RESUMO
BACKGROUND: Gene therapy with plasmid DNA is emerging as a promising strategy for the treatment of many diseases. One of the major obstacles to such therapy is the poor transfection efficiency of DNA in vivo. METHODS: In this report, we employed a very low power, near-infrared femtosecond laser technique to enhance the transfection efficiency of intradermally and intratumorally administered DNA plasmid. RESULTS: We found that femtosecond laser treatment can significantly enhance the delivery of DNA into the skin and into established tumors in mice. In addition, we found that both laser power density as well as duration of laser treatment are critical parameters for augmenting DNA transfection efficiency. The femtosecond laser technique employs a relatively unfocused laser beam that maximizes the transfected area, minimizes damage to tissue and simplifies its implementation. CONCLUSION: This femtosecond new laser technology represents a safe and innovative technology for enhancing DNA gene transfer in vivo.
Assuntos
DNA , Técnicas de Transferência de Genes , Terapia Genética , Lasers , Transfecção , Animais , DNA/administração & dosagem , DNA/genética , Feminino , Técnicas de Transferência de Genes/instrumentação , Terapia Genética/instrumentação , Terapia Genética/métodos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Fatores de Tempo , Transfecção/instrumentação , Transfecção/métodosAssuntos
Traumatismos Abdominais/cirurgia , Hérnia Ventral/complicações , Obstrução Intestinal/etiologia , Complicações Pós-Operatórias/etiologia , Ferimentos por Arma de Fogo/cirurgia , Traumatismos Abdominais/complicações , Adulto , Humanos , Intestino Delgado , Laparotomia , Masculino , Espaço Retroperitoneal , Ferimentos por Arma de Fogo/complicaçõesRESUMO
BACKGROUND: Radiopaque markers (otherwise known as fiducials) are used clinically to mark sites of biopsy or resection, which aids with targeting of local therapy, including surgery and radiation therapy. We performed a human cadaveric imaging series with a novel, injectable, radiopaque, absorbable hydrogel marker to demonstrate its potential in the management of thoracic malignancies. METHODS: Baseline CT imaging was performed on three unfixed cadaveric specimens. Hydrogel marker implants were placed in the submucosa of the esophagus, the mediastinum, and lung parenchyma by an endoscopic approach with real-time endobronchial and esophageal ultrasound guidance. Subpleural implants in peripheral lung parenchyma were also performed through an anterolateral thoracotomy. Postimplant simulation CT imaging, T2-weighted MRI, and cone-beam CT imaging were performed. Gross dissection of the lung parenchyma was used to evaluate localization of the hydrogel. RESULTS: Transthoracic and endoscopic marker placement was readily achieved. The hydrogel appeared hyperechoic by ultrasound, hyperenhancing on T2-weighted MRI, and demonstrated radiopacity of ~300 Hounsfield Units in simulation CT imaging and cone-beam CT imaging. Gross dissection of the lung revealed well-localized blebs of hydrogel marker within lung parenchyma. CONCLUSIONS: This cadaveric series demonstrates the excellent visibility of a radiopaque injectable hydrogel marker in the human thorax by multiple common imaging techniques. The hydrogel marker forms a well-localized bleb within tissue, which can assist with triangulation of disease during minimally invasive thoracic surgery. Esophageal applications include radiographic delineation of tumor defined by endoscopy and image guidance for radiotherapy. Future in vivo studies are warranted because radiopaque injectable compounds are promising alternatives to metal fiducials.
Assuntos
Esôfago/anatomia & histologia , Marcadores Fiduciais , Hidrogel de Polietilenoglicol-Dimetacrilato/administração & dosagem , Pulmão/anatomia & histologia , Mediastino/anatomia & histologia , Cadáver , Tomografia Computadorizada de Feixe Cônico , Humanos , Injeções , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios X , Ultrassonografia de IntervençãoRESUMO
Thymic malignancies are rare tumors of the chest that express a broad range of biological behaviors. Surgery remains the mainstay of therapy, and complete surgical resection is the primary predictor of long-term survival. Although there is a paucity of clinical trials assessing the role of induction/adjuvant chemotherapy and/or radiation therapy in the treatment of thymic malignancies, existing data suggest that induction therapy should be offered for the treatment of advanced-stage disease, and postoperative radiation for specific stages.
Assuntos
Neoplasias do Timo/terapia , Terapia Combinada , Humanos , Estadiamento de Neoplasias , Neoplasias do Timo/patologia , Resultado do TratamentoRESUMO
BACKGROUND: The purpose of this study was to assess the effect of human immunodeficiency virus (HIV) infection on postoperative survival among non-small cell lung cancer (NSCLC) patients. METHODS: A retrospective cohort study compared 22 HIV-infected lung cancer patients to 2,430 lung cancer patients with HIV-unspecified status who underwent resection at Johns Hopkins Hospital from 1985 to 2009. Subcohort comparative analyses were performed using individual matching methods. RESULTS: Thirty-day mortality rates did not differ between HIV-infected and HIV-unspecified patients. Survival rates for HIV-infected lung cancer patients were significantly shorter than for HIV-unspecified patients (median, 26 versus 48 months; p=0.001). After adjustment, the relative hazard of mortality among HIV-infected NSCLC patients was more than threefold that of HIV-unspecified patients (adjusted hazard ratio, 3.08; 95% confidence interval: 1.85 to 5.13). When additional surgical characteristics were modeled in a matched subcohort, the association remained statistically significant (adjusted hazard ratio, 2.31; 95% confidence interval: 1.11 to 4.81). Moreover, HIV-infected lung cancer patients with CD4 counts less than 200 cells/mm3 had shortened median survival compared with patients whose CD4 counts were 200 cells/mm3 or greater (8 versus 40 months; p=0.031). Postoperative pulmonary and infectious complications were also elevated in the HIV-infected group (p=0.001 and p<0.001, respectively). After surgery, median time to cancer progression was shorter among HIV-infected patients (20.4 months) versus HIV-unspecified patients (p=0.061). CONCLUSIONS: The HIV-infected NSCLC patients have more postoperative complications, rapid progression to disease recurrence, and poorer postoperative survival. Optimizing immune status before surgery and careful patient selection based on diffusion capacity of lung for carbon monoxide may improve patient outcomes.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Infecções por HIV/epidemiologia , Neoplasias Pulmonares/epidemiologia , Pneumonectomia/estatística & dados numéricos , Adulto , Idoso , Monóxido de Carbono/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/cirurgia , Masculino , Maryland/epidemiologia , Pessoa de Meia-Idade , Seleção de Pacientes , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Capacidade de Difusão Pulmonar , Estudos Retrospectivos , Fumar/epidemiologia , Fatores SocioeconômicosRESUMO
OBJECTIVES: This study was conducted to determine if pulmonary metastasectomy (PM) for isolated pancreatic cancer metastases is safe and effective. METHODS: This was a retrospective case-control study of patients undergoing PM at our institution from 2000 to 2009 for isolated lung metastasis after resection for pancreatic cancer. Clinical and pathologic data were compared with a matched reference group. Resected neoplasms were immunolabeled for the Dpc4 protein. Kaplan-Meier analysis compared overall survival and survival after relapse. RESULTS: Of 31 patients with isolated lung metastasis, 9 underwent 10 pulmonary resections. At initial pancreas resection, all patients were stage I or II. Other baseline characteristics were similar between the two groups. Median time from pancreatectomy to PM was 34 months (interquartile range 21-49). During the study, 29/31(90.6%) patients died. There were no in-hospital mortalities or complications after PM. Median cumulative survival was significantly improved in the PM group (51 vs. 23 months, p = 0.04). There was a trend toward greater 2-year survival after relapse in the PM group (40% vs. 27%, p = 0.2). CONCLUSIONS: In patients with isolated lung metastasis from pancreatic adenocarcinoma, this is the first study to show that pulmonary resection can be performed safely with low morbidity and mortality. The improved survival in the PM group may result in part from selection bias but may also represent a benefit of the procedure.
Assuntos
Adenocarcinoma/cirurgia , Neoplasias Pulmonares/cirurgia , Neoplasias Pancreáticas/patologia , Adenocarcinoma/química , Adenocarcinoma/secundário , Idoso , Estudos de Casos e Controles , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/química , Neoplasias Pulmonares/secundário , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/química , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Proteína Smad4/análise , Resultado do TratamentoRESUMO
Xanthine oxidoreductase (XOR) is a ubiquitous metalloflavoprotein that appears in two interconvertible yet functionally distinct forms: xanthine dehydrogenase (XD), which is constitutively expressed in vivo; and xanthine oxidase (XO), which is generated by the posttranslational modification of XD, either through the reversible, incremental thiol oxidation of sulfhydryl residues on XD or the irreversible proteolytic cleavage of a segment of XD, which occurs at low oxygen tension and in the presence of several proinflammatory mediators. Functionally, both XD and XO catalyze the oxidation of purines to urate. However, whereas XD requires NAD+ as an electron acceptor for these redox reactions, thereby generating the stable product NADH, XO is unable to use NAD+ as an electron acceptor, requiring instead the reduction of molecular oxygen for this purine oxidation and generating the highly reactive superoxide free radical. Nearly 100 years of study has documented the physiologic role of XD in urate catabolism. However, the rapid, posttranslational conversion of XD to the oxidant-generating form XO provides a possible physiologic mechanism for rapid, posttranslational, oxidant-mediated signaling. XO-generated reactive oxygen species (ROS) have been implicated in various clinicopathologic entities, including ischemia/reperfusion injury and multisystem organ failure. More recently, the concept of physiologic signal transduction mediated by ROS has been proposed, and the possibility of XD to XO conversion, with subsequent ROS generation, serving as the trigger of the microvascular inflammatory response in vivo has been hypothesized. This review presents the evidence and basis for this hypothesis.
Assuntos
Endotélio Vascular/enzimologia , Xantina Oxidase/metabolismo , Animais , Humanos , Traumatismo por Reperfusão/enzimologia , Transdução de Sinais/fisiologia , Ácido Úrico/metabolismo , Vasculite/enzimologiaRESUMO
Endothelial cell ICAM-1 upregulation in response to TNF-alpha is mediated in part by reactive oxygen species (ROS) generated by the endothelial membrane-associated NADPH oxidase and occurs maximally after 4 h as the synthesis of new protein is required. However, thrombin-stimulated P-selectin upregulation is bimodal, the first peak occurring within minutes. We hypothesize that this early peak, which results from the release of preformed P-selectin from within Weibel-Palade bodies, is mediated in part by ROS generated from the endothelial membrane-associated xanthine oxidase. We found that this rapid expression of P-selectin on the surface of endothelial cells was accompanied by qualitatively parallel increases in ROS generation. Both P-selectin expression and ROS generation were inhibited, dose dependently, by the exogenous administration of disparate cell-permeable antioxidants and also by the inhibition of either of the known membrane-associated ROS-generating enzymes NADPH oxidase or xanthine oxidase. This rapid, posttranslational cell signaling response, mediated by ROS generated not only by the classical NADPH oxidase but also by xanthine oxidase, may well represent an important physiological trigger of the microvascular inflammatory response.