Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations.

Cancer and cardiovascular (CV) disease are the most prevalent diseases in the developed world. Evidence increasingly shows that these conditions are interlinked through common risk factors, coincident in an ageing population, and are connected biologically through some deleterious effects of anticancer treatment on CV health. Anticancer therapies can cause a wide spectrum of short- and long-term cardiotoxic effects. An explosion of novel cancer therapies has revolutionised this field and dramatically altered cancer prognosis. Nevertheless, these new therapies have introduced unexpected CV complications beyond heart failure. Common CV toxicities related to cancer therapy are defined, along with suggested strategies for prevention, detection and treatment. This ESMO consensus article proposes to define CV toxicities related to cancer or its therapies and provide guidance regarding prevention, screening, monitoring and treatment of CV toxicity. The majority of anticancer therapies are associated with some CV toxicity, ranging from asymptomatic and transient to more clinically significant and long-lasting cardiac events. It is critical however, that concerns about potential CV damage resulting from anticancer therapies should be weighed against the potential benefits of cancer therapy, including benefits in overall survival. CV disease in patients with cancer is complex and treatment needs to be individualised. The scope of cardio-oncology is wide and includes prevention, detection, monitoring and treatment of CV toxicity related to cancer therapy, and also ensuring the safe development of future novel cancer treatments that minimise the impact on CV health. It is anticipated that the management strategies discussed herein will be suitable for the majority of patients. Nonetheless, the clinical judgment of physicians remains extremely important; hence, when using these best clinical practices to inform treatment options and decisions, practitioners should also consider the individual circumstances of their patients on a case-by-case basis.

A Bayesian network meta-analysis on the effect of inodilatory agents on mortality.

BACKGROUND: Inodilators are commonly used in critically ill patients, but their effect on survival has not been properly studied to date. The objective of this work was to conduct a network meta-analysis on the effects of inodilators on survival in adult cardiac surgery patients, and to compare and rank drugs that have not been adequately compared in head-to-head trials. METHODS: Relevant studies were independently searched in BioMedCentral, MEDLINE/PubMed, Embase, and the Cochrane Central Register of clinical trials (updated on May 1, 2014). The criteria for inclusion were: random allocation to treatment with at least one group receiving dobutamine, enoximone, levosimendan, or milrinone and at least another group receiving the above inodilators or placebo, performed in cardiac surgical patients. The endpoint was to identify differences in mortality at longest follow-up available. RESULTS: The 46 included trials were published between 1995 and 2014 and randomised 2647 patients. The Bayesian network meta-analysis found that only the use of levosimendan was associated with a decrease in mortality when compared with placebo (posterior mean of OR=0.48, 95% CrI 0.28 to 0.80). The posterior distribution of the probability for each inodilator to be the best and the worst drug showed that levosimendan is the best agent to improve survival after cardiac surgery. The sensitivity analyses performed did not produce different interpretative result. CONCLUSION: Levosimendan seems to be the most efficacious inodilator to improve survival in cardiac surgery.

A new phosphorylcholine-coated polymethylpentene oxygenator for extracorporeal membrane oxygenation: a preliminary experience.

Phosphorylcholine coating has a major role in the improvement of biocompatibility, durability and antihrombogenicity of the circuit for extracorporeal membrane oxygenation (ECMO). Moreover, if heparin-induced thrombocytopenia ensues, removal of all the sources of heparin is challenging if the circuit is coated with heparin. We report our preliminary experience with the new EUROSETS A.L.ONE ECMO oxygenator (Eurosets, Medolla, MO, Italy), which is aimed at providing better biocompatibility thanks to its full coating with phosphorylcholine. We retrospectively collected data on the 16 patients supported with ECMO and with the EUROSETS A.L.ONE ECMO oxygenator at San Raffaele Hospital. Mean ECMO duration was 6 ± 4 days, and 37.5% of the patients died on ECMO. Four episodes of major bleeding and three episodes of minor bleeding were recorded. The oxygenator had an excellent performance in gas exchange and the median pressure drop was 57 (26-85) mmHg at full blood flow (2.5 L/m2/min). The EUROSETS A.L.ONE ECMO oxygenator was an excellent device in our preliminary experience. Further evaluation on a larger sample is encouraged.

Detection by denaturant gradient gel electrophoresis of tumor-specific mutations in biopsies and relative bronchoalveolar lavage fluid from resectable non-small cell lung cancer.

A PCR-denaturant gradient gel electrophoresis (DGGE) method was developed for the detection of p53 and K-ras mutations in primary operable tumors and paired BAL samples of non-small cell lung cancer. Among 36 patients, 9 showed p53 exon V mutations in biopsies and in three paired bronchoalveolar lavage (BAL) specimens with a 33% concordance. Five patients presented p53 exon VI mutations in biopsies and in two paired BALs with a 40% concordance. No mutations were found in p53 exon VII either in biopsies or in paired BAL samples with 100% concordance. Exon VIII mutations were found in six primary tumors and in two BALs with a 33% concordance. Of 36 patients, we detected 7 (19.4%) with K-ras exon I mutations on tumor samples. DGGE analysis of DNA from BAL samples revealed three mutations distributed on K-ras exon I with a 42% overall concordance with respect to tumor tissue. Molecular screening by DGGE of p53-amplified DNA from BAL had cumulative 46.6% sensitivity, 100% specificity, and 77.7% accuracy. DGGE K-ras detection showed 43% sensitivity, 100% specificity, and 88.8% test accuracy. The method proposed demonstrated to be specific, accurate, and at relatively low cost but limited by low sensitivity in detecting the presence of neoplastic cells in patients with resectable non-small cell lung cancer.

Effect of tamoxifen on GH and IGF-1 serum level in stage I-II breast cancer patients.

OBJECTIVE: Tamoxifen suppresses insulin-like growth factor-1 (IGF-1) plasma levels in early and advanced breast cancer patients. Relationships between tamoxifen (GH) and IGF-1 are complex and not completely described yet. The present investigation was performed to evaluate the effect of acute and chronic tamoxifen administration on GH response to growth hormone-releasing hormone (GHRH), as well as on IGF-1 serum levels. MATERIALS AND METHODS: Evaluation of GH after administration of GHRH was performed (a) at baseline, (b) 3 hours after 20 mg oral administration of tamoxifen and (c) after 12 weeks of 20 mg a day oral tamoxifen treatment, in fifteen postmenopausal stage I-II breast cancer patients. IGF-I was measured at baseline and after chronic tamoxifen administration. RESULTS: The GH response to GHRH was significantly reduced after 12 weeks of tamoxifen 10 mg administered twice a day orally (mean peak 3.2 +/- 0.2 micrograms/l, mean AUC 261.3 +/- 18.2 micrograms/minute p < 0.01 versus basal AUC). A concomitant significant reduction of IGF-1 was observed after 3 months of tamoxifen treatment. Basal pretreatment levels of 113.2 +/- 15.5 micrograms/l were suppressed to 70 +/- 7.9 micrograms/l (p < 0.01). CONCLUSION: Our study confirm the inhibitory effect of tamoxifen on IGF-I and suggested, as shown in previous in vitro data, that its suppression could be directly related to GH reduction in response to GHRH stimulation.

GSTM1, P53 and K-ras molecular detection in resectable non-small cell lung cancer by denaturing gradient gel electrophoresis-bronchoalveolar lavage fluid analysis.

BACKGROUND: Understanding molecular abnormalities could potentially lead to novel investigational approaches in the molecular epidemiology of lung cancer. These might include the identification of patients at high risk for primary NSCLC and the surveillance of patients with known NSCLC who are being treated using lung-sparing surgical strategies. MATERIALS AND METHODS: The PCR-Denaturing Gradient Gel Electrophoresis (DGGE) strategy was used for primary tumors and corresponding bronchalveolare lavage (BAL) samples. RESULTS: We recruited 36 consecutive patients with NSCLC, 28 (77.7%) males and 8 females (22.3%). DGGE showed a good rate of accuracy in the genetic screening of K-ras and p53 mutations in BAL specimens. Specific mutations were more often detected in BAL fluid from patients with not peripheral tumors than parenchymal or peripheral tumors (p53: 85.7%, p=0.0004; K-ras: 75%, p=0.001). p53 mutations were more frequent in BAL fluid from squamous cell carcinomas (22%) than from adenocarcinomas (15%). A significant correlation was observed between null GST-Ml genotype and p53 overall mutations (p=0.0003), K-ras mutations (p=0.02), non peripheral tumors (p=0.04) and smoking habits (p=0.002). CONCLUSIONS: We observed that null GSTMl genotype is strongly related to p53 mutations. Individuals at high risk for primary NSCLC, such as heavy smokers or individuals exposed to occupational carcinogens, could be screened by BAL-analysis for cancer biomarkers of susceptibility like GSTM-1 in large scale molecular epidemiology studies.

Diagnosis of T1 bladder transitional cell carcinoma by denaturing gradient gel electrophoresis urinalysis.

OBJECTIVE: The diagnosis and follow-up of patients with T1 bladder cancer relies invasive procedures. We developed a non-invasive method for detection of T1 bladder cancer based on a feasible non-radioactive molecular approach. MATERIALS AND METHODS: Urine DNA samples were collected from 24 patients with T1 transitional cell carcinoma (TCC) of the bladder and were processed by denaturing gradient gel electrophoresis (DGGE) analysis. Urine samples obtained from 10 individuals with no clinical evidence of genitourinary malignancy were used as controls. RESULTS: Ten patients out of 24 (41%) had p53 mutations in their tumor samples. Seven of these presented the same mutation in matched urine samples. The p53 mutation pattern found in urine was always identical to that identified in the primary tumor. Decision diagnostic criteria showed that molecular screening by DGGE of amplified DNA from urine sediment had 69.2 % sensitivity, 100% specificity, 95.8 % accuracy, 100% prediction of positive result and 95.4 % prediction of negative result, respectively. No p53 mutation was found in the urine from control subjects. CONCLUSION: DGGE analysis of urine samples could be a useful tool for the early detection of T1 bladder cancer or its recurrence, potentially leading to a reduction in the frequency of invasive procedures used for the management of this disease.

Cardiac protection by volatile anesthetics in non-cardiac surgery? A meta-analysis of randomized controlled studies on clinically relevant endpoints.

INTRODUCTION: Volatile anesthetics improve post-ischemic recovery. A meta-analysis suggested that the cardioprotective properties of desflurane and sevoflurane could reduce mortality and cardiac morbidity in cardiac surgery. Recent American College of Cardiology / American Heart Association Guidelines recommended volatile anesthetic agents during non-cardiac surgery for the maintenance of general anesthesia in patients at risk for myocardial infarction but whether these cardioprotective properties exist in non-cardiac surgery settings is controversial. We therefore performed a meta-analysis of randomized studies to investigate this issue. METHODS: Two investigators independently searched PubMed. Inclusion criteria were random allocation to treatment, comparison of a total intravenous anesthesia regimen vs an anesthesia plan including desflurane or sevoflurane, performed on adult patients undergoing non-cardiac surgery. The primary endpoints were the incidence of perioperative myocardial infarction and death. RESULTS: A total of 6219 patients from 79 randomized trials were identified. No myocardial infarctions or deaths were reported in any of the studies we examined. CONCLUSIONS: This meta-analysis highlights a weakness in the literature and the results can be used to design future studies: the cardioprotective properties of desflurane and sevoflurane have never been studied in noncardiac surgery. No randomized study, among those which compared desflurane or sevoflurane to intravenous anesthetics, has addressed major outcomes such as myocardial infarction or mortality. Large, multicentre, randomized clinical trials including patients undergoing high-risk non-cardiac surgery and reporting clinically relevant outcomes such as myocardial infarction and mortality are needed.

Myocardial necrosis biomarkers after different cardiac surgical operations.

AIM: A high postoperative peak of cardiac Troponin I is associated to an increased risk of morbidity and mortality after cardiac operations. The aim of this study was to investigate the release of cardiac Troponin I in different cardiac surgical procedures. METHODS: This was a prospective, single-centre study performed at the IRCCS San Raffaele Hospital in Milan, Italy. The study group consisted of 194 consecutive patients undergoing cardiac surgery. For each of them creatinkinase MB and cardiac Troponin I were assayed preoperatively, at ICU arrival, 4 h and 18 h postoperatively. RESULTS: Different cardiac surgical procedures were characterized by different release of cardiac biomarkers (P<0.001, ANOVA test). Off-pump coronary artery bypass grafting (CABG) was associated to the smallest amount of myocardial injury while mitral valve replacement produced the largest amount of biomarkers release. Patients who suffered a postoperative cardiac event released more myocardial necrosis biomarkers than those with an uneventful course (P=0.01). CONCLUSION: We showed that each type of cardiac operation has a peculiar amount of myocardial necrosis biomarkers: mitral valve replacement in particular is associated to the highest release of cardiac biomarkers.

Cardiac protection by volatile anaesthetics: a multicentre randomized controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.

BACKGROUND AND OBJECTIVES: To evaluate the effects of total intravenous anaesthesia vs. volatile anaesthesia on cardiac troponin release in coronary artery bypass grafting with cardiopulmonary bypass, we performed a multicentre randomized controlled study to compare postoperative cardiac troponin release in patients receiving two different anaesthesia plans. METHODS: We randomly assigned 75 patients to propofol (intravenous anaesthetic) and 75 patients to desflurane (volatile anaesthetic) in addition to an opiate-based anaesthesia for coronary artery bypass grafting. Peak postoperative troponin I release was measured as a marker of myocardial necrosis. RESULTS: There was a significant (P < 0.001) difference in the postoperative median (25th-75th percentiles) peak of troponin I in patients receiving propofol 5,5 (2,3-9,5) ng dL(-1) when compared to patients receiving desflurane 2,5 (1,1-5,3) ng dL(-1). The median (interquartile) troponin I area under the curve analysis confirmed the results: 68 (30.5-104.8) vs. 36.3 (17.9-86.6) h ng dL(-1) (P = 0.002). Patients receiving volatile anaesthetics had reduced need for postoperative inotropic support (24/75, 32.0% vs. 31/75, 41.3%, P = 0.04), and tends toward a reduction in number of Q-wave myocardial infarction, time on mechanical ventilation, intensive care unit and overall hospital stay. CONCLUSIONS: Myocardial damage measured by cardiac troponin release could be reduced by volatile anaesthetics in coronary artery bypass surgery.

Long-term outcome of patients who require renal replacement therapy after cardiac surgery.

BACKGROUND AND OBJECTIVE: Acute renal failure is a serious complication of cardiac surgery. We studied the long-term survival and quality of life of patients requiring renal replacement therapy after cardiac surgery, since they represent a heavy burden on hospital resources and their outcome has never been adequately evaluated. METHODS: Out of 7846 consecutive cardiac surgical patients, 126 (1.6%) required postoperative renal replacement therapy: their preoperative status and hospital course was compared with patients who had no need of postoperative renal replacement therapy. A multivariate analysis identified predictors of renal replacement therapy. Long-term survival and quality of life was collected in patients who had renal replacement therapy and in case-matched controls. RESULTS: Hospital mortality in the study group was 84/126 (66.7%) vs. 118/7720 (1.5%) in the control population (P 1000 mL, chronic obstructive pulmonary disease and age. CONCLUSIONS: This study confirms that the in-hospital mortality of patients requiring renal replacement therapy is high and shows a low long-term mortality with reasonable quality of life in patients discharged from hospital alive.