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One of the most common conundrums in all cardiovascular medicine pertains to the care of patients with atrial fibrillation after percutaneous coronary intervention, because of both dual antiplatelet therapy and oral anticoagulant therapy would seem to be necessary to reduce risks of stent thrombosis and thromboembolism, respectively, but also with an inevitable trade-off of more bleeding. Patients who require triple therapy are at high risk of both ischaemia and bleeding; therefore, defining a personalised secondary prevention strategy aimed at achieving the best net clinical benefit is essential. The good news is that we have entered an era of increased perceived and tangible safety that applies to both non-vitamin K-antagonist oral anticoagulants and newer drug-eluting stents. Even if the consistency across the major trials and the significantly lower risk of bleeding with dual therapy make it hard to argue that triple therapy should be used routinely, the aggregate evidence suggests that the net clinical benefit of dual therapy should give cardiologists confidence to drop aspirin when they are using a contemporary percutaneous coronary intervention strategy with drug-eluting stents. Waiting for more randomised trials and meta-analyses, for the time being, in patients not in clinical trials, full-dose oral triple therapy with dual antiplatelet agents and full-dose anticoagulation should be avoided as a routine practice, and the choice of the proper, that is, safer, oral anticoagulant, namely a non-vitamin K-antagonist oral anticoagulant, may be regarded by now as an additional bleeding avoiding strategy in patients with atrial fibrillation undergoing percutaneous coronary intervention.

The benefits of exercise training in virtually all humans, including those with a clinically stable chronic disease are numerous. The potential value lies in the fact that functional capacity is oftentimes significantly compromised. Exercise training not only play a role in reversing some of the pathophysiologic processes associated with chronic diseases but also improves clinical trajectory. Given the significant pathologic consequences associated with pulmonary hypertension and its implications for deteriorating right ventricular function as well as the perceived potential for a precipitous and possibly critical drop in cardiac output during periods of physical exertion, exercise training was historically not recommended for these patients. More recently, a promising body of literature demonstrating the safety and efficacy of exercise training (with benefit on exercise capacity, peak oxygen consumption and quality of life) in pulmonary hypertension patients has emerged, but the conclusion about the effects of exercise training were non-exhaustive and therefore there is still a lack of knowledge regarding exercise training for these patients. Thus, we aim to ascertain the current effectiveness of exercise rehabilitation for pulmonary hypertension by performing a brief overview on the latest currently available evidences in such an "at a glance" synopsis addressed to summarize/quantify the more recent existing body of literature. KEY MESSAGES Exercise training was historically not recommended in pulmonary hypertension. Recently, exercise training safety-efficacy in pulmonary hypertension has emerged. Exercise training should be recommended in addition to optimal medical therapy.

Obesity is a growing global health concern, with a rapid increase being observed in morbid obesity. Obesity is associated with an increased cardiovascular risk and earlier onset of cardiovascular morbidity. The growing obesity epidemic is a major source of unsustainable health costs and morbidity and mortality because of hypertension, type 2 diabetes mellitus, dyslipidemia, certain cancers and major cardiovascular diseases. Similar to obesity, hypertension is a key unfavorable health metric that has disastrous health implications: currently, hypertension is the leading contributor to global disease burden, and the direct and indirect costs of treating hypertension are exponentially higher. Poor lifestyle characteristics and health metrics often cluster together to create complex and difficult-to-treat phenotypes: excess body mass is such an example, facilitating a cascade of pathophysiological sequelae that create such as a direct obesity-hypertension link, which consequently increases cardiovascular risk. Although some significant issues regarding assessment/management of obesity remain to be addressed and the underlying mechanisms governing these disparate effects of obesity on cardiovascular disease are complex and not completely understood, a variety of factors could have a critical role. Consequently, a comprehensive and exhaustive investigation of this relationship should analyze the pathogenetic factors and pathophysiological mechanisms linking obesity to hypertension as they provide the basis for a rational therapeutic strategy in the aim to fully describe and understand the obesity-hypertension link and discuss strategies to address the potential negative consequences from the perspective of both primordial prevention and treatment for those already impacted by this condition.

The diagnostic and prognostic implication of exaggerated blood pressure response to exercise has been controversial, with opinions ranging from a benign process to a harbinger of potential cardiovascular morbidity. Nonetheless, lowering of blood pressure and prevention of hypertension is in first instance preferable by lifestyle changes, and many studies have shown the inverse association between physical activity level and the incidence of cardiovascular diseases suggesting low aerobic fitness as a strong predictor for future cardiovascular disease and all-cause mortality in both healthy and cardiovascular disease patients, including those with hypertension. Endothelial function, large artery stiffness and neurohormonal response are surely implicated both in the development of exaggerated blood pressure response to exercise and in the positive effect of physical exercise in the prevention and management of hypertension and cardiovascular disease in general. In their interesting and well documented review published in this issue Kim and Ha broadly described the possible pathophysiologic mechanisms of exaggerated blood pressure response to exercise and its clinical implications: in this regard, a very interesting issue could be represented by the role of exercise training. In fact, there is an the ample evidence in the literature that physical activity could positively affect endothelial function, arterial stiffness, neurohormonal response and finally blood pressure levels both in healthy men and in hypertensive patients and so should be considered a very important element in the prevention and management of cardiovascular disease.

Background: Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s)., Methods: A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m(2) together with 6S-leucovorin 200 mg/m(2) on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m(2), every 2 weeks. Assessment of response was performed every four cycles according to RECIST criteria., Results: Median patient age was 74 years (range, 70-83 years). Overall response rate was 34.9% [95% confidence interval (CI), 20.6-49.1, with 3 complete responses and 12 partial responses. Grade 3 neutropenia occurred in 4 patients (9.3%), fatigue in 3 patients (7.0%), and vomiting in 2 patients (4.6%). Grade 2 and 3 peripheral neuropathy was observed in 5 patients (11.6%) and 1 patient (2.3%), respectively. No treatment-related death was observed. Median progression-free and overall survival were 6.8 and 10.5 months, respectively., Conclusions: This modified FOLFOX regimen is an active and well-tolerated treatment for elderly patients with metastatic gastric cancer and also represents a good therapeutic option in patients with associated disease(s).

Background: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients., Methods: Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50 mg/m(2) as a 30-min infusion on day 1, leucovorin 200 mg/m(2) in a 2-h infusion, and 5-FU 2,800 mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75 mg/m(2), every 3 weeks)., Results: Thirty-four patients were enrolled, with an average age of 64 years (range 34-69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9-54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6 months, respectively., Conclusions: For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.

Aims: HtrA1 is a member of the HtrA (high-temperature requirement factor A) family of serine proteases. HtrA1 plays a protective role in various malignancies due to its tumour suppressive properties. The aim of this study was to determine HtrA1 expression as a predictor of chemoresponse in patients with advanced gastric cancer., Methods and Results: HtrA1 expression was determined by immunohistochemistry on specimens of primary gastric cancer from 80 patients treated consecutively with cisplatin-based combination chemotherapy. Response to chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Our population consisted of males/females [51/29; median age 64 years (range 32-82)]. A complete or partial response was observed in 71.4% [95% confidence interval (CI) 54.7-88.2], 66.7% (95% CI 47.8-85.5) and 28.6% (95 CI 11.8-45.3) of tumours showing high, medium and low HtrA1 expression, respectively. A statistically significant association between HtrA1 expression and the clinical response was observed (P = 0.002). The median overall survival for patients with high/medium expression was 17 months compared to 9.5 months for patients with low HtrA1 expression (P = 0.037)., Conclusions: Identification of HtrA1 in gastric cancer prior to chemotherapy indicates that levels of HtrA1 could be used to predict response to platinum-based combination therapies. Further assessment of HtrA1 expression is highly warranted in large, prospective studies., (© 2011 Blackwell Publishing Limited.)

Aim: IGF binding protein-3 (IGFBP-3) displays growth inhibitory/proapoptotic action and counteracts the IGF-1 tumor-promoting effects by downregulating its bioavailability. We investigated whether IGFBP-3 SNPs determining high IGFBP-3 circulating levels are associated with improved survival of patients with advanced gastric cancer treated with palliative chemotherapy., Materials & Methods: A total of 185 patients undergoing combination chemotherapy for relapsed/metastatic disease were considered eligible for the present clinical investigation. Four functional IGFBP-3 SNPs (rs3110697, rs2854746, rs2864744 and rs2960436) were studied for association with overall survival (OS)., Results: In the multivariate model including SNPs and clinicopathologic features, the rs285744 A allele and the rs2960436 A allele showed favorable association with survival. The hazard ratios for rs285744 C/A and A/A genotypes were 0.38 (95% CI: 0.18-0.66) and 0.20 (95% CI: 0.09-0.39), respectively. The hazard ratios for rs2960436 G/A and A/A genotypes were 0.41 (95% CI: 0.25-0.68) and 0.35 (95% CI: 0.16-0.58), respectively. Bonferroni-corrected p-values for the rs285744 A/A genotype and the rs2960436 A/A genotype were 0.012 and 0.024, respectively. There was linkage disequilibrium between the four variants and there were four common haplotypes (>5% estimated frequency). The most common haplotype (GCAA) included all alleles causing IGFBP-3 upregulation and their carriers demonstrated the best outcome in the log-rank comparison of survival curves., Conclusion: Genetic regulation of the IGFBP-3 impacts on survival of patients with advanced gastric cancer. This finding deserves additional studies because of its prognostic and therapeutic implications.

We investigated the clinical significance of tumour-infiltrating FOXP3-positive regulatory T cells (Tregs) in radically resected (R0) gastric cancer. From a single-institution database, tumors of 110 patients who underwent R0 resection for stage II-III disease were studied for FOXP3-positive Tregs by immunohistochemistry. The observed median number of FOXP3-positive Tregs was used as the cut-point in analyses (<6 versus >or=6 count). Tregs were significantly higher in gastric carcinomas than in normal tissue (P = 0.0001). Tregs count >or=6 was significantly associated with vascular/lymphatic/perineural invasion (VELIPI) in the tumour (P = 0.03). Multivariate analysis showed association between adverse relapse-free survival and grading 3, stage III, VELIPI and Tregs count >or=6 (P = 0.02). Adverse overall survival was associated with grading 3, stage III, VELIPI and Tregs count >or=6 (P = 0.006). FOXP3-positive Tregs may be a novel marker for identifying high-risk gastric cancer patients. Present findings deserve additional investigation as Tregs may also represent an innovative therapeutic target.