Analysis of endothelin-1 and endothelin-1 receptor A gene polymorphisms in patients with pulmonary arterial hypertension

This study analyses the frequency and the potential role of two polymorphisms, the +134del/insA, located in the gene encoding for Endothelin-1 (EDN1), and the His323His in the gene encoding for Endothelin receptor type A (EDNRA) in a cohort of 98 consecutive patients with pulmonary arterial hypertension from two different Cardiology Units (Mid-South of Italy), and in 100 healthy Caucasian subjects randomly recruited from the same area. Cardiac anatomy and function were analysed by non invasive diagnostic imaging techniques (Echocardiography standard m-mode, 2D, colour-Doppler) and by invasive studies (cardiac catheterization). Molecular screening of the region of interest was performed by automated sequencing. At univariate analysis, patients with the His323His TT genotype show a lower cardiac index (2 ± 0.6 vs. 2.3 ± 0.6; p = 0.05) and a higher indexed pulmonary vascular resistance (18.8 ± 9.6 vs. 14.2 ± 6.9; p = 0.01) at cardiac catheterization. A logistic multivariate model shows idiopathic disease (p = 0.01; OR = 3.8; CI = 1.3-11) and indexed pulmonary vascular resistances (p = 0.01; OR = 1.1; CI = 1-1.2) as independent predictors of TT genotype. Our findings may suggest a potential link between specific genotypes in the EDNRA gene and susceptibility for PAH.     

Off-pump versus on-pump coronary artery bypass surgery in patients aged 80 years and older: institutional results and meta-analysis

Patients aged ≥80 years are at high risk of adverse events after coronary artery bypass grafting. This study was performed to evaluate whether off-pump coronary artery bypass surgery (OPCAB) is superior to conventional surgery (CCAB) in these high-risk patients. The outcome of 185 patients aged ≥80 years who underwent OPCAB or CCAB at our institution was reviewed and a meta-analysis on this issue was performed. Similar immediate postoperative results were observed after OPCAB and CCAB at our institution, despite significantly different operative risk (mean logistic EuroSCORE, OPCAB 20.3% vs CCAB 13.4%, P = 0.003). Among 56 propensity score matched pairs a trend toward lower postoperative stroke (0%, 95% CI 0–0 vs 3.6%, 95% CI 0–10.0, P = 0.50) was observed after OPCAB. No significant differences were observed in the other outcome end points. Five-year survival was 81.0% after OPCAB and 78.1% after CCAB (P = 0.239). Pooled analysis of eight studies including 3416 patients showed a significantly higher risk of postoperative stroke after CCAB (pooled rates: 4.2%, 95% confidence interval (95% CI) 2.4–7.1 vs 1.5%, 95% CI 0.9–2.5, risk ratio (RR) 2.15, 95% CI 1.17–3.96, P = 0.01). A trend toward higher immediate postoperative mortality was observed after CCAB (15 studies including 4409 patients, pooled rates: 6.5%, 95% CI 5.2–8.0 vs 5.6%, 95% CI 4.2–7.4, RR 1.29, 95% CI 0.86–1.93, P = 0.21). Generic inverse variance analysis showed similar intermediate survival after CCAB and OPCAB (RR 1.31, 95% CI 0.85–2.01, P = 0.22). At 2 years, survival was 82.8% (95% CI 76.4–89.2) after CCAB and 88.3% (95% CI 82.9–93.7) after OPCAB. Current results indicate that OPCAB compared with CCAB in patients aged ≥80 years is associated with significantly lower postoperative stroke and with a trend toward better early survival. However, suboptimal quality of the available studies, particularly the lack of comparability of the study groups, prevents conclusive results on this controversial issue.     

Cardiac amyloidosis: the heart of the matter

Amyloidosis comprises a unique group of diseases that share in common the extracellular deposition of insoluble fibrillar proteins in organs and tissue including the heart. Cardiac amyloidosis could be primary a part of systemic acquired amyloidosis, or a result of heredofamilial amyloidosis. Although the infiltration of the heart from different types of amyloid results in restrictive cardiomyopathy that manifests with refractory congestive heart failure and conduction abnormalities, unequivocal identification of the deposited amyloidogenic protein is mandatory in order to avoid misdiagnosis and inappropriate treatment. Recent developments in imaging techniques and extracardiac tissue biopsy have minimized the need for invasive endomyocardial biopsy for amyloidosis. Despite advances in treatment, the prognosis of a patient with amyloidosis is still poor and depends upon the underlying disease, and the type and degree of dysfunction of the involved organs. Thus, early diagnosis is mandatory because patients with advanced disease are usually too ill for intensive therapy. This review outlines current approaches to diagnosis, assessment of disease severity, and treatment of cardiac amyloidosis.     

Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study

AIM: To confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer(CRC)in Italy.METHODS: This multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival(PFS). Secondary end-points included time to overall response(TOR), duration of response(DOR), time to treatment failure(TTF) and overall survival(OS).The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life(QoL)was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit.RESULTS: The intention-to-treat population included197 patients(mean age: 62.3 ± 9.9 years, 56.4%males). At baseline, 16/34 evaluable subjects(47.1%)harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 ± 14.3. First-line therapy was given for 223.7 ± 175.9 d, and after a mean followup of 387.7 ± 238.8 d all patients discontinued from the study mainly for disease progression(PD, 45.4%)and AEs(25.4%). Median PFS was 9.7 mo(95%CI:8.4-10.5) and the median values for secondary endpoints were: TOR = 3.9 mo(95%CI: 2.6-4.7), DOR= 8.5 mo(95%CI: 7.3-10.3), TTF = 6.7 mo(95%CI:6.0-7.7) and OS = 23.2 mo(95%CI: 20.1-27.2).Patients carrying at least one lesion had a lower overall response rate(66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant(P =0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 ± 19.1 at the last visit(signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good.CONCLUSION: The efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed, with acceptable toxicity.     

Prevalence,severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes

The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher‐risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher‐risk MDS patients. Pre‐treatment patient‐reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)‐Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 (EORTC QLQ‐C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2–4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient‐reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue.     

Myocardial localization of coronavirus in COVID‐19 cardiogenic shock

We describe the first case of acute cardiac injury directly linked to myocardial localization of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in a 69‐year‐old patient with flu‐like symptoms rapidly degenerating into respiratory distress, hypotension, and cardiogenic shock. The patient was successfully treated with venous‐arterial extracorporeal membrane oxygenation (ECMO) and mechanical ventilation. Cardiac function fully recovered in 5 days and ECMO was removed. Endomyocardial biopsy demonstrated low‐grade myocardial inflammation and viral particles in the myocardium suggesting either a viraemic phase or, alternatively, infected macrophage migration from the lung.     

Don't lose sight of the importance of the individual in effective falls prevention interventions

Falls remain a major public health problem, despite strong growth in the research evidence of effective single and multifactorial interventions, particularly in the community setting. A number of aspects of falls prevention require individual tailoring, despite limitations being reported regarding some of these, including questions being raised regarding the role of falls risk screening and falls risk assessment. Being able to personalise an individual's specific risk and risk factors, increase their understanding of what interventions are likely to be effective, and exploring options of choice and preference, can all impact upon whether or not an individual undertakes and sustains participation in one or more recommendations, which will ultimately influence outcomes. On all of these fronts, the individual patient receiving appropriate and targeted interventions that are meaningful, feasible and that they are motivated to implement, remains central to effective translation of falls prevention research evidence into practice.     

Th17 lymphocyte-dependent degradation of joint cartilage by synovial fibroblasts in a humanized mouse model of arthritis and reversal by secukinumab

How T-helper (Th) lymphocyte subpopulations identified in synovial fluid from patients with juvenile idiopathic arthritis (JIA) (Th17, classic Th1, or nonclassic Th1) drive joint damage is of great interest for the possible use of biological drugs that inhibit the specific cytokines. Our objective was to clarify the role of such Th subpopulations in the pathogenesis of articular cartilage destruction by synovial fibroblasts (SFbs), and the effect of Th17 blockage in an animal model. SFbs were isolated from healthy subjects and patients with JIA, and peripheral blood Th lymphocytes subsets were obtained from healthy subjects. Fragments of human cartilage from healthy subjects in a collagen matrix containing JIA or normal SFbs grafted underskin in SCID mice were used to measure cartilage degradation under the effects of Th supernatants. JIA SFbs overexpress MMP9 and MMP2 and Th17 induce both MMPs in normal SFbs, while nonclassic Th1 upregulate urokinase plasminogen activator (uPA) activity. In vitro invasive phenotype of normal SFbs is stimulated with conditioned medium of Th17 and nonclassic-Th1. In the in vivo “inverse wrap” model, normal SFbs stimulated with supernatants of Th17-lymphocytes and nonclassic Th1 produced a cartilage invasion and degradation similar to JIA SFbs. Secukinumab inhibits the cartilage damage triggered by factors produced by Th17.     

Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

With the development of targeted therapeutics, especially for small-molecule inhibitors, it is important to understand whether the observed in vivo efficacy correlates with the modulation of desired/intended target in vivo. We have developed a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors (VEGFR), platelet-derived growth factor receptor, and c-Kit tyrosine kinases, pazopanib (GW786034), which selectively inhibits VEGF-induced endothelial cell proliferation. It has good oral exposure and inhibits angiogenesis and tumor growth in mice. Because bolus administration of the compound results in large differences in C(max) and C(trough), we investigated the effect of continuous infusion of a VEGFR inhibitor on tumor growth and angiogenesis. GW771806, which has similar enzyme and cellular profiles to GW786034, was used for these studies due to higher solubility requirements for infusion studies. Comparing the pharmacokinetics by two different routes of administration (bolus p.o. dosing and continuous infusion), we showed that the antitumor and antiangiogenic activity of VEGFR inhibitors is dependent on steady-state concentration of the compound above a threshold. The steady-state concentration required for these effects is consistent with the concentration required for the inhibition of VEGF-induced VEGFR2 phosphorylation in mouse lungs. Furthermore, the steady-state concentration of pazopanib determined from preclinical activity showed a strong correlation with the pharmacodynamic effects and antitumor activity in the phase I clinical trial.