The measurement of the left ventricle ejection fraction by a bedside FoCUS examination.

The use of point-of-care ultrasound is rapidly increasing in medical practice. This study aims to evaluate the left ventricle systolic function by the bedside focus cardiac ultrasound (FoCUS). We consecutively enrolled n.59 patients of the Emergency Medicine Unit of S. Andrea Hospital. Every patient received a bedside FoCUS examination to estimate the left ventricle (LV) ejection fraction (EF); the LV EF measurements were compared with those obtained by standard echocardiography (as gold standard). The LV EF obtained by the bedside FoCUS examination and the standard echocardiography, resulted, respectively: 50.2 ± 15.1% (by the Quinones equation), 39.5 + 12.0% (by the Lvivo app) and 53.7 + 11.1% (by the standard echocardiography). The correlations between the bedside FoCUS EF measurements versus standard echocardiography were statistically significant: r = + 0.694 p < 1.9 × 10-6 (Quinones equation, Bland-Altman analysis mean = - 2.3%) and r = + 0.571 p < 0.01 (Lvivo app, Bland-Altman analysis mean = - 13.3%). In conclusion, the present study showed a high accuracy of the bedside FoCUS EF evaluations, which may support the diagnosis of the heart failure in an emergency setting without delaying. The EF measurements by the operational method are more precise than those obtained by the unselected images of the software application.

Safety and efficacy of induction immunochemotherapy with rituximab, methotrexate, ifosfamide, and vincristine (R-MIV) in patients with primary CNS lymphoma including recent COVID-19 pandemic experience.

Clinical data on primary central nervous system (CNS) lymphoma (PCNSL) patients is mostly generated from prospective studies, and many frail real-world patients are not included. Recently,the diagnosis and treatment of PCNSL patients was confounded by the COVID-19 pandemic. In particular, treatment with high-dose cytarabine was linked to increased risk of pneumonia and virus persistence. We report on outcome of the induction regimen R-MIV (rituximab, methotrexate, ifosfamide, and vincristine) involving intensive administration of high-dose methotrexate (3.5 g/m2 ) with ifosfamide, every 2 weeks and rituximab once per week for six doses. The median age and performance status (PS) for 64 patients was 58 years and 2 (PS 3; 22%) respectively. The overall response rate by magnetic resonance imaging/computed tomography (MRI/CT) was 73% (n = 46/63), with an additional 17.5% (n = 11/63) patients without measurable disease at baseline. Grade 3-4 haematological toxicity was low for R-MIV (neutropenia: 25% and thrombocytopenia: 1%). Three patients (4.7%) died from treatment-related toxicity. Co-existence of SARS-CoV-2 infection with cytomegalovirus reactivation and the varicella-zoster virus in two patients was fatal. Fifty patients (78%) were eligible for consolidation. Median progression-free and overall survival were not reached (median follow-up: 44 months). In conclusion, the R-MIV regimen is feasible in routine practice, effective and safe, even during the COVID-19 pandemic.

High efficacy of intensive immunochemotherapy for primary mediastinal B-cell lymphoma with prolonged follow up.

Primary mediastinal B-cell lymphoma (PMBL) is currently curable in 85-95% of patients. Treatment regimens frequently used include RCHOP ± radiotherapy, DAEPOCH-R, or occasionally more intensive protocols. Here we present results of treatment of 124 patients with PMBL over a period between 2004 and 2017 with the use of a protocol designed for aggressive B-cell lymphoma GMALL/B-ALL/NHL2002 including 6 cycles of alternating immunochemotherapy with intermediate-dose methotrexate in each cycle, and reduced total doxorubicin dose (100 mg/m2 for whole treatment). Majority of patients (77%) received consolidative radiotherapy. A median (range) age of patients was 30 (18-59) years, and 60% were female. With a median (range) follow up of 9 (1-17) years, 5-year overall survival (OS) and 5-year progression free survival (PFS) were 94% and 92%, respectively. Positron emission tomography-computed tomography (PET-CT) results at the end of chemotherapy were predictive for outcome: OS and PFS at 5 year were 96% and 94% in PET-CT negative patients, respectively, and 70% and 70% in PET-CT-positive patients (p = 0.004 for OS, p = 0.01 for PFS). Eight (6%) patients had recurrent/refractory disease, however, no central nervous system (CNS) relapse was observed. Acute toxicity included pancytopenia grade 3/4, neutropenic fever, and treatment related mortality rate of 0.8%. Second malignancies and late cardiotoxicity occurred in 2.4% and 2.4% of patients, respectively. Intensive alternating immunochemotherapy protocol GMALL/B-ALL/NHL2002 is curative for more than 90% of PMBL patients and late toxicity in young patients is moderated. The attenuated dose of doxorubicin and intermediate dose of methotrexate may contribute to low incidence of late cardiotoxicity and effective CNS prophylaxis.

Ofatumumab with iphosphamide, etoposide and cytarabine for patients with transplantation-ineligible relapsed and refractory diffuse large B-cell lymphoma.

The efficacy of salvage treatment of diffuse large B-cell lymphoma (DLBCL) patients who relapse or progress (rrDLBCL) after initial therapy is limited. Efficacy and safety of ofatumumab with iphosphamide, etoposide and cytarabine (O-IVAC) was evaluated in a single-arm study. Dosing was modified for elderly patients. Patients received up to six cycles of treatment. The primary end-point was the overall response rate (ORR). Patients were evaluated every two cycles and then six and 12 months after treatment. Other end-points included progression-free survival (PFS), event-free survival (EFS), overall survival (OS) and safety. Seventy-seven patients received salvage treatment with O-IVAC. The average age was 56.8 years; 39% had an Eastern Cooperative Oncology Group (ECOG) performance status of at least 3; 78% had disease of Ann Arbor stage 3 or 4; 58% received one or more prior salvage therapies. The ORR for O-IVAC was 54.5%. The median duration of study follow-up was 70 months. The median PFS and EFS were 16.3 months each. The median OS was 22.7 months. Age, ECOG performance status and the number of prior therapy lines were independent predictors of survival. Treatment-related mortality was 15.5%. O-IVAC showed a high response rate in a difficult-to-treat population and is an attractive treatment to bridge to potentially curative therapies.

Prognostic Value of the Immunological Subtypes of Adolescent and Adult T-Cell Lymphoblastic Lymphoma; an Ultra-High-Risk Pro-T/CD2(-) Subtype.

(1) Background: T-cell lymphoblastic lymphoma (T-LBL) is extremely rare and highly aggressive, with no practical risk model defined yet. The prognostic value of T-LBL immunological subtypes is still a matter of controversy. (2) Methods: We re-evaluated 49 subsequent adult T-LBL patients treated according to the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL) protocols, 05/93 (n = 20) and T-LBL 1/2004 (n = 29), 85.7% of which achieved complete remission (CR). (3) Results: The 5/10-year overall survival (OS) and event-free survival (EFS) were 62%/59% and 48%/43%, respectively. In 96% of patients, flow cytometry analyses defining the WHO 2008 immunophenotypes were available. Cortical, early/pro-T/CD2(-), early/pre-T/CD2(+), and mature subtypes were identified in 59.5%, 19%, 15%, and 6.5% of patients, respectively. Overall, 20% of patients had the early T-cell precursor (ETP)-LBL immunophenotype, as proposed by the WHO 2017 classification. For the early/pro-T/CD2(-) subtype, the five-year OS and EFS were 13% and 13%, while for all the other, non-pro-T subtypes, they were 69% and 67%. By multivariate analysis, only CD2(-) status and age > 35 years emerged as strong, independent factors influencing OS and EFS, while the risk of CR failure was influenced by age only (>35 years). (4) Conclusions: ETP was non-significant for OS, unless an ultra-high-risk pro-T/CD2(-) subtype was concerned.

Tumor and Cerebrospinal Fluid microRNAs in Primary Central Nervous System Lymphomas.

Primary central nervous system lymphoma (PCNSL) is a rare, highly aggressive, extranodal form of non-Hodgkin lymphoma, predominantly diagnosed as primary diffuse large B-cell lymphoma of the central nervous system (CNS DLBCL). Fast and precise diagnosis of PCNSL is critical yet challenging. microRNAs, important regulators in physiology and pathology are potential biomarkers. In 131 patients with CNS DLBCL and with non-malignant brain lesions (n-ML), miR-21, miR-19b and miR-92a, miR-155, miR-196b, miR-let-7b, miR-125b, and miR-9 were examined by RT-qPCR in brain biopsy samples (formalin-fixed paraffin-embedded tissues, FFPET; CNS DLBCL, n = 52; n-ML, n = 42) and cerebrospinal fluid samples (CSF; CNS DLBCL, n = 30; n-ML, n = 23) taken for routine diagnosis. FFPET samples were split into study and validation sets. Significantly higher CSF levels of miR-21, miR-19b, and miR-92a were identified in PCNSL but not in n-ML, and differentiated PCNSL from n-ML with 63.33% sensitivity and 80.77% specificity. In FFPETs, miR-155 and miR-196b were significantly overexpressed and miR-let-7b, miR-125b, and miR-9 were downregulated in PCNSL as compared to n-ML. Combined miR-155 and miR-let-7b expression levels in FFPETs discriminated PCNSL and n-ML with a 97% accuracy. In conclusion, tissue miR-155, miR-196b, miR-9, miR-125b, and miR-let-7b expression profiles differentiate PCNSL from n-ML. PCNSL CSFs and the relevant biopsy samples are characterized by specific, different microRNA profiles. A logistic regression model is proposed to discriminate between PCNSL and non-malignant brain lesions. None of the examined microRNAs influenced overall survival of PCNSL patients. Further ongoing developments involve next generation sequencing-based profiling of biopsy and CSF samples.

The renin-angiotensin system as a risk factor and therapeutic target for cardiovascular and renal disease.

The renin-angiotensin system (RAS) plays an important homeostatic role in BP regulation, water and salt balance, and tissue growth control under physiologic conditions. On the other hand, a pivotal involvement of the RAS in the pathophysiology of cardiovascular and renal disease is extensively supported by both basic and clinical evidence. In particular, it is today recognized that angiotensin II (AngII), the biologic effector of the RAS, may prompt a number of relevant structural and functional abnormalities through the activation of a complex of cellular effects mostly mediated via its binding with the AT(1) subtype receptors. The key role of these AngII-linked mechanisms of disease is strongly corroborated by large interventional studies. In fact, pharmacologic interference with RAS activity, by both preventing AngII formation with angiotensin-converting enzyme inhibitors or antagonizing its binding to cell membrane receptors by selective antagonists, is associated with highly beneficial outcomes in major disease conditions (hypertension, diabetes, renal failure, heart failure, myocardial infarction, stroke, and others). This article briefly reviews the current views on the biologic organization of RAS evidence supporting a pathogenic role of the RAS activity in promoting cardiac, vascular, and renal disease, and finally provides the basis for considering inhibition of RAS activity a major target for therapeutic interventions in these conditions.