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Abstract Background Ocular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. We sought a treatment targeting the tumor microenvironment as well as the tumor cells. Methods Migration of HUVEC cells, the ability of HUVEC cells to form tubes, and proliferative capacity of a human ocular melanoma cell line were tested in the presence of lenalidomide and sorafenib alone and in combination. The compounds were also tested in a rat aortic ring assay and were tested in a highly aggressive human ocular melanoma xenograft model. Results Lenalidomide and Sorafenib inhibit HUVEC ability to migrate and form tubes and when used in combination the inhibition is increased. The agents alone and in combination inhibit outgrowth in the rat aortic ring model. The combination of the agents improved the inhibition over either single agent. In a xenograft model, combination therapy inhibited tumor growth over inhibition by single agent alone in a significant fashion (p < 0.004: lenalidomide and p < 0.0035: sorafenib). Furthermore, spontaneous lung metastasis development was completely inhibited in the combination treated animals. Sixty percent of vehicle treated animals developed lung metastases compared to 50% of lenalidomide treated animals, and 33% of sorafenib treated animals. Conclusion Lenalidomide and sorafenib are effective at targeting endothelial cells, inhibiting growth of ocular melanoma cells and can inhibit growth of tumors in a xenograft model as well as inhibit development of metastases. Combining these agents works in an additive to synergistic way to inhibit the growth of tumors and development of metastases.

The TGFβ receptor inhibitor galunisertib showed promising efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the phase 2 H9H-MC-JBAJ study. Identifying biomarkers for this treatment remains essential. Baseline plasma levels of chemokine CCL3 were integrated with clinical outcomes in PDAC patients treated with galunisertib plus gemcitabine (n = 104) or placebo plus gemcitabine (n = 52). High CCL3 was a poor prognostic factor in the placebo group (mOS 3.6 vs. 10.1 months; p < 0.01) but a positive predictor for galunisertib (mOS 9.2 vs. 3.6 months; p < 0.01). Mechanistically, tumor-derived CCL3 activates Tgfβ signaling in macrophages, inducing their M2 phenotype and Lif secretion, sustaining a mesenchymal/basal-like ecotype. TGFβ inhibition redirects macrophage polarization to M1, reducing Lif and shifting PDAC cells to a more epithelial/classical phenotype, improving gemcitabine sensitivity. This study supports exploring TGFβ-targeting agents in PDAC with a mesenchymal/basal-like ecotype driven by high CCL3 levels., (© 2024. The Author(s).)

The development of efficient and biocompatible contrast agents is particularly urgent for modern clinical surgery. Nanostructured materials raised great interest as contrast agents for different imaging techniques, for which essential features are high contrasts, and in the case of precise clinical surgery, minimization of the signal spatial dispersion when embedded in biological tissues. This study deals with the development of a multimodal contrast agent based on an injectable hydrogel nanocomposite containing a lanthanide-activated layered double hydroxide coupled to a biocompatible dye (indocyanine green), emitting in the first biological window. This novel nanostructured thermogelling hydrogel behaves as an efficient tissue marker for optical and magnetic resonance imaging because the particular formulation strongly limits its spatial diffusion in biological tissue by exploiting a simple injection. The synergistic combination of these properties permits to employ the hydrogel ink simultaneously for both optical and magnetic resonance imaging, easy monitoring of the biological target, and, at the same time, increasing the spatial resolution during a clinical surgery. The biocompatibility and excellent performance as contrast agents are very promising for possible use in image-guided surgery, which is currently one of the most challenging topics in clinical research.

The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer-associated fibroblasts (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NFκB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NFκB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression-free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared with those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib., Significance: TGFβ inhibition skews cancer-associated fibroblasts toward an inflammatory phenotype that secretes autotaxin to drive adaptive resistance in PDAC, revealing autotaxin as a therapeutic target and biomarker of galunisertib response., (©2023 The Authors; Published by the American Association for Cancer Research.)

Poorly cohesive (PC) gastric cancer (GC) is extremely aggressive in progression, and there is an urgent need to identify the molecular pathways involved. We hypothesized the essential role of the RhoA-YAP axis in these mechanisms. The present observational multicenter retrospective study included 133 patients with PC GC treated at two dedicated European surgical centers between 2004 and 2014. YAP nuclear localization was measured by immunohistochemical (IHC) analysis of tissue biopsies. The complete absence of nuclear reactivity was coded as negative expression; we considered "any positive" as low nuclear expression (>0% but <10% of cells) and high nuclear expression (≥10% of cells). Women represented about half of the present series (52%), and the median age was 64 years (p25-p75 range: 53-75). Neoadjuvant and adjuvant treatments were administered to 10% and 54% of the cases, respectively. Extended systemic lymphadenectomy (D2) was the most common (54%). In nearly all cases, the number of retrieved nodes was ≥15, i.e., adequate for tumor staging (94%). An R0 resection was achieved in 80% of the cases. Most patients were pathological T stage 3 and 4 (pT3/pT4 = 79.0%) and pathological N stage 2, 3a, and 3b (pN2/pN3a/pN3b = 47.0%) at the pathological examination. Twenty patients (15%) presented distant metastases. Five-year overall survival (OS) was significantly higher ( p = 0.029) in patients with negative YAP (46%, 95% CI 31.1-60.0%) than in the other patients (27%, 17.5-38.1%). Moreover, when controlling for sex, age, pT, pN, and percentage of signet ring cells in the multivariable analysis, YAP expression was a significant predictor of OS (HR 2.03, 95% CI: 1.18-3.51, p = 0.011). Our results provide new insights into the role of the YAP signaling cascade, as its activation was associated with a worse prognosis in PC GC.

Trastuzumab plus chemotherapy is the standard of care for the first-line treatment of patients with HER2+ advanced esophagogastric (EG) cancer. Nevertheless, patients frequently develop resistance. In preclinical models, we identified the overexpression of Fibroblast Growth Factor Receptor (FGFR) 3 as a mechanism potentially involved in trastuzumab-acquired resistance. FGFR inhibition could be a potential mechanism as a second-line treatment. In this Simon's two-stage phase 2, single arm study, patients with advanced EG cancer refractory to trastuzumab-containing therapies received pemigatinib, an inhibitor of FGFR. The primary end point was the 12-week progression-free survival rate. Translational analyses were performed on tissue and plasma samples. Eight patients were enrolled in the first stage. Although the 6-week disease control rate was 25%, only one patient achieved a stable disease after 12 weeks of treatment. The trial was discontinued before the second stage. Two out of six evaluable tumor samples expressed FGFR3. No FGFRs amplification was detected. HER2 amplification was lost in three out of eight patients. Three patients had an high Tumor Mutational Burden, and two of them are significantly long-term survivors. These results do not support the therapeutic efficacy of targeting FGFR in unselected patients with advanced EG cancer, who are refractory to trastuzumab-containing therapies.

Despite recent advances in the development of BRAF kinase inhibitors (BRAFi) for BRAF-mutant melanomas, development of resistance remains a major clinical problem. In addition to genetic alterations associated with intrinsic resistance, several adaptive response mechanisms are known to be rapidly activated to allow cell survival in response to treatment, limiting efficacy. A better understanding of the mechanisms driving resistance is urgently needed to improve the success of BRAF-targeted therapies and to make therapeutic intervention more durable. In this study, we identify the mitogen-activated protein kinase (MAPK) p38 as a novel mediator of the adaptive response of melanoma cells to BRAF-targeted therapy. Our findings demonstrate that BRAFi leads to an early increase in p38 activation, which promotes phosphorylation of the transcription factor SOX2 at Ser251, enhancing SOX2 stability, nuclear localization, and transcriptional activity. Furthermore, functional studies show that SOX2 depletion increases sensitivity of melanoma cells to BRAFi, whereas overexpression of a phosphomimetic SOX2-S251E mutant is sufficient to drive resistance and desensitize melanoma cells to BRAFi in vitro and in a zebrafish xenograft model. We also found that SOX2 phosphorylation at Ser251 confers resistance to BRAFi by binding to the promoter and increasing transcriptional activation of the ATP-binding cassette drug efflux transporter ABCG2. In summary, we unveil a p38/SOX2-mediated mechanism of adaptive response to BRAFi, which provides prosurvival signals to melanoma cells against the cytotoxic effects of BRAFi prior to acquiring resistance., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The mainstay treatment for patients with immediate resectable pancreatic cancer remains upfront surgery, which represents the only potentially curative strategy. Nevertheless, the majority of patients surgically resected for pancreatic cancer experiences disease relapse, even when a combination adjuvant therapy is offered. Therefore, aiming at improving disease free survival and overall survival of these patients, there is an increasing interest in evaluating the activity and efficacy of neoadjuvant and perioperative treatments. In this view, it is of utmost importance to find biomarkers able to select patients who may benefit from a preoperative therapy rather than upfront surgical resection. Defined genomic alterations and a dynamic inflammatory microenvironment are the major culprits for disease recurrence and resistance to chemotherapeutic treatments in pancreatic cancer patients. Signal transduction pathways or tumor immune microenvironment could predict early recurrence and response to chemotherapy. In the last decade, distinct molecular subtypes of pancreatic cancer have been described, laying the bases to a tailored therapeutic approach, started firstly in the treatment of advanced disease. Patients with homologous repair deficiency, in particular with mutant germline BRCA genes, represent the first subgroup demonstrating to benefit from specific therapies. A fraction of patients with pancreatic cancer could take advantage of genome sequencing with the aim of identifying possible targetable mutations. These genomic driven strategies could be even more relevant in a potentially curative setting. In this review, we outline putative predictive markers that could help in the next future in tailoring the best therapeutic strategy for pancreatic cancer patients with a potentially curable disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Merz, Mangiameli, Zecchetto, Quinzii, Pietrobono, Messina, Casalino, Gaule, Pesoni, Vitale, Trentin, Frisinghelli, Caffo and Melisi.)

Transforming growth factor-beta (TGF-β) is a secreted cytokine that signals via serine/threonine kinase receptors and SMAD effectors. Although TGF-β acts as a tumor suppressor during the early stages of tumorigenesis, it supports tumor progression in advanced stages. Indeed, TGF-β can modulate the tumor microenvironment by modifying the extracellular matrix and by sustaining a paracrine interaction between neighboring cells. Due to its critical role in cancer development and progression, a wide range of molecules targeting the TGF-β signaling pathway are currently under active clinical development in different diseases. Here, we focused on the role of TGF-β in modulating different pathological processes with a particular emphasis on gastrointestinal tumors.

Purpose: Recent studies have identified suggestive prenatal features of RASopathies (e.g., increased nuchal translucency [NT], cystic hygroma [CH], hydrops, effusions, congenital heart diseases [CHD], polyhydramnios, renal anomalies). Our objective is to clarify indications for RASopathy prenatal testing. We compare genotype distributions between pre- and postnatal populations and propose genotype-phenotype correlations., Methods: Three hundred fifty-two chromosomal microarray-negative cases sent for prenatal RASopathy testing between 2012 and 2019 were collected. For most, 11 RASopathy genes were tested. Postnatal cohorts (25 patients with available prenatal information and 108 institutional database genotypes) and the NSeuroNet database were used for genotypic comparisons., Results: The overall diagnostic yield was 14% (50/352), with rates >20% for effusions, hydrops, and CHD. Diagnostic yield was significantly improved in presence of hypertrophic cardiomyopathy (HCM), persistent or associated CH, any suggestive finding combined with renal anomaly or polyhydramnios, or ≥2 ultrasound findings. Largest prenatal contributors of pathogenic variants were PTPN11 (30%), RIT1 (16%), RAF1 (14%), and HRAS (12%), which considerably differ from their prevalence in postnatal populations. HRAS, LZTR1, and RAF1 variants correlated with hydrops/effusions, and RIT1 with prenatal onset HCM., Conclusion: After normal chromosomal microarray, RASopathies should be considered when any ultrasound finding of lymphatic dysplasia or suggestive CHD is found alone or in association.

Mutations of the proto-oncogene KRAS are the most frequent gain-of-function alterations found in cancer. KRAS is mutated in about 30% of all human tumors, but it could reach more than 90% in certain cancer types such as pancreatic adenocarcinoma. Although historically considered to be undruggable, a particular KRAS mutation, the G12C variant, has recently emerged as an actionable alteration especially in non-small cell lung cancer (NSCLC). KRAS G12C and pan-KRAS inhibitors are being tested in clinical trials and have recently shown promising activity. Due to the difficulties in direct targeting of KRAS, other approaches are being explored. The inhibition of target upstream activators or downstream effectors of KRAS pathway has shown to be moderately effective given the evidence of emerging mechanisms of resistance. Various synthetic lethal partners of KRAS have recently being identified and the inhibition of some of those might prove to be successful in the future. The study of escape mechanisms to KRAS inhibition could support the utility of combination strategies in overcoming intrinsic and adaptive resistance and enhancing clinical benefit of KRAS G12C inhibitors. Considering the role of the microenvironment in influencing tumor initiation and promotion, the immune tumor niche of KRAS mutant tumors has been deeply explored and characterized for its unique immunosuppressive skewing. However, a number of aspects remains to be fully understood, and modulating this tumor niche might revert the immunoresistance of KRAS mutant tumors. Synergistic associations of KRAS G12C and immune checkpoint inhibitors are being tested., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Merz, Gaule, Zecchetto, Cavaliere, Casalino, Pesoni, Contarelli, Sabbadini, Bertolini, Mangiameli, Milella, Fedele and Melisi.)

Purpose: Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting., Experimental Design: In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients' outcome were obtained on the basis of the maximization of the Youden's statistics., Results: Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39-4.67; P = 0.0017; median overall survival 8.9 months vs 5.3 months; HR, 3.51; 95% CI, 0.84-6.68; P = 4.9e-05). These results were confirmed in a validation cohort of 50 patients., Conclusions: Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer., (©2020 American Association for Cancer Research.)

A 76-year-old woman with permanent atrial fibrillation and a mechanical aortic valve came to our attention. Echocardiography showed a 50-55% ejection fraction (EF) with good prosthesis performance. For symptomatic bradyarrhythmia, she received a VVI pacemaker (Proponent MRI L2010 model; Boston Scientific.). During follow-up, frequent symptomatic (presyncopal) episodes of nonsustained episodes of ventricular tachycardia (VT) were detected. Amiodarone proved unsuccessful; she was then offered an upgrade to an implantable cardioverter defibrillator (ICD) and a subcutaneous ICD (S-ICD) was chosen by the patient. A few weeks later, two sustained VT were detected and effectively treated with 80-J shock delivery. In both cases, device interrogation revealed a VT rate around 163 bpm (370 ms cycle length), below the lowest device detection cutoff. The report is a case-based review., (© 2020 Wiley Periodicals, Inc.)

Purpose: Valve mediated hemodynamics have been postulated to contribute to pathology of the ascending aorta (AAo). The objective of this study is to assess the association of aortic valve morphology and hemodynamics with downstream AAo size in subjects with bicuspid aortic valve (BAV) disease., Materials and Methods: Four-dimensional flow MRI at 1.5 or 3 Tesla was used to evaluate the hemodynamics in the proximal AAo of 52 subjects: size-matched controls with tricuspid aortic valves (n = 24, mid ascending aorta [MAA] diameter = 38.0 ± 4.9 mm) and BAV patients with aortic dilatation (n = 14 right and left coronary leaflet fusion [RL]-BAV, MAA diameter = 38.1 ± 5.3 mm; n = 14 right and noncoronary leaflet fusion [RN]-BAV, MAA diameter = 36.5 ± 6.6 mm). A validated semi-automated technique was used to evaluate hemodynamic metrics (flow angle, flow displacement, and jet quadrant) and valve morphology (orifice circularity) for all subjects. Regression analysis of these metrics to AAo diameter was performed., Results: RN-BAV subjects displayed a stronger correlation between hemodynamic metrics in the proximal AAo with diameter in the distal AAo compared with size-matched tricuspid aortic valve (TAV) controls and RL-BAV subjects. The distal AAo diameter was found to be strongly correlated to the upstream flow displacement (R 2 adjusted = 0.75) and flow angle (R 2 adjusted = 0.66) measured at the sino-tubular junction (STJ). Orifice circularity was also strongly correlated (R 2 adjusted = 0.53) to the distal AAo diameter in RN-BAV subjects. For TAV controls and RL-BAV subjects, correlations were weaker (R 2 adjusted < 0.2)., Conclusion: Hemodynamics in the STJ were strongly correlated to the distal AAo diameter for the RN-BAV subjects. Hemodynamic metrics were more strongly correlated to the downstream aortic size when compared with valve morphology metrics., Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:246-254., (© 2017 International Society for Magnetic Resonance in Medicine.)

Aim: Evaluate the relationship between neonatal weight and pregnancy-associated plasma protein-A., Methods: Retrospective study on 2564 singleton pregnancies with healthy term neonates in three groups of women with different values of pregnancy-associated plasma protein-A who underwent the combined test during the first trimester. Non-parametric test and correlation analysis for statistical elaboration were carried out., Results: There exists a correlation between the serum levels of pregnancy-associated plasma protein-A in the first trimester of pregnancy and neonatal weight. Values of pregnancy-associated plasma protein-A lower than the 25th percentile are associated with neonatal weight in a significant way. There was no significant association between pregnancy-associated plasma protein-A values above 1.50 MoM and neonatal weight., Conclusion: This study confirms the positive correlation between circulating concentrations of pregnancy-associated plasma protein-A and fetal growth. Low neonatal weight and factors that can cause this could be determined from the first trimester by measuring the concentrations of pregnancy-associated plasma protein-A in maternal serum. Even if the association between the levels of pregnancy-associated plasma protein-A and a low neonatal weight has been demonstrated, however, we have to say that the sensitivity of a such screening method for the prediction of low birth weight and perinatal complications seems to be rather low. The variations of pregnancy-associated plasma protein-A during the first trimester cannot be used as a marker of excessive fetal growth.

Cancer development and progression is a complex process that involves a host of functional and genetic abnormalities. Genomic perturbations and the gene expression they lead to, can now be globally identified with the use of DNA microarray. This relatively new technology has forever changed the scale of biological investigation. The enormous amount of data generated via a single chip has led to major global studies of the cellular processes underlying malignant transformation and progression. The multiplicity of platforms from different proprietors has offered investigators flexibility in their experimental design. Additionally, there are several more recent microarrays whose designs were inspired by the nucleotide-based technology. These include protein, multi-tissue, cell, and interference RNA microarrays. Combinations of microarray and other contemporary scientific methods, such as, laser capture microdissection (LCM), comparative genomic hybridization (CGH), single nucleotide polymorphism analysis (SNP) and chromatin immunoprecipitation (ChIP), have created entirely new fields of interest in the more global quest to better define the molecular basis of malignancy. In addition to basic science applications, many clinical inquiries have been performed. These queries have shown microarray to have clinical utility in cancer diagnosis, risk stratification, and patient management.

Background: The study sought to evaluate whether electrogram-aided identification of hot spot targets produces additional clinical and/or procedure benefits when using a non-traditional focal cryo ablation method to treat common atrial flutter., Methods: A preliminary study identified a specific electrogram criterion (e.g., a stimulus to onset of electrogram time of 74 [+/- 5] ms) that produced successful cryo testing plus subsequent cryoablation with demonstrable bi-directional isthmus block created at intervention site. In the present study, 26 consecutive patients with symptomatic common atrial flutter were ablated with a 9FR 8 mm tip cryo catheter using electrogram-aided identification of hot spot targets with a stimulus to onset of electrogram time of > or =70 ms. Outcomes measured were bi-directional isthmus block at intervention, symptom and conduction recurrence at 3 month follow-up, symptom recurrence at 6 month follow-up, and procedure characteristics., Results: Acute success rate at intervention was 100%. The percentage of patients with symptom recurrence by 3 month follow-up was 4.5% and no additional patients had arrhythmia symptoms documented by 12 month follow-up. Repeat electrophysiological study (EPS) at 3 month follow-up identified 44% of patients with conduction recurrence. The mean +/- SD number of cryo tests and ablations were 11 +/- 9 and 2 +/- 1, respectively. Procedure, fluoroscopy and cryoapplication times were 77 +/- 29 min, 11 +/- 7 min, and 28 +/- 11 min, respectively., Conclusions: A high acute success rate, plus low long-term clinical recurrence rate and procedure benefits may be achieved with electrogram-aided identification of hot spots for focal cryo ablation treatment of common atrial flutter using a 9FR 8 mm tip cryo catheter. The population of patients who were asymptomatic and had demonstrated conduction recurrence on repeat EPS at 3 month follow-up require close scrutiny over the long-term to ascertain whether they eventually experience arrhythmic symptoms. However, should these patients remain symptom-free over the long-term it would suggest that the entire isthmus may not be needed to support symptomatic common atrial flutter.

Background: Larger tipped cryothermal catheters may deliver efficacy and procedure benefits in the treatment of patients with atrial flutter., Objective: To compare 7 French 6 mm and 9 French 8 mm tip cryothermal catheters (Freezor, Xtra or Freezor, MAX, CryoCath Technologies Inc., Kirkland, Canada) in terms of acute and chronic efficacy, and procedure characteristics in the treatment of atrial flutter., Methods: This non-randomized clinical investigation determined bi-directional isthmus block at intervention, procedure characteristics, and symptom and conduction recurrence rates post procedure in consecutive patients with symptomatic atrial flutter ablated either with the 7 French 6 mm tip cryothermal catheter (n = 43) at -75 degrees C for 4 minutes or the 9 French 8 mm tip cryothermal catheter (n = 51) at -75 degrees C for 8 minutes., Results: Clinical data showed a higher acute success rate for the larger tipped catheter (100% vs. 88%). Symptom recurrence rates were 0% for both catheters at 3, 6, and 9 month follow-up. Conduction recurrence rates were similar for both catheters on repeat electrophysiological study at 3 months post procedure (35% vs. 32%). Procedure benefits were fewer cryotests (20 +/- 17 vs. 26 +/- 21) and ablations (4 +/- 4 vs. 12 +/- 18), and shorter procedure (80 +/- 61 min vs. 87 +/- 48 min), fluoroscopy (14 +/- 9 min vs. 24 +/- 10 min), and cryoapplication times (37 +/- 18 min vs. 44 +/- 23 min) with the larger tipped catheter. There were no adverse events reported., Conclusions: Clinical results showed differences in catheter performance that favoured the larger tipped catheter. However, increased acute success rate did not translate into reduced conduction recurrence rate post ablation, although clinical recurrence was completely absent long-term.

Objectives: We investigated the long-term efficacy of cryo ablation for treatment of atrial flutter., Background: To our knowledge, no study has assessed the long-term efficacy of cryo ablation by assessing both symptom and conduction recurrence., Methods: A total of 45 consecutive patients with symptomatic atrial flutter were ablated with a 7-F, 6-mm-tip, quadripolar cryo catheter (Freezor Xtra, CryoCath Technologies Inc., Kirkland, Canada). Electrophysiologic studies (EPS) were performed with diagnostic catheters. Cryo ablation was at -75 degrees C for 4 min, beginning at the inferior rim of the coronary sinus os and creating a posterior line to the Eustachian ridge. Safety, bi-directional isthmus block at intervention, and recurrence at three, six, and nine months post procedure were assessed., Results: There were no adverse events reported. All patients were free of discomfort on cryo energy delivery. The acute success rate at intervention was 87%. Follow-up data from 39 acutely successful patients showed 27 (69%) without conduction recurrence on repeat EPS at three months, and none (0%) had symptom recurrence documented by Holter monitoring, electrocardiogram, and/or patient diary records at three, six, and nine months follow-up., Conclusions: Our experience with a new 7-F, 6-mm-tip, quadripolar cryo catheter yielded a fairly high success rate at intervention, an excellent safety profile, and a good chronic success rate in terms of symptom recurrence. However, further monitoring is necessary to determine whether all asymptomatic patients continue to remain free of symptoms, given the small pool of patients demonstrated to have conduction recurrence.

Introduction: At the present time, several techniques are used or are under investigation for atrial fibrillation (AF) therapy. Nowadays, no well-defined target for such therapies has been yet completely identified. Furthermore, AF is an arrhythmia with high rates of recurrences, both symptomatic and asymptotic. Thus the measure of therapy success rates not only based on symptom perception remains a goal to be reached., Aims of the Study: This study investigates the role of an implantable loop recorder (ILR) as an additional tool to identify initiating and perpetuating mechanisms of AF. The role of right atrial linear ablation (RALA) procedures is also investigated using the monitoring capabilities of the ILR., Methods and Results: Nine patients (mean age 63.8 +/- 5.9) with paroxysmal AF were referred to our institution as candidates for AF ablation. All patients (pts) had in their medical history several years of AF episodes. Therefore pts were aware of AF related symptoms. Six of them were implanted with an ILR before ablation and were monitored one month before and six months after the procedure. The ILRs stored 54 patient activated events (PAE) and 124 automatically activated events (AAE). 68% of PAEs and 67% of AAEs were classified as appropriate. Most common reasons for inappropriate detections were premature atrial or ventricular contractions among PAEs and undersensing among AAEs. The arrhythmia onset was properly identified in 4 pts (44%). The average AF recurrence rate was 10.8 +/- 3.5 ep/month before ablation and 5.0 +/- 1.8 ep/month after the procedure ( p = 0.042)., Conclusion: The ILR may be a helpful tool in monitoring pts undergoing ablation. Dedicated AF detection characteristics could give additional value to the device. RALA appears as a feasible, safe and relatively effective first approach in AF therapy.

Objectives: The aims of this study were to compare the efficacy of a 2- versus a 3 RF lesions ablation procedure in the RA in patients with paroxysmal AF, and to map right atrial activation during AF., Background: RF catheter-mediated ablation lines mimicking the Maze operation have been proposed as a novel curative approach for AF. The relationship between this type of ablation and right atrial mapping has not been extensively studied., Methods: Twenty-four patients with recurrent, drug-refractory, paroxysmal AF underwent an extensive mapping of the RA before attempting linear lesion RF ablation. Patients were divided into two groups: 15 patients received two linear lesions (Group 1), 9 patients three linear lesions (Group 2)., Results: One-month success rate AF did not recur in 40% of Group 1 patients (6/15) and in 66% (6/9) of Group 2 patients. 27% of patients in Group 1 and 11% of patients in Group 2 had recurrences controlled by drugs. No benefit in 33% of Group 1 patients and 22% of Group 2. Long-term follow-up In the absence of any drug treatment, no AF recurrences were observed in 26% of Group 1 patients (FU: 23 to 47 months) and 55% of Group 2 (FU: 14 to 23 months). No complications were reported., Conclusions: Right atrial linear ablation is safe and may be proposed for AF treatment in selected patients.

In selected patients suffering from variant angina, an implantable cardioverter-defibrillator (ICD) and coronary stenting can be helpful to prevent sudden death and treat coronary artery spasm. We report a case of a 47-year-old woman suffering from variant angina, who experienced an episode of ventricular fibrillation promptly cardioverted. After coronary angiography documentation of a mild atherosclerosis, an ICD was implanted and oral nitrates and calcium antagonists were prescribed. The recurrence of chest pain and palpitations prompted us to perform a second coronary angiography that documented a focal coronary artery spasm successfully treated with stent implantation. No other episodes of angina or ventricular arrhythmia were documented during the following 6 months of follow-up.

Right atrial (RA) mapping has been recently more carefully examined in patients with idiopathic atrial fibrillation (AF) in order to improve radiofrequency (RF) catheter-mediated ablation lines to control recurrences. The aim of this study was to map right atrial activation during AF to analyze relationship between anatomy and atrial activation for specific sites. Twenty-four patients with recurrent, drug-refractory, paroxysmal AF underwent an extensive mapping of the RA before attempting RF linear lesion catheter ablation. A typical pattern of atrial activation was recorded in all patients which was consistent with a more regular activity on the trabeculated right atrium (type I AF) and a more fragmented and complex activation on the posterior and the anterior septum (type II and III AF). This paper helps to understand the influence of the anatomic barriers to atrial activation during atrial fibrillation.