Pleural Effusion Secondary to Multiple Myeloma: Is Daratumumab an Effective Treatment? A Case Report

Extramedullary (EM) plasmacytoma disease is an aggressive presentation at diagnosis and relapse for multiple myeloma (MM) patients. EM plasmacytoma is divided into two groups: the first group comprises tumors that extend directly from osteolytic bone lesions, while the second results from plasmacytoma infiltration into soft tissues, with no relation to the bone. Despite new therapies and monoclonal antibodies, the survival for patients with EM plasmacytoma is poor. The involvement of pleural effusion is uncommon in multiple myeloma

Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients

Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced "inflammatory/oxidative status", together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing

Residual peripheral blood CD26+leukemic stem cells in chronic myeloid leukemia patients during TKI therapy and during treatment-free remission

Chronic myeloid leukemia (CML) patients in sustained “deep molecular response” may stop TKI treatment without disease recurrence; however, half of them lose molecular response shortly after TKI withdrawing. Well-defined eligibility criteria to predict a safe discontinuation up-front are still missing. Relapse is probably due to residual quiescent TKI-resistant leukemic stem cells (LSCs) supposedly transcriptionally low/silent and not easily detectable by BCR-ABL1 qRT-PCR. Bone marrow Ph+ CML CD34+/CD38− LSCs were found to specifically co-express CD26 (dipeptidylpeptidase-IV). We explored feasibility of detecting and quantifying CD26+ LSCs by flow cytometry in peripheral blood (PB). Over 400 CML patients (at diagnosis and during/after therapy) entered this cross-sectional study in which CD26 expression was evaluated by a standardized multiparametric flow cytometry analysis on PB CD45+/CD34+/CD38− stem cell population. All 120 CP-CML patients at diagnosis showed measurable PB CD26+ LSCs (median 19.20/μL, range 0.27–698.6). PB CD26+ LSCs were also detectable in 169/236 (71.6%) CP-CML patients in first-line TKI treatment (median 0.014 cells/μL; range 0.0012–0.66) and in 74/112 (66%), additional patients studied on treatment-free remission (TFR) (median 0.015/μL; range 0.006–0.76). Notably, no correlation between BCR-ABL/ABLIS ratio and number of residual LSCs was found both in patients on or off TKIs. This is the first evidence that “circulating” CML LSCs persist in the majority of CML patients in molecular response while on TKI treatment and even after TKI discontinuation. Prospective studies evaluating the dynamics of PB CD26+ LSCs during TKI treatment and the role of a “stem cell response” threshold to achieve and maintain TFR are ongoing

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Flow-cytometry evaluation of residual Leukemia Stem Cells in Chronic Myeloid Leukemia patients: feasibility and clinical application.

Chronic Myeloid Leukemia (CML) is a myeloproliferative disorder characterized by the presence of the BCR-ABL1 oncogene, deriving from the t(9;22)-(q34;q11) balanced translocation. The deriving BCR-ABL1 fusion protein has tyrosine kinase activity, and it is capable of inducing the proliferation and expansion of myeloid precursors. Tyrosine kinase inhibitors, drugs capable of blocking the malignant proliferation of cells by directly targeting the BCR-ABL1 kinase activity, have dramatically changed patients’s outcome and improved survival rate. Dormant CML-Leukemia Stem Cells (LSCs) are intrinsically refractory to TKIs and for this reason, only few patients can discontinue TKI therapy. CML LSCs are transcriptionally silent and probably not detectable by qRT-PCR. Several studies tried to find a specific marker able to detect CML LSCs and distinguish them from normal hematopoietic stem cells (HSCs). CD26 (dipeptidylpeptidase IV) was very recently identified as the most specific surface marker for flow-cytometry quantification and isolation of CML LSCs mainly in the bone marrow while rare samples of peripheral blood have been tested so far. Thus, principal aim of this study was to evaluate the presence of circulating LSCs in peripheral blood samples of patients during TKI therapy, avoiding in this way the need of routine bone marrow aspirate. Secondary we investigated a correlation, if any, between LSCs value and degree of molecular response. The analysis was conducted on 202 CML subjects. We have tested by flow-cytometry analysis the expression on peripheral blood cells of stem cells markers such as CD45, CD34, CD38 and, in particular, we have exploited the co-expression of the PE-conjugated anti-CD26. In our experiments we confirmed that CD26 is a specific marker able to discriminate normal HSCs from CML LSCs also in peripheral blood and that it is not expressed on LSCs of other myeloid disorders. The results of our study also showed that circulating CD26+ LSCs are easily detected in CML patients while on TKIs treatment and when comparing bone marrow and peripheral blood actual amount of CD26+ LSCs in the same patient, values were superimposable. However, no correlation was found between CD26+ LSCs count and BCR-ABL/ABLIS ratio molecular analysis. This study assesses for the first time that flow-cytometry analysis of circulating CD45+/CD34+/CD38-/CD26+ LSCs is a powerful tool that could be of great help to identify the residual leukemic cells during follow-up of CML patients, just with routine peripheral blood testing. Further future investigations are required to establish possible roles of flow-cytometry LSCs detection during management of CML patients and to evaluate a potential relationship between undetectable CML LSCs and safe treatment discontinuation

FLT3 inhibitors in the management of acute myeloid leukemia

In recent years there has been a great improvement in molecular characterization of acute myeloid leukemia (AML) allowing the stratification of patients in different rate of risk. Patients with FLT3 mutated AML have poor prognosis because of resistance to induction chemotherapy or early relapse. Several first and second generation molecules, able to inhibit FLT3 signaling have been developed and many single agent or combination studies are ongoing. Of these, quizartinib seems to have the best clinical activity. Unfortunately, resistance to FLT3 inhibitors have been observed and many scientists are currently investigating new strategy to restore sensitivity to FLT3 inhibitors