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INTRODUCTION: Despite several therapeutic advancements, the proportion of patients with advanced biliary tract cancers (BTC) surviving 5 years from diagnosis remains dismal. The increasing recognition of targetable genetic alterations in BTCs has ushered in a new era in the treatment of these patients. Newer therapeutic agents targeting mutations such as isocitrate dehydrogenase (IDH), fibroblastic growth factor receptor (FGFR), human epidermal growth factor receptor (HER), and so on have established a new standard of care for treatment upon progression on frontline therapy in patients with disease harboring these mutations. AREAS COVERED: The current review aims to concisely summarize progress with various targeted therapy options for BTC. We also briefly discuss future directions in clinical and translational research for the adoption of a personalized approach for the treatment of unresectable or advanced BTC. EXPERT OPINION: Several new agents continue to emerge as feasible treatment options for patients with advanced BTC harboring targetable mutations. There is a growing need to identify mechanisms to conquer primary and acquired resistance to these agents. The identification of potential biomarkers that predict response to targeted therapy may be helpful in adopting a more tailored approach. All patients receiving treatment for advanced BTC should undergo tissue genomic profiling at diagnosis.
Assuntos
Antineoplásicos , Neoplasias do Sistema Biliar , Terapia de Alvo Molecular , Mutação , Medicina de Precisão , Humanos , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/genética , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Taxa de Sobrevida , Progressão da Doença , AnimaisRESUMO
ABSTRACT: Venous thromboembolic events are significant contributors to morbidity and mortality in patients with stroke. Neutrophils are among the first cells in the blood to respond to stroke and are known to promote deep vein thrombosis (DVT). Integrin α9 is a transmembrane glycoprotein highly expressed on neutrophils and stabilizes neutrophil adhesion to activated endothelium via vascular cell adhesion molecule 1 (VCAM-1). Nevertheless, the causative role of neutrophil integrin α9 in poststroke DVT remains unknown. Here, we found higher neutrophil integrin α9 and plasma VCAM-1 levels in humans and mice with stroke. Using mice with embolic stroke, we observed enhanced DVT severity in a novel model of poststroke DVT. Neutrophil-specific integrin α9-deficient mice (α9fl/flMrp8Cre+/-) exhibited a significant reduction in poststroke DVT severity along with decreased neutrophils and citrullinated histone H3 in thrombi. Unbiased transcriptomics indicated that α9/VCAM-1 interactions induced pathways related to neutrophil inflammation, exocytosis, NF-κB signaling, and chemotaxis. Mechanistic studies revealed that integrin α9/VCAM-1 interactions mediate neutrophil adhesion at the venous shear rate, promote neutrophil hyperactivation, increase phosphorylation of extracellular signal-regulated kinase, and induce endothelial cell apoptosis. Using pharmacogenomic profiling, virtual screening, and in vitro assays, we identified macitentan as a potent inhibitor of integrin α9/VCAM-1 interactions and neutrophil adhesion to activated endothelial cells. Macitentan reduced DVT severity in control mice with and without stroke, but not in α9fl/flMrp8Cre+/- mice, suggesting that macitentan improves DVT outcomes by inhibiting neutrophil integrin α9. Collectively, we uncovered a previously unrecognized and critical pathway involving the α9/VCAM-1 axis in neutrophil hyperactivation and DVT.
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Integrinas , Neutrófilos , Acidente Vascular Cerebral , Molécula 1 de Adesão de Célula Vascular , Trombose Venosa , Animais , Humanos , Masculino , Camundongos , Adesão Celular , Modelos Animais de Doenças , Integrinas/metabolismo , Camundongos Knockout , Ativação de Neutrófilo , Neutrófilos/metabolismo , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/etiologia , Molécula 1 de Adesão de Célula Vascular/metabolismo , Trombose Venosa/metabolismo , Trombose Venosa/etiologiaRESUMO
Chronic myeloproliferative neoplasms (MPN) include polycythemia vera (PV), primary myelofibrosis, essential thrombocythemia (ET) and chronic myeloid leukemia (CML). Overlapping MPNs are rare; however, they can occur in the same individual. The present case report describes a patient with both triple-negative ET and CML. A 64-year-old woman was followed-up at our hematology clinic at Feist Weiller Cancer Center, Louisiana State University Health Shreveport (Shreveport, LA, USA) since 2000 after she was diagnosed with JAK2V617F-negative ET. The patient remained stable on hydroxyurea until 2012, when they underwent a bone marrow biopsy for progressively increasing white blood cell counts, and the pathology was consistent with CML; PCR for BCR-ABL was positive for both P210 and P190 transcripts. The patient was then initiated on dasatinib. After dasatinib, they were given a trial of imatinib, and were later transitioned to nilotinib and finally to bosutinib (2019) due to unchanged thrombocytosis. Next-generation sequencing from a bone marrow biopsy in 2019 demonstrated an EZH2 mutation that may be associated with triple-negative ET. CML was in major molecular response at that time. The patient was continued on bosutinib with hydroxyurea, after which hydroxyurea was changed to anagrelide due to worsening anemia and persistent thrombocytosis. However, bosutinib and anagrelide were discontinued due to worsening pulmonary hypertension. The patient was noted to have peripheral blasts of 14% by flow cytometry, after which they underwent a repeat bone marrow biopsy in 2022, which showed extensive myelofibrosis. BCR-ABL transcripts were undetectable. Given their accelerated myelofibrosis, the patient was started on a hypomethylating agent, decitabine/cedazuridine, along with darbepoetin for anemia in June 2022. Given their persistent thrombocytosis, the patient was also started on peginterferon α. Most studies reporting two clonal processes in the same patient have been for PV and CML. To the best of our knowledge, this is the first reported case of triple-negative ET with double transcript CML in the same individual.
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Background: The novel corona virus has changed the way individuals interact with each other and society. In the medical sector, this has affected the residents and fellows who spend the majority of their time on the front lines. Methods: We conducted a cross-sectional survey to assess the impact of the COVID-19 pandemic on the lives and training of house-staff across the USA. Respondents in our survey reported feeling significantly overwhelmed by the ongoing pandemic. Results: The majority of house-staff were significantly concerned about the lack of protective equipment, inability to safeguard themselves from infection and inability to look after their families. Concerns regarding contracting the infection and transmitting it to their loved ones were reported as a cause of mental distress among resident physicians. Increasing patient load, lack of protective equipment, and disruption of educational and academic activities during the COVID-19 pandemic have all reportedly affected the training and overall well-being of resident physicians. Conslusion: Our study adds further support for measures to safeguard house-staff with proper protective equipment and ensure adequate support for both mental and physical well-being during these challenging times.