Blood and skin-derived Sezary cells: differences in proliferation-index, activation of PI3K/AKT/mTORC1 pathway and its prognostic relevance

Sézary syndrome (SS) is a rare and aggressive variant of Cutaneous T-Cell Lymphoma characterized by neoplastic distribution mainly involving blood, skin, and lymph-node. Although a role of the skin microenvironment in SS pathogenesis has long been hypothesized, its function in vivo is poorly characterized. To deepen this aspect, here we compared skin to blood-derived SS cells concurrently obtained from SS patients highlighting a greater proliferation-index and a PI3K/AKT/mTORC1 pathway activation level, particularly of mTOR protein, in skin-derived-SS cells. We proved that SDF-1 and CCL21 chemokines, both overexpressed in SS tissues, induce mTORC1 signaling activation, cell proliferation and Ki67 up-regulation in a SS-derived cell line and primary-SS cells. In a cohort of 43 SS cases, we observed recurrent copy number variations (CNV) of members belonging to this cascade, namely: loss of LKB1 (48%), PTEN (39%) and PDCD4 (35%) and gains of P70S6K (30%). These alterations represent druggable targets unraveling new therapeutic treatments as metformin here evaluated in vitro. Moreover, CNV of PTEN, PDCD4, and P70S6K, evaluated individually or in combination, are associated with reduced survival of SS patients. These data shed light on effects in vivo of skin-SS cells interaction underlying the prognostic and therapeutic relevance of mTORC1 pathway in SS

Multimodality Imaging in Sarcomeric Hypertrophic Cardiomyopathy: Get It Right…on Time

Hypertrophic cardiomyopathy (HCM) follows highly variable paradigms and disease-specific patterns of progression towards heart failure, arrhythmias and sudden cardiac death. Therefore, a generalized standard approach, shared with other cardiomyopathies, can be misleading in this setting. A multimodality imaging approach facilitates differential diagnosis of phenocopies and improves clinical and therapeutic management of the disease. However, only a profound knowledge of the progression patterns, including clinical features and imaging data, enables an appropriate use of all these resources in clinical practice. Combinations of various imaging tools and novel techniques of artificial intelligence have a potentially relevant role in diagnosis, clinical management and definition of prognosis. Nonetheless, several barriers persist such as unclear appropriate timing of imaging or universal standardization of measures and normal reference limits. This review provides an overview of the current knowledge on multimodality imaging and potentialities of novel tools, including artificial intelligence, in the management of patients with sarcomeric HCM, highlighting the importance of specific "red alerts" to understand the phenotype-genotype linkage

Two-Period Study Results from a Large Italian Hospital Laboratory Attesting SARS-CoV-2 Variant PCR Assay Evolution

In keeping with the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the COVID-19 causative agent, PCR assays have been developed to rapidly detect SARS-CoV-2 variants, which have emerged since the first (Alpha) variant was identified. Based on specific assortment of SARS-CoV-2 spike-protein mutations (ΔH69/V70, E484K, N501Y, W152C, L452R, K417N, and K417T) among the major variants known to date, Seegene Allplex SARS-CoV-2 Variants I and Variants II assays have been available since a few months before the last (Omicron) variant became predominant. Using S gene next-generation sequencing (NGS) as the SARS-CoV-2 variant identification reference method, we assessed the results of SARS-CoV-2-positive nasopharyngeal swab samples from two testing periods, before (n = 288, using only Variants I) and after (n = 77, using both Variants I and Variants II) the appearance of Omicron. The Variants I assay allowed correct identification for Alpha (37/37), Beta/Gamma (28/30), or Delta (220/221) variant-positive samples. The combination of the Variants I and Variants II assays allowed correct identification for 61/77 Omicron variant-positive samples. While 16 samples had the K417N mutation undetected with the Variants II assay, 74/77 samples had both ΔH69/V70 and N501Y mutations detected with the Variants I assay. If considering only the results by the Variants I assay, 6 (2 Beta variant positive, 1 Delta variant positive, and 3 Omicron variant positive) of 365 samples tested in total provided incorrect identification. We showed that the Variants I assay alone might be more suitable than both the Variants I and Variants II assays to identify currently circulating SARS-CoV-2 variants. Inclusion of additional variant-specific mutations should be expected in the development of future assays. IMPORTANCE Omicron variants of SARS-CoV-2 pose more important public health concerns than the previously circulating Alpha or Delta variants, particularly regarding the efficacy of anti-SARS-CoV-2 vaccines and therapeutics. Precise identification of these variants highly requires performant PCR-based assays that allow us to reduce the reliance on NGS-based assays, which remain the reference method in this topic. While the current epidemiological SARS-CoV-2 pandemic context suggests that PCR assays such as the Seegene Variants II may be dispensable, we took advantage of NGS data obtained in this study to show that the array of SARS-CoV-2 spike protein mutations in the Seegene Variants II assay may be suboptimal. This reinforces the concept that initially developed PCR assays for SARS-CoV-2 variant detection could be no longer helpful if the SARS-CoV-2 pandemic evolves to newly emerging variants

Multimodality Imaging in Sarcomeric Hypertrophic Cardiomyopathy: Get It Right…on Time

Hypertrophic cardiomyopathy (HCM) follows highly variable paradigms and disease-specific patterns of progression towards heart failure, arrhythmias and sudden cardiac death. Therefore, a generalized standard approach, shared with other cardiomyopathies, can be misleading in this setting. A multimodality imaging approach facilitates differential diagnosis of phenocopies and improves clinical and therapeutic management of the disease. However, only a profound knowledge of the progression patterns, including clinical features and imaging data, enables an appropriate use of all these resources in clinical practice. Combinations of various imaging tools and novel techniques of artificial intelligence have a potentially relevant role in diagnosis, clinical management and definition of prognosis. Nonetheless, several barriers persist such as unclear appropriate timing of imaging or universal standardization of measures and normal reference limits. This review provides an overview of the current knowledge on multimodality imaging and potentialities of novel tools, including artificial intelligence, in the management of patients with sarcomeric HCM, highlighting the importance of specific “red alerts” to understand the phenotype–genotype linkage

Electrocardiographic characteristics of right-bundle-branch-block premature ventricular complexes predicting absence of left ventricular scar in athletes with apparently structural normal heart

Background and aims: Left ventricular scar is an arrhythmic substrate that may be missed by echocardiography and diagnosed only by cardiac magnetic resonance (CMR), which is a time-consuming and expensive imaging modality. Premature ventricular complexes (PVCs) with a right-bundle-branch-block (RBBB) pattern are independent predictors of late gadolinium enhancement (LGE) but their positive predictive value is low. We studied which electrocardiographic features of PVBs with a RBBB pattern are associated with a higher probability of absence of an underlying LGE. Methods and results: The study included 121 athletes (36±16 years; 48.8% men) with monomorphic PVCs with a RBBB configuration and normal standard clinical investigations who underwent CMR. LGE was identified in 35 patients (29%), predominantly in those with PVCs with a superior/intermediate axis (SA-IntA) compared to inferior axis (IA) (38% vs 10%, p=0.002). Among patients with SA-IntA morphology, the contemporary presence of qR pattern in lead aVR and V1 was exclusively found in patient without LGE at CMR (51.0% vs 0%, p< 0.0001). Among patients with IA, the absence of LGE correlated to a narrow ectopic QRS (145±16 vs 184±27 msec, p< 0.001). Conclusions: Among athletes with apparently idiopathic PVCs with a RBBB configuration, the presence of a concealed LGE at CMR was documented in 29% of cases, mostly in those with a SA-IntA. In our experience, the contemporary presence of qR pattern in lead aVR and V1 in PVCs with RBBB/SA-IntA morphology or, on the other hand, a relatively narrow QRS in PVCs with an IA, predicted absence of LGE

Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era

Aims: To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs). Methods and Results: We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P &lt; 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P &lt; 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P &lt; 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009). Conclusion: Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies

Reduction of Hospitalizations for Myocardial Infarction in Italy in the COVID-19 Era

Aims: To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs). Methods and results: We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009). Conclusion: Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies