Identification of Drugs Acting as Perpetrators in Common Drug Interactions in a Cohort of Geriatric Patients from Southern Italy and Analysis of the Gene Polymorphisms That Affect Their Interacting Potential.

BACKGROUND: Pharmacogenomic factors affect the susceptibility to drug-drug interactions (DDI). We identified drug interaction perpetrators among the drugs prescribed to a cohort of 290 older adults and analysed the prevalence of gene polymorphisms that can increase their interacting potential. We also pinpointed clinical decision support systems (CDSSs) that incorporate pharmacogenomic factors in DDI risk evaluation. METHODS: Perpetrator drugs were identified using the Drug Interactions Flockhart Table, the DRUGBANK website, and the Mayo Clinic Pharmacogenomics Association Table. Allelic variants affecting their activity were identified with the PharmVar, PharmGKB, dbSNP, ensembl and 1000 genome databases. RESULTS: Amiodarone, amlodipine, atorvastatin, digoxin, esomperazole, omeprazole, pantoprazole, simvastatin and rosuvastatin were perpetrator drugs prescribed to >5% of our patients. Few allelic variants affecting their perpetrator activity showed a prevalence >2% in the European population: CYP3A4/5*22, *1G, *3, CYP2C9*2 and *3, CYP2C19*17 and *2, CYP2D6*4, *41, *5, *10 and *9 and SLC1B1*15 and *5. Few commercial CDSS include pharmacogenomic factors in DDI-risk evaluation and none of them was designed for use in older adults. CONCLUSIONS: We provided a list of the allelic variants influencing the activity of drug perpetrators in older adults which should be included in pharmacogenomics-oriented CDSSs to be used in geriatric medicine.

Cardiovascular Side Effects of Anthracyclines and HER2 Inhibitors among Patients with Breast Cancer: A Multidisciplinary Stepwise Approach for Prevention, Early Detection, and Treatment.

Cardiovascular (CV) diseases (CVD) are a major cause of long-term morbidity and mortality affecting life expectancy amongst cancer survivors. In recent years, because of the possibility of early diagnosis and the increased efficacy of neo-adjuvant and adjuvant systemic treatments (targeting specific molecular pathways), the high percentage of survival from breast cancer led CVD to become the first cause of death among survivors. Therefore, it is mandatory to adopt cardioprotective strategies to minimize CV side effects and CVD in general in breast cancer patients. Cancer therapeutics-related cardiac dysfunction (CTRCD) is a common group of side effects of chemotherapeutics widely employed in breast cancer (e.g., anthracycline and human epidermal growth factor receptor 2 inhibitors). The aim of the present manuscript is to propose a pragmatic multidisciplinary stepwise approach for prevention, early detection, and treatment of cardiotoxicity in patients with breast cancer.

Validation of the ONKOTEV Risk Prediction Model for Venous Thromboembolism in Outpatients With Cancer.

Importance: The assessment of the risk of venous thromboembolism (VTE) among outpatients with cancer represents an unsolved topic. Current international guidelines recommend primary prophylaxis for patients at intermediate to high risk of VTE, indicated by a Khorana score of 2 or more. A previous prospective study developed the ONKOTEV score, a 4-variable risk assessment model (RAM) consisting of a Khorana score of more than 2, metastatic disease, vascular or lymphatic compression, and previous VTE event. Objective: To validate the ONKOTEV score as a novel RAM to assess the risk of VTE among outpatients with cancer. Design, Setting, and Participants: ONKOTEV-2 is a noninterventional prognostic study conducted in 3 European centers located in Italy, Germany, and the United Kingdom among a prospective cohort of 425 ambulatory patients with a histologically confirmed diagnosis of a solid tumor who were receiving active treatments. The total study duration was 52 months, with an accrual period of 28 months (from May 1, 2015, to September 30, 2017) and an overall follow up-period of 24 months (data were censored September 30, 2019). Statistical analysis was performed in October 2019. Exposures: The ONKOTEV score was calculated for each patient at baseline by collecting clinical, laboratory, and imaging data from tests performed for routine practice. Each patient was then observed to detect any thromboembolic event throughout the study period. Main Outcomes and Measures: The primary outcome of the study was the incidence of VTE, including deep vein thrombosis and pulmonary embolism. Results: A total of 425 patients (242 women [56.9%]; median age, 61 years [range, 20-92 years]) were included in the validation cohort of the study. The cumulative incidences for the risk of developing VTE at 6 months were 2.6% (95% CI, 0.7%-6.9%), 9.1% (95% CI, 5.8%-13.2%), 32.3% (95% CI, 21.0%-44.1%), and 19.3% (95% CI, 2.5%-48.0%), respectively, among 425 patients with an ONKOTEV score of 0, 1, 2, and greater than 2 (P < .001). The time-dependent area under the curve at 3, 6, and 12 months was 70.1% (95% CI, 62.1%-78.7%), 72.9% (95% CI, 65.6%-79.1%), and 72.2% (95% CI, 65.2%-77.3%), respectively. Conclusions and Relevance: This study suggests that, because the ONKOTEV score has been validated in this independent study population as a novel predictive RAM for cancer-associated thrombosis, it can be adopted into practice and into clinical interventional trials as a decision-making tool for primary prophylaxis.

Exploring the Cardiotoxicity Spectrum of Anti-Cancer Treatments: Definition, Classification, and Diagnostic Pathways.

Early detection and treatment of cancer have led to a noticeable reduction in both mortality and morbidity. However, chemotherapy and radiotherapy could exert cardiovascular (CV) side effects, impacting survival and quality of life, independent of the oncologic prognosis. In this regard, a high clinical index of suspicion is required by the multidisciplinary care team in order to trigger specific laboratory tests (namely natriuretic peptides and high-sensitivity cardiac troponin) and appropriate imaging techniques (transthoracic echocardiography along with cardiac magnetic resonance, cardiac computed tomography, and nuclear testing (if clinically indicated)), leading to timely diagnosis. In the near future, we do expect a more tailored approach to patient care within the respective community along with the widespread implementation of digital health tools.

Early Left Ventricular Diastolic Dysfunction in Females with Chronic Hyperprolactinemia: A Doppler Echocardiographic Study.

Despite the myocardial prolactin (PRL) binding activity and the known effect of enhancing contractility in the isolated rat heart, little information is available concerning the cardiovascular consequences of hyperprolactinemia in humans. To elucidate the effects of chronic hyperprolactinemia on cardiac structure and function, twenty-four patients with isolated PRL-secreting adenoma and twenty-four controls underwent a complete mono- and two-dimensional Doppler-echocardiography. Blood pressure and heart rate were similar in the two groups, and no significant differences were observed as to left ventricular (LV) geometry between patients and controls. Resting LV systolic function was normal in patients with hyperprolactinemia, as shown by similar values of fractional shortening and cardiac output. Conversely, hyperprolactinemic patients exhibited a slight impairment of LV diastolic filling, as demonstrated by the prolongation of the isovolumetric relaxation time and the increase of the atrial filling wave of mitral Doppler velocimetry (58 ± 13 vs. 47 ± 8 cm/s, p < 0.05) with a subgroup of females (16%) having a clear diastolic dysfunction, and a worse exercise capacity (6 min walking test 452 ± 70 vs. 524 ± 56; p < 0.05). In conclusion, hyperprolactinemia in humans may be associated with a slight impairment of diastolic function, with an overt diastolic dysfunction in a subgroup of females which correlated with poorer exercise performance, in the absence of significant abnormalities of LV structure and systolic function.

Progressive right ventricular dysfunction and exercise impairment in patients with heart failure and diabetes mellitus: insights from the T.O.S.CA. Registry.

BACKGROUND: Findings from the T.O.S.CA. Registry recently reported that patients with concomitant chronic heart failure (CHF) and impairment of insulin axis (either insulin resistance-IR or diabetes mellitus-T2D) display increased morbidity and mortality. However, little information is available on the relative impact of IR and T2D on cardiac structure and function, cardiopulmonary performance, and their longitudinal changes in CHF. METHODS: Patients enrolled in the T.O.S.CA. Registry performed echocardiography and cardiopulmonary exercise test at baseline and at a patient-average follow-up of 36 months. Patients were divided into three groups based on the degree of insulin impairment: euglycemic without IR (EU), euglycemic with IR (IR), and T2D. RESULTS: Compared with EU and IR, T2D was associated with increased filling pressures (E/e'ratio: 15.9 ± 8.9, 12.0 ± 6.5, and 14.5 ± 8.1 respectively, p < 0.01) and worse right ventricular(RV)-arterial uncoupling (RVAUC) (TAPSE/PASP ratio 0.52 ± 0.2, 0.6 ± 0.3, and 0.6 ± 0.3 in T2D, EU and IR, respectively, p < 0.05). Likewise, impairment in peak oxygen consumption (peak VO2) in TD2 vs EU and IR patients was recorded (respectively, 15.8 ± 3.8 ml/Kg/min, 18.4 ± 4.3 ml/Kg/min and 16.5 ± 4.3 ml/Kg/min, p < 0.003). Longitudinal data demonstrated higher deterioration of RVAUC, RV dimension, and peak VO2 in the T2D group (+ 13% increase in RV dimension, - 21% decline in TAPSE/PAPS ratio and - 20% decrease in peak VO2). CONCLUSION: The higher risk of death and CV hospitalizations exhibited by HF-T2D patients in the T.O.S.CA. Registry is associated with progressive RV ventricular dysfunction and exercise impairment when compared to euglycemic CHF patients, supporting the pivotal importance of hyperglycaemia and right chambers in HF prognosis. Trial registration ClinicalTrials.gov identifier: NCT023358017.

Myocardial expression of somatotropic axis, adrenergic signalling, and calcium handling genes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction.

AIMS: Limited data are available regarding cardiac expression of molecules involved in heart failure (HF) pathophysiology. The majority of the studies have focused on end-stage HF with reduced ejection fraction (HFrEF) without comparison with healthy subjects, while no data are available with regard to HF with preserved ejection fraction (HFpEF). HFpEF is a condition whose multiple pathophysiological mechanisms are still not fully defined, with many proposed hypotheses remaining speculative due to limited access to human heart tissue. This study aimed at evaluating cardiac expression levels of key genes of interest in human biopsy samples from patients affected with HFrEF and HFpEF in order to possibly point out distinct phenotypes. METHODS AND RESULTS: Total RNA was extracted from left ventricular cardiac biopsies collected from stable patients with HFrEF (n = 6) and HFpEF (n = 7) and healthy subjects (n = 9) undergoing elective cardiac surgery for valvular replacement, mitral valvuloplasty, aortic surgery, or coronary artery bypass. Real-time PCR was performed to evaluate the mRNA expression levels of genes involved in somatotropic axis regulation [IGF-1, IGF-1 receptor (IGF-1R), and GH receptor (GHR)], in adrenergic signalling (GRK2, GRK5, ADRB1, and ADRB2), in myocardial calcium handling (SERCA2), and in TNF-α. Patients with HFrEF and HFpEF showed reduced serum IGF-1 circulating levels when compared with controls (102 ± 35.6, 138 ± 11.5, and 160 ± 13.2 ng/mL, P < 0.001, respectively). At myocardial level, HFrEF showed significant decreased GHR and increased IGF-1R expressions when compared with HFpEF and controls (0.54 ± 0.27, 0.94 ± 0.25, and 0.84 ± 0.2, P < 0.05 and 1.52 ± 0.9, 1.06 ± 0.21, and 0.72 ± 0.12, P < 0.05, respectively), while no differences in the local expression of IGF-1 mRNA were detected among the groups (0.80 ± 0.45, 0.97 ± 0.18, and 0.63 ± 0.23, P = 0.09, respectively). With regard to calcium handling and adrenergic signalling, HFrEF displayed significant decreased levels of SERCA2 (0.19 ± 0.39, 0.82 ± 0.15, and 0.87 ± 0.32, P < 0.01) and increased levels of GRK2 (3.45 ± 2.94, 0.93 ± 0.12, and 0.80 ± 0.14, P < 0.01) and GRK5 (1.32 ± 0.70, 0.71 ± 0.14, and 0.77 ± 0.15, P < 0.05), while no significant difference was found in ADRB1 (0.66 ± 0.4, 0.83 ± 0.3, and 0.86 ± 0.4) and ADRB2 mRNA expression (0.65 ± 0.3, 0.66 ± 0.2, and 0.68 ± 0.1) when compared with HFpEF and controls. Finally, no changes in the local expression of TNF-α were detected among groups. CONCLUSIONS: Heart failure with reduced ejection fraction and HFpEF patients with stable clinical condition display a distinct molecular milieu of genes involved in somatotropic axis regulation, calcium handling, and adrenergic derangement at a myocardial level. The unique opportunity to compare these results with a control group, as reference population, may contribute to better understand HF pathophysiology and to identify novel potential therapeutic targets that could be modulated to improve ventricular function in patients with HF.

Safety and efficacy of prophylactic resorbable biosynthetic mesh in loop-ileostomy reversal: a case-control study.

Loop ileostomy (LI) is a widely used temporary stoma technique. Reversal of LI is generally considered a minor and safe procedure, with very low short-term postoperative mortality and morbidity rates. Complications include incisional hernia (IH), carrying a high probability of surgical repair. Clinical measures to reduce the IH rate warrant consideration. Recent researches suggest the use of a prophylactic non-absorbable mesh to reduce IH rate; however, surgeons are reluctant to implant a permanent foreign material in contaminated operative fields, because of a higher risk of mesh-related complications, infection, seroma, and pain. The aim of the present study is to assess feasibility, potential benefits, and safety of a prophylactic biosynthetic mesh placed during LI reversal. From January 2016 to December 2018, 26 consecutive patients underwent LI reversal positioning a resorbable biosynthetic mesh in an on-lay position [mesh group (MG)]. The mesh used was a GORE BIO-A tissue reinforcement, a biosynthetic mesh composed of a bioabsorbable polyglycolide-trimethylene carbonate copolymer. The MG was matched with 58 patients [control group (CG)], undergoing LI reversal without mesh placement from January 2013 to December 2018. To detect IH, abdominal wall was studied according to clinical and ultrasonographic criteria. Primary endpoint was IH rate on LI site, at 6 and 12 months after stomal reversal. Secondary endpoints included incidence of wound events. Thirty-day morbidity was classified according to Clavien-Dindo score; mortality and length of hospital stay were also collected. Mean follow-up was 15.4 ± 2.3 months (range 12.4-22.0) for MG vs 37.2 ± 26.9 (range 24.9-49.7) for. CG. At 1 year of follow-up, IH rate was lower in MG (n = 1/26 [3.8%]) vs CG (n = 19/58 [32.7%]; P < 0.05). A clinically evident IH was less frequent in MG (n = 0 [0%]) vs CG (n = 13 [68%]; P < 0.05). A radiologic IH was less frequent in MG (n = 1 [3%]) vs CG (n = 6 [31%]; P < 0.05). Stoma site hernia was repaired in 9/19 patients (47%) in CG; no patient of MG has hernia repaired. Incarcerated IH was observed in one patient of CG. No postoperative mortality was reported. Overall postoperative morbidity showed no difference comparing MG and MG (n = 5 [17%] vs n = 15 [19%], respectively; P > 0.05). Surgical site infections (SSI) were treated with antibiotic therapy, no debridement was necessary. Seroma occurred in two patients, one for each group. No statistically significant difference for surgical outcomes was found between the two groups at 30 days. Early results of the present study suggest that an on-lay prophylactic placement of GORE BIO-A tissue reinforcement might lower IH rate at LI site. The procedure seems to be safe and effective, even long-term results and further studies are needed.

Preventing Venous Thromboembolism in Ambulatory Cancer Patients: The ONKOTEV Study.

BACKGROUND: The efficacy of risk model scores to predict venous thromboembolism (VTE) in ambulatory cancer patients is under investigation, aiming to stratify on an individual risk basis the subset of the cancer population that could mostly benefit from primary thromboprophylaxis. MATERIALS AND METHODS: We prospectively assessed 843 patients with active cancers, collecting clinical and laboratory data. We screened all the patients with a duplex ultrasound (B-mode imaging and Doppler waveform analysis) of the upper and lower limbs to evaluate the right incidence of VTE (both asymptomatic and symptomatic). The efficacy of the existing Khorana risk model in preventing VTE was also explored in our population. Several risk factors associated with VTE were analyzed, leading to the construction of a risk model. The Fine and Gray model was used to account for death as a competing risk in the derivation of the new model. RESULTS: The risk factors significantly associated with VTE at univariate analysis and further confirmed in the multivariate analysis, after bootstrap validation, were the presence of metastatic disease, the compression of vascular/lymphatic structures by tumor, a history of previous VTE, and a Khorana score >2. Time-dependent receiving operating characteristic (ROC) curve analysis showed a significant improvement in the area under the curve of the new score over the Khorana model at 3 months (71.9% vs. 57.9%, p = .001), 6 months (75.4% vs. 58.6%, p < .001), and 12 months (69.8% vs. 58.3%, p = .014). CONCLUSION: ONKOTEV score steps into history of cancer-related-VTE as a promising tool to drive the decision about primary prophylaxis in cancer outpatients. The validation represents the goal of the prospective ONKOTEV-2 study, endorsed and approved by the European Organization for Research and Treatment of Cancer Young Investigators Program. The Oncologist 2017;22:601-608 IMPLICATIONS FOR PRACTICE: Preventing venous thromboembolism in cancer outpatients with a risk model score will drive physicians' decision of starting thromboprophylaxis in high-risk patients.

Bowel Angiodysplasia and Myocardial Infarction secondary to an ischaemic imbalance: a case report.

Angiodysplasia, defined as a vascular ectasia or arteriovenous malformation, is the most frequent cause of occult bleeding in patients older than 60 years and a significant association with several cardiac condition is described. Patients with anemia and negative findings on upper endoscopy and colonoscopy should be referred for further investigation of the small bowel. The investigation of choice, when available, is wireless capsule endoscopy. Several therapeutic options are available in this cases, as we reviewed in this report. We report a case of 78-year old man admitted to our Intensive Coronary Unit for dyspnea and chest pain. A diagnosis of non-ST-segment elevation acute coronary syndrome was made and a concomintant, significant anemia was found (hemoglobin 8.2 g/dl). No cororary disease was found by an angiography though the past medical history revealed systemic hypertension, chronic kidney disease (KDOQY stage III), and diabetes mellitus type II on insuline therapy. A Wireless Video capsule examination was positive for jejunum angiodysplasia and an argon plasma coagulation was chosen as terapeutic option. No subsequent supportive therapy and interventions were required in subsequent one year of follow-up.

[Anti remodeling therapy: new strategies and future perspective in post-ischemic heart failure: Part I]. / Terapie antiremodeling: nuove strategie e prospettive future nell'insufficienza cardiaca cronica post ischemica: Parte I.

In recent years, the remarkable progress achieved in terms of survival after myocardial infarction have led to an increased incidence of chronic heart failure in survivors. This phenomenon is due to the still incomplete knowledge we possess about the complex pathophysiological mechanisms that regulate the response of cardiac tissue to ischemic injury. These involve various cell types such as fibroblasts, cells of the immune system, endothelial cells, cardiomyocytes and stem cells, as well as a myriad of mediators belonging to the system of cytokines and not only. In parallel with the latest findings on post-infarct remodeling, new potential therapeutic targets are arising to halt the progression of disease. In this review, we evaluate the results obtained from four new therapeutic strategies: in this part we evaluate gene therapy and novel aspect of stem cells therapy in remodeling; in the second part we will investigate, micro-RNA, posttranslational modification and microspheres based therapy.

[Anti remodeling therapy: new strategies and future perspective in post-ischemic heart failure. Part II]. / Terapie antiremodeling: nuove strategie e prospettive future nell'insufficienza cardiaca cronica post ischemica: Parte II.

In recent years, the remarkable progress achieved in terms of survival after myocardial infarction have led to an increased incidence of chronic heart failure in survivors. This phenomenon is due to the still incomplete knowledge we possess about the complex pathophysiological mechanisms that regulate the response of cardiac tissue to ischemic injury. These involve various cell types such as fibroblasts, cells of the immune system, endothelial cells, cardiomyocytes and stem cells, as well as a myriad of mediators belonging to the system of cytokines and not only. In parallel with the latest findings on post-infarct remodeling, new potential therapeutic targets are arising to halt the progression of disease. After the evaluation of the results obtained from gene therapy and stem cells, in this part we evaluate micro-RNA, post-translational modification and microspheres based therapy.

The GH/IGF-1 axis in chronic heart failure.

The classic model of Chronic Heart Failure (CHF) is rooted in the overexpression of neurohormonal molecules. To complement this paradigm, increasing evidence indicates that a variety of hormones may be down-regulated in CHF patients. The list includes growth hormone (GH) and its tissue effector insulin-like growth factor-1 (IGF-1). The GH/IGF-1 axis regulates cardiac growth, stimulates myocardial contractility, and influences the vascular system. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous studies in animals models and confirmed by the cardiac derangements secondary to both GH excess and deficiency in humans. Impaired activity of the GH/IGF-1 axis in CHF has been described by several independent groups and includes a wide array of abnormalities, including low IGF-1 levels, GH deficiency (GHD), and GH resistance that may be related to the severity of heart disease. According to several observations, these derangements are associated with poor clinical status and outcome. Since the first study of GH therapy in CHF in 1996, several placebo-controlled trials have been conducted with conflicting results. These discordant findings are likely explained by the degree of CHF-associated GH/IGF-1 impairment that may impact on individual responsiveness to GH administration. Biological actions of GH and IGF-1, cardiovascular implication of GH deficiency and GH excess, relation between somatotrophic axis and CHF are discussed. Results from trials of GH therapy, emerging therapeutic strategies, safety issues, and lack in evidence are also reported.