Matrix Metalloproteinase Inhibitors: Applications in Oncology

Matrix metalloproteinases (MMP) are a group of zinc dependentenzymes which include the interstitial collagenases, stromelysins,gelatinases and membrane-type metalloproteinases. They are involvedin the remodelling and turnover of the extracellular matrixproteins. They play a role in wound healing and the pathogenesis ofarthritis. In malignancies they play a role in tumor invasion,metastasis and angiogenesis. A number of synthetic matrixmetalloproteinase inhibitors (MMPIs) have been developed forclinical use. In preclinical tumor models they have shown promisingactivity in achievinginhibition of MMPs and reducing tumor growth and metastatic spread.Some have also shown additive or synergistic effects with cytotoxicagents. Phase I and II studies in human subjects have defined themain side effects of these agents as beingmusculoskeletal pains or arthralgias. As they are cytostatic agentsrather than cytotoxic in activity conventional measurements ofradiological response for assessment are not applicable in trials.Biological activity has been demonstrated in certain cancers by theeffects on levels of tumor markers as surrogate markers of tumorresponse and also by a fibrotic stromal reaction seen in tumortissue. Newer agents have been developed withselective inhibition of certain MMPs in an attempt to reduce theside effects. A number of phase III human clinical trialsevaluating MMPs are being carried out at present but onlyone has been formally reported so far. This study suggested thatmarimastat had no survival advantage when compared to chemotherapywith gemcitabine in advanced pancreatic carcinoma. Current trialsare assessing efficacy of MMPIs in maintenance of remission afterother modalities of therapy or in combination with cytotoxicagents. MMPs have also been demonstrated to play an important rolein the articular cartilage destruction seen in both rheumatoidarthritis and osteoarthritis. The use of MMPIs in both exvivoand in vivomodels have shown promising resultsand trials are in process to assess their potential role in thecontrol of articular destruction. The true therapeutic role ofMMPIs await the results of these randomized studies.     

Thyroid Hormones and Cardiovascular Function and Diseases

Thyroid hormone (TH) receptors are present in the myocardium and vascular tissue, and minor alterations in TH concentration can affect cardiovascular (CV) physiology. The potential mechanisms that link CV disease with thyroid dysfunction are endothelial dysfunction, changes in blood pressure, myocardial systolic and diastolic dysfunction, and dyslipidemia. In addition, cardiac disease itself may lead to alterations in TH concentrations (notably, low triiodothyronine syndrome) that are associated with higher morbidity and mortality. Experimental data and small clinical trials have suggested a beneficial role of TH in ameliorating CV disease. The aim of this review is to provide clinicians dealing with CV conditions with an overview of the current knowledge of TH perturbations in CV disease.     

GLI inhibitor GANT-61 diminishes embryonal and alveolar rhabdomyosarcoma growth by inhibiting Shh/AKT-mTOR axis

Rhabdomyosarcoma (RMS) typically arises from skeletal muscle. Currently, RMS in patients with recurrent and metastatic disease have no successful treatment. The molecular pathogenesis of RMS varies based on cancer sub-types. Some embryonal RMS but not other sub-types are driven by sonic hedgehog (Shh) signaling pathway. However, Shh pathway inhibitors particularly smoothened inhibitors are not highly effective in animals. Here, we show that Shh pathway effectors GLI1 and/or GLI2 are over-expressed in the majority of RMS cells and that GANT-61, a specific GLI1/2 inhibitor dampens the proliferation of both embryonal and alveolar RMS cells-derived xenograft tumors thereby blocking their growth. As compared to vehicle-treated control, about 50% tumor growth inhibition occurs in mice receiving GANT-61 treatment. The proliferation inhibition was associated with slowing of cell cycle progression which was mediated by the reduced expression of cyclins D1/2/3 & E and the concomitant induction of p21. GANT-61 not only reduced expression of GLI1/2 in these RMS but also significantly diminished AKT/mTOR signaling. The therapeutic action of GANT-61 was significantly augmented when combined with chemotherapeutic agents employed for RMS therapy such as temsirolimus or vincristine. Finally, reduced expression of proteins driving epithelial mesenchymal transition (EMT) characterized the residual tumors.     

Pulmonary artery pulsatility index predicts prolonged inotrope/pulmonary vasodilator use after implantation of continuous flow left ventricular assist device

Objective: Predictors of right ventricle (RV) dysfunction after continuous‐flow left ventricular assist device (CF‐LVAD) implantation in children are not well described. We explored the association of preimplantation Pulmonary Artery Pulsatility index (PAPi) and other hemodynamic parameters as predictors of prolonged postoperative inotropes/pulmonary vasodilator use after CF‐LVAD implantation.
Design: Retrospective chart review.
Setting: Single tertiary care pediatric referral center.
Patients: Patients who underwent CF‐LVAD implantation from January 2012 to October 2017.
Interventions: Preimplantation invasive hemodynamic parameters were analyzed to evaluate the association with post‐CF‐LVAD need for prolonged (>72 hours) use of inotropes/pulmonary vasodilators.
Measurements and main results: Preimplantation cardiac catheterization data was available for 12 of 44 patients who underwent CF‐LVAD implant during the study period. Median (IQR) age and BSA of the cohort were 15.3 years (10.2, 18) and 1.74 m2 (0.98, 2.03). Group 1 (n = 6) included patients with need for prolonged inotropes/pulmonary vasodilator use after CF‐LVAD implantation and Group 2 (n = 6) included those without. Baseline demographic parameters, cardiopulmonary bypass time, and markers of RV afterload (pulmonary vascular resistance, PA compliance and elastance) were similar among the two groups. PAPi was significantly lower in group 1 compared to group 2 (0.96 vs 3.6, respectively; P = .004). Post‐LVAD stay in the intensive care unit was longer for patients in group 1 (46 vs 23 days, P = .52). Brain natriuretic peptide was significantly higher at 3 months after implantation in group 1; P = .01.
Conclusions: The need for inotropes/pulmonary vasodilators in the postoperative period can be predicted by the preimplantation intrinsic RV contractile reserve as assessed by PAPi rather than the markers of RV afterload. Further investigation and correlation with clinical outcomes is needed.     

Percutaneous coronary revascularization reduces plasma N-terminal pro-B-type natriuretic peptide concentration in stable coronary artery disease.

OBJECTIVES: The purpose of this work was to assess the effect of percutaneous coronary revascularization (PCR) on plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration. BACKGROUND: Left ventricular (LV) dysfunction is associated with increased plasma natriuretic peptide concentrations. The effect of ischemia resolution on plasma natriuretic peptide is not known. METHODS: Twenty-six patients with stable angina, normal LV systolic function, and isolated stenoses of the left anterior descending (LAD) coronary artery were studied. All patients had angiographically and physiologically significant lesions defined by cine-angiography and intracoronary pressure wire. RESULTS: After revascularization, 24 patients demonstrated significant decrease in mean plasma NT-proBNP 8 weeks after PCR (from 177.2 +/- 190.8 pg/ml to 105.0 +/- 92.4 pg/ml, p = 0.03). The mean decrease in log NT-proBNP was 0.533, corresponding to geometric mean decrease of NT-proBNP by a factor of 59% (95% confidence interval 48.2% to 71.4%, p < 0.00005). Reduction in NT-proBNP was independent of change in LV systolic function. CONCLUSIONS: This study demonstrates that removal of fixed LAD stenosis reduces plasma NT-proBNP concentration. This has implications for interpretation of natriuretic peptide levels in clinical settings and as screening tool for LV systolic dysfunction.     

Angiotensin-converting enzyme inhibitors as adjunctive therapy in patients with persistent atrial fibrillation

Objectives

The purpose of the current study was to assess the effect of angiotensin-converting enzyme inhibitor (ACEI) therapy in facilitating cardioversion from persistent atrial fibrillation (AF) and maintaining sinus rhythm.

Background

Pharmacologic therapy and electrical cardioversion for AF are often unsuccessful in maintaining long-term sinus rhythm.

Methods

The current study, a 1-year, prospective follow-up, comprised 47 patients with persistent AF undergoing electrical cardioversion. Patients receiving ACEI were compared with those receiving other medications. The study end point was the number of defibrillation attempts required for atrial defibrillation and the number of hospital admissions. A secondary end point was change in signal-averaged P-wave duration (SAPD) 1 year after successful electrical cardioversion.

Results

Of those admitted and requiring electrical defibrillation, the number of defibrillation attempts required for successful cardioversion was significantly less in the ACEI group (P < .001). The incidence rate ratio for admissions comparing recipients of ACEI with others was 0.14 (P = .03). Patients receiving ACEI therapy had significantly lower SAPD at 1 year when compared with the no-ACEI group (135 ms ± 3 vs 150 ms ± 2, P = .002).

Conclusions

The use of long-term ACEI therapy facilitated electrical defibrillation in patients with persistent AF. ACEI therapy also reduced SAPD, suggesting amelioration of the arrhythmogenic substrate. Furthermore, we confirmed that SAPD is prolonged in patients with persistent AF.     

Application of transcatheter valves for aortic valve replacement in pediatric patients: A case series

• Diabetic patients are frequently affected by coronary artery disease (CAD) and are at increased risk of CAD‐related adverse events, even after drug‐eluting stent (DES) implantation. If currently available DES have similar safety and efficacy in diabetic and nondiabetic patients is still debated.
• This prospective, multicenter registry showed similar 3‐year outcome in patients undergoing different DES implantation, although diabetic patients, especially those requiring insulin treatment, had significantly higher risk of adverse events than nondiabetic patients.
• Specific efforts to improve the performance of DES in diabetic patients are mandatory to adequately address the unsolved issue of diabetic patients affected by CAD.