RESUMO
PURPOSE: Cyclin inhibitors plus endocrine therapy represent the reference standard for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) locally advanced or metastatic breast cancer (ABC). Efficacy results on hard end points such as overall survival come from well-designed randomized clinical trials (RCTs). However, a limitation of RCTs is the low external results validity, and their extrapolation to a broader population may not be appropriate. Real-world studies can overcome these limitations, also increasing the reliability of RCTs. MATERIALS AND METHODS: The BrasiLEEira was an observational, longitudinal, retrospective, multicenter study to evaluate the effectiveness and safety of ribociclib plus nonsteroidal aromatase inhibitors in Brazilian women age 18 years or older with HR+/HER2- ABC. The study was approved by the institutional review boards of all 11 hospitals. Data were collected anonymously from medical records using an electronic case report form designed by an independent academic research organization, which conducted the study considering all recommendations of international guidelines. The primary end point was 1-year progression-free survival (PFS) rate. Secondary end points included mortality, dose reduction, and safety. RESULTS: The mean age of 76 patients was 57 years, and 28.9% were Black/Brown. The most prevalent comorbidity was arterial hypertension (34.7%). About 26.0% had endocrine-resistant disease, and 54.1% had more than three metastatic sites. The PFS rate was 77.6%. Three patients died (3.9%). Dose reductions occurred in 37.7% of patients. The most common adverse event was neutropenia (68.4%). CONCLUSION: The high-quality evidence from the BrasiLEEira study corroborates the RCTs' findings, expanding its validity to a broader spectrum and underrepresented population who may benefit from ribociclib treatment.
Assuntos
Inibidores da Aromatase , Neoplasias da Mama , Purinas , Feminino , Humanos , Aminopiridinas/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-IdadeRESUMO
Antimicrobial resistance is a global health problem. In 2021, it was estimated almost half a million of multidrug-resistant tuberculosis (MDR-TB) cases. Besides, non-tuberculous mycobacteria (NTM) are highly resistant to several drugs and the emergence of fluoroquinolone (FQ) resistant M. tuberculosis (Mtb) is also a global concern making treatments difficult and with variable outcome. The aim of this study was to evaluate the activity of the FQ, DC-159a, against Mtb and NTM and to explore the cross-resistance with the currently used FQs.A total of 12 pre-extensively drug-resistant (XDR) Mtb, 2 XDR, 36 fully drug susceptible strains and 41 NTM isolates were included to estimate the in vitro activity of DC-159a, moxifloxacin (MOX) and levofloxacin (LX), using minimal inhibitory and bactericidal concentration (MIC and MBC). The activity inside the human macrophages and pulmonary epithelial cells were also determined.DC-159a was active in vitro and ex vivo against mycobacteria. Besides, it was more active than MOX/LX. Moreover, no cross-resistance was evidenced between DC-159a and LX/MOX as DC-159a could inhibit Mtb and MAC strains that were already resistant to LX/MOX.DC-159a could be a possible candidate in new therapeutic regimens for MDR/ XDR-TB and mycobacterioses cases.
Assuntos
Aminopiridinas , Fluoroquinolonas , Testes de Sensibilidade Microbiana , Moxifloxacina , Mycobacterium tuberculosis , Fluoroquinolonas/farmacologia , Humanos , Mycobacterium tuberculosis/efeitos dos fármacos , Moxifloxacina/farmacologia , Antituberculosos/farmacologia , Micobactérias não Tuberculosas/efeitos dos fármacos , Levofloxacino/farmacologia , Macrófagos/efeitos dos fármacos , Antibacterianos/farmacologia , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacosRESUMO
Neuroimaging data in humans and neurobiological studies in rodents have suggested an involvement of the insular cortex (IC) in anxiety manifestations. However, the local neurochemical mechanisms involved are still poorly understood. Corticotropin-releasing factor (CRF) neurotransmission has been described as a prominent neurochemical mechanism involved in the expression of anxiety-like behaviors, but the brain sites related are poorly understood. Additionally, several findings indicate that control of physiological and behavioral responses by the IC occurs in a site-specific manner along its rostrocaudal axis. Thus, this study is aimed at evaluating the effect of CRF receptor agonism and antagonism within the anterior and posterior subregions of the IC in controlling anxiety-related behaviors in the elevated plus maze (EPM). For this, independent groups (six groups) of animals received bilateral microinjections of vehicle, the selective CRF1 receptor antagonist CP376395, or CRF into either the anterior or posterior subregions of the IC. Ten minutes later, the behavior in the EPM was evaluated for five minutes. Treatment of the anterior IC with CP376395, but not with CRF, increased the time and number of entries into the open arms of the EPM. CRF, but not the CRF1 receptor antagonist, microinjected into the posterior IC also increased exploration of the EPM open arms. Taken together, these data indicate that CRFergic neurotransmission in the anterior IC is involved in the expression of anxiety-related behaviors in the EPM. This neurochemical mechanism does not seem to be activated within the posterior IC during exposure to the EPM, but the effects caused by CRF microinjection indicate that activation of CRF receptors in this IC subregion might evoke anxiolytic-like effects.
Assuntos
Aminopiridinas , Ansiolíticos , Receptores de Hormônio Liberador da Corticotropina , Humanos , Ratos , Animais , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Hormônio Liberador da Corticotropina/metabolismo , Teste de Labirinto em Cruz Elevado , Córtex Insular , Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Ansiolíticos/farmacologiaRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Two years of adjuvant abemaciclib combined with endocrine therapy (ET) resulted in a significant improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) that persisted beyond the 2-year treatment period in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer (EBC). Here, we report 5-year efficacy results from a prespecified overall survival (OS) interim analysis. In the intent-to-treat population, with a median follow-up of 54 months, the benefit of abemaciclib was sustained with hazard ratios of 0.680 (95% CI, 0.599 to 0.772) for IDFS and 0.675 (95% CI, 0.588 to 0.774) for DRFS. This persistence of abemaciclib benefit translated to continuous separation of the curves with a deepening in 5-year absolute improvement in IDFS and DRFS rates of 7.6% and 6.7%, respectively, compared with rates of 6% and 5.3% at 4 years and 4.8% and 4.1% at 3 years. With fewer deaths in the abemaciclib plus ET arm compared with the ET-alone arm (208 v 234), statistical significance was not reached for OS. No new safety signals were observed. In conclusion, abemaciclib plus ET continued to reduce the risk of developing invasive and distant disease recurrence beyond the completion of treatment. The increasing absolute improvement at 5 years is consistent with a carryover effect and further supports the use of abemaciclib in patients with high-risk EBC.
Assuntos
Aminopiridinas , Benzimidazóis , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia , Adjuvantes Imunológicos , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: To estimate the cost-effectiveness of adding a CDK4/6 inhibitor to standard endocrine therapy in the first-line setting for advanced HR+/HER2- breast cancer in postmenopausal and premenopausal women, from the perspective of the Mexican public healthcare system. METHODS: We used a partitioned survival model to simulate relevant health outcomes in a synthetic cohort of patients with breast cancer derived from the PALOMA-2, MONALEESA-2, MONARCH-3 trials for postmenopausal patients, and from the MONALEESA-7 study for premenopausal patients. Effectiveness was measured in life years gained. Cost-effectiveness is reported through incremental cost-effectiveness ratios (ICER). RESULTS: In postmenopausal patients, palbociclib led to an increase of 1.51 life years, ribociclib of 1.58 years, and abemaciclib of 1.75 years, compared to letrozole alone. The ICER was 36,648 USD, 32,422 USD, and 26,888 USD, respectively. In premenopausal patients, ribociclib led to an increase of 1.82 life years when added to goserelin and endocrine therapy, with an ICER of 44,579 USD. In the cost minimization analysis, for postmenopausal patients, ribociclib was the treatment with the highest costs due to follow-up requirements. CONCLUSION: Palbociclib, ribociclib, and abemaciclib demonstrated a significant increase in effectiveness in postmenopausal patients, and ribociclib in premenopausal patients, when added to standard endocrine therapy for patients with advanced HR+/HER2- breast cancer. At the national stablished willingness to pay, only the addition of abemaciclib to standard endocrine therapy in postmenopausal women would be considered cost-effective. However, differences on results between therapies for postmenopausal patients were not statistically significant.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Análise Custo-Benefício , México , Aminopiridinas/uso terapêutico , Proteínas Inibidoras de Quinase Dependente de Ciclina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Receptor ErbB-2 , Quinase 4 Dependente de CiclinaRESUMO
INTRODUCTION: Cystic fibrosis (CF) is the most frequent recessive autosomal disorder in the Caucasian population. It is caused by mutations that result in a deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein activity. Among CFTR modulators, potentiator compounds increase channel opening, whereas corrector compounds increase CFTR quantity in the cell surface. OBJECTIVE: To report real-life effects of a generic formulation of lumacaftor-ivacaftor use in patients with CF homozygous for the Phe508del CFTR mutation. PATIENTS AND METHODS: Clinical variables (body mass index [BMI], pulmonary exacerbations, sweat test, and pulmonary function) were analyzed in 30 CF patients homozygous for the Phe508del CFTR mutation, treated with lumacaftor-ivacaftor for 12 months, at the Respiratory Center of Hospital de Niños Ricardo Gutiérrez. These clinical variables were compared with those before the use of modulators. RESULTS: A total of 30 patients with CF homozygous for the Phe508del CFTR mutation receiving lumacaftor-ivacaftor therapy were included in this study. The median (interquartile range [IQR]) age at the start of treatment was 10.79 (7.08-14.05) years. Nineteen patients were male. Before treatment, median (IQR) sweat chloride concentration was 80 (72-92) mEq/L, and it had decreased to 74 (68-78) mEq/L (p = .05) 12 months after treatment. Median (IQR) BMI z-score improved from -0.33 (-0.86 to 0.21) to -0.13 (-0.66 to 0.54) (p = .003). A spirometry was performed in 28 of 30 patients. Median (IQR) ppFEV1 was 83.5 (71-91) before treatment and 86.5 (67-103) after treatment (p = .38), 73.3% of patients referred decreased sputum production and 40% reported improvement in their dyspnea at 12 months. Severe pulmonary exacerbations significantly decreased from 60% in the year before treatment, to 30% at 12 months after treatment (p = .037); 13 patients showed an improvement in their exacerbation rates, 2 showed an increased rate, and 15 showed no change. CONCLUSIONS: The use of a generic formulation of lumacaftor-ivacaftor in patients homozygous for the Phe508del CFTR mutation was associated with improvement in nutritional status and respiratory symptoms, and a significant reduction in severe pulmonary exacerbations.
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Fibrose Cística , Humanos , Masculino , Criança , Adolescente , Feminino , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/uso terapêutico , Combinação de Medicamentos , Aminofenóis , Aminopiridinas , Benzodioxóis/efeitos adversos , MutaçãoRESUMO
PURPOSE: Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting OXPHOS in AML is urgently needed. MATERIALS AND METHODS: Bioinformatical analysis of TCGA AML dataset was performed to identify the molecular signaling of OXPHOS. The OXPHOS level was measured through a Seahorse XFe96 cell metabolic analyzer. Flow cytometry was applied to measure mitochondrial status. Real-time qPCR and western blot were used to analyze the expression of mitochondrial or inflammatory factors. MLL-AF9-induced leukemic mice were conducted to measure the anti-leukemia effect of chidamide. RESULTS: Here, we reported that AML patients with high OXPHOS level were in a poor prognosis, which was associated with high expression of HDAC1/3 (TCGA). Inhibition of HDAC1/3 by chidamide inhibited cell proliferation and induced apoptotic cell death in AML cells. Intriguingly, chidamide could disrupt mitochondrial OXPHOS as assessed by inducing mitochondrial superoxide and reducing oxygen consumption rate, as well as decreasing mitochondrial ATP production. We also observed that chidamide augmented HK1 expression, while glycolysis inhibitor 2-DG could reduce the elevation of HK1 and improve the sensitivity of AML cells exposed to chidamide. Furthermore, HDAC3 was correlated with hyperinflammatory status, while chidamide could downregulate the inflammatory signaling in AML. Notably, chidamide eradicated leukemic cells in vivo and prolonged the survival time of MLL-AF9-induced AML mice. CONCLUSION: Chidamide disrupted mitochondrial OXPHOS, promoted cell apoptosis and reduced inflammation in AML cells. These findings exhibited a novel mechanism that targeting OXPHOS would be a novel strategy for AML treatment.
Assuntos
Leucemia Mieloide Aguda , Animais , Camundongos , Leucemia Mieloide Aguda/tratamento farmacológico , Fosforilação Oxidativa , Aminopiridinas/farmacologia , Benzamidas , Apoptose , Linhagem Celular TumoralRESUMO
BACKGROUND: The Creutzfeldt-Jakob disease (CJD) is a spongiform encephalopathy that manifests as a rapidly progressive dementia syndrome. Currently, CJD has no cure, and many patients die within the first year, but some drugs are being studied as options for managing this condition. OBJECTIVE: To evaluate the effectiveness of pharmacological treatments offered to patients with CJD as a means to increase survival and reduce cognitive deterioration. METHODS: A systematic review of the literature was performed using 4 independent reviewers and 1 extra reviewer to resolve possible divergences in the search and analysis of papers indexed in MedLINE (PubMed), SciELO and Lilacs databases. The Medical Subject Heading (MeSH) terms used were: prion diseases, Creutzfeldt-Jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine, and pentosan polysulfate, with the Boolean operators AND and OR. This search included controlled clinical trials, uncontrolled clinical trials, and case series published from the year 2000 onwards, in the English language. RESULTS: A total of 85 papers were found using the descriptors used. At the end of the selection analyses, 9 articles remained, which were analyzed fully and individually. CONCLUSIONS: None of the drugs evaluated proved significantly effective in increasing survival in patients with CJD. Flupirtine appears to have a beneficial effect in reducing cognitive deterioration in patients with CJD. However, additional studies are needed to establish better evidence and therapeutic options for the management of patients with CJD.
ANTECEDENTES: A doença de Creutzfeldt-Jakob (DCJ) é uma encefalopatia espongiforme que se manifesta como síndrome demencial rapidamente progressiva. Atualmente, a DCJ não possui cura e muitos pacientes morrem no primeiro ano de doença, mas alguns medicamentos vêm sendo estudados como opções no manejo desta condição. OBJETIVO: Avaliar a eficácia dos tratamentos farmacológicos oferecidos aos pacientes com DCJ no aumento de sobrevida e na redução da deterioração cognitiva. MéTODOS: Foi realizada uma revisão sistemática da literatura utilizando 4 revisores independentes e 1 extra para resolver divergências eventuais na busca e na análise de trabalhos indexados nas bases de dados MedLINE (via PubMed), SciELO e Lilacs. Os termos Medical Subjects Heading (MeSH) utilizados foram: prion diseases, creutzfeldt jakob disease, pharmacologic therapy, therapeutics, quinacrine, doxycycline, flupirtine e pentosan polysulfate, com os operadores booleanos AND e OR. Essa pesquisa incluiu ensaios clínicos controlados, não controlados e séries de casos, publicados a partir do ano 2000 no idioma inglês. RESULTADOS: Ao todo, foram encontrados 85 trabalhos através dos descritores utilizados. Ao final das análises de seleção, restaram 9 artigos, que foram analisados na íntegra individualmente. CONCLUSõES: Nenhuma das drogas avaliadas se mostrou significativamente eficaz no aumento da sobrevida dos pacientes com DCJ. A flupirtina parece ter um efeito benéfico na redução da deterioração cognitiva dos pacientes com DCJ. Entretanto, estudos adicionais são necessários para o estabelecimento de melhores evidências e opções terapêuticas para o manejo dos pacientes com DCJ.
Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Aminopiridinas , Síndrome de Creutzfeldt-Jakob/tratamento farmacológico , Síndrome de Creutzfeldt-Jakob/psicologia , Doxiciclina/uso terapêutico , Humanos , Poliéster Sulfúrico de Pentosana/uso terapêutico , Quinacrina/uso terapêuticoRESUMO
PURPOSE: Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionized the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function, sensitizing PI3K inhibitors, metabolism reprogramming, kinome rewiring, modulation of the proteosome, and many others. The ubiquitin-proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. METHODS: We performed transcriptional profiling of the HR(+) breast cancer cell lines MCF7 and T47D treated with Palbociclib. Differential expressed genes were analyzed for novel pathways enriched. The results were further validated with biochemical assays and with real world clinical database cohorts. RESULTS: We uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. Further validation in the HR(+) cell lines show that Palbociclib and ribociclib decrease UBE2C at both the mRNA and protein level, but this phenomenon was not shared with abemaciclib. These three E2 enzymes modulate several E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. We further demonstrate the UBE2C/UBE2T expression levels are associated with breast cancer survival, and HR(+) breast cancer cells demonstrate dependence on the UBE2C. CONCLUSIONS: Our study suggests a novel link between CDK4/6 inhibitor and UPP pathway, adding to the potential mechanisms of their clinical efficacy in cancer.
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Neoplasias da Mama , Aminopiridinas , Benzimidazóis , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Feminino , Hormônios/uso terapêutico , Humanos , Fosfatidilinositol 3-Quinases , Complexo de Endopeptidases do Proteassoma/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Purinas , RNA Mensageiro , Enzimas de Conjugação de Ubiquitina/genética , Enzimas de Conjugação de Ubiquitina/metabolismo , Ubiquitinas/uso terapêuticoRESUMO
PURPOSE: Although lorlatinib, the third generation of echinoderm microtubule protein 4-anaplastic lymphoma kinase (EML4-ALK) tyrosine kinase inhibitor (TKI), overcame the previous generation ALK-TKIs' drug resistance problems, but the mechanism of lorlatinib resistance remained unclear. Furthermore, optimal chemotherapy for lorlatinib-resistant non-small cell lung cancer (NSCLC) patients was still unknown. METHODS: A lorlatinib-resistant NSCLC cell line SNU-2535LR was generated by gradually increasing dose of lorlatinib to crizotinib-resistant cell line SNU-2535 in vitro. To study the resistance mechanism of SNU-2535LR cells, we applied CCK-8 assay to detect the sensitivity of crizotinib and the reverse effect of APR-246, a p53 activator, on lorlatinib-induced resistance and different chemotherapy drugs to SNU-2535LR cells. We also detected the expressions of EML4-ALK-related proteins of SNU-2535LR cells via western blot.Please confirm that author names have been identified correctly and are presented in the right order.Dear Editor: I have carefully confirmed that the author names have been identified correctly and are presented in right order.Thank you very much! Your sincerely BoXie RESULTS: The sensitivity of SNU-2535LR cells to lorlatinib was decreased significantly than that of SNU-2535 cells. EML4-ALK fusion was decreased both at protein level and DNA level in SNU-2535LR cells. More interesting, the crizotinib-resistant mutation ALK p.G1269A disappeared, while new TP53 mutation emerged in SNU-2535LR cells. APR-246 can reverse the lorlatinib resistance in SNU-2535LR cells, with a reversal index of 4.768. Compared with SNU-2535 cells, the sensitivity of SNU-2535LR cells to gemcitabine, docetaxel and paclitaxel was significantly increased (P < 0.05), but decreased to cisplatin (P < 0.05). CONCLUSION: This study demonstrated that the combination of p53 protein agonist and lorlatinib may provide a new therapeutic strategy for NSCLC patients with lorlatinib resistance and TP53 mutation. Furthermore, the results also provide guidance for selecting optimal chemo-regimens for NSCLC patients after ALK-TKIs failure.