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Despite progress in the prevention and diagnosis of cancer, current technologies for tumor detection present several limitations including invasiveness, toxicity, inaccuracy, lengthy testing duration and high cost. Therefore, innovative diagnostic techniques that integrate knowledge from biology, oncology, medicinal and analytical chemistry are now quickly emerging in the attempt to address these issues. Following this approach, here we developed a paper-based electrochemical device for detecting cancer-derived Small Extracellular Vesicles (S-EVs) in fluids. S-EVs were obtained from cancer cell lines known to express, at a different level, the αvβ6 integrin receptor, a well-established hallmark of numerous epithelial cancer types. The resulting biosensor turned out to recognize αvβ6-containing S-EVs down to a limit of 0.7*10 3 S-EVs/mL with a linear range up to 10 5 S-EVs /mL, and a relative standard deviation of 11%, thus it may represent a novel opportunity for αvβ6 expressing cancers detection., (© 2024. The Author(s).)

Aims: Myotonic dystrophy type 1 (DM1) predisposes to the development of life-threatening arrhythmias and sudden cardiac death. Our study aimed to evaluate the prognostic value of programmed ventricular stimulation (PVS) in DM1 patients with conduction system disease., Methods and Results: Arrhythmic CArdiac DEath in MYotonic dystrophy type 1 patients (ACADEMY 1) is a double-arm non-randomized interventional prospective study. Myotonic dystrophy type 1 patients with permanent cardiac pacing indication were eligible for the inclusion. The study population underwent to pacemaker (PM) or implantable cardioverter-defibrillator (ICD) implantation according to the inducibility of ventricular tachyarrhythmias at PVS. Primary endpoint of the study was a composite of appropriate ICD therapy and cardiac arrhythmic death. The secondary study endpoint was all-cause mortality. Seventy-two adult-onset DM1 patients (51 ± 12 years; 39 male) were enrolled in the study. A ventricular tachyarrhythmia was induced in 25 patients (34.7%) at PVS (PVS+) who underwent dual chambers ICD implantation. The remaining 47 patients (65.3%) without inducible ventricular tachyarrhythmia (PVS-) were treated with dual-chamber PM. During an average observation period of 44.7 ± 10.2 months, nine patients (12.5%) met the primary endpoint, four in the ICD group (16%) and five (10.6%) in the PM group. Thirteen patients died (18.5%), 2 in the ICD group (8%) and 11 in PM group (23.4%). The Kaplan-Meier analysis did not show a significantly different risk of both primary and secondary endpoint event rates between the two groups., Conclusions: The inducibility of ventricular tachyarrhythmias has shown a limited value in the arrhythmic risk stratification among DM1 patients., (© Crown copyright 2021.)

Background: Triple negative breast cancer (TNBC) is an aggressive disease characterized by high risk of relapse and development of resistance to different chemotherapy agents. Several targeted therapies have been investigated in TNBC with modest results in clinical trials. Among these, PI3K/AKT inhibitors have been evaluated in addition to standard therapies, yielding conflicting results and making attempts on elucidating inherent mechanisms of resistance of great interest. Increasing evidences suggest that PI3K/AKT inhibitors can induce autophagy in different cancers. Autophagy represents a supposed mechanism of drug-resistance in aggressive tumors, like TNBC. We, therefore, investigated if two PI3K/AKT inhibitors, ipatasertib and taselisib, could induce autophagy in breast cancer models, and whether chloroquine (CQ), a well known autophagy inhibitor, could potentiate ipatasertib and taselisib anti-cancer effect in combination with conventional chemotherapy., Methods: The induction of autophagy after ipatasertib and taselisib treatment was evaluated in MDAMB231, MDAM468, MCF7, SKBR3 and MDAB361 breast cancer cell lines by assaying LC3-I conversion to LC3-II through immunoblotting and immunofluorescence. Other autophagy-markers as p62/SQSTM1 and ATG5 were evaluated by immunoblotting. Synergistic antiproliferative effect of double and triple combinations of ipatasertib/taselisib plus CQ and/or paclitaxel were evaluated by SRB assay and clonogenic assay. Anti-apoptotic effect of double combination of ipatasertib/taselisib plus CQ was evaluated by increased cleaved-PARP by immunoblot and by Annexin V- flow cytometric analysis. In vivo experiments were performed on xenograft model of MDAMB231 in NOD/SCID mice., Results: Our results suggested that ipatasertib and taselisib induce increased autophagy signaling in different breast cancer models. This effect was particularly evident in PI3K/AKT resistant TNBC cells, where the inhibition of autophagy by CQ potentiates the therapeutic effect of PI3K/AKT inhibitors in vitro and in vivo TNBC models, synergizing with taxane-based chemotherapy., Conclusion: These data suggest that inhibition of authophagy with CQ could overcome mechanism of drug resistance to PI3K/AKT inhibitors plus paclitaxel in TNBC making the evaluation of such combinations in clinical trials warranted., (© 2022. The Author(s).)

Background: The effects of lockdown on non-COVID patients are varied and unexpected. The aim is to evaluate the burden of cardiac arrhythmias during a lockdown period because of COVID-19 pandemics in a population implanted with cardiac defibrillators and followed by remote monitoring., Methods: In this retrospective, multicentre cohort study, we included 574 remotely monitored implantable cardioverter defibrillator (ICD) and cardiac resynchronization therapy-defibrillator (CRT-D) recipients implanted before January 1, 2019, at seven hospitals in the Campania region, comparing the burden of arrhythmias occurred during the lockdown period because of COVID-19 epidemics (from March 9 to May 1, 2020) with the arrhythmias burden of the corresponding period in 2019 (reference period). Data collection was performed through remote monitoring., Results: During the lockdown period, we observed ventricular tachyarrhythmias (ventricular tachycardia or fibrillation) in 25 (4.8%) patients while in seasonal reference period we documented ventricular tachyarrhythmias in 12 (2.3%) patients; the comparison between the periods is statistically significant ( P  < .04). Atrial arrhythmias were detected in 38 (8.2%) subjects during the lockdown period and in 24 (5.2%) during the reference period ( P  < .004)., Conclusion: In seven hospitals in the Campania region, during the pandemic lockdown period, we observed a higher burden of arrhythmic events in ICD/CRT-D patients through device remote monitoring., Competing Interests: No conflict of interest to declare., (© 2022 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

When planning an implant-supported restoration, the dentist is faced with surgical and prosthetic technical issues as well as the patient's expectations. Many patients wish an immediate solution to an edentulous condition. This may be especially true in the esthetic zone, and that zone is determined by the patient. The dentist may consider when it is feasible to load the supporting implants with definitive or provisional prosthetics. In this work, many parameters were theoretically assessed for inclusion: bone density, cortical thickness, insertion torque, parafunction, bite load capacity, number of implants under load, implant/crown ratio, implant diameter, and length. After assessment, the most influential parameters were selected. An iteration, using patient age, implant diameter, bite load capacity, and cortical thickness, is now presented to aid the implant dentist in determining the feasibility for immediate functional loading of a just-placed dental implant in a healed site. Extensive testing is required to develop this concept. According to this iteration, most immediate functional loaded implants would fail. A future refined and definitive formula may enable the clinician to safely and immediately functionally load an implant with a definitive prosthesis. For access to the applet, please go to https://implantloading.shinyapps.io/shiny&#95;app/.

Study Objectives: Whether the cause of daytime sleepiness in narcolepsy type 1 (NT1) is a direct consequence of the loss of orexin (ORX) neurons or whether low orexin reduces the efficacy of the monoaminergic systems to promote wakefulness is unclear. The neurobiology underlying sleepiness in other central hypersomnolence disorders, narcolepsy type 2 (NT2), and idiopathic hypersomnia (IH), is currently unknown., Methods: Eleven biogenic amines including the monoaminergic neurotransmitters and their metabolites and five trace amines were measured in the cerebrospinal fluid (CSF) of 94 drug-free subjects evaluated at the French National Reference Center for Narcolepsy: 39 NT1(orexin-deficient) patients, 31 patients with objective sleepiness non orexin-deficient (NT2 and IH), and 24 patients without objective sleepiness., Results: Three trace amines were undetectable in the sample: tryptamine, octopamine, and 3-iodothyronamine. No significant differences were found among the three groups for quantified monoamines and their metabolites in crude and adjusted models; however, CSF 5-hydroxyindoleacetic acid (5-HIAA) levels tended to increase in NT1 compared to other patients after adjustment. Most of the biomarkers were not associated with ORX-A levels, clinical or neurophysiological parameters, but a few biomarkers (e.g. 3-methoxy-4-hydroxyphenylglycol and norepinephrine) correlated with daytime sleepiness and high rapid eye movement (REM) sleep propensity., Conclusions: We found no striking differences among CSF monoamines, their metabolites and trace amine levels, and few associations between them and key clinical or neurophysiological parameters in NT1, NT2/IH, and patients without objective sleepiness. Although mostly negative, these findings are a significant contribution to our understanding of the neurobiology of hypersomnolence in these disorders that remain mysterious and deserve further exploration., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

A retrospective comparison between two groups of patients who underwent one-step or two-step triple innervation was performed to reveal the role of scar tissue in axonal regeneration. The surgical technique used was the same in all cases, but the first group underwent a one-time triple innervation procedure, while patients in the second group underwent delayed performance of neurorrhaphies between the distal ends of the cross-face grafts and the terminal branches of the injured facial nerve. The Wilcoxon signed-rank test for paired groups showed a statistically significant improvement in both facial symmetry and voluntary movements in both groups of patients. Separately, the Mann-Whitney test confirmed no statistically significant difference between the two groups regarding the restoration of facial symmetry and voluntary movements, and the development of postoperative synkinesis. A comparison of median values for each spontaneous parameter between the groups revealed greater effectiveness of the two-step surgery, with both blinking and laughing demonstrating better results. The greater effectiveness of the double-step technique in restoring spontaneous movements strongly supports the use of a two-stage triple innervation technique in patients with facial palsy., Competing Interests: Declaration of competing interest None., (Copyright © 2021 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a significant impact on people's behavior. The aim of this study has been to evaluate how the SARS-CoV-2 pandemic has impacted the incidence and the features of maxillofacial fractures presented at 6 Italian tertiary centers. Clinical records of all the patients diagnosed for facial fractures between February 23 and May 23, 2019 and 2020 were retrospectively reviewed. Any differences in patient number and characteristics and fracture etiology and site between the 2 groups were then statistically analyzed.There has been a 69.1% decrease in the number of incoming patients during the pandemic. The number of foreign patients has decreased significantly (23.3% versus 9.6%, P = 0.011) while the average age has increased (38.6 versus 45.6 years old, P = 0.01). Specific statistical significant differences for accidental falls (31.8% versus 50.1%, P = 0.005) and sports injuries (16.9% versus 1.4%, P < 0.001) were found. Concerning fracture sites, significant differences have been found in relation to nasal (22.5% versus 11.4%, P = 0.009) and frontal sinus (0.9% versus 4.4%, P = 0.037) fractures. In conclusion, SARS-CoV-2 pandemic has significantly changed the epidemiology and the etiology of facial traumas., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by Mutaz B. Habal, MD.)

Background: Preoperative screening had a key role in planning elective surgical activity for head and neck cancer (HNC) during the COVID-19 pandemic., Methods: All patients undergoing surgery for HNC at two Italian referral hospitals (University of Padua and National Cancer Institute [NCI]) during the peak of the COVID-19 epidemic in Italy were included. Accuracy of screening protocols was assessed., Results: In the Padua protocol, 41 patients were screened by pharyngeal swab. The entire sample (100%) was admitted to surgery, diagnostic accuracy was 100%. In the NCI protocol, 23 patients underwent a telephone interview, blood test, and chest CT. Twenty patients (87%) were negative and were directly admitted to surgery. In the remaining 3 (13%), pharyngeal swab was performed. The screening was repeated until a negative chest CT was found. Diagnostic accuracy was 85%., Conclusions: Dedicated screening protocols for COVID-19 allow to safely perform elective HNC surgery., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Optimization of the atrioventricular (AV) and interventricular (VV) timings of the CRT is the most supposed correctable variable to improve the rate of CRT responder. The aim of the present study has been to evaluate if there is a specific subgroup of patients who can actually benefit the most from a hemodynamic optimization of AV. This is a prospective, observational single-center study that enrolled consecutive patients with clinical indication for CRT; all patients were implanted with CRT-D devices with SonR technology, able to automatically adjust AV and VV delay on a weekly basis. Among 57 patients, 39 (69%) showed a LVESV reduction > 15%. The SonR was able to modify the pacing parameters, but an increase of left atrial diameter was associated to a reduced AV variability, suggesting that an impaired left atrial function could potentially reduce the ability of the SonR algorithm to adjust the correct timing of pacing. Graphical abstract Patients with respectively a high (A) and low (B) AV timing variability, among several parameters that could potentially influence the AV timing, only left atrial dimensions demonstrated a significant impact. In fact an increase of left atrial diameter was associated to a reduced AV variability, suggesting that an impaired left atrial function could potentially reduce the ability of the SonR algorithm to adjust the correct timing of pacing.

Background: Despite the introduction of several novel therapeutic approaches that improved survival, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Herein we report the synergistic antitumor interaction between two well-known drugs used for years in clinical practice, the antiepileptic agent with histone deacetylase inhibitory activity valproic acid and the cholesterol lowering agent simvastatin, in mCRPC models., Methods: Synergistic anti-tumor effect was assessed on PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells, by calculating combination index (CI), caspase 3/7 activation and colony formation assays as well as on tumor spheroids and microtissues scored with luminescence 3D-cell viability assay. Cancer stem cells (CSC) compartment was studied evaluating specific markers by RT-PCR, western blotting and flow cytometry as well as by limiting dilution assay. Cholesterol content was evaluated by 1 H-NMR. Overexpression of wild-type YAP and constitutively active YAP5SA were obtained by lipofectamine-based transfection and evaluated by immunofluorescence, western blotting and RT-PCR. 22Rv1 R&#95;39 docetaxel resistant cells were selected by stepwise exposure to increasing drug concentrations. In vivo experiments were performed on xenograft models of DU145R80, 22Rv1 parental and docetaxel resistant cells, in athymic mice., Results: We demonstrated the capacity of the combined approach to target CSC compartment by a novel molecular mechanism based on the inhibition of YAP oncogene via concurrent modulation of mevalonate pathway and AMPK. Because both CSCs and YAP activation have been associated with chemo-resistance, we tested if the combined approach can potentiate docetaxel, a standard of care in mCRCP treatment. Indeed, we demonstrated, both in vitro and in vivo models, the ability of valproic acid/simvastatin combination to sensitize mCRPC cells to docetaxel and to revert docetaxel-resistance, by mevalonate pathway/YAP axis modulation., Conclusion: Overall, mCRPC progression and therapeutic resistance driven by CSCs via YAP, can be tackled by the combined repurposing of two generic and safe drugs, an approach that warrants further clinical development in this disease.

Recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. The combination of cisplatin (CDDP) plus cetuximab (CX) is one of the standard first-line treatments in this disease. However, this therapeutic regimen is often associated with high toxicity and resistance, suggesting that new combinatorial strategies are needed to improve its therapeutic index. In our study, we evaluated the antitumor effects of valproic acid (VPA), a well-known antiepileptic agent with histone deacetylase inhibitory activity, in combination with CDDP/CX doublet in head and neck squamous cell carcinoma (HNSCC) models. We demonstrated, in HNSCC cell lines, but not in normal human fibroblasts, that simultaneous exposure to equitoxic doses of VPA plus CDDP/CX resulted in a clear synergistic antiproliferative and pro-apoptotic effects. The synergistic antitumor effect was confirmed in four different 3D-self-assembled spheroid models, suggesting the ability of the combined approach to affect also the cancer stem cells compartment. Mechanistically, VPA enhanced DNA damage in combination treatment by reducing the mRNA expression of ERCC Excision Repair 1, a critical player in DNA repair, and by increasing CDDP intracellular concentration via upregulation at transcriptional level of CDDP influx channel copper transporter 1 and downregulation of the ATPAse ATP7B involved in CDDP-export. Valproic acid also induced a dose-dependent downregulation of epidermal growth factor receptor (EGFR) expression and of MAPK and AKT downstream signaling pathways and prevent CDDP- and/or CX-induced EGFR nuclear translocation, a well-known mechanism of resistance to chemotherapy. Indeed, VPA impaired the transcription of genes induced by non-canonical activity of nuclear EGFR, such as cyclin D1 and thymidylate synthase. Finally, we confirmed the synergistic antitumor effect also in vivo in both heterotopic and orthotopic models, demonstrating that the combined treatment completely blocked HNSCC xenograft tumors growth in nude mice. Overall, the introduction of a safe and generic drug such as VPA into the conventional treatment for R/M HNSCC represents an innovative and feasible antitumor strategy that warrants further clinical evaluation. A phase II clinical trial exploring the combination of VPA and CDDP/CX in R/M HNSCC patients is currently ongoing in our institute., (Copyright © 2020 Iannelli, Zotti, Roca, Grumetti, Lombardi, Moccia, Vitagliano, Milone, Ciardiello, Bruzzese, Leone, Cavalcanti, De Cecio, Iachetta, Valiante, Ionna, Caponigro, Di Gennaro and Budillon.)

Lagophthalmos is one of the most unpleasant and dangerous conditions that affect patients with facial palsy. The lack of ocular protection leads to corneal problems (such as conjunctival infections, acute and chronic keratitis, corneal ulcerations, and blindness). A dynamic reanimation of blinking eyelids is the therapeutic gold standard. However, success is not guaranteed with these dynamic techniques; even if results are good, blinking is usually restored within a year of the initial operation. Procedures that act more rapidly and have a higher success rate are needed. We proposed that lipofilling of the upper eyelid would improve eye closure, exploit the advantages of using autologous fat, and avoid the risks of exposure or migration associated with loading the lid with gold. Between 2012 and September 2018, we did upper eyelid lipofilling procedures for 75 patients with unilateral facial palsy. The main favourable result of lipofilling of the upper lid was the immediate improvement in corneal discomfort. Everybody described a partial to total increase in corneal comfort postoperatively. In the treatment of paralytic lagophthalmos, lipofilling of the upper eyelid produces favourable aesthetic and functional results, ocular health is restored, and the patients' quality of life is improved., (Copyright © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)

Extracellular Vesicles (EVs) represent a heterogeneous population of particles naturally released from all cells, delimited by a lipid bilayer and able to horizontally transfer their cargos to recipient cells. These features imply the growing interest on EVs in cancer biology as biomarkers and therapeutic targets. In this review, we will highlight the specific process related to biogenesis and release of large EVs (L-EVs) derived from the plasma membrane (PM) compared to the small and well described exosomes, generated through the classical endosome-multivesicular body (MVB) pathway. The control of PM rigidity by cells depends on lipid/protein composition, cytoskeleton dynamics, cytoplasmic viscosity, ions balance, metabolic reprogramming and specific intracellular signaling pathways, all critical determinants of L-EVs biogenesis. We will focus in details on a specific class of L-EVs, named Large Oncosomes (LO), exclusively shed by cancer cells and with a size ranging from 1 μm up to 10 μm. We will examine LO specific cargos, either proteins or nucleic acids (i.e. mRNA, microRNAs, single/double-stranded DNA), as well as their functional role in cancer development and progression, also discussing the mechanisms of L-EVs internalization by recipient cells. Overall we will highlight the potential of LO as specific diagnostic/prognostic cancer biomarkers discussing the associated challenges., Competing Interests: Declaration of Competing Interest The authors declare no potential conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Molecular markers for prostate cancer (PCa) are required to improve the early definition of patient outcomes. Atypically large extracellular vesicles (EVs), referred as "Large Oncosomes" (LO), have been identified in highly migratory and invasive PCa cells. We recently developed and characterized the DU145R80 subline, selected from parental DU145 cells as resistant to inhibitors of mevalonate pathway. DU145R80 showed different proteomic profile compared to parental DU145 cells, along with altered cytoskeleton dynamics and a more aggressive phenotype., Methods: Immunofluorescence staining and western blotting were used to identify blebbing and EVs protein cargo. EVs, purified by gradient ultra-centrifugations, were analyzed by tunable resistive pulse sensing and multi-parametric flow cytometry approach coupled with high-resolution imaging technologies. LO functional effects were tested in vitro by adhesion and invasion assays and in vivo xenograft model in nude mice. Xenograft and patient tumor tissues were analyzed by immunohistochemistry., Results: We found spontaneous blebbing and increased shedding of LO from DU145R80 compared to DU145 cells. LO from DU145R80, compared to those from DU145, carried increased amounts of key-molecules involved in PCa progression including integrin alpha V (αV-integrin). By incubating DU145 cells with DU145R80-derived LO we demonstrated that αV-integrin on LO surface was functionally involved in the increased adhesion and invasion of recipient cells, via AKT. Indeed either the pre-incubation of LO with an αV-integrin blocking antibody, or a specific AKT inhibition in recipient cells are able to revert the LO-induced functional effects. Moreover, DU145R80-derived LO also increased DU145 tumor engraftment in a mice model. Finally, we identified αV-integrin positive LO-like structures in tumor xenografts as well as in PCa patient tissues. Increased αV-integrin tumor expression correlated with high Gleason score and lymph node status., Conclusions: Overall, this study is the first to demonstrate the critical role of αV-integrin positive LO in PCa aggressive features, adding new insights in biological function of these large EVs and suggesting their potential use as PCa prognostic markers.

Several evidences nowadays demonstrated the critical role of the microenvironment in regulating cancer stem cells and their involvement in tumor progression. Extracellular vesicles (EVs) are considered as one of the most effective vehicles of information among cells. Accordingly, a number of studies led to the recognition of stem cell-associated EVs as new complexes able to contribute to cell fate determination of either normal or tumor cells. In this review, we aim to highlight an existing bidirectional role of EV-mediated communication-from cancer stem cells to microenvironment and also from microenvironment to cancer stem cells-in the most widespread solid cancers as prostate, breast, lung, and colon tumors.

Background: Atrial fibrillation (AF) is a common finding in the myotonic dystrophy type 1 (DM1) population. Pacemakers (PMs) may facilitate the diagnosis and management of frequent subclinical asymptomatic AF episodes., Objective: The purpose of this study was to evaluate the effect of minimal ventricular pacing on paroxysmal AF incidence in DM1 patients during a 24-month follow-up period., Methods: We enrolled 70 DM1 patients (age 43.4 ± 13.8 years; 39 women) who underwent dual-chamber PM implantation. Patients were randomized to minimizing ventricular pacing features (ON) or not (OFF). Patients crossed over to the opposite pacing programming 12 months later. We counted the number of DM1 patients with at least 1 episode of AF, the AF total duration, and the burden recorded by PM diagnostics during the MVP ON and OFF phases., Results: Twenty-five DM1 patients (41.7%) showed at least 1 AF episode. Seven patients (11.7%) demonstrated AF episodes during MVP ON phase and 25 patients (41.7%) during MVP OFF phase (P <.001). Thirty-five patients had no AF during MVP ON or OFF phase, 3 patients had AF episodes only during MVP ON phase, 21 patients had AF episodes only during MVP OFF phase, and 4 patients had AF episodes during MVP ON and OFF phases. Activation of the MVP algorithm was associated with a 44% reduction in relative risk of developing AF. Furthermore, during the MVP ON phases, the study population showed a shorter total AF duration and a lower AF burden., Conclusion: MVP is an efficacy strategy for reducing the risk of AF in DM1 patients who have undergone PM implantation., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Aim: To evaluate at a 12-month follow-up, the clinical and echocardiographic outcomes in postmyocardial infarction (MI) heart failure patients who underwent cardiac resynchronization therapy (CRT) device implantation., Materials & Methods: A total of 100 patients received a CRT device, and the study population was divided into three groups, according to the site of MI and left ventricular (LV) lead placed downstream of the ischemic area, as evaluated by echocardiography., Results: At the end of the 12-month follow-up, we reported a general improvement of LV ejection fraction from 28 ± 7% to 35 ± 9% (p < 0.001) and a significant reverse remodeling: LV end-systolic volume changed from 147 ± 54 to 125 ± 63 (p = 0.001) with a 53% of echocardiographic responders. We also observed 67% of CRT responders in the group with optimal LV lead placement compared with 38% in the remaining population (p = 0.01)., Conclusion: The optimal positioning of LV lead is a feasible method to improve the percentage of CRT responders in post-MI heart failure patients.

Paroxysmal atrial fibrillation frequently occurs in Myotonic dystrophy type 1 (DM1) patients. Interatrial block is recognized as predictor of atrial arrhythmias, particularly atrial fibrillation (AF). The aim of this study was to evaluate the role of interatrial block in predicting the onset of atrial fibrillation during 2-year follow-up in DM1 patients who underwent pacemaker implantation for conduction system disorders. The study prospectively enrolled 70 DM1 patients (aged 36-69; 31 M) who underwent pacemaker implantation for cardiac rhythm abnormalities in accordance with the current guidelines. All DM1 patients underwent 12-lead surface ECG, 2D color Doppler echocardiogram and device interrogation at implantation, one month after and every six months thereafter for a minimum of 2-year follow-up. 12-lead surface ECGs were analyzed to diagnose interatrial block (IAB), defined as a P-wave duration ≥120 ms without (partial IAB) or with (advanced IAB) biphasic morphology (±) in the inferior leads. Device interrogation was performed to evaluate the development of new onset atrial high rate electrograms compatible with paroxysmal atrial fibrillation episodes. Interatrial block was detected in 22 patients (31.4%): 18 partial (25.7%) and 4 advanced (5.7%). During follow-up, AF episodes were detected in 18 DM1 patients (25.7%). The study population was divided into 2 groups according to the presence of AF (AF+ Group vs AF- Group). The AF+ Group was older and showed higher prevalence of IAB than the AF- Group. IAB was found to be independent predictor of AF in DM1 population (P < 0.001). A cut-off value of 121 ms for IAB had a sensitivity of 83.3% and specificity of 90.3% in identifying DM1 patients at high risk of developing AF. Interatrial block represents an independent predictor of AF occurrence in our DM1 population with conduction disturbances who had previously undergone pacemaker implantation., (Published by Elsevier B.V.)

Purpose: Subclavian access is a reliable technique for lead insertion in pacemaker and defibrillator (ICD) implantation, but it is often accompanied by complications. The aim of this study was to compare the efficacy of the ultrasound-guided axillary approach to the subclavian method., Methods: This randomized comparative study was performed on 174 patients: as a first attempt, 116 patients underwent the ultrasound-guided axillary access and 58 patients underwent the subclavian approach. A total of 364 leads were placed. Operators were trained in ultrasound-guided vein access technique., Results: Axillary access was successful in 69% of patients (32/46), in the training phase and, as a first attempt, in 91.4% of patients (106/116), in the randomized phase. When axillary approach failed, we performed the following: subclavian access in 5.2% of patients (6/116), cephalic approach in 2.6% of patients (3/116), surgical method in 0.9% of patients (1/116). The subclavian technique was effective, as a first attempt, in 55 patients (94.8%). When the subclavian access failed, the ultrasound axillary approach successfully performed in all three cases. During a mean follow-up of 18 ± 6 months, the number of lead complications was similar in the subclavian group compared to the axillary group (p = 0.664)., Conclusions: As first attempt, ultrasound-guided axillary method showed similarly high-success rate than subclavian approach and well performed when the first attempt in subclavian group failed. Axillary access can be considered a safe and effective alternative technique to the conventional subclavian method for device implantation.

Background: Paroxysmal atrial tachyarrhythmias frequently occur in beta-thalassemia major (β-TM) patients. The aim of the current study was to evaluate the atrial electromechanical delay (AEMD) in a large β-TM population with normal cardiac function and its relationship to atrial fibrillation (AF) onset., Methods: Eighty β-TM patients (44 men, 36 women), with a mean age of 36.2 ± 11.1 years, and 80 healthy subjects used as controls, matched for age and gender, were studied for the occurrence of AF during a 5-year follow-up, through 30-day external loop recorder (ELR) monitoring performed every 6 months. Intra-AEMD and inter-AEMD of both atria were measured through tissue Doppler echocardiography. P-wave dispersion (PD) was carefully measured using 12-lead electrocardiogram (ECG)., Results: Compared to the healthy control group, the β-TM patients showed a statistically significant increase in inter-AEMD, intra-left AEMD, maximum P-wave duration, and PD. Dividing the β-TM group into two subgroups (patients with or without AF), the inter-AEMD, intra-left AEMD, maximum P-wave duration, and PD were significantly higher in the subgroup with AF compared to the subgroup without AF. There were significant good correlations of intra-left AEMD and inter-AEMD with PD. A cut-off value of 40.1 ms for intra-left AEMD had a sensitivity of 76.2% and a specificity of 97.5% in identifying β-TM patients with AF risk. A cut-off value of 44.8 ms for inter-AEMD had a sensitivity of 81.2% and a specificity of 98.7% in identifying this category of patients., Conclusions: Our results showed that the echocardiographic atrial electromechanical delay indices (intra-left and inter-AEMD) and the PD were significantly increased in β-TM subjects with normal cardiac function. PD and AEMD represent non-invasive, inexpensive, useful, and simple parameters to assess the AF risk in β-TM patients.

The role of altered redox status and high reactive oxygen species (ROS) is still controversial in cancer development and progression. Intracellular levels of ROS are elevated in cancer cells suggesting a role in cancer initiation and progression; on the contrary, ROS elevated levels may induce programmed cell death and have been associated with cancer suppression. Thus, it is crucial to consider the double-face of ROS, for novel therapeutic strategies targeting redox regulatory mechanisms. In this review, in order to derive cancer-type specific oxidative stress genes' profile and their potential prognostic role, we integrated a publicly available oxidative stress gene signature with patient survival data from the Cancer Genome Atlas database. Overall, we found several genes statistically significant associated with poor prognosis in the examined six tumor types. Among them, FoxM1 and thioredoxin reductase1 expression showed the same pattern in four out of six cancers, suggesting their specific critical role in cancer-related oxidative stress adaptation. Our analysis also unveiled an enriched cellular network, highlighting specific pathways, in which many genes are strictly correlated. Finally, we discussed novel findings on the correlation between oxidative stress and cancer stem cells in order to define those pathways to be prioritized in drug development.

A successful case of maximum voltage-directed cavo-tricuspid isthmus (CTI) ablation using a novel ablation catheter mapping technology in a myotonic dystrophy type I (DM1) patient is reported. The patient complained recurrent episodes of atrial flutter, revealed by the atrio-ventricular electrograms analysis during the routine pacemaker controls.

ErbB3, a member of the ErbB family receptors, has a key role in the development and progression of several cancers, including non-small cell lung cancer (NSCLC), and in the establishment of resistance to therapies, leading to the development of anti-ErbB3 therapies.In this study we demonstrated, in a set of malignant pleural effusion-derived cultures of NSCLC, the synergistic antitumor effect of a histone deacetylase inhibitor (HDACi), such as vorinostat or valproic acid (VPA), in combination with the anti-ErbB3 monoclonal antibody (MoAb) A3. Synergistic interaction was observed in 2D and in 3D cultures conditions, both in fully epithelial cells expressing all ErbB receptors, and in cells that had undergone epithelial to mesenchymal transition and expressed low levels of ErbB3. We provided evidences suggesting that differential modulation of ErbB receptors by vorinostat or VPA, also at low doses corresponding to plasma levels easily reached in treated patients, is responsible for the observed synergism. In details, we showed in epithelial cells that both vorinostat and VPA induced time- and dose-dependent down-regulation of all three ErbB receptors and of downstream signaling. On the contrary, in A3-resistant mesenchymal cells, we observed time- and dose-dependent increase of mRNA and protein levels as well as surface expression of ErbB3, paralleled by down-regulation of EGFR and ErbB2. Our results suggest that the combination of a HDACi plus an anti-ErbB3 MoAb represents a viable strategy that warrants further evaluation for the treatment of NSCLC patients.

Background: High urine flow rate (UFR) has been suggested as a target for effective prevention of contrast-induced acute kidney injury (CI-AKI). The RenalGuard therapy (saline infusion plus furosemide controlled by the RenalGuard system) facilitates the achievement of this target., Methods: Four hundred consecutive patients with an estimated glomerular filtration rate ≤30 mL/min per 1.73 m(2) and/or a high predicted risk (according to the Mehran score ≥11 and/or the Gurm score >7%) treated by the RenalGuard therapy were analyzed. The primary end points were (1) the relationship between CI-AKI and UFR during preprocedural, intraprocedural, and postprocedural phases of the RenalGuard therapy and (2) the rate of acute pulmonary edema and impairment in electrolytes balance., Results: Urine flow rate was significantly lower in the patients with CI-AKI in the preprocedural phase (208 ± 117 vs 283 ± 160 mL/h, P < .001) and in the intraprocedural phase (389 ± 198 vs 483 ± 225 mL/h, P = .009). The best threshold for CI-AKI prevention was a mean intraprocedural phase UFR ≥450 mL/h (area under curve 0.62, P = .009, sensitivity 80%, specificity 46%). Performance of percutaneous coronary intervention (hazard ratio [HR] 4.13, 95% CI 1.81-9.10, P < .001), the intraprocedural phase UFR <450 mL/h (HR 2.27, 95% CI 1.05-2.01, P = .012), and total furosemide dose >0.32 mg/kg (HR 5.03, 95% CI 2.33-10.87, P < .001) were independent predictors of CI-AKI. Pulmonary edema occurred in 4 patients (1%). Potassium replacement was required in 16 patients (4%). No patients developed severe hypomagnesemia, hyponatremia, or hypernatremia., Conclusions: RenalGuard therapy is safe and effective in reaching high UFR. Mean intraprocedural UFR ≥450 mL/h should be the target for optimal CI-AKI prevention., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Extracellular Vesicles (EVs) have received considerable attention in recent years, both as mediators of intercellular communication pathways that lead to tumor progression, and as potential sources for discovery of novel cancer biomarkers. For many years, research on EVs has mainly investigated either the mechanism of biogenesis and cargo selection and incorporation, or the methods of EV isolation from available body fluids for biomarker discovery. Recent studies have highlighted the existence of different populations of cancer-derived EVs, with distinct molecular cargo, thus pointing to the possibility that the various EV populations might play diverse roles in cancer and that this does not happen randomly. However, data attributing cancer specific intercellular functions to given populations of EVs are still limited. A deeper functional, biochemical and molecular characterization of the various EV classes might identify more selective clinical markers, and significantly advance our knowledge of the pathogenesis and disease progression of many cancer types.

Background: Paroxysmal atrial tachyarrhythmias frequently occur in myotonic dystrophy type 1 (DM1) patients. The aim of the current study was to evaluate the atrial electromechanical-delay (AEMD) in a DM1-population with normal cardiac function and its relationship to atrial fibrillation (AF) onset., Methods and Results: Fifty DM1 patients (28 male; mean age 34.2 ± 11.4 years) and 50 healthy subjects used as controls, matched for age and gender, were studied for the occurrence of atrial fibrillation during a 4-year follow-up, through 30-day external loop recorder (ELR) monitoring performed every 6 months. Intra-AEMD and inter-AEMD of both atrium were measured through tissue-Doppler echocardiography. Compared to the healthy control group, the DM1 group showed a statistically significant increase in inter-AEMD and intraleft-AEMD. Dividing the DM1-group into 2 subgroups (patients with or without AF), the inter-AEMD and intraleft-AEMD were significantly higher in the subgroup with AF compared to the subgroup without AF. A cut off value of 39.2 milliseconds for intraleft-AEMD had a sensitivity of 90% and a specificity of 90% in identifying DM1 patients with AF risk. A cut off value of 57.7 milliseconds for inter-AEMD had a sensitivity of 84.2% and a specificity of 93.5% in identifying this category of patients., Conclusion: Our results showed that the echocardiographic atrial electromechanical delay indices (intraleft and inter-AEMD) were significantly increased in DM1 subjects with normal cardiac function. Intraleft and inter-AEMD represent noninvasive, inexpensive, useful and simple parameters to assess the AF risk in DM1 patients., (© 2015 Wiley Periodicals, Inc.)

In non-small-cell lung cancer (NSCLC) patients, the activation of alternative pathways contributes to the limited efficacy of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. The present study examines a panel of EGFR wild-type, K-Ras mutated, NSCLC lines, which were all intrinsically resistant to EGFR-TKIs, and demonstrates that the histone deacetylase inhibitor vorinostat can improve the therapeutic efficacy of gefitinib or erlotinib, inducing strong synergistic antiproliferative and pro-apoptotic effects that are paralleled by reactive oxygen species accumulation and by increased DNA damage. By knockdown experiments, we suggested that the up-regulation of voltage-dependent anion-selective channel protein 1 (VDAC1), the major mitochondrial porin of the outer mitochondrial membrane, which was induced by vorinostat and further increased by the combination, could be functionally involved in oxidative stress-dependent apoptosis. Significantly, we also observed the attenuation of the expression of both the enzyme hexokinase1, a negative VDAC1 regulator, and the anti-apoptotic porin VDAC2, only in the combination setting, suggesting convergent mechanisms that enhanced mitochondria-dependent apoptosis by targeting VDAC protein functions. Furthermore, the prosurvival capacities of the cells were also inhibited by the combination treatments, as shown by complete pAKT deactivation, increased GSK3β expression, and c-Myc down-regulation. Finally, we observed that the combination treatment of vorinostat and either of the EGFR-TKIs induced the down-regulation of the c-Myc-regulated nuclear factor erythroid 2-related factor 2 (NRF2) transcription factor and the up-regulation of the NRF2 repressor Kelch-like ECH-associated protein 1 regulator (KEAP1). These two genes are crucial for the redox stress response, often dysfunctional in NSCLC, and involved in EGFR-TKI resistance. Taken together, these results are the first to demonstrate that altering redox homeostasis is a new mechanism underlying the observed synergism between vorinostat and EGFR TKIs in NSCLC., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Paroxysmal supraventricular arrhythmias (SVAs) frequently occur in patients with atrial septal aneurysm (ASA). The aim of the current study was to evaluate the electrocardiographic (P-wave duration and dispersion) and echocardiographic (atrial electromechanical delay, AEMD) noninvasive indicators of atrial conduction heterogeneity in healthy ASA subjects without interatrial shunt and to assess the AEMD role in predicting the SVAs onset in this population., Materials and Methods: One hundered ASA patients (41 males, mean age of 32.5 ± 8 years) and 100 healthy subjects used as controls, matched for age and gender, were studied for the occurrence of SVAs during a 4-year follow-up, through 30-day external loop recorder (ELR) monitoring performed every 3 months. ASAs were diagnosed by transthoracic echocardiography based on the criteria of a minimal aneurismal base of ≥15 mm and an excursion of ≥10 mm. Intra-AEMD and inter-AEMD of both atria were measured through tissue Doppler echocardiography. P-wave dispersion (PD) was carefully measured using 12-lead electrocardiogram (ECG)., Results: Compared to the healthy control group, the ASA group showed a statistically significant increase in inter-AEMD, intra-left AEMD, maximum P-wave duration, and PD. Dividing the ASA group into 2 subgroups (patients with or without SVAs), the inter-AEMD, intra-left AEMD, P max, and PD were significantly higher in the subgroup with SVAs compared to the subgroup without SVAs. There were significant good correlations of intra-left AEMD and inter-AEMD with PD. A cutoff value of 40.1 msec for intra-left AEMD had a sensitivity of 82% and a specificity of 83% in identifying ASA patients at risk for SVA., Conclusion: Our results showed that the echocardiographic AEMD indices (intra-left and inter-AEMD) and the PD were significantly increased in healthy ASA subjects without interatrial shunt. PD and AEMD represent noninvasive, inexpensive, useful, and simple parameters to assess the SVAs' risk in ASA patients., (© 2015, Wiley Periodicals, Inc.)

Large oncosomes (LO) are atypically large (1-10 µm diameter) cancer-derived extracellular vesicles (EVs), originating from the shedding of membrane blebs and associated with advanced disease. We report that 25% of the proteins, identified by a quantitative proteomics analysis, are differentially represented in large and nano-sized EVs from prostate cancer cells. Proteins enriched in large EVs included enzymes involved in glucose, glutamine and amino acid metabolism, all metabolic processes relevant to cancer. Glutamine metabolism was altered in cancer cells exposed to large EVs, an effect that was not observed upon treatment with exosomes. Large EVs exhibited discrete buoyant densities in iodixanol (OptiPrep(TM)) gradients. Fluorescent microscopy of large EVs revealed an appearance consistent with LO morphology, indicating that these structures can be categorized as LO. Among the proteins enriched in LO, cytokeratin 18 (CK18) was one of the most abundant (within the top 5th percentile) and was used to develop an assay to detect LO in the circulation and tissues of mice and patients with prostate cancer. These observations indicate that LO represent a discrete EV type that may play a distinct role in tumor progression and that may be a source of cancer-specific markers.

Introduction: We evaluated the potential ability of the electrophysiological (EP) inducibility of ventricular arrhythmias to predict the likelihood of appropriate ICD intervention over the long-term in ischemic and nonischemic patients with current primary prevention indications for ICD implantation., Methods: Between 2006 and 2008, 206 consecutive heart failure patients who were candidates for ICD implantation for the primary prevention of sudden cardiac death according to standard indications underwent EP testing, usually on ICD implantation., Results: On EP testing, 15 (7%) patients had inducible monomorphic ventricular tachycardia (VT) and 14 (7%) ventricular fibrillation (VF). Over 24 months, 64 (31%) patients received appropriate ICD therapies: 51 (25%) for VT and 16 (8%) for VF. The time to the first appropriate ICD therapy trended to be shorter in the group of patients who were inducible on EP testing (p=0.072). Among patients receiving appropriate therapies, the median number of arrhythmic episodes was 2, and the proportion of patients with 2 treated arrhythmic episodes was higher in the group of inducible patients (34% versus 14%, p=0.005). On multivariate analysis, inducibility proved to be an independent predictor of frequent (2) arrhythmic episodes, as did a history of coronary artery bypass grafting. Moreover, patients with 2 treated arrhythmic episodes showed higher mortality (log-rank test, p=0.042)., Conclusion: Patients with inducibility of VT or VF are more likely to experience frequent appropriate ICD therapies during follow up.

Background: The aim of our study was to identify the early hemodynamic predictors of head-up tilt test (HUTT) outcome in healthy patients with recurrent unexplained syncope., Methods and Results: The study involved 95 patients (mean age 38 ± 15; 42 male) who were referred for the evaluation of the syncopal episodes from October 2012 to May 2013. According to the nitroglycerin-potentiated diagnostic tilt test response, the study population was divided into two groups: HUTT+ Group (61 patients, mean age 37 ± 10; 27 male) and HUTT- Group (34 patients, mean age 38 ± 11; 15 male) with no tilt-induced syncope. Finger arterial blood pressure (BP) was recorded during tilt testing. Left ventricular stroke volume (SV), cardiac output (CO), and total peripheral resistance (TPR) were computed from the pressure pulsations. After nitroglycerin administration, the HUTT+ Group showed a significant increase in heart rate (92.0 ± 7.3 beats/min vs 68.9 ± 8.7 beats/min, P < 0.0001), with well-maintained systolic BP (111.6 ± 14.1 mm Hg vs 108.8 ± 11.5 mm Hg; P = 0.332) and diastolic BP (66.1 ± 8.5 mm Hg vs 63.1 ± 6.9 mm Hg; P = 0.0913); a significant decrease in SV (53.9 ± 8.0 mL vs 78.6 ± 8.2 mL; P < 0.0001) and CO (4.0 ± 0.5 L/min vs 5.8 ± 1.0 L/min; P < 0.001), and a significant increase in TPR (1.3 ± 0.3 U vs 0.9 ± 0.2 U, P < 0.0011). We tested three hemodynamic parameters (SV, CO, and TPR) as predictors of positive tilt test response with receiver-operating characteristic curve analysis., Conclusions: Our results show that, 2 minutes after nitroglycerin administration, a statistically significant decrease of SV values (<67 mL) strongly predicts (area under the curve, 0.985; P < 0.0001) the HUTT-positive response in healthy patients with recurrent unexplained syncope., (© 2015 Wiley Periodicals, Inc.)

Proteomic analysis identified differentially expressed proteins between zoledronic acid-resistant and aggressive DU145R80 prostate cancer (PCa) cells and their parental DU145 cells. Ingenuity Pathway Analysis (IPA) showed a strong relationship between the identified proteins within a network associated with cancer and with homogeneous cellular functions prevalently related with regulation of cell organization, movement and consistent with the smaller and reduced cell-cell contact morphology of DU145R80 cells. The identified proteins correlated in publically available human PCa genomic data with increased tumor expression and aggressiveness. DU145R80 exhibit also a clear increase of alpha-v-(αv) integrin, and of urokinase receptor (uPAR), both included within the same network of the identified proteins. Interestingly, the actin-rich structures localized at the cell periphery of DU145R80 cells are rich of Filamin A, one of the identified proteins and uPAR which, in turn, co-localizes with αv-integrin, in podosomes and/or invadopodia. Notably, the invasive feature of DU145R80 may be prevented by blocking anti-αv antibody. Overall, we unveil a signaling network that physically links the interior of the nucleus via the cytoskeleton to the extracellular matrix and that could dictate PCa aggressiveness suggesting novel potential prognostic markers and therapeutic targets for PCa patients.

Introduction: The left ventricular (LV) pacing site and the magnitude of the electrical delay within the LV, as expressed by prolonged QRS duration, are major determinants of cardiac resynchronization therapy (CRT) efficacy. We investigated the incremental value of positioning the LV lead in areas of late activation in order to enhance the response to CRT in patients with different degrees of QRS complex lengthening., Methods and Results: This analysis was performed on 301 heart failure patients who received a CRT defibrillator. On implantation, the right ventricular (RV)-to-LV interval was measured as the delay between local activations recorded through the RV and LV leads in the final position. After 1 year, 171 (57%) patients displayed reverse LV remodeling, as measured by a ≥15% reduction in the LV end-systolic volume. Both the RV-to-LV interval and its percentage value corrected for the QRS duration were significantly associated with a positive response to CRT. An RV-to-LV interval >80 milliseconds and an RV-to-LV interval/QRS >58% yielded the best prediction of reverse remodeling. Although the response to CRT decreased with shorter QRS duration in the overall population, patients with an RV-to-LV interval >80 milliseconds showed a response rate >65% in all QRS subgroups., Conclusion: A longer RV-to-LV interval is associated with reverse LV remodeling after CRT. On implantation attempts could be made to maximize it when selecting the LV lead position, especially in patients with shorter QRS duration, and thus less likely to respond positively to CRT., (© 2014 Wiley Periodicals, Inc.)

The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from high-density lipoproteins (HDL) to triglyceride (TG)-rich lipoproteins. A consistent number of investigations has suggested an association between the TaqIB polymorphism of the CETP gene, plasma HDL-C levels and the risk of cardiovascular disease, but the results are controversial. The aim of this study was to determine if the TaqIB polymorphism might be related to the presence of atrial fibrillation (AF). We conducted a case-control study, enrolling 109 Caucasian unrelated patients coming from Salento (Southern Italy) with documented AF and 109 controls selected from the same ward. The CETP TaqIB genotypes were determined by RFLP-PCR. The subjects with the B2B2 genotype seem to be more susceptible to AF development (OR=2.28, 95% CI 1.06-4.89, p=0.032). The AF incidence is higher if we consider only the female subgroup (OR=5.14, 95% CI 1.57-16.82, p=0.0061). In the AF female subgroup the B2B2 patients had a statistically significant decrease of HDL-C levels (1.50 ± 0.35 vs 2.07 ± 0.42; p=0.012) and statistically higher TG levels (1.34 ± 0.46 vs 0.77 ± 0.14; p=0.027) and TG/HDL-C ratio (2.14 ± 0.80 vs 0.88 ± 0.23; p=0.007) when compared to B2B2 female control subjects. When we analyzed the linkage between the TaqIB polymorphism and the promoter variant (-629C/A), we found that 100% of the B2 alleles of the TaqIB polymorphism were associated with the A alleles of the -629 promoter polymorphism in our subjects. This study suggests that in post-menopausal women atrial fibrillation could be promoted by the association of CETP B2B2/AA genotype with higher triglycerides values.

Purpose: In spite of technological breakthroughs, the choice of a suitable location for the coronary sinus (CS) lead in biventricular implants is still mostly empiric. The aim of this study was to investigate the utility of a radiological index-the distance between the right ventricular (RV) and CS lead tips on fluoroscopic recordings, measured by means of a new method-as a tool for selecting the most profitable left ventricular (LV) lead position., Methods: Forty-nine consecutive patients (36 male, 13female; mean age 63 ± 19 year), in whom the LV electrode was implanted in a lateral/postero-lateral position in the CS, were evaluated immediately after implantation. The fluoroscopic distances between the RV and LV lead tips were calculated off-line in antero-posterior (2DAP) and latero-lateral (2DLL) projections by means of integrated software., Results: On 1-year follow-up evaluation, 53 % patients were classed as responders (R) (>15 % reduction in LV end-systolic volume) and 47 % as non-responders (NR). On receiver-operating curve analysis, 2DAP and 2DLL showed cut-off values of 81 mm and 51 mm, respectively. In discriminating between R and NR, 2DAP >81 mm displayed 95 % specificity and 74 % sensitivity, while 2DLL >51 mm displayed 74 % specificity and 92 % sensitivity. On multivariate analysis, the cut-off values of 2DAP and 2DLL were significantly predictive of R to CRT., Conclusions: In our single-center prospective experience, RV-LV interlead distance measured by means of a novel method on fluorographic recordings correlated with CRT response. The use of this method as an intra-operative guide to identifying suitable lead placement in the CS needs evaluating on-line and on a large scale.

Patients with advanced prostate cancer (PCa) and multiple myeloma (MM) have limited long-term responses to available therapies. The histone deacetylase inhibitor panobinostat has shown significant preclinical and clinical anticancer activity in both hematological and solid malignancies and is currently in phase III trials for relapsed MM. Bisphosphonates (BPs), such as zoledronic acid (ZOL), inhibit osteoclast-mediated bone resorption and are indicated for the treatment of bone metastasis. BPs, including ZOL, have also shown anticancer activity in several preclinical and clinical studies. In the present report, we found a potent synergistic antiproliferative effect of panobinostat/ZOL treatment in three PCa and three MM cell lines as well as in a PCa ZOL-resistant subline, independently of p53/KRAS status, androgen dependency, or the schedule of administration. The synergistic effect was also observed in an anchorage-independent agar assay in both ZOL-sensitive and ZOL-resistant cells and was confirmed in vivo in a PCa xenograft model. The co-administration of the antioxidant N-acetyl-L-cysteine blocked the increased reactive oxygen species generation and apoptosis observed in the combination setting compared with control or single-agent treatments, suggesting that oxidative injury plays a functional role in the synergism. Proapoptotic synergy was also partially antagonized by the addition of geranyl-geraniol, which bypasses the inhibition of farnesylpyrophosphate synthase by ZOL in the mevalonate pathway, supporting the involvement of this pathway in the synergy. Finally, at the molecular level, the inhibition of basal and ZOL-induced activation of p38-MAPK by panobinostat in sensitive and ZOL-resistant cells and in tumor xenografts could explain, at least in part, the observed synergism.

Aim: The aim of this study was to assess the incidence and clinical predictors of the development of new-onset heart failure (HF) over medium-term follow-up, in patients treated with permanent pacing in daily clinical practice., Methods and Results: We retrospectively enrolled all consecutive patients who underwent single- or dual-chamber pacemaker implantation at the study centre. Patients with a left ventricular ejection fraction (LVEF) ≤35% or a prior diagnosis of HF were excluded. Ventricular leads were routinely implanted in the right apex. Pacemakers were implanted in 490 patients with a standard pacemaker indication and LVEF >35%. Left bundle-branch block (LBBB) was reported in 30 (8%) patients, and an LVEF <50% in 64 (13%) patients. During a follow-up of 27 ± 21 months, 32 (7%) patients reached the combined endpoint of HF death or hospitalization. On multivariate analysis, LBBB (HR, 3.50; 95% CI, 1.1-11.1; P = 0.033) and LVEF <50% (HR, 5.1; 95% CI, 1.9-14.2; P = 0.002) were confirmed as independent predictors of HF death or hospitalization. Patients with LVEF <50% and/or LBBB displayed significantly higher rates of HF death or hospitalization (log-rank test, all P<0.001)., Conclusion: The majority of patients with a standard indication for permanent pacing and normal LV function remained in a clinically stable condition after pacemaker implantation. However, ∼7% of patients developed new-onset HF over a period of follow-up of 27 months, and the presence of LBBB and LVEF <50% at the baseline predicted HF death or hospitalization.

Aims: In candidates for cardiac resynchronization therapy (CRT), the choice between pacemaker (CRT-P) and defibrillator (CRT-D) implantation is still debated. We compared the long-term prognosis of patients who received CRT-D or CRT-P according to class IA recommendations of the European Society of Cardiology (ESC) and who were enrolled in a multicentre prospective registry., Methods and Results: A total of 620 heart failure patients underwent successful implantation of a CRT device and were enrolled in the Contak Italian Registry. This analysis included 266 patients who received a CRT-D and 108 who received a CRT-P according to class IA ESC indications. Their survival status was verified after a median follow-up of 55 months. During follow-up, 73 CRT-D and 44 CRT-P patients died (rate 6.6 vs. 10.4%/year; log-rank test, P = 0.020). Patients receiving CRT-P were predominantly older, female, had no history of life-threatening ventricular arrhythmias, and more frequently presented non-ischaemic aetiology of heart failure, longer QRS durations, and worse renal function. However, the only independent predictor of death from any cause was the use of CRT-P (hazard ratio, 1.97; 95% confidence interval, 1.21-3.16; P = 0.007)., Conclusion: The implantation of CRT-D, rather than CRT-P, may be preferable in patients presenting with current class IA ESC indications for CRT. Indeed, CRT-D resulted in greater long-term survival and was independently associated with a better prognosis.

Background: Current recommendations require a QRS duration of ≥120 ms as a condition for prescribing cardiac resynchronization therapy (CRT). This study was designed to test the hypothesis that patients with heart failure (HF) of ischemic origin, current indications for defibrillator implantation, and QRS <120 ms may benefit from CRT in the presence of marked mechanical dyssynchrony., Methods and Results: Patients with intraventricular dyssynchrony on echocardiography were randomly assigned to CRT or dual-chamber defibrillator implantation (CRT defibrillator and dual-chamber implantable cardioverter-defibrillator arm, respectively). The primary end point was the HF clinical composite response, which scores patients as improved, unchanged, or worsened. The secondary end point was the cumulative survival from HF hospitalization and HF death. An additional secondary end point was the composite of HF hospitalization, HF death, and spontaneous ventricular fibrillation. Twenty-three of 56 patients with CRT defibrillator showed an improvement in their clinical composite response at 1 year, compared with 9 of 55 patients with dual-chamber implantable cardioverter-defibrillator (41% versus 16%; P=0.004). After a median follow-up of 16 months, the CRT defibrillator arm showed a nonsignificant higher survival from HF hospitalization and HF death (P=0.077), and a significantly higher survival from the combined end point of HF hospitalization, HF death, and spontaneous ventricular fibrillation (P=0.028)., Conclusions: In this comparison of CRT defibrillator and dual-chamber implantable cardioverter-defibrillator, CRT improved clinical status in some patients with ischemic cardiomyopathy, mild-to-moderate symptoms, narrow QRS duration, and mechanical dyssynchrony on echocardiography., Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT01577446.

Background: Less than 50% of patients implanted with an implantable cardioverter-defibrillator (ICD) receive device therapy during the follow-up. The aim of our study was to prospectively evaluate the predictive role of appropriate ICD therapy on long-term survival of patients implanted for primary or secondary sudden death prevention., Methods: From 2002 to 2003, 139 consecutive patients [mean age 66±9 years, male 77%, ischemic heart disease 56%, New York Heart Association functional class >II (74%), primary prevention 74%, mean left ventricular ejection fraction 30±9%, cardiac resynchronization ICD 65%] were enrolled. We collected and evaluated device therapies for at least 18 months and recorded survival status for more than 5 years., Results: Over a median follow-up of 18 months, 54 (39%) patients received at least one ICD intervention, with 28 patients receiving only appropriate ICD therapies, 13 only inappropriate therapies and 13 receiving both therapies. At a mean follow-up of 63±12 months, 30 deaths occurred in 130 patients (23%); for nine patients, we had no survival status information. Death was classified as cardiac in 22 (73%) patients, the most common cause was progressive heart failure. In a Cox proportional regression model, an appropriate ICD therapy was associated with a significant increase in the subsequent risk of death (hazard ratio 3.02, P=0.003)., Conclusion: In patients implanted with ICD or cardiac resynchronization therapy with ICD devices, for primary or secondary sudden cardiac death prevention, appropriate ICD therapy predicts a three-fold greater risk of death.

Purpose: Patients with permanent atrial fibrillation (AF) who undergo cardiac resynchronization therapy (CRT) may spontaneously recover sinus rhythm during follow-up. We tested the feasibility and efficacy of electrical cardioversion attempted after 3 months of CRT in patients with permanent AF and measured the long-term maintenance of sinus rhythm., Methods: Twenty-eight consecutive patients with permanent AF in whom CRT defibrillators had been implanted were scheduled for internal electrical cardioversion after 3 months (group A) and were compared with a control group of 27 patients (group B)., Results: In group A, 22 patients (79 %) were eligible for cardioversion; sinus rhythm was restored in 18 (82 %) of these, with no procedural complications. After 12 months, 16 patients (58 %) in group A were in sinus rhythm, compared with one group B patient who spontaneously recovered sinus rhythm (4 %, p < 0.001). On 12-month evaluation, ejection fraction had improved in both groups, but a reduction in left ventricular end-systolic volume was recorded only in group A patients (p = 0.018 versus baseline)., Conclusions: In patients with permanent AF, the rhythm control strategy consisting of internal cardioversion, performed by means of the implanted cardioverter-defibrillator after 3 months of CRT, was associated with a high rate of sinus rhythm resumption on long-term follow-up and with a better echocardiographic response to CRT than that seen in patients treated according to a rate control strategy.

Objectives: Little is known about coronary sinus lead performance in patients with cardiac resynchronization therapy devices. We evaluated the impact of clinical and technical parameters on coronary sinus lead performance over long-term follow-up., Methods: From February 1999 to July 2004, 235 patients (181 men; mean age, 68 +/- 9 years; mean left ventricular ejection fraction, 26.5 +/- 6.5%; idiopathic dilated cardiomyopathy, 49%; ischemic, 48%; and other cause, 3%) underwent cardiac resynchronization therapy (pacemaker or defibrillator) implantation., Results: On implantation, the only statistically significant difference was observed in mean pacing impedance, which was lower for unipolar leads than for bipolar leads (763 +/- 250 vs. 847 +/- 270 Omega, P = 0.02), and lower in patients with ischemic cardiomyopathy than in those with idiopathic cardiomyopathy (758 +/- 204 vs. 837 +/- 291 Omega, P = 0.03). After a mean follow-up of 41.7 +/- 14.7 months, a significant decrease was observed in mean pacing impedance (from 811 +/- 261 to 717 +/- 284 Omega, P = 0.0026) and mean R-wave amplitude (from 13.2 +/- 6.7 to 10.5 +/- 5.5 mV, P = 0.002), whereas the mean pacing energy threshold increased from 3.6 +/- 10.4 to 9.5 +/- 28 microJ (P = 0.004). On analysis of variance, unipolar lead (P = 0.016) and posterior coronary sinus position (P = 0.049) were related to a greater energy threshold increase. On multivariate analysis (Cox regression), only posterior coronary sinus lead position (P = 0.013) proved to be an independent predictor of long-term significant increase in the stimulation energy threshold., Conclusion: Over the long-term follow-up of coronary sinus leads, pacing impedance and R-wave amplitude decreased, whereas the energy threshold increased; unipolar leads and posterior lead location in the coronary sinus were related to a greater energy threshold increase.

Current evidence-based guidelines recommend an implantable cardioverter-defibrillator for the primary prevention of sudden cardiac death in selected patients with impaired left ventricular function, and cardiac resynchronization therapy for improvement of symptoms and survival in selected patients with impaired left ventricular function and abnormal ventricular conduction. Many patients may be eligible for both treatments, but it does not necessarily follow that such patients would obtain additional benefit from the combined treatment over one treatment alone. A simple pragmatic approach would be to use resynchronisation therapy, in order to reduce symptoms and extend life in patients with New York Heart Association class III or IV heart failure, with the addition of an implantable cardioverter-defibrillator left to clinical judgment on an individual basis when additional indications exist. When such an addition is contemplated the hypothesized incremental benefits in survival would need to be balanced by the possible increase in morbidity owing to, for example, inappropriate shocks.

Background: Much information is available regarding the possible negative effects of long-term right ventricular (RV) apical pacing, which may cause worsening of heart failure. However, very limited data are available regarding the effects of RV pacing in patients with a previous myocardial infarction (MI)., Methods and Results: We screened 115 consecutive post-MI patients and matched a group of 29 pacemaker (PM) recipients with a group of 49 unpaced patients, for age, left ventricular (LV) ejection fraction, and site of MI. During a median follow-up of 54 months, echocardiograms showed a decrease in LV ejection fraction in the paced group, from 51 +/- 10 to 39 +/- 11 (P < 0.01), and a minimal change in the unpaced group, from 57 +/- 8 to 56 +/- 7 (P = 0.98). Similar change was observed in systolic and diastolic diameters and volumes., Conclusions: The study showed that, in post-MI patients, RV apical pacing was associated with a worsening of LV function, suggesting that, among MI survivors, the need for a PM is a marker of worse outcome.

Objective: To compare the rates of all-cause mortality in recipients of cardiac resynchronization therapy devices without (CRT-PM) versus with defibrillator (CRT-D)., Methods: Between February 1999 and July 2004, 233 patients (mean age = 69 +/- 8 years, 180 men) underwent implantation of CRT-PM or CRT-D devices. New York Heart Association (NYHA) heart failure functional class II was present in 11%, class III in 69%, and class IV in 20% of patients; mean left ventricle ejection fraction (LVEF) was 26.5 +/- 6.5 %, 48% presented with idiopathic dilated cardiomyopathy and 49% with ischemic heart disease. Cox multiple variable regression analysis was performed in search of predictors of death., Results: The clinical characteristics of the 117 CRT-PM and 116 CRT-D recipients were similar, except for LVEF (28.2 +/- 6.2% vs 25.0 +/- 6.5%, respectively; P < 0.001), and ischemic versus nonischemic etiology of heart failure (41% vs 56%, respectively P = 0.02). Over a mean follow-up of 58 +/- 15 months, no significance difference in overall mortality rate was observed between the two study groups. Male sex, NYHA functional class IV, and atrial fibrillation at implant were significant predictors of death., Conclusions: There was no difference in long-term survival rate among patients with CRT-D versus CRT-PM, although CRT-D more effectively lowered the sudden death rate. Male sex, NYHA functional class IV, and atrial fibrillation predicted the worst prognosis.