Clonal heterogeneity in chronic lymphocytic leukemia cells: superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells.

Background Patients with chronic lymphocytic leukemia whose cells express CD38 and ZAP-70 and utilize unmutated Ig VH region genes have a very poor prognosis. We studied whether cells expressing CD38 and ZAP-70 are more susceptible to stimulation through B-cell receptors than are cells that do not express CD38 and ZAP-70.Design and Methods CD38-positive and CD38-negative leukemic cells were separated from single cases and compared for their response to B-cell receptor cross-linking and ZAP-70 expression. Cohort studies were also carried out by measuring the apoptotic response to surface immunoglobulin M (IgM) cross-linking in 82 patients with chronic lymphocytic leukemia and the protein tyrosine phosphorylation induced by surface IgM in 21 patients.Results CD38-positive cells, isolated from cases of chronic lymphocytic leukemia classified as CD38-positive or CD38-negative, expressed more ZAP-70 than the corresponding CD38-negative cells, exhibited more robust protein tyrosine phosphorylation and had a greater tendency to apoptosis upon B-cell receptor cross-linking. In the cohort studies, surface IgM-induced protein tyrosine phosphorylation correlated significantly with CD38 and ZAP-70 expression and with the absence of Ig VH gene mutations. Apoptosis induced by surface IgM cross-linking correlated significantly only with the proportion of CD38-positive cells. Difficulties in finding more definitive correlations were probably related to imprecision in the in vitro test system and in the definition of cases as positive or negative.Conclusions Collectively, these data indicate that CD38-positive, ZAP-70-positive cells have a greater capacity for signaling through the B-cell receptor and suggest a function for B-cell receptor signaling in promoting chronic lymphocytic leukemia cell expansion, especially within the CD38-positive fraction of the leukemic clone

Flow cytometric immunobead assay for detection of BCR-ABL1 fusion proteins in chronic myleoid leukemia: Comparison with FISH and PCR techniques

Chronic Myeloid Leukemia (CML) is characterized by a balanced translocation juxtaposing the Abelson (ABL) and breakpoint cluster region (BCR) genes. The resulting BCR-ABL1 oncogene leads to increased proliferation and survival of leukemic cells. Successful treatment of CML has been accompanied by steady improvements in our capacity to accurately and sensitively monitor therapy response. Currently, measurement of BCR-ABL1 mRNA transcript levels by real-time quantitative PCR (RQ-PCR) defines critical response endpoints. An antibody-based technique for BCR-ABL1 protein recognition could be an attractive alternative to RQ-PCR. To date, there have been no studies evaluating whether flow-cytometry based assays could be of clinical utility in evaluating residual disease in CML patients. Here we describe a flow-cytometry assay that detects the presence of BCR-ABL1 fusion proteins in CML lysates to determine the applicability, reliability, and specificity of this method for both diagnosis and monitoring of CML patients for initial response to therapy. We show that: i) CML can be properly diagnosed at onset, (ii) follow-up assessments show detectable fusion protein (i.e. relative mean fluorescent intensity, rMFI%>1) when BCR-ABL1IS transcripts are between 1-10%, and (iii) rMFI% levels predict CCyR as defined by FISH analysis. Overall, the FCBA assay is a rapid technique, fully translatable to the routine management of CML patients

Elotuzumab plus pomalidomide and dexamethasone in relapsed/refractory multiple myeloma: a multicenter, retrospective real-world experience with 200 cases outside of controlled clinical trials

In the ELOQUENT-3 trial, the combination of elotuzumab, pomalidomide and dexamethasone (EloPd) proved a superior clinical benefit over Pd with a manageable toxicity profile, leading to its approval in relapsed/refractory multiple myeloma (RRMM), who had received at least two prior therapies, including lenalidomide and a proteasome inhibitor (PI). We report here a real-world experience of 200 RRMMs treated with EloPd in 35 Italian centers outside of clinical trials. In our dataset, the median number of prior lines of therapy was 2, with 51% of cases undergoing autologous stem cell transplant (ASCT) and 73% exposed to daratumumab. After a median follow-up of 9 months, 126 patients stopped EloPd, most of them (88.9%) because of disease progression. The overall response rate (ORR) was 55.4%, in line with the pivotal trial results. Regarding adverse events, our cohort experienced a toxicity profile similar to the ELOQUENT-3 trial, with no significant differences between younger (<70 years) and older patients. The median progression-free survival (PFS) was 7 months, shorter than that observed in the ELOQUENT-3, probably due to the different clinical characteristics of the two cohorts. Interestingly, the ISS stage III (HR:2.55) was associated with worse PFS. Finally, our series's median overall survival (OS) was shorter than that observed in the ELOQUENT-3 trial (17.5 versus 29.8 months). In conclusion, our real-world study confirms EloPd as a safe and possible therapeutic choice for RRMM who received at least two prior therapies, including lenalidomide and a PI

Flow and volume response to bronchodilator in patients with COPD

The response to a bronchodilator is considered as crucial to diagnose COPD and to distinguish COPD from asthma. COPD is characterized by progressive airflow obstruction that is only partly reversible, whereas asthma is associated with airflow obstruction that is often reversible either spontaneously or with treatment. In spite of the partly reversible airflow obstruction, patients with COPD may show a significant bronchodilator response both in terms of an increase in forced expiratory volume in 1 second (FEV1) or in forced vital capacity (FVC) after an adequate dose of an inhaled bronchodilator. Changes in FEV1 or FVC characterize, respectively, flow or volume response after bronchodilator administration. This overview will deal with the reversibility testing characteristics and its clinical significance in COPD patients

Legge di Stevino e principio di Archimede

E' descritto un percorso didattico, rivolto a studenti della scuola secondaria di secondo grado e basato su attività sperimentali per la comprensione della legge di Stefino e del principio di Archimed

Prevalence of Small-Airway Dysfunction among COPD Patients with Different GOLD Stages and Its Role in the Impact of Disease

In chronic obstructive pulmonary disease (COPD) patients, small-airway dysfunction (SAD) is considered a functional hallmark of disease. However, the exact role of SAD in the clinical presentation of COPD is not yet completely understood; moreover, it is not known whether SAD may have a relationship with the impact of disease

Heart rate recovery is associated with ventilatory constraints and excess ventilation during exercise in patients with chronic obstructive pulmonary disease

Background: Heart rate recovery delay is a marker of cardiac autonomic dysfunction. In chronic obstructive pulmonary disease patients, the ventilatory response to exercise during incremental cardiopulmonary exercise test may add information about dynamic hyperinflation by low values of inspiratory capacity/total lung capacity ratio (at peak) and excess ventilation by the slope of minute ventilation to carbon dioxide output ratio (VE/VCO2 slope). We aimed to assess if the ventilatory response to exercise might be a determinant for heart rate recovery delay. Design: An observational, prospective study. Methods: Anthropometric characteristics, lung function and cardiopulmonary exercise test data were recorded in chronic obstructive pulmonary disease outpatients. A cut-off of heart rate recovery of 12 or more beats was used to define heart rate recovery delay. Results: Of 254 patients enrolled, 156 (61%) showed heart rate recovery delay. As compared to patients with normal heart rate recovery, patients with delay were older, with a worse lung function and with lower values of peak oxygen uptake, maximal workload, oxygen pulse at rest and at peak, and inspiratory capacity/total lung capacity at peak. Conversely, VE/VCO2 slopeand dyspnoea and leg fatigue perception at peak were higher in patients with heart rate recovery delay. In the multivariate regression model adjusted for age, sex, fat-free mass, heart rate at rest and use of β-blockers, we found that inspiratory capacity/total lung capacity at peak (32) (odds ratio 2.26; P = 0.018) predict the risk of heart rate recovery delay. Conclusions: In chronic obstructive pulmonary disease outpatients, heart rate recovery is associated with dynamic hyperinflation and excess ventilation during exercise

Eltrombopag treatment for severe immune thrombocytopenia during pregnancy: a case report

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia (platelet count <100 × 109/l) in the absence of other causes or disorders associated. The incidence of ITP in pregnancy is one to two cases per 1000 gestations. ITP could be diagnosed before or during pregnancy; sometimes a relapse of a previously diagnosed ITP can occur. Intravenous immune globulins (IVIg) and corticosteroids are the standard frontline therapy because of their well known safety profile either for the mother or for the neonate. Treatments for refractory patients are limited by potential fetal risk. We report the case of a patient with ITP along pregnancy, refractory to corticosteroids and IVIg, successfully treated with, the thrombopoietin receptor agonist (TPO-RA) eltrombopag. Patient received this compound for almost the whole pregnancy and in particular for the whole first trimester, without any complication for the mother and the neonate. Although transient administration of TPO-RAs in pregnancy seems to be well tolerated, their use during the whole gestation is still controversial; this is the reason of the description of this case, which did not show any complications, and thus it could add useful information on this field