Aggressive systemic mastocytosis with the co-occurrence of PRKG2::PDGFRB, KAT6A::NCOA2, and RXRA::NOTCH1 fusion transcripts and a heterozygous RUNX1 frameshift mutation.

Systemic mastocytosis (SM) is a myeloproliferative neoplasm displaying abnormal mast cell proliferation. It is subdivided into different forms, including aggressive systemic mastocytosis (ASM) and systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Oncogenic genetic alterations include point mutations, mainly the KIT D816V, conferring poor prognosis and therapy resistance, and fusion genes, with those involving PDGFRA/PDGFRB as the most recurrent events. We here describe an ASM case negative to the KIT D816V and JAK2 V617F alterations but showing a RUNX1 frameshift heterozygous mutation and the co-occurrence of three fusion transcripts. The first one, PRKG2::PDGFRB, was generated by a balanced t(4;5)(q24;q32) translocation as the sole abnormality. Other two novel chimeras, KAT6A::NCOA2 and RXRA::NOTCH1, originated from cryptic intra-chromosomal abnormalities. The patient rapidly evolved towards SM-AHN, characterized by the persistence of the PRKG2::PDGFRB chimera, due to the presence of an extra copy of the der(5)t(4;5)(q24;q34) chromosome and an increase in the RUNX1 mutation allelic frequency. The results indicated that the transcriptional landscape and the mutational profile of SM deserve attention to predict the evolution and prognosis of this complex disease, whose classification criteria are still a matter of debate.

Pulmonary Embolism in COVID-19 Patients Is Not Related to a Deterioration of Tissue Oxygenation.

BACKGROUND: COVID-19 induces robust systemic inflammation. One of the main complications is the increased coagulation due to endotheliitis. There is an increased incidence of pulmonary embolism (PE) in COVID-19 patients. However, clinical characteristics for a strict analysis are yet to be determined. AIM: We evaluated oxygenation and characteristics in patients with COVID-19 PE (CPE). MATERIAL AND METHODS: We evaluated 215 COVID-19 patients from 1 January to 30 April 2021. We found 18 patients affected by PE (CPE, 50.0% males, aged 67.00 ± 10.86 years). As controls, we used data from patients affected by PE evaluated in our ward between 1 January 2015 and 31 December 2019 (64 patients, 53.1% males, aged 70.88 ± 16.44 years). All patients underwent a complete physical examination, pulmonary computerised tomography, laboratory tests, D-dimers and blood gas analysis at the time of diagnosis. RESULTS: There were no differences in laboratory tests nor in D-dimers between the two groups. In the CPE group we found a significantly increased pO2 (92.83 ± 42.52 vs. 76.11 ± 32.58 mmHg; p < 0.05), difference of oxygen between alveoli and arteries (A-aDO2; 169.3 ± 171.9 vs. 52.97 ± 39.65 mmHg; p < 0.05), and oxygen saturation % (97.06 ± 2.59 vs. 93.77 ± 5.53%; p < 0.05) compared to controls. No difference was found in pCO2 and the ratio between pO2 and percentage of inspired oxygen (P/F). Finally, a significantly decreased urate (3.67 ± 1.49 vs. 5.60 ± 2.10; p < 0.05) was found in CPE compared to controls. In CPE, platelets count presents an inverse correlation to P/F (r = -0.389, p = 0.02) but a direct correlation to A-aDO2 (r = 0.699, p = 0.001). No similar findings were present in controls. DISCUSSION: COVID-19 PE appears to have a different clinical setting. Reduced oxygenation described in PE may not to be considered as a sign of disease. The increased A-aDO2 may indicate that COVID-19 PE involved smaller vessels compared to classical PE. A possible diffuse capillary thrombosis could explain these results.

Cardiovascular Risk Score and Pulmonary Gas Exchange in COVID-19 Patients Show No Correlation.

BACKGROUND: COVID-19 induces robust systemic inflammation. Patients with cardiovascular disease (CVD) are at an increased risk of death. However, much effort is being spent to identify possible predictors of negative outcomes in order to have a more specific clinical setting. CVD scores are a useful tool in evaluating risk of cardiovascular events. AIM: We evaluated oxygenation and characteristics in COVID-19 patients according to cardiovascular risk stratification performed using the Framingham risk score (FRS) for cardiovascular disease. MATERIALS AND METHODS: We evaluated 155 COVID-19 patients (110 males and 45 females, aged 67.43 ± 14.72 years). All patients underwent a complete physical examination, chest imaging, laboratory tests and blood gas analysis at the time of diagnosis. Seventeen patients died (10 males and 7 females, aged 74.71 ± 7.23 years) while the remaining 138 patients (100 males and 38 females, aged 66.07 ± 15.16 years) were alive at discharge. RESULTS: Deceased patients have an increased FRS compared to those that survived (27.37 ± 5.03 vs. 21.33 ± 9.49, p < 0.05). Compared to survivors, the deceased group presents with a significant increase in white blood cells (p < 0.05) and D-dimers (p < 0.05). There was no difference in pCO2, SO2, and in alveolar arteriolar oxygen difference (A-aDO2). On the contrary, in deceased patients there was an increased pO2 (p < 0.05) and a decreased ratio between oxygen inspired and pO2 (P/F; p < 0.05). FRS shows a negative correlation to P/F (r = 0.42, p < 0.05) in the deceased while no correlation was found in the survivors. No other correlation has been found with blood gas parameters or in the inflammation parameters evaluated in the two groups. DISCUSSION: CVD may be considered as a major risk factor for death in COVID-19 patients. The increased risk relates to a reduced lung capacity but it is not related to blood gas values. Similarly, CV risk score results are independent from the inflammatory status of the patients.

Bamlanivimab and Etesevimab administered in an outpatient setting for SARS-CoV-2 infection.

The early administration of anti-SARS-CoV-2 monoclonal antibodies (mAb) could decrease the risk of severe disease and the need of inpatients care. Herein, our clinical experience with Bamlanivimab/Etesevimab for the treatment of early SARS-CoV-2 infection through an outpatient service was described. Patients with confirmed COVID-19 were selected by General Practitioners (GPs) if eligible to mAb administration, according to manufacturer and AIFA (Agenzia-Italiana-del-Farmaco) criteria. If suitability was confirmed by the Multidisciplinary Team, the patient was evaluated within the next 48-72 hours. Then, all patients underwent a medical evaluation, followed by mAb infusion or hospitalization if the medical condition had worsened. Overall, from March 29th to June 4th, 2021, 106 patients with confirmed COVID-19 were identified by GPs; 26 were considered not eligible and then excluded, while 9 refused treatment. Among the 71 remaining, 6 were not treated because of worsening of symptoms soon after selection. Finally, 65 received mAb therapy. All treated patients survived. However, 2/65 developed adverse events (allergic reaction and atrial fibrillation, respectively) and 6/65 needed hospitalization. By performing univariate logistic regression analysis, diabetes was the only risk factor for hospitalization after mAb administration [aOR = 9.34, 95%CI = 1.31-66.49, p= .026]. Importantly, subjects who worsened awaiting mAb were more frequently obese (OR = 16.66, 95%CI = 1.80-153.9, p= .013) and received home corticosteroid therapy for COVID-19 (OR = 14.11, 95%CI = 1.53-129.6, p= .019). Establishing a network among GPs and COVID units could be an effective strategy to provide mAb treatment to patients with early SARS-CoV-2 infection to reduce hospitalizations and pressure on healthcare systems.

Worldwide prevalence, genotype distribution and management of hepatitis C.

Hepatitis C virus (HCV) is one of the leading causes of chronic liver disease, cirrhosis, and hepatocellular carcinoma, resulting in major global public health concerns. The HCV infection is unevenly distributed worldwide, with variations in prevalence across and within countries. The studies on molecular epidemiology conducted in several countries provide an essential supplement for a comprehensive knowledge of HCV epidemiology, genotypes, and subtypes, along with providing information on the impact of current and earlier migratory flows. HCV is phylogenetically classified into 8 major genotypes and 57 subtypes. HCV genotype and subtype distribution differ according to geographic origin and transmission risk category. Unless people with HCV infection are detected and treated appropriately, the number of deaths due to the disease will continue to increase. In 2015, 1.75 million new viral infections were mostly due to unsafe healthcare procedures and drug use injections. In the same year, access to direct-acting antivirals was challenging and varied in developing and developed countries, affecting HCV cure rates based on their availability. The World Health Assembly, in 2016, approved a global strategy to achieve the elimination of the HCV public health threat by 2030 (by reducing new infections by 90% and deaths by 65%). Globally, countries are implementing policies and measures to eliminate HCV risk based on their distribution of genotypes and prevalence.

JAM-A as a prognostic factor and new therapeutic target in multiple myeloma.

Cell adhesion in the multiple myeloma (MM) microenvironment has been recognized as a major mechanism of MM cell survival and the development of drug resistance. Here we addressed the hypothesis that the protein junctional adhesion molecule-A (JAM-A) may represent a novel target and a clinical biomarker in MM. We evaluated JAM-A expression in MM cell lines and in 147 MM patient bone marrow aspirates and biopsies at different disease stages. Elevated JAM-A levels in patient-derived plasma cells were correlated with poor prognosis. Moreover, circulating soluble JAM-A (sJAM-A) levels were significantly increased in MM patients as compared with controls. Notably, in vitro JAM-A inhibition impaired MM migration, colony formation, chemotaxis, proliferation and viability. In vivo treatment with an anti-JAM-A monoclonal antibody (αJAM-A moAb) impaired tumor progression in a murine xenograft MM model. These results demonstrate that therapeutic targeting of JAM-A has the potential to prevent MM progression, and lead us to propose JAM-A as a biomarker in MM, and sJAM-A as a serum-based marker for clinical stratification.