Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.037
Filtrar
1.
Cancer Treat Rev ; 82: 101931, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31756590

RESUMO

Hodgkin lymphoma is a B cell derived malignancy characterized by a low number of tumor cells within an environment consisting of inflammatory cells. Recently, immune checkpoint blockade targeting the PD-1-PD-L1 axis has shown to be a great success in relapsed and refractory Hodgkin lymphoma patients. However, complete responses are scarce and median progression-free survival is limited to around 11-15 months. Efficiency of PD-1 blockade in HL might be dependent on CD4+ T cells, but also tumor associated macrophages (TAMs) and NK cells are implicated. The aim of this review is to highlight currently known prominent immune evasion strategies and discuss their possible contribution to primary or acquired resistance to immune checkpoint blockade in Hodgkin lymphoma. These include T cell dependent mechanisms such as shaping of the inflammatory infiltrate, lack of presentation of antigens and neoantigens and production of molecules involved in suppression of T cell functionality such as other immune checkpoints, indoleamine 2,3-dioxygenase and adenosine. Moreover, the role of NK cells and TAMs in efficient PD-1 blockade will be discussed. Targeting these mechanisms in parallel to PD-1 may potentially increase efficiency of PD-1 blockade therapy.


Assuntos
Doença de Hodgkin , Terapia de Alvo Molecular , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/imunologia , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Humanos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Evasão Tumoral/imunologia
2.
Gut ; 69(2): 231-242, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31068366

RESUMO

OBJECTIVE: Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that hepatocyte nuclear factor-4α (HNF4α) is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes. DESIGN: We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of in vitro and in vivo relevance. To investigate mechanistic roles of HNF4α and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments. RESULTS: Gene expression analysis across 19 tumour types revealed HNF4α to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top HNF4α-regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 (IDH1) emerged as a convergent HNF4α direct target gene regulating GC metabolism. We show that wild-type IDH1 is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors. CONCLUSIONS: Our results highlight a role for HNF4α in sustaining GC oncogenic metabolism, through the regulation of IDH1. Drugs targeting wild-type IDH1 may thus have clinical utility in GCs exhibiting HNF4α overexpression, expanding the role of IDH1 in cancer beyond IDH1/2 mutated malignancies.


Assuntos
Fator 4 Nuclear de Hepatócito/genética , Isocitrato Desidrogenase/metabolismo , Neoplasias Gástricas/genética , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Marcação de Genes/métodos , Fator 4 Nuclear de Hepatócito/metabolismo , Humanos , Isocitrato Desidrogenase/antagonistas & inibidores , Camundongos Endogâmicos NOD , Terapia de Alvo Molecular/métodos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Regiões Promotoras Genéticas/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima/genética , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Gut ; 69(1): 18-31, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31171626

RESUMO

OBJECTIVE: Peritoneal carcinomatosis (PC) occurs frequently in patients with gastric adenocarcinoma (GAC) and confers a poor prognosis. Multiplex profiling of primary GACs has been insightful but the underpinnings of PC's development/progression remain largely unknown. We characterised exome/transcriptome/immune landscapes of PC cells from patients with GAC aiming to identify novel therapeutic targets. DESIGN: We performed whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-seq) on 44 PC specimens (43 patients with PC) including an integrative analysis of WES, RNA-seq, immune profile, clinical and pathological phenotypes to dissect the molecular pathogenesis, identifying actionable targets and/or biomarkers and comparison with TCGA primary GACs. RESULTS: We identified distinct alterations in PC versus primary GACs, such as more frequent CDH1 and TAF1 mutations, 6q loss and chr19 gain. Alterations associated with aggressive PC phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of 'clock-like' mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: 'mesenchymal-like' and 'epithelial-like' with discriminating response to chemotherapy (31% vs 71%). Patients with the less responsive 'mesenchymal-like' subtype had high expression of immune checkpoint T-Cell Immunoglobulin And Mucin Domain-Containing Protein 3 (TIM-3), its ligand galectin-9, V-domain Ig suppressor of T cell activation (VISTA) and transforming growth factor-ß as potential therapeutic immune targets. CONCLUSIONS: We have uncovered the unique mutational landscape, copy number alteration and gene expression profile of PC cells and defined PC molecular subtypes, which correlated with PC therapy resistance/response. Novel targets and immune checkpoint proteins have been identified with a potential to be translated into clinics.


Assuntos
Adenocarcinoma/secundário , Neoplasias Peritoneais/secundário , Neoplasias Gástricas/genética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Instabilidade Cromossômica , Variações do Número de Cópias de DNA/genética , DNA de Neoplasias/genética , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/genética , Neoplasias Peritoneais/imunologia , Ploidias , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/imunologia , Sequenciamento Completo do Exoma/métodos
4.
Surg Clin North Am ; 100(1): 175-188, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31753111

RESUMO

Targeted BRAF and MEK inhibition has become an appropriate first-line treatment of BRAF-mutant advanced cutaneous melanoma. The authors present an overview of the MAPK pathway as well as the other major pathways implicated in melanoma development. Melanoma brain metastases are a devastating complication of melanoma that can be traced to derangements in cell signaling pathways, and the current evidence for targeted therapy is reviewed. Finally, activating KIT mutations are rarely found to cause melanomas and may provide an actionable target for therapy. The authors review the current evidence for targeted KIT therapy and summarize the ongoing clinical trials.


Assuntos
Melanoma/genética , Melanoma/terapia , Terapia de Alvo Molecular/métodos , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Humanos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
5.
Semin Oncol ; 46(6): 433-436, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31784041

RESUMO

Guidelines for the diagnosis, management, and surveillance of cancer patients have evolved with the single goal of improving patient care based on established data when available, or in the absence of firm data, on the standard practices of those with broad experience in actual hands-on patient care. Two initiatives intended to disseminate information to cardio-oncologists, were discussed in this session: the first, from the American Society of Clinical Oncology was focused on available data and the confidence level of that data; the second, from The European Society of Cardiology was a position paper. Interestingly, notwithstanding the somewhat different focus, there is considerable agreement between these two initiatives. Nevertheless, guidelines my not be applicable to all afflicted patients, and may raise questions as to when deviations from published standards should be considered. Such deviations may result in allegations of failure to meet standards of care or legal liability.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cardiovasculares/etiologia , Neoplasias/complicações , Radioterapia/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/terapia , Gerenciamento Clínico , Humanos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Neoplasias/terapia , Oncologistas , Papel do Médico , Guias de Prática Clínica como Assunto , Radioterapia/métodos
6.
Semin Oncol ; 46(6): 408-413, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31784042

RESUMO

Session III of the Second International Colloquium on Cardio-Oncology focused on the diagnosis, management, and prevention of cardiovascular toxicity of cancer drugs. With a large menu of biomarkers and imaging modalities available to the cardio oncologist, there continues to be no consensus regarding the best use of each modality alone and in combination and whether we can actually prevent early and late cardiotoxicity using these tests to guide a preventive strategy. It has become increasingly clear that early diagnosis and intervention leads to less late cardiotoxicity and fewer cardiac-related events. This can be accomplished by taking a thorough history and performing a goal directed physical examination coupled with use of biomarkers and imaging studies. This session attempted to provide rationale for a current and integrated approach to these issues.


Assuntos
Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cardiovasculares/etiologia , Oncologia , Neoplasias/complicações , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/terapia , Gerenciamento Clínico , Humanos , Oncologia/métodos , Oncologia/normas , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Neoplasias/terapia
7.
Semin Oncol ; 46(6): 421-425, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31767270

RESUMO

Session V of the Colloquium was chaired by Professors Teresa López-Fernández of Spain and Grzegorz Opolski of Poland. The 3 speakers addressed cardio-oncology issues as they relate to both clinical studies and real life situations. Professor Susan Dent discussed cardio-oncology networks for patients, emphasizing the importance of establishing a framework where the expertise of the cardiology consultant can supplement and reinforce the goals of optimal cancer therapy. Professor Thomas Suter moved the discussion further, sharing his insight into cardiac monitoring in clinical trials, emphasizing the lack of uniform criteria and lack of consensus regarding reversibility of cardiac events and long-term implications of modest declines in systolic function frequently found in clinical trials for which long-term follow-up may not be a component of the trial. Professor Giorgio Minotti added important considerations to the discussion of clinical trials. He emphasized that the usual reporting of cardiac systolic function omits important diastolic dysfunction data generated but often ignored during the routine cardiac exams. The inclusion of cardiac biomarker changes would also help to broaden the perspective of cardiac effects and events seen in patients enrolled in clinical trials.


Assuntos
Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cardiovasculares/etiologia , Neoplasias/complicações , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/prevenção & controle , Doenças Cardiovasculares/terapia , Gerenciamento Clínico , Humanos , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Neoplasias/mortalidade , Neoplasias/terapia
8.
Semin Oncol ; 46(6): 403-407, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31748121

RESUMO

Session II of the Second International Colloquium on Cardio-Oncology, chaired by Dr Breccia (Rome, Italy) and Dr Jurczak (Krakòw, Poland), focused on mechanisms and clinical course of cardiovascular toxicity of cancer treatment. Whereas the venerable anthracyclines keep challenging patients and clinicians with risk of left ventricular dysfunction and heart failure, other newer drugs cause substantially different clinical phenotypes of cardiovascular toxicity. In particular, Session II not only focused on arterial thrombosis and venous thromboembolism, but also hypertension or cardiomyopathy or atrial fibrillation induced by many otherwise life-saving drugs. Dr Breccia (Rome, Italy) reviewed incidence, mechanisms, risk factors, and principles for prevention of cardiovascular events induced by tyrosine kinase inhibitors of hematologic interest, such as those used to treat chronic myeloid leukemia. Dr Carver (Philadelphia) reviewed the incidence, predisposing factors, and principles for proactive management of cardiovascular events in patients treated by conventional chemotherapy or new drugs for treatment of multiple myeloma. Dr Szmit (Warsaw, Poland) discussed on how coagulation disorders should be classified according to patient- or drug-related factors and how they should be diagnosed and treated in patients with solid or hematologic tumors. Dr Minotti (Rome. Italy) illustrated some potential pitfalls of accelerated drug development and approval and their possible impact on clinical incidence of cardiovascular events induced by tyrosine kinase inhibitors of hematologic interest. Session II therefore offered a broad perspective of the risk-benefit ratio of new drugs that are plagued with concerns about cardiovascular events.


Assuntos
Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças Cardiovasculares/etiologia , Neoplasias Hematológicas/complicações , Neoplasias/complicações , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cardiotoxicidade , Doenças Cardiovasculares/diagnóstico , Neoplasias Hematológicas/terapia , Hematologia , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Neoplasias/terapia
9.
Lancet ; 394(10210): 1765-1774, 2019 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-31668411

RESUMO

Migraine is one of the most prevalent and disabling diseases worldwide, but until recently, few migraine-specific therapies had been developed. Extensive basic and clinical scientific investigation has provided strong evidence that the neuropeptide calcitonin gene-related peptide (CGRP) has a key role in migraine. This evidence led to the development of small molecule CGRP receptor antagonists and monoclonal antibodies targeting either CGRP or its receptor. Clinical trials investigating these therapies have consistently shown statistically significant efficacy for either the acute or preventive treatment of migraine. No serious safety or tolerability issues have been identified in the trials of the monoclonal antibody therapies. Although the appropriate place of these new migraine-specific therapies relative to other available acute and preventive treatments remains to be determined, a growing body of evidence shows that therapeutic approaches targeting CGRP have the potential to transform the clinical management of migraine.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/antagonistas & inibidores , Transtornos de Enxaqueca/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , Transtornos de Enxaqueca/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico
10.
Pharm Res ; 36(12): 176, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31686241

RESUMO

PURPOSE: This study aimed to explore the potential of sialic acid - related selectin targeting strategy in the treatment of leukemia and some solid tumors. We expected it could "actively" bind tumor cells and kill them, reducing non-specific toxicity to normal cells. METHODS: BOR-SA prodrug was synthesized by reacting an ortho-dihydroxy group in SA with a boronic acid group in BOR. Two kinds of leukemia cells (RAW264.7 and HL60 cells), one solid sarcoma cell model (S180 cells) and their corresponding normal cells (monocytes (MO), neutrophil (NE) and fibroblast (L929)) were selected for the in vitro cell experiments (cytotoxicity, cellular uptake, cell cycle and apoptosis experiments). The S180 tumor-bearing Kunming mice model was established for anti-tumor pharmacodynamic experiments. RESULTS: In vitro cell assay results showed that uptake of BOR-SA by HL60 and S180 cells were increased compared with the control group. BOR-SA induced a lower IC50, higher ratio of apoptosis and cell cycle arrest of tumor cells. In vivo anti-S180 tumor pharmacodynamics experiments showed that mice in the BOR-SA group had higher tumor inhibition rate, higher body weight and lower immune organ toxicity compared with the control group. CONCLUSIONS: sialic acid-mediated selectin targeting strategy may have great potential in the treatment of related tumors.


Assuntos
Antineoplásicos/farmacocinética , Bortezomib/farmacocinética , Leucemia/tratamento farmacológico , Ácido N-Acetilneuramínico/química , Pró-Fármacos/farmacocinética , Selectinas/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Bortezomib/administração & dosagem , Bortezomib/síntese química , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Manitol/química , Manitol/metabolismo , Camundongos , Terapia de Alvo Molecular/métodos , Ácido N-Acetilneuramínico/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/síntese química , Selectinas/genética
11.
Pharm Res ; 36(12): 168, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31654226

RESUMO

PURPOSE: Transferrin receptors (TfRs) are overexpressed in tumor cells but are scarce in normal tissues, which makes TfR an attractive target for drug treatment of cancer. The objective of this study was to evaluate the potential of BP9a (CAHLHNRS) as a peptide vector for constructing TfR targeted peptide-drug conjugates and selective drug delivery. METHODS: Doxorubicin (DOX) was connected to BP9a via a disulfide-intercalating linker to afford a reduction-responsive BP9a-SS-DOX conjugate. By using HepG2 human liver cancer cells and L-O2 normal hepatic cells as TfR over-expressing and low-expressing in vitro models, respectively, TfR mediated cellular uptake of this conjugate was studied by using flow cytometry and confocal laser scanning microscopy. The in vitro cytotoxicities of the conjugate against HepG2 and L-O2 cells were examined by cell counting kit-8 (CCK-8) assay to evaluate its tumorous specificity. RESULTS: Cellular uptake and TfR blockage test results showed that the BP9a-SS-DOX conjugate gained entry into HepG2 cells via endocytosis mediated by TfR and mainly accumulated in cytoplasm. The in vitro antiproliferative activity of this conjugate against HepG2 cells (IC50 6.21 ± 1.12 µM) was approximately one-sixth of that of free DOX (IC50 1.03 ± 0.13 µM). However, its cytotoxic effect on L-O2 cells was obviously reduced compared with that of free DOX. CONCLUSIONS: The BP9a-SS-DOX conjugate showed specific antiproliferative activity against HepG2 liver cancer cells. Our study suggests that BP9a has the potential to target chemotherapeutic agents to tumor cells over-expressing TfR and facilitate selective drug delivery.


Assuntos
Antibióticos Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/química , Peptídeos/química , Receptores da Transferrina/metabolismo , Linhagem Celular , Permeabilidade da Membrana Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Endocitose , Humanos , Terapia de Alvo Molecular/métodos , Oxirredução , Transdução de Sinais
12.
Br J Radiol ; 92(1104): 20190380, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31600089

RESUMO

OBJECTIVE: To evaluate the therapeutic response, progression free survival (PFS), overall survival (OS) and clinical toxicity of 177Lu-PSMA-617 PSMA targeted radioligand therapy (PRLT) in the setting of heavily pre-treated metastatic castrate-resistant prostate cancer (mCPRC) patients and also examine the association of prognostic variables with therapeutic outcome in such patient cohort. METHODS: We examined the medical records of mCRPC patients who had undergone 177Lu-PSMA-617 PRLT from March 2017 to February 2019 in our institute. Patients receiving equal to or more than two cycles were included and analyzed in this retroprospective study.The 68Ga-PSMA-11 PET-CT and 18-fludeoxyglucose positron emission tomography (18FDG PET)-CT scan findings, serum prostate-specific antigen (PSA) change, health-related quality of life (HRQoL) scales (Eastern Cooperative Oncology Group/Karnofsky score) and Gleason score were assessed for their implications on the outcome of therapy. The treatment response was evaluated under three categories: (a) symptomatic (b) biochemical and (c) imaging response.The PFS and OS following first PRLT were determined and the association of various variables with PSA doubling time (DT) and FDG uptake in the lesions were analyzed. Toxicity assessment was undertaken objectively by National Cancer Institute-Common Terminology Criteria for Adverse Events scale v. 5.0 for haematological and nephrotoxicity, and salivary gland toxicity assessed by xerostomia inventory score. RESULTS: A total of 40 mCRPC patients (age range: 46-84 years; median 63 years), who had undergone 177Lu-PSMA-617 PRLT, of at least two cycles was identified and selected for the analysis. FDG uptake was noted in 87.5% of patients (n = 35). Out of 40 cases, 21 were responders (CR, PR and SD) and 19 were non-responders (PD) on symptomatic and biochemical scales while on molecular imaging response, 16 (43%) were responders and remaining 21 (57%) were non-responders. Lesion-wise, 68Ga-PSMA-11 avid metastatic nodal disease responded well with 177Lu PSMA-617 PRLT, as compared to hepatic and skeletal lesions. The median OS and PFS was 12 and 7 months respectively following first PRLT. Patients with negative serum PSA-DT demonstrated superior 1 year PFS as compared to those with positive serum PSA-DT (52.5 vs 47.5%) (p = 0.029). Patients receiving greater than two cycles PRLT demonstrated a higher negative PSA-DT as compared to those receiving two cycles (p-value = 0.03). Grade 1 xerostomia was observed in two patients (5%) (mean xerostomia score of 23), haematotoxicity in seven patients [Grade I (n = 2, 5%) and Grade II (n = 5, 14%)]. CONCLUSION: 177Lu-PSMA-617 PRLT was well-tolerated and able to produce disease control with good symptomatic and biochemical responses in the context of heavily pre-treated mCRPC with progressive disease, with low toxicity profile. Evident association of high FDG uptake was observed with aggressive disease biology coupled with increasing Gleason score and poorer 12 months PFS. Negative PSA-DT following therapy demonstrated longer PFS. The results demonstrate important future role of 177Lu-PSMA-617 PRLT in the treatment of mCRPC. ADVANCES IN KNOWLEDGE: The present work explored in a large teriary cancer care setting, the efficacy of 177Lu-PSMA-617 PRLT, in an aggressive and unselected subset of mCRPC. The response and outcome was correlated with a number of prognostic variables, including molecular imaging findings (FDG uptake in the metastatic lesions), PSA DT and Gleason score.


Assuntos
Dipeptídeos/uso terapêutico , Fluordesoxiglucose F18/farmacocinética , Glutamato Carboxipeptidase II/antagonistas & inibidores , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Antígenos de Superfície , Dipeptídeos/efeitos adversos , Radioisótopos de Gálio/uso terapêutico , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Lutécio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Gradação de Tumores , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Intervalo Livre de Progressão , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/mortalidade , Neoplasias de Próstata Resistentes à Castração/patologia , Qualidade de Vida , Radioisótopos/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento
13.
Expert Rev Pharmacoecon Outcomes Res ; 19(6): 645-661, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31623476

RESUMO

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is a clinically heterogeneous disease. Treatment pathways for DLBCL are diverse and integrate established and novel therapies.Areas covered: We review the cost burden of DLBCL and the cost-effectiveness of DLBCL management including precision and cellular medicine. We utilized Medical Subject Heading (MeSH) terms and keywords to search the National Library of Medicine online MEDLINE database (PubMed) for articles related to cost, cost burden, and cost-of-illness of DLBCL and cost-effectiveness of DLBCL management strategies published in English as of June 2019.Expert commentary: Available and developing DLBCL therapies offer improved outcomes and often curative treatment at considerable financial expense, and the total cost burden for DLBCL management is substantial for patients and the healthcare system. In the era of personalized medicine, CAR T cells and targeted therapies provide exciting avenues for current and future DLBCL care and can further increase treatment cost. Determinations of cost and cost-effectiveness in DLBCL treatment pathways should continue to guide care providers and systems in identifying cost reduction strategies to provide appropriate therapies to the greatest number of patients in treating DLBCL.


Assuntos
Efeitos Psicossociais da Doença , Linfoma Difuso de Grandes Células B/terapia , Medicina de Precisão/métodos , Análise Custo-Benefício , Humanos , Imunoterapia Adotiva/economia , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/economia , Terapia de Alvo Molecular/economia , Terapia de Alvo Molecular/métodos , Medicina de Precisão/economia
14.
J Photochem Photobiol B ; 199: 111630, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31610429

RESUMO

Cancer disease is a foremost health concern and top basis of death in comparison with many diseases including cardiovascular disorders. During initial diagnosis (usually late diagnosis), a majority of cancer patients suffer from metastatic and advanced cancer stages which resulted in limited therapeutic modalities based interventions and effectiveness. Though considerable advancement has been made in combating the disease, continuous and intense efforts are ongoing for early diagnosis and development of therapies. Generally applied treatment options for cancer are surgery, chemotherapy and radiotherapy, which are restricted by failure to early diagnose, insufficient on-targeted drug delivery, systemic toxicity, and lack of real-time monitoring of therapeutic responses in cancer. Noninvasive imaging or minimally invasive imaging methodology is valuable in clinical diagnostic settings. Specifically, noninvasive optical imaging integrated with polymeric nanomaterial have been extensively investigated in the field of cancer diagnostics and therapy. Currently, optical imaging methods go together with polymer-based fluorescent nanoparticles in accomplishing the molecular level detection of tumor boundaries. NIR probe tagged polymeric nanoparticles have potential to provide an advantage in the early cancer detection, therapeutic monitoring and image guided surgery procedures. This article review the recent progress in state-of-the-art NIRF polymeric nanoparticles used for optical imaging particularly on cancer diagnosis.


Assuntos
Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Imagem Óptica/métodos , Polímeros/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Materiais Biocompatíveis/química , Sistemas de Liberação de Medicamentos/métodos , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacocinética , Humanos , Raios Infravermelhos , Terapia de Alvo Molecular/métodos , Fosfolipídeos/química , Propriedades de Superfície
15.
Magy Onkol ; 63(3): 239-245, 2019 09 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31538441

RESUMO

Skin cancers represent the most common type of malignancy. The incidence rate of melanoma and non-melanoma skin cancer depicts a continuous rise worldwide, which is attributed mainly (but not exclusively) to the growing incidence of non-melanoma skin cancer in the elderly population. Most skin cancer types are sensitive to immunotherapy. Melanoma, Merkel cell carcinoma, cutaneous squamous cell carcinoma showed response rates of at least 40% for PD-1 inhibitor therapy as reported in recent articles. In this article we review the current and future immunotherapy agents and procedures for skin cancers.


Assuntos
Imunoterapia/mortalidade , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Carcinoma de Célula de Merkel/imunologia , Carcinoma de Célula de Merkel/patologia , Carcinoma de Célula de Merkel/terapia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Intervalo Livre de Doença , Feminino , Humanos , Hungria , Masculino , Melanoma/imunologia , Melanoma/patologia , Melanoma/terapia , Terapia de Alvo Molecular/métodos , Prognóstico , Medição de Risco , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Resultado do Tratamento
16.
Magy Onkol ; 63(3): 209-216, 2019 Sep 18.
Artigo em Húngaro | MEDLINE | ID: mdl-31533141

RESUMO

Immunotherapy is getting more and more successful therapeutic option in case of many cancer types. Despite the clinical effectiveness of checkpoint inhibitor antibodies, long-lasting advantages can only be seen in a part of the patients, which makes necessary to examine immunotherapy more thoroughly. Immunity is influenced by the tumor, its microenvironment, and patient's characteristic and environmental factors. These elements control the strength and duration of antitumor response. Immunotherapeutic response may be more significant and may even last for years in case of hot tumors, while in most of the cases immunotherapy is not so effective in poorly immunogenic cold tumors. Combined therapies potentially increase efficiency. In our article T-cell activation phases of antitumor immune response, possible defects, their consequences and the potentially effective therapeutic opportunities are summarized shortly. Combined immunotherapy is a novel, promising possibility for modern oncology.


Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Neoplasias/terapia , Humanos , Imunoterapia/normas , Microambiente Tumoral/imunologia
17.
Zhonghua Zhong Liu Za Zhi ; 41(9): 648-653, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550853

RESUMO

Malignant peripheral nerve sheath tumor (MPNST) is a rare invasive soft tissue sarcoma that originates from peripheral nerve branches and peripheral nerve sheaths. Early radical surgery is an effective treatment for MPNST. Since it is insensitive to radiotherapy and chemotherapy, the disease manifests a rapid progression, poor prognosis and high mortality. In recent years, the translational researches on the driving factors and therapeutic targets of MPNST have been rapidly developed, including the pathways of NF1-Ras, Raf-MEK-ERK, PI3K-AKT-mTOR, Wnt signaling, and abnormal expressions of apoptotic proteins, the general loss of polycomb repressive complex 2 (PRC2), upregulation of the HDAC family, abnormal expressions of receptor tyrosine kinases, expressions of programmed cell death ligand (PD-L1), aurora kinase and various microRNAs.This review summarizes the current translational researches on potential therapeutic targets of MPNST, and the clinical trials which provide helpful information for MPNST targeted therapy.


Assuntos
Terapia de Alvo Molecular/métodos , Neoplasias da Bainha Neural/terapia , Neurofibrossarcoma/terapia , Humanos , Neoplasias da Bainha Neural/patologia , Neurofibrossarcoma/patologia , Fosfatidilinositol 3-Quinases , Transdução de Sinais , Pesquisa Médica Translacional
19.
Gynecol Oncol ; 155(2): 201-206, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31522837

RESUMO

OBJECTIVES: Patients with epithelial ovarian cancer (EOC) recurring between 6 and 12 months after primary platinum chemotherapy have worse prognosis than those recurring in >12 months. Artificially prolonging the platinum-free interval (PFI) with cytotoxic chemotherapy was tested in MITO-8 with poor outcomes. This study aimed to determine the impact of using non-platinum or targeted therapy in 2nd line treatment of EOC patients recurring 6-12 months after completion of primary platinum-based chemotherapy. METHODS: A multi-institutional retrospective review of 177 patients with recurrent EOC and PFI of 6-12 months following primary chemotherapy was performed comparing platinum versus non-platinum chemotherapy or targeted therapy for 2nd line treatment. PFI1 was defined as the date of last chemotherapy to date of recurrence. PFS2/3 were defined as start of 2nd or 3rd line chemotherapy to start of subsequent line. RESULTS: Of 177 patients, the majority of patients were Caucasian, had serous histology, and underwent primary cytoreductive surgery. Median PFI1 was 8.2 months (95% CI 8-9 months). Second line platinum was omitted in 28% of patients. Bevacizumab was used in 2nd line in 16% of patients; 19% received other targeted therapies. Median PFS2 for platinum chemotherapy was longer than non-platinum (7.1 vs 3 months, p = 0.0114). Median PFS2 was significantly longer for platinum vs. targeted therapy (7.1 vs. 3 months p = 0.0431). Median OS for platinum in 2nd line vs. no platinum was 43.6 vs. 37.6 months (p = 0.0174). CONCLUSIONS: Use of non-platinum chemotherapy and even targeted therapy to prolong PFI in patients with EOC recurring between 6 and 12 months leads to worse survival.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Compostos de Platina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/uso terapêutico , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/mortalidade , Recidiva Local de Neoplasia/etiologia , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
20.
Eur J Pharm Sci ; 140: 105071, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525433

RESUMO

Multidrug resistance (MDR) is a major reason for anticancer chemotherapy failure, and P-glycoprotein (P-gp) over-expressing on tumor cells is considered as the important target to overcome MDR. Emerging reports have showed that vitamin E (VE) can cause significant reversal of MDR due to inhibition of ATPase activity. Accordingly, we synthesized hyaluronic acid (HA) conjugated vitamin E succinate (VES) polymer, which can self-assemble into micelles and thus achieve high drug (paclitaxel (PTX) used as model drug) encapsulation as well as tumor accumulation owing to the enhanced permeability and retention (EPR) effect and HA active targeting ability. In addition, the linker between HA and VES utilized in this work was disulfide bond with reduction-sensitive property, which would respond to high glutathione (GSH) concentration in tumor cytoplasmic environment and trigger HA-CYS-VES polymer disassociation and drug release. In vitro, PTX loaded HA-CYS-VES demonstrated enhanced cytotoxicity, high apoptosis-inducing activities and reversal effects of PTX on MCF-7/Adr cells, compared to PTX. Also, cellular uptake and intracellular PTX accumulation tests displayed that PTX loaded HA-CYS-VES could more efficiently enter tumor cells and selectively release drug in cytosol so as to facilitate its function on microtubule. More importantly, PTX loaded HA-CYS-VES showed better tumor targeting ability, improved antitumor efficacy and low adverse effects on tumor-bearing mice. In conclusion, PTX loaded HA-CYS-VES exhibited a great potential for reversing MDR in anticancer chemotherapeutics.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Hialurônico/química , Micelas , Paclitaxel/química , alfa-Tocoferol/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Citosol/metabolismo , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/métodos , Polímeros/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA