RESUMEN
BACKGROUND: Objectives: Pancreatic cancer (PC) is a costly disease with a limited life-expectancy as it generally presents as an advanced, metastatic disease. Though current literature suggests cost varies by first line treatment, there is limited real-world knowledge about the economic burden of pancreatic cancer. This study describes the economic burden of pancreatic cancer patients overall and by observed first line treatments. METHODS: The IBM MarketScan databases were used to identify adult metastatic PC patients from January 1, 2010 through 3/31/2017. Those without other primary cancers, pregnancy, or prior PC treatment, and with 6 months of continuous enrollment prior to PC were included. Treatment patterns and healthcare utilization and expenditures were measured during the variable-length follow-up period. Continuous measures were presented as per patient per month (PPPM). RESULTS: A total of 6,360 patients met all inclusion criteria. Almost half (46.8%) of patients were untreated. Gemcitabine alone (15.6%) and FOLFIRINOX (11.4%) were the most commonly observed first line regimens. Treated patients incurred $17,513 PPPM (Gemcitabine alone) to $27,889 PPPM (FOLFIRINOX) during follow-up. Untreated patients incurred the highest unadjusted ($30,777 PPPM) and adjusted ($20,392 PPPM) cost. CONCLUSIONS: Metastatic PC patients incur a high economic burden driven by high utilization of healthcare resources, which varies by first line treatment. Also, the high proportion of untreated patients is alarming as these patients may be the most expensive of all patients. There is an unmet need in these patients for effective treatments that also reduce their economic burden.
Asunto(s)
Costo de Enfermedad , Neoplasias Pancreáticas/economía , Anciano , Antimetabolitos Antineoplásicos/economía , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Costos y Análisis de Costo , Bases de Datos Factuales , Desoxicitidina/análogos & derivados , Desoxicitidina/economía , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/economía , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Costos de la Atención en Salud , Recursos en Salud , Humanos , Irinotecán/economía , Irinotecán/uso terapéutico , Leucovorina/economía , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Evaluación de Necesidades , Metástasis de la Neoplasia , Oxaliplatino/economía , Oxaliplatino/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Estudios Retrospectivos , GemcitabinaRESUMEN
BACKGROUND: Pancreatic cancer represents the third leading cause of US cancer deaths, with median survival <1 year. The goal of this study was to describe systemic treatments, healthcare utilization and costs, and overall survival among patients with unresectable/metastatic disease. METHODS: This study used healthcare claims for commercial and Medicare Advantage enrollees diagnosed with pancreatic adenocarcinoma (at index date) during January 01 2010 to 31 May 2017. Included patients were aged ≥18 years, with continuous 6-month preindex enrollment. Patients were excluded by resectable disease, another primary cancer, or pregnancy. Cohorts were based on first-line (LOT1) chemotherapy regimen. RESULTS: Overall, 12 978 patients (mean age 70 years, 51% male) were included, among which 5610 (43%) received chemotherapy. Of those, 23% received gemcitabine monotherapy, 22% gemcitabine-nab paclitaxel, 22% FOLFIRINOX, 3% FOLFOX, and 29% received other regimens. Mean LOT1 duration was 112 days; 60% did not undergo subsequent lines of therapy. Moreover, 50% of patients had an emergency room visit and 45% were hospitalized during LOT1. Among treated and untreated patients, mean total 6-month costs were $52 101. We found that patients receiving FOLFIRINOX had the highest costs, whereas those who received gemcitabine monotherapy had the lowest. Median overall survival (mOS) was 335 days with any first-line treatment. FOLFIRINOX-treated patients had the highest mOS (492 days), whereas gemcitabine monotherapy-treated patients had the lowest (223 days). CONCLUSIONS: A large proportion (57%) of patients with unresectable/metastatic pancreatic cancer did not receive chemotherapy. Healthcare costs were higher for fluorouracil-based regimens, while lower for gemcitabine-based regimens. Survival rates were within expectations for advanced pancreatic cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Costos de la Atención en Salud , Neoplasias Pancreáticas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Albúminas/administración & dosificación , Atención Ambulatoria/economía , Atención Ambulatoria/estadística & datos numéricos , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Carcinoma Ductal Pancreático/economía , Carcinoma Ductal Pancreático/patología , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Duración de la Terapia , Servicio de Urgencia en Hospital/economía , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Fluorouracilo/uso terapéutico , Hospitalización/economía , Hospitalización/estadística & datos numéricos , Humanos , Seguro de Salud , Irinotecán/uso terapéutico , Leucovorina/uso terapéutico , Masculino , Medicare Part C , Persona de Mediana Edad , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino/uso terapéutico , Paclitaxel/administración & dosificación , Neoplasias Pancreáticas/economía , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos , GemcitabinaRESUMEN
Serum amyloid A (SAA) production is increased by inflamed arthritic synovial tissue, where it acts as a cytokine/chemoattractant for inflammatory and immune cells and as an inducer of matrix degrading enzymes. SAA has been shown to bind lipoxin A4 receptor, a member of the formyl-peptide related 2 G-protein coupled receptor family (ALX) and elicit proinflammatory activities in human primary fibroblast-like synoviocytes (FLS). We report on the identification of uteroglobin, a small globular protein with potent anti-inflammatory activities, as a possible ligand of ALX. Uteroglobin-specific association with ALX was demonstrated by an enzyme immunoassay experiment employing a cell line engineered to express the human ALX receptor. Uteroglobin's interaction with ALX resulted in the inhibition of SAA responses, such as attenuation of phospholipase A2 activation and cellular chemotaxis. In FLS, uteroglobin showed an antagonism against SAA-induced interleukin-8 release and decreased cell migration. These novel roles described for uteroglobin via ALX may help elucidate genetic and clinical observations indicating that a polymorphism in the uteroglobin promoter is linked to disease outcome, specifically prediction of bone erosion in patients with rheumatoid arthritis or severity of IgA glomerulonephritis and sarcoidosis.
Asunto(s)
Receptores de Lipoxina/metabolismo , Proteína Amiloide A Sérica/metabolismo , Uteroglobina/metabolismo , Animales , Células CHO , Movimiento Celular , Quimiotaxis , Cricetulus , Endometrio/citología , Femenino , Fibroblastos/citología , Células HL-60 , Humanos , Técnicas para Inmunoenzimas , Inflamación , Ligandos , Fosfolipasas A2/metabolismo , Regiones Promotoras Genéticas , Membrana Sinovial/citologíaRESUMEN
There is emerging evidence that, beyond their cholesterol-lowering properties, statins exhibit important antileukemic effects in vitro and in vivo, but the precise mechanisms by which they generate such responses remain to be determined. We have previously shown that statins promote differentiation of acute promyelocytic leukemia cells and enhance generation of all-trans retinoic acid (ATRA)-dependent antileukemic responses. We now provide evidence that statin-dependent leukemic cell differentiation requires engagement and activation of the c-Jun NH2-terminal kinase kinase pathway. In addition, in experiments, to define the molecular targets and mediators of statin-induced differentiation, we found a remarkable effect of statins on ATRA-dependent gene transcription, evidenced by the selective induction of over 400 genes by the combination of atorvastatin and ATRA. Altogether, our studies identify novel statin molecular targets linked to differentiation, establish that statins modulate ATRA-dependent transcription, and suggest that combined use of statins with retinoids may provide a novel approach to enhance antileukemic responses in acute promyelocytic leukemia and possibly other leukemias.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Leucemia/patología , Retinoides/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Atorvastatina , Diferenciación Celular/genética , Sinergismo Farmacológico , Perfilación de la Expresión Génica , Redes Reguladoras de Genes/efectos de los fármacos , Ácidos Heptanoicos/administración & dosificación , Ácidos Heptanoicos/farmacología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Leucemia/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Pirroles/administración & dosificación , Pirroles/farmacología , Retinoides/administración & dosificación , Factores de Tiempo , Tretinoina/administración & dosificación , Tretinoina/farmacología , Células Tumorales CultivadasRESUMEN
High expression of Notch-1 and Jagged-1 mRNA correlates with poor prognosis in breast cancer. Elucidating the cross-talk between Notch and other major breast cancer pathways is necessary to determine which patients may benefit from Notch inhibitors, which agents should be combined with them, and which biomarkers indicate Notch activity in vivo. We explored expression of Notch receptors and ligands in clinical specimens, as well as activity, regulation, and effectors of Notch signaling using cell lines and xenografts. Ductal and lobular carcinomas commonly expressed Notch-1, Notch-4, and Jagged-1 at variable levels. However, in breast cancer cell lines, Notch-induced transcriptional activity did not correlate with Notch receptor levels and was highest in estrogen receptor alpha-negative (ERalpha(-)), Her2/Neu nonoverexpressing cells. In ERalpha(+) cells, estradiol inhibited Notch activity and Notch-1(IC) nuclear levels and affected Notch-1 cellular distribution. Tamoxifen and raloxifene blocked this effect, reactivating Notch. Notch-1 induced Notch-4. Notch-4 expression in clinical specimens correlated with proliferation (Ki67). In MDA-MB231 (ERalpha(-)) cells, Notch-1 knockdown or gamma-secretase inhibition decreased cyclins A and B1, causing G(2) arrest, p53-independent induction of NOXA, and death. In T47D:A18 (ERalpha(+)) cells, the same targets were affected, and Notch inhibition potentiated the effects of tamoxifen. In vivo, gamma-secretase inhibitor treatment arrested the growth of MDA-MB231 tumors and, in combination with tamoxifen, caused regression of T47D:A18 tumors. Our data indicate that combinations of antiestrogens and Notch inhibitors may be effective in ERalpha(+) breast cancers and that Notch signaling is a potential therapeutic target in ERalpha(-) breast cancers.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Receptor alfa de Estrógeno/fisiología , Receptor Cross-Talk/fisiología , Receptores Notch/fisiología , Animales , Antineoplásicos Hormonales/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Estradiol/administración & dosificación , Estradiol/farmacología , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Invasividad Neoplásica , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Proteínas Proto-Oncogénicas/metabolismo , ARN Interferente Pequeño/administración & dosificación , Receptor Notch1/metabolismo , Receptor Notch4 , Receptores Notch/antagonistas & inhibidores , Receptores Notch/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Elevations of serum prolactin (PRL) are associated with an increased risk for breast cancer. PRL signaling through its prolactin receptor (PRLr) involves the Jak2/Stat5 pathway. Luciferase-based reporter assays have been widely used to evaluate the activity of this pathway. However, the existing reporters are often not sensitive enough to monitor the effect of PRL in this pathway. RESULTS: In this study, a new biologically relevant reporter, pGL4-CISH, was generated to study the PRL/Jak2/Stat5 signaling pathway. The sensitivity of pGL4-CISH to detect PRL was superior to that of several other commonly utilized Stat5-responsive reporters. Interestingly, the enhanced function pGL4-CISH was restricted to the estrogen receptor positive (ER+) human breast cancer cell lines T47D and MCF7, but not in the ER-MDA-231, BT-474, or MCF10A cell lines. Overexpression of Stat5 further enhanced the effect of PRL on pGL4-CISH. CONCLUSION: These studies demonstrate that pGL4-CISH is a novel and sensitive reporter for assessing the activity of the PRL/Stat5 signaling pathway in the ER+ human breast cancer cells.
Asunto(s)
Neoplasias de la Mama/metabolismo , Perfilación de la Expresión Génica/métodos , Prolactina/metabolismo , Receptores de Estrógenos/metabolismo , Factor de Transcripción STAT5/metabolismo , Transducción de Señal , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Neoplasias de la Mama/genética , Línea Celular Tumoral , Genes Reporteros/genética , Humanos , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genéticaRESUMEN
The family of statins includes pharmacologic inhibitors of the 3-hydroxy-3-methylglutaryl-CoA reductase that are potent regulators of cholesterol biosynthesis. In addition to their cholesterol-lowering effects, statins inhibit cell proliferation and promote apoptosis of malignant cells in vitro, but their potential therapeutic roles in the treatment of malignancies remain to be defined. We examined the effects of statins on the growth and differentiation of acute myeloid leukemia (AML) cells. Atorvastatin and fluvastatin were found to be potent inducers of cell differentiation and apoptosis of the NB4 acute promyelocytic leukemia (APL) cell line. Such effects correlated with activation of the small G-proteins Rac1/Cdc42 and downstream engagement of the c-Jun NH(2)-terminal kinase kinase pathway, whose function was found to be essential for the generation of proapoptotic responses. Importantly, different statins were found to enhance all-trans-retinoic acid (ATRA)-dependent differentiation of APL blasts and reverse resistance to the antileukemic effects of ATRA. In addition, fluvastatin exhibited growth-inhibitory properties on primary bone marrow-derived leukemic progenitors from patients with AML and enhanced the suppressive effects of ATRA on leukemic progenitor colony formation. Altogether, these studies establish that statins exhibit potent antileukemic properties in vitro and raise the possibility that combinations of statins with ATRA may be an effective approach to overcome the development of ATRA resistance by the leukemic cells.
Asunto(s)
Ácidos Grasos Monoinsaturados/farmacología , Ácidos Heptanoicos/farmacología , Indoles/farmacología , Leucemia Promielocítica Aguda/tratamiento farmacológico , Pirroles/farmacología , Atorvastatina , Diferenciación Celular/efectos de los fármacos , Procesos de Crecimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Fluvastatina , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Leucemia Promielocítica Aguda/patología , Tretinoina/farmacología , Proteína de Unión al GTP cdc42/metabolismo , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Uteroglobin (UG) or Clara Cell 10 kDa protein (CC10) is a small, stable, epithelial secretory anti-inflammatory protein. Uteroglobin has been shown to inhibit neointimal formation in vivo after balloon angioplasty through an unknown mechanism. An interaction between UG and plasma fibronectin (Fn) has been demonstrated in mice. Since Fn plays a key role in endothelial cell (EC) migration and angiogenesis, we investigated whether recombinant human UG (rhUG) affects EC migration via Fn binding. In this report, we show a saturable binding of rhUG to Fn depending on Fn conformation and that rhUG is covalently cross-linked to Fn by transglutaminase (TGase). Additionally, our study highlights that rhUG can also bind to exogenously added or self-secreted Fn on the membrane of human primary microvascular endothelial cells (HMVEC), although these complexes are weakly associated with the plasmalemma. Upon the interaction with Fn in solid phase, rhUG strongly inhibits HMVEC attachment on Fn, but not on other ECM proteins. Consequently, rhUG also inhibits cell migration in a dose dependent fashion (I.C.50 = 65 nM) and hinders the "wound healing" in vitro. The small size, stability and human tolerability of rhUG suggest that rhUG in slow-release form or genetically delivered could be used in humans to modulate cell/Fn interactions in the context of tumor microenvironment or in the context of inflammation and fibrosis.