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1.
Nature ; 624(7992): 513-515, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38114672
2.
Sci Rep ; 10(1): 17536, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33067482

RESUMO

Clinical trials establish the standard of cancer care, yet the evolution and characteristics of the social dynamics between the people conducting this work remain understudied. We performed a social network analysis of authors publishing chemotherapy-based prospective trials from 1946 to 2018 to understand how social influences, including the role of gender, have influenced the growth and development of this network, which has expanded exponentially from fewer than 50 authors in 1946 to 29,197 in 2018. While 99.4% of authors were directly or indirectly connected by 2018, our results indicate a tendency to predominantly connect with others in the same or similar fields, as well as an increasing disparity in author impact and number of connections. Scale-free effects were evident, with small numbers of individuals having disproportionate impact. Women were under-represented and likelier to have lower impact, shorter productive periods (P < 0.001 for both comparisons), less centrality, and a greater proportion of co-authors in their same subspecialty. The past 30 years were characterized by a trend towards increased authorship by women, with new author parity anticipated in 2032. The network of cancer clinical trialists is best characterized as strategic or mixed-motive, with cooperative and competitive elements influencing its appearance. Network effects such as low centrality, which may limit access to high-profile individuals, likely contribute to the observed disparities.


Assuntos
Antineoplásicos/uso terapêutico , Ensaios Clínicos como Assunto , Oncologia/história , Neoplasias/tratamento farmacológico , Editoração/tendências , Análise de Rede Social , Algoritmos , Autoria , Feminino , História do Século XX , História do Século XXI , Humanos , Masculino , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Pesquisadores
3.
JCO Clin Cancer Inform ; 2: 1-11, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30652575

RESUMO

PURPOSE: With rapidly evolving treatment options in cancer, the complexity in the clinical decision-making process for oncologists represents a growing challenge magnified by oncologists' disposition of intuition-based assessment of treatment risks and overall mortality. Given the unmet need for accurate prognostication with meaningful clinical rationale, we developed a highly interpretable prediction tool to identify patients with high mortality risk before the start of treatment regimens. METHODS: We obtained electronic health record data between 2004 and 2014 from a large national cancer center and extracted 401 predictors, including demographics, diagnosis, gene mutations, treatment history, comorbidities, resource utilization, vital signs, and laboratory test results. We built an actionable tool using novel developments in modern machine learning to predict 60-, 90- and 180-day mortality from the start of an anticancer regimen. The model was validated in unseen data against benchmark models. RESULTS: We identified 23,983 patients who initiated 46,646 anticancer treatment lines, with a median survival of 514 days. Our proposed prediction models achieved significantly higher estimation quality in unseen data (area under the curve, 0.83 to 0.86) compared with benchmark models. We identified key predictors of mortality, such as change in weight and albumin levels. The results are presented in an interactive and interpretable tool ( www.oncomortality.com ). CONCLUSION: Our fully transparent prediction model was able to distinguish with high precision between highest- and lowest-risk patients. Given the rich data available in electronic health records and advances in machine learning methods, this tool can have significant implications for value-based shared decision making at the point of care and personalized goals-of-care management to catalyze practice reforms.


Assuntos
Algoritmos , Tomada de Decisão Clínica , Registros Eletrônicos de Saúde/estatística & dados numéricos , Informática/estatística & dados numéricos , Neoplasias/mortalidade , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Neoplasias/terapia , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Sinais Vitais
4.
Am J Emerg Med ; 34(10): 1934-1938, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27412915

RESUMO

INTRODUCTION: Unplanned hospitalizations are common in patients with cancer, and most hospitalizations originate in the emergency department (ED). METHODS: We implemented an ED-based pilot intervention designed to reduce hospitalizations among patients with solid tumors. The intervention, piloted at a single academic medical center, involved a medical oncologist embedded in the ED during evening hours. We used a quasiexperimental preimplementation/postimplementation study design to evaluate the proportion of ED visits that resulted in inpatient hospital admission, before and after pilot implementation. General estimating equations were used to evaluate the association between the intervention and hospital admission. RESULTS: There were 390 ED visits by eligible cancer patients in the preintervention period and 418 visits in the intervention period. During the intervention period, 158 (38%) of 418 ED visits were identified by the embedded oncologist during the evening intervention shift. The proportion of ED visits leading to hospitalization was 70% vs 69% in the preintervention and intervention periods (odds ratio, 0.93 [95% confidence interval, 0.69-1.24]; P= .62). There were no differences between periods in ED length of stay or subsequent use of acute care. Among patients with initial ED presentation during the operating hours of the intervention, the proportion of ED visits leading to hospitalization was 77% vs 67% in the preintervention and intervention periods (odds ratio, 0.62 [0.36-1.08]; P= .08). CONCLUSION: Embedding an oncologist in the ED of an academic medical center did not significantly reduce hospital admissions. Novel approaches are needed to strengthen outpatient acute care for patients with cancer.


Assuntos
Assistência Ambulatorial/organização & administração , Serviço Hospitalar de Emergência/organização & administração , Neoplasias/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Assistência Ambulatorial/métodos , Estudos Controlados Antes e Depois , Cuidados Críticos/métodos , Cuidados Críticos/organização & administração , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Tempo de Internação/estatística & dados numéricos , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Projetos Piloto , Adulto Jovem
5.
Clin Cancer Res ; 21(6): 1273-80, 2015 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-25320358

RESUMO

PURPOSE: The CYP17A1 inhibitor abiraterone markedly reduces androgen precursors and is thereby effective in castration-resistant prostate cancer (CRPC). However, abiraterone increases progesterone, which can activate certain mutant androgen receptors (AR) identified previously in flutamide-resistant tumors. Therefore, we sought to determine if CYP17A1 inhibitor treatment selects for progesterone-activated mutant ARs. EXPERIMENTAL DESIGN: AR was examined by targeted sequencing in metastatic tumor biopsies from 18 patients with CRPC who were progressing on a CYP17A1 inhibitor (17 on abiraterone, 1 on ketoconazole), alone or in combination with dutasteride, and by whole-exome sequencing in residual tumor in one patient treated with neoadjuvant leuprolide plus abiraterone. RESULTS: The progesterone-activated T878A-mutant AR was present at high allele frequency in 3 of the 18 CRPC cases. It was also present in one focus of resistant tumor in the neoadjuvant-treated patient, but not in a second clonally related resistant focus that instead had lost one copy of PTEN and both copies of CHD1. The T878A mutation appeared to be less common in the subset of patients with CRPC treated with abiraterone plus dutasteride, and transfection studies showed that dutasteride was a more potent direct antagonist of the T878A versus the wild-type AR. CONCLUSIONS: These findings indicate that selection for tumor cells expressing progesterone-activated mutant ARs is a mechanism of resistance to CYP17A1 inhibition.


Assuntos
Androstenos/uso terapêutico , Progesterona/metabolismo , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Receptores Androgênicos/genética , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , DNA Helicases/genética , Proteínas de Ligação a DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Dutasterida/uso terapêutico , Humanos , Cetoconazol/uso terapêutico , Leuprolida/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação/genética , PTEN Fosfo-Hidrolase/genética , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/metabolismo
6.
Scand J Infect Dis ; 38(4): 301-3, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16709531

RESUMO

Cardiobacterium hominis, an uncommon cause of bacterial endocarditis, is rarely implicated in infections outside the vascular system. We report the isolation of C. hominis from the peritoneal fluid of a patient on continuous ambulatory peritoneal dialysis with a presentation suggestive of peritonitis but no evidence of infective endocarditis.


Assuntos
Líquido Ascítico/microbiologia , Cardiobacterium/patogenicidade , Infecções por Bactérias Gram-Negativas/fisiopatologia , Diálise Peritoneal Ambulatorial Contínua , Adulto , Antibacterianos/uso terapêutico , Cardiobacterium/isolamento & purificação , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Falência Renal Crônica/terapia , Masculino
7.
Cancer Res ; 62(1): 113-21, 2002 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11782367

RESUMO

Reduction of BRCA-1 expression through nonmutational events may be a predisposing event in the onset of sporadic breast cancer. In this study, we investigated the mechanisms through which the environmental carcinogen benzo[a]pyrene (B[a]P) lowered BRCA-1 mRNA levels in breast cancer MCF-7 cells. We report that B[a]P does not compromise the stability of BRCA-1 mRNA, but represses transcriptional activity of a 1.69-kb BRCA-1 (pGL3-BRCA-1) promoter fragment that contains both exon-1A and exon-1B transcription start sites. The loss of BRCA-1 promoter activity was accompanied by accumulation of CYP1A1 and BAX-alpha mRNA and p53 and p21 protein, whereas levels of Bcl-2 mRNA were reduced. The aromatic hydrocarbon receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is not metabolized, did not affect BRCA-1 promoter activity or the cellular levels of BRCA-1 and p53 protein, but it did induce a CYP1A1-like promoter. Conversely, treatment with the B[a]P metabolite 7r,8t-dihydroxy-9t,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) repressed BRCA-1 promoter activity and protein, while increasing p53 and p21 protein levels. Transient expression of dominant-negative p53 ((175)Arg-->His) counteracted the detrimental effects of BPDE on BRCA-1 promoter activity and protein levels. Similarly, treatment with B[a]P, TCDD, or BPDE failed to repress transcription from the pGL3-BRCA-1 construct transfected into ZR75.1 breast cancer cells containing mutated p53 ((152)Pro-->Leu). We conclude that activation of the aromatic hydrocarbon receptor is not sufficient for down-regulation of BRCA-1 transcription, which is, however, inhibited by the B[a]P metabolite BPDE through a p53-dependent pathway.


Assuntos
7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/metabolismo , Proteína BRCA1/biossíntese , Benzo(a)pireno/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinógenos/metabolismo , Receptores de Hidrocarboneto Arílico/fisiologia , Transcrição Gênica/efeitos dos fármacos , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido/toxicidade , Proteína BRCA1/genética , Benzo(a)pireno/toxicidade , Biotransformação , Neoplasias da Mama/induzido quimicamente , Carcinógenos/toxicidade , Regulação para Baixo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Genes BRCA1/efeitos dos fármacos , Humanos , Dibenzodioxinas Policloradas/toxicidade , Regiões Promotoras Genéticas/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transcrição Gênica/fisiologia , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/fisiologia
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