RESUMO
Intrinsic and acquired antineoplastic drug resistance remain a major problem for advanced prostate cancer treatment. In order to characterize mechanisms of anti-neoplastic drug resistance in human prostate cancer cell lines, resistant sublines of four of the commonly studied prostate cancer cell lines (DU 145, PC-3, PPC-1, and TSU-PR1) were selected following exposure to increasing concentrations of doxorubicin (from 10-1000 nM). Sensitivity patterns of the parent and doxorubicin-resistant sublines to various anti-neoplastic drugs, including adriamycin, amsacrine, etoposide, camptothecin, vinblastine, vincristine, fluorodeoxyuridine, and melphalan, were determined using a sulforhodamine B growth inhibition assay. The expression of three well-described antineoplastic drug resistance proteins, P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and lung resistance protein (LRP), was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR) assays specific for each of the mRNA species, and using immunocytochemical staining procedures specific for each of the polypeptides. All four of the doxorubicin-selected prostate cancer cell lines exhibited a multidrug resistance phenotype; administration of verapamil restored doxorubicin sensitivity for each of the drug resistant sublines. Although significant MDR1 expression was not detected in any of the parent cell lines before drug exposure by RT-PCR analysis or by immunocytochemistry, both MDR1 mRNA and P-gp protein were expressed by the TSU-PR1 Adr 1000 subline. In contrast, MRP mRNA and protein were present in each of the prostate cancer cell lines before doxorubicin-selection, and an increase in MRP expression appeared to accompany the acquisition of drug resistance in DU 145, PC-3, and PPC-1 doxorubicin-resistant sublines. LRP was variably expressed by each of the parent and resistant cell lines. These data suggest that drug resistance in human prostate cancer may be multifactorial, with MRP and LRP frequently expressed in prostate cancer cells before antineoplastic drug treatment and P-gp expression occasionally acquired after drug exposure.
Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Adenocarcinoma/patologia , Antibióticos Antineoplásicos/farmacologia , Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Resistência a Múltiplos Medicamentos/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/fisiologia , Neoplasias da Próstata/patologia , Partículas de Ribonucleoproteínas em Forma de Abóbada/fisiologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/fisiologia , Transportadores de Cassetes de Ligação de ATP/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Doxorrubicina/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes MDR , Humanos , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Proteínas de Neoplasias/genética , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas/efeitos dos fármacos , Partículas de Ribonucleoproteínas em Forma de Abóbada/genéticaRESUMO
BACKGROUND: Stroke remains a devastating complication of cardiac surgery, but stroke prevention remains elusive. Evaluation of early and long-term clinical outcomes and brain-imaging findings may provide insight into stroke prognosis, etiology, and prevention. METHODS: Five thousand nine hundred seventy-one cardiac surgery patients were prospectively studied for clinical evidence of stroke. Stroke and nonstroke patients were compared by early outcomes. Data collected for stroke patients included brain imaging results, long-term functional status, and survival. Outcome predictors were then determined. RESULTS: Stroke was diagnosed in 214 (3.6%) patients. Brain imaging demonstrated acute infarction in 72%; embolic in 83%, and watershed in 24%. Survival for stroke patients was 67% at 1 year and 47% at 5 years. Independent predictors of survival were cerebral infarct type, creatinine elevation, cardiopulmonary bypass time, preoperative intensive care days, postoperative awakening time, and postoperative intensive care days. Long-term disability was moderate to severe in 69%. CONCLUSIONS: Stroke after cardiac surgery has profound repercussions that are independently related to infarct type and clinical factors. These data are essential for clinical decision making and prognosis determination.
Assuntos
Infarto Cerebral/mortalidade , Cardiopatias/cirurgia , Embolia Intracraniana/mortalidade , Complicações Pós-Operatórias/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Avaliação da Deficiência , Feminino , Seguimentos , Cardiopatias/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
Biliary leaks and injuries are not an uncommon occurrence following laparoscopic cholecystectomy. Bile leaks associated with the biliary anatomic variant of a low-inserting right segmental hepatic duct can be particularly difficult to diagnose in that results of endoscopic retrograde cholangiography (ERC) are usually interpreted as "normal" with no leaks demonstrated. The aim of this study was to describe a single institution's experience with nine patients with biliary leaks associated with this anatomic variant and to discuss their management. A retrospective analysis of the hospital records of all patients with bile duct injuries managed at a single institution between 1980 and July 1998, inclusive, was performed. Nine patients were identified as having an isolated right segmental hepatic duct injury associated with a biliary leak. Seven (78%) of the nine patients had undergone a laparoscopic cholecystectomy, whereas the remaining two patients (22%) had undergone an open cholecystectomy. All of the patients had undergone endoscopic retrograde cholangiography at outside institutions, the results of which had been interpreted as normal with no apparent leaks. The median interval from the time of cholecystectomy to referral was 1.4 months. All patients were managed with initial percutaneous access of the involved right segmental biliary system, with placement of a percutaneous transhepatic stent. After the biliary leak was controlled, all patients underwent Roux-en-Y hepaticojejunostomy to the isolated biliary segment. All patients had an uncomplicated postoperative course. There were no postoperative anastomotic leaks. Postoperative stenting was maintained for a mean of 8 months. Six (67%) of the nine patients had a long-term successful outcome with minimal or no symptoms. In three patients, recurrent symptoms with pain and/or cholangitis developed at a mean of 34 months. All three patients underwent percutaneous cholangiography, which demonstrated an anastomotic stricture, and all were managed with percutaneous balloon dilatation with a successful outcome. Currently eight (89%) of the nine patients are asymptomatic, with a mean follow-up of 70.4 months (range 12 to 226 months). One patient had intermittent right upper quadrant pain with normal liver function tests but has not required intervention. Isolated right segmental hepatic ductal injury with biliary leakage is an uncommon complication following laparoscopic cholecystectomy. A diagnostic dilemma is created by the presence of a bile leak with a normal endoscopic retrograde cholangiogram. Management begins with percutaneous access of the transected isolated ductal system followed by reconstruction as a Roux-en-Y hepaticojejunostomy.