Acute aortic dissection associated with use of cocaine.

PURPOSE: Cocaine use can result in a variety of cardiovascular complications, including myocardial infarction, arterial thrombosis, coronary dissection, and cardiomyopathy. Cocaine-induced aortic dissection is uncommon and has been described largely in case reports. The purpose of this study was to review our experience with aortic dissection associated with cocaine abuse. METHODS: A retrospective chart review was performed of all hospital records during a 15-year period in patients diagnosed with aortic dissection. Among the 164 cases of acute aortic dissection, 16 patients (9.8%) had used cocaine or its derivative, crack cocaine, within 24 hours prior to the onset of symptoms. The remaining 148 patients (90.2%) had no history of cocaine usage. Clinical features, management, and outcome in these two groups were compared. RESULTS: In the cocaine group, powder cocaine was inhaled intranasally in 11 patients (69%) and crack cocaine was smoked in five cases (31%). The mean duration between cocaine use and the onset of aortic dissection was 12.8 hours (range, 4 to 24 hours). Patients in the cocaine group were younger in age and more likely to have a history of polysubstance abuse than the non-cocaine cohort. In the cocaine group, the incidence of DeBakey dissection type I, II, IIIa, and IIIb was 19%, 25%, 38%, and 19%, respectively. In the group without cocaine use, the incidence of DeBakey dissection type I, II, IIIa, and IIIb was 18%, 23%, 39%, and 20%, respectively. Surgical intervention for aortic dissection was performed in 50% of the cocaine group and 45% of the non-cocaine group. In patients who underwent surgical repair, greater pulmonary complications occurred in the cocaine group than the non-cocaine group (n = 0.02). No difference was noted in the hospital length of stay or 30-day operative mortality among the two groups. CONCLUSIONS: Cocaine-associated aortic dissection occurs in predominantly male patients with illicit drug abuse who were younger than patients with aortic dissection without cocaine use. Greater pulmonary complications can occur in patients with cocaine-related aortic dissection following surgical interventions.

Receptor tyrosine kinase and phosphoinositide-3 kinase signaling in malignant mesothelioma.

OBJECTIVE: The phosphoinositide-3 kinase signaling pathway is implicated in the development of malignancy and promotes cell-cycle progression and resistance to apoptosis. Malignant mesothelioma tumor specimens demonstrate high levels of the phosphoinositide-3 kinase downstream mediator phosphorylated Akt. Exposure of mesothelioma cell lines to LY294002, a phosphoinositide-3 kinase inhibitor, results in apoptotic cell death and decreased phosphorylated Akt in vitro and tumor burden reduction in vivo. Phosphoinositide-3 kinase is activated by cell-surface receptor tyrosine kinases. We sought to determine which receptors are present in mesothelioma and their role in cellular survival and phosphoinositide-3 kinase signaling. METHODS: Western blot analysis was performed to determine the relative expression of epidermal growth factor receptor, insulin-like growth factor receptor, and platelet-derived growth factor receptor in the mesothelioma cell lines I-45 and REN and the mesothelial line Met5a. After exposure of mesothelioma lines to kinase inhibitors, a cell viability assay was performed, cell-cycle analysis was performed to determine the percentage of apoptosis, and Western blot analysis was performed for phosphorylated Akt. RESULTS: Inhibition of epidermal growth factor receptor resulted in apoptotic cell death and Akt hypophosphorylation in mesothelioma cell lines. Insulin-like growth factor receptor inhibition led to apoptotic cell death without affecting Akt phosphorylation. Platelet-derived growth factor receptor inhibition did not affect cellular survival or phosphoinositide-3 kinase signaling. CONCLUSION: In malignant mesothelioma constitutive activation of phosphoinositide-3 kinase/Akt results in cellular survival and contributes to the malignant phenotype. We have demonstrated that epidermal growth factor receptor inhibition leads to apoptotic cell death through downregulation of phosphoinositide-3 kinase signaling in mesothelioma cell lines, whereas insulin-like growth factor receptor inhibition leads to apoptosis independent of phosphoinositide-3 kinase. Epidermal growth factor receptor, insulin-like growth factor receptor, and phosphoinositide-3 kinase inhibition might be clinically relevant in malignant mesothelioma.

Gene therapy for sarcoma utilizing adenoviral transfer of the beta-glucuronidase and bax genes and an anthracyline prodrug.

BACKGROUND: When acted on by beta-glucuronidase (BG), HMR1826 is metabolized to doxorubicin. Use of this prodrug with adenoviral transfer of beta-glucuronidase (AdBG) is limited by the drug's inability to enter cells and intracellular retention of BG after transduction. We evaluated a system combining AdBG, transfer of the proapoptotic gene bax (AdBax) at a low multiplicity of infection, and HMR1826 administration. MATERIALS AND METHODS: Fibrosarcoma cells were treated with AdBG alone, AdBG plus HMR1826, AdBG followed by beta-galactosidase (AdLacZ) plus HMR1826, and AdBG followed by AdBax with no prodrug. In the experimental group, cells were transfected with AdBG, followed by AdBax plus HMR1826. Viability was measured 24 h after transfection and prodrug administration. Western blots for BG were performed on cell lysates and supernatants. RESULTS: Minimal cellular killing was noted in the AdBG alone, AdBG plus HMR 1826, or AdBG:AdLacZ plus HMR 1826 groups, and Western blot did not demonstrate BG in the supernatant even though all AdBG-transfected cell lysates were positive. Cell killing was noted in the AdBG:AdBax group, but less than in the AdBG:AdBax plus HMR 1826 group (without prodrug versus with prodrug: 1:1 to 55.5% versus 75.9%, 5:1 to 10.0% versus 75.9%, 10:1 7.6% versus 49.0%, 20:1 4.6% versus 24.9%, P = 0.037). Western blot demonstrated BG in the supernatant of the AdBG:AdBax groups. CONCLUSIONS: We have devised a novel enzyme prodrug method of killing tumor cells and engendering a bystander effect. AdBax leads to BG release from dying cells after AdBG transduction and conversion of HMR1826 to an active anthracycline.

The role of Bcl-2 family members in non-small cell lung cancer.

The treatment of advanced nonsmall cell lung cancer (NSCLC) continues to pose great challenges for the thoracic surgeon. Current therapeutic strategies with chemotherapy and radiation are often ineffective adjuncts to surgery. Accordingly, preclinical research concentration has turned to molecular targets that may prove to be more effective. The Bcl-2 family consists of a homologous network of genes that regulate apoptosis or programmed cell death. Altered expression of members in this family leads to aberrant cell proliferation and malignant growth. This review will discuss the expression and significance of Bcl-2 family members in NSCLC and consider potential methods of intervention that are currently being tested and may have clinical applicability. In addition, the current experience with clinical trials involving Bcl-2 down-regulation in solid organ tumors will be summarized.

Gene therapy of lung cancer.

It is estimated that there will be 157,200 deaths from lung cancer in 2003. Current regimens of surgery, chemotherapy and radiation have not significantly changed overall 5-year survival rates for this disease. Thanks to intensive molecular studies over the last three decades, new targets for treatment have been identified, including replacement of tumor suppressor genes, prevention of angiogenesis and tumor growth, and regulation of programmed cell death. Promising advances have been made but obstacles still abound before effective use of these strategies at the patient bedside can occur. One area of concentration lies in developing more accurate and complete delivery of the therapeutic constructs. In the evolution of gene therapy approaches, from beginning theory to translational research, investigators in thoracic malignancies have played a leading role, utilizing a number of methods and delivery vehicles. The objective of this review is to discuss some of the major molecular targets available for manipulation in lung cancer, describe vectors and techniques currently used by thoracic researchers to deliver therapy, and provide the p53 model as an example of progression from bench research to clinical treatment.