Apoptosis block as a barrier to effective therapy in non small cell lung cancer.

Lung cancer, is the most common cause of cancer death in men and second only to breast cancer in women. Currently, the first line therapy of choice is platinum-based combination chemotherapy. A therapeutic plateau has been reached with the prognosis for patients with advanced non-small cell lung cancer (NSCLC) remaining poor. New biomarkers of prognosis as well as new therapies focusing on molecular targets are emerging helping to identify patients who are likely to benefit from therapy. Despite this, drug resistance remains the major cause for treatment failure. In this article we review the role of apoptosis in mediating drug resistance in NSCLC. Better understanding of this fundamental biological process may provide a rationale for overcoming the current therapeutic plateau.

Traumatic left anterior descending artery-to-pulmonary artery fistula with delayed pericardial tamponade.

Traumatic coronary artery fistulas are rare, but 80% are secondary to penetrating injuries. Although the left coronary artery is involved in 46% of cases, these are usually associated with fistulas to the right ventricle. We describe a successful repair of a traumatic fistula from the proximal left anterior descending artery to the pulmonary artery after delayed presentation.

Pericardiocutaneous fistula: presentation with acute hemorrhage 8 years following aortic valve replacement.

Pericardiocutaneous fistula is a rare complication of cardiac surgery. A 35-year-old female presented with acute severe hemorrhage from a pericardiocutaneous fistula eight years following aortic valve replacement. Computed tomography showed a large, pericardial collection causing tamponade, connected to a smaller subcutaneous cavity, with a tract leading to the skin. The patient underwent emergency surgical exploration with removal of hematoma, hemostasis, and partial pericardectomy. One year following the operation, the patient remains stable. Factors in the development of pericardiocutaneous fistula were valve replacement, infection, and warfarin anticoagulation.

Concomitant mitral valve surgery with aortic valve replacement: a 21-year experience with a single mechanical prosthesis.

BACKGROUND: Long-term survival for combined aortic and mitral valve replacement appears to be determined by the mitral valve prosthesis from our previous studies. This 21-year retrospective study assess long-term outcome and durability of aortic valve replacement (AVR) with either concomitant mitral valve replacement (MVR) or mitral valve repair (MVrep). We consider only a single mechanical prosthesis. METHODS: Three hundred and sixteen patients underwent double valve replacement (DVR) (n = 273) or AVR+MVrep (n = 43), in the period 1977 to 1997. Follow up of 100% was achieved via telephone questionnaire and review of patients' medical records. Actuarial analysis of long-term survival was determined by Kaplan-Meier method. The Cox regression model was used to evaluate potential predictors of mortality. RESULTS: There were seventeen cases (5.4%) of early mortality and ninety-six cases of late mortality. Fifteen-year survival was similar in both groups at 44% and 57% for DVR and AVR+MVrep respectively. There were no significant differences in valve related deaths, anticoagulation related complications, or prosthetic valve endocarditis between the groups. There were 6 cases of periprosthetic leak in the DVR group. Sex, pre-operative mitral and aortic valve pathology or previous cardiac surgery did not significantly affect outcome. CONCLUSION: The mitral valve appears to be the determinant of survival following double valve surgery and survival is not significantly influenced by mitral valve repair.

Plasma fibrinogen and serum C-reactive protein are associated with non-small cell lung cancer.

OBJECTIVES: There is an association between coagulation and lung cancer. Therefore, pre-operative plasma fibrinogen and serum C-reactive protein (CRP) concentration were assessed to determine their association with tumour characteristics and to ascertain any role in patient selection for curative resection. METHODS: These parameters were compared with tumour size, pTNM stage, and possibility of complete resection in 93 patients with non-small cell lung cancer who underwent surgical resection. RESULTS: Plasma fibrinogen concentration (r(s)=0.34, P=0.001) and serum CRP concentration (r(s)=0.34, P=0.001) were positively correlated with maximum pathological tumour size. A higher plasma fibrinogen concentration was associated with squamous cell carcinoma versus adenocarcinoma (4.5+/-0.13 g/L versus 3.6+/-0.28 g/L; P=0.008), with a trend towards a similar association for CRP (P=0.06). Pathological T stage was also associated with mean plasma fibrinogen and serum CRP concentration (P=0.01 and 0.04, respectively), but pN stage was not associated with either parameter. Incomplete resection occurred in 23% of patients with plasma fibrinogen > 5 g/L or serum CRP > 40 mg/L (versus only 8% when fibrinogen < or = 5 g/L and CRP < or = 40 mg/L; P=0.09). CONCLUSIONS: Plasma fibrinogen and serum CRP are associated with tumour characteristics. High values were associated with inability to achieve complete resection which may refine patient selection for thoracotomy when used with other staging modalities. Attempted resection may be justified in a patient of borderline fitness who has favourable plasma fibrinogen and serum CRP concentration, where a high resection rate is possible. As the relationship was with T stage rather than N stage it may be complimentary to PET scanning, which has only marginally better accuracy for T stage than CT scanning.

Impact of coronary artery bypass grafting on survival after aortic valve replacement.

Treatment of coronary artery disease by coronary artery bypass grafting (CABG) concurrently with aortic valve replacement (AVR) improves outcome but survival compared to isolated AVR remains uncertain, as does the role of the left internal mammary artery (LIMA) graft to the left anterior descending (LAD) artery. All 799 patients undergoing elective primary AVR, using the St. Jude Medical mechanical prosthesis, with or without CABG, between March 1986 and May 2000, were reviewed with 100% follow-up. Operative mortality was 1.6% in 574 patients undergoing isolated AVR, 2.6% in 78 patients undergoing combined AVR and CABG with LIMA to LAD grafting (LIMA-AVR), 6.25% in 64 patients receiving vein grafts only to circumflex or right coronary artery territories (Non-LAD VG-AVR) and 2.4% in 83 patients receiving vein grafts to vessels including the LAD (LAD VG-AVR). Cox regression analysis showed improved survival after AVR compared to LAD VG-AVR (P=0.008), but with no significant difference to survival after LIMA-AVR (P=0.18) and Non-LAD VG-AVR (P=0.08). Multivariable regression analysis identified advanced age (P<0.001), male sex (P<0.001), absence of diabetes (P=0.02), number of grafts performed during surgery (P=0.04), non-congenital valvular pathology (P=0.001) and regurgitant valve disease (P=0.008) as independent predictors of reduced survival. LIMA-LAD grafting was not a significant variable in the multivariable model.

Gene therapy approaches to cardiovascular disease.

The potential of enhanced cardiovascular function via gene therapy has aroused extensive interest. Both viral and nonviral vectors have shown promise in the realm of cardiovascular gene therapy. Modification of vectors or addition of further transgenes to the expression cassette has permitted targeted and regulated gene expression. The many potential targets of cardiovascular gene therapy can be considered under the following headings: vascular, congenital heart disease, and myocardial. Cardiac gene delivery may be to either the endothelium of either native coronary vessels or coronary artery bypass grafts, or to the myocardium. Myocardial gene delivery is possible either via direct myocardial injection or via the coronary vasculature. However, alteration of any cardiac cellular signaling pathway may have cardiotoxic effects. Thus, any genes that appear to cause enhanced cardiac function, must undergo extensive toxicity studies in animals before similar experiments are performed in human subjects. The techniques described may be utilized in the future to deliver various genes targeted to combat many different disease processes, in different animal models, and ultimately to provide feasible gene therapy approaches to human cardiovascular disease.

Cardiac gene delivery using DNA-adenoviral constructs.

In view of the limitations of current cardiac gene transfer techniques by direct myocardial injection, or via the coronary vasculature, we have been attempting to develop potentially clinically applicable methods. Selective catheterization of the coronary arteries has been performed, but the duration of exposure of the heart to the virus is limited. Present systems require high infusion pressure to inject the virus, which could result in endothelial or myocardial injury, and extracardiac transgene expression occurs. An alternative method has been developed in which the adenoviral vector is administered following cardioplegic arrest of the heart during cardiopulmonary bypass (CPB), which allows prolonged myocardial contact with the adenoviral vector. This may be advantageous since intracoronary delivery of vector in a Langendorff perfused heart model has shown that prolonged contact time with the virus improves gene transfer. Despite the detrimental effect of cold temperatures and contact with blood on transgene expression in the in vitro and ex vivo studies, we have demonstrated that these factors are unimportant in this in vivo model. Exposure of extracardiac tissues to the vector is limited. Moreover, administration of the beta2AR transgene has resulted in amelioration of impaired cardiac function following CPB and cardioplegic arrest.

beta2 adrenoceptor gene therapy ameliorates left ventricular dysfunction following cardiac surgery.

OBJECTIVE: Heart surgery is associated with impairment of the myocardial beta-adrenoceptor (betaAR) system. Effective therapies for post-operative ventricular dysfunction are limited. Prolonged inotrope exposure is associated with further betaAR down-regulation. Left ventricular (LV) dysfunction and myocardial betaAR impairment were assessed following cardiopulmonary bypass (CPB) and cardioplegic arrest in a pig model. Transfer of the human beta2-adrenoceptor transgene (Adeno-beta2AR) during cardioplegic arrest was then tested as a potential therapy. METHODS: Five groups of six neonatal piglets were studied. One group did not undergo surgery (Group A). Adeno-beta2AR or phosphate buffered saline (PBS) were delivered via the aortic root during cardioplegic arrest. Groups B (PBS) and C (Adeno-beta2AR) were assessed at 2 days while Groups D (PBS) and E (Adeno-beta2AR) were assessed at 2 weeks from the time of surgery. An LV micromanometer was inserted under sedation to obtain pressure recordings following surgery. betaAR density was measured subsequently. RESULTS: Following cardiac surgery LV betaAR density was reduced (104+/-5.7 vs 135+/-6.1 fmol/mg membrane protein; P=0.007), and, in response to beta agonist stimulation, LV dP/dtmax was reduced (4337+/-405 vs 5328+/-194 mmHg/s; P<0.05) compared to animals which did not undergo surgery. Adeno-beta2AR therapy during cardiac surgery resulted in elevated LV betaAR density (520+/-250.9 fmol/mg) 2 days post-operatively compared to PBS (104+/-5.7 fmol/mg; P=0.002) and compared to the no surgery group (135+/-6.1 fmol/mg; P=0.002). Elevated LV betaAR density was also present at 2 weeks (315+/-74.1 vs 119+/-7.1 fmol/mg; P=0.002). In addition, Adeno-beta2AR therapy enhanced beta agonist stimulated LV dP/dtmax (5348+/-121 vs 4337+/-405 mmHg/s; P<0.05) and heart rate (209+/-6.9 vs 173+/-11.0 bpm; P<0.05), and reduced LVEDP (2.1+/-0.4 vs 6.4+/-1.8 mmHg; P<0.05) compared to PBS treatment. Interestingly, gene delivery was cardiac-selective and beneficial effects on function persisted for 2 weeks. Moreover, beta2AR gene transfer ameliorated LV dysfunction following surgery such that there were no significant differences between non-operated controls and animals treated with Adeno-beta2AR during CPB and cardioplegic arrest. CONCLUSIONS: Reduced betaAR density and impaired LV function were present following CPB and cardioplegic arrest. Cardiac-selective beta2AR gene transfer during CPB resulted in amelioration of LV dysfunction after cardiac surgery. Such a technique may offer a new approach to post-operative ventricular support.

Dose dependent effects of cardiac beta2 adrenoceptor gene therapy.

BACKGROUND: Adenoviral-mediated gene transfer during cardiopulmonary bypass (CPB) achieves efficient myocardial transgene expression. The optimal vector dose required to produce not only increased beta adrenoceptor (betaAR) density but, more importantly, enhanced left ventricular (LV) function is unknown. In addition, it is unclear if absent extracardiac expression in preliminary studies represented cardiac specific, as opposed to selective gene delivery, as a consequence of low vector doses. MATERIALS AND METHODS: Adenoviral vector encoding the human beta(2) adrenoceptor (Adeno-beta(2)AR) was delivered to cardioplegic arrested hearts of neonatal piglets during CPB in three doses ranging from 5 x 10(11) total viral particles (tvp) to 2 x 10(12) tvp. Control animals received adenoviral vector encoding beta galactosidase (Adeno-betagal) or PBS (PBS). LV and liver betaAR density and in vivo LV function were assessed 5 days later. RESULTS: Elevated LV betaAR density was present after delivery of Adeno-beta(2)AR at all doses. Piglets which received 5 x 10(11) tvp and 1 x 10(12) tvp Adeno-beta(2)AR demonstrated enhanced LV dP/dt(max) but in those receiving 2 x 10(12) tvp LV dP/dt(max) was unchanged. Moreover, at this higher dose of adenoviral vector the detrimental effects of cardiac inflammation and extracardiac gene overexpression became apparent. CONCLUSIONS: Although the highest increase in cardiac betaAR density occurred after high-dose Adeno-beta(2)AR, LV dP/dt(max) was not enhanced. Moreover, significant extracardiac gene expression was present at this dose, emphasizing the need for careful dose response studies in gene therapy. However, cardiac selective beta(2)AR overexpression does occur following adenoviral vector delivery during CPB and cardioplegic arrest resulting in enhanced LV dP/dt(max).