Anti-tumor activity of selinexor in combination with antineoplastic agents in chronic lymphocytic leukemia.

Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3Kδ inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects. Interestingly, this drug synergism was exerted also in the presence of the protective effect of stromal cells. From the molecular standpoint, the synergistic cytotoxic activity of selinexor plus idelalisib was associated with increased regulatory effects of this drug combination on the tumor suppressors FOXO3A and IkBα compared to each single compound. Finally, selinexor was also effective in potentiating the in vivo anti-tumor effects of the PI3Kδ inhibitor in mice treated with the drug combination compared to single agents. Our data provide preclinical evidence of the synergism and potential efficacy of a combination treatment targeting XPO1 and PI3Kδ in CLL.

Targeting HIF-1α Regulatory Pathways as a Strategy to Hamper Tumor-Microenvironment Interactions in CLL.

The hypoxia-inducible factor 1 (HIF-1) and the CXCL12/CXCR4 axis regulate the interaction of chronic lymphocytic leukemia cells and the tumor microenvironment. However, the interconnections occurring between HIF-1 and the CXCL12/CXCR4 axis are not fully elucidated. Here, we demonstrate that the CXCL12/CXCR4 axis plays a pivotal role in the positive regulation of the α subunit of HIF-1 (HIF-1α) that occurs in CLL cells co-cultured with stromal cells (SC). Inhibitors acting at different levels on CXCR4 downstream signalling counteract the SC-induced HIF-1α upregulation in CLL cells, also hindering the SC-mediated pro-survival effect. HIF-1α inhibition also exerts off-tumor effects on the SC component, inducing the downregulation of target genes, including CXCL12. Consistently, our data show that pretreatment of leukemic cells and/or SC with idelalisib effectively abrogates the SC-mediated survival support. A combined on-tumor and off-tumor inhibition of HIF-1α was also observed in idelalisib-treated patients, who showed, along with a downregulation of HIF-1α target genes in leukemic cells, a significant decrease in CXCL12 serum concentration and changes in the bone marrow microenvironment. Our data demonstrate that the targeting of HIF-1α or its regulatory pathways acts at the tumor- and SC-level, and may be an appealing strategy to overcome the microenvironment-mediated protection of CLL cells.

Conformable AlN Piezoelectric Sensors as a Non-invasive Approach for Swallowing Disorder Assessment.

Deglutition disorders (dysphagia) are common symptoms of a large number of diseases and can lead to severe deterioration of the patient's quality of life. The clinical evaluation of this problem involves an invasive screening, whose results are subjective and do not provide a precise and quantitative assessment. To overcome these issues, alternative possibilities based on wearable technologies have been proposed. We explore the use of ultrathin, compliant, and flexible piezoelectric patches that are able to convert the laryngeal movement into a well-defined electrical signal, with extremely low anatomical obstruction and high strain resolution. The sensor is based on an aluminum nitride thin film, grown on a soft Kapton substrate, integrated with an electrical charge amplifier and low-power, wireless connection to a smartphone. An ad-hoc designed laryngeal motion simulator (LMS), which is able to mimic the motions of the laryngeal prominence, was used to evaluate its performances. The physiological deglutition waveforms were then extrapolated on a healthy volunteer and compared with the sEMG (surface electromyography) of the submental muscles. Finally, different tests were conducted to assess the ability of the sensor to provide clinically relevant information. The reliability of these features permits an unbiased evaluation of the swallowing ability, paving the way to the creation of a system that is able to provide a point-of-care automatic, unobtrusive, and real-time extrapolation of the patient's swallowing quality even during normal behavior.

Echocardiographic evaluation of right ventricular-arterial coupling in pulmonary hypertension.

Pulmonary hypertension (PH) is a hemodynamic condition characterized by chronically elevated mean pulmonary artery pressure (m-PAP ≥ 25 mmHg) measured at rest by right heart catheterization (RHC). It includes a pre-capillary and a post-capillary form. Pulmonary artery hypertension (PAH) is a pre-capillary form of PH potentially generated by several heterogeneous systemic disorders, whose main hemodynamic change is represented by severely increased pulmonary vascular resistance (PVR). In order to preserve an efficient right ventricular-arterial (RV-PA) coupling, the right ventricle (RV) adapts to this chronic increase of its afterload, with a compensatory hypertrophy, until RV dilatation and dysfunction occur. Right ventricular (RV) function and especially RV-PA coupling assessment showed to be very important prognostic markers in this subset of patients, especially for those with pre-capillary PH. The aim of this review is to provide a pathophysiological insight into the spectrum of RV adaptive changes occurring in response to chronic increase of RV afterload and to present the role of echocardiographic parameters as possible tools for early non-invasive evaluation of RV-PA coupling, before overt heart failure ensues.

A body-weight-supported visual feedback system for gait recovering in stroke patients: A randomized controlled study.

OBJECTIVE: The aim of this study was to determine the effectiveness of a novel body-weight-supported (BWS) gait training system with visual feedback, called Copernicus® (Rehalife, Italy). This computerized device provides comfortable, regular and repeatable locomotion in hemiplegic patients. Through visual real-time monitoring of gait parameters, patients are trained to transfer weight loading alternately on both feet. DESIGN: A single-blind, randomized controlled study. A single center used a computer-generated randomization code to allocate treatments. SETTING: Intensive rehabilitation unit (IRU) at the Institute S. Anna (Italy). PARTICIPANTS: 63 first-ever stroke patients (39 men, age: 66.1 ± 9.6 years; 61.6 % with left-sided lesion) randomly distributed into three demographically/clinically matched groups. TREATMENTS: All groups were treated five times a week for 2 -h sessions for six consecutive weeks. The first group ("control") underwent a conventional physical therapy; the second group performed advanced BWS gait training sessions without visual feedback (Experimental VF- group); whereas the third group used BWS with visual feedback stimulation (Experimental VF+ group). MAIN OUTCOME MEASURES: Absolute changes were recorded using conventional clinical scales and kinematic measurement of static gait balance from baseline to follow-up. RESULTS: Significant interaction Group*Time effects scales (F2,126 = 5.1, p-level = 0.005, η²p = 0.25; F2,126 = 4.7, p-level = 0.007, η²p = 0.19; respectively) were detected in the Functional Independence Measure and Tinetti-Balance scales. Post hoc analysis demonstrated that the recovery of motor functioning was greater for the VF + group with respect to other groups (all p's ≤ 0.001). A similar pattern of findings was also obtained with a stabilometric analysis, demonstrating a better clinical improvement in static balance after VF + treatment. CONCLUSION: The proposed advanced rehabilitation system with visual feedback was more effective in improving gait recovery with respect to conventional and high-tech therapies without a sensor feedback.

Piezoelectricity and Biocompatibility of Flexible ScxAl(1-x)N Thin Films for Compliant MEMS Transducers.

There is huge research activity in the development of flexible and biocompatible piezoelectric materials for next-generation compliant micro electro-mechanical systems (MEMS) transducers to be exploited in wearable devices and implants. This work reports for the first time on the development of flexible ScxAl(1-x)N films deposited by sputtering technique onto polyimide substrates, assessing their piezoelectricity and biocompatibility. Flexible ScxAl(1-x)N films have been analyzed in terms of morphological, structural, and piezoelectric properties. ScxAl(1-x)N layer exhibits a good surface roughness of 4.40 nm and moderate piezoelectricity with an extracted effective piezoelectric coefficient (d33eff) value of 1.87 ± 0.06 pm/V, in good agreement with the diffraction pattern analysis results. Cell viability assay, performed to study the interaction of the ScxAl(1-x)N films with human cell lines, shows that this material does not have significant effects on tested cells. Furthermore, the ScxAl(1-x)N layer, integrated onto a flexible device and analyzed by bending/unbending measurements, shows a peak-to-peak open-circuit voltage (VOC) of 0.32 V and a short-circuit current (ISC) of 0.27 µA, with a generated power of 19.28 nW under optimal resistive load, thus demonstrating the potential of flexible ScxAl(1-x)N films as active layers for next-generation wearable/implantable piezoelectrics.

Impaired myocardial strain in early stage of Duchenne muscular dystrophy: its relation with age and motor performance.

Duchenne muscular dystrophy (DMD) is complicated by an early and progressive left ventricular (LV) dysfunction. Despite the reduction of ejection fraction (EF) usually manifests in the second decade, subtle alterations in LV mechanics can be detected earlier. Longitudinal and circumferential LV deformation, evaluated by speckle tracking echocardiography (STE), are considered sensitive markers of early dysfunction. We retrospectively examined clinical and echocardiographic data of 32 DMD children with preserved LV function. According to the median age, patients were then divided into younger and older than 9 years, and compared to 24 age-matched healthy subjects. Six-minute-walk test (6MWT), North Star Ambulatory Assessment (NSAA), and a comprehensive cardiac evaluation were performed. Although EF was within the normal range, DMD patients had significantly lower values than healthy controls, and the same occurred for the remaining conventional systolic and diastolic indices. Global longitudinal strain (GLS) was reduced in all patients (older and younger, both p < 0.001). Global circumferential strain (GCS) was reduced only in older patients (< 0.001). Both GLS and GCS worsened with age in DMD patients (GLS p = 0.005; GCS p = 0.024). GLS was significantly worse in the apical segments and in the postero-lateral wall. GCS in the antero-septal, anterior and antero-lateral segments was significantly reduced in older patients, with a prevalent involvement of the sole septal wall in the younger boys. 6MWT appeared to be correlated inversely to GLS and directly to EF. A longitudinal evaluation should be scheduled in DMD boys to assess the global cardiac performance over time and to evaluate the impact of therapies.

HIF-1α is over-expressed in leukemic cells from TP53-disrupted patients and is a promising therapeutic target in chronic lymphocytic leukemia.

In chronic lymphocytic leukemia (CLL), the hypoxia-inducible factor 1 (HIF-1) regulates the response of tumor cells to hypoxia and their protective interactions with the leukemic microenvironment. In this study, we demonstrate that CLL cells from TP53-disrupted (TP53 dis) patients have constitutively higher expression levels of the α-subunit of HIF-1 (HIF-1α) and increased HIF-1 transcriptional activity compared to the wild-type counterpart. In the TP53 dis subset, HIF-1α upregulation is due to reduced expression of the HIF-1α ubiquitin ligase von Hippel-Lindau protein (pVHL). Hypoxia and stromal cells further enhance HIF-1α accumulation, independently of TP53 status. Hypoxia acts through the downmodulation of pVHL and the activation of the PI3K/AKT and RAS/ERK1-2 pathways, whereas stromal cells induce an increased activity of the RAS/ERK1-2, RHOA/RHOA kinase and PI3K/AKT pathways, without affecting pVHL expression. Interestingly, we observed that higher levels of HIF-1A mRNA correlate with a lower susceptibility of leukemic cells to spontaneous apoptosis, and associate with the fludarabine resistance that mainly characterizes TP53 dis tumor cells. The HIF-1α inhibitor BAY87-2243 exerts cytotoxic effects toward leukemic cells, regardless of the TP53 status, and has anti-tumor activity in Em-TCL1 mice. BAY87-2243 also overcomes the constitutive fludarabine resistance of TP53 dis leukemic cells and elicits a strongly synergistic cytotoxic effect in combination with ibrutinib, thus providing preclinical evidence to stimulate further investigation into use as a potential new drug in CLL.

Multimodality imaging for thromboembolic risk assessment in atrial fibrillation.

: Atrial fibrillation is the most widely represented sustained arrhythmia in the world. Thromboembolic risk assessment represents the main clinical challenge associated with this condition, requiring enormous medical, social and economical efforts. Several pieces of evidence in literature highlight how clinical risk factors are not enough for a correct thromboembolic risk stratification of patients with atrial fibrillation, since thromboembolic events have been proven to occur even in patients with low clinical risk scores. A comprehensive multimodality imaging approach, with special regard to echocardiography and new technologies seems to be the best method for this purpose. The aim of this review is to propose a hybrid thromboembolic risk stratification system that combinines clinical evaluation with instrumental clues on left atrial remodeling, fibrosis and deformation which, could be useful especially for patients classified at low thromboembolic risk according to clinical scores.

Tailoring CD19xCD3-DART exposure enhances T-cells to eradication of B-cell neoplasms.

Many patients with B-cell malignancies can be successfully treated, although tumor eradication is rarely achieved. T-cell-directed killing of tumor cells using engineered T-cells or bispecific antibodies is a promising approach for the treatment of hematologic malignancies. We investigated the efficacy of CD19xCD3 DART bispecific antibody in a broad panel of human primary B-cell malignancies. The CD19xCD3 DART identified 2 distinct subsets of patients, in which the neoplastic lymphocytes were eliminated with rapid or slow kinetics. Delayed responses were always overcome by a prolonged or repeated DART exposure. Both CD4 and CD8 effector cytotoxic cells were generated, and DART-mediated killing of CD4+ cells into cytotoxic effectors required the presence of CD8+ cells. Serial exposures to DART led to the exponential expansion of CD4 + and CD8 + cells and to the sequential ablation of neoplastic cells in absence of a PD-L1-mediated exhaustion. Lastly, patient-derived neoplastic B-cells (B-Acute Lymphoblast Leukemia and Diffuse Large B Cell Lymphoma) could be proficiently eradicated in a xenograft mouse model by DART-armed cytokine induced killer (CIK) cells. Collectively, patient tailored DART exposures can result in the effective elimination of CD19 positive leukemia and B-cell lymphoma and the association of bispecific antibodies with unmatched CIK cells represents an effective modality for the treatment of CD19 positive leukemia/lymphoma.

Ten Years of 2D Longitudinal Strain for Early Myocardial Dysfunction Detection: A Clinical Overview.

In recent years, the role of left ventricular ejection fraction (EF) as the gold standard parameter for the evaluation of systolic function has been questioned, and many efforts have been concentrated in the clinical validation of new noninvasive tools for the study of myocardial contractility. Improvement in the accuracy of speckle-tracking echocardiography has resulted in a large amount of research showing the ability of two-dimensional strain to overcome EF limitations in the majority of primary and secondary heart diseases. Currently, global longitudinal strain (GLS) is considered the most accurate and sensitive parameter for the assessment of early left ventricular dysfunction. This review summarizes the advantages that this measurement can provide in several clinical settings. Moreover, the important cautions that should be considered in making the choice to use GLS also are addressed. Finally, a special focus on bull's-eye polar maps for the assessment of regional changes of longitudinal function and the usefulness of these maps in the differential diagnosis of several diseases is provided.

Impairment of elastic properties of the aorta in bicuspid aortic valve: relationship between biomolecular and aortic strain patterns.

Aims: Bicuspid aortic valve (BAV) is associated with aortic wall alterations. We aimed to detect any correlation between aortic elasticity and genetic and biomolecular patterns of elastin. Methods and results: Forty-nine BAV patients (mean age: 38 ± 17.05) were prospectively enrolled. A blood sample was drawn for analysis of a single nucleotide polymorphism of elastin gene (ELN rs2071307) responsible for misfolding of elastin, and for the amount of elastin soluble fragments (ESF) in the plasma. Aortic dimensions and elastic properties were determined by echocardiography, aortic stiffness (AS) by M-mode analysis, and longitudinal strain (LS) of the ascending aorta (AA) by speckle-tracking echocardiography; values of aortic strain were compared with 45 age-matched subjects (mean age: 33 ± 9.67) with tricuspid aortic valve (TAV). BAV patients had greater aortic dimensions [Valsalva sinus (P = 0.004), sinotubular junction (P = 0.013), AA (P < 0.001)] and stiffness (P = 0.002) but lower LS (P = 0.04) than those with TAV. Results from comparisons of mutated genotype patients (AA, n = 10) with heterozygous (GA, n = 21) and wild-types ones (GG, n = 16) revealed that the presence of mutation was associated with increased ESF (P = 0.010 GG vs. GA; P = 0.035 GA vs. AA), larger AA (P = 0.019 GG vs. GA; P = 0.001 GG vs. AA), and lower LS (P = 0.032 GG vs. AA). Patients with a dilated AA showed greater ESF (P < 0.001), greater AS (P = 0.007), and lower LS of the AA (P = 0.002) than those with a normal AA. The same parameters were not significantly different comparing patients with moderate or severe aortic valve disease and patients with less than moderate valve disease. Conclusions: Our results show a close correlation between genetic and biomolecular patterns of elastin and mechanical properties of the aorta in patients with BAV.

[A case of pulmonary artery sarcoma and review of the literature]. / Un caso di angiosarcoma polmonare e revisione della letteratura.

Pulmonary artery sarcoma (PAS) is a highly malignant tumor that originates in the pulmonary artery. This disease has a poor prognosis. Early diagnosis followed by radical surgical resection constitutes the only chance of survival for patients. However, owing to the rare and nonspecific clinical manifesta-tions and imaging findings, PAS is frequently misdiagnosed as various pulmonary thromboembolic diseases. We report the case of a 49-year-old woman who presented to our emergency department for dyspnea, hemoptysis, cough, and asthenia. A diagnosis of pulmonary thromboembolism was initially postulated. However, the rapid clinical progression of the disease, characterized by multiorgan involvement, together with the persistence of pulmonary filling defects despite appropriate anticoagulation therapy, induced to a late diagnosis of metastasized PAS. The peculiarity of our case consists of two main factors: the first is the atypical clinical presentation characterized by severe neurological impairment that finally led to patient's death; the second is the histopathological aspect of the lesion with a prevalent histiocytic cell component that is described in the literature as the less frequent pathological variant of this tumor.

An Unusual Case of Aortic-Right Atrium Fistula: A Diagnostic and Therapeutic Challenge.

An aorta-to-right atrium (RA) fistula is an anomalous communication between the ascending or descending thoracic aorta and the RA. In this report, we describe a case of an idiopathic aortic root-to-RA fistula occasionally found during a coronary angiography performed in a young patient admitted for acute chest pain with evidence of multivessel coronary artery disease. The anatomical peculiarity of this fistulous communication is that it gave origin to collateral vessels furnishing the inferolateral wall of the left ventricle. The case represented a diagnostic and therapeutic challenge that required a multimodality imaging and a multidisciplinary team approach.

Magic pills: new oral drugs to treat chronic lymphocytic leukemia.

INTRODUCTION: A deeper understanding of chronic lymphocytic leukemia (CLL) biology has led to the identification of new promising therapeutic targets. Different classes of molecules are currently under investigation and novel oral drugs have recently been approved or are in a late stage of clinical development. Areas covered: We present biological data illustrating the heterogeneous mechanisms of action of new oral drugs in CLL. Moreover, we provide clinical data from phase I to III studies, and discuss efficacy and side effects profile of these new therapies. Data are derived from peer-reviewed articles indexed in PubMed and from abstracts presented at major international meetings. Expert opinion: Novel oral drugs represent a valuable alternative to chemo-immunotherapy for patients with CLL, especially when high-risk disease features are present and when age or comorbidities preclude the use of standard treatments. Based on data from ongoing clinical trials, the indications of already approved agents will most likely be expanded and new options will soon be available. Moreover, treatment combinations will broaden the therapeutic armamentarium of physicians treating CLL. The availability of multiple choices is of benefit for patients with CLL, but also represents a challenge for the need of choosing the right drug for each patient.

[Combined left atrial appendage percutaneous closure and atrial fibrillation ablation: a single center experience]. / Procedura combinata di chiusura percutanea di auricola sinistra e ablazione di fibrillazione atriale: esperienza di un singolo centro.

BACKGROUND: We evaluated long-term safety and efficacy of concomitant left atrial appendage (LAA) closure and atrial fibrillation (AF) ablation. METHODS: From February 2013 to June 2017, all patients referred for AF ablation and LAA closure (group 1) were enrolled in the study and compared with a matched control group undergoing AF ablation only (group 2). Pulmonary vein isolation was achieved in all cases with radiofrequency or cryoballoon. LAA was occluded with Watchman or Amplatzer Cardiac Plug or Amulet (ACP) devices. All patients were treated with oral anticoagulation therapy for at least 3 months after the procedure ("blanking period"), and then switched to dual antiplatelet therapy with aspirin and clopidogrel for other 3 months, and then to single antiplatelet therapy with aspirin in case of LAA closure, while group 2 was treated with long-term oral anticoagulation therapy according to CHA2DS2-VASc score. Follow-up was performed with transesophageal echocardiography and clinical visit at 3, 6 and 12 months after the procedure. AF burden was evaluated by loop recorder or pacemaker interrogation in all patients. RESULTS: Overall, 42 patients were enrolled, 21 in each group. Mean age was 66.86 ± 10.35 years in group 1 vs 68.42 ± 10.61 in group 2 (p=NS); mean CHA2DS2-VASc score was 2.8 ± 1.22 in group 1 vs 2.01 ± 0.93 in group 2 (p=NS), mean HAS-BLED score was 3.2 ± 0.83 in group 1 vs 3.1 ± 0.95 in group 2 (p=NS). Persistent AF was present in 80% of patients in group 1 and in 85% in group 2. LAA closure was successful in all cases (14 Watchman, 7 ACP devices). Procedural and fluoroscopy times were shorter in group 2 (68 ± 17 vs 52 ± 15 min, p <0.05; 23 ± 5 vs 18 ± 3 min, p <0.05, respectively). No procedural complications were observed in group 2, while in group 1 one case of self-terminating pericardial effusion and one arteriovenous fistula were observed. At a mean follow-up of 14.93 ± 10.05 months, complete seal of LAA was documented in all patients, with neither dislocations nor thromboembolic events. Similarly, no long-term complications were observed in group 2. Maintenance of sinus rhythm was overlapping, with an AF relapse rate of 36% in group 1 vs 38% in group 2 (p=NS). CONCLUSIONS: Combined LAA percutaneous closure and AF ablation appears to be feasible in high-risk patients.

Therapeutic efficacy of the bromodomain inhibitor OTX015/MK-8628 in ALK-positive anaplastic large cell lymphoma: an alternative modality to overcome resistant phenotypes.

Anaplastic large cell lymphomas (ALCL) represent a peripheral T-cell lymphoma subgroup, stratified based on the presence or absence of anaplastic lymphoma kinase (ALK) chimeras. Although ALK-positive ALCLs have a more favorable outcome than ALK-negative ALCL, refractory and/or relapsed forms are common and novel treatments are needed. Here we investigated the therapeutic potential of a novel bromodomain inhibitor, OTX015/MK-8628 in ALK-positive ALCLs.The effects of OTX015 on a panel of ALK+ ALCL cell lines was evaluated in terms of proliferation, cell cycle and downstream signaling, including gene expression profiling analyses. Synergy was tested with combination targeted therapies.Bromodomain inhibition with OTX015 led primarily to ALCL cell cycle arrest in a dose-dependent manner, along with downregulation of MYC and its downstream regulated genes. MYC overexpression did not compensate this OTX015-mediated phenotype. Transcriptomic analysis of OTX015-treated ALCL cells identified a gene signature common to various hematologic malignancies treated with bromodomain inhibitors, notably large cell lymphoma. OTX015-modulated genes included transcription factors (E2F2, NFKBIZ, FOS, JUNB, ID1, HOXA5 and HOXC6), members of multiple signaling pathways (ITK, PRKCH, and MKNK2), and histones (clusters 1-3). Combination of OTX015 with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib led to cell cycle arrest then cell death, and combination with suboptimal doses of the ALK inhibitor CEP28122 caused cell cycle arrest. When OTX015 was associated with GANT61, a selective GLI1/2 inhibitor, C1156Y-resistant ALK ALCL growth was impaired.These findings support OTX015 clinical trials in refractory ALCL in combination with inhibitors of interleukin-2-inducible kinase or SHH/GLI1.

Apical hypertrophic cardiomyopathy: Present status.

Since the first description of apical hypertrophic cardiomyopathy in Japan 40years ago, contrasting information from all over the world has emerged regarding the natural history of the disease. This review provides an overview of incidence, phenotypic expressions, clinical features, prognosis, and management of this heterogeneous clinical entity, which may play a more relevant role in the burden of sudden cardiac death than previously thought.

PFO: Button me up, but wait Comprehensive evaluation of the patient.

Patent foramen ovale (PFO) is a slit or tunnel-like communication in the atrial septum occurring in approximately 25% of the population. A wide number of pathological conditions have been linked to its presence, most notably, cryptogenic stroke (CS) and migraine. However, in the setting of a neurological event, it is not often clear whether the PFO is pathogenically related to the index event or an incidental finding. Therefore, a detailed analysis of several clues is needed for understanding PFO's clinical significance, with a frequent case-by-case decision about destination therapy. Indeed, the controversy about PFO's pathogenicity prompted a paradigm shift of research interest from medical therapy with antiplatelets or anticoagulants to percutaneous transcatheter closure, in secondary prevention. Observational data and meta-analysis of observational studies had previously suggested that PFO closure with a device was a safe procedure with a low recurrence rate of stroke. To date, however, recent randomized controlled trials have not shown the superiority of PFO closure over medical therapy. Thus, the optimal strategy for secondary prevention of paradoxical embolism in patients with a PFO remains unclear. Moreover, the latest guidelines for the prevention on stroke restricted indications for PFO closure to patients with deep vein thrombosis and high-risk of its recurrence. Given these recent data, in the present review, we critically discuss current treatment options, pointing out the role of a comprehensive patient evaluation in overcoming PFO closure restrictions and planning the best management for each patient.