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1.
BMC Infect Dis ; 22(1): 558, 2022 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-35718768

RESUMO

BACKGROUND: A global pandemic has been declared for coronavirus disease 2019 (COVID-19), which has serious impacts on human health and healthcare systems in the affected areas, including Vietnam. None of the previous studies have a framework to provide summary statistics of the virus variants and assess the severity associated with virus proteins and host cells in COVID-19 patients in Vietnam. METHOD: In this paper, we comprehensively investigated SARS-CoV-2 variants and immune responses in COVID-19 patients. We provided summary statistics of target sequences of SARS-CoV-2 in Vietnam and other countries for data scientists to use in downstream analysis for therapeutic targets. For host cells, we proposed a predictive model of the severity of COVID-19 based on public datasets of hospitalization status in Vietnam, incorporating a polygenic risk score. This score uses immunogenic SNP biomarkers as indicators of COVID-19 severity. RESULT: We identified that the Delta variant of SARS-CoV-2 is most prevalent in southern areas of Vietnam and it is different from other areas in the world using various data sources. Our predictive models of COVID-19 severity had high accuracy (Random Forest AUC = 0.81, Elastic Net AUC = 0.7, and SVM AUC = 0.69) and showed that the use of polygenic risk scores increased the models' predictive capabilities. CONCLUSION: We provided a comprehensive analysis for COVID-19 severity in Vietnam. This investigation is not only helpful for COVID-19 treatment in therapeutic target studies, but also could influence further research on the disease progression and personalized clinical outcomes.


Assuntos
COVID-19 , Infecções por Coronavirus , Pneumonia Viral , Betacoronavirus , COVID-19/tratamento farmacológico , COVID-19/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , SARS-CoV-2/genética , Vietnã/epidemiologia
2.
Mol Ther ; 30(1): 184-197, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34740791

RESUMO

B cells have been engineered ex vivo to express an HIV-1 broadly neutralizing antibody (bNAb). B cell reprograming may be scientifically and therapeutically useful, but current approaches limit B cell repertoire diversity and disrupt the organization of the heavy-chain locus. A more diverse and physiologic B cell repertoire targeting a key HIV-1 epitope could facilitate evaluation of vaccines designed to elicit bNAbs, help identify more potent and bioavailable bNAb variants, or directly enhance viral control in vivo. Here we address the challenges of generating such a repertoire by replacing the heavy-chain CDR3 (HCDR3) regions of primary human B cells. To do so, we identified and utilized an uncharacterized Cas12a ortholog that recognizes PAM motifs present in human JH genes. We also optimized the design of 200 nucleotide homology-directed repair templates (HDRT) by minimizing the required 3'-5' deletion of the HDRT-complementary strand. Using these techniques, we edited primary human B cells to express a hemagglutinin epitope tag and the HCDR3 regions of the bNAbs PG9 and PG16. Those edited with bNAb HCDR3 efficiently bound trimeric HIV-1 antigens, implying they could affinity mature in vivo in response to the same antigens. This approach generates diverse B cell repertoires recognizing a key HIV-1 neutralizing epitope.


Assuntos
Infecções por HIV , HIV-1 , Anticorpos Neutralizantes , Anticorpos Amplamente Neutralizantes , Epitopos/genética , Anticorpos Anti-HIV/genética , Infecções por HIV/genética , Infecções por HIV/terapia , HIV-1/genética , Humanos
3.
Clin Transl Immunology ; 10(4): e1269, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33841880

RESUMO

OBJECTIVES: Efforts to develop and deploy effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue at pace. Here, we describe rational antigen design through to manufacturability and vaccine efficacy of a prefusion-stabilised spike (S) protein, Sclamp, in combination with the licensed adjuvant MF59 'MF59C.1' (Seqirus, Parkville, Australia). METHODS: A panel recombinant Sclamp proteins were produced in Chinese hamster ovary and screened in vitro to select a lead vaccine candidate. The structure of this antigen was determined by cryo-electron microscopy and assessed in mouse immunogenicity studies, hamster challenge studies and safety and toxicology studies in rat. RESULTS: In mice, the Sclamp vaccine elicits high levels of neutralising antibodies, as well as broadly reactive and polyfunctional S-specific CD4+ and cytotoxic CD8+ T cells in vivo. In the Syrian hamster challenge model (n = 70), vaccination results in reduced viral load within the lung, protection from pulmonary disease and decreased viral shedding in daily throat swabs which correlated strongly with the neutralising antibody level. CONCLUSION: The SARS-CoV-2 Sclamp vaccine candidate is compatible with large-scale commercial manufacture, stable at 2-8°C. When formulated with MF59 adjuvant, it elicits neutralising antibodies and T-cell responses and provides protection in animal challenge models.

4.
Lancet Infect Dis ; 21(10): 1383-1394, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33887208

RESUMO

BACKGROUND: Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). METHODS: We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 µg, 15 µg, or 45 µg, or one dose of sclamp vaccine at 45 µg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933. FINDINGS: Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 µg dose (geometric mean titre [GMT] 6400, 95% CI 3683-11 122), with 15 µg dose (7492, 4959-11 319), and the two 45 µg dose cohorts (8770, 5526-13 920 in the two-dose 45 µg cohort; 8793, 5570-13 881 in the single-dose 45 µg cohort); 4 weeks after the second dose (day 57) with two 5 µg doses (102 400, 64 857-161 676), with two 15 µg doses (74 725, 51 300-108 847), with two 45 µg doses (79 586, 55 430-114 268), only a single 45 µg dose (4795, 2858-8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 µg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 µg doses (GMT 228, 95% CI 146-356), two 15 µg doses (230, 170-312), and two 45 µg doses (239, 187-307). INTERPRETATION: This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. FUNDING: Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.


Assuntos
Adjuvantes Imunológicos/farmacologia , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Glicoproteína da Espícula de Coronavírus/imunologia , Esqualeno/imunologia , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Austrália , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pandemias/prevenção & controle , Polissorbatos , Vacinação/efeitos adversos , Adulto Jovem
5.
Mol Ther Nucleic Acids ; 24: 40-53, 2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-33738137

RESUMO

CRISPR effector proteins introduce double-stranded breaks into the mammalian genome, facilitating gene editing by non-homologous end-joining or homology-directed repair. Unlike the more commonly studied Cas9, the CRISPR effector protein Cas12a/Cpf1 recognizes a T-rich protospacer adjacent motif (PAM) and can process its own CRISPR RNA (crRNA) array, simplifying the use of multiple guide RNAs. We observed that the Cas12a ortholog of Lachnospiraceae bacterium MA2020 (Lb2Cas12a) edited mammalian genes with efficiencies comparable to those of AsCas12a and LbCas12a. Compared to these well-characterized Cas12a orthologs, Lb2Cas12a is smaller and recognizes a narrow set of PAM TTTV. We introduced two mutations into Lb2Cas12a, Q571K and C1003Y, that increased its cleavage efficiency for a range of target sequences beyond those of the commonly used Cas12a orthologs AsCas12a and LbCas12a. In addition to the canonical TTTV PAM, this variant, Lb2-KY, also efficiently cleaved target regions with CTTN PAMs. Finally, we demonstrated that Lb2-KY ribonucleoprotein (RNP) complexes edited two hemoglobin target regions useful for correcting common forms of sickle-cell anemia more efficiently than commercial AsCas12a RNP complexes. Thus, Lb2-KY has distinctive properties useful for modifying a range of clinically relevant targets in the human genome.

6.
Nat Biotechnol ; 38(2): 169-175, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31873216

RESUMO

Widespread use of gene therapy technologies is limited in part by the lack of small genetic switches with wide dynamic ranges that control transgene expression without the requirement of additional protein components1-5. In this study, we engineered a class of type III hammerhead ribozymes to develop RNA switches that are highly efficient at cis-cleaving mammalian mRNAs and showed that they can be tightly regulated by a steric-blocking antisense oligonucleotide. Our variant ribozymes enabled in vivo regulation of adeno-associated virus (AAV)-delivered transgenes, allowing dose-dependent and up to 223-fold regulation of protein expression over at least 43 weeks. To test the potential of these reversible on-switches in gene therapy for anemia of chronic kidney disease6, we demonstrated regulated expression of physiological levels of erythropoietin with a well-tolerated dose of the inducer oligonucleotide. These small, modular and efficient RNA switches may improve the safety and efficacy of gene therapies and broaden their use.


Assuntos
Dependovirus/genética , Regulação da Expressão Gênica , Terapia Genética , RNA/genética , Animais , Linhagem Celular , Feminino , Genes Reporter , Humanos , Masculino , Camundongos Endogâmicos BALB C , Oligonucleotídeos Antissenso/metabolismo , RNA Catalítico/química , RNA Catalítico/genética , Transgenes
7.
J Am Soc Hypertens ; 12(9): 671-680, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30049626

RESUMO

A single clinic measurement of blood pressure (BP) may be common in low- and middle-income countries because of limited medical resources. This study aimed to examine the potential misclassification error when only one BP measurement is used. Participants (n = 14,706, 53.5% females) aged 25-64 years were selected by multistage stratified cluster sampling from eight provinces, each representing one of the eight geographical regions of Vietnam. Measurements were made using the World Health Organization STEPS protocols. Data were analyzed using complex survey methods. For systolic BP, 62.7% had a higher first reading whereas 30.0% had a lower first reading, and 27.3% had a reduction of at least 5 mmHg whereas 9.6% had an increase of at least 5 mmHg. Irrespective of direction of change, increased variability in BP was associated with greater age, urban living, greater body size and fatness, reduced physical activity levels, elevated glucose, and raised total cholesterol. These measurement variations would lead to substantial misclassification in diagnosis of hypertension based on a single reading because almost 20% of subjects would receive a different diagnosis based on the mean of two readings.

8.
Nat Chem Biol ; 13(8): 839-841, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28628097

RESUMO

Cpf1 is a CRISPR effector protein that has greater specificity than Streptococcus pyogenes Cas9 (SpCas9) in genome-editing applications. Here we show that Lachnospiraceae bacterium (Lb) and Acidaminococus sp. (As) Cpf1 orthologs have RNase activities that can excise multiple CRISPR RNAs (crRNAs) from a single RNA polymerase II-driven RNA transcript expressed in mammalian cells. This property simplifies modification of multiple genomic targets and can be used to increase the efficiency of Cpf1-mediated editing.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , RNA Mensageiro/genética , Transcrição Genética/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/química , Células Cultivadas , Clostridiales/química , Células HEK293 , Humanos
9.
Aging Cell ; 14(1): 102-11, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25407919

RESUMO

Senescent endothelial cells (EC) have been identified in cardiovascular disease, in angiogenic tumour associated vessels and in aged individuals. We have previously identified a novel anti-inflammatory senescent phenotype of EC. We show here that caveolae are critical in the induction of this anti-inflammatory senescent state. Senescent EC induced by either the overexpression of ARHGAP18/SENEX or by H2O2 showed significantly increased numbers of caveolae and associated proteins Caveolin-1, cavin-1 and cavin-2. Depletion of these proteins by RNA interference decreased senescence induced by ARHGAP18 and by H2O2. ARHGAP18 overexpression induced a predominantly anti-inflammatory senescent population and depletion of the caveolae-associated proteins resulted in the preferential reduction in this senescent population as measured by neutrophil adhesion and adhesion protein expression after TNFα treatment. In confirmation, EC isolated from the aortas of CAV-1(-/-) mice failed to induce this anti-inflammatory senescent cell population upon expression of ARHGAP18, whereas EC from wild-type mice showed a significant increase. NF-κB is one of the major transcription factors mediating the induction of E-selectin and VCAM-1 expression, adhesion molecules responsible for leucocyte attachment to EC. TNFα-induced activation of NF-κB was suppressed in ARHGAP18-induced senescent EC, and this inhibition was reversed by Caveolin-1 knock-down. Thus, out results demonstrate that an increase in caveolae and its component proteins in senescent ECs is associated with inhibition of the NF-kB signalling pathway and promotion of the anti-inflammatory senescent pathway.


Assuntos
Anti-Inflamatórios/metabolismo , Cavéolas/metabolismo , Senescência Celular , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Inflamação/patologia , Animais , Proteínas de Transporte/metabolismo , Caveolina 1/metabolismo , Proteínas Ativadoras de GTPase/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Camundongos , NF-kappa B/metabolismo , Fenótipo , Proteínas de Ligação a Fosfato , Proteínas de Ligação a RNA/metabolismo , Fator de Transcrição AP-1/metabolismo , Regulação para Cima
10.
PLoS Pathog ; 6(4): e1000840, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20419145

RESUMO

Schistosomes express a family of integral membrane proteins, called tetraspanins (TSPs), in the outer surface membranes of the tegument. Two of these tetraspanins, Sm-TSP-1 and Sm-TSP-2, confer protection as vaccines in mice, and individuals who are naturally resistant to S. mansoni infection mount a strong IgG response to Sm-TSP-2. To determine their functions in the tegument of S. mansoni we used RNA interference to silence expression of Sm-tsp-1 and Sm-tsp-2 mRNAs. Soaking of parasites in Sm-tsp dsRNAs resulted in 61% (p = 0.009) and 74% (p = 0.009) reductions in Sm-tsp-1 and Sm-tsp-2 transcription levels, respectively, in adult worms, and 67%-75% (p = 0.011) and 69%-89% (p = 0.004) reductions in Sm-tsp-1 and Sm-tsp-2 transcription levels, respectively, in schistosomula compared to worms treated with irrelevant control (luciferase) dsRNA. Ultrastructural morphology of adult worms treated in vitro with Sm-tsp-2 dsRNA displayed a distinctly vacuolated and thinner tegument compared with controls. Schistosomula exposed in vitro to Sm-tsp-2 dsRNA had a significantly thinner and more vacuolated tegument, and morphology consistent with a failure of tegumentary invaginations to close. Injection of mice with schistosomula that had been electroporated with Sm-tsp-1 and Sm-tsp-2 dsRNAs resulted in 61% (p = 0.005) and 83% (p = 0.002) reductions in the numbers of parasites recovered from the mesenteries four weeks later when compared to dsRNA-treated controls. These results imply that tetraspanins play important structural roles impacting tegument development, maturation or stability.


Assuntos
Proteínas de Membrana/genética , Schistosoma mansoni/genética , Schistosoma mansoni/metabolismo , Esquistossomose mansoni/genética , Animais , Western Blotting , Imunofluorescência , Expressão Gênica , Genes de Helmintos , Proteínas de Helminto/genética , Proteínas de Helminto/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Microscopia Eletrônica de Transmissão , Interferência de RNA , RNA Mensageiro , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Schistosoma mansoni/ultraestrutura
11.
PLoS Negl Trop Dis ; 4(2): e600, 2010 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-20161728

RESUMO

BACKGROUND: Schistosomes cause more mortality and morbidity than any other human helminth, but control primarily relies on a single drug that kills adult worms. The newly transformed schistosomulum stage is susceptible to the immune response and is a target for vaccine development and rational drug design. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes which are up-regulated during the maturation of Schistosoma mansoni schistosomula in vitro, we cultured newly transformed parasites for 3 h or 5 days with and without erythrocytes and compared their transcriptional profiles using cDNA microarrays. The most apparent changes were in the up-regulation of genes between 3 h and 5 day schistosomula involved in blood feeding, tegument and cytoskeletal development, cell adhesion, and stress responses. The most highly up-regulated genes included a tegument tetraspanin Sm-tsp-3 (1,600-fold up-regulation), a protein kinase, a novel serine protease and serine protease inhibitor, and intestinal proteases belonging to distinct mechanistic classes. The inclusion of erythrocytes in the culture medium resulted in a general but less pronounced increase in transcriptional activity, with the highest up-regulation of genes involved in iron metabolism, proteolysis, and transport of fatty acids and sugars. CONCLUSIONS: We have identified the genes that are up-regulated during the first 5 days of schistosomula development in vitro. Using a combination of gene silencing techniques and murine protection studies, some of these highly up-regulated transcripts can be targeted for future development of new vaccines and drugs.


Assuntos
Eritrócitos/parasitologia , Regulação da Expressão Gênica no Desenvolvimento , Schistosoma mansoni/crescimento & desenvolvimento , Schistosoma mansoni/genética , Animais , Genes de Helmintos , Humanos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Regulação para Cima
12.
Nat Med ; 12(7): 835-40, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16783371

RESUMO

Schistosomes are blood-dwelling flukes that infect 200 million people worldwide and are responsible for hundreds of thousands of deaths annually. Using a signal sequence trap, we cloned from Schistosoma mansoni two cDNAs, Sm-tsp-1 and Sm-tsp-2, encoding the tetraspanin (TSP) integral membrane proteins TSP-1 and TSP-2. We raised antibodies to recombinant TSP fusion proteins and showed that both proteins are exposed on the surface of S. mansoni. Recombinant TSP-2, but not TSP-1, is strongly recognized by IgG1 and IgG3 (but not IgE) from naturally resistant individuals but is not recognized by IgG from chronically infected or unexposed individuals. Vaccination of mice with the recombinant proteins followed by challenge infection with S. mansoni resulted in reductions of 57% and 64% (TSP-2) and 34% and 52% (TSP-1) for mean adult worm burdens and liver egg burdens, respectively, over two independent trials. Fecal egg counts were reduced by 65-69% in both test groups. TSP-2 in particular provided protection in excess of the 40% benchmark set by the World Health Organization for progression of schistosome vaccine antigens into clinical trials. When coupled with its selective recognition by naturally resistant people, TSP-2 seems to be an effective vaccine antigen against S. mansoni.


Assuntos
Proteínas de Helminto/imunologia , Proteínas de Membrana/imunologia , Schistosoma mansoni/imunologia , Esquistossomose mansoni/imunologia , Animais , Fezes/parasitologia , Feminino , Humanos , Proteínas do Tecido Nervoso/imunologia , Contagem de Ovos de Parasitas , Proteínas Recombinantes/imunologia , Schistosoma mansoni/isolamento & purificação , Tetraspaninas
13.
Addict Behav ; 28(7): 1333-42, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12915173

RESUMO

The aim of this study is to examine the prevalence of smoking during pregnancy by the individual mother's sociodemographic characteristics and ecological factors at the community level (suburbs). This analysis combined 1996 Australia Census and data on 3424 women attending Well-Baby-Clinics (WBC) between January 1996 and February 1998 within a region in South Western Sydney (SWS), Australia. The prevalence of maternal smoking was 31%. Maternal factors such as marital status, country of birth, education, occupation, socioeconomic status (SES), and types of antenatal care (ANC) were independent risk factors for maternal smoking. Small area analysis revealed suburbs within SWS with high rates of maternal smoking (47-57%). Community level characteristics such as low income, low educational level, young mothers, and unemployment can explain 85.7% of the variation in maternal smoking in SWS. Smoking during pregnancy is recognised as a serious risk factor to the unborn child. The present study draws attention to local community level factors, other than individual SES, which may be important when developing strategies for maternal smoking prevention programs.


Assuntos
Comportamento Materno/psicologia , Fumar/psicologia , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Mães/estatística & dados numéricos , New South Wales/epidemiologia , Gravidez , Resultado da Gravidez , Fatores de Risco , Análise de Pequenas Áreas , Fumar/epidemiologia , Fatores Socioeconômicos
14.
Australas Radiol ; 46(4): 390-5, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12452910

RESUMO

The onset of intracranial metastases is a common development during the course of malignancy. The treatment of these patients represents a significant workload in any radiation oncology department. Much debate has occurred regarding the most appropriate fractionation schedules employed given the perception of limited life expectancy and symptomatic relief following cranial radiation. The aim of this study was to identify the spectrum of primary sites in patients developing intracranial metastases and to assess survival postradiation for the group overall and for selected subgroups. The records of 378 patients undergoing palliative cranial radiation in the years 1993-1998 at Sydney's Mater and Royal North Shore hospitals were analysed retrospectively. Major primary sites were lung (42%), breast (18%), colorectal (9%), melanoma (7%), and unknown primary (7%). Overall median survival post-treatment was 3 months. Lung cancer patients showed a median survival of 6 months, breast 5 months, colorectal 4 months and melanoma 3 months. Long-term survivors were noted with up to 15% of certain groups alive beyond 12 months and 2% alive at 24 months. Multivariate analysis revealed improved survival in patients undergoing resection, and those receiving higher dose radiation justifying a more aggressive approach in selected patients.


Assuntos
Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundário , Cuidados Paliativos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
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