Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER-mitochondria-associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance.

Transcatheter non-acute retrieval of the tine-based leadless ventricular pacemaker.

AIMS: We report our single-centre experience of mid-term to long-term retrieval and reimplantation of a tine-based leadless pacemaker [Micra transcatheter pacing system (TPS)]. The TPS is a clinically effective alternative to transvenous single-chamber ventricular pacemakers. Whereas it is currently recommended to abandon the TPS at the end of device life, catheter-based retrieval may be favourable in specific scenarios. METHODS AND RESULTS: We report on nine consecutive patients with the implanted TPS who subsequently underwent transcatheter retrieval attempts. The retrieval system consists of the original TPS delivery catheter and an off-the-shelf single-loop 7 mm snare. The procedure was guided by fluoroscopy and intracardiac echocardiography. After an implantation duration of 3.1 ± 2.8 years (range 0.4-9.0), the overall retrieval success rate was 88.9% (8 of 9 patients). The mean procedure time was 89 ± 16 min, and the fluoroscopy time was 18.0 ± 6.6 min. No procedure-related adverse device events occurred. In the one unsuccessful retrieval, intracardiac echocardiography revealed that the TPS was partially embedded in the ventricular tissue surrounding the leadless pacemaker body in the right ventricle. After retrieval, three patients were reimplanted with a new TPS device. All implantations were successful without complications. CONCLUSION: A series of transvenous late retrievals of implanted TPS devices demonstrated safety and feasibility, followed by elective replacement with a new leadless pacing device or conventional transvenous pacing system. This provides a viable end-of-life management alternative to simple abandonment of this leadless pacemaker.

Emerging roles of prominin-1 (CD133) in the dynamics of plasma membrane architecture and cell signaling pathways in health and disease.

Prominin-1 (CD133) is a cholesterol-binding membrane glycoprotein selectively associated with highly curved and prominent membrane structures. It is widely recognized as an antigenic marker of stem cells and cancer stem cells and is frequently used to isolate them from biological and clinical samples. Recent progress in understanding various aspects of CD133 biology in different cell types has revealed the involvement of CD133 in the architecture and dynamics of plasma membrane protrusions, such as microvilli and cilia, including the release of extracellular vesicles, as well as in various signaling pathways, which may be regulated in part by posttranslational modifications of CD133 and its interactions with a variety of proteins and lipids. Hence, CD133 appears to be a master regulator of cell signaling as its engagement in PI3K/Akt, Src-FAK, Wnt/ß-catenin, TGF-ß/Smad and MAPK/ERK pathways may explain its broad action in many cellular processes, including cell proliferation, differentiation, and migration or intercellular communication. Here, we summarize early studies on CD133, as they are essential to grasp its novel features, and describe recent evidence demonstrating that this unique molecule is involved in membrane dynamics and molecular signaling that affects various facets of tissue homeostasis and cancer development. We hope this review will provide an informative resource for future efforts to elucidate the details of CD133's molecular function in health and disease.

Thiosemicarbazones Can Act Synergistically with Anthracyclines to Downregulate CHEK1 Expression and Induce DNA Damage in Cell Lines Derived from Pediatric Solid Tumors.

Anticancer therapy by anthracyclines often leads to the development of multidrug resistance (MDR), with subsequent treatment failure. Thiosemicarbazones have been previously suggested as suitable anthracycline partners due to their ability to overcome drug resistance through dual Pgp-dependent cytotoxicity-inducing effects. Here, we focused on combining anthracyclines (doxorubicin, daunorubicin, and mitoxantrone) and two thiosemicarbazones (DpC and Dp44mT) for treating cell types derived from the most frequent pediatric solid tumors. Our results showed synergistic effects for all combinations of treatments in all tested cell types. Nevertheless, further experiments revealed that this synergism was independent of Pgp expression but rather resulted from impaired DNA repair control leading to cell death via mitotic catastrophe. The downregulation of checkpoint kinase 1 (CHEK1) expression by thiosemicarbazones and the ability of both types of agents to induce double-strand breaks in DNA may explain the Pgp-independent synergism between anthracyclines and thiosemicarbazones. Moreover, the concomitant application of these agents was found to be the most efficient approach, achieving the strongest synergistic effect with lower concentrations of these drugs. Overall, our study identified a new mechanism that offers an avenue for combining thiosemicarbazones with anthracyclines to treat tumors regardless the Pgp status.

Left atrial thickness and acute thermal injury in patients undergoing ablation for atrial fibrillation: Laser versus radiofrequency energies.

INTRODUCTION: Thermally induced cardiac lesions result in necrosis, edema, and inflammation. This tissue change may be seen with ultrasound. In this study, we sought to use intracardiac echocardiography (ICE) to evaluate pulmonary vein tissue morphology and assess the acute tissue changes that occur following radiofrequency (RF) or laser ablation for atrial fibrillation (AF). METHODS AND RESULTS: Patients with AF underwent pulmonary vein isolation (PVI) using irrigated RF or laser balloon. Pre- and post-ablation ICE imaging was performed from within each pulmonary vein (PV). At least 10 transverse imaging planes per PV were evaluated and each plane was divided into eight segments. The PV/atrial wall thickness and the luminal area were measured at each segment. Twenty-seven patients underwent PVI (15 with laser, 12 with RF). Ninety-eight pulmonary veins were analyzed (58 PVs laser; 40 PVs RF). At baseline, there were no regional differences in PV wall thickness in the right-sided veins. The anterior regions of left superior pulmonary vein (LSPV) and left inferior pulmonary vein (LIPV) were significantly thicker compared with the posterior and inferior regions (p < .01). Post-ablation, PV wall thickness in RF group increased 24.1% interquartile range (IQR) (17.2%-36.7%) compared with 1.2% IQR (0.4%-8.9%) in laser group, p = .004. In all PVs, RF ablation resulted in significantly greater percent increase in wall thickness compared with laser. Additionally, RF resulted in more variable changes in regional PV wall thickness; with more increases in wall thickness in anterior versus posterior LSPV (75.4 ± 58.5% vs. 46.8 ± 55.6%, p < .01), anterior versus posterior right superior pulmonary vein (RSPV) (62.9 ± 63.9% vs. 44.6 ± 51.7%, p < .05), and superior versus inferior RSPV (69.1 ± 45.4% vs. 35.9 ± 45%, p < .05). There were no significant regional differences in PV wall thickness changes for the laser group. CONCLUSIONS: Rotational ICE can be used to measure acute tissue changes with ablation. Regional variability in baseline wall thickness was nonuniformly present in PVs. Acute tissue changes occurred immediately post-ablation. Compared with laser balloon, RF shows markedly more thickening post-ablation with significant regional variations.

Iron-Chelation Treatment by Novel Thiosemicarbazone Targets Major Signaling Pathways in Neuroblastoma.

Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.

Repurposing Tyrosine Kinase Inhibitors to Overcome Multidrug Resistance in Cancer: A Focus on Transporters and Lysosomal Sequestration.

Tyrosine kinase inhibitors (TKIs) are being increasingly used to treat various malignancies. Although they were designed to target aberrant tyrosine kinases, they are also intimately linked with the mechanisms of multidrug resistance (MDR) in cancer cells. MDR-related solute carrier (SLC) and ATB-binding cassette (ABC) transporters are responsible for TKI uptake and efflux, respectively. However, the role of TKIs appears to be dual because they can act as substrates and/or inhibitors of these transporters. In addition, several TKIs have been identified to be sequestered into lysosomes either due to their physiochemical properties or via ABC transporters expressed on the lysosomal membrane. Since the development of MDR represents a great concern in anticancer treatment, it is important to elucidate the interactions of TKIs with MDR-related transporters as well as to improve the properties that would prevent TKIs from diffusing into lysosomes. These findings not only help to avoid MDR, but also help to define the possible impact of combining TKIs with other anticancer drugs, leading to more efficient therapy and fewer adverse effects in patients.

Pharmacological targeting of mitochondria in cancer stem cells: An ancient organelle at the crossroad of novel anti-cancer therapies.

Mitochondria play vital roles in various cellular processes, ranging from cellular metabolism to signal transduction and cell death regulation. As these properties are critical for cancer growth, the mitochondrion has recently become an attractive target for anti-cancer therapies. In addition, it has come to light that mitochondria are crucially involved in the regulation of stem cell identity, differentiation and fate. A similar role for mitochondria has been also demonstrated in malignant stem-like cells termed cancer stem cells (CSCs), which are implicated in progression and resistance of many tumors. In this review, we summarize different mitochondrial functions reported to promote acquisition and maintenance of CSC phenotype and discuss the rationale for their therapeutic targeting. Particular emphasis is given to therapeutics that act directly through modulation of these mitochondrial functions and have recently emerged as promising anti-CSC drugs in pre-clinical studies. This review highlights the intriguing aspects of mitochondrial biology that may have a crucial role in cancer initiation, progression, and resistance and which might facilitate pharmacological targeting. Indeed, understanding of mitochondrial function in the regulation of CSCs will promote the development of novel CSC-targeted therapeutic strategies, which could significantly improve the long-term survival of cancer patients.

Cancer stem cells in sarcomas: Getting to the stemness core.

BACKGROUND: Sarcomas are rare tumors but represent the third most common malignancy in children. The cancer stem cell (CSC) paradigm is well established, and CSCs have been intensively studied in sarcomas in the past decade. SCOPE OF REVIEW: This review summarizes current knowledge on CSCs in sarcomas and provides new perspectives on the role of a deregulated stemness program in sarcomagenesis. MAJOR CONCLUSIONS: Cell surface markers have so far failed to specifically target sarcoma CSCs. Sarcomas likely arise from immature cells that undergo pathological reprogramming. Transcription factor Sox2, which is frequently upregulated in sarcomas, is directly involved in this process, and its crucial role in the acquisition and maintenance of the CSC phenotype has been demonstrated in various sarcomas. GENERAL SIGNIFICANCE: Sox2 is a core functional regulator of the stem-like state and is an outstanding marker of sarcoma CSCs. Fluorescence protein-based reporters of Sox2 expression might provide useful tools for subsequent studies of sarcoma CSCs.

Capillary Blood GSH Level Monitoring, Using an Electrochemical Method Adapted for Micro Volumes.

Glutathione (γ-glutamyl-cysteinyl-glycine; also known as GSH) is an endogenous antioxidant that plays a crucial role in cell defense mechanisms against oxidative stress. It is thus not surprising that this molecule can serve as a biomarker for oxidative stress monitoring. As capillary blood is a highly accessible target for biomarking, it is a valuable bodily fluid for diagnosing human GSH levels. This study focused on the optimization of GSH measurements from micro volumes of capillary blood prior to using electrochemical detection. The optimization of experimental parameters, including the sample volume and its stability, was performed and evaluated. Moreover, we tested the optimized method as part of a short-term study. The study consisted of examining 10 subjects within 96 h of their consumption of high amounts of antioxidants, attained from a daily dose of 2 g/150 mL of green tea. The subjects' capillary blood (5 µL) was taken at 0 h, 48 h, and 96 h for subsequent analysis. The short-term supplementation of diet with green tea showed an increase of GSH pool by approximately 38% (between 0 and 48 h) within all subjects.

Catheter Ablation of Ischemic Ventricular Tachycardia With Remote Magnetic Navigation: STOP-VT Multicenter Trial.

INTRODUCTION: Catheter ablation is an effective treatment of scar-related ventricular tachycardia (VT), but the overall complexity of the procedure has precluded its widespread use. Remote magnetic navigation (RMN) has been shown to facilitate cardiac mapping and ablation of VT in a retrospective series. STOP-VT is the first multicenter, prospective, single-arm and single-procedure study evaluating RMN-based mapping and ablation of post-infarction VT. METHODS: Patients with documented VT and prior MI, in whom an ICD was implanted either for primary or secondary prevention, were recruited from four EU and US centers. Either a transseptal (48 patients) or transaortic (5 patients) approach was employed to gain access for ventricular endocardial mapping/ablation during VT (entrainment mapping, activation mapping) and/or substrate mapping in sinus rhythm (elimination of fractionated/late potentials, variable extent of substrate modification) with RMN and irrigated RF ablation. The primary endpoints were as follows: (i) non-inducibility of the target VT or any other sustained VT; (ii) elimination of sustained VT/VF during ICD follow-up of up to 12 months. RESULTS: The cohort included 53 consecutive patients (median age 67 years, 49 men, median LVEF 31%). One hemodynamically unstable patient was excluded at the onset of mapping. Inducibility of sustained VT was achieved an average of 2.2 times per patient (1-8), with mean tachycardia cycle length (TCL) 374 milliseconds (179-510). Mean total procedure and fluoroscopy times were 223 minutes and 8.7 minutes, respectively; mean cumulative fluoroscopy time during mapping and ablation was 0.95 minutes; maximum power averaged 42.3 W with nominal saline 30 cc/min irrigation; mean cumulative RF time was 38 minutes. Non-inducibility of the target VT was achieved in 49/52 patients (94.2%) and non-inducibility of any VT was achieved in 38/52 patients (73.1%). A combination of RMN and manual ablation was performed in two patients, rendering one non-inducible. During the 12-month ICD follow-up period, freedom from any sustained VT/VF was observed in 30 patients (62%), of which 19 (63%) were off antiarrhythmic medications. Five patients expired during follow-up: one presented with a VT storm, but for the others, death was not related to VT/VF (MI-cardiogenic shock, pulmonary embolism, bronchogenic carcinoma, end stage heart failure). No procedural complications were reported. CONCLUSIONS: This first prospective, single-procedure, multicenter study indicates that remote magnetic navigation is a safe and effective method for catheter ablation of post-infarction VT.

Cancer stem cell markers in pediatric sarcomas: Sox2 is associated with tumorigenicity in immunodeficient mice.

The three most frequent pediatric sarcomas, i.e., Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, were examined in this study: three cell lines derived from three primary tumor samples were analyzed from each of these tumor types. Detailed comparative analysis of the expression of three putative cancer stem cell markers related to sarcomas-ABCG2, CD133, and nestin-was performed on both primary tumor tissues and corresponding cell lines. The obtained results showed that the frequency of ABCG2-positive and CD133-positive cells was predominantly increased in the respective cell lines but that the high levels of nestin expression were reduced in both osteosarcomas and rhabdomyosarcomas under in vitro conditions. These findings suggest the selection advantage of cells expressing ABCG2 or CD133, but the functional tests in NOD/SCID gamma mice did not confirm the tumorigenic potential of cells harboring this phenotype. Subsequent analysis of the expression of common stem cell markers revealed an evident relationship between the expression of the transcription factor Sox2 and the tumorigenicity of the cell lines in immunodeficient mice: the Sox2 levels were highest in the two cell lines that were demonstrated as tumorigenic. Furthermore, Sox2-positive cells were found in the respective primary tumors and all xenograft tumors showed apparent accumulation of these cells. All of these findings support our conclusion that regardless of the expression of ABCG2, CD133 and nestin, only cells displaying increased Sox2 expression are directly involved in tumor initiation and growth; therefore, these cells fit the definition of the cancer stem cell phenotype.

Influence of Long-Distance Bicycle Riding on Serum/Urinary Biomarkers of Prostate Cancer.

Herein, we present a study focused on the determination of the influence of long-distance (53 km) bicycle riding on levels of chosen biochemical urinary and serum prostate cancer (PCa) biomarkers total prostate-specific antigen (tPSA), free PSA (fPSA) and sarcosine. Fourteen healthy participants with no evidence of prostate diseases, in the age range from 49-57 years with a median of 52 years, underwent physical exercise (mean race time of 150 ± 20 min, elevation increase of 472 m) and pre- and post-ride blood/urine sampling. It was found that bicycle riding resulted in elevated serum uric acid (p = 0.001, median 271.76 vs. 308.44 µmol/L pre- and post-ride, respectively), lactate (p = 0.01, median 2.98 vs. 4.8 mmol/L) and C-reactive protein (p = 0.01, 0.0-0.01 mg/L). It is noteworthy that our work supports the studies demonstrating an increased PSA after mechanical manipulation of the prostate. The subjects exhibited either significantly higher post-ride tPSA (p = 0.002, median 0.69 vs. 1.1 ng/mL pre- and post-ride, respectively) and fPSA (p = 0.028, median 0.25 vs. 0.35 ng/mL). Contrary to that, sarcosine levels were not significantly affected by physical exercise (p = 0.20, median 1.64 vs. 1.92 µmol/mL for serum sarcosine, and p = 0.15, median 0.02 µmol/mmol of creatinine vs. 0.01 µmol/mmol of creatinine for urinary sarcosine). Taken together, our pilot study provides the first evidence that the potential biomarker of PCa-sarcosine does not have a drawback by means of a bicycle riding-induced false positivity, as was shown in the case of PSA.

Durability of Pulmonary Vein Isolation with Cryoballoon Ablation: Results from the Sustained PV Isolation with Arctic Front Advance (SUPIR) Study.

INTRODUCTION: Pulmonary vein (PV) reconnection remains the most important cause of AF recurrence after AF ablation. The second-generation cryoballoon catheter's ability to achieve durable PV isolation was assessed in a prospective nonrandomized clinical trial. METHODS AND RESULTS: PV isolation was performed by 4-minute ablations. Following verification of electrical isolation by a multielectrode mapping catheter, 1 additional lesion per PV was applied. Esophageal temperatures were monitored and all patients underwent postprocedure esophageal endoscopy. All patients underwent a second PV remapping procedure at ∼3 months to assess for PVI durability. Eighty-four (100%) veins were acutely isolated using only the 28 mm cryoballoon in 21 consecutive PAF patients with 2.2 ± 0.6 cryoapplications per vein, with the majority (83%) occurring after a single freeze. One patient presented with hematemesis and an esophageal ulceration that was treated conservatively; there were no episodes of esophageal fistula or phrenic nerve palsy. At 3.4 (2.9-4.1) months postablation, 68/75 veins (91%) remained electrically isolated; all PVs remained durably isolated in 79% of patients. Two patients accounted for 5 of 7 reconducting veins. The most common site for reconnection was the inferior aspect of the RIPV (3/7 reconnections). Reconnected veins had poorer occlusion at the index ablation procedure than veins that maintained chronic isolation (occlusion grade 2.9 ± 0.7 vs. 3.4 ± 0.7, P = 0.001). Clinical AF recurrence was detected in 2 patients (11%) at follow-up. CONCLUSIONS: The improved thermodynamic characteristics of the second-generation cryoballoon led to a high rate of both single-shot PVI and chronic lesion durability. This high rate of durable PV isolation is anticipated to translate to improved clinical outcome.

EFFICAS II: optimization of catheter contact force improves outcome of pulmonary vein isolation for paroxysmal atrial fibrillation.

AIMS: A challenge of pulmonary vein isolation (PVI) in catheter ablation for paroxysmal atrial fibrillation (PAF) is electrical reconnection of the PV. EFFICAS I showed correlation between contact force (CF) parameters and PV durable isolation but no prospective evaluation was made. EFFICAS II was a multicentre study to prospectively assess the impact of CF guidance for an effective reduction of PVI gaps. METHODS AND RESULTS: Pulmonary vein isolation using a radiofrequency (RF) ablation catheter with an integrated force sensor (TactiCath™) was performed in patients with PAF. Operators were provided EFFICAS I-based CF guidelines [target 20 g, range 10-30 g, minimum 400 g s force-time integral (FTI)]. Conduction gaps were assessed by remapping of PVs after 3 months, and gap rate was compared with EFFICAS I outcome. At follow up, 24 patients had 85% of PVs remaining isolated, compared with 72% in EFFICAS I (P = 0.037) in which CF guidelines were not used. The remaining 15% of gaps correlated to the number of catheter moves at creating the PVI line, quantified as Continuity Index. For PV lines with contiguous lesions and low catheter moves, durable isolation was 81% in EFFICAS I and 98% in EFFICAS II (P = 0.005). At index procedure, the number of lesions was reduced by 15% in EFFICAS II vs. EFFICAS I. CONCLUSION: The use of CF with the above guidelines and contiguous deployment of RF lesions in EFFICAS II study resulted in more durable PVI in catheter ablation of PAF.

Visually guided laser ablation: a single-centre long-term experience.

AIMS: Durable isolation of the pulmonary veins (PVs) remains the cornerstone of treatment for paroxysmal atrial fibrillation (PAF) and is also used in the treatment of some patients with persistent atrial fibrillation. Visually guided laser ablation (VGLA) has been proven to be safe and effective as a treatment for atrial fibrillation (AF). It has shown high levels of durable PV isolation (PVI), even in the hands of less experienced users. This paper presents the long-term clinical outcomes of all patients treated with VGLA over the course of 4 years in the world's most experienced centre: from early product feasibility work treating only PAF patients to our work using the commercially available product, when we also treated persistent AF patients. METHODS AND RESULTS: One hundred and ninety-four patients (63 females, mean age 61 years) with either a history of drug-refractory PAF (time since initial diagnosis: 60.73 months) or persistent AF (time since initial diagnosis: 62.75 months) were treated in our laboratory with VGLA between 7 January 2009 and 17 May 2013. Follow-up of all patients was consistent with our standard clinical practice with a 7-day Holter being performed at the first clinical visit between 4 and 6 months and, for most patients, again at 12 months post-procedure. Twelve lead electrocardiograms were performed at all clinical visits. Recurrence of AF is defined as any documented AF episode >30 s. Acute procedural results show that 692 veins were acutely isolated with a mean procedure and fluoroscopy time of 226 and 20.4 min, respectively. One hundred and seventy (158 PAF and 12 persistent AF) patients reached 1 year of follow-up, 130 (82.3%) patients remained free of AF in the PAF group, and 9 (75%) in the persistent group. Eighty-seven PAF patients have now reached 24 months follow-up and 66 (75.9%) remain free of AF. Fifty-four PAF patients have reached 36 months follow-up with 41 (75.9%) remaining free of AF. Thirty-two PAF patients have reached 48 months follow-up and 24 (75%) remain free of AF. The peri-procedural complications we encountered were phrenic nerve injury in four patients (2.06%), tamponade or pericardial effusion in one patient (0.51%), stroke or transient ischaemic attack in one patient (0.514%), and vascular injury in six patients (3.09%). We experienced no cases of PV stenosis or atrio-oesophageal fistula. CONCLUSION: Our single-centre experience using VGLA over 4 years shows that it can be used safely and effectively in normal clinical practice and gives high levels of acute PVI accompanied by good clinical outcomes, even after long-term follow-up.

Asymptomatic brain lesions following laserballoon-based pulmonary vein isolation.

AIMS: Laserballoon-based pulmonary vein isolation (PVI) for the treatment of atrial fibrillation (AF) has proven safe and effective. Silent brain lesions after AF ablation detected on magnetic resonance imaging (MRI) have been described for several technologies, but its incidence following laserballoon PVI is unknown. The current study sought to assess the incidence of new asymptomatic brain lesions in patients undergoing laserballoon-based PVI. METHODS AND RESULTS: Patients referred for PVI underwent pre- and post-procedural MRI of the brain. A total of 86 patients were enroled into the study (laserballoon group: 44 patients, 15 female, age 63 ± 9 years, left atrial (LA) diameter 43 ± 5 mm; cryoballoon group: 20 patients, 6 female, age 61 ± 9 years, LA diameter 41 ± 4 mm; and irrigated radiofrequency (RF) group: 22 patients, 11 female, age 64 ± 8 years, LA diameter 43 ± 6 mm). There was no statistically significant difference between the groups with regard to new asymptomatic brain lesions detected on post-procedural MRI: 5 of 44 (11.4%) patients in the laserballoon group, 1 of 20 (5.0%) patients in the cryoballoon group, and 4 of 22 (18.2%) patients in the irrigated RF group, respectively. In the laserballoon group, one additional patient with a new cerebral lesion experienced transient diplopia. In a multivariate regression model the only risk factor for asymptomatic new lesions was the CHA2DS2VASc score. CONCLUSION: Following laserballoon-based PVI, new asymptomatic brain lesions were detected in 11.4% of patients. A higher CHA2DS2VASc score, but not the ablation technology utilized, was the only associated risk factor.

Acute and long-term results with the 3rd generation visually guided laser balloon ablation system for pv isolation.

BACKGROUND: Visually guided laser balloon ablation is known as an effective pulmonary vein (PV) isolation device. The third-generation laser balloon ablation system (X3) equipped with compliant balloon and an automated motor-driven laser output mechanism, namely RAPID mode, has been clinically proven for PV isolation. METHODS: PV isolation with X3 was performed in all the patients with paroxysmal and early-stage persistent atrial fibrillation (AF). Acute data for PV isolation and clinical outcomes including supraventricular tachyarrhythmia (SVT: AF, atrial flutter, or atrial tachycardia)-free survival rate beyond 1 year were analyzed. RESULTS: A total of 110 patients (62 ± 13 years old, 80% of paroxysmal AF) were treated with X3. RAPID mode with was utilized to achieve PV isolation in all cases. In combination with RAPID mode and spot mode laser ablation, 91.1% (380/417) of veins were isolated on the first circumferential lesion set and did not require touch-up ablation and during the index procedure 100% of attempted veins were isolated. The mean procedure time was 77.0 ± 22.7 min and LA dwell time was 61.9 ± 22.0 min. Total duration of laser application was 5.1 ± 2.3 min per vein. At 1 year, SVT-free survival rate was 93.7% in paroxysmal AF patients, and 81.1% in persistent AF patients. CONCLUSIONS: A novel continuous automatic laser balloon ablation system was proved to be safe and effective for both paroxysmal and persistent AF patients. The clinical result demonstrated that PV isolation with X3 could achieve a high SVT-free survival rate.

AF ablation using a novel "single-shot" map-and-ablate spherical array pulsed field ablation catheter: 1-Year outcomes of the first-in-human PULSE-EU trial.

BACKGROUND: During pulsed field ablation (PFA), electrode-tissue proximity optimizes lesion quality. A novel "single-shot" map-and-ablate spherical multielectrode PFA array catheter that is able to verify electrode-tissue contact was recently studied in a first-in-human trial of atrial fibrillation (AF). OBJECTIVE: The aim of this study was to report lesion durability data, safety, and 12-month effectiveness outcomes. METHODS: The spherical PFA catheter, an all-in-one mapping and ablation system, was used to render anatomy and to deliver biphasic pulses (ungated 1.7 kV pulses; ∼40 seconds/application). Ablation sites included pulmonary veins (PVs) and, in selected patients, posterior wall and mitral isthmus. Follow-up was invasive remapping at ∼3 months, electrocardiograms, Holter monitoring at 6 and 12 months, and symptomatic and scheduled transtelephonic monitoring. The primary and secondary efficacy end points were acute PV isolation (PVI), PVI durability, and atrial arrhythmia recurrence. RESULTS: In the 48-patient AF cohort (paroxysmal, 48%; persistent, 52%), lesion sets included PVI (n = 48; 1.2 applications/PV), posterior wall (n = 20; 3.6 applications/posterior wall), and mitral isthmus (n = 11; 2.9 applications/mitral isthmus). Lesions were acutely successful for all 187 of 187 PVs (100%), 20 of 20 posterior walls (100%), and 10 of 11 mitral isthmuses (91%). Pulse delivery time, left atrial catheter dwell time, and procedure time were 61.5 ± 32.8 seconds, 53.9 ± 26.5 minutes, and 87.8 ± 29.8 minutes, respectively. Remapping (43/48 patients [89.5%]) revealed that 158 of 169 PVs (93.5%) were durably isolated. The only complication was a drug-responsive pericarditis. The 1-year Kaplan-Meier estimates of freedom from atrial arrhythmia were 84.2% (paroxysmal AF) and 80.0% (persistent AF). CONCLUSION: The single-shot spherical array PFA catheter can safely achieve durable lesions, translating into good clinical efficacy.

Cancer stem cells: Masters of all traits.

Cancer is a heterogeneous disease, which contributes to its rapid progression and therapeutic failure. Besides interpatient tumor heterogeneity, tumors within a single patient can present with a heterogeneous mix of genetically and phenotypically distinct subclones. These unique subclones can significantly impact the traits of cancer. With the plasticity that intratumoral heterogeneity provides, cancers can easily adapt to changes in their microenvironment and therapeutic exposure. Indeed, tumor cells dynamically shift between a more differentiated, rapidly proliferating state with limited tumorigenic potential and a cancer stem cell (CSC)-like state that resembles undifferentiated cellular precursors and is associated with high tumorigenicity. In this context, CSCs are functionally located at the apex of the tumor hierarchy, contributing to the initiation, maintenance, and progression of tumors, as they also represent the subpopulation of tumor cells most resistant to conventional anti-cancer therapies. Although the CSC model is well established, it is constantly evolving and being reshaped by advancing knowledge on the roles of CSCs in different cancer types. Here, we review the current evidence of how CSCs play a pivotal role in providing the many traits of aggressive tumors while simultaneously evading immunosurveillance and anti-cancer therapy in several cancer types. We discuss the key traits and characteristics of CSCs to provide updated insights into CSC biology and highlight its implications for therapeutic development and improved treatment of aggressive cancers.