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1.
World Neurosurg ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32142947

RESUMO

BACKGROUND: Recent literature has shown significant differences in meningioma incidence among different races, but minimal conclusive data exist on the role of race and ethnicity in overall survival for patients with high-grade intracranial meningioma. We conducted a systematic review to investigate the impact of race and ethnicity on survival in patients with high-grade intracranial meningioma. METHODS: A systematic literature review was conducted for studies using Ovid, PubMed, Cochrane, Embase, and Scopus databases. Databases were queried for the following: Meningioma AND [Ethnic OR Demography, OR African American OR Arab OR Hispanic OR Asian, OR White OR race OR racial] AND [survival OR survival analysis OR survival rate OR treatment outcome OR Survivor OR Outcome]. RESULTS: A literature search yielded a total of 412 abstracts, which were screened according to criteria that were determined a priori, and a total of 129 full-text articles were reviewed. Four articles were included in the final analysis, reporting on a total of 13,424 patients. Three studies saw an overall survival benefit in White non-Hispanics compared with Black non-Hispanics, and 1 reported a survival benefit in White non-Hispanics and Black non-Hispanics among patients who received gross total resection. One study additionally reported an increased likelihood of White patients receiving gross total resection when compared with non-White patients. CONCLUSIONS: The limited data available suggest that White patients have improved measures of survival compared with nonw-White patients, for reasons that are likely complex and multifactorial. Further studies are needed to explore these survival differences seen.

2.
BMC Ophthalmol ; 20(1): 92, 2020 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-32143590

RESUMO

BACKGROUND: Retinoblastoma (RB) is the most frequent pediatric retinal tumor. In the present study, to elucidate chemoresistance mechanisms and identify potential biomarkers in RB, we utilized RNA sequencing (RNAseq) technological platforms to reveal transcriptome profiles and identify any differentially expressed genes (DEGs) between an etoposide drug-resistant subline (Y79/EDR) and parental Y79 cells. METHODS: To test whether Y79/EDR cells showed resistance to antineoplastic agents for RB, we treated the cells with etoposide, carboplatin and vincristine and analyzed them with a Cell Counting Kit-8 (CCK-8). Y79/EDR and parental Y79 cells were used for RNAseq and bioinformatics analysis to enable a genome-wide review of DEGs between the two lines using the DESeq R package (1.10.1). Then, DEG enrichment in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was analyzed with KOBAS software. Next, real-time quantitative reverse transcription polymerase chain reaction (real time QRT-PCR) and cytotoxicity assays were performed to experimentally and functionally validate the identified candidate biomarkers. RESULTS: Y79/EDR cells showed resistance to etoposide, carboplatin and vincristine at different concentrations. In total, 524 transcripts were differentially expressed in Y79/EDR cells based on analysis of fragments per kilobase of transcript per million fragments mapped (FPKM); among these, 57 genes were downregulated and 467 genes were upregulated in Y79/EDR cells compared to parental Y79 cells. We selected candidate DEGs, including ARHGAP9, HIST1H4H, RELN, DDIT4, HK2, STC1 and PFKFB4, for mRNA expression validation with real time QRT-PCR assays and found that the expression levels determined by real time QRT-PCR were consistent with the RNAseq data. Further studies involving downregulation of ARHGAP9 with a specific siRNA showed that ARHGAP9 altered the cellular sensitivity of Y79 cells to etoposide and carboplatin. CONCLUSION: Our initial findings provided a genomic view of the transcription profiles of etoposide-induced acquired resistance in RB. Follow-up studies indicated that ARHGAP9 might be a chemoresistance biomarker in RB, providing insight into potential therapeutic targets for overcoming acquired chemoresistance in RB. These findings can aid in understanding and overcoming chemoresistance during treatment of RB in the clinic.

3.
J Drug Target ; : 1-12, 2020 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-32118494

RESUMO

Non-small cell lung carcinoma (NSCLC) is a malignant tumour with poor prognosis and high mortality. Platinum-based dual-agent chemotherapy is the main therapeutic regimen for this disease. In recent years, because of the introduction of molecular targeted therapy, various targeted therapeutic agents against epidermal growth factor receptor (EGFR) have been rapidly developed, which has become a research hotspot for NSCLC treatment. Here, we review the latest studies describing the features and types of EGFR pathogenic mutations, currently established EGFR-tyrosine kinase inhibitors from the first to fourth generation, including their action mechanisms, acquired resistance, and clinical applications, and potential challenges and perspectives that current researchers should address.

4.
Biotech Histochem ; : 1-7, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32067515

RESUMO

Acute liver injury can be caused by chemicals and can lead to liver failure. We investigated the protective effect of helicid (HEL) on acute liver injury caused by CCl4 in mice. We found that ALT and AST levels as well as hepatic pathological damage in mice treated with CCl4 was increased significantly, while the effects were decreased by HEL treatment. HEL treatment increased the activity of T-SOD, GSH and CAT and reduced the level of MDA in CCl4 treated mice. HEL improved the histopathology of liver caused by CCl4. HEL also reduced TNF-α, IL-1ß and IL- 6 activity caused by CCl4. We investigated the phosphorylation of p65 and IκB protein and found that HEL can alleviate liver damage via the NF-κB signaling pathway. Our findings indicate that HEL protects against acute liver injury induced by CCl4. The protective effect of HEL appears to be due to its antioxidative and anti-inflammatory properties through the NF-κB signaling pathway.

5.
J Neurosurg ; : 1-9, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31978878

RESUMO

OBJECTIVE: Mechanical thrombectomy is effective in acute ischemic stroke secondary to emergent large-vessel occlusion, but optimal efficacy is contingent on fast and complete recanalization. First-pass recanalization does not occur in the majority of patients. The authors undertook this study to determine if anatomical parameters of the intracranial vessels impact the likelihood of first-pass complete recanalization. METHODS: The authors retrospectively evaluated data obtained in 230 patients who underwent mechanical thrombectomy for acute ischemic stroke secondary to large-vessel occlusion at their institution from 2016 to 2018. Eighty-six patients were identified as having pure M1 occlusions, and 76 were included in the final analysis. The authors recorded and measured clinical and anatomical parameters and evaluated their relationships to the first-pass effect. RESULTS: The first-pass effect was achieved in 46% of the patients. When a single device was employed, aspiration thrombectomy was more effective than stent retriever thrombectomy. A larger M1 diameter (p = 0.001), decreased vessel diameter tapering between the petrous segment of the internal carotid artery (ICA) and M1 (p < 0.001), and distal collateral grading (p = 0.044) were associated with first-pass recanalization. LASSO (least absolute shrinkage and selection operator) was used to generate a predictive model for recanalization using anatomical variables. CONCLUSIONS: The authors demonstrated that a larger M1 vessel diameter, low rate of vessel diameter tapering along the course of the intracranial ICA, and distal collateral status are associated with first-pass recanalization for patients with M1 occlusions.

6.
Drug Metab Dispos ; 48(3): 217-229, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31911485

RESUMO

Alisertib (MLN8237) is an investigational, orally available, selective aurora A kinase inhibitor in clinical development for the treatment of solid tumors and hematologic malignancies. This metabolic profiling analysis was conducted as part of a broader phase 1 study evaluating mass balance, pharmacokinetics, metabolism, and routes of excretion of alisertib following a single 35-mg dose of [14C]alisertib oral solution (∼80 µCi) in three patients with advanced malignancies. On average, 87.8% and 2.7% of the administered dose was recovered in feces and urine, respectively, for a total recovery of 90.5% by 14 days postdose. Unchanged [14C]alisertib was the predominant drug-related component in plasma, followed by O-desmethyl alisertib (M2), and alisertib acyl glucuronide (M1), which were present at 47.8%, 34.6%, and 12.0% of total plasma radioactivity. In urine, of the 2.7% of the dose excreted, unchanged [14C]alisertib was a negligible component (trace), with M1 (0.84% of dose) and glucuronide conjugate of hydroxy alisertib (M9; 0.66% of dose) representing the primary drug-related components in urine. Hydroxy alisertib (M3; 20.8% of the dose administered) and unchanged [14C]alisertib (26.3% of the dose administered) were the major drug-related components in feces. In vitro, oxidative metabolism of alisertib was primarily mediated by CYP3A. The acyl glucuronidation of alisertib was primarily mediated by uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A3, and 1A8 and was stable in 0.1 M phosphate buffer and in plasma and urine. Further in vitro evaluation of alisertib and its metabolites M1 and M2 for cytochrome P450-based drug-drug interaction (DDI) showed minimal potential for perpetrating DDI with coadministered drugs. Overall, renal elimination played an insignificant role in the disposition of alisertib, and metabolites resulting from phase 1 oxidative pathways contributed to >58% of the alisertib dose recovered in urine and feces over 192 hours postdose. SIGNIFICANCE STATEMENT: This study describes the primary clearance pathways of alisertib and illustrates the value of timely conduct of human absorption, distribution, metabolism, and excretion studies in providing guidance to the clinical pharmacology development program for oncology drugs, for which a careful understanding of sources of exposure variability is crucial to inform risk management for drug-drug interactions given the generally limited therapeutic window for anticancer drugs and polypharmacy that is common in cancer patients.

7.
Nat Cell Biol ; 21(12): 1604-1614, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31792381

RESUMO

TANK-binding kinase 1 (TBK1) responds to microbial stimuli and mediates the induction of type I interferon (IFN). Here, we show that TBK1 is also a central mediator of growth factor signalling; this function of TBK1 relies on a specific adaptor-TBK-binding protein 1 (TBKBP1). TBKBP1 recruits TBK1 to protein kinase C-theta (PKCθ) through a scaffold protein, CARD10. This enables PKCθ to phosphorylate TBK1 at Ser 716, a crucial step for TBK1 activation by growth factors but not by innate immune stimuli. Although the TBK1-TBKBP1 signalling axis is not required for the induction of type I IFN, it mediates mTORC1 activation and oncogenesis. Conditional deletion of either TBK1 or TBKBP1 in lung epithelial cells inhibits tumourigenesis in a mouse model of lung cancer. In addition to promoting tumour growth, the TBK1-TBKBP1 axis facilitates tumour-mediated immunosuppression through a mechanism that involves induction of the checkpoint molecule PD-L1 and stimulation of glycolysis. These findings suggest a PKCθ-TBKBP1-TBK1 growth factor signalling axis that mediates both tumour growth and immunosuppression.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinogênese/genética , Tolerância Imunológica/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/genética , Células A549 , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Células Cultivadas , Células Epiteliais/patologia , Células HEK293 , Humanos , Imunidade Inata/genética , Interferon Tipo I/genética , Pulmão/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL
9.
Opt Express ; 27(16): 23173-23185, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31510600

RESUMO

Two-dimensional phase unwrapping algorithms are widely used in optical metrology and measurements. The high noise from interference measurements, however, often leads to the failure of conventional phase unwrapping algorithms. In this paper, we propose a deep convolutional neural network (DCNN) based method to perform rapid and robust two-dimensional phase unwrapping. In our approach, we employ a DCNN architecture, DeepLabV3+, with noise suppression and strong feature representation capabilities. The employed DCNN is first used to perform semantic segmentation to obtain the segmentation result of the wrapped phase map. We then combine the wrapped phase map with the segmentation result to generate the unwrapped phase. We benchmarked our results by comparing them with well-established methods. The reported approach out-performed the conventional path-dependent and path-independent algorithms. We also tested the robustness of the reported approach using interference measurements from optical metrology setups. Our results, again, clearly out-performed the conventional phase unwrap algorithms. The reported approach may find applications in optical metrology and microscopy imaging.

11.
Br J Clin Pharmacol ; 85(11): 2568-2579, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31355467

RESUMO

AIMS: A population pharmacokinetic (PK) analysis was conducted to quantify the impact of patient-specific and concurrent medication factors on pevonedistat PK. METHODS: Data were pooled from 6 clinical studies consisting of 335 patients with solid tumours or haematological malignancies administered pevonedistat alone or in combination with azacitidine, docetaxel, carboplatin + paclitaxel, or gemcitabine. Model development and covariate analysis followed standard methods. Parameters and bootstrap 95% confidence intervals were estimated using nonlinear mixed-effects modelling. The final model was evaluated using visual predictive checks and other goodness-of-fit criteria. RESULTS: A linear 2-compartment model best described pevonedistat PK. The final model included the effect of body surface area (BSA) on clearance (CL and Q) and volume of distribution of pevonedistat, effect of concomitantly administered carboplatin + paclitaxel on CL, and effect of albumin on Q. Race, sex, age, tumour type (haematological vs solid), mild or moderate renal impairment (creatinine clearance ≥30 mL/min), or mild hepatic impairment, had no impact on pevonedistat PK. CONCLUSIONS: The clinical PK profile of pevonedistat is comparable in patients with solid tumours or haematological malignancies. All PK parameters exhibited ≥20% change over the observed BSA range (1.38-3 m2 ) with CL ranging from 75.5 to 208% of the reference value, with simulations supporting BSA-based dosing to minimize interindividual variability in drug exposures. Concurrent administration of carboplatin + paclitaxel decreased pevonedistat CL by approximately 44%, while coadministration with azacitidine, gemcitabine or docetaxel did not alter pevonedistat CL. No other factors were identified as influencing pevonedistat PK.

12.
World Neurosurg ; 130: e1061-e1069, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31323408

RESUMO

BACKGROUND: Patients with hematologic disorders who present with subdural hematomas (SDH) present a surgical decision-making challenge. Because of intrinsic coagulopathy, platelet dysfunction, and immunosuppression, surgical intervention poses a unique set of risks. OBJECTIVE: To describe a clinical sample of patients with hematologic disorders and concurrent SDH, to compare baseline and outcome variables, including complication rates and survival, in surgical versus nonsurgical management, and to identify clinical variables that may predict outcomes. METHODS: A 12-year retrospective case-control study was carried out of 50 adult patients with hematologic malignancies and SDH. Patients underwent surgical evacuation for SDH. Controls did not. Outcomes included discharge disposition, Glasgow Outcome Scale score, 30-day mortality, and overall survival. Complications included seizure, reoperation, and readmission. A Fisher exact test or χ2 analysis compared categorical variables; continuous outcomes were compared with a Student t test. A Kaplan-Meier survival analysis was performed and multivariable Cox logistic regression evaluated variables associated with overall mortality. RESULTS: Surgical and nonsurgical groups differed only by Glasgow Coma Scale score, with slightly lower Glasgow Coma Scale scores in the surgical group. Complication rates did not differ; however, the 30-day reoperation rate was 35% for the surgical cohort. Overall, seizure incidence was 18%, readmission was 30%, 30-day mortality was 38%, median survival was 140.5 days, and 75% had a Glasgow Outcome Scale score of 1-3 at censorship. Increased age, low hemoglobin levels, and low platelet levels were associated with increased risk of mortality. CONCLUSIONS: Low platelet and hemoglobin levels are consistent markers of poor prognosis and surgical intervention, either as a proxy of or as a cause for clinical deterioration, is associated with increased mortality risk.


Assuntos
Gerenciamento Clínico , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Hematoma Subdural/epidemiologia , Hematoma Subdural/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Neoplasias Hematológicas/diagnóstico , Hematoma Subdural/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
13.
Nat Immunol ; 20(7): 879-889, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31182807

RESUMO

CD8+ T cells and natural killer (NK) cells are central cellular components of immune responses against pathogens and cancer, which rely on interleukin (IL)-15 for homeostasis. Here we show that IL-15 also mediates homeostatic priming of CD8+ T cells for antigen-stimulated activation, which is controlled by a deubiquitinase, Otub1. IL-15 mediates membrane recruitment of Otub1, which inhibits ubiquitin-dependent activation of AKT, a kinase that is pivotal for T cell activation and metabolism. Otub1 deficiency in mice causes aberrant responses of CD8+ T cells to IL-15, rendering naive CD8+ T cells hypersensitive to antigen stimulation characterized by enhanced metabolic reprograming and effector functions. Otub1 also controls the maturation and activation of NK cells. Deletion of Otub1 profoundly enhances anticancer immunity by unleashing the activity of CD8+ T cells and NK cells. These findings suggest that Otub1 controls the activation of CD8+ T cells and NK cells by functioning as a checkpoint of IL-15-mediated priming.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cisteína Endopeptidases/metabolismo , Interleucina-15/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Cisteína Endopeptidases/deficiência , Enzimas Desubiquitinantes/metabolismo , Modelos Animais de Doenças , Metabolismo Energético , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Interleucina-15/genética , Melanoma Experimental , Camundongos , Camundongos Transgênicos , Ligação Proteica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Interleucina-15/metabolismo , Tolerância a Antígenos Próprios/genética , Tolerância a Antígenos Próprios/imunologia , Transdução de Sinais , Especificidade do Receptor de Antígeno de Linfócitos T , Ubiquitinação
14.
Nanoscale ; 11(22): 10684-10694, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31120086

RESUMO

The applications of two-dimensional transition metal dichalcogenides (2D TMDCs) pose an increased risk to both the environment and human health. Due to the large surface area of 2D nanosheets, they often form multi-layered nanoclusters of various thicknesses in aqueous solution. In this work, we address the safety issue of 2D TMDCs with focus on the cellular effects of the thickness of WS2 nanosheets. At a very low and non-lethal concentration (4 cm2 mL-1 or 25 µg mL-1), 4-layered WS2 nanosheets (WS2-4) were primarily bound to the cell surface with less internalization, while 30-layered WS2 nanosheets (WS2-30) were mostly internalized by human bronchial epithelial cells. Although the cellular interactions at this low concentration caused no alterations in the cell cycle, apoptosis, necrosis and cytotoxicity, cell autophagy was induced in both cases through mTOR-dependent pathways by perturbing a number of signaling molecules, such as amyloid precursor protein (APP) and cysteine-X-cysteine chemokine receptor 4 (CXCR-4). The finding of activation of cell autophagy from both outside and inside of cells reveals a novel feature of biological perturbations by 2D nanosheets. This finding will help in the formulation of general guidelines for the safe application of 2D nanomaterials.


Assuntos
Autofagia , Células Epiteliais/metabolismo , Nanoestruturas/química , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular , Células Epiteliais/citologia , Humanos
15.
Cell Res ; 29(6): 474-485, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31086255

RESUMO

NF-κB, a family of transcription factors regulating diverse biological processes including immune responses, is activated by canonical and noncanonical pathways based on degradation of IκBα and processing of the IκB-like protein p100, respectively. Although p100 responds to noncanonical NF-κB stimuli for processing, it does not undergo degradation, but rather becomes accumulated, along with canonical NF-κB activation. We show here that the stability of p100 is tightly controlled by a deubiquitinase, Otub1. Otub1 deficiency not only promotes signal-induced p100 processing and noncanonical NF-κB activation but also causes steady-state p100 degradation, leading to aberrant NF-κB activation in the canonical pathway. B-cell-conditional deletion of Otub1 results in B-cell hyperplasia, antibody hyper-production, and lupus-like autoimmunity. Otub1-deficient B cells display aberrantly activated phenotypes and overproduce the cytokine IL-6, contributing to autoimmunity induction. Thus, maintenance of p100 stability by Otub1 serves as an unusual mechanism of NF-κB regulation that prevents autoimmunity.

16.
Aesthetic Plast Surg ; 43(4): 1044-1053, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31093710

RESUMO

OBJECTIVE: To establish botulinum toxin-A (BTX-A) rejuvenation as an innovative technique to treat facial sagging with descent of the mid and lower face in Asian females. METHODS: Between March 2016 and March 2017, 512 female patients with facial sagging were treated with regional platysma BTX-A injection. Droplet injection into the dermis was performed. Among the patients, 192 were recruited into our retrospective study. Eligible patients were divided into a pre-senile group (28-39 years old) and a senile group (> 40 years old). We analyzed the patient/physician-graded improvement, the mean scores of the 5-point improvement scale, and any reported complications. RESULTS: The overall degree of both patient- and physician-graded mid-face aesthetic improvement was very high. Improvement ratings reached 97.92% for patients and 94.79% for physicians. Improvement ratings were significantly greater in the pre-senile group compared to the senile group (p < 0.001), suggesting that the pre-senile patients were more satisfied with their improvement. Moreover, the percent of patients who reported as "much improved" was significantly higher than the percent of physicians (p < 0.05), suggesting that patients felt more positively about their aesthetic results than the physicians. No severe side effects were reported. CONCLUSIONS: Our results demonstrated that regional BTX-A injection in the dermis for the purpose of aesthetical platysma rejuvenation is safe and effective in patients with facial sagging with descent of the mid and lower face. Specifically, regional platysma injections of BTX-A (BTX-A rejuvenation) can correct descent of the mid and lower face in Asian females, demonstrating clinical utility of this treatment strategy. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

17.
J Neurooncol ; 143(2): 349-357, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30989622

RESUMO

PURPOSE: Gliosarcoma is characterized by the World Health Organization as a Grade IV malignant neoplasm and a variant of glioblastoma. The association of race and ethnicity with survival has been established for numerous CNS malignancies, however, no epidemiological studies have reported these findings for patients with gliosarcoma. The aim of this study was to examine differences by race and ethnicity in overall survival, 30-day mortality, 90-day mortality, and 30-day readmission. METHODS: Data were obtained by query of the National Cancer Database (NCDB) for years 2004-2014. Patients with gliosarcoma were identified by International Classification of Diseases for Oncology, Third Edition (ICD-O-3)-Oncology morphologic code 9442/3 and topographical codes C71.0-C71.9. Differences in survival by race/ethnicity were examined using univariable and multivariable Cox proportional hazards models. Readmission and mortality outcomes were examined with univariable and multivariable logistic regression. RESULTS: A total of 1988 patients diagnosed with gliosarcoma were identified (White Non-Hispanic n = 1,682, Black Non-Hispanic n = 165, Asian n = 40, Hispanic n = 101). There were no differences in overall survival, 30- and 90-day mortality, or 30-day readmission between the races and ethnicities examined. Median survival was 10.4 months for White Non-Hispanics (95% CI 9.8, 11.2), 10.2 months for Black Non-Hispanics (95% CI 8.6, 13.1), 9.0 months for Asian Non-Hispanics (95% CI 5.1, 18.2), and 10.6 months for Hispanics (95% CI 8.3,16.2). 7.3% of all patients examined had an unplanned readmission within 30 days. CONCLUSION: Race/ethnicity are not associated with differences in overall survival, 30-day mortality, 90-day mortality, or 30-day readmission following surgical intervention for gliosarcoma.


Assuntos
Grupos de Populações Continentais/estatística & dados numéricos , Bases de Dados Factuais , Grupos Étnicos/estatística & dados numéricos , Gliossarcoma/etnologia , Gliossarcoma/mortalidade , Procedimentos Neurocirúrgicos/mortalidade , Readmissão do Paciente/estatística & dados numéricos , Feminino , Seguimentos , Gliossarcoma/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
18.
J Clin Pharmacol ; 59(9): 1204-1215, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30985952

RESUMO

This clinical trial was designed to evaluate the effect of moderate or severe hepatic impairment on the single-dose pharmacokinetics (PK) of the investigational anticancer agent, alisertib, in adult patients with advanced solid tumors or lymphoma. Patients with normal hepatic function (total bilirubin and alanine transaminase [ALT] ≤ upper limit of normal [ULN]), moderate hepatic impairment (1.5 × ULN < total bilirubin ≤ 3 × ULN, with any ALT) or severe hepatic impairment (total bilirubin > 3 × ULN, with any ALT), received a single 50-mg oral dose of alisertib. Blood samples for PK were collected up to 168 hours postdose. Predose samples were also used to assess alisertib plasma protein binding. Patients could continue to receive alisertib for 7 days in 21-day cycles (50, 30, or 10 mg twice daily for normal hepatic function, moderate hepatic impairment, and severe hepatic impairment, respectively). Alisertib was approximately 99% protein bound in all hepatic function groups. Alisertib exposure was similar in moderate and severe hepatic impairment groups, but higher than the normal hepatic function group. The geometric least-squares mean ratios (90% confidence intervals) for unbound alisertib area under the curve extrapolated to infinity for moderate/severe impairment groups versus the normal hepatic function group was 254% (184%, 353%). Patients with moderate or severe hepatic impairment have approximately 150% higher unbound alisertib exposures compared with patients with normal hepatic function. An approximately 60% reduction of the starting dose of alisertib in patients with moderate/severe hepatic impairment is recommended based on pharmacokinetic considerations.

19.
Taiwan J Obstet Gynecol ; 58(2): 218-222, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30910142

RESUMO

OBJECTIVE: The purpose of this study was to observe the efficacy of Danefukang (DEFK) soft extract for the treatment of symptoms associated with endometriosis, and its effect on quality of life, the Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS) scores, and on levels of carbohydrate antigen (CA)-125, tumor necrosis factor (TNF)-α, and interleukin (IL)-6. MATERIALS AND METHODS: A total of 174 patients with endometriosis treated from January 2010 to December 2013 were randomly divided into a control group treated with mifepristone (n = 87) or DEFK (n = 87). Both groups were treated for 3 months. Symptoms, quality of life, SAS, SD scores, and levels of CA-125, TNF-α, and IL-6 were evaluated before and after treatment. RESULTS: The effectiveness rate was 93.10% in the DEFK group and 81.61% in the mifepristone control group (χ2 = 4.215, P < 0.05). Treatment with DEFK resulted in a greater improvement in quality of life, SDS, and SAS scores compared with mifepristone (all, P < 0.05). DEFK treatment also resulted in a greater decrease of CA-125, TNF-α, and IL-6 levels compared with mifepristone (all, P < 0.05). CONCLUSION: Based on the current results - improved symptoms, attenuated depression and anxiety, and reduced the levels of pro-inflammatory cytokines and CA-125 -treatment with DEFK is a meaningful option for patients with endometriosis. DEFK fills an unmet need in the pharmacologic treatment of endometriosis.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Endometriose/tratamento farmacológico , Qualidade de Vida , Ansiedade/complicações , Ansiedade/diagnóstico , Biomarcadores/sangue , Antígeno Ca-125/sangue , Estudos de Casos e Controles , Depressão/complicações , Depressão/diagnóstico , Endometriose/complicações , Endometriose/psicologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-6/sangue , Índice de Gravidade de Doença , Inquéritos e Questionários , Fator de Necrose Tumoral alfa/sangue
20.
Br J Clin Pharmacol ; 85(7): 1464-1473, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30845347

RESUMO

AIMS: This phase I study evaluated the effects of the moderate cytochrome P450 (CYP) 3A inhibitor fluconazole and the strong CYP3A/P-glycoprotein (P-gp) inhibitor itraconazole on the pharmacokinetics of the investigational neural precursor cell expressed, developmentally downregulated 8 (NEDD8)-activating enzyme inhibitor pevonedistat in patients with advanced solid tumours. METHODS: Patients received single doses of intravenous pevonedistat 8 mg m-2 , alone and with fluconazole (loading: 400 mg; maintenance: 200 mg once daily), or pevonedistat 8, 15 or 20 mg m-2 , alone and with itraconazole 200 mg once daily. Serial blood samples for pevonedistat pharmacokinetics were obtained pre- and post-infusion on days 1 (alone) and 8 (with fluconazole/itraconazole). After completing the pharmacokinetic portion, patients remaining on study received pevonedistat with docetaxel or carboplatin and paclitaxel. RESULTS: The ratios of geometric mean area under the concentration-time curves (n; 90% confidence interval) of pevonedistat in the presence vs. absence of fluconazole or itraconazole were 1.11 (12; 1.03-1.19) and 1.14 (33; 1.07-1.23), respectively. Fifty patients (98%) experienced at least one adverse event (AE), with maximum severity of grade 1-2 in 28 patients (55%) and of grade ≥3 in 22 patients (43%). The most common drug-related AEs were vomiting (12%), diarrhoea (10%) and nausea (8%). No new safety findings were observed for pevonedistat. CONCLUSIONS: Fluconazole or itraconazole had insignificant effects on pevonedistat pharmacokinetics, indicating minor contributions of CYP3A/P-gp to pevonedistat clearance. The safety profile of single doses of pevonedistat plus steady-state fluconazole or itraconazole was consistent with prior clinical experience, with no new safety signals observed.

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