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1.
ESMO Open ; 5(2)2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132106

RESUMO

Soft tissue sarcoma (STS), although heterogeneous in histopathology presentation, has mostly been treated with chemotherapy agents as one entity. Our understanding of crucial genomic alterations in different STS histologies and the advent of molecular-targeted agents have reshaped the treatment paradigm for advanced STS. Small-molecule inhibitors of c-KIT, plate-derived growth factor receptor alpha, c-MET, BRAF, anaplastic lymphoma kinase, ROS1 and colony-stimulating factor-1 receptor have been successfully validated in clinical studies to yield practice-changing results. Inhibitors of other novel genomic targets including mouse double minute 2 homolog, cyclin-dependent kinase 4/6, mitogen-activated protein kinase and epigenetic regulators are expected to be developed in the near future. Furthermore, with the advancement and accessibility of molecular diagnosis and next-generation sequencing, a genomic-based therapeutic approach should be widely applicable to advanced STS patients. This review will focus on the progress of genomic-guided therapy tailored to each molecular alteration of different STS histologies.

2.
Nature ; 577(7791): 556-560, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31942077

RESUMO

Soft-tissue sarcomas represent a heterogeneous group of cancer, with more than 50 histological subtypes1,2. The clinical presentation of patients with different subtypes is often atypical, and responses to therapies such as immune checkpoint blockade vary widely3,4. To explain this clinical variability, here we study gene expression profiles in 608 tumours across subtypes of soft-tissue sarcoma. We establish an immune-based classification on the basis of the composition of the tumour microenvironment and identify five distinct phenotypes: immune-low (A and B), immune-high (D and E), and highly vascularized (C) groups. In situ analysis of an independent validation cohort shows that class E was characterized by the presence of tertiary lymphoid structures that contain T cells and follicular dendritic cells and are particularly rich in B cells. B cells are the strongest prognostic factor even in the context of high or low CD8+ T cells and cytotoxic contents. The class-E group demonstrated improved survival and a high response rate to PD1 blockade with pembrolizumab in a phase 2 clinical trial. Together, this work confirms the immune subtypes in patients with soft-tissue sarcoma, and unravels the potential of B-cell-rich tertiary lymphoid structures to guide clinical decision-making and treatments, which could have broader applications in other diseases.

3.
Invest New Drugs ; 38(1): 99-110, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-30825104

RESUMO

Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).

4.
J Food Sci ; 84(12): 3535-3545, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31777961

RESUMO

Beta-carotene (BC) degradation was studied by liquid chromatography coupled to a quadrupole time of flight mass spectrometer. Throughout/After 21 days of dark storage, 56 nonvolatile degradants were chromatographically separated from pure BC crystal and their molecular formulas were identified. Their structure information was gained by comparing the fragments to a different, but structure-related compound. For example, a newly formed double bond position in dehydrogenated BC was determined by comparing the fragments between BC and dehydrogenated BC. One of their chemical structures was confirmed by comparing its precursor ion mass, retention time, isotopic ratio, and fragmentation to a pure trans-beta-apo-8'-apocarotenal. BC cleavage was observed on double bonds as well as single bonds in BC conjugation chain. PRACTICAL APPLICATION: As evidenced in this study, beta-carotene (BC) degradation is a spontaneous process initiated when the compound is exposed to air. The stoichiometric ratio of BC to oxygen is 1:0.03 at the first oxidation, therefore, only 0.3 mg oxygen or 1.2 mL air will degrade 10 mg BC, an average daily recommended intake. Not like in enzymatic BC degradation, spontaneous BC oxidation did not produce provitamin A, either in retina C20H38O or retinol C20H40O forms. For BC application in vitamin A deficiency, spontaneous BC oxidation should be avoided.


Assuntos
beta Caroteno/química , Carotenoides , Espectrometria de Massas , Estrutura Molecular , Oxirredução
5.
Biometrics ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31625596

RESUMO

Standard sample size calculation formulas for stepped wedge cluster randomized trials (SW-CRTs) assume that cluster sizes are equal. When cluster sizes vary substantially, ignoring this variation may lead to an under-powered study. We investigate the relative efficiency of a SW-CRT with varying cluster sizes to equal cluster sizes, and derive variance estimators for the intervention effect that account for this variation under a mixed effects model-a commonly used approach for analyzing data from cluster randomized trials. When cluster sizes vary, the power of a SW-CRT depends on the order in which clusters receive the intervention, which is determined through randomization. We first derive a variance formula that corresponds to any particular realization of the randomized sequence and propose efficient algorithms to identify upper and lower bounds of the power. We then obtain an "expected" power based on a first-order approximation to the variance formula, where the expectation is taken with respect to all possible randomization sequences. Finally, we provide a variance formula for more general settings where only the cluster size arithmetic mean and coefficient of variation, instead of exact cluster sizes, are known in the design stage. We evaluate our methods through simulations and illustrate that the average power of a SW-CRT decreases as the variation in cluster sizes increases, and the impact is largest when the number of clusters is small.

6.
Am J Surg Pathol ; 43(7): 928-942, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31094921

RESUMO

Uterine mesenchymal tumors are genetically heterogenous; those with uniform cytomorphology, best exemplified by endometrial stromal tumors, often contain various fusion genes. Novel fusions involving ESR1 and GREB1, key factors in sex hormone pathways, have been implicated in rare uterine mesenchymal tumors. Particularly, the fusions between 5'-ESR1/GREB1 and 3'-NCOA2/NCOA3 were recently identified in 4 uterine tumors resembling ovarian sex-cord tumor (UTROSCT). By RNA sequencing, pathology review, and FISH screening, we identified 4 uterine sarcomas harboring rearranged GREB1, including GREB1-NCOA2 and the novel GREB1-NR4A3, GREB1-SS18, and GREB1-NCOA1, validated by RT-PCR and/or FISH. They occurred in the myometrium of postmenopausal women and were pathologically similar despite minor differences. Tumor cells were generally uniform and epithelioid, with vesicular nuclei and distinct to prominent nucleoli. Growth patterns included solid sheets, trabeculae/cords, nests, and fascicles. Only 1 tumor showed small foci of definitive sex-cord components featuring well-formed tubules, retiform structures, Leydig-like cells, and lipid-laden cells and exhibiting convincing immunoreactivity to sex-cord markers (calretinin, α-inhibin, and Melan-A). In contrast, all the 4 classic UTROSCT we collected occurred in premenopausal patients, consisted predominantly of unequivocal sex-cord elements, prominently expressed multiple sex-cord markers, and harbored ESR1-NCOA3 fusion. Combined with previously reported cases, GREB1-rearranged tumors involved significantly older women (P=0.001), tended to be larger and more mitotically active, showed more variable and often inconspicuous sex-cord differentiation, and appeared to behave more aggressively than ESR1-rearranged UTROSCT. Therefore, these 2 groups of tumors might deserve separate consideration, despite some overlapping features and the possibility of belonging to the same disease spectrum.

7.
J Environ Manage ; 237: 569-575, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30826638

RESUMO

BACKGROUND: China and other developing countries in Asia follow similar economic growth patterns described by the flying geese (FG) model, which explains the "catching-up" process of industrialization in latecomer economies. Japan, newly industrialized economies, and China have followed this path, with similar economic development trajectories. Based on the FG model, we postulated a "flying S" hypothesis stating that if a country is located within an FG region and its energy matrix is relatively constant, its per capita CO2 emission curve will mirror that of "leading geese" countries in the same FG group. METHOD: Historical CO2 emissions data were obtained from literature review and national reports and were calculated using bottom-up methods. A sigmoid-shaped, non-linear mixed effect model was applied to examine ex post data with 1000 simulated predictions to construct 95% empirical bands from these fits. By multiplying by estimated population, we predicted total emissions of selected FG countries. RESULTS: Per capita CO2 emissions from the same FG group mirror each other, especially among second and third industrial sectors. We estimated an annual 18,252.24 million tons of CO2 emissions (MtCO2) (95% CI = 9458.88-23,972.88) in China and 8281.76 MtCO2 (95% CI = 2765.68-14,959.12) in India in 2030. CONCLUSION: This study bridges the macroeconomic FG paradigm to study climate change and proposes a "flying S" hypothesis to predict greenhouse gas emissions in East Asia. By applying our theory to empirical data, we provide an alternative framework to predict CO2 emissions in 2030 and beyond.


Assuntos
Dióxido de Carbono , Carbono , Ásia , China , Índia , Japão
9.
Environ Health ; 18(1): 9, 2019 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-30691464

RESUMO

BACKGROUND: Exposure to ambient particulate matter generated from coal-fired power plants induces long-term health consequences. However, epidemiologic studies have not yet focused on attributing these health burdens specifically to energy consumption, impeding targeted intervention policies. We hypothesize that the generating capacity of coal-fired power plants may be associated with lung cancer incidence at the national level. METHODS: Age- and sex-adjusted lung cancer incidence from every country with electrical plants using coal as primary energy supply were followed from 2000 to 2016. We applied a Poisson regression longitudinal model, fitted using generalized estimating equations, to estimate the association between lung cancer incidence and per capita coal capacity, adjusting for various behavioral and demographic determinants and lag periods. RESULTS: The average coal capacity increased by 1.43 times from 16.01 gigawatts (GW) (2000~2004) to 22.82 GW (2010~2016). With 1 kW (KW) increase of coal capacity per person in a country, the relative risk of lung cancer increases by a factor of 59% (95% CI = 7.0%~ 135%) among males and 85% (95% CI = 22%~ 182%) among females. Based on the model, we estimate a total of 1.37 (range = 1.34 ~ 1.40) million standardized incident cases from lung cancer will be associated with coal-fired power plants in 2025. CONCLUSIONS: These analyses suggest an association between lung cancer incidence and increased reliance on coal for energy generation. Such data may be helpful in addressing a key policy question about the externality costs and estimates of the global disease burden from preventable lung cancer attributable to coal-fired power plants at the national level.


Assuntos
Carvão Mineral , Neoplasias Pulmonares/epidemiologia , Centrais Elétricas , Feminino , Saúde Global , Humanos , Incidência , Masculino , Risco
10.
J Formos Med Assoc ; 118(1 Pt 2): 230-236, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29709339

RESUMO

BACKGROUND/PURPOSE: There are scarce reports on the prognostic factors and treatment outcomes of patients with malignant pleural mesothelioma (MPM) in Asia. This study aimed to address these matters in a real-world setting. METHODS: Medical records of patients with histologically proven MPM diagnosed between 1977 and 2016 at the National Taiwan University Hospital were reviewed. Variables including age, gender, performance status, asbestos exposure, smoking history, histology subtype, staging, and treatment received were recorded. All patients were followed until death or March 1st, 2017. Survival and prognostic factors were analyzed by the Kaplan-Meir method and the Cox proportional hazard model. RESULTS: A total of 93 patients was identified, including 65 men and 28 women. An increasing trend of MPM cases diagnosed was observed in the past 40 years. Stage I/II disease (HR 0.24, 95% CI 0.13-0.46) and epithelioid histology (HR 0.42, 95% CI 0.23-0.75) were associated with favorable prognosis, whereas age ≥70 years (HR 2.66, 95% CI 1.36-5.22) and ECOG ≥2 (HR 5.03, 95% CI 2.69-9.4) were poor prognostic factors. After adjustment for prognostic factors, surgery in stage I-III MPM (HR 0.36, 95% CI 0.15-0.83) and systemic therapy in stage III/IV disease (HR 0.42, 95% CI 0.19-0.94) conferred a survival benefit. CONCLUSION: This is one of the largest case series of MPM reported in Asia outside of Japan. Prognostic factors in the study population included age, performance status, stage, and histology subtype. Surgery in potentially resectable disease and systemic therapy in advanced MPM confer a survival benefit in Asian patients.


Assuntos
Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/terapia , Mesotelioma/mortalidade , Mesotelioma/terapia , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/terapia , Idoso , Bases de Dados Factuais , Feminino , Hospitais Universitários , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Mesotelioma/diagnóstico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pleurais/diagnóstico , Prognóstico , Análise de Sobrevida , Taiwan/epidemiologia
11.
Int J Gynecol Pathol ; 38(5): 470-473, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30085939

RESUMO

Ewing sarcoma and peripheral primitive neuroectodermal tumor constitute the Ewing family of tumors (EFT). EFTs primarily arising in the ovary are extremely rare. We report the case of a 22-yr-old nulliparous woman with a primary EFT in the ovary that initially presented as a 3-cm teratoma-like ovarian tumor, with rapid progression to a 15-cm-sized tumor with liver metastasis in 3 mo. The patient underwent suboptimal debulking surgery and salvage chemotherapy with vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide. In conclusion, primary EFT in the ovary is extremely rare with highly aggressive behavior and poor outcome for metastatic disease. Demonstration of EWSR1 rearrangement, observed in a variety of soft tissue tumors, is very helpful in the diagnosis of EFT when interpreted on the basis morphology and immunohistochemistry.


Assuntos
Tumores Neuroectodérmicos Primitivos Periféricos/patologia , Neoplasias Ovarianas/patologia , Sarcoma de Ewing/patologia , Adulto , Feminino , Humanos , Tumores Neuroectodérmicos Primitivos Periféricos/terapia , Neoplasias Ovarianas/terapia , Sarcoma de Ewing/terapia
12.
Cancer Med ; 8(1): 104-110, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30575309

RESUMO

BACKGROUND: Primary cardiac sarcoma (PCS) is a rare but often fatal disease. The current study aimed to analyze the impact of baseline demographics, local and systemic therapies in a contemporary cohort. METHODS: Clinical records of PCS across six institutions in three continents were reviewed. Kaplan-Meier method was used to estimate survival. Cox proportional hazard model was used to determine variables impacting progression-free survival (PFS) or overall survival (OS). RESULTS: Sixty-one patients with PCS (1996-2016) were identified. The median age at diagnosis was 46 (range 18-79); 36% (n = 22) presented with metastatic disease. The most common histology was angiosarcoma (n = 24, 39%). A total of 46 patients received surgery (75%) but only 5 (8%) patients achieved R0 resection. Multi-modality treatment to the primary tumor was given to 28 patients (46%; localized disease 23/39 (59%); metastatic disease 5/22 (23%)). The median OS for the entire cohort was 17.5 months (95% CI 9.5-20.6), with seven (11%) patients surviving longer than 36 months. On multi-variate analysis, age <65 (P = 0.01) was the only significant favorable prognostic factor. For first-line palliative chemotherapy, the median PFS was 4.4 months (95% CI 2.9-7.7 months). The best response for first-line chemotherapy was 32% (CR = 1, PR = 9). No significant improvement in OS was identified in patients presenting throughout the 20-year period of this review. CONCLUSION: Younger age at diagnosis was associated with improved outcome although the prognosis of PCS remains poor. Given the lack of improvement in survival, further dedicated research is required.

13.
Biosens Bioelectron ; 126: 615-623, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30508786

RESUMO

This paper presents the development of a multi-sensor platform capable of simultaneous measurement of dissolved oxygen (DO) concentration, glucose and lactate concentrations in a micro-chamber for real-time evaluation of metabolic flux in bovine embryos. A micro-chamber containing all three sensors (DO, glucose, and lactate) was made to evaluate metabolic flux of single oocytes or embryos at different stages of development in ≤ 120 µL of respiration buffer. The ability of the sensor to detect a metabolic shift from oxidative phosphorylation (OXPHOS) to glycolysis was demonstrated in embryos by an ablation of oxygen consumption and an increase in lactate production following addition of oligomycin, an inhibitor of mitochondrial adenosine triphosphate (ATP) synthesis. An increased reliance upon glycolysis relative to OXPHOS was demonstrated in embryos as they developed from morula to hatched blastocysts by a progressive increase in the lactate/oxygen flux ratio, consistent with isolated metabolic assessments reported previously. These studies highlight the utility of a metabolic multi-sensor for integrative real-time monitoring of aerobic and anaerobic energy metabolism in bovine embryos, with potential applications in the study of metabolic processes in oocyte and early embryonic development.


Assuntos
Técnicas Biossensoriais , Embrião de Mamíferos/metabolismo , Metabolismo Energético , Ácido Láctico/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Blastocisto/metabolismo , Bovinos , Desenvolvimento Embrionário/genética , Feminino , Oócitos/metabolismo , Gravidez
14.
Chin Clin Oncol ; 7(4): 43, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30173533

RESUMO

Soft tissue sarcoma (STS) is a heterogeneous disease with more than 50 subtypes. Once the disease reached locally advanced or metastatic status, the standard treatment remains to be chemotherapy. Current understanding of the underlying molecular and genomic mechanisms of different histology subtypes have led to encouraging development of new drugs in treating STS. Besides molecular targeted therapy, immunotherapy have also shown promising advancement in solid tumor treatments. This review will be in two parts. The first part will focus on the molecular targeted agents aiming at molecular or genetic alterations that are more specific in STS, including antiangiogenic molecules, plate-derived growth factor receptor alpha (PDGFRA) monoclonal antibody, colony-stimulating factor-1 receptor (CSF-1R), selective inhibitors of nuclear export (SINE), cyclin-dependent kinase 4/6 (CDK 4/6), mdm2, and epigenetic regulators. We also discussed in depth about how current precision medicine influences the treatment paradigm in STS. In the second part, we focus on the landscape of immunotherapy in STS including immune checkpoint inhibitors (ICIs) and the combinations of immunotherapies or with other molecules that could modulate the tumor microenvironment. These included the program cell death-1 receptor and its ligand (PD-1/PD-L1), cytotoxic T lymphocyte associated protein-4 (CTLA-4) and the combination with anti-angiogenic agents that could facilitate the trafficking of T cells. Strategies targeting the tumor-associated antigen NY-ESO-1, which is commonly observed in synovial sarcoma and myxoid round cell liposarcoma, via viral vaccines and adoptive T cells will also be discussed. These new frontiers of treatment that are developed with better insights into sarcoma and immune biology hopefully will change the treatment paradigm of advanced STS in the future.


Assuntos
Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Medicina de Precisão/métodos , Sarcoma/terapia , Humanos , Sarcoma/patologia
15.
Biosens Bioelectron ; 114: 78-88, 2018 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-29783145

RESUMO

The ability to view biological events in real time has contributed significantly to research in the life sciences. While video capture of real time changes in anatomical relationships is important, it is equally important to visualize real time changes in the chemical communications that drive cell behaviors. This paper describes an electrochemical imaging system capable of capturing changes in chemical gradients in live tissue slices. The system consists of a CMOS microchip with 8192 configurable Pt surface electrodes, on-chip potentiostat, on-chip control logic, and a microfluidic device designed to interface with the CMOS chip to support ex vivo tissue experimentation. All data processing and visualization methods, sensor calibrations, microfluidics fabrication, and tissue preparation and handling procedures are described. Using norepinephrine as a target analyte for proof of concept, the system is capable of differentiating concentrations of norepinephrine as low as 8 µM and up to 1024 µM with a linear response and a spatial resolution of 25.5 µm × 30.4 µm. Electrochemical imaging was tested using murine adrenal tissue as a biological model and successfully showed caffeine-stimulated release of catecholamines from live slices of adrenal tissue with temporal sensitivity. This system successfully demonstrates the use of a high-density microelectrode array for electrochemical analysis with high spatiotemporal resolution to gather chemical gradient information in parallel with optical microscopy recordings.


Assuntos
Técnicas Biossensoriais/instrumentação , Catecolaminas/análise , Técnicas Eletroquímicas/instrumentação , Norepinefrina/análise , Glândulas Suprarrenais/metabolismo , Animais , Cafeína/farmacologia , Catecolaminas/metabolismo , Desenho de Equipamento , Feminino , Dispositivos Lab-On-A-Chip , Limite de Detecção , Masculino , Camundongos , Microeletrodos , Norepinefrina/metabolismo , Oxirredução , Estudo de Prova de Conceito
16.
Eur Radiol ; 28(11): 4860-4870, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29770848

RESUMO

OBJECTIVES: The aim of this study is to investigate the correlation of survival outcomes with imaging biomarkers from multiparametric magnetic resonance imaging (MRI) in patients with brain metastases from breast cancer (BMBC). METHODS: This study was approved by the institutional review board. Twenty-two patients with BMBC who underwent treatment involving bevacizumab on day 1, etoposide on days 2-4, and cisplatin on day 2 in 21-day cycles were prospectively enrolled for a phase II study. Three brain MRIs were performed: before the treatment, on day 1, and on day 21. Eight imaging biomarkers were derived from dynamic contrast-enhanced MRI (Peak, IAUC60, Ktrans, kep, ve), diffusion-weighted imaging [apparent diffusion coefficient (ADC)], and MR spectroscopy (choline/N-acetylaspartate and choline/creatine ratios). The relative changes (Δ) in these biomarkers were correlated with the central nervous system (CNS)-specific progression-free survival (PFS) and overall survival (OS) using the Kaplan-Meier and Cox proportional hazard models. RESULTS: There were no significant differences in the survival outcomes as per the changes in the biomarkers on day 1. On day 21, those with a low ΔKtrans (p = 0.024) or ΔADC (p = 0.053) reduction had shorter CNS-specific PFS; further, those with a low ΔPeak (p = 0.012) or ΔIAUC60 (p = 0.04) reduction had shorter OS compared with those with high reductions. In multivariate analyses, ΔKtrans and ΔPeak were independent prognostic factors for CNS-specific PFS and OS, respectively, after controlling for age, size, hormone receptors, and performance status. CONCLUSIONS: Multiparametric MRI may help predict the survival outcomes in patients with BMBC. KEY POINTS: • Decreased angiogenesis after chemotherapy on day 21 indicated good survival outcome. • ΔK trans was an independent prognostic factors for CNS-specific PFS. • ΔPeak was an independent prognostic factors for OS. • Multiparametric MRI helps clinicians to assess patients with BMBC. • High-risk patients may benefit from more intensive follow-up or treatment strategies.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Imagem por Ressonância Magnética/métodos , Adulto , Idoso , Antineoplásicos/uso terapêutico , Ácido Aspártico/análogos & derivados , Ácido Aspártico/análise , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Colina/análise , Creatinina/análise , Feminino , Humanos , Estimativa de Kaplan-Meier , Espectroscopia de Ressonância Magnética , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos
17.
Jpn J Clin Oncol ; 48(3): 242-247, 2018 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-29315394

RESUMO

Background: The combination of lapatinib and oral vinorelbine for HER2 positive metastatic breast cancer (MBC) is convenient but with uncertain toxicity profiles. A Phase I/II study was designed to understand the tolerability and efficacy of this combination treatment. Method: Female MBC patients with HER2 positive were eligible. Lapatinib was given once daily and oral vinorelbine was given on Days 1 and 8 of a 21-day cycle. A 3 + 3 standard dose-escalation rule was applied in the Phase I study. The primary endpoint of the Phase II study was PFS. In the Phase II part, because no DLT was observed in the first 20 patients, vinorelbine dose-escalation was permitted if no significant toxicities after the first cycle was observed. Result: From June 2009 to February 2013, 46 patients were enrolled in Phase I (n = 15) and II (n = 31) studies. Median age was 52.8 (range 34.3-84.0); 28 (60.9%) patients were ER positive. In the Phase I study, two patients had DLTs (neutropenia (n = 2), diarrhea (n = 1)). The MTD was determined at lapatinib 1000 mg plus oral vinorelbine 50 mg/m2. In the Phase II study, 11 patients safely had vinorelbine escalated to 60 mg/m2 on cycle 2. The median PFS was 5.6 months (95% CI 5.2-5.9); 6 (19.4%) patients had PR; the clinical benefit rate was 38.7%. Six patients had disease control over 2 years. Conclusion: Lapatinib 1000 mg and oral vinorelbine 50 mg/m2 were tolerable with manageable toxicities. Escalation to vinorelbine 60 mg/m2 is feasible if no significant toxicities after the first cycle. Clinical efficacy was demonstrated with long-term responders observed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quinazolinas/uso terapêutico , Vimblastina/análogos & derivados , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Demografia , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Lapatinib , Pessoa de Meia-Idade , Metástase Neoplásica , Quinazolinas/efeitos adversos , Receptor ErbB-2/metabolismo , Resultado do Tratamento , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/uso terapêutico , Vinorelbina
18.
Breast Cancer Res Treat ; 168(1): 159-168, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29177603

RESUMO

PURPOSE: Next-generation sequencing (NGS) has identified recurrent genomic alterations in metastatic breast cancer (MBC); however, the clinical utility of incorporating routine sequencing to guide treatment decisions in this setting is unclear. We examine the frequency of genomic alterations in MBC patients from academic and community hospitals and correlate with clinical outcomes. METHODS: MBC patients with good performance status were prospectively recruited at the Princess Margaret Cancer Centre (PM) in Canada. Molecular profiling on DNA extracted from FFPE archival tissues was performed on the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel (TSACP) on the MiSeq platform. Clinical trial outcomes by RECIST 1.1 and time on treatment were reviewed retrospectively. RESULTS: From January 2012 to November 2015, 483 MBC patients were enrolled and 440 were genotyped. At least one somatic mutation was identified in 46% of patients, most commonly in PIK3CA (28%) or TP53 (13%). Of 203 patients with ≥ 1 mutation(s), 15% were treated on genotype-matched and 9% on non-matched trials. There was no significant difference for median time on treatment for patients treated on matched vs. non-matched therapies (3.6 vs. 3.8 months; p = 0.89). CONCLUSIONS: This study provides real-world outcomes on hotspot genotyping and small targeted panel sequencing of MBC patients from academic and community settings. Few patients were matched to clinical trials with targeted therapies. More comprehensive profiling and improved access to clinical trials may increase therapeutic options for patients with actionable mutations. Further studies are needed to evaluate if this approach leads to improved clinical outcomes.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Técnicas de Genotipagem/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Adulto , Idoso , Idoso de 80 Anos ou mais , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Análise Mutacional de DNA/métodos , Feminino , Genômica/métodos , Humanos , Mastectomia , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Estudos Retrospectivos , Análise de Sobrevida , Adulto Jovem
19.
Sci Rep ; 7(1): 9842, 2017 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-28852212

RESUMO

Tamoxifen is the standard first-line hormonal therapy for premenopausal women with estrogen receptor (ER)-positive metastatic breast cancer (BC). One of the crucial mechanisms underlying hormonal therapy resistance is the collateral activation of the phosphatidylinositol-3 kinase (PI3K)/AKT pathway. We explored whether PI3K inhibitors, buparlisib and alpelisib, enhance the efficacy of tamoxifen against ER-positive BC cells. We have observed a synergism between alpelisib or buparlisib and tamoxifen in the treatment for ER-positive BC cell lines harboring different PI3K alterations. Immunoblotting analysis showed alpelisib, buparlisib, or either drug in combination with tamoxifen downregulated the PI3K downstream targets in the MCF-7 and ZR75-1 cells. In the MCF-7 cells transfected with a constitutive active (myristoylated) AKT1 construct or mutant ER, the synergistic effect between alpelisib and tamoxifen was markedly attenuated, indicating that synergism depends on AKT inhibition or normally functioning ER. Combining alpelisib or buparlisib with tamoxifen also attenuated MCF-7 tumor growth in Balb/c nude mice. Our data suggest that additional PI3K blockade might be effective in enhancing the therapeutic effect of tamoxifen in ER-positive BC and support the rationale combination in clinical trials.


Assuntos
Aminopiridinas/farmacologia , Antineoplásicos Hormonais/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Morfolinas/farmacologia , Receptores Estrogênicos/metabolismo , Tamoxifeno/farmacologia , Tiazóis/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sinergismo Farmacológico , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Estrogênicos/genética , Transdução de Sinais/efeitos dos fármacos
20.
Biosens Bioelectron ; 87: 646-653, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27619528

RESUMO

This paper presents a label-free affinity-based capacitive biosensor using interdigitated electrodes. Using an optimized process of DNA probe preparation to minimize the effect of contaminants in commercial thiolated DNA probe, the electrode surface was functionalized with the 24-nucleotide DNA probes based on the West Nile virus sequence (Kunjin strain). The biosensor has the ability to detect complementary DNA fragments with a detection limit down to 20 DNA target molecules (1.5aM range), making it suitable for a practical point-of-care (POC) platform for low target count clinical applications without the need for amplification. The reproducibility of the biosensor detection was improved with efficient covalent immobilization of purified single-stranded DNA probe oligomers on cleaned gold microelectrodes. In addition to the low detection limit, the biosensor showed a dynamic range of detection from 1µL-1 to 105µL-1 target molecules (20 to 2 million targets), making it suitable for sample analysis in a typical clinical application environment. The binding results presented in this paper were validated using fluorescent oligomers.


Assuntos
Sondas de DNA/química , DNA de Cadeia Simples/química , DNA/análise , Capacitância Elétrica , Técnicas Eletroquímicas/instrumentação , Ácidos Nucleicos Imobilizados/química , Hibridização de Ácido Nucleico , Sequência de Bases , Técnicas Biossensoriais/instrumentação , Eletrodos , Desenho de Equipamento , Ouro , Humanos , Limite de Detecção , Sistemas Automatizados de Assistência Junto ao Leito , Reprodutibilidade dos Testes , Compostos de Sulfidrila/química , Febre do Nilo Ocidental/virologia , Vírus do Nilo Ocidental/química
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