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1.
Artigo em Inglês | MEDLINE | ID: mdl-32088126

RESUMO

BACKGROUND: The Bismuth-Corlette (BC) classification is used to categorize hilar cholangiocarcinoma by proximal extension along the biliary tree. As the right hepatic artery crosses just behind the left bile duct, we hypothesized that BC IIIb tumors would have a higher likelihood of local unresectability due to involvement of the contralateral artery. METHODS: A retrospective review of a prospectively maintained database identified patients with hilar cholangiocarcinoma taken to the operating room for intended curative resection between April 2008 and September 2016. Cases were assigned BC stages based on preoperative imaging. RESULTS: Sixty-eight patients were included in the study. All underwent staging laparoscopy after which 16 cases were aborted for metastatic disease. Of the remaining 52 cases, 14 cases were explored and aborted for locally advanced disease. Thirty-eight underwent attempt at curative resection. After excluding cases aborted for metastatic disease, the chance of proceeding with resection was 55.6% for BC IIIb staged lesions compared to 80.0% of BC IIIa lesions and to 82.4% for BC I-IIIa staged lesions (P < 0.05). About 44.4% of BC IIIb lesions were aborted for locally advanced disease versus 17.6% of remaining BC stages. CONCLUSIONS: When hilar cholangiocarcinoma is preoperatively staged as BC IIIb, surgeons should anticipate higher rates of locally unresectable disease, likely involving the right hepatic artery.

2.
Am Surg ; 85(9): 1033-1039, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31638520

RESUMO

Regionalization of complex surgical care has increased interhospital transfers to quaternary centers within large health-care systems. Risk-based patient selection is imperative to improve resource allocation without compromising care. This study aimed to develop predictive models for identifying low-risk patients for transfer to a fully integrated satellite hepatopancreatobiliary (HPB) service in the northeast region of the health-care system. HPB transfers to the quaternary center over 15 months from hospitals in proximity to the satellite HPB center. A predictive tool was developed based on simple pretransfer variables and outcomes for 30-day major complications (Clavien grade ≥ 3), readmission, and mortality. Thresholds for "low risk" were set at different SDs below mean for each model. Predictive models were developed from 51 eligible northeast region patient transfers for major complications (Brier score 0.1948, receiver operator characteristic (ROC) 0.7123, P = 0.0009), readmission (Brier score 0.0615, ROC 0.7368, P = 0.0020), and mortality (Brier score 0.0943, ROC 0.7989, P = 0.0023). Thresholds set from 2 SD below the mean for all models identified 2 as "low risk." Adjusting the threshold for the serious complication model to only 1 SD below the mean increased the "low-risk" cohort to five patients. These models demonstrate an easy-to-use tool to assist surgeons in identifying low-risk patients for diversion to a fully integrated satellite center. Improved interhospital transfers within a region could begin a transition from centers of excellence toward health-care systems of excellence.


Assuntos
Doenças Biliares/cirurgia , Hepatopatias/cirurgia , Modelos Logísticos , Pancreatopatias/cirurgia , Transferência de Pacientes , Medição de Risco/estatística & dados numéricos , Tomada de Decisão Clínica , Cuidados Críticos , Feminino , Mortalidade Hospitalar , Planejamento Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina , Readmissão do Paciente , Complicações Pós-Operatórias , Medição de Risco/métodos
3.
Am Surg ; 85(8): 813-820, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31560300

RESUMO

Management of pyogenic hepatic abscesses (PHA) varies among surgeons and institutions. Recent studies have advocated for first-line percutaneous drainage (PD) of all accessible hepatic abscesses, with surgery reserved as rescue only. Our study aimed to internally validate an established multimodal algorithm for PHA at a high-volume hepatopancreatobiliary center. Patients treated by the hepatopancreatobiliary service for PHA were retrospectively reviewed from 2008 through 2018. The algorithm defined intended first-line treatment as antibiotics for type I abscesses (<3 cm), PD for type II (≥3, unilocular), and surgical intervention (minimally invasive drainage or resection, when possible) for type III (≥3 cm, multilocular). Outcomes were compared between patients who received first-line treatment following the algorithm versus alternate therapy. Of 330 patients with PHA, 201 met inclusion criteria. Type III abscesses had significantly lower failure following algorithmic approach with surgery compared with PD (4% vs 28%, P = 0.018). Type II abscesses failed first-line PD in 27 per cent (13/48) with 11 patients requiring surgical rescue, whereas first-line surgery failed in only 13 per cent (2/15). No deaths occurred after any surgical intervention, and there was no statistical difference in major complications between first-line surgical intervention and PD for type II or III abscesses. These results support the algorithmic approach and demonstrate that minimally invasive surgical intervention is a safe and effective modality for large PHA. We recommend that select patients with large, complex abscesses should be considered for a first-line minimally invasive surgical approach depending on surgical experience and available resources.


Assuntos
Abscesso Hepático Piogênico/cirurgia , Procedimentos Cirúrgicos Minimamente Invasivos , Algoritmos , Drenagem/métodos , Feminino , Humanos , Abscesso Hepático Piogênico/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
4.
Am Surg ; 85(8): 883-894, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31560308

RESUMO

Postoperative laboratory testing is an underrecognized but substantial contributor to health-care costs. We aimed to develop and validate a clinically meaningful laboratory (CML) protocol with individual risk stratification using generalizable and institution-specific predictive analytics to reduce laboratory testing and maximize cost savings for low-risk patients. An institutionally based risk model was developed for pancreaticoduodenectomy and hepatectomy, and an ACS-NSQIP®-based model was developed for distal pancreatectomy. Patients were stratified in each model to the CML by individual risk of major complications, readmission, or death. Clinical outcomes and estimated cost savings were compared with those of a historical cohort with standard of care. Over 34 months, 394 patients stratified to the CML for pancreaticoduodenectomy or hepatectomy saved an estimated $803,391 (44.4%). Over 13 months, 52 patients stratified to the CML for distal pancreatectomy saved an estimated $81,259 (30.5%). Clinical outcomes for 30-day major complications, readmission, and mortality were unchanged after implementation of either model. Predictive analytics can target low-risk patients to reduce laboratory testing and improve cost savings, regardless of whether an institutional or a generalized risk model is implemented. Broader application is important in patient-centered health care and should transition from predictive to prescriptive analytics to guide individual care in real time.


Assuntos
Protocolos Clínicos , Controle de Custos , Testes Diagnósticos de Rotina/economia , Hepatectomia , Preços Hospitalares/estatística & dados numéricos , Pancreatectomia , Pancreaticoduodenectomia , Cuidados Pós-Operatórios/economia , Medição de Risco/métodos , Algoritmos , Feminino , Humanos , Masculino , Estudos Prospectivos , Melhoria de Qualidade , Estados Unidos
5.
Surg Clin North Am ; 99(2): 175-184, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30846028

RESUMO

Acute cholangitis remains a potentially lethal disease if not appropriately diagnosed in a timely fashion. Modern diagnostic and therapeutic modalities have greatly decreased mortality from acute cholangitis. This article aims to provide an up-to-date synopsis of empirically tested diagnostic criteria as well as an overview of the expanding interventions available.


Assuntos
Colangite , Antibacterianos/uso terapêutico , Colangite/diagnóstico , Colangite/etiologia , Colangite/terapia , Drenagem , Endoscopia , Humanos
6.
Am Surg ; 85(8): 909-917, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32051068

RESUMO

Patient-reported outcomes (PROs) are essential for patient-centered health care. This pilot study implemented a mobile application customized to an hepatopancreatobiliary Enhanced Recovery After Surgery (ERAS®) program-a novel environment-for real-time collection of PROs, including ERAS® pathway compliance. Patients undergoing hepatectomy, distal pancreatectomy, or pancreaticoduodenectomy through the ERAS® program were prospectively enrolled over 10 months. The application provided education and questionnaires before surgery through 30 days postdischarge. Thresholds were set for initial adoption of the application (75%), PRO response rate (50%), and patient satisfaction (75%). Daily postdischarge health checks integrated customized responses to guide out-of-hospital care. Of 165 enrolled patients, 122 met inclusion criteria. Application adoption was 93 per cent (114/122) and in-hospital engagement remained high at 88 per cent (107/122). Patients completed 62 per cent of PRO on quality of life, postoperative pain, nausea, opioid consumption, and compliance to ERAS® pathway items, including ambulation and breathing exercises. During postcharge tracking, 12 patients reported that the application prevented a phone call to the hospital and three patients reported prevention of an emergency room visit. PRO collection through this mobile device created an integrated platform for comprehensive perioperative care, patient-initiated outcome tracking with automatic reporting, and real-time feedback for process change. Improving proactive outpatient management of complex patients through mobile technology could help restructure health-care delivery and improve resource utilization for all patients.


Assuntos
Hepatectomia , Aplicativos Móveis/estatística & dados numéricos , Pancreatectomia , Pancreaticoduodenectomia , Medidas de Resultados Relatados pelo Paciente , Satisfação do Paciente/estatística & dados numéricos , Cuidados Pós-Operatórios/métodos , Analgésicos Opioides , Sistemas de Computação , Convalescença , Procedimentos Cirúrgicos Eletivos , Humanos , Dor Pós-Operatória , Cooperação do Paciente/estatística & dados numéricos , Assistência Perioperatória , Projetos Piloto , Cuidados Pós-Operatórios/estatística & dados numéricos , Náusea e Vômito Pós-Operatórios , Avaliação de Programas e Projetos de Saúde , Estudos Prospectivos , Qualidade de Vida
7.
Am Surg ; 85(8): 840-847, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32051069

RESUMO

The role of surgical intervention for necrotizing pancreatitis has evolved; however, no widely accepted algorithm has been established to guide timing and optimal modality in the minimally invasive era. This study aimed to retrospectively validate an established institutional timing- and physiologic-based algorithm constructed from evidence-based guidelines in a high-volume hepatopancreatobiliary center. Patients with necrotizing pancreatitis requiring early (≤six weeks from symptom onset) or delayed (>six weeks) surgical intervention were reviewed over a four-year period (n = 100). Early intervention was provided through laparoscopic drain-guided retroperitoneal debridement (n = 15) after failed percutaneous drainage unless they required an emergent laparotomy (due to abdominal compartment syndrome, bowel necrosis/perforation, or hemorrhage) after which conservative, sequential open necrosectomy was performed (n = 47). Robot-assisted (n = 16) versus laparoscopic (n = 22) transgastric cystgastrostomy for the delayed management of walled-off pancreatic necrosis was compared, including patient factors, operative characteristics, and 90-day clinical outcomes. Major complications after early debridement were similarly high (open 25% and drain-guided 27%), yet 90-day mortality was low (open 8.5% and drain-guided 7.1%). Patient and operative characteristics and 90-day outcomes were statistically similar for robotic versus laparoscopic transgastric cystogastrostomy. Our evidence-based algorithm provides a stepwise approach for the management of necrotizing pancreatitis, emphasizing minimally invasive early and late interventions when feasible with low morbidity and mortality. Robot-assisted transgastric cystogastrostomy is an acceptable alternative to a laparoscopic approach for the delayed treatment of walled-off pancreatic necrosis.


Assuntos
Algoritmos , Pancreatite Necrosante Aguda/cirurgia , Tempo para o Tratamento , Adulto , Cistotomia/métodos , Cistotomia/estatística & dados numéricos , Desbridamento/efeitos adversos , Desbridamento/métodos , Drenagem/mortalidade , Drenagem/estatística & dados numéricos , Medicina Baseada em Evidências , Feminino , Gastrostomia/métodos , Gastrostomia/estatística & dados numéricos , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Pancreatite Necrosante Aguda/mortalidade , Pancreatite Necrosante Aguda/patologia , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/estatística & dados numéricos , Resultado do Tratamento
8.
J Gastrointest Oncol ; 8(4): 696-704, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28890820

RESUMO

BACKGROUND: The role of adjuvant chemoradiotherapy (CRT) following pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PDA) remains controversial. Recent data suggest that increased margin clearance (MC: distance between tumor and cut surface) is associated with improved survival after PD, but the role of adjuvant CRT in patients with known MC is undefined. We sought to delineate the impact of adjuvant CRT on survival based on MC following PD. METHODS: Patients who underwent PD for PDA between 2002 and 2014 were retrospectively stratified into three groups based on MC: 0 mm, ≤1 mm, and >1 mm. The impact of CRT on survival in each MC group was determined by univariate and multivariate analysis. RESULTS: Three hundred and ten patients with known MC were analyzed (0 mm =67, ≤1 mm =113, and >1 mm =130). Increasing MC was independently associated with improved OS (≤1 mm, HR 0.66, 95% CI 0.46-0.96, P=0.03; >1 mm, HR 0.51, 95% CI 0.35-0.75, P=0.001; compared to 0 mm). Adjuvant CRT was administered to 62 patients (20%). On margin-stratified multivariate analysis, adjuvant CRT was independently associated with increased OS in patients with ≤1 mm margins (HR 0.36; 95% CI 0.18-0.69, P=0.002) but not for 0 mm and >1 mm margins. CONCLUSIONS: This analysis suggests that the benefit of adjuvant CRT may be restricted to patients with ≤1 mm MC after PD for pancreatic cancer.

9.
Ann Surg Oncol ; 24(8): 2387-2396, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28534079

RESUMO

BACKGROUND: National Cancer Database analysis showed 70% of patients with stage I pancreatic adenocarcinoma (PDA) did not have surgery. We sought to analyze adherence to expected treatment (ET) by stage for PDA and identify factors that led to no treatment (NT) or unexpected treatment (UT) in a recent cohort. METHODS: Using our Institutional Cancer Registry (ICR), we identified patients with PDA from 2004 to 2013. ET was defined as surgery ± chemotherapy ± radiation for stages I and II, chemotherapy ± radiation for stage III, and chemotherapy for stage IV, while UT was defined as no surgery for stages I and II, surgery for stage III, or ± surgery ± XRT for stage IV. RESULTS: Overall, 2340 patients were identified (stages I and II = 51%, stage III = 11%, stage IV = 38%; ET = 58%, UT = 18%, NT = 24%). A total of 1183 patients had resectable PDA (stages I and II; ET = 57%, UT = 27%, NT = 16%), with ET demonstrating the best overall survival, but UT showing better survival than NT (p < 0.0001). In addition, 261 patients had unresectable PDA (stage III; ET = 69%, UT = 12%, NT = 18%), and survival was best in UT, but ET had a survival advantage over NT (p < 0.0001). Finally, 896 patients had metastatic PDA (stage IV; ET = 55%; UT = 9%; NT = 36%), with the NT group showing worse survival than the ET and UT groups (p < 0.0001). CONCLUSIONS: Unlike previous reports, most patients with early-stage disease had ET. ET and UT were associated with better survival than NT in all stages, and surgical cohorts have improved survival regardless of stage. Younger age, male sex, white race, and less comorbidity were predictors of receiving treatment.


Assuntos
Adenocarcinoma/terapia , Bases de Dados Factuais , Neoplasias Pancreáticas/terapia , Padrões de Prática Médica , Sistema de Registros/estatística & dados numéricos , Adenocarcinoma/patologia , Idoso , Estudos de Coortes , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Neoplasias Pancreáticas/patologia , Taxa de Sobrevida , Fatores de Tempo , Falha de Tratamento
10.
Ann Surg Oncol ; 24(5): 1406-1413, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27896518

RESUMO

BACKGROUND: Locally advanced unresectable pancreatic cancer (LAPC) historically portends a poor prognosis. FOLFIRINOX and gemcitabine/nab-paclitaxel have proven effective in the metastatic setting. We sought to evaluate the outcomes of these regimens compared with older regimens in LAPC. METHODS: A retrospective, single institutional review of all consecutive LAPC treated with "new" (FOLFIRINOX and/or gemcitabine/nab-paclitaxel) and "old" (gemcitabine or 5-FU) chemotherapy from 2010 to 2014 was performed. Univariate and multivariate predictors of resection and survival were determined. RESULTS: A total of 92 patients (new chemotherapy = 61, old chemotherapy = 31) were analyzed, of which 19 (21%) underwent eventual resection (median overall survival [OS] = 32 vs. 14.3 months for unresected patients, P = 0.0002). For the overall cohort, resection (hazard ratio [HR] 0.261, P = 0.014), radiation therapy (HR 0.458, P = 0.004), number of lines of chemotherapy (HR 0.486, P = 0.012), and new chemotherapy (HR 0.593 vs. old regimens, P = 0.065) were independent predictors of OS on multivariate analyses (MVA). On MVA, predictors of eventual resection were head and neck tumors (OR 0.307, P = 0.033) or SMA involvement (OR 0.285, P = 0.023). In nonresected patients (73), MVA showed treatment with new chemotherapy (HR 0.452, P = 0.006), radiation (HR 0.459, P = 0.006), and number of lines of CT (HR 0.705, P = 0.013) to be predictors of survival. CONCLUSIONS: In LAPC, use of FOLFIRNOX and/or gemcitabine/nab-paclitaxel is associated with improved survival compared with older chemotherapy regimens, regardless of eventual resection. Tumor location and relationship to certain vasculature are important determinants of resection in this cohort.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Adenocarcinoma/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Humanos , Metástase Linfática , Masculino , Artéria Mesentérica Superior/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/administração & dosagem , Pâncreas/patologia , Pancreatectomia , Radioterapia , Estudos Retrospectivos , Taxa de Sobrevida
11.
HPB (Oxford) ; 18(10): 835-842, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27506992

RESUMO

BACKGROUND: Distal pancreatectomy with celiac axis resection (DP-CAR) is an option for T4 tumors of the pancreatic body. We examined the perioperative and oncologic outcomes of open and robotic DP-CAR at a high-volume pancreatic center. METHODS: Retrospective review of all consecutive DP-CARs. Patient demographics, 90-day perioperative outcomes, and disease specific survival were collected. RESULTS: 30 DP-CARs were performed (11 Robotic, 19 Open). Both groups had similar preoperative/tumor characteristics, and 27 of 28 PDA patients received neoadjuvant chemotherapy. Robotic DP-CAR was associated with decreased OT (316 vs. 476 min), reduced EBL (393 vs. 1736 ml) and lower rates of blood transfusion (0% vs. 54%) (all p < 0.05). No robotic DP-CAR required conversion. Both groups had similar rates of 90-day mortality, major morbidity, LOS, readmission, and receipt of adjuvant therapy. Similarly, both approaches were associated with high R0 resection rates (82% vs. 79%). At a median follow-up of 33 months, median overall survival for the PDA cohort was 35 months, with no difference in the robotic and open approach (33 and 40 months, p = 0.310). CONCLUSIONS: With a median survival approaching 3 years, DP-CAR represents an effective treatment for select patients with locally advanced pancreatic body cancer, regardless of approach.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Artéria Celíaca/cirurgia , Pancreatectomia/métodos , Neoplasias Pancreáticas/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Idoso , Transfusão de Sangue , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante , Feminino , Hospitais com Alto Volume de Atendimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Neoplasia Residual , Duração da Cirurgia , Pancreatectomia/efeitos adversos , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Pennsylvania , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Fatores de Risco , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Procedimentos Cirúrgicos Robóticos/mortalidade , Fatores de Tempo , Resultado do Tratamento
12.
Surg Clin North Am ; 96(2): 299-313, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27017866

RESUMO

This review provides an overview of the background and progress that has been made in minimally invasive liver surgery. The essential steps of minimally invasive right and left lobectomy as well as left lateral sectionectomy are reviewed. In addition, existing data regarding the feasibility and oncologic outcomes of minimally invasive hepatic resection for malignancy are discussed.


Assuntos
Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos
13.
J Surg Oncol ; 112(3): 295-301, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26119652

RESUMO

Utilization of robotic techniques for resection of the liver is slowly gaining acceptance in specific situations and is now being applied to more challenging endeavors, such as major hepatectomy for cancer. This review provides a summary of robotic applications in liver surgery, with specific attention perioperative outcomes, oncologic outcomes, cost, and comparison to conventional laparoscopic techniques of liver resection. We also discuss future applications of robotic-assisted liver surgery.


Assuntos
Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Previsões , Humanos , Laparoscopia/métodos , Procedimentos Cirúrgicos Robóticos/tendências , Resultado do Tratamento
14.
J Exp Med ; 210(13): 2873-86, 2013 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-24323358

RESUMO

Tumor-associated macrophages (TAMs) are a major component of the cancer microenvironment. Modulation of TAMs is under intense investigation because they are thought to be nearly always of the M2 subtype, which supports tumor growth. Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically results from an activating mutation in the KIT oncogene. Using a spontaneous mouse model of GIST and 57 freshly procured human GISTs, we discovered that TAMs displayed an M1-like phenotype and function at baseline. In both mice and humans, the KIT oncoprotein inhibitor imatinib polarized TAMs to become M2-like, a process which involved TAM interaction with apoptotic tumor cells leading to the induction of CCAAT/enhancer binding protein (C/EBP) transcription factors. In human GISTs that eventually developed resistance to imatinib, TAMs reverted to an M1-like phenotype and had a similar gene expression profile as TAMs from untreated human GISTs. Therefore, TAM polarization depends on tumor cell oncogene activity and has important implications for immunotherapeutic strategies in human cancers.


Assuntos
Tumores do Estroma Gastrointestinal/metabolismo , Macrófagos/imunologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Sarcoma/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Benzamidas/química , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proliferação de Células , Feminino , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/genética , Humanos , Mesilato de Imatinib , Inflamação , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Fenótipo , Piperazinas/química , Pirimidinas/química , Sarcoma/tratamento farmacológico , Sarcoma/genética
15.
Ann Surg Oncol ; 20(13): 4298-304, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23884754

RESUMO

BACKGROUND: Analysis of portal lymph node (LN) metastases following resection of biliary carcinomas at or above the cystic duct (BC) is used to select patients for adjuvant therapy, but no guidelines exist and LN yield is low. Some consider analysis of 7 LNs necessary for accurate staging. Conventional LN analysis may understage patients. METHODS: Portal LNs from 38 node-negative patients following resection of BC from 2000 to 2008 were re-examined in detail for occult metastases (OM) using a modified Weaver protocol. Outcomes measured were discordance in LN positivity and patient survival. RESULTS: On detailed examination, 5 of 38 patients had OM. There was no difference in survival between patients with and without OM (24 vs 17 months; p = .382). There was no association between OM and patient demographics or adverse tumor characteristics. The median LN yield was 3. Of the 27 patients with <7 LNs retrieved, 1 had OM, compared with 4 of 11 patients with ≥7 LNs retrieved (p = .030). OM in these well-staged patients were associated with reduced survival (9 vs 41 months; p = .032). CONCLUSIONS: There is discordance between conventional and detailed LN analysis in resected BC. LN yield ≥7 was associated with OM. The presence of OM may be associated with decreased survival. Conventional LN analysis may understage patients with resected BC.


Assuntos
Neoplasias do Sistema Biliar/patologia , Ducto Cístico/patologia , Excisão de Linfonodo , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/cirurgia , Ducto Cístico/cirurgia , Feminino , Seguimentos , Humanos , Linfonodos/cirurgia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
16.
J Hepatol ; 57(4): 766-73, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22641092

RESUMO

BACKGROUND & AIMS: The mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinase (JNK), and p38, mediate liver ischemia/reperfusion (I/R) injury via cell death and inflammatory cytokine expression, respectively. Nilotinib is an orally available receptor tyrosine kinase inhibitor used for chronic myelogenous leukemia that also has in vitro activity against JNK and p38. In this study, we examine its therapeutic potential against hepatic I/R injury. METHODS: The effects of nilotinib on liver I/R injury were tested using a murine model of warm, segmental liver I/R. Serum ALT was measured and livers were analyzed by histology, RT-PCR, Western blot, and flow cytometry. The in vitro effects of nilotinib on hepatocyte and non-parenchymal cell (NPC) MAPK activation and cytokine production were also tested. RESULTS: Mice receiving nilotinib had markedly lower serum ALT levels and less histologic injury and apoptosis following liver I/R. Nilotinib did not inhibit its known receptor tyrosine kinases. Nilotinib lowered intrahepatic expression of IL-1ß, IL-6, MCP-1, and MIP-2 and systemic levels of IL-6, MCP-1, and TNF. Nilotinib reduced NPC activation of p38 MAPK signaling and decreased the recruitment of inflammatory monocytes and their production of TNF. Nilotinib attenuated JNK phosphorylation and hepatocellular apoptosis. In vitro, nilotinib demonstrated direct inhibition of JNK activation in isolated hepatocytes cultured under hypoxic conditions, and blocked activation of p38 MAPK and cytokine production by stimulated NPCs. CONCLUSIONS: Nilotinib lowers both liver JNK activation and NPC p38 MAPK activation and may be useful for ameliorating liver I/R injury in humans.


Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Alanina Transaminase/sangue , Animais , Apoptose/efeitos dos fármacos , Benzamidas , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CXCL2/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hepatócitos , Mesilato de Imatinib , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Fosforilação/efeitos dos fármacos , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-abl/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Traumatismo por Reperfusão/patologia
17.
Nat Med ; 17(9): 1094-100, 2011 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-21873989

RESUMO

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Tumores do Estroma Gastrointestinal/imunologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunoterapia/métodos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Benzamidas , Western Blotting , Linfócitos T CD8-Positivos/efeitos dos fármacos , Imunoprecipitação da Cromatina , Citometria de Fluxo , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Tumores do Estroma Gastrointestinal/terapia , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Mesilato de Imatinib , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas c-kit/metabolismo , Pirimidinas/uso terapêutico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Reguladores/efeitos dos fármacos
18.
J Leukoc Biol ; 89(3): 423-32, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21106642

RESUMO

Septic peritonitis remains a major cause of death. Neutrophils and inflammatory monocytes are principal components of the innate immune system and are essential for defense against a range of microbial pathogens. Their role and interaction in polymicrobial sepsis have not been defined clearly. Using a murine model of CLP to induce moderate sepsis, we found that neutrophil depletion did not alter survival, whereas depletion of neutrophils and inflammatory monocytes markedly reduced survival. After neutrophil depletion, inflammatory monocytes had greater phagocytic capacity and oxidative burst, and increased expression of costimulatory molecules, TNF, and iNOS. Notably, peritoneal neutrophils produced IL-10 following CLP. Adoptive i.p. transfer of WT but not IL-10(-/-) neutrophils into septic mice reduced monocyte expression of TNF. In vitro experiments confirmed that monocyte suppression was mediated by neutrophil-derived IL-10. Thus, during septic peritonitis, neutrophils suppress peritoneal inflammatory monocytes through IL-10 and are dispensable for survival.


Assuntos
Interleucina-10/imunologia , Monócitos/patologia , Neutrófilos/imunologia , Peritonite/complicações , Peritonite/imunologia , Sepse/imunologia , Sepse/microbiologia , Animais , Inflamação/complicações , Inflamação/imunologia , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/enzimologia , Neutrófilos/enzimologia , Óxido Nítrico Sintase Tipo II/metabolismo , Peritonite/patologia , Sepse/complicações , Sepse/patologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/metabolismo
19.
J Clin Invest ; 120(2): 559-69, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20093775

RESUMO

TLRs are recognized as promoters of tissue damage, even in the absence of pathogens. TLR binding to damage-associated molecular patterns (DAMPs) released by injured host cells unleashes an inflammatory cascade that amplifies tissue destruction. However, whether TLRs possess the reciprocal ability to curtail the extent of sterile inflammation is uncertain. Here, we investigated this possibility in mice by studying the role of conventional DCs (cDCs) in liver ischemia/reperfusion (I/R) injury, a model of sterile inflammation. Targeted depletion of mouse cDCs increased liver injury after I/R, as assessed by serum alanine aminotransferase and histologic analysis. In vitro, we identified hepatocyte DNA as an endogenous ligand to TLR9 that promoted cDCs to secrete IL-10. In vivo, cDC production of IL-10 required TLR9 and reduced liver injury. In addition, we found that inflammatory monocytes recruited to the liver via chemokine receptor 2 were downstream targets of cDC IL-10. IL-10 from cDCs reduced production of TNF, IL-6, and ROS by inflammatory monocytes. Our results implicate inflammatory monocytes as mediators of liver I/R injury and reveal that cDCs respond to DAMPS during sterile inflammation, providing the host with protection from progressive tissue damage.


Assuntos
Células Dendríticas/imunologia , Interleucina-10/metabolismo , Traumatismo por Reperfusão/prevenção & controle , Animais , Antígeno B7-1/biossíntese , Antígeno B7-2/biossíntese , Antígenos CD40/biossíntese , DNA/metabolismo , Citometria de Fluxo , Hepatócitos/fisiologia , Inflamação/imunologia , Interleucina-10/imunologia , Camundongos , Monócitos/fisiologia , Receptores CCR2/fisiologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Receptor Toll-Like 9/imunologia
20.
Hepatology ; 51(2): 621-32, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19902481

RESUMO

UNLABELLED: Endogenous ligands such as high-mobility group box 1 (HMGB1) and nucleic acids are released by dying cells and bind Toll-like receptors (TLRs). Because TLR9 sits at the interface of microbial and sterile inflammation by detecting both bacterial and endogenous DNA, we investigated its role in a model of segmental liver ischemia-reperfusion (I/R) injury. Mice were subjected to 1 hour of ischemia and 12 hours of reperfusion before assessment of liver injury, cytokines, and reactive oxygen species (ROS). Wild-type (WT) mice treated with an inhibitory cytosine-guanosine dinucleotide (iCpG) sequence and TLR9(-/-) mice had markedly reduced serum alanine aminotransferase (ALT) and inflammatory cytokines after liver I/R. Liver damage was mediated by bone marrow-derived cells because WT mice transplanted with TLR9(-/-) bone marrow were protected from hepatic I/R injury. Injury in WT mice partly depended on TLR9 signaling in neutrophils, which enhanced production of ROS, interleukin-6 (IL-6), and tumor necrosis factor (TNF). In vitro, DNA released from necrotic hepatocytes increased liver nonparenchymal cell (NPC) and neutrophil cytokine secretion through a TLR9-dependent mechanism. Inhibition of both TLR9 and HMGB1 caused maximal inflammatory cytokine suppression in neutrophil cultures and conferred even greater protection from I/R injury in vivo. CONCLUSION: TLR9 serves as an endogenous sensor of tissue necrosis that exacerbates the innate immune response during liver I/R. Combined blockade of TLR9 and HMGB1 represents a clinically relevant, novel approach to limiting I/R injury.


Assuntos
Proteína HMGB1/antagonistas & inibidores , Proteína HMGB1/fisiologia , Fígado/irrigação sanguínea , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/prevenção & controle , Receptor Toll-Like 9/antagonistas & inibidores , Receptor Toll-Like 9/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL
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