Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Más filtros

Bases de datos
País/Región como asunto
Tipo del documento
Intervalo de año de publicación
1.
Ann Surg ; 2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39045699

RESUMEN

OBJECTIVE: We evaluated the efficacy of risk-based, protocol-driven management versus (vs) usual management after elective major cancer surgery to reduce 30-day rates of postoperative death or serious complications (DSC) . SUMMARY BACKGROUND DATA: Major cancer surgery is associated with significant perioperative risks which result in worse long-term outcomes. METHODS: Adults scheduled for elective major cancer surgery were stratified/randomized to risk-based escalating levels of care, monitoring, and co-management vs usual management. The primary study outcome was 30-day rate of DSC. Additional outcomes included complications, adverse events, health care utilization, health-related quality of life (HRQOL), and disease-free and overall survival (DFS and OS). RESULTS: Between August 2014 and June 2020, 1529 patients were enrolled and randomly allocated to the study arms; 738 patients in the Intervention Arm and 732 patients in the Control Arm were eligible for analysis. 30-day rate of DSC with the intervention was 15.0% (95% CI, 12.5-17.6%) vs 14.1%, (95% CI, 11.6-16.6%) with usual management (P=0.65). There were no differences in 30-day rates of complications or adverse events (including return to the operating room); postoperative length of stay; rate of discharge to home; or 30, 60, or 90-day HRQOL or rates of hospital readmission or receipt of anti-neoplastic therapy between the study arms. At median follow-up of 48 months, OS (P=0.57) and DFS (P=0.91) were similar. CONCLUSIONS: Risk-based, protocol-driven management did not reduce 30-day rate of DSC after elective major cancer surgery compared to usual management, nor improve postoperative health care utilization, HRQOL, or cancer outcomes. Trials are needed to identify cost-effective, tailored perioperative strategies to optimize outcomes after major cancer surgery.

2.
Ann Surg ; 277(2): e339-e345, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34913904

RESUMEN

OBJECTIVE: We sought to define criteria associated with low lymph node metastasis risk in patients with submucosal (pT1b) gastric cancer from 3 Western and 3 Eastern countries. SUMMARY BACKGROUND DATA: Accurate prediction of lymph node metastasis risk is essential when determining the need for gastrectomy with lymph node dissection following endoscopic resection. Under present guidelines, endoscopic resection is considered definitive treatment if submucosal invasion is only superficial, but this is not routinely assessed. METHODS: Lymph node metastasis rates were determined for patient groups defined according to tumor pathological characteristics. Clinicopathological predictors of lymph node metastasis were determined by multivariable logistic regression and used to develop a nomogram in a randomly selected subset that was validated in the remainder. Overall survival was compared between Eastern and Western countries. RESULTS: Lymph node metastasis was found in 701 of 3166 (22.1%) Eastern and 153 of 560 (27.3%) Western patients. Independent predictors of lymph node metastasis were female sex, tumor size, distal stomach location, lymphovascular invasion, and moderate or poor differentiation. Patients fulfilling the National Comprehensive Cancer Network guideline criteria, excluding the requirement that invasion not extend beyond the superficial submucosa, had a lymph node metastasis rate of 8.9% (53/594). Excluding moderately differentiated tumors lowered the rate to 3.4% (10/296). The nomogram's area under the curve was 0.690. Regardless of lymph node status, overall survival was better in Eastern patients. CONCLUSIONS: The lymph node metastasis rate was lowest in patients with well differentiated tumors that were ≤3 cm and lacked lymphovascular invasion. These criteria may be useful in decisions regarding endoscopic resection as definitive treatment for pT1b gastric cancer.


Asunto(s)
Neoplasias Gástricas , Humanos , Femenino , Masculino , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Metástasis Linfática , Estudios Retrospectivos , Escisión del Ganglio Linfático
3.
J Natl Compr Canc Netw ; 21(7): 694-704, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37433432

RESUMEN

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.


Asunto(s)
Neoplasias de los Conductos Biliares , Neoplasias del Sistema Biliar , Colangiocarcinoma , Neoplasias de la Vesícula Biliar , Neoplasias Hepáticas , Humanos , Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/terapia , Neoplasias de la Vesícula Biliar/diagnóstico , Neoplasias de la Vesícula Biliar/terapia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Conductos Biliares Intrahepáticos
4.
Gastroenterology ; 149(7): 1932-1943.e9, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26255562

RESUMEN

BACKGROUND & AIMS: A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense desmoplastic reaction (stroma) that impedes drug delivery to the tumor. Attempts to deplete the tumor stroma have resulted in formation of more aggressive tumors. We have identified signal transducer and activator of transcription (STAT) 3 as a biomarker of resistance to cytotoxic and molecularly targeted therapy in PDAC. The purpose of this study is to investigate the effects of targeting STAT3 on the PDAC stroma and on therapeutic resistance. METHODS: Activated STAT3 protein expression was determined in human pancreatic tissues and tumor cell lines. In vivo effects of AZD1480, a JAK/STAT3 inhibitor, gemcitabine or the combination were determined in Ptf1a(cre/+);LSL-Kras(G12D/+);Tgfbr2(flox/flox) (PKT) mice and in orthotopic tumor xenografts. Drug delivery was analyzed by matrix-assisted laser desorption/ionization imaging mass spectrometry. Collagen second harmonic generation imaging quantified tumor collagen alignment and density. RESULTS: STAT3 activation correlates with decreased survival and advanced tumor stage in patients with PDAC. STAT3 inhibition combined with gemcitabine significantly inhibits tumor growth in both an orthotopic and the PKT mouse model of PDAC. This combined therapy attenuates in vivo expression of SPARC, increases microvessel density, and enhances drug delivery to the tumor without depletion of stromal collagen or hyaluronan. Instead, the PDAC tumors demonstrate vascular normalization, remodeling of the tumor stroma, and down-regulation of cytidine deaminase. CONCLUSIONS: Targeted inhibition of STAT3 combined with gemcitabine enhances in vivo drug delivery and therapeutic response in PDAC. These effects occur through tumor stromal remodeling and down-regulation of cytidine deaminase without depletion of tumor stromal content.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Factor de Transcripción STAT3/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Células del Estroma/efectos de los fármacos , Microambiente Tumoral , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Colágeno/metabolismo , Desoxicitidina/metabolismo , Desoxicitidina/farmacología , Resistencia a Antineoplásicos , Técnicas de Silenciamiento del Gen , Humanos , Ratones Endogámicos C57BL , Ratones Desnudos , Ratones Transgénicos , Terapia Molecular Dirigida , Estadificación de Neoplasias , Osteonectina/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Pirazoles/metabolismo , Pirimidinas/metabolismo , Receptor Tipo II de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Células del Estroma/metabolismo , Células del Estroma/patología , Factores de Tiempo , Factores de Transcripción/genética , Transfección , Carga Tumoral , Ensayos Antitumor por Modelo de Xenoinjerto , Gemcitabina
5.
Ann Surg Oncol ; 21(3): 747-51, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24092447

RESUMEN

The prognosis of patients diagnosed with pancreatic adenocarcinoma remains dismal. Of the 15-20 % of patients who are candidates for potentially curative resection, 66-92 % will develop recurrent disease. Although guidelines for surveillance in the postoperative setting exist, they are not evidence based, and there is wide variability of strategies utilized. Current surveillance guidelines as suggested by the National Comprehensive Cancer Network (NCCN) include routine history and physical, measurement of serum cancer-associated antigen 19-9 (CA19-9) levels, and computed tomographic imaging at 3- to 6-month intervals for the first 2 years, and annually thereafter. However, the lack of prospective clinical data examining the efficacy of different surveillance strategies has led to a variability of the intensity of follow-up and a lack of consensus on its necessity and efficacy. Recent therapeutic advances may have the potential to significantly alter survival after recurrence, but a careful consideration of current surveillance strategies should be undertaken to optimize existing approaches in the face of high recurrence and low survival rates.


Asunto(s)
Continuidad de la Atención al Paciente , Pruebas Diagnósticas de Rutina/estadística & datos numéricos , Neoplasias Pancreáticas/cirugía , Pruebas Diagnósticas de Rutina/tendencias , Estudios de Seguimiento , Humanos , Neoplasias Pancreáticas/mortalidad , Vigilancia de la Población , Pronóstico , Tasa de Supervivencia , Sobrevivientes
6.
Am J Surg ; 225(4): 728-734, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36333156

RESUMEN

BACKGROUND: The extent by which conversion to open (CTO) during minimally invasive procedures for pancreatic cancer impact survival outcomes is not fully understood. METHODS: The 2010-2017 National Cancer Database identified 12,424 non-metastatic patients who underwent pancreatoduodenectomy for ductal adenocarcinoma. Patients were stratified into three cohorts: open (OPD), completed MIPD (cMIPD), and CTO. Subgroups were dichotomized by hospital MIPD volume. RESULTS: Across the study period, 80.6% of patients underwent OPD, 19.4% MIPD, and 24% were CTO. Median overall survival was worse after CTO (21.8 months) than for OPD (23.6 months) or cMIPD (25.2 months) (p < 0.001). Although this effect persisted for <10 MIPD/year, CTO did comparably to OPD at hospitals performing ≥10MIPD/year (CTO = 26.8 months, OPD = 27.9 months; p = 0.128). Ninety-day mortality after CTO was worse at ≤ 10 MIPD/year hospitals (9.3% vs. 2.6%). CONCLUSIONS: Short and long-term survival is impacted by CTO after MIPD, especially at lower surgical volumes, stressing careful adoption while ascending the learning curve.


Asunto(s)
Laparoscopía , Neoplasias , Neoplasias Pancreáticas , Humanos , Pancreaticoduodenectomía/métodos , Neoplasias/cirugía , Páncreas/cirugía , Hospitales , Bases de Datos Factuales , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos
7.
Am J Surg ; 225(4): 715-723, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36344305

RESUMEN

BACKGROUND: A paucity of data exists on how social determinants of health (SDOH) influence treatment for Hepatocellular carcinoma (HCC). We investigated associations between SDOH (healthcare access, education, social/community context, economic stability, and built/neighborhood environment) and receipt of surgery. METHODS: The Pennsylvania Liver Cancer Registry was linked with neighborhood SDOH from the American Community Survey. Multilevel logistic regression models with patient and neighborhood SDOH variables were developed. RESULTS: Of 9423 HCC patients, 2393 were stage I. Only 36.3% of stage I patients received surgery. Black patients had significantly lower odds of surgery vs Whites (OR = 0.73; p < 0.01), but not after adjustments for SDOH. All 5 SDOH domains were associated with odds of surgery overall; 2 domains were associated in Stage I patients, social context (e.g., racial concentration, p = 0.03) and insurance access (p < 0.01). CONCLUSIONS: SDOH impact utilization of surgery for HCC. Findings can guide healthcare professionals to create programs for populations at risk for poor liver cancer outcomes.


Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/patología , Determinantes Sociales de la Salud , Grupos Raciales , Blanco
8.
Mol Cancer Ther ; 20(7): 1246-1256, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-34001634

RESUMEN

Activating KRAS mutations, a defining feature of pancreatic ductal adenocarcinoma (PDAC), promote tumor growth in part through the activation of cyclin-dependent kinases (CDK) that induce cell-cycle progression. p16INK4a (p16), encoded by the gene CDKN2A, is a potent inhibitor of CDK4/6 and serves as a critical checkpoint of cell proliferation. Mutations in and subsequent loss of the p16 gene occur in PDAC at a rate higher than that reported in any other tumor type and results in Rb inactivation and unrestricted cellular growth. Therefore, strategies targeting downstream RAS pathway effectors combined with CDK4/6 inhibition (CDK4/6i) may have the potential to improve outcomes in this disease. Herein, we show that expression of p16 is markedly reduced in PDAC tumors compared with normal pancreatic or pre-neoplastic tissues. Combined MEK inhibition (MEKi) and CDK4/6i results in sustained downregulation of both ERK and Rb phosphorylation and a significant reduction in cell proliferation compared with monotherapy in human PDAC cells. MEKi with CDK4/6i reduces tumor cell proliferation by promoting senescence-mediated growth arrest, independent of apoptosis in vitro We show that combined MEKi and CDK4/6i treatment attenuates tumor growth in xenograft models of PDAC and improves overall survival over 200% compared with treatment with vehicle or individual agents alone in Ptf1acre/+ ;LSL-KRASG12D/+ ;Tgfbr2flox/flox (PKT) mice. Histologic analysis of PKT tumor lysates reveal a significant decrease in markers of cell proliferation and an increase in senescence-associated markers without any significant change in apoptosis. These results demonstrate that combined targeting of both MEK and CDK4/6 represents a novel therapeutic strategy to synergistically reduce tumor growth through induction of cellular senescence in PDAC.


Asunto(s)
Senescencia Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica , Genes p16 , Humanos , Ratones , Ratones Noqueados , Ratones Transgénicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Oncotarget ; 10(10): 1056-1069, 2019 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-30800218

RESUMEN

The Src family of non-receptor tyrosine kinases are frequently activated in pancreatic ductal adenocarcinoma (PDAC), contributing to disease progression through downregulation of E-cadherin and induction of epithelial-to-mesenchymal transition (EMT). The purpose of this study was to examine the efficacy of Src kinase inhibition in restoring E-cadherin levels in PDAC. Immunohistochemical analysis of human PDAC samples showed Src activation is inversely correlated with E-cadherin levels. Protein and mRNA levels of E-cadherin, the gene expression of its various transcriptional repressors (Zeb1, Snail, Slug, LEF-1, TWIST), and changes in sub-cellular localization of E-cadherin/ß-catenin in PDAC cells were characterized in response to treatment with the Src inhibitor, dasatinib (DST). DST repressed Slug mRNA expression, promoted E-cadherin transcription, and increased total and membranous E-cadherin/ß-catenin levels in drug-sensitive PDAC cells (BxPC3 and SW1990), however no change was observed in drug-resistant PANC1 cells. BxPC3, PANC1, and MiaPaCa-2 flank tumor xenografts were treated with DST to examine changes in E-cadherin levels in vivo. Although DST inhibited Src phosphorylation in all xenograft models, E-cadherin levels were only restored in BxPC3 xenograft tumors. These results suggest that Src kinase inhibition reverses EMT in drug-sensitive PDAC cells through Slug-mediated repression of E-cadherin and identifies E-cadherin as potential biomarker for determining response to DST treatment.

10.
Mol Cancer Ther ; 18(2): 301-311, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30404927

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A-treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.


Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Carcinoma Ductal Pancreático/tratamiento farmacológico , Cumarinas/administración & dosificación , Lythraceae/química , Neoplasias Pancreáticas/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Antineoplásicos Fitogénicos/farmacología , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cumarinas/farmacología , Humanos , Ratones , Neoplasias Pancreáticas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Cancer Res ; 78(21): 6235-6246, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30154150

RESUMEN

Major contributors to therapeutic resistance in pancreatic ductal adenocarcinoma (PDAC) include Kras mutations, a dense desmoplastic stroma that prevents drug delivery to the tumor, and activation of redundant signaling pathways. We have previously identified a mechanistic rationale for targeting STAT3 signaling to overcome therapeutic resistance in PDAC. In this study, we investigate the molecular mechanisms underlying the heterogeneous response to STAT3 and RAS pathway inhibition in PDAC. Effects of JAK/STAT3 inhibition (STAT3i) or MEK inhibition (MEKi) were established in Ptf1acre/+; LSL-KrasG12D/+ ; and Tgfbr2flox/flox (PKT) mice and patient-derived xenografts (PDX). Amphiregulin (AREG) levels were determined in serum from human patients with PDAC, LSL-KrasG12D/+;Trp53R172H/+;Pdx1Cre/+ (KPC), and PKT mice. MEKi/STAT3i-treated tumors were analyzed for integrity of the pancreas and the presence of cancer stem cells (CSC). We observed an inverse correlation between ERK and STAT3 phosphorylation. MEKi resulted in an immediate activation of STAT3, whereas STAT3i resulted in TACE-induced, AREG-dependent activation of EGFR and ERK. Combined MEKi/STAT3i sustained blockade of ERK, EGFR, and STAT3 signaling, overcoming resistance to individual MEKi or STAT3i. This combined inhibition attenuated tumor growth in PDX and increased survival of PKT mice while reducing serum AREG levels. Furthermore, MEKi/STAT3i altered the PDAC tumor microenvironment by depleting tumor fibrosis, maintaining pancreatic integrity, and downregulating CD44+ and CD133+ CSCs. These results demonstrate that resistance to MEKi is mediated through activation of STAT3, whereas TACE-AREG-EGFR-dependent activation of RAS pathway signaling confers resistance to STAT3 inhibition. Combined MEKi/STAT3i overcomes these resistances and provides a novel therapeutic strategy to target the RAS and STAT3 pathway in PDAC.Significance: This report describes an inverse correlation between MEK and STAT3 signaling as key mechanisms of resistance in PDAC and shows that combined inhibition of MEK and STAT3 overcomes this resistance and provides an improved therapeutic strategy to target the RAS pathway in PDAC.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6235/F1.large.jpg Cancer Res; 78(21); 6235-46. ©2018 AACR.


Asunto(s)
MAP Quinasa Quinasa 1/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Factor de Transcripción STAT3/metabolismo , Proteínas ras/metabolismo , Anfirregulina/metabolismo , Animales , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Ligandos , Ratones , Ratones Desnudos , Mutación , Trasplante de Neoplasias , Fosforilación , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de Señal , Análisis de Matrices Tisulares , Microambiente Tumoral
12.
Cancer Res ; 78(21): 6146-6158, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30232221

RESUMEN

Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF-mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC.Significance: These findings identify GM-CSF-induced CREB as a driver of pancreatic cancer in smokers and demonstrate the therapeutic potential of targeting CREB to reduce PDAC tumor growth.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6146/F1.large.jpg Cancer Res; 78(21); 6146-58. ©2018 AACR.


Asunto(s)
Carcinógenos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Regulación Neoplásica de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Nicotiana/efectos adversos , Neoplasias Pancreáticas/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Humanos , Sistema Inmunológico , Macrófagos/metabolismo , Ratones , Ratones Desnudos , Ratones Transgénicos , Trasplante de Neoplasias , Nitrosaminas/química , Neoplasias Pancreáticas/etiología , ARN Interferente Pequeño/metabolismo , Factores de Riesgo , Fumar/efectos adversos
13.
Oncotarget ; 8(49): 85378-85391, 2017 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-29156726

RESUMEN

Obesity is a significant risk factor for pancreatic cancer, harboring a chronic inflammatory condition characterized by dysregulation of the adipokines, leptin and adiponectin, that in turn alter oncogenic signaling pathways. We and others have shown that leptin promotes the proliferation and an invasive potential of pancreatic cancer cells through STAT3 mediated signaling. However, the role of adiponectin on the tumorigenicity of pancreatic cancer has not been elucidated. Adiponectin represents an important negative regulator of cytokines, which acts through two receptors, ADIPOR1 and ADIPOR2, to elicit pro-apoptotic, anti-inflammatory, and anti-angiogenic responses. We show that the level and expression of both adiponectin receptors are decreased in pancreatic tumors relative to normal pancreatic tissue. In vitro stimulation with adiponectin or a small molecule adiponectin receptor agonist, AdipoRon, increases apoptosis while inhibiting pancreatic cancer cell proliferation, colony formation, and anchorage independent growth. In addition, adiponectin receptor agonism inhibits leptin mediated STAT3 activation. In vivo, treatment of mice with AdipoRon inhibits orthotopic pancreatic tumor growth. These results demonstrate that adiponectin receptor activation is a key regulator of pancreatic cancer growth and AdipoRon provides a rational agent for the development of novel therapeutic strategies for pancreatic cancer.

14.
Pancreas ; 45(6): 863-9, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-26495796

RESUMEN

OBJECTIVES: Three-dimensional organoids derived from primary pancreatic ductal adenocarcinomas are an attractive platform for testing potential anticancer drugs on patient-specific tissue. Optical metabolic imaging (OMI) is a novel tool used to assess drug-induced changes in cellular metabolism, and its quantitative end point, the OMI index, is evaluated as a biomarker of drug response in pancreatic cancer organoids. METHODS: Optical metabolic imaging is used to assess both malignant cell and fibroblast drug response within primary murine and human pancreatic cancer organoids. RESULTS: Anticancer drugs induce significant reductions in the OMI index of murine and human pancreatic cancer organoids. Subpopulation analysis of OMI data revealed heterogeneous drug response and elucidated responding and nonresponding cell populations for a 7-day time course. Optical metabolic imaging index significantly correlates with immunofluorescence detection of cell proliferation and cell death. CONCLUSIONS: Optical metabolic imaging of primary pancreatic ductal adenocarcinoma organoids is highly sensitive to drug-induced metabolic changes, provides a nondestructive method for monitoring dynamic drug response, and presents a novel platform for patient-specific drug testing and drug development.


Asunto(s)
Carcinoma Ductal Pancreático/diagnóstico por imagen , Imagen Óptica/métodos , Organoides/diagnóstico por imagen , Neoplasias Pancreáticas/diagnóstico por imagen , Animales , Antineoplásicos/farmacología , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Ratones Noqueados , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Organoides/efectos de los fármacos , Organoides/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Factores de Tiempo
15.
Oncotarget ; 7(40): 65982-65992, 2016 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-27602757

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) is a dynamic tumor supported by several stromal elements such as pancreatic stellate cells (PSC). Significant crosstalk exists between PSCs and tumor cells to stimulate oncogenic signaling and malignant progression of PDAC. However, how PSCs activate intercellular signaling in PDAC cells remains to be elucidated. We have previously shown that activated signal transducer and activator of transcription 3 (STAT3) signaling is a key component in the progression of pancreatic neoplasia. We hypothesize that PSC secreted IL-6 activates STAT3 signaling to promote PanIN progression to PDAC. Human PDAC and mouse PanIN cells were treated with PSC-conditioned media (PSC-CM), and phospho- and total-STAT3 levels by immunoblot analysis were determined. IL-6 was quantified in PSC-CM and cell invasion and colony formation assays were performed in the presence or absence of a neutralizing IL-6 antibody and the JAK/STAT3 inhibitor AZD1480. Serum from Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) and LSL-KrasG12D/+; Trp53R172H/+; Pdx1Cre/+ (KPC) mice demonstrated increased levels of IL-6 compared to serum from non-PDAC bearing KC and PK mice. PSC secreted IL-6 activated STAT3 signaling in noninvasive, precursor PanIN cells as well as PDAC cells, resulting in enhanced cell invasion and colony formation in both cell types. There was a significant positive linear correlation between IL-6 concentration and the ratio of phosphorylated STAT3/total STAT3. IL-6 neutralization or STAT3 inhibition attenuated PSC-CM induced activation of STAT3 signaling and tumorigenicity. These data provide evidence that PSCs are directly involved in promoting the progression of PanINs towards invasive carcinoma. This study demonstrates a novel role of PSC secreted IL-6 in transitioning noninvasive pancreatic precursor cells into invasive PDAC through the activation of STAT3 signaling.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma in Situ/patología , Carcinoma Ductal Pancreático/patología , Interleucina-6/farmacología , Neoplasias Pancreáticas/patología , Células Estrelladas Pancreáticas/patología , Factor de Transcripción STAT3/metabolismo , Animales , Apoptosis , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Interleucina-6/metabolismo , Ratones , Ratones Noqueados , Invasividad Neoplásica , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/efectos de los fármacos , Células Estrelladas Pancreáticas/metabolismo , Transducción de Señal , Células Tumorales Cultivadas , Neoplasias Pancreáticas
16.
J Am Coll Surg ; 223(4): 644-51, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27545100

RESUMEN

BACKGROUND: Earlier work suggested that telephone follow-up could be used in lieu of in-person follow-up after surgery, saving patients time and travel and maximizing use of scarce surgeon and facility resources. We report our experience implementing and evaluating telephone postoperative follow-up within an integrated health system. STUDY DESIGN: We conducted a pre-post evaluation of a general surgery telephone postoperative clinic at a tertiary care Veterans Affairs facility from April 2015 to February 2016. Patients were offered a telephone postoperative visit from a surgical provider in lieu of an in-person clinic visit. Telephone clinic operating procedures were refined through iterative cycles of change using the Plan-Do-Study-Act method. The study period included 2 months pre-intervention and 9 months post-intervention. The primary end point was mean number of clinic visits per eligible patient before and after telephone clinic implementation. Secondary outcomes were rates of emergency department visits and readmissions before vs after telephone clinic implementation and complication rates in patients scheduled for telephone vs in-person postoperative care. RESULTS: During the study period, 200 patients underwent eligible operations, 29 pre-intervention and 171 post-intervention. In-person clinic use decreased from 0.83 visits per eligible patient pre-intervention to 0.40 after implementation of the telephone clinic (p < 0.01). There was no difference in rates of emergency department presentation or readmission in eligible patients (0.17 visits/patient pre-intervention vs 0.12 post-intervention; p = 0.36). Complication rates were comparable for eligible patients who were and were not scheduled for telephone care (6% vs 8%; p = 0.31). CONCLUSIONS: Telephone postoperative care can be used in select populations as a triage tool to identify patients who require in-person care and decrease overall in-person clinic use.


Asunto(s)
Cuidados Posteriores/métodos , Prestación Integrada de Atención de Salud/métodos , Cuidados Posoperatorios/métodos , Telemedicina/métodos , Adulto , Cuidados Posteriores/organización & administración , Anciano , Prestación Integrada de Atención de Salud/organización & administración , Servicio de Urgencia en Hospital/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Hospitales de Veteranos/organización & administración , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Readmisión del Paciente/estadística & datos numéricos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Telemedicina/organización & administración , Teléfono , Tennessee
19.
Curr Surg Rep ; 2: 62, 2014 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-25431745

RESUMEN

The management of synchronous presentation of colorectal cancer and liver metastases has long been a topic of debate and discussion for surgeons due to the unique dilemma of balancing operative timing along with treatment strategy. Operative strategies for resection include staged resection with colon first approach, "reverse" staged resection with liver metastases resected first, and one-stage, or simultaneous, resection of both the primary tumor and liver metastases approach. These operative strategies can be further augmented with perioperative chemotherapy and other novel approaches that may improve resectability and patient survival. The decision on operative timing and approach, however, remains largely dependent on the surgeon's determination of disease resectability, patient fitness, and the need for neoadjuvant chemotherapy.

20.
Onco Targets Ther ; 6: 1261-7, 2013 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-24049451

RESUMEN

Pancreatic ductal adenocarcinoma is one of the most aggressive solid malignancies and is characterized by poor response to current therapy and a dismal survival rate. Recent insights regarding the role of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) in tumorigenesis have brought further understanding to the field and have highlighted new therapeutic targets. CSCs are a distinct subset of cancer cells, with the ability to differentiate into other cell types and self-renew in order to fuel the maintenance of tumor amplification. Transition of a cancer cell from an EMT leads to increased migratory and invasive properties, and thus facilitates initiation of metastasis. EMT is regulated by a complex network of factors that includes cytokines, growth factors, aberrant signaling pathways, transcription factors, and the tumor microenvironment. There is emerging evidence that the EMT process may give rise to CSCs, or at least cells with stem cell-like properties. We review the key pathways involved in both of these processes, the biomarkers used to identify CSCs, and new therapeutic approaches targeting CSCs and EMT in pancreatic ductal adenocarcinoma.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA