Assuntos
Mitocôndrias/fisiologia , Ferimentos e Lesões/fisiopatologia , Animais , Sistema Cardiovascular/fisiopatologia , Membrana Celular/fisiologia , Sistema Endócrino/fisiopatologia , Feminino , Humanos , Imunidade Celular , Masculino , Camundongos , Microcirculação , Fluxo Sanguíneo Regional , Caracteres Sexuais , Ferimentos e Lesões/imunologiaRESUMO
Current surgical treatments for hepatocellular carcinoma (HCC) include radio-frequency ablation (RFA), resection, and orthotropic liver transplant (OLT). RFA is particularly attractive in these high-risk patients because surgery is associated with high mortality and there is a relative scarcity of organs available for those in need of transplants. This study was performed to evaluate the management of cirrhotic patients with HCC undergoing RFA at a single Western institution. A retrospective study from March 1999 to June 2002 was performed to evaluate the clinicopathologic and treatment-related variables in cirrhotic patients with HCC. Forty-nine lesions in 26 patients with HCC and cirrhosis underwent RFA. Data was analyzed for safety and overall survival as the main endpoints. The mean age was 60.4 +/- 11 years, 19 patients were male, 5 had hepatitis B virus, and 19 had hepatitis C virus. The Child classification was 26 per cent, 39 per cent, and 35 per cent for A, B, and C; the number of lesions was 1 in 62 per cent, 2 in 23 per cent, and more than 2 in 15 per cent. The approach was laparoscopic in 58 per cent, percutaneous in 15 per cent, and open in 27 per cent. There were no mortalities and only 1 complication. Average hospital stay was 2.7 +/- 2 days. Subsequent to RFA, 9 patients underwent an OLT within a median of 4.1 months. The median follow-up of the whole group was 13 months and the disease-free survival 9.3 months. Tumor recurrence was identified in 3 previously ablated lesions, nonablated liver in 11, and as pulmonary metastases in 3. Overall survival (P = 0.03) was prolonged for those treated with RFA + OLT over RFA alone. We conclude that RFA is a safe ablative technique in high-risk cirrhotic patients with HCC. This technique may provide a bridge to OLT; however, it remains to be proven whether it prolongs survival in those who do not undergo OLT.
Assuntos
Carcinoma Hepatocelular/cirurgia , Ablação por Cateter , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/mortalidade , Feminino , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-IdadeRESUMO
Molecular biomarkers for breast cancer are of several types. Risk biomarkers are those associated with increased cancer risk and include mammographic abnormalities, proliferative breast disease with or without atypia, family clustering and inherited germ-line abnormalities. Surrogate endpoint biomarkers are tissue, cellular or molecular alterations that occur between cancer initiation and progression. These biomarkers are utilized as endpoints in short-term chemoprevention trials. Prognostic biomarkers provide information regarding outcome irrespective of therapy, while predictive biomarkers provide information regarding response to therapy. Candidate prognostic biomarkers for breast cancer include elevated proliferation indices such as Ki-67 and proliferating cell nuclear antigen (PCNA); ER and PR overexpression; markers of oncogene overexpression such as c-erbB-2, TGF-a and EGFr; indicators of apoptotic imbalance including overexpression of bcl-2 and an increased bax/bcl-2 ratio; markers of disordered cell signaling such as p53 nuclear protein accumulation; alteration of differentiation signals such as overexpression of c-myc and related proteins; loss of differentiation markers such as TGF-b II receptor and retinoic acid receptor; and alteration of angiogenesis proteins such as VEGF overexpression. As our knowledge regarding molecular biomarkers for breast cancer increases, prognostic indices will be developed that combine the predictive power of individual molecular biomarkers with specific clinical and pathologic factors.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Adulto , Idoso , Animais , Antineoplásicos/uso terapêutico , Apoptose , Biópsia , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto , Receptores ErbB/genética , Feminino , Genes p53 , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Metástase Linfática , Mamografia , Pessoa de Meia-Idade , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Prognóstico , Antígeno Nuclear de Célula em Proliferação/análise , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Regressão , Fatores de RiscoRESUMO
The object of the study was to determine whether male and female sex steroids produce divergent effects on Th1 and Th2 cytokine release following trauma-haemorrhage. Recent studies indicate that androgens are responsible for the depressed splenocyte Th1 cytokine release in males following trauma-haemorrhage. In contrast, female mice maintain their Th1 cytokine release capacity following trauma-haemorrhage. Nonetheless, the effect of male and female sex steroids on Th1 and Th2 cytokine release following trauma-haemorrhage remains unknown. Male C3H/HeN mice were castrated and treated with pellets containing either vehicle, 5alpha-dihydrotestosterone (DHT), 17beta-estradiol (estradiol), or a combination of both steroid hormones, for 14 days prior to soft-tissue trauma (i.e. laparotomy) and haemorrhagic shock (35+/-5 mmHg for 90 min followed by adequate fluid resuscitation) or sham operation. Untreated male and female mice, as well as DHT treated female mice, served as control groups. Twenty-four hours later the animals were sacrificed, plasma obtained and splenocytes harvested. Plasma DHT and estradiol levels in treated animals were comparable with intact male and female mice, respectively. A significant depression of splenocyte Th1 cytokines, i.e. IL-2, IFN-gamma, was observed in DHT treated castrated animals, DHT treated females, and untreated males following trauma-haemorrhage, as opposed to maintained Th1 cytokine release in estradiol treated and estradiol/DHT treated castrated animals and females. The release of the anti-inflammatory cytokine IL-10 was markedly increased in DHT treated mice and males subjected to trauma-haemorrhage compared to shams, but decreased in estrogen treated mice and females under such conditions. These results suggest that male and female sex steroids differentially affect the release of Th1 and Th2 cytokines following trauma-haemorrhage and should be further studied for their potential to modulate splenocyte function in trauma victims.
Assuntos
Citocinas/metabolismo , Di-Hidrotestosterona/farmacologia , Estradiol/farmacologia , Choque Hemorrágico/metabolismo , Lesões dos Tecidos Moles/metabolismo , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C3H , Orquiectomia , Radioimunoensaio , Baço/citologiaRESUMO
HYPOTHESIS: The salutary effects of the testosterone receptor antagonist flutamide on the depressed immune and cardiovascular functions after hemorrhage and resuscitation are related to improved endothelial cell function, which can subsequently lead to an increase in organ blood flow, oxygen delivery, and tissue oxygen consumption. DESIGN, INTERVENTIONS, AND MAIN OUTCOME MEASURES: Male adult rats underwent a 5-cm midline laparotomy (ie, trauma) and were bled to and maintained at a mean systemic arterial pressure of 40 mm Hg until 40% maximal blood-out volume was returned in the form of Ringer lactate). The animals were then resuscitated with 4 times the total volume of shed blood with Ringer lactate for 60 minutes. Flutamide (25 mg/kg) or an equivalent volume of the vehicle propanediol was injected subcutaneously 15 minutes before the end of resuscitation. At 20 hours after resuscitation, aortic rings (approximately 2.5 mm in length) were isolated and mounted in an organ chamber. Dose responses for an endothelium-dependent vasodilator (acetylcholine chloride) and endothelium-independent vasodilator (nitroglycerine) were determined. Organ blood flow was measured using strontium 85-labeled microspheres. Total hemoglobin and oxygen content in the femoral artery and portal, hepatic, and renal veins were determined. Oxygen delivery and consumption in liver, small intestine, and kidneys were calculated. RESULTS: Administration of flutamide after trauma-hemorrhage attenuated the depressed endothelial function. Furthermore, flutamide treatment restored the reduced blood flow and oxygen delivery and consumption in all organs tested after trauma-hemorrhage and resuscitation. CONCLUSION: Flutamide appears to be a useful adjunct for improving vascular endothelial function and regional hemodynamics after trauma-hemorrhage and resuscitation.
Assuntos
Endotélio Vascular/fisiopatologia , Receptores Androgênicos/fisiologia , Choque Hemorrágico/fisiopatologia , Ferimentos e Lesões/complicações , Acetilcolina/farmacologia , Antagonistas de Androgênios/farmacologia , Antagonistas de Receptores de Andrógenos , Animais , Aorta/fisiopatologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Flutamida/farmacologia , Hemoglobinas/análise , Técnicas In Vitro , Masculino , Nitroglicerina/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Ressuscitação , Choque Hemorrágico/etiologia , Choque Hemorrágico/terapia , Vasodilatadores/farmacologiaRESUMO
Recent studies indicate that immune responses in proestrus females are maintained after trauma-hemorrhage but markedly depressed in ovariectomized females under such conditions. The current study tested the hypothesis that the decreased estrogen levels after ovariectomy are responsible for this immune depression. To study this hypothesis, ovariectomized female CBA/J mice were subjected to laparotomy (i.e., soft tissue trauma) and hemorrhagic shock (35 +/- 5 mmHg for 90 min, then resuscitated) or sham operation. The mice received either 17 beta-estradiol (E2; 100 microg/25 g body wt) or vehicle subcutaneously during resuscitation. Immune cells were isolated 24 h thereafter. Splenocyte proliferation and interferon-gamma, interleukin (IL)-2, and IL-3 release were significantly depressed after trauma-hemorrhage in vehicle-treated mice, whereas these functions were maintained in E2-treated mice. Peritoneal macrophage IL-1 beta and IL-6 release and splenic macrophage IL-6 and IL-12 release were also significantly depressed in vehicle-treated mice after trauma-hemorrhage, and release of these cytokines was restored by E2 treatment. In summary our findings indicate that the depressed splenic and peritoneal immune responses after trauma-hemorrhage can be normalized by a single dose of E2. Thus estrogen appears to be the causative factor in the maintenance of immunocompetence in females after trauma-hemorrhage, and its administration to ovariectomized or postmenopausal females should be helpful in preventing immune depression under such conditions.
Assuntos
Estradiol/farmacologia , Hemorragia/imunologia , Tolerância Imunológica/efeitos dos fármacos , Ovariectomia , Animais , Divisão Celular/imunologia , Citocinas/metabolismo , Estradiol/imunologia , Feminino , Laparotomia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos CBA , Fatores Sexuais , Lesões dos Tecidos Moles/imunologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
The activation of a macrophage (Mphi)-dependent proinflammatory cascade following thermal injury plays an important role in the development of immunosuppression and increased susceptibility to subsequent sepsis in burn patients. In contrast, although interleukin (IL)-10, an anti-inflammatory cytokine that can downregulate M phi activity, has also been implicated in postburn immune dysfunction, its role in the regulation of M phi function postburn remains unclear. To study this, C57BL/6 female mice were subjected to a 25% total body surface area third-degree scald burn, and splenic Mphis were isolated 7 days later. Lipopolysaccharide (LPS)-stimulated IL-10, IL-6, tumor necrosis factor (TNF)-alpha, and nitric oxide (NO) production were significantly increased in the burn group compared with shams. Blockade of endogenous IL-10 activity enhanced IL-6 and TNF-alpha release, but not NO release, in both groups. The addition of exogenous IL-10 to the M phi cultures dose dependently suppressed production of these inflammatory mediators in both groups. The timing of IL-10 addition to the cultures in relation to LPS stimulation, however, was critical. The suppressive effect of exogenous IL-10 was attenuated in both groups when the cells were exposed to IL-10 at 4-6 h after LPS stimulation; however, Mphis from injured mice were significantly better able to maintain inflammatory mediator-productive capacity. The resistance of Mphis from injured mice to IL-10-mediated suppression correlated with decreased IL-10 receptor (IL-10R) expression and increased CD11b expression. These findings suggest that Mphis, following thermal injury, display resistance to suppression by IL-10 due in part to downregulation of IL-10R expression.
Assuntos
Queimaduras/imunologia , Tolerância Imunológica/imunologia , Interleucina-10/imunologia , Macrófagos/imunologia , Animais , Células Cultivadas , Feminino , Tolerância Imunológica/efeitos dos fármacos , Interleucina-10/metabolismo , Interleucina-10/farmacologia , Interleucina-6/imunologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Antígeno de Macrófago 1/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Receptores de Interleucina/imunologia , Receptores de Interleucina/metabolismo , Receptores de Interleucina-10 , Baço/citologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Studies have shown gender dimorphism in cell-mediated immune responses following haemorrhage, with depressed responses in young males and maintained or enhanced responses in proestrus females. However, it remains unknown whether or not the sexually dimorphic immune response to haemorrhage provides any protection against a subsequent in vivo polymicrobial septic challenge. To study this, male and proestrus female C3H/HeN mice were subjected to haemorrhage (35+/-5 mmHg for 90 min followed by fluid resuscitation) or sham operation. Twenty-four hours thereafter, all mice were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP) and survival was assessed over a 10 day period. Haemorrhage prior to CLP significantly increased mortality in males as compared to shams. In contrast, mortality in females following CLP was comparable between the sham and haemorrhage groups. Plasma levels of interleukin (IL-)6, tumour necrosis factor (TNF)-alpha and prostaglandin E(2)(PGE(2)) at 5 h after CLP were significantly increased in males subjected to prior haemorrhage. In contrast, plasma levels of IL-6 and TNF-alpha in females did not increase under such conditions. PGE(2)levels were comparable in males and females following CLP, however prior haemorrhage significantly reduced PGE(2)levels in females, whereas no change was observed in males. Liver and splenic expression of cyclooxygenase-2 protein paralleled the changes in plasma PGE(2). Female sex hormones, therefore, appear to play an important role not only in maintaining immune function following haemorrhage, but also provide a survival advantage against subsequent septic challenge.
Assuntos
Sepse/mortalidade , Sepse/patologia , Caracteres Sexuais , Choque Hemorrágico/mortalidade , Choque Hemorrágico/patologia , Animais , Ciclo-Oxigenase 2 , Dinoprostona/sangue , Dinoprostona/imunologia , Feminino , Inflamação/imunologia , Inflamação/mortalidade , Inflamação/fisiopatologia , Interleucina-6/sangue , Isoenzimas/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C3H , Prostaglandina-Endoperóxido Sintases/biossíntese , Sepse/imunologia , Sepse/fisiopatologia , Choque Hemorrágico/imunologia , Choque Hemorrágico/fisiopatologia , Análise de Sobrevida , Fator de Necrose Tumoral alfa/metabolismoRESUMO
INTRODUCTION: Recent studies have shown that administration of the sex steroid dehydroepiandrosterone (DHEA) in males following trauma-hemorrhagic shock has salutary effects on the depressed cardiovascular and immunological functions under those conditions. Since the effects of sex steroids are gender specific, we examined whether administration of DHEA has any beneficial effects on hepatocellular function in female rats with low estrogen levels following trauma-hemorrhage. METHODS: Ovariectomy was performed in female Sprague-Dawley rats 14 days prior to the experiments. The animals then underwent a 5-cm midline laparotomy and were subjected to hemorrhagic shock (40 mm Hg for 90 min). This was followed by fluid resuscitation (Ringer's lactate over 60 min) and administration of DHEA (30 mg/kg BW) or vehicle subcutaneously at the end of resuscitation. At 24 h after resuscitation hepatocellular function, i.e., clearance of indocyanine green (ICG), and hepatocyte damage (serum alanine aminotransferase) were measured. Plasma levels of DHEA and 17beta-estradiol were also assayed. RESULTS: Vehicle-treated rats had significantly reduced hepatocellular function, increased ALT activity, and decreased levels of 17beta-estradiol following trauma-hemorrhage compared to sham-operated animals (P < 0.05, ANOVA and Student-Newman-Keuls test). In animals receiving DHEA following trauma-hemorrhage, hepatocellular function and ALT activity were similar to those of shams. However, administration of DHEA did not influence the plasma levels of 17beta-estradiol. CONCLUSIONS: Administration of DHEA following trauma-hemorrhage restored hepatocellular function and reduced hepatic damage that was observed in ovariectomized female rats under such conditions. This salutary effect of DHEA did not appear to be due to elevated levels of plasma 17beta-estradiol. We therefore propose that DHEA should be considered a novel, safe, and useful adjunct in the treatment of trauma-induced hepatocellular dysfunction in ovariectomized and postmenopausal females.
Assuntos
Adjuvantes Imunológicos/farmacologia , Desidroepiandrosterona/farmacologia , Estradiol/deficiência , Hemorragia/metabolismo , Fígado/lesões , Fígado/fisiologia , Adjuvantes Imunológicos/sangue , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Corantes/farmacocinética , Desidroepiandrosterona/sangue , Estradiol/sangue , Feminino , Hemorragia/tratamento farmacológico , Verde de Indocianina/farmacocinética , Fígado/irrigação sanguínea , Ovariectomia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Although acute fluid replacement after trauma and severe hemorrhage remains the cornerstone in the management of trauma victims, it remains unknown whether continuous resuscitation after trauma-hemorrhage and acute fluid replacement produces salutary effects on cardiovascular function and reduces proinflammatory cytokine release. METHODS: Adult male rats underwent laparotomy (ie, soft tissue trauma) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the shed blood volume was returned in the form of Ringer's lactate (RL). The animals were then resuscitated with 4 times the volume of shed blood with RL for 60 minutes, followed by continuous resuscitation with RL at 5 mL/h/kg for 48 hours after the acute fluid replacement. At 48 hours after hemorrhage, mean arterial pressure, cardiac output, and left ventricular contractility parameters, such as the maximal rates of ventricular pressure increase (+dP/dt(max)) and decrease (-dP/dt(max)), were determined. Microvascular blood flow in the intestine and kidney was assessed by laser Doppler flowmetry. In addition, plasma levels of TNF-alpha were assayed by enzyme-linked immunosorbent assay. RESULTS: The mean arterial pressure and cardiac output were decreased by 34% and 18%, respectively, at 48 hours after hemorrhage and acute resuscitation. Continuous resuscitation, however, markedly improved these parameters. Similarly, +dP/dt(max) and -dP/dt(max) decreased significantly after hemorrhage and acute fluid replacement but was restored to sham values after continuous resuscitation. Microvascular blood flow in the gut and kidneys was decreased after hemorrhage and acute resuscitation by 34% and 35%, respectively. However, intestinal and renal perfusion was maintained at the sham levels at 48 hours after continuous resuscitation. In addition, the upregulated TNF-alpha after acute resuscitation alone was reduced after continuous resuscitation. CONCLUSIONS: Continuous resuscitation after acute fluid replacement appears to be a useful approach for restoring and maintaining cardiovascular function and organ perfusion after trauma and severe hemorrhage.
Assuntos
Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Hidratação/métodos , Hemorragia/terapia , Ressuscitação/métodos , Doença Aguda , Animais , Volume Sanguíneo/fisiologia , Modelos Animais de Doenças , Intestinos/irrigação sanguínea , Laparotomia , Masculino , Microcirculação/fisiologia , Contração Miocárdica/fisiologia , Ratos , Ratos Sprague-Dawley , Circulação Renal/fisiologia , Fator de Necrose Tumoral alfa/metabolismo , Urina , Função Ventricular Esquerda/fisiologia , Água/metabolismoRESUMO
BACKGROUND: Merkel cell carcinoma (MCC) is an unusual and potentially aggressive cancer of the skin. There is no consensus regarding the optimal therapeutic approach, and the relative roles of surgery, radiotherapy, and chemotherapy still are controversial The aim of this study is to analyze the roles of these therapeutic options. METHODS: The medical records of 16 patients with a diagnosis of localized, primary MCC treated at the University of Alabama at Birmingham were reviewed. An extensive review of the English-language literature also was performed. The Kaplan-Meier method was used to develop the survival curves. Comparisons were made using Fisher's exact test. Significance was defined as P < .05. RESULTS: MCC presented primarily in Caucasians (98.3%) with a median age of 69 years. Immunosuppressive therapy appeared to play a role in the development of this cancer. In the UAB experience, 3-year actuarial survival was 31%. The only factor significantly associated with overall survival was the stage of disease at presentation: median survivals were 97 vs. 15 months for stages I and II, respectively (log-rank, P = .02). From the literature review, adjuvant radiotherapy was associated with a reduced risk of local recurrence (P < .00001). CONCLUSIONS: MCC is an aggressive cancer, with a high tendency for local recurrence and distant spread. Surgery and adjuvant radiotherapy appear to provide optimal local control. The role of chemotherapy remains to be defined.
Assuntos
Carcinoma de Célula de Merkel/radioterapia , Carcinoma de Célula de Merkel/cirurgia , Neoplasias Cutâneas/radioterapia , Neoplasias Cutâneas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alabama/epidemiologia , Carcinoma de Célula de Merkel/mortalidade , Carcinoma de Célula de Merkel/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Análise de SobrevidaRESUMO
OBJECTIVE: To assess the prognostic significance of molecular biomarkers, particularly c-erbB-2 and p53, through study of prospective clinical data and archival breast cancer tissues for women accrued to the Alabama Breast Cancer Project. SUMMARY BACKGROUND DATA: Defining molecular abnormalities in breast cancer is an important strategy for early detection, assessment of prognosis, and treatment selection. Evidence is strong that selective biomarkers, including c-erbB-2 and p53, have prognostic significance in breast cancer. Few studies have analyzed the prognostic significance of coexpression of biomarkers. METHODS: Study patients were those accrued to the Alabama Breast Cancer Project (1975-1978) who had archival breast cancer tissues available for analysis. Criteria for entrance into the Alabama Breast Cancer Project were T1-3 breast cancer with M0 status. Age, nodal status, and histologic grade were also documented. Patients were randomized to radical versus modified radical mastectomy, and node-positive patients were also randomized to adjuvant chemotherapy (cyclophosphamide, methotrexate, and 5-fluorouracil [CMF]) versus melphalan. Archival breast cancer tissues were studied for c-erbB-2, TGF-alpha, p53, cathepsin D, bcl-2, and estrogen and progesterone receptor expression using immunohistochemistry. Survival curves were developed using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test, multivariate analysis using a rank regression model. RESULTS: Three hundred eleven patients were accrued to the Alabama Breast Cancer Project, and paraffin-embedded breast cancer tissues for 90 patients were available for immunohistochemical analysis of molecular biomarkers. Univariate analysis showed nodal status, c-erbB-2 expression, and p53 expression to have prognostic significance. Coexpression of c-erbB-2 and p53 was also found to have prognostic significance by the log-rank test. Multivariate analysis showed T stage, nodal status, c-erbB-2 expression, and p53 expression to have independent prognostic significance. CONCLUSIONS: These data suggest that c-erbB-2 and p53 expression in breast cancer have prognostic significance. After median follow-up of 16 years, coexpression of c-erbB-2 and p53 may have more prognostic significance than traditional prognostic factors such as T stage and nodal status. Prospective study of large numbers of patients with breast cancer is encouraged to validate these findings.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Receptor ErbB-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Feminino , Humanos , Imuno-Histoquímica , Mastectomia Radical , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Studies indicate that trauma-hemorrhage results in activation of Kupffer cells to release inflammatory mediators and it leads to immunosuppression and increased susceptibility to subsequent sepsis. The cyclooxygenase (COX) product prostaglandin (PG) E2 appears to be central to this process, however, non-selective inhibition of COX activity with non-steroidal anti-inflammatory agents that block both the constitutive (COX-1) and inducible (COX-2) isoforms of cyclooxygenase has not yielded promising results in trauma patients. Nonetheless, it remains unknown whether selective inhibition of COX-2 activity has any salutary effect following trauma-hemorrhage and subsequent induction of sepsis. To study this, male C3H/HeN mice were subjected to laparotomy (i.e., soft-tissue trauma) and hemorrhagic shock (35 +/- 5 mmHg for 90 min, then resuscitated) or to sham operation. Twenty-four hours later, the mice were subjected to sepsis by cecal ligation and puncture (CLP) or to sham CLP. The mice were treated with the COX-2 inhibitor NS-398 (10 mg/kg body weight, intraperitoneally) or vehicle immediately after trauma-hemorrhage or sham operation, 12 h thereafter, and following CLP or sham CLP. At 5 h after CLP, plasma PGE2, Interleukin-(IL) 6, and TNF-alpha levels were determined along with Kupffer cell IL-6 and TNF-alpha production in vitro. NS-398 treatment markedly suppressed the elevation in plasma PGE2 levels following CLP. The increase in plasma IL-6 levels after CLP were also significantly attenuated by NS-398 treatment. In vitro Kupffer cell IL-6 production after CLP was significantly reduced by in vivo NS-398 treatment. However, NS-398 had no effect on TNF-alpha levels, in vivo and in vitro. These findings indicate that activation of COX-2 following trauma-hemorrhage and subsequent sepsis up-regulates Kupffer cell IL-6 production. Thus, selective inhibition of COX-2 activity may reduce the deleterious consequences of sepsis under such conditions.
Assuntos
Interleucina-6/biossíntese , Isoenzimas/metabolismo , Células de Kupffer/enzimologia , Células de Kupffer/imunologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Sepse/enzimologia , Sepse/imunologia , Choque Hemorrágico/enzimologia , Choque Hemorrágico/imunologia , Ferimentos e Lesões/enzimologia , Ferimentos e Lesões/imunologia , Animais , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase/farmacologia , Dinoprostona/biossíntese , Dinoprostona/sangue , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Interleucina-6/sangue , Células de Kupffer/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Nitrobenzenos/farmacologia , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
OBJECTIVE: To determine whether female sex steroids have any salutary effects on the depressed cardiovascular and hepatocellular functions following trauma and hemorrhage in male animals. SUMMARY BACKGROUND DATA: Studies indicate that gender difference exists in the immune and cardiovascular responses to trauma-hemorrhage, and that male sex steroids appear to be responsible for producing immune and organ dysfunction, but it remains unknown if female sex steroids produce any salutary effects on the depressed cellular and organ functions in males following trauma and hemorrhage. METHOD: Adult male Sprague-Dawley rats underwent a midline laparotomy (i.e., trauma induction), and were bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximum bleed-out volume was returned in the form of Ringer's lactate (RL). Animals were then resuscitated with RL at 4 times the shed blood over 60 minutes. 17beta-estradiol (50 microg/kg) or an equal volume of vehicle was injected subcutaneously 15 minutes before the end of resuscitation. The maximal rate of ventricular pressure increase or decrease (+/-dP/dtmax), cardiac output, and hepatocellular function (i.e., maximal velocity and overall efficiency of in vivo indocyanine green clearance) were assessed at 24 hours after hemorrhage and resuscitation. Plasma levels of interleukin (IL)-6 were also measured. RESULTS: Left ventricular performance, cardiac output, and hepatocellular function decreased significantly at 24 hours after trauma-hemorrhage and resuscitation. Plasma levels of IL-6 were elevated. Administration of 17beta-estradiol significantly improved cardiac performance, cardiac output, and hepatocellular function, and attenuated the increase in plasma IL-6 levels. CONCLUSION: Administration of estrogen appears to be a useful adjunct for restoring cardiovascular and hepatocellular functions after trauma-hemorrhage in male rats.
Assuntos
Estradiol/uso terapêutico , Hemodinâmica/efeitos dos fármacos , Hemorragia/tratamento farmacológico , Hemorragia/fisiopatologia , Fígado/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/fisiopatologia , Análise de Variância , Animais , Débito Cardíaco/efeitos dos fármacos , Corantes/farmacocinética , Estradiol/farmacologia , Verde de Indocianina/farmacocinética , Interleucina-6/sangue , Fígado/metabolismo , Fígado/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Análise de Regressão , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND: Although depression in hepatocellular function occurs early after trauma and severe hemorrhage and persists despite fluid resuscitation, it remains unknown whether reactive oxygen species (ROS) play any role in the initiation of hepatocellular depression and damage under those conditions. We hypothesized that administration of a ROS scavenger at the beginning of resuscitation will attenuate organ injury after severe shock. METHODS: Male Sprague-Dawley rats (275-325 g) underwent laparotomy (i.e., induction of soft tissue trauma) and were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out volume was returned in the form of Ringer's lactate. The animals were then resuscitated with four times the volume of maximal bleed-out with RL over 60 minutes. The ROS scavenger 2-mercaptopropionyl glycine (30 mg/kg) or vehicle was administered intravenously as a bolus at the beginning of resuscitation. At 2 hours after the completion of crystalloid resuscitation or the equivalent interval after sham-operation, cardiac index was measured by a dye dilution technique. Hepatocellular function, i.e., the maximum velocity of indocyanine green clearance (Vmax) and the efficiency of the active transport (Km), was determined using an in vivo hemoreflectometer. Serum levels of tumor necrosis factor (TNF)-alpha and alanine aminotransferase were determined with ELISA and colorimetrically, respectively. RESULTS: The results indicate that at 2 hours after trauma hemorrhage and resuscitation, cardiac index and hepatocellular function were markedly depressed with concomitantly increased serum levels of TNF-alpha and alanine aminotransferase (p < 0.05). Administration of 2-mercaptopropionyl glycine, however, restored the depressed cardiac and hepatic function and markedly attenuated liver enzyme release and serum levels of TNF-alpha (p < 0.05). CONCLUSION: Our data suggest that ROS play a role in producing the depression in organ functions after severe hemorrhagic shock. Thus, adjuncts that attenuate the detrimental effects of ROS may be useful for improving the depressed cardiac and hepatocellular functions after trauma hemorrhage and resuscitation.
Assuntos
Antioxidantes/uso terapêutico , Sequestradores de Radicais Livres/uso terapêutico , Glicina/análogos & derivados , Glicina/uso terapêutico , Falência Hepática/etiologia , Falência Hepática/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Choque Hemorrágico/complicações , Compostos de Sulfidrila/uso terapêutico , Alanina Transaminase/sangue , Animais , Débito Cardíaco , Modelos Animais de Doenças , Verde de Indocianina/farmacocinética , Injeções Intravenosas , Falência Hepática/diagnóstico , Falência Hepática/tratamento farmacológico , Testes de Função Hepática , Masculino , Taxa de Depuração Metabólica , Ratos , Ratos Sprague-Dawley , Ressuscitação/métodos , Fatores de Tempo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: Despite evidence regarding the effectiveness of post-surgical treatments for early-stage breast cancer, older women are less likely to receive appropriate therapy. We evaluated the impact of surgeon-specific "performance reports" on adherence to treatment guidelines among older women with breast cancer. METHODS: We obtained diagnostic and treatment data from hospital tumor registries supplemented with self-reported adjuvant therapy information on 1099 patients with stage I or II breast cancer diagnosed between November 1, 1992, and January 31, 1997, at 6 Rhode Island hospitals. We compared rates of appropriate treatment receipt before and after distribution of performance reports. Hierarchical analysis was used to account for the nesting of patients within surgeons. Separate analyses of mastectomy and breast-conserving surgery were performed. RESULTS: Age was negatively associated with post-surgical treatment, with patients who had breast-conserving surgery and who were older than 80 years significantly less likely to undergo radiation therapy (adjusted odds ratio = 0.08 [0.04, 0.14]) or appropriate adjuvant therapies (adjusted odds ratio = 0.14 [0.08, 0.22]) or both relative to 70- to 79-year-old patients. This effect did not improve post-intervention. While there was much variability in compliance with guidelines, surgeons' characteristics did not explain this variation. CONCLUSIONS: In Rhode Island, advanced age continues to be associated with less than adequate breast cancer therapy. Providing surgeons with "feedback" on the appropriateness of adjuvant treatment for older patients was insufficient to alter established practices. Using guideline compliance data as standard "quality indicators" of physician practice may be required.
Assuntos
Neoplasias da Mama/cirurgia , Cirurgia Geral , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Garantia da Qualidade dos Cuidados de Saúde , Idoso , Idoso de 80 Anos ou mais , Feminino , Hospitais , Humanos , Cuidados Pós-Operatórios/normas , Sistema de Registros , Rhode IslandRESUMO
OBJECTIVE: Early management of trauma victims includes control of bleeding and rapid restoration of intravascular volume. However, it remains controversial whether infusion of blood products is superior to crystalloids alone. Therefore, it was the aim of the present study to determine whether resuscitation with red blood cells plus lactated Ringer's solution (RL) is more effective than RL alone in improving the cardiovascular and hepatocellular functions after trauma and severe hemorrhage. DESIGN: Prospective study. SETTING: Laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS AND MEASUREMENTS: Male adult rats were anesthetized and underwent a laparotomy to induce tissue trauma before hemorrhage. The animals were then bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of the maximal bleed-out (MB) volume was returned in the form of RL, and were then resuscitated with either four times the volume of MB with RL or washed red blood cells (RBC) (-45% the volume of MB) in three times the volume of RL over 60 mins. Various in vivo heart performance variables, cardiac output, and hepatocellular function (ie, the maximum velocity and the overall efficiency of indocyanine green clearance) were determined at 4 hrs after resuscitation. Hemoglobin, systemic oxygen delivery, circulating blood volume, and plasma levels of interleukin-6 were also measured. MAIN RESULTS: At 4 hrs after RL resuscitation, heart performance, cardiac output and hepatocellular function were significantly depressed and plasma levels of interleukin-6 were significantly increased. Although infusion of RBC significantly increased mean arterial pressure, hemoglobin, and oxygen delivery compared with animals resuscitated with RL only, infusion of RBC did not further improve the depressed cardiovascular and hepatocellular functions under such conditions. CONCLUSION: Because infusion of RBC and RL resuscitation do not improve organ functions compared with RL resuscitation without RBC, it appears that pharmacologic agents in addition to fluid resuscitation are needed to restore cardiovascular and hepatocellular functions after trauma and hemorrhage.
Assuntos
Transfusão de Eritrócitos/métodos , Hidratação/métodos , Soluções Isotônicas/uso terapêutico , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/prevenção & controle , Ressuscitação/métodos , Choque Hemorrágico/etiologia , Choque Hemorrágico/terapia , Ferimentos e Lesões/complicações , Animais , Terapia Combinada , Modelos Animais de Doenças , Hemodinâmica , Interleucina-6/sangue , Masculino , Consumo de Oxigênio , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Lactato de Ringer , Choque Hemorrágico/metabolismo , Choque Hemorrágico/fisiopatologiaRESUMO
A gender dimorphic immune response has been observed after trauma and severe hemorrhage, a condition believed to be associated with tissue hypoxia. Although studies have shown that hypoxemia per se in males causes a systemic inflammatory response, it is unclear if the inflammatory response to hypoxemia exhibits gender dimorphic characteristics. To study this, male and female C3H/HeN mice in the proestrus state of the estrous cycle were subjected to hypoxemia (95% N(2)-5% O(2)) or sham hypoxemia (room air) for 60 min. Later (2 h), plasma interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha levels were determined along with splenic immune responses. Plasma IL-6 and TNF-alpha concentrations after hypoxemia were significantly increased in males but not in females. Splenocyte proliferation was depressed in males after hypoxemia but not in females. A shift toward an immunosuppressive Th-2 cytokine profile was observed in males after hypoxemia [decreased interferon-gamma (Th-1) and increased IL-10 (Th-2)], whereas no such shift was observed in females. Splenic macrophage IL-6, IL-10, and IL-12 production were suppressed in males after hypoxemia; however, such suppression was not observed in females. These findings therefore indicate that a gender dimorphic immune response also exists after hypoxemia in the absence of blood loss and tissue trauma, similar to trauma-hemorrhage. Furthermore, because no systemic inflammatory response or alterations in T lymphocyte or macrophage functions are observed in proestrus females but such parameters are markedly altered after severe hypoxemia in males, these studies indicate that proestrus females can tolerate hypoxemia better than males.
Assuntos
Hipóxia/imunologia , Proestro/imunologia , Caracteres Sexuais , Animais , Pressão Sanguínea , Divisão Celular/imunologia , Feminino , Hemorragia , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-3/metabolismo , Interleucina-6/sangue , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Oxigênio/sangue , Baço/citologia , Baço/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Studies have shown that immune responses are depressed in male mice, but not in proestrus females after trauma-hemorrhage (TH), resulting in increased mortality from subsequent sepsis in male mice compared with female mice. These gender-specific alterations in immune function are believed to be due to differences in sex steroid levels. Aromatase is a key enzyme in the sex steroid biosynthesis. Although earlier studies have shown that aromatase inhibitors prevent thymic atrophy in aged male rats, it remains unknown whether the use of 4-hydroxy-androstenedione (4-OHA) after TH in male mice has any salutary effects on the depressed immune responses. Male C3H/HeN mice were sham operated or subjected to trauma (i.e., midline laparotomy) and hemorrhagic shock (30+/-5 mmHg for 90 min) followed by adequate fluid resuscitation. 4-OHA (5 mg/kg) or vehicle was administrated s.c. just before resuscitation. At 2 h after resuscitation, the mice were killed, and spleens were harvested. Splenocyte proliferation, interleukin (IL-2), interferon (IFN-gamma), and IL-10 release and expression of androgen (AR) and estrogen receptors (ER)-alpha and -beta by immunoblot and reverse transcription-polymerase chain reaction (RT-PCR) were assessed. In another group, sepsis was induced by cecal ligation and puncture (CLP) 3 days after resuscitation, and survival was measured over a period of 10 days. A significant decrease in splenocyte proliferation, IL-2, and IFN-gamma release and increased release of IL-10 were observed in vehicle-treated mice. Animals treated with 4-OHA showed increased splenocyte proliferation, IL-2, and IFN-gamma release, and decreased IL-10 release. Immunoblot analysis showed decreased expression of the cytosolic AR, but no significant difference in the cytosolic and nuclear ER-alpha and -beta expression was observed in the vehicle-treated group after TH. In addition, AR and ER-beta mRNA expression was increased, whereas ER-alpha expression decreased in the vehicle-treated group after TH. ER-alpha expression decreased and ER-beta expression increased in the nucleus of 4-OHA treated mice as determined by immunoblot. There was no difference in the cytosolic AR expression in the 4-OHA-treated group after TH. AR and ER-beta mRNA expression was unaffected, whereas ER-alpha expression increased under such conditions. In additional groups, the increased mortality rate after TH and subsequent sepsis was significantly reduced by 4-OHA treatment. Thus, 4-OHA seems to be a novel and useful adjunct for restoring the depressed immune functions in males after TH and for decreasing mortality rates from subsequent sepsis.