RESUMO
BACKGROUND: Patients may use crowdfunding to solicit donations, typically from multiple small donors using internet-based means, to offset the financial toxicity of cancer care. OBJECTIVE: To describe crowdfunding campaigns by gynecologic cancer patients and to compare campaign characteristics and needs expressed between patients with cervical, uterine, and ovarian cancer. STUDY DESIGN: We queried the public crowdfunding forum GoFundMe.com for "cervical cancer," "uterine cancer," and "ovarian cancer." The first 200 consecutive posts for each cancer type fundraising within the United States were analyzed. Data on campaign goals and needs expressed were manually extracted. Descriptive statistics and bivariate analyses were performed. RESULTS: Among the 600 fundraising pages, the median campaign goal was $10,000 [IQR $5000-$23,000]. Campaigns raised a median of 28.6% of their goal with only 8.7% of campaigns reaching their goal after a median of 54 days online. On average, ovarian cancer campaigns had higher monetary goals, more donors, and larger donation amounts than cervical cancer campaigns and raised more money than both cervical and uterine cancer campaigns. Campaigns were fundraising to support medical costs (80-85%) followed by lost wages (36-56%) or living expenses (27-41%). Cervical cancer campaigns reported need for non-medical costs more frequently than uterine or ovarian cancer campaigns. States without Medicaid expansions (31% of the national population) were over-represented among cervical cancer and uterine cancer, but not ovarian cancer campaigns. CONCLUSIONS: Crowdfunding pages reveal patients fundraising for out-of-pocket costs in the thousands of dollars and a wide range of unmet financial needs based on cancer type.
Assuntos
Obtenção de Fundos , Neoplasias dos Genitais Femininos , Humanos , Feminino , Obtenção de Fundos/economia , Neoplasias dos Genitais Femininos/economia , Neoplasias dos Genitais Femininos/terapia , Estados Unidos , Crowdsourcing/economia , Neoplasias do Colo do Útero/economia , Neoplasias do Colo do Útero/terapia , Neoplasias Ovarianas/economia , Neoplasias Ovarianas/terapiaRESUMO
OBJECTIVE: To identify correlations between disease recurrence and adherence to NCCN posttreatment surveillance guidelines in patients who develop recurrent uterine cancer. METHODS: Retrospective analysis identified patients (n = 60) with recurrent uterine cancer and at least one surveillance visit with a gynecologic oncologist between 2011 and 2020. Adherence to NCCN guidelines and details of recurrence were recorded. RESULTS: Recurrent uterine cancer was identified in 60 patients with an average time to recurrence (TTR) of 25 months. Of those, 39 (65%) were adherent to NCCN surveillance guidelines and 36 (60%) were symptomatic at the time of recurrence diagnosis. Asymptomatic recurrence was diagnosed by imaging in 11 (46%), physical exam in 7 (29%), and blood work in 6 (25%) patients. Patients who were adherent to NCCN guidelines were diagnosed with recurrence on average 11 months earlier (p = 0.0336). Adherence was an independent predictor of TTR for all patients regardless of symptoms. There was no significant effect of age, race, primary language, or stage of disease on adherence. CONCLUSION: Adherence to NCCN posttreatment surveillance guidelines for uterine cancer is independently associated with an earlier diagnosis of recurrence.
Assuntos
Neoplasias do Endométrio , Neoplasias Uterinas , Humanos , Feminino , Estudos Retrospectivos , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/terapia , Fidelidade a DiretrizesRESUMO
OBJECTIVE: To determine whether Black race is associated with treatment and survival among women with low-risk endometrial cancer. METHODS: Black and White women with Stage IA grade 1-2 endometrioid endometrial carcinoma diagnosed from 2010 to 2016 in the SEER 18 dataset were identified (n = 23,431), and clinical and socioeconomic attributes obtained. Five-year cancer-specific survival (CSS) and relative survival (RS) were calculated using SEER*Stat 8.3.9. Cox proportional hazards model was used to determine predictors of overall survival (OS) and CSS. RESULTS: There was a significantly higher proportion of Black women who did not have surgery compared to White women (3% vs 1%, respectively; p < 0.0001). Residing in the South, being insured with Medicaid, and residing in a county with low median income were also associated with non-receipt of surgery. Black women remained less likely to undergo hysterectomy on multivariable analysis (OR 0.44, 95% CI 0.32-0.60). Non-receipt of hysterectomy was predictive of decreased CSS (HR 0.14, 95% CI 0.09-0.21) and OS (HR 0.18, 95% 0.14-0.23) on adjusted analysis. Black race was also an independent predictor of increased cancer-specific death (HR 2.07, 95% CI 1.50-2.86) as well as death from any cause (HR 1.74, 95% CI 1.44-2.09) on adjusted analysis. CONCLUSIONS: Black women with low-risk endometrial cancer were less likely to undergo hysterectomy and experienced decreased survival relative to White women. Further investigation is warranted to better understand the socioeconomic, geographic, and biologic factors that influence this disparity.
Assuntos
Negro ou Afro-Americano , Carcinoma Endometrioide , Neoplasias do Endométrio , Disparidades em Assistência à Saúde , Histerectomia , Brancos , Feminino , Humanos , Neoplasias do Endométrio/etnologia , Neoplasias do Endométrio/mortalidade , Neoplasias do Endométrio/patologia , Neoplasias do Endométrio/cirurgia , Histerectomia/estatística & dados numéricos , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Estados Unidos/epidemiologia , Carcinoma Endometrioide/etnologia , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Programa de SEER , Disparidades em Assistência à Saúde/etnologia , Disparidades em Assistência à Saúde/estatística & dados numéricosRESUMO
Despite huge promises, bioanalysis of protein biomarkers in formalin-fixed paraffin-embedded (FFPE) tissues by liquid chromatography-tandem mass spectrometry (LC-MS/MS) for clinical applications is still very challenging. Here, we describe a sensitive and robust LC-MS/MS assay to quantify clinical protein biomarkers in FFPE tumor sections using automated antipeptide antibody immunocapture followed by in-sample calibration curve (ISCC) strategy with multiple isotopologue reaction monitoring (MIRM) technique. ISCC approach with MIRM of stable isotopically labeled (SIL) peptides eliminated the need for authentic matrices for external calibration curves, overcame the matrix effects, and validated the quantification range in each individual sample. Specifically, after deparaffinization, rehydration, antigen retrieval, and homogenization, the protein analytes in FFPE tumor tissues were spiked with a known concentration of one SIL peptide for each analyte, followed by trypsin digestion and antipeptide immunocapture enrichment prior to MIRM-ISCC-based LC-MS/MS analysis. This approach has been successfully used for sensitive quantification of programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) in 15 representative FFPE tumor samples from lung, colorectal, and head and neck cancer patients. Except for one sample, PD-L1 and PD-1 in all samples were quantifiable using this assay with concentrations of 27.85-798.43 (amol/µg protein) for PD-L1 and 16.96-129.89 (amol/µg protein) for PD-1. These results were generally in agreement with the immunohistochemistry (IHC) data but with some exceptions. This approach demonstrated the feasibility to quantify low abundant protein biomarkers in FFPE tissues with improved sensitivity, specificity, and robustness and showed great potential as an orthogonal analytical approach to IHC for clinical applications.
Assuntos
Biomarcadores Tumorais/análise , Cromatografia Líquida/métodos , Neoplasias/patologia , Inclusão em Parafina , Peptídeos/imunologia , Espectrometria de Massas em Tandem/métodos , Fixação de Tecidos , Calibragem , Formaldeído , Humanos , Limite de Detecção , Neoplasias/metabolismoRESUMO
We report a novel immunocapture (IC)-LC-MS/MS methodology to directly measure real time in vivo receptor occupancy (RO) for a covalent binding drug in blood lysate. A small molecule quencher was added immediately after sample collection to convert the free receptor to a quencher-bound receptor (QB-R) which was measured with the drug-bound receptor (DB-R) simultaneously by LC-MS/MS after immunocapture enrichment, followed by trypsin digestion. Addition of the quencher is necessary to prevent the free receptor from ex vivo binding with the drug. The real time RO was calculated based on the concentrations of DB-R and the free receptor (which is now QB-R) that were obtained from each sample. This strategy has been successfully applied to the measurement of the RO for Bruton's tyrosine kinase (BTK) in the blood lysate of monkeys after dosing with branebrutinib (BMS-986195), a covalent BTK inhibitor being evaluated to treat rheumatoid arthritis. A custom-made quencher, which is more reactive to BTK than branebrutinib, was added in excess amount to bind with all available free BTK to form quencher-bound BTK (QB-BTK) during blood sample collection. To measure a wide range of % BTK RO, including those of <5% or >95%, the required LLOQ at 0.125 nM for QB-BTK and 0.250 nM for drug-bound BTK (DB-BTK) in blood lysate were successfully achieved by using this IC-LC-MS/MS strategy. This proof-of-concept assay demonstrated its suitability with high throughput for real time in vivo BTK RO measurement as a pharmacodynamic (PD) biomarker for clinical drug development.
Assuntos
Tirosina Quinase da Agamaglobulinemia/metabolismo , Anticorpos Imobilizados/imunologia , Biomarcadores/metabolismo , Cromatografia Líquida/métodos , Inibidores de Proteínas Quinases/metabolismo , Receptores de Droga/metabolismo , Espectrometria de Massas em Tandem/métodos , Tirosina Quinase da Agamaglobulinemia/imunologia , Animais , Anticorpos Imobilizados/metabolismo , Bioensaio , Macaca fascicularisRESUMO
AIMS/HYPOTHESIS: This multicentre randomised double-blind placebo-controlled clinical trial assessed the efficacy and safety of a methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib, in individuals with obesity (BMI ≥30 kg/m2) and type 2 diabetes (HbA1c 53-97 mmol/mol [7-11%] and fasting glucose <15.6 mmol/l). METHODS: Participants were randomised (via a centralised interactive web response system) to placebo, 1.2 or 1.8 mg beloranib s.c. twice weekly for 26 weeks. Participants, investigators and the sponsor were blinded to group assignment. The primary endpoint was the change in weight from baseline to week 26. The trial was terminated early when beloranib development was stopped because of an imbalance of venous thromboembolism events in beloranib-treated individuals vs placebo that became evident during late-stage development of the drug. RESULTS: In total, 153 participants were randomised, 51 to placebo, 52 to 1.2 mg beloranib and 50 to 1.8 mg beloranib. In participants who completed week 26, the least squares mean ± SE weight change (baseline 111 kg) was -3.1 ± 1.2% with placebo (n = 22) vs -13.5 ± 1.1% and -12.7 ± 1.3% with 1.2 and 1.8 mg beloranib, respectively (n = 25; n = 19; p < 0.0001). The change in HbA1c (baseline 67 mmol/mol [8.3%]) was -6.6 ± 2.2 mmol/mol (-0.6 ± 0.2%) with placebo vs -21.9 ± 2.2 mmol/mol (-2.0 ± 0.2%) or -21.9 ± 3.3 mmol/mol (-2.0 ± 0.3%) with 1.2 or 1.8 mg beloranib (p < 0.0001), respectively. The most common beloranib adverse events were sleep related. One beloranib-treated participant experienced a non-fatal pulmonary embolism. CONCLUSIONS/INTERPRETATION: MetAP2 inhibitors represent a novel mechanism for producing meaningful weight loss and improvement in HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov NCT02324491 FUNDING: The study was funded by Zafgen, Inc.
Assuntos
Aminopeptidases/antagonistas & inibidores , Cinamatos/uso terapêutico , Cicloexanos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Compostos de Epóxi/uso terapêutico , Metaloendopeptidases/antagonistas & inibidores , Sesquiterpenos/uso terapêutico , Adolescente , Adulto , Idoso , Aminopeptidases/metabolismo , Fármacos Antiobesidade/uso terapêutico , Glicemia/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Glucose/metabolismo , Hemoglobinas Glicadas/metabolismo , Glicoproteínas , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metaloendopeptidases/metabolismo , Metionil Aminopeptidases , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Redução de Peso/efeitos dos fármacos , Adulto JovemRESUMO
AIMS: Methionine aminopeptidase 2 (MetAP2) inhibition has been shown to result in significant weight loss and improved glucose control. This Phase 1 clinical trial assessed the safety and tolerability, pharmacokinetics and preliminary efficacy of a novel MetAP2 inhibitor, ZGN-1061. METHODS: This clinical trial included a single ascending dose (SAD) phase in healthy subjects (BMI, 23 to <30 kg/m2 ) and a multiple ascending dose (MAD) phase in otherwise healthy subjects (BMI, 27 to 40 kg/m2 ). SAD phase doses, administered subcutaneously (SC), were 0.2, 0.6, 1.2, 2.4, 3.6 and 4.8 mg and the MAD phase evaluated doses of 0.2, 0.6 and 1.8 mg twice weekly SC for 4 weeks. RESULTS: The SAD phase included 39 subjects (ZGN-1061, N = 28; placebo, N = 11); 90% were male and BMI was 26.4 kg/m2 . ZGN-1061 was well tolerated across all doses, with the most frequent adverse events being mild headache and procedural-related irritation. There were no severe or serious adverse events. All doses of ZGN-1061 were rapidly absorbed and cleared, resulting in short duration of exposure that is anticipated to minimize potential off-drug target risks. The MAD phase included 29 subjects (ZGN-1061, N = 22; placebo, N = 7); 76% were male and BMI was 33.5 kg/m2 . Safety observations were consistent with SAD findings. Efficacy measures in the MAD phase indicated trends for weight change (-1.5 kg total ZGN-1061 vs -0.2 kg placebo) and other biomarker changes. CONCLUSIONS: ZGN-1061 was well tolerated with no safety signals in all doses tested. In addition, the desired pharmacokinetic profile and preliminary efficacy observations with ZGN-1061 support evaluation in larger and longer clinical trials.
Assuntos
Aminopeptidases/antagonistas & inibidores , Fármacos Antiobesidade/administração & dosagem , Azetidinas/administração & dosagem , Drogas em Investigação/administração & dosagem , Glicoproteínas/antagonistas & inibidores , Morfolinas/administração & dosagem , Obesidade/tratamento farmacológico , Sobrepeso/tratamento farmacológico , Inibidores de Proteases/administração & dosagem , Absorção Fisiológica , Adulto , Aminopeptidases/metabolismo , Fármacos Antiobesidade/efeitos adversos , Fármacos Antiobesidade/farmacocinética , Azetidinas/efeitos adversos , Azetidinas/farmacocinética , Biomarcadores/sangue , Biomarcadores/urina , Índice de Massa Corporal , Estudos de Coortes , Relação Dose-Resposta a Droga , Método Duplo-Cego , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Feminino , Seguimentos , Glicoproteínas/metabolismo , Meia-Vida , Humanos , Injeções Subcutâneas , Masculino , Taxa de Depuração Metabólica , Metionil Aminopeptidases , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Obesidade/sangue , Obesidade/metabolismo , Obesidade/urina , Sobrepeso/sangue , Sobrepeso/metabolismo , Sobrepeso/urina , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacocinética , Redução de Peso/efeitos dos fármacos , Adulto JovemRESUMO
Clostridium difficile infection (CDI) is a major cause of nosocomial diarrhea with the potential for significant morbidity and mortality. Colonization in a susceptible individual, with risk factors such as prior antibiotic use, advanced age, or medical comorbidities, may result in symptomatic infection. Although patients with a gynecologic malignancy may be at a higher risk of developing CDI due to an increased likelihood of having one or more risk factors, data do not consistently support the idea that chemotherapy or cancer itself are independently associated with CDI. For diagnosis of CDI, we recommended using a multi-step approach, with a highly sensitive initial rapid test such as the enzyme immunoassay (EIA) for glutamate dehydrogenase (GDH) or nucleic acid amplification testing (NAAT), followed by confirmatory testing with of the above two tests or EIA toxin A/B, which has high specificity. Treatment varies based on the severity of disease. We recommend vancomycin as first-line therapy for an initial episode of mild/moderate or severe CDI, with consideration of fidaxomicin for patients at particularly high risk for recurrence. Rectal vancomycin may play an adjunctive role for some severe cases, while surgical intervention is indicated for fulminant CDI if no improvement six or more days after initiating medical therapy. For non-severe recurrent disease, the initial treatment regimen should be repeated, while subsequent episodes are more appropriately treated with a tapered and pulsed dose of vancomycin, fidaxomicin, or fecal microbiota transplantation.
Assuntos
Enterocolite Pseudomembranosa/diagnóstico , Enterocolite Pseudomembranosa/terapia , Neoplasias dos Genitais Femininos/complicações , Proteínas de Bactérias/análise , Toxinas Bacterianas/análise , Enterocolite Pseudomembranosa/etiologia , Enterotoxinas/análise , Feminino , Humanos , Técnicas de Amplificação de Ácido Nucleico , Índice de Gravidade de DoençaRESUMO
AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.
Assuntos
Aminopeptidases/antagonistas & inibidores , Depressores do Apetite/uso terapêutico , Cinamatos/uso terapêutico , Cicloexanos/uso terapêutico , Compostos de Epóxi/uso terapêutico , Glicoproteínas/antagonistas & inibidores , Hiperfagia/prevenção & controle , Obesidade/prevenção & controle , Síndrome de Prader-Willi/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Sesquiterpenos/uso terapêutico , Adolescente , Adulto , Aminopeptidases/metabolismo , Depressores do Apetite/administração & dosagem , Depressores do Apetite/efeitos adversos , Índice de Massa Corporal , Cinamatos/administração & dosagem , Cinamatos/efeitos adversos , Cicloexanos/administração & dosagem , Cicloexanos/efeitos adversos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Término Precoce de Ensaios Clínicos , Compostos de Epóxi/administração & dosagem , Compostos de Epóxi/efeitos adversos , Feminino , Glicoproteínas/metabolismo , Humanos , Hiperfagia/etiologia , Hiperfagia/fisiopatologia , Análise de Intenção de Tratamento , Masculino , Metionil Aminopeptidases , Obesidade/etiologia , Síndrome de Prader-Willi/fisiopatologia , Inibidores de Proteases/administração & dosagem , Inibidores de Proteases/efeitos adversos , Sesquiterpenos/administração & dosagem , Sesquiterpenos/efeitos adversos , Índice de Gravidade de Doença , Trombose Venosa/induzido quimicamente , Trombose Venosa/fisiopatologia , Redução de Peso/efeitos dos fármacos , Adulto JovemRESUMO
Organic cation transporter (OCT) 2, multidrug and toxin extrusion protein (MATE) 1, and MATE2K mediate the renal secretion of various cationic drugs and can serve as the loci of drug-drug interactions (DDI). To support the evaluation of cynomolgus monkey as a surrogate model for studying human organic cation transporters, monkey genes were cloned and shown to have a high degree of amino acid sequence identity versus their human counterparts (93.7, 94.7, and 95.4% for OCT2, MATE1, and MATE2K, respectively). Subsequently, the three transporters were individually stably expressed in human embryonic kidney (HEK) 293 cells and their properties (substrate selectivity, time course, pH dependence, and kinetics) were found to be comparable to the corresponding human form. For example, six known human cation transporter inhibitors, including pyrimethamine (PYR), showed generally similar IC50 values against the monkey transporters (within sixfold). Consistent with the in vitro inhibition of metformin (MFM) transport by PYR (IC50 for cynomolgus OCT2, MATE1, and MATE2K; 1.2 ± 0.38, 0.17 ± 0.04, and 0.25 ± 0.04 µM, respectively), intravenous pretreatment of monkeys with PYR (0.5 mg/kg) decreased the clearance (54 ± 9%) and increased in the area under the plasma concentration-time curve of MFM (AUC ratio versus control = 2.23; 90% confidence interval of 1.57 to 3.17). These findings suggest that the cynomolgus monkey may have some utility in support of in vitro-in vivo extrapolations (IVIVEs) involving the inhibition of renal OCT2 and MATEs. In turn, cynomolgus monkey-enabled IVIVEs may inform human DDI risk assessment.
Assuntos
Cátions/metabolismo , Rim/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Animais , Linhagem Celular , Interações Medicamentosas/fisiologia , Células HEK293 , Humanos , Cinética , Macaca fascicularis , Metformina/metabolismo , Pirimetamina/metabolismoRESUMO
OBJECTIVES: We aimed to compare progression-free survival (PFS) and overall survival (OS) among patients with stage I-to-IV uterine leiomyosarcoma (uLMS) who received adjuvant gemcitabine-docetaxel, were observed, received radiation only, or were treated with a chemotherapy regimen other than gemcitabine-docetaxel. METHODS/MATERIALS: This is a retrospective cohort study of 128 women with uLMS. Data included age, body mass index, race, stage, mitotic count, residual disease, adjuvant treatment, PFS, and OS. Variables were compared by Fisher exact or Wilcoxon rank-sum tests. Time to progression or death was plotted using Kaplan-Meier curves. Cox proportional hazards regression was used to estimate hazard ratios for progression or death by patient and tumor characteristics. RESULTS: Fifty-six (44%) women received adjuvant chemotherapy, 41 (32%) received adjuvant radiation, and 31 (24%) were observed. Of those receiving chemotherapy, 30 received gemcitabine-docetaxel, and 26 received other chemotherapy. Disease stage for the chemotherapy groups was evenly distributed. In the radiation group, 80% of patients had early-stage disease. Age, body mass index, and residual disease were similar between the groups. Mitotic count was uniformly 10 or greater only in the gemcitabine-docetaxel group. Age, stage, and residual disease were associated with worst PFS and OS. After adjusting for these variables, there was no difference in PFS or OS between gemcitabine-docetaxel and the other treatment groups. CONCLUSIONS: There was no difference in PFS or OS in women with uLMS treated with adjuvant gemcitabine-docetaxel versus those who were observed or received radiation only or a chemotherapy regimen other than gemcitabine-docetaxel. There is a need to identify novel therapies to treat this aggressive disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leiomiossarcoma/terapia , Recidiva Local de Neoplasia/terapia , Neoplasias Uterinas/terapia , Idoso , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Docetaxel , Feminino , Seguimentos , Humanos , Leiomiossarcoma/patologia , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Taxa de Sobrevida , Taxoides/administração & dosagem , Neoplasias Uterinas/patologia , GencitabinaRESUMO
Myoepithelioma-like hyalinizing epithelioid tumors are rare neoplasms that share morphological characteristics of myoepitheliomas but lack traditional immunophenotypic findings. Though little is known about these tumors at present, a handful of recent studies have confirmed that they harbor a novel fusion gene known as "OGT-FOXO." Though closely resembling myoeptheliomas, Myoepithelioma-like hyalinizing epithelioid tumors are considered a distinct tumor entity, and few studies have explored their clinical characteristics or their potential for malignancy. Furthermore, literature describing imaging findings of these tumors is virtually non-existent. Understanding the radiological and pathological differences between Myoepithelioma-like hyalinizing epithelioid tumors and myoepitheliomas is helpful in developing a comprehensive differential for soft tissue neoplasms of the foot. We describe a case of MHET of the foot and correlate MRI findings with pathology in addition to describing surgical technique and implications to care.
RESUMO
Whereas policy change is often characterized as a gradual and incremental process, effective crisis response necessitates that organizations adapt to evolving problems in near real time. Nowhere is this dynamic more evident than in the case of COVID-19, which forced subnational governments to constantly adjust and recalibrate public health and disease mitigation measures in the face of changing patterns of viral transmission and the emergence of new information. This study assesses (a) the extent to which subnational policies changed over the course of the pandemic; (b) whether these changes are emblematic of policy learning; and (c) the drivers of these changes, namely changing political and public health conditions. Using a novel dataset analyzing each policy's content, including its timing of enactment, substantive focus, stringency, and similar variables, results indicate the pandemic response varied significantly across states. The states examined were responsive to both changing public health and political conditions. This study identifies patterns of preemptive policy learning, which denotes learning in anticipation of an emerging hazard. In doing so, the study provides important insights into the dynamics of policy learning and change during disaster.
Mientras que el cambio de política a menudo se caracteriza como un proceso gradual e incremental, la respuesta efectiva a la crisis requiere que las organizaciones se adapten a los problemas en evolución casi en tiempo real. En ninguna parte esta dinámica es más evidente que en el caso de COVID19, que obligó a los gobiernos subnacionales a ajustar y recalibrar constantemente las medidas de salud pública y mitigación de enfermedades ante los patrones cambiantes de transmisión viral y la aparición de nueva información. Este estudio evalúa (a) la medida en que las políticas subnacionales cambiaron en el transcurso de la pandemia; (b) si estos cambios son emblemáticos del aprendizaje de políticas; y (c) los impulsores de estos cambios, a saber, las cambiantes condiciones políticas y de salud pública. Usando un nuevo conjunto de datos que analiza el contenido de cada política, incluido el momento de la promulgación, el enfoque sustantivo, el rigor y variables similares, los resultados indican que la respuesta a la pandemia varió significativamente entre los estados. Los estados examinados respondieron a cambios tanto en la salud pública como en las condiciones políticas. Este estudio identifica patrones de aprendizaje de políticas preventivas, lo que denota aprendizaje en previsión de un peligro emergente. Al hacerlo, el estudio proporciona información importante sobre la dinámica del aprendizaje y el cambio de políticas durante un desastre.
RESUMO
In the face of vaccine hesitancy, public health officials are seeking more effective risk communication approaches to increase vaccination rates. We test the influence of visual policy narratives on COVID-19 vaccination behavior through a panel survey experiment conducted in early 2021 (n = 3,900) and then 8 weeks later (n = 2,268). We examine the effects of three visual policy narrative messages that test the narrative mechanism of character selection (yourself, your circle, and your community) and a nonnarrative control on COVID-19 vaccine behavior. Visual risk messages that use narratives positively influence COVID-19 vaccination through serial mediation of affective response to the messages and motivation to get the COVID-19 vaccination. Additionally, character selection matters, as messages focusing on protecting others (i.e. your circle and your community) perform stronger than those of yourself. Political ideology moderated some of the effects, with conservative respondents in the nonnarrative control condition having a higher probability of vaccination in comparison to the protect yourself condition. Taken together, these results suggest that public health officials should use narrative-based visual communication messages that emphasize communal benefits of vaccinations.
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BACKGROUND: Diabetes treatments are needed that are convenient, provide effective glycaemic control, and do not cause weight gain. We aimed to test the hypothesis that improvement in haemoglobin A(1c) (HbA(1c)) achieved with once weekly exenatide was superior to that achieved with insulin glargine titrated to glucose targets. METHODS: In this 26-week, open-label, randomised, parallel study, we compared exenatide with insulin glargine in adults with type 2 diabetes who had suboptimum glycaemic control despite use of maximum tolerated doses of blood-glucose-lowering drugs for 3 months or longer. Patients were randomly assigned to add exenatide (2 mg, once-a-week injection) or insulin glargine (once-daily injection, starting dose 10 IU, target glucose range 4.0-5.5 mmol/L) to their blood-glucose-lowering regimens. Randomisation was with a one-to-one allocation and block size four, stratified according to country and concomitant treatment (70% metformin only; 30% metformin plus sulphonylurea). Participants and clinical investigators were not masked to assignment, but investigators analysing data were. The primary endpoint was change in HbA(1c) from baseline, and analysis of this outcome was by modified intention to treat for all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00641056. FINDINGS: 456 patients were randomly allocated to treatment and were included in the modified intention-to-treat analysis (233 exenatide, 223 insulin glargine). Participants who received at least one dose of study drug and for whom baseline and at least one postbaseline measurement of HbA(1c) were available were included in the primary efficacy analysis. Change in HbA(1c) at 26 weeks was greater in patients taking exenatide (n=228; -1.5%, SE 0.05) than in those taking insulin glargine (n=220; -1.3%, 0.06; treatment difference -0.16%, 0.07, 95% CI -0.29 to -0.03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p=0.012). A planned extension period (up to 2.5 years' duration) is in progress. INTERPRETATION: Once weekly exenatide is an important therapeutic option for patients for whom risk of hypoglycaemia, weight loss, and convenience are particular concerns. FUNDING: Amylin Pharmaceuticals; Eli Lilly and Company.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/análogos & derivados , Peptídeos/administração & dosagem , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Esquema de Medicação , Exenatida , Feminino , Peptídeo 1 Semelhante ao Glucagon/agonistas , Hemoglobinas Glicadas/análise , Humanos , Injeções Subcutâneas , Insulina/uso terapêutico , Insulina Glargina , Insulina de Ação Prolongada , Masculino , Pessoa de Meia-Idade , PeçonhasRESUMO
BACKGROUND: The secretory form of acid sphingomyelinase (ASM) is postulated to play a key role in the retention and aggregation of lipoproteins in the subendothelial space of the arterial wall by converting sphingomyelin in lipoproteins into ceramide. The present study aimed to determine whether the level of circulating ASM activity affects lesion development in mouse model of atherosclerosis. METHODS: Apolipoprotein E deficient (ApoE(-/-) ) mice were injected intravenously with a recombinant adeno-associated virus (AAV8-ASM) that constitutively expressed high levels of human ASM in liver and plasma. RESULTS: Plasma sphingomyelin levels were reduced at early but not later time points after the administration of AAV8-ASM despite persistently elevated circulating ASM. No change in serum lipoprotein levels was observed. Thirteen or 17 weeks after the administration of AAV8-ASM, the amount of plaque formation in the aortic sinus was comparable to that of mice treated with a control AAV. CONCLUSIONS: Unexpectedly, the lesion area of the entire aorta was reduced significantly in the AAV8-ASM virus-treated group. Hepatic expression and secretion of ASM into the circulation did not accelerate or exacerbate, but rather decreased, lesion formation in ApoE(-/-) mice. Thus, plasma ASM activity does not appear to be rate limiting for plaque formation during atherogenesis.
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Aorta/patologia , Apolipoproteínas E/genética , Dependovirus/metabolismo , Placa Aterosclerótica/enzimologia , Esfingomielina Fosfodiesterase/metabolismo , Análise de Variância , Animais , Técnicas Histológicas , Humanos , Lipoproteínas/sangue , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placa Aterosclerótica/patologia , Esfingomielina Fosfodiesterase/administração & dosagem , Esfingomielina Fosfodiesterase/sangueRESUMO
BACKGROUND: The once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes. METHODS: A 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 µg for the first 4 weeks and 10 µg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean ± SE) for these patients were: A1C, 8.2 ± 0.1%; FPG, 168.4 ± 43.0 mg/dL; body weight, 101.1 ± 18.7 kg; and diabetes duration, 7 ± 5 years. RESULTS: In the completer population, significant improvements (LS mean ± SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 ± 0.08% [-1.86 to -1.55%]), FPG (-40.1 ± 2.9 mg/dL [-45.7 to -34.5 mg/dL]), and body weight (-2.61 ± 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and ≤6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 ± 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 ± 2.7% [-21% to -10%]), total cholesterol (-8.6 ± 2.8 mg/dL [-14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 ± 2.2 mg/dL [-8.9 to -0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed. CONCLUSIONS: Exenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW. TRIAL REGISTRATION: ClinicalTrials.gov NCT00308139.
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The efficacy of recombinant enzyme therapy for genetic diseases is limited in some patients by the generation of a humoral immune response to the therapeutic protein. Inducing immune tolerance to the protein prior to treatment has the potential to increase therapeutic efficacy. Using an AAV8 vector encoding human acid α-glucosidase (hGAA), we have evaluated direct intrathymic injection for inducing tolerance. We have also compared the final tolerogenic states achieved by intrathymic and intravenous injection. Intrathymic vector delivery induced tolerance equivalent to that generated by intravenous delivery, but at a 25-fold lower dose, the thymic hGAA expression level was 10,000-fold lower than the liver expression necessary for systemic tolerance induction. Splenic regulatory T cells (Tregs) were apparent after delivery by both routes, but with different phenotypes. Intrathymic delivery resulted in Tregs with higher FoxP3, TGFß, and IL-10 mRNA levels. These differences may account for the differences noted in splenic T cells, where only intravenous delivery appeared to inhibit their activation. Our results imply that different mechanisms may be operating to generate immune tolerance by intrathymic and intravenous delivery of an AAV vector, and suggest that the intrathymic route may hold promise for decreasing the humoral immune response to therapeutic proteins in genetic disease indications.
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Técnicas de Transferência de Genes , Terapia Genética , Tolerância Imunológica/genética , Linfócitos T Reguladores/imunologia , Timo , alfa-Glucosidases/genética , Adenoviridae/genética , Humanos , Injeções Intravenosas , Ativação Linfocitária , Linfócitos T Reguladores/citologia , alfa-Glucosidases/administração & dosagem , alfa-Glucosidases/farmacologiaRESUMO
Chronic exertional compartment syndrome is a subset of compartment syndrome that most frequently affects the lower extremities, often in athletic persons. It is most often characterized by calf pain shortly after the initiation of exercise and resolution of the pain soon after rest. While the pathophysiology is not completely understood, it is believed that compartment a lack of fascial compliance and increased compartment fluid leads to increased pressure, ultimately leading to a reversible ischemic state. Chronic exertional compartment syndrome was once considered a diagnosis of exclusion; however, needle manometry is an invasive way to measure intracompartmental pressure. Similarly, fasciotomy is the treatment of choice but is not without complications. We describe a case of chronic exertional compartment syndrome diagnosed by two-stage MRI and successfully treated by endoscopically-assisted fasciotomy.
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Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1-2years of age to a more slowly progressive course that causes significant morbidity and early mortality in children and adults. Recombinant human GAA (rhGAA) improves clinical outcomes with variable results. Adjunct therapy that increases the effectiveness of rhGAA may benefit some Pompe patients. Co-administration of the mTORC1 inhibitor rapamycin with rhGAA in a GAA knockout mouse reduced muscle glycogen content more than rhGAA or rapamycin alone. These results suggest mTORC1 inhibition may benefit GSDs that involve glycogen accumulation in muscle.