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1.
AJR Am J Roentgenol ; 215(3): 770-780, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32755160

RESUMO

OBJECTIVE. The purpose of this review is to elucidate the mechanisms, types, and clinical significance of molecular targeted therapy (MTT) and immune checkpoint inhibitors (ICIs) and their related toxicity, emphasizing the radiologic manifestations. CONCLUSION. The related toxicities of MTT and ICIs can have acute, recurrent, chronic, and delayed presentations. These toxicities may serve as markers of response and survival. By understanding the clinical significance of drug toxicities, radiologists can play an important role in personalized cancer therapy.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico por imagem , Imunoterapia/efeitos adversos , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Medicina de Precisão/efeitos adversos , Humanos
3.
Eur J Cancer ; 133: 25-28, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32422506

RESUMO

It has recently been suggested that precision oncology studies should be reanalysed using the intention-to-treat (ITT) methodology developed for randomized controlled clinical trials. This reanalysis dramatically decreases response rates in precision medicine studies. We contend that the ITT analysis of precision oncology trials is invalid. The ITT methodology was developed three decades ago to mitigate the problems of randomized trials, which try to ensure that both arms have an unselected patient population free from confounders. In contrast, precision oncology trials specifically select patients for confounders (that is biomarkers) that predict response. To demonstrate the issues inherent in an ITT reanalysis for precision cancer medicine studies, we take as an example the drug larotrectinib (TRK inhibitor) approved because of remarkable responses in malignancies harbouring NTRK fusions. Based on large-scale studies, NTRK fusions are found in ~0.31% of tumours. In a non-randomized pivotal study of larotrectinib, 75% of the 55 treated patients responded. Based upon the prevalence of NTRK fusions, ~18,000 patients would need to be screened to enrol the 55 treated patients. Utilizing the ITT methodology, the revised response rate to larotrectinib would be 0.23%. This is, of course, a dramatic underestimation of the efficacy of this now Food and Drug Administration (FDA)-approved drug. Similar issues can be shown for virtually any biomarker-based precision clinical trial. Therefore, retrofitting the ITT analysis developed for unselected patient populations in randomized trials yields misleading conclusions in precision medicine studies.


Assuntos
Análise de Intenção de Tratamento , Oncologia , Neoplasias/terapia , Medicina de Precisão , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Viés , Reações Falso-Positivas , Humanos , Análise de Intenção de Tratamento/métodos , Análise de Intenção de Tratamento/normas , Oncologia/métodos , Oncologia/estatística & dados numéricos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/normas , Terapia de Alvo Molecular/estatística & dados numéricos , Neoplasias/epidemiologia , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Medicina de Precisão/estatística & dados numéricos , Inibidores de Proteínas Quinases/uso terapêutico , Projetos de Pesquisa , Resultado do Tratamento
5.
Trials ; 20(1): 751, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856912

RESUMO

BACKGROUND: Regorafenib is an oral multikinase inhibitor for metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidines, irinotecan, oxaliplatin, monoclonal antibodies targeting vascular endothelial growth factor, and monoclonal antibodies targeting epidermal growth factor receptor. A dose reduction from 160 mg to 120 mg regorafenib reduces regorafenib-associated adverse events (AEs). Dose adjustment of irinotecan in a 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) regimen on the basis of an individual uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) genotype provides optimal oncological outcomes with acceptable AEs. The aim of this study is to address the efficacy and safety of a dose-adjusted combination of regorafenib and FOLFIRI for patients with mCRC. METHODS: A prospective, multicenter, randomized in a 2:1 ratio, controlled, clinical trial with two parallel arms will be conducted to compare irinotecan dose-escalated FOLFIRI according to UGT1A1 genotyping plus 120 mg regorafenib with 120 mg regorafenib alone in previously treated patients with mCRC. The primary endpoint is progression-free survival, and the secondary endpoints are overall survival, disease control rate, time to progression, and duration of treatment. Safety assessments will also be recorded. DISCUSSION: Dose adjustment for regorafenib and irinotecan makes treatment-related AEs tolerable and makes the concomitant treatment practicable. This study will provide initial evidence regarding the efficacy and safety of a new combination of chemotherapy and a targeted agent for mCRC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03880877. Prospectively registered on 19 March 2019.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/tratamento farmacológico , Glucuronosiltransferase/genética , Irinotecano/administração & dosagem , Compostos de Fenilureia/administração & dosagem , Piridinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Ensaios Clínicos Fase II como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/farmacocinética , Técnicas de Genotipagem , Humanos , Irinotecano/efeitos adversos , Irinotecano/farmacocinética , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Leucovorina/farmacocinética , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinética , Intervalo Livre de Progressão , Piridinas/efeitos adversos , Piridinas/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Tempo , Adulto Jovem
6.
Value Health ; 22(4): 439-445, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30975395

RESUMO

OBJECTIVE: The fields of medicine and public health are undergoing a data revolution. An increasing availability of data has brought about a growing interest in machine-learning algorithms. Our objective is to present the reader with an introduction to a knowledge representation and machine-learning tool for risk estimation in medical science known as Bayesian networks (BNs). STUDY DESIGN: In this article we review how BNs are compact and intuitive graphical representations of joint probability distributions (JPDs) that can be used to conduct causal reasoning and risk estimation analysis and offer several advantages over regression-based methods. We discuss how BNs represent a different approach to risk estimation in that they are graphical representations of JPDs that take the form of a network representing model random variables and the influences between them, respectively. METHODS: We explore some of the challenges associated with traditional risk prediction methods and then describe BNs, their construction, application, and advantages in risk prediction based on examples in cancer and heart disease. RESULTS: Risk modeling with BNs has advantages over regression-based approaches, and in this article we focus on three that are relevant to health outcomes research: (1) the generation of network structures in which relationships between variables can be easily communicated; (2) their ability to apply Bayes's theorem to conduct individual-level risk estimation; and (3) their easy transformation into decision models. CONCLUSIONS: Bayesian networks represent a powerful and flexible tool for the analysis of health economics and outcomes research data in the era of precision medicine.


Assuntos
Mineração de Dados/métodos , Aprendizado de Máquina , Medicina de Precisão/métodos , Teorema de Bayes , Interpretação Estatística de Dados , Mineração de Dados/estatística & dados numéricos , Cardiopatias/epidemiologia , Cardiopatias/terapia , Humanos , Modelos Estatísticos , Neoplasias/epidemiologia , Neoplasias/terapia , Medicina de Precisão/efeitos adversos , Medicina de Precisão/estatística & dados numéricos , Medição de Risco , Fatores de Risco , Resultado do Tratamento
7.
Nat Commun ; 10(1): 1842, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015529

RESUMO

The CRISPR-Cas9 system has raised hopes for developing personalized gene therapies for complex diseases. Its application for genetic and epigenetic therapies in humans raises concerns over immunogenicity of the bacterially derived Cas9 protein. Here we detect antibodies to Streptococcus pyogenes Cas9 (SpCas9) in at least 5% of 143 healthy individuals. We also report pre-existing human CD8+T cell immunity in the majority of healthy individuals screened. We identify two immunodominant SpCas9 T cell epitopes for HLA-A*02:01 using an enhanced prediction algorithm that incorporates T cell receptor contact residue hydrophobicity and HLA binding and evaluated them by T cell assays using healthy donor PBMCs. In a proof-of-principle study, we demonstrate that Cas9 protein can be modified to eliminate immunodominant epitopes through targeted mutation while preserving its function and specificity. Our study highlights the problem of pre-existing immunity against CRISPR-associated nucleases and offers a potential solution to mitigate the T cell immune response.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Proteína 9 Associada à CRISPR/imunologia , Epitopos de Linfócito T/genética , Mutagênese/imunologia , Streptococcus pyogenes/imunologia , Anticorpos Antibacterianos/sangue , Anticorpos Antibacterianos/imunologia , Células Apresentadoras de Antígenos/imunologia , Proteína 9 Associada à CRISPR/genética , Engenharia Celular/métodos , Mapeamento de Epitopos/métodos , Epitopos de Linfócito T/imunologia , Terapia Genética/efeitos adversos , Terapia Genética/métodos , Células HEK293 , Antígenos HLA-A/imunologia , Voluntários Saudáveis , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Streptococcus pyogenes/genética
8.
Trials ; 20(1): 156, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832742

RESUMO

BACKGROUND: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum). METHODS/DESIGN: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival. DISCUSSION: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine. TRIAL REGISTRATION: EudraCT, 2016-001788-34; ClinicalTrials.gov, NCT03334006 . Registered on 17 Nov 2017. Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).


Assuntos
Imunoglobulina A/administração & dosagem , Imunoglobulina G/administração & dosagem , Imunoglobulina M/administração & dosagem , Imunoglobulinas Intravenosas/administração & dosagem , Imunoterapia/métodos , Peritonite/terapia , Medicina de Precisão/métodos , Sepse/terapia , Antibacterianos/uso terapêutico , Áustria , Biomarcadores/sangue , Tomada de Decisão Clínica , Alemanha , Humanos , Imunoglobulina A/efeitos adversos , Imunoglobulina G/efeitos adversos , Imunoglobulina M/efeitos adversos , Imunoglobulinas Intravenosas/efeitos adversos , Imunoterapia/efeitos adversos , Infusões Intravenosas , Estudos Multicêntricos como Assunto , Seleção de Pacientes , Peritonite/diagnóstico , Peritonite/imunologia , Peritonite/microbiologia , Medicina de Precisão/efeitos adversos , Valor Preditivo dos Testes , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sepse/diagnóstico , Sepse/imunologia , Sepse/microbiologia , Fatores de Tempo , Resultado do Tratamento
9.
Rev Epidemiol Sante Publique ; 67 Suppl 1: S19-S23, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30635133

RESUMO

Big Data, the production of a massive amount of heterogeneous data, is often presented as a means to ensure the economic survival and sustainability of health systems. According to this perspective, Big Data could help save the spirit of our welfare states based on the principles of risks-sharing and equal access to care for all. According to a second perspective, opposed to the first, Big Data would fuel a process of demutualization, transferring to individuals a growing share of responsibility for managing their health. This article proposes to develop a third approach: Big Data does not induce a loss of solidarity but a transformation of the European model of welfare states. These are the data that are now the objects of the pooling. Individual and collective responsibilities are thus redistributed. However, this model, as new as it is, remains liberal in its inspiration; it basically allows the continuation of political liberalism by other means.


Assuntos
Altruísmo , Conjuntos de Dados como Assunto , Assistência à Saúde , Invenções , Ciências Biocomportamentais , Conjuntos de Dados como Assunto/normas , Conjuntos de Dados como Assunto/provisão & distribução , Conjuntos de Dados como Assunto/tendências , Assistência à Saúde/organização & administração , Assistência à Saúde/normas , Assistência à Saúde/tendências , Testes Genéticos/tendências , Ensaios de Triagem em Larga Escala/normas , Ensaios de Triagem em Larga Escala/estatística & dados numéricos , Ensaios de Triagem em Larga Escala/tendências , Humanos , Individualidade , Invenções/tendências , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Medicina de Precisão/normas , Medicina de Precisão/tendências , Melhoria de Qualidade/tendências , Fatores de Risco , Justiça Social , Seguridade Social
10.
Immunol Allergy Clin North Am ; 39(1): 95-111, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30466775

RESUMO

Immunoglobulin replacement therapy is the cornerstone of management for most primary immunodeficiency disease patients. The selection of a particular product, dose, and route of administration requires an understanding of the features of therapeutic immunoglobulin as well as patient-specific risk factors in order to maximize efficacy and tolerability and minimize risk. Individualizing therapy, taking into consideration the burdens of care, is necessary in order to optimize patient outcomes.


Assuntos
Agamaglobulinemia/terapia , Medicina de Precisão , Agamaglobulinemia/complicações , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/etiologia , Animais , Tomada de Decisão Clínica , Efeitos Psicossociais da Doença , Gerenciamento Clínico , Vias de Administração de Medicamentos , Acesso aos Serviços de Saúde , Humanos , Imunização Passiva/efeitos adversos , Imunização Passiva/métodos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/efeitos adversos , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/efeitos adversos , Imunoglobulinas Intravenosas/farmacocinética , Imunoglobulinas Intravenosas/uso terapêutico , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Resultado do Tratamento
11.
Lancet Oncol ; 19(12): e683-e695, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30507435

RESUMO

Although muscle-invasive bladder cancer is commonly treated with radical cystectomy, a standard alternative is bladder preservation therapy, consisting of maximum transurethral bladder tumour resection followed by radiotherapy with concurrent chemotherapy. Although no successfully completed randomised comparisons are available, the two treatment paradigms seem to have similar long-term outcomes; however, clinicopathologic parameters can be insufficient to provide clear guidance in the selection of one treatment over the other. Recent advances in the molecular understanding of bladder cancer have led to the identification of new predictive biomarkers that ultimately might help guide the tailored selection of therapy on the basis of the intrinsic biology of the tumour. In this Review, we discuss the existing evidence for molecular alterations and genomic signatures as prognostic or predictive biomarkers for bladder preservation therapy. If validated in prospective clinical trials, such biomarkers could enable the identification of subgroups of patients who are more likely to benefit from one treatment over another, and guide the use of combination therapies that include other modalities, such as immunotherapy, which might act synergistically with radiotherapy.


Assuntos
Biomarcadores Tumorais/genética , Cistectomia , Técnicas de Diagnóstico Molecular , Tratamentos com Preservação do Órgão/métodos , Medicina de Precisão/métodos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/terapia , Animais , Quimioterapia Adjuvante , Tomada de Decisão Clínica , Cistectomia/efeitos adversos , Cistectomia/mortalidade , Humanos , Biópsia Líquida , Imagem Molecular , Invasividade Neoplásica , Tratamentos com Preservação do Órgão/efeitos adversos , Tratamentos com Preservação do Órgão/mortalidade , Medicina de Precisão/efeitos adversos , Medicina de Precisão/mortalidade , Valor Preditivo dos Testes , Fatores de Risco , Resultado do Tratamento , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia
12.
Oral Oncol ; 86: 91-99, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30409326

RESUMO

Radiotherapy (RT) is an integral component in the management of head and neck cancer. Despite progress in several respects, a noteworthy proportion of the treated patients do not achieve complete response after RT. Regardless of novel dose delivery technologies, RT for head and neck cancer is still associated with acute as well as late toxicity. These challenges could potentially be addressed by means of personalized treatment. In this paper, we discuss the possibilities for dose escalation, dose de-escalation and allocation to systemic concomitant treatment based on prognostic and predictive markers for tumor control as well as predictive markers for normal tissue radiosensitivity.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias de Cabeça e Pescoço/terapia , Medicina de Precisão/métodos , Lesões por Radiação/prevenção & controle , Radioterapia de Intensidade Modulada/métodos , Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Aberrações Cromossômicas , Relação Dose-Resposta à Radiação , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Medicina de Precisão/efeitos adversos , Prognóstico , Lesões por Radiação/etiologia , Tolerância a Radiação/genética , Tolerância a Radiação/efeitos da radiação , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/efeitos adversos , Análise de Sobrevida , Resultado do Tratamento
13.
Diabetes Obes Metab ; 20 Suppl 3: 14-18, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30294954

RESUMO

Despite advances in pharmacotherapy, diabetic kidney disease (DKD) remains associated with a high burden of micro- and macrovascular complications often leading to premature mortality. New therapies are highly desirable to mitigate the burden of this disease. However, there are a number of barriers that hamper drug development in DKD. These include, amongst others, the lengthy and complex clinical trials required to prove drug efficacy and safety, inefficiencies in clinical trial conduct, and the high costs associated with these development programs. In this review a number of aspects are discussed, aiming to identify opportunities to transform and innovate drug development for DKD. Many clinical trials in DKD, as well as in other areas, face difficulties in timely and efficient enrolment of participants. To address this issue a network of sites should be created that are continuously recruiting individuals with DKD and collecting crucial information that can be used to understand prognosis and prognostic factors, and more importantly to serve as a pool of participants for recruitment to randomized trials. Second, the current clinical endpoints are late events in the progression of DKD. Endpoints based on lesser declines in estimated glomerular filtration rate (eGFR) or changes in albuminuria can shorten follow-up and/or lead to smaller and cheaper trials. Enrichment by enrolling clinical trial populations based on biomarker profiles is another approach that may facilitate clinical trial efficiency and conduct. Biomarkers can be used to individualize treatment by targeting populations more likely to respond leading to smaller and more efficient trials. Finally, using new trial design such as basket, umbrella or more broadly platform trials to assess a number of therapies simultaneously offers the potential to transform the drug development process in DKD. There are a number of opportunities to transform development approaches for new therapies for DKD. Platform trials along with appropriate biomarker-based enrichment strategies offer the possibility to foster drug development in a precision medicine era.


Assuntos
Ensaios Clínicos como Assunto/métodos , Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Medicina de Precisão/métodos , Desenvolvimento de Medicamentos , Previsões , Humanos , Medicina de Precisão/efeitos adversos , Medicina de Precisão/tendências , Projetos de Pesquisa , Terminologia como Assunto
14.
Am Soc Clin Oncol Educ Book ; 38: 415-431, 2018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-30231361

RESUMO

The majority of patients with cancer are older adults. A comprehensive geriatric assessment (CGA) will help the clinical team identify underlying medical and functional status issues that can affect cancer treatment delivery, cancer prognosis, and treatment tolerability. The CGA, as well as more abbreviated assessments and geriatric screening tools, can aid in the treatment decision-making process through improved individualized prediction of mortality, toxicity of cancer therapy, and postoperative complications and can also help clinicians develop an integrated care plan for the older adult with cancer. In this article, we will review the latest evidence with regard to the use of CGA in oncology. In addition, we will describe the benefits of conducting a CGA and the types of interventions that can be taken by the interprofessional team to improve the treatment outcomes and well-being of older adults.


Assuntos
Avaliação Geriátrica , Neoplasias/complicações , Neoplasias/psicologia , Resiliência Psicológica , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Humanos , Neoplasias/terapia , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos
15.
Drugs Today (Barc) ; 54(8): 479-488, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30209442

RESUMO

Lung cancer is the leading cause of cancer-related mortality worldwide and is the second most common cancer in both sexes. The small cell lung cancer (SCLC) subtype constitutes about 13% to 15% of all diagnosed lung cancers with an expected 5-year mortality of about 90%. In the past decades, various strategies used to treat newly diagnosed, relapsed or refractory SCLC have shown no significant improvement in clinical outcomes. In the genomic era of oncology, with a better understanding of tumor biology and pathway specific investigations, multiple investigational agents have been studied with the aim to improve clinical outcomes. Some of them include epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), BCR-ABL TKIs, mammalian target of rapamycin (mTOR) inhibitors, vascular endothelial growth factor (VEGF) inhibitors, etc. All of them have been unsuccessful in adding any survival advantage. DNA repair inhibitors, immunotherapies and anti-delta-like protein 3 (DLL3) antibody-drug conjugates have also been tested so far. This article aims to review the current literature and investigational approaches to improving clinical outcomes of SCLC.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Tomada de Decisão Clínica , Reparo do DNA/efeitos dos fármacos , Terapia Genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular/efeitos adversos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Medicina de Precisão/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
16.
Expert Rev Respir Med ; 12(9): 733-743, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30084271

RESUMO

INTRODUCTION: Asthma, a common, non-communicable chronic disease affects over 300 million individuals worldwide. The Western world lifestyle is claimed to be responsible for this high and increasing prevalence. Asthma has been defined as a syndrome with various phenotypes and endotypes, allergic asthma and type 2 asthma being the most frequent. A great increase in prevalence of allergic diseases has necessitated intensive investigations both for understanding the underlying mechanisms and for the development of novel therapy options with long-term efficacy and limited side-effects. Allergic patients demonstrate unique presentations with variable visible characteristics and disease outcomes depending on different molecular mechanisms, related to influence of genes and epigenetic control by micro- and macro-environment. Areas covered: This article reviews the definition of asthma phenotypes and possible endotypes, advances in allergy-immunology field and contemporary personalized therapy options for asthma. Expert commentary: Better understanding of the complex immune network of allergic inflammation and key players of immunity is continuously being provided for clarification of asthma sub-types. Successful therapy of asthma requires better definition of underlying pathogenesis, which sequentially could end up with 'custom-tailored' individualized, evidence-based and more precise therapy options; a new era termed as 'precision medicine'. Endotype, phenotype, theratype and biomarker terms arise as major keywords in precision/personalized medicine.


Assuntos
Asma/terapia , Asma/complicações , Biomarcadores , Humanos , Hipersensibilidade/etiologia , Hipersensibilidade/terapia , Inflamação/etiologia , Inflamação/terapia , Fenótipo , Medicina de Precisão/efeitos adversos
17.
Surg Innov ; 25(5): 470-475, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30024349

RESUMO

BACKGROUND: Patient-specific instruments (PSIs) were developed to improve mechanical axis alignment for patients undergoing total knee arthroplasty (TKA) as neutral alignment (180°) is a predictor of long-term success. This study examines alignment accuracy and functional outcomes of PSI as compared with standard instruments (SIs). METHODS: We retrospectively reviewed a consecutive series of TKA procedures using PSI. A total of 85 PSI procedures were identified, and these were compared with a matched cohort of 85 TKAs using SI. Intraoperative decision-making, estimated blood loss, efficiency, Knee Society Scores, and postoperative radiographs were evaluated. RESULTS: One hundred and seventy patients with comparable patient demographics were reviewed. Eighty-one percent of the PSI procedures were within target (180 ± 3°) mechanical alignment, while the SI group had 70% of cases within the target plane ( P = .132). Mean target alignment (2.0° PSI vs 2.2° SI, P = .477) was similar between groups. Twenty-seven percent of patients in the PSI group had surgeon-directed intraoperative recuts to improve the perceived coronal alignment. The change in hematocrit was reduced in the PSI group (8.89 vs 7.21, P = .000). Procedure time and total operating room time were equivalent. Knee Society Scores did not differ between groups at 6 months or at 1 year. CONCLUSION: Patient-specific instrumentation decreased change in hematocrit, though coronal alignment and efficiency were equivalent between groups. Surgeons must evaluate cuts intraoperatively to confirm alignment. Functional outcomes are equivalent for PSI and SI groups.


Assuntos
Artroplastia do Joelho/instrumentação , Artroplastia do Joelho/estatística & dados numéricos , Medicina de Precisão/instrumentação , Medicina de Precisão/estatística & dados numéricos , Cirurgia Assistida por Computador/estatística & dados numéricos , Idoso , Feminino , Humanos , Joelho/fisiopatologia , Joelho/cirurgia , Masculino , Pessoa de Meia-Idade , Medicina de Precisão/efeitos adversos , Amplitude de Movimento Articular , Estudos Retrospectivos , Cirurgia Assistida por Computador/instrumentação , Resultado do Tratamento
18.
Crit Rev Oncog ; 23(1-2): 93-112, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29953369

RESUMO

Although modern radiation therapy delivers a localized distribution of ionizing energy that can be used to cure primary cancers for many patients, the inevitable radiation exposure to non-targeted normal tissue leads to a risk of a radiation-related new cancer. Modern therapies often produce a complex spectrum of secondary particles, both charged and uncharged, that must be considered both in their physical radiation transport throughout the patient and their potential to induce biological damage, which depends on the microscopic energy deposition from the cascade of primary, secondary, and downstream particles. This work summarizes the experimental data for relative biological effectiveness for particles associated with modern radiotherapy in light of their capacity to induce secondary malignancies in patients. A distinction is highlighted between the radiobiological experimental data and the coarser metrics used frequently in radiation protection. For critical assessment of the risks of secondary malignancies for patients undergoing radiation therapy, a detailed description of primary and secondary radiation fields is needed, though not routinely considered for individual patient treatments. Furthermore, not only the particle type, but also the microscopic dose and track structure, must be considered, which points to a demand for detailed physics models and high-performance computing strategies to model the risks.


Assuntos
Segunda Neoplasia Primária/etiologia , Medicina de Precisão , Radioterapia/efeitos adversos , Animais , Transformação Celular Neoplásica/efeitos da radiação , Humanos , Neoplasias/radioterapia , Segunda Neoplasia Primária/diagnóstico , Segunda Neoplasia Primária/epidemiologia , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Radiação Ionizante , Radioterapia/métodos , Dosagem Radioterapêutica , Medição de Risco
19.
J Clin Oncol ; 36(21): 2231-2240, 2018 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-29874142

RESUMO

Incremental improvements in the treatment of children and adolescents with cancer have led to 5-year survival rates reaching nearly 85%. In the past decade, impressive progress has been made in understanding the biology of many pediatric cancers. With that understanding, multiple new agents have become available that offer the promise of more-effective and less-toxic treatment. These include agents that target various cell surface antigens and engage the adaptive immune system, as well as those that interfere with key signaling pathways involved in tumor development and growth. For local control, surgery and radiation techniques also have evolved, becoming less invasive or featuring new techniques and particles that more precisely target the tumor and limit the dose to normal tissue. Nevertheless, targeted agents, like conventional chemotherapy, radiotherapy, and surgery, may have off-target effects and deserve long-term follow-up of their safety and efficacy. These include injury to the endocrine, cardiovascular, and immunologic systems. New radiation and surgical techniques that theoretically reduce morbidity and improve long-term quality of life must also be validated with actual patient outcomes. Finally, with advances in genomics, information on host susceptibility to late effects is beginning to emerge. Such knowledge, coupled with improved metrics that better describe the spectrum of potential late effects across the entire lifespan, can lead to the development of decision models that project the potential long-term health outcomes associated with various treatment and follow-up strategies. These developments will help extend the current focus on precision medicine to precision survivorship, where clinicians, patients, and families will have a better grasp of the potential risks, benefits, and tradeoffs associated with the growing number of cancer treatment options.


Assuntos
Antineoplásicos/efeitos adversos , Sobreviventes de Câncer , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Antineoplásicos/administração & dosagem , Criança , Humanos , Neoplasias/mortalidade , Medicina de Precisão/efeitos adversos
20.
Crit Rev Oncol Hematol ; 127: 1-5, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29891106

RESUMO

There is a rising evidence that the proverbial statement "No pain, No gain" first coined at the light of pioneering clinical experiences with canonical chemotherapy still holds true in the era of modern treatments of cancer. This close relationship between the occurrence of specific drug-related toxicity and treatment outcome has been confirmed since then with a large variety of treatments, ranging from cytotoxics, hormonotherapy, targeted therapy and much interestingly even with the latest immune checkpoint inhibitors. In the current context of precision medicine, and along with the constant quest for identifying predictive biomarkers, close monitoring of treatment-related toxicities could therefore be convenient to help predicting therapeutic response, but presents several caveats. The purpose of this review is to briefly describe these relationships across the different treatments, to comment on possible underlying mechanisms and to comment on possible strategies aiming at exploiting this relationship while keeping the maximal safety ensured in patients with cancer. In particular, this review will investigate on how drug exposure along with germinal and somatic genetic issues does impact on the "No Pain, No Gain" aphorism, and why the temptation to use treatment-related toxicities as a cheap and convenient way to predict clinical outcome or to adapt dosing should be resisted. We do advocate instead for developing comprehensive genomic support along with extensive biomathematical modeling to better customize dosing and shift towards a new "No Pain, Maximal Gain" paradigm.


Assuntos
Biomarcadores Tumorais , Imunoterapia/efeitos adversos , Neoplasias/diagnóstico , Neoplasias/terapia , Dor/etiologia , Medicina de Precisão , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Genômica/métodos , Humanos , Dor/diagnóstico , Medicina de Precisão/efeitos adversos , Medicina de Precisão/métodos , Medicina de Precisão/tendências , Prognóstico , Resultado do Tratamento
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