow-up of 8.34 years. Absent PR expression was significantly associated with poorer prognosis for OS, BCSS and DFS (P<0.0001, log-rank), even within the ER-positive, LN-negative group (hazard ratio for BCSS 3.17, 95% CI 1.43-7.01) and was not influenced by endocrine therapy. Cox's regression analysis demonstrated that PR expression was an independent prognostic variable. CONCLUSION: Absence of PR expression is a powerful, independent prognostic variable in operable, primary breast cancer even in ER-positive, LN-negative patients receiving endocrine therapy. Absence of PR expression should be re-evaluated as a biomarker for poor prognosis in ER-positive breast cancer and such patients considered for additional systemic therapy.


Assuntos
Biomarcadores Tumorais/biossíntese , Neoplasias da Mama/genética , Detecção Precoce de Câncer , Receptores de Progesterona/biossíntese , Adulto , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética
5.
Br J Cancer ; 108(7): 1515-24, 2013 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-23519057

RESUMO

BACKGROUND: Adjuvant endocrine therapy is recommended for women with oestrogen receptor-positive breast cancer, but many women do not take the medication as directed and they stop treatment before completing the standard 5-year duration. METHODS: This retrospective cohort study conducted between 1993 and 2008 of all women with incident breast cancer, who are residing in the Tayside region of Scotland, examined adherence to prescribed adjuvant tamoxifen or aromatase inhibitors (AIs). Survival analysis examined the effect of adherence on all-cause mortality, breast cancer death and recurrence, using linked prescribing, cancer registry, clinical cancer audit, hospital discharge and death records. RESULTS: A total of 3361 women with breast cancer were followed for a median 4.47 years (interquartile range (IQR)=2.04-8.55). The median overall adherence was 90% (IQR=90-100%), but the annual adherence reduced after a longer period from diagnosis. Low adherence of <80% was associated with poorer survival (hazard ratios=1.20; 95% confidence interval=1.03-1.40, P=0.019). There was no significant difference for low adherence over the treatment period and recurrence, or breast cancer death, but patients with high annual adherence for 5 years had better outcomes than those with 3 or less. CONCLUSION: Low adherence to all adjuvant endocrine therapy for women with breast cancer, whether tamoxifen or AI, increases the risk of death.


Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Adesão à Medicação/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/mortalidade , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Estudos Retrospectivos , Escócia/epidemiologia , Análise de Sobrevida , Tamoxifeno/administração & dosagem
6.
Br J Cancer ; 104(8): 1246-8, 2011 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-21448166

RESUMO

BACKGROUND: We analysed the outcomes of 726 cases of primary head and neck cancer patients managed between 1996 and 2008, including those managed in the multidisciplinary clinic or team setting (MDT) and those managed outside of an MDT by individual disciplines (non-MDT) in the same institution. METHODS: Data were collected from the Hospital Based Cancer Registry and a database within the Head and Neck Cancer Clinic. Univariable comparisons and multivariable analyses were performed using a logistic regression model. Survival by staging was analysed. Comparisons of management and outcomes were made between MDT and non-MDT patients. RESULTS: 395 patients (54%) had been managed in the MDT vs 331 patients (46%) non-MDT. MDT patients were more likely to have advanced disease (likelihood ratio χ(2)=44.7, P<0.001). Stage IV MDT patients had significantly improved 5-year survival compared with non-MDT patients (hazard ratio=0.69, 95% CI=0.51-0.88, P=0.004) and more synchronous chemotherapy and radiotherapy (P=0.004), and the non-MDT group had more radiotherapy as a single modality (P=0.002). CONCLUSIONS: The improved survival of MDT-managed stage IV patients probably represents both the selection of multimodality treatment and chemotherapeutic advances that these patients received in a multidisciplinary team setting by head and neck cancer specialists as opposed to cancer generalists in a non-MDT setting.


Assuntos
Carcinoma/terapia , Terapia Combinada/métodos , Neoplasias de Cabeça e Pescoço/terapia , Comunicação Interdisciplinar , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/mortalidade , Carcinoma/patologia , Terapia Combinada/tendências , Cirurgia Geral/estatística & dados numéricos , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estadiamento de Neoplasias , Radioterapia/estatística & dados numéricos , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
7.
J Infect Dis ; 202 Suppl: S139-47, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20684694

RESUMO

Rotavirus infection is the most common cause of severe dehydrating gastroenteritis in infants and young children and remains a significant clinical problem worldwide. The severity and the burden of rotavirus disease could be reduced through the implementation of an effective vaccine. The aim of this study was to characterize rotavirus strains circulating in the local community as part of an ongoing hospital burden of disease study when a G1P[8] rotavirus vaccine candidate was being evaluated in the same community. From 2003 through 2006, 729 rotavirus-positive stool specimens were collected from children <5 years of age who were treated for diarrhea at Dr George Mukhari Hospital, Ga-Rankuwa, South Africa. Molecular characterization of the strains was performed by polyacrylamide gel electrophoresis and genotyping of the VP4 and VP7 alleles using well-established seminested multiplex reverse-transcription polymerase chain reaction methods. In 2003, 62% of strains exhibited the short rotavirus electropherotype, and the most common rotavirus strain was G2P[4]. In subsequent years, predominant rotavirus strains included G1P[8] and G1P[6] in 2004, G3P[8] and G3P[6] in 2005, and G1P[8] in 2006. For the 4 years of the study, rotavirus strains with P[6] genotype were detected in 25% of all rotavirus-positive specimens. In addition, unusual G12P[6] and G8 strains were detected at a low frequency. These results reflect the diversity of rotavirus strains circulating in South African communities.


Assuntos
Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/virologia , Rotavirus/genética , Antígenos Virais/genética , Antígenos Virais/metabolismo , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Regulação Viral da Expressão Gênica , Variação Genética , Genótipo , Humanos , Epidemiologia Molecular , Dados de Sequência Molecular , Filogenia , Rotavirus/classificação , Alinhamento de Sequência , África do Sul/epidemiologia
8.
J Infect Dis ; 202 Suppl: S198-204, 2010 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-20684703

RESUMO

BACKGROUND: Nigeria has recently been ranked third among the 10 countries with the greatest number of rotavirus disease-associated deaths per year. Estimates attribute up to 33,000 deaths annually to rotavirus disease in Nigerian children <5 years old. Although the introduction of the new oral, live attenuated rotavirus vaccines may not occur for another 4-6 years in developing countries, background data on burden of disease, cost of rotavirus disease, and characterization of circulating strains is required to hasten this introduction to children who would clearly benefit from the intervention. METHODS: Between July 2002 and July 2004, fecal specimens were collected from 869 infants and young children <5 years of age presenting with diarrhea in Kaduna, Kebbi, Sokoto, and Zamfara states in northwestern Nigeria. In addition, 194 control specimens were also collected from children matched for age. Specimens were screened for the presence of rotavirus antigens. Rotavirus-positive specimens were further analyzed to determine electropherotype, subgroup specificity, and G and P genotypes. RESULTS: Rotavirus was detected in 18% of children with diarrhea and 7.2% of the age-matched case control subjects. The highest rotavirus burden was detected in children aged <6 months. The majority of the rotavirus-positive specimens revealed viruses of long electropherotypes, subgroup II specificity, and G1P[8] genotypes. Furthermore, more than a quarter of specimens (37%) displayed mixed G and P genotypes, and almost a third could not be genotyped. CONCLUSIONS: The high numbers of mixed rotavirus infections highlight the multitude of enteric pathogens to which children in African countries are exposed. Data on circulating rotavirus strains serve to inform African government officials to the serious health threat posed by rotavirus in their respective countries and to document the diversity of strains before vaccine introduction.


Assuntos
Antígenos Virais/genética , Proteínas do Capsídeo/genética , Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/virologia , Rotavirus/genética , Distribuição por Idade , Estudos de Casos e Controles , Pré-Escolar , Diarreia/epidemiologia , Diarreia/virologia , Fezes/virologia , Variação Genética , Genótipo , Humanos , Lactente , Recém-Nascido , Nigéria/epidemiologia , Rotavirus/imunologia , Rotavirus/isolamento & purificação , Estações do Ano , Especificidade da Espécie , Fatores de Tempo
9.
Br J Cancer ; 102(4): 719-26, 2010 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-20104224

RESUMO

BACKGROUND: The deprivation gap for breast cancer survival remains unexplained by stage at presentation, treatment, or co-morbidities. We hypothesised that p53 mutation might contribute to the impaired outcome observed in patients from deprived communities. METHODS: p53 mutation status was determined using the Roche Amplichip research test in 246 women with primary breast cancer attending a single cancer centre and related to deprivation, pathology, overall, and disease-free survival. RESULTS: p53 mutation, identified in 64/246 (26%) of cancers, was most common in 10 out of 17 (58.8%) of the lowest (10th) deprivation decile. Those patients with p53 mutation in the 10th decile had a significantly worse disease-free survival of only 20% at 5 years (Kaplan-Meier logrank chi(2)=6.050, P=0.014) and worse overall survival of 24% at 5 years (Kaplan-Meier logrank chi(2)=6.791, P=0.009) than women of deciles 1-9 with p53 mutation (c.f. 56% and 72%, respectively) or patients in the 10th decile with wild-type p53 (no disease relapse or deaths). CONCLUSION: p53 mutation in breast cancer is associated with socio-economic deprivation and may provide a molecular basis, with therapeutic implications, for the poorer outcome in women from deprived communities.


Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Carência Psicossocial , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/mortalidade , Neoplasias da Mama/psicologia , Feminino , Frequência do Gene , Humanos , Pessoa de Meia-Idade , Mutação , Prognóstico , Classe Social , Análise de Sobrevida
10.
Br J Cancer ; 103(4): 475-81, 2010 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-20664587

RESUMO

BACKGROUND: This study assessed the impact of human epidermal growth factor receptor 2 (HER2) status on the outcomes in an unselected population of breast cancer patients who did not receive HER2-targeted therapy. METHODS: HER2 status by immunohistochemistry and fluorescence in situ hybridisation was compared with clinicopathological data, overall survival (OS) and disease-free survival (DFS) for all patients presenting with breast cancer over 3 years. RESULTS: In 865 patients (median follow up 6.02 years), HER2 positivity was identified in 13.3% of all cancers and was associated with higher tumour grade (P<10(-8)), lymphovascular invasion (P<0.001) and axillary nodal metastasis (P=0.003). There was a negative association with oestrogen-receptor (ER) and progesterone-receptor expression (P<10(-8)), but the majority (57%) of HER2+tumours were ER+HER2 positivity was associated with poorer OS (P=0.0046) and DFS (P=0.0001) confined to the lymph node-positive (LN+) and ER+ subgroups. CONCLUSION: HER2-positive cancers were less common in this population-based cohort than most selected series. The association of HER2 positivity with poor prognosis was confined to the ER+ and LN+ subgroups. The survival deficit for the 7.5% of patients with ER+/HER2+ cancer compared with ER+/HER2- patients points to a significant subgroup of women who may not (currently) be considered for HER2-directed therapy.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Análise de Sobrevida
11.
J Med Genet ; 46(5): 319-23, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19279022

RESUMO

AIM: To establish health related costs and benefits of clinical services for women at increased familial risk of breast cancer. METHODS: Analysis of costs and outcomes for one UK regional service, supplemented with data from a multinational collaborative study. Main outcome measures were aggregate costs for regular clinical examination, mammographic screening and further investigations; breast cancer incidence; proportion of cancers detected at "early" or "late" stage, compared with corresponding data for unscreened women of comparable age; survival in relation to stage at diagnosis; itemised and aggregate costs of management for "early" and "late" stage breast cancer; hence direct health care costs per quality adjusted life-year (QALY) gained. RESULTS: The surveillance programme costs pound1500 (euro1600, US$2100) per woman (over 15 years). Breast cancer incidence is close to 6 per thousand examinations; 75% of tumours are detected through screening and 77% are "early" (path stage 1 or 2). Corresponding figures for unscreened women (including relatives of those attending the breast cancer family clinic) indicate that surveillance achieves a beneficial "stage shift", with reduction in treatment costs and improvement in survival, in about 22% of cases. CONCLUSIONS: The current clinical service for women at familial risk of breast cancer costs about pound4800 (euro5200, US$6800) per QALY gained. That figure is sensitive to the rate of detection of breast cancer and the degree of beneficial stage shift achieved. Within the realistic range of estimates for these two parameters, the cost per QALY may be as high as pound14,000 (euro15,300, US$20,000) or as low as pound1000 (euro1100, US$1400).


Assuntos
Neoplasias da Mama/terapia , Vigilância da População/métodos , Adulto , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/economia , Neoplasias da Mama/genética , Análise Custo-Benefício/métodos , Saúde da Família , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Anos de Vida Ajustados por Qualidade de Vida , Análise de Sobrevida
12.
Br J Cancer ; 100(12): 1867-72, 2009 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-19471276

RESUMO

The aim of the study was to achieve earlier diagnosis of malignant cord compression (MCC) using urgent magnetic resonance imaging (MRI) for selected patients. A comparison was carried out of the current prospective audit of 100 patients referred by a general practitioner or a consultant over 32 months with both a previous national Clinical Research and Audit Group (CRAG) prospective audit (324 cases of MCC) and an earlier retrospective audit of 104 patients referred with suspected MCC. A telephone hotline rapid-referral process for patients with known malignancy and new symptoms (severe nerve root pain +/- severe back pain) was designed. Patients were considered for urgent MRI after discussion with a senior clinician responsible for the hotline. Appropriate referrals were discussed with radiology and oncology ensuring timely MRI reporting and intervention. The main outcome measures are as follows: time from referral to diagnosis; time from the onset of symptoms to diagnosis; and mobility at diagnosis. A total of 50 patients (52%) of those scanned had either MCC (44) or malignant nerve root compression (6) compared with the earlier rate of 23 out of 104 patients (22%). Ten out of 44 MCC patients (23%) were paralysed at diagnosis, compared with 149 out of 324 (46%) in the CRAG audit. Time from reporting pain to diagnosis was 32 days compared with 89 days in the CRAG audit. Median time from referral to diagnosis was 1 day, again considerably shorter than the CRAG audit time of 15 days (interquartile (IQ) range: 3-66). In patients at risk of MCC, fast-track referral with rapid access to MRI reduces time between symptom onset and diagnosis, improves mobility at diagnosis and reduces the number of negative MRI scans.


Assuntos
Dor nas Costas/diagnóstico , Imageamento por Ressonância Magnética , Auditoria Médica , Neoplasias da Próstata/patologia , Compressão da Medula Espinal/diagnóstico , Idoso de 80 Anos ou mais , Dor nas Costas/etiologia , Diagnóstico Diferencial , Diagnóstico Precoce , Humanos , Masculino , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Encaminhamento e Consulta , Estudos Retrospectivos , Compressão da Medula Espinal/etiologia , Fatores de Tempo
13.
Lancet ; 371(9618): 1098-107, 2008 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-18355913

RESUMO

BACKGROUND: The international standard radiotherapy schedule for early breast cancer delivers 50 Gy in 25 fractions of 2.0 Gy over 5 weeks, but there is a long history of non-standard regimens delivering a lower total dose using fewer, larger fractions (hypofractionation). We aimed to test the benefits of radiotherapy schedules using fraction sizes larger than 2.0 Gy in terms of local-regional tumour control, normal tissue responses, quality of life, and economic consequences in women prescribed post-operative radiotherapy. METHODS: Between 1999 and 2001, 2215 women with early breast cancer (pT1-3a pN0-1 M0) at 23 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy over 5 weeks or 40 Gy in 15 fractions of 2.67 Gy over 3 weeks. Women were eligible for the trial if they were aged over 18 years, did not have an immediate reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 1105 women were assigned to the 50 Gy group and 1110 to the 40 Gy group. After a median follow up of 6.0 years (IQR 5.0-6.2) the rate of local-regional tumour relapse at 5 years was 2.2% (95% CI 1.3-3.1) in the 40 Gy group and 3.3% (95% CI 2.2 to 4.5) in the 50 Gy group, representing an absolute difference of -0.7% (95% CI -1.7% to 0.9%)--ie, the absolute difference in local-regional relapse could be up to 1.7% better and at most 1% worse after 40 Gy than after 50 Gy. Photographic and patient self-assessments indicated lower rates of late adverse effects after 40 Gy than after 50 Gy. INTERPRETATION: A radiation schedule delivering 40 Gy in 15 fractions seems to offer rates of local-regional tumour relapse and late adverse effects at least as favourable as the standard schedule of 50 Gy in 25 fractions.


Assuntos
Neoplasias da Mama/radioterapia , Radioterapia de Alta Energia/normas , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/cirurgia , Fracionamento da Dose de Radiação , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Modelos de Riscos Proporcionais , Qualidade de Vida , Dosagem Radioterapêutica , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Reino Unido
14.
Genetics ; 180(4): 2251-66, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18845848

RESUMO

In Saccharomyces cerevisiae, Cdc13 binds telomeric DNA to recruit telomerase and to "cap" chromosome ends. In temperature-sensitive cdc13-1 mutants telomeric DNA is degraded and cell-cycle progression is inhibited. To identify novel proteins and pathways that cap telomeres, or that respond to uncapped telomeres, we combined cdc13-1 with the yeast gene deletion collection and used high-throughput spot-test assays to measure growth. We identified 369 gene deletions, in eight different phenotypic classes, that reproducibly demonstrated subtle genetic interactions with the cdc13-1 mutation. As expected, we identified DNA damage checkpoint, nonsense-mediated decay and telomerase components in our screen. However, we also identified genes affecting casein kinase II activity, cell polarity, mRNA degradation, mitochondrial function, phosphate transport, iron transport, protein degradation, and other functions. We also identified a number of genes of previously unknown function that we term RTC, for restriction of telomere capping, or MTC, for maintenance of telomere capping. It seems likely that many of the newly identified pathways/processes that affect growth of budding yeast cdc13-1 mutants will play evolutionarily conserved roles at telomeres. The high-throughput spot-testing approach that we describe is generally applicable and could aid in understanding other aspects of eukaryotic cell biology.


Assuntos
Genoma Fúngico , Mutação , Proteínas de Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/genética , Proteínas de Ligação a Telômeros/genética , Telômero/metabolismo , Reparo do DNA , DNA Fúngico , Deleção de Genes , Genes Supressores , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Proteínas de Ligação a Telômeros/metabolismo
15.
J Med Virol ; 81(1): 106-13, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19031449

RESUMO

The last decade has seen an increase in the detection of rotavirus strains other than G1-G4 emerging or even predominating in some settings. The performance of the current rotavirus vaccines against unusual or rare circulating rotavirus serotypes cannot be predicted and continuous monitoring of wild type rotaviruses will remain a priority. Routine molecular rotavirus surveillance conducted in the Gauteng Province, South Africa during 2004, resulted in the detection of strains that could not typed using standard G specific genotyping primers. Sequencing of the first round amplicons revealed 19 serotype G12P[6] strains and one G12P[8] strain. Phylogenetic analyses of the G12 strains indicated that these strains are probably a recent introduction into South Africa and emerged from a strain related to the Indian isolate ISO-5. The association of the South African G12s with the P[6] genotype may suggest a mechanism for unusual strains to become more ecologically suited to local population transmission dynamics. This is the first report of serotype G12 strains on the African continent and continued surveillance will be required to track the emergence of G12 strains in Africa.


Assuntos
Infecções por Rotavirus/epidemiologia , Infecções por Rotavirus/virologia , Rotavirus/classificação , Rotavirus/isolamento & purificação , Pré-Escolar , Análise por Conglomerados , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Dados de Sequência Molecular , Filogenia , RNA Viral/genética , Rotavirus/genética , Análise de Sequência de DNA , África do Sul/epidemiologia
16.
Br J Surg ; 96(10): 1135-40, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19787763

RESUMO

BACKGROUND: The effect of postoperative radiotherapy following autologous flap breast reconstruction is controversial. The aim of this study was to measure whether adjuvant radiotherapy following immediate deep inferior epigastric perforator (DIEP) free flap breast reconstruction affected flap volume. METHODS: Sixty-eight women underwent immediate autologous DIEP flap reconstruction following mastectomy for breast cancer. Twenty-two of the 68 received postoperative radiotherapy (45Gy in 20 fractions over 4 weeks). Intraoperative flap volume data were collected prospectively. Volumetric assessment was carried out a minimum of 1 year after surgery. Patients who had volume adjustment surgery after initial reconstruction were analysed separately. RESULTS: The mean age of the women was 52 (range 37-69) years and median follow-up was 3.5 (range 1-10) years. There was no statistically significant difference in volume change between patients who had and those who did not have postreconstruction radiotherapy for the whole cohort (median reduction 65 versus 0 ml) or when women who had undergone further volume adjustment surgery were excluded. CONCLUSION: In this study postoperative radiotherapy did not significantly affect breast volume after DIEP flap reconstruction. The potential need for postoperative radiotherapy should not deter women from undergoing immediate DIEP flap breast reconstruction.


Assuntos
Neoplasias da Mama/cirurgia , Mama/efeitos da radiação , Mamoplastia/métodos , Mastectomia/métodos , Retalhos Cirúrgicos/patologia , Adulto , Idoso , Mama/patologia , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Feminino , Humanos , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos da radiação , Cuidados Pós-Operatórios/métodos , Radioterapia Adjuvante
17.
Lancet Oncol ; 9(4): 331-41, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18356109

RESUMO

BACKGROUND: The international standard radiotherapy schedule for breast cancer treatment delivers a high total dose in 25 small daily doses (fractions). However, a lower total dose delivered in fewer, larger fractions (hypofractionation) is hypothesised to be at least as safe and effective as the standard treatment. We tested two dose levels of a 13-fraction schedule against the standard regimen with the aim of measuring the sensitivity of normal and malignant tissues to fraction size. METHODS: Between 1998 and 2002, 2236 women with early breast cancer (pT1-3a pN0-1 M0) at 17 centres in the UK were randomly assigned after primary surgery to receive 50 Gy in 25 fractions of 2.0 Gy versus 41.6 Gy or 39 Gy in 13 fractions of 3.2 Gy or 3.0 Gy over 5 weeks. Women were eligible if they were aged over 18 years, did not have an immediate surgical reconstruction, and were available for follow-up. Randomisation method was computer generated and was not blinded. The protocol-specified principal endpoints were local-regional tumour relapse, defined as reappearance of cancer at irradiated sites, late normal tissue effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN59368779. FINDINGS: 749 women were assigned to the 50 Gy group, 750 to the 41.6 Gy group, and 737 to the 39 Gy group. After a median follow up of 5.1 years (IQR 4.4-6.0) the rate of local-regional tumour relapse at 5 years was 3.6% (95% CI 2.2-5.1) after 50 Gy, 3.5% (95% CI 2.1-4.3) after 41.6 Gy, and 5.2% (95% CI 3.5-6.9) after 39 Gy. The estimated absolute differences in 5-year local-regional relapse rates compared with 50 Gy were 0.2% (95% CI -1.3% to 2.6%) after 41.6 Gy and 0.9% (95% CI -0.8% to 3.7%) after 39 Gy. Photographic and patient self-assessments suggested lower rates of late adverse effects after 39 Gy than with 50 Gy, with an HR for late change in breast appearance (photographic) of 0.69 (95% CI 0.52-0.91, p=0.01). From a planned meta-analysis with the pilot trial, the adjusted estimates of alpha/beta value for tumour control was 4.6 Gy (95% CI 1.1-8.1) and for late change in breast appearance (photographic) was 3.4 Gy (95% CI 2.3-4.5). INTERPRETATION: The data are consistent with the hypothesis that breast cancer and the dose-limiting normal tissues respond similarly to change in radiotherapy fraction size. 41.6 Gy in 13 fractions was similar to the control regimen of 50 Gy in 25 fractions in terms of local-regional tumour control and late normal tissue effects, a result consistent with the result of START Trial B. A lower total dose in a smaller number of fractions could offer similar rates of tumour control and normal tissue damage as the international standard fractionation schedule of 50 Gy in 25 fractions.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/radioterapia , Fracionamento da Dose de Radiação , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Intervalos de Confiança , Relação Dose-Resposta à Radiação , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Mastectomia Segmentar/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Projetos Piloto , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica/normas , Radioterapia Adjuvante , Valores de Referência , Medição de Risco , Fatores Sexuais , Análise de Sobrevida , Resultado do Tratamento , Reino Unido
19.
Br J Cancer ; 99(11): 1763-8, 2008 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-18985046

RESUMO

Increasing duration of tamoxifen therapy improves survival in women with breast cancer but the impact of adherence to tamoxifen on mortality is unclear. This study investigated whether women prescribed tamoxifen after surgery for breast cancer adhered to their prescription and whether adherence influenced survival. A retrospective cohort study of all women with incident breast cancer in the Tayside region of Scotland between 1993 and 2002 was linked to encashed prescription records to calculate adherence to tamoxifen. Survival analysis was used to determine the effect of adherence on all-cause mortality. In all 2080 patients formed the study cohort with 1633 (79%) prescribed tamoxifen. The median duration of use was 2.42 years (IQR=1.04-4.89 years). Longer duration was associated with better survival but this varied over time. The hazard ratio for mortality in relation to duration at 2.4 years was 0.85, 95% CI=0.83-0.87. Median adherence to tamoxifen was 93% (interquartile range=84-100%). Adherence <80% was associated with poorer survival, hazard ratio 1.10, 95% CI=1.001-1.21. Persistence with tamoxifen was modest with only 49% continuing therapy for 5 years of those followed up for 5 years or more. Increased duration of tamoxifen reduces the risk of death, although one in two women do not complete the recommended 5-year course of treatment. A significant proportion of women have low adherence to tamoxifen and are at increased risk of death.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Adesão à Medicação/estatística & dados numéricos , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Tamoxifeno/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
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