Search

Multiple myeloma (MM) is characterized by multiple relapse and, despite the introduction of novel therapies, the disease becomes ultimately drug-resistant. The tumor microenvironment (TME) within the bone marrow niche includes dendritic cells, T-cytotoxic, T-helper, reactive B-lymphoid cells and macrophages, with a complex cross-talk between these cells and the MM tumor cells. Tumor-associated macrophages (TAM) have an important role in the MM pathogenesis, since they could promote plasma cells proliferation and angiogenesis, further supporting MM immune evasion and progression. TAM are polarized towards M1 (classically activated, antitumor activity) and M2 (alternatively activated, pro-tumor activity) subtypes. Many studies demonstrated a correlation between TAM, disease progression, drug-resistance and reduced survival in lymphoproliferative neoplasms, including MM. MM plasma cells in vitro could favor an M2 TAM polarization. Moreover, a possible correlation between the pro-tumor effect of M2 TAM and a reduced sensitivity to proteasome inhibitors and immunomodulatory drugs was hypothesized. Several clinical studies confirmed CD68/CD163 double-positive M2 TAM were associated with increased microvessel density, chemoresistance and reduced survival, independently of the MM stage. This review provided an overview of the biology and clinical relevance of TAM in MM, as well as a comprehensive evaluation of a potential TAM-targeted immunotherapy.

Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR.Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation.Results: After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss.Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of “fluctuating” values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs “burden” playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs’ ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.

Acquired factor XIII (FXIII) deficiency is an extremely rare and potentially fatal bleeding disorder. Immune-mediated FXIII deficiency is due to the development of anti-FXIII autoantibodies which may develop with concomitant conditions that cause immune dysregulation such as malignancies or autoimmune disorders. Clinical presentation includes delayed post-operative bleeding or spontaneous soft tissue hematomas and/or cerebral bleeding. Since screening coagulation laboratory tests (prothrombin time, activated partial thromboplastin time, and fibrinogen) are typically normal, acquired FXIII deficiency is likely to be overlooked and underdiagnosed. The management of immune-mediated FXIII deficiency is based on hemostatic therapy, autoantibody removal and eradication of the underlying etiology; however, no treatment guidelines are still available. Here we report a case of acquired FXIII deficiency associated with plasmablastic lymphoma, in order to raise awareness of this rare bleeding disorder and consent prompt life-saving management.

Vaccination against SARS-CoV-2 using mRNA-based vaccines has been highly recommended for fragile subjects, including myelofibrosis patients (MF). Available data on the immune responsiveness of MF patients to mRNA SARS-CoV-2 vaccination, and the impact of the therapy with the JAK inhibitor ruxolitinib, are still fragmented. Here, we profile the spike-specific IgG and memory B-cell response in MF patients, treated or not with ruxolitinib, after the second and the third dose of SARS-CoV-2 BNT162b2 (BioNTech) and mRNA-1273 (Moderna) vaccines. Plasma and peripheral blood mononuclear cells samples were collected before vaccination, post the second and the third doses and tested for spike-specific antibodies, ACE2/RBD antibody inhibition binding activity and spike-specific B cells. The third vaccine dose significantly increased the spike-specific IgG titers in both ruxolitinib-treated and untreated patients, and strongly enhanced the percentage of subjects with antibodies capable of in vitro blocking ACE2/RBD interaction, from 50% up to 80%. While a very low frequency of spike-specific B cells was measured in blood 7 days after the second vaccination dose, a strong and significant increase was elicited by the third dose administration, generating a B cell response similar to the one detected in healthy controls. Despite the overall positive impact of the third dose in MF patients, two patients that were under active concomitant immunosuppressive treatment at the time of vaccination, and a patient that received lymphodepleting therapies in the past, remained low responders. The third mRNA vaccine dose strongly increases the SARS-CoV-2 specific humoral and B cell responses in MF patients, promoting a reactivation of the immune response similar to the one observed in healthy controls.

Tyrosine kinase inhibitors (TKI) may offer a normal life expectancy to Chronic Myeloid Leukemia (CML) patients. However, a higher than expected incidence of arterial occlusive events (AOEs) was observed during treatment with nilotinib. We previously showed an “inflammatory status” during nilotinib that may explain the increased incidence of AOEs. Thus, we conducted this prospective KIARO study involving 186 CML patients (89 imatinib, 59 nilotinib, 38 dasatinib). Interleukin 6 (IL6), interleukin 10 (IL10), Tumor Necrosis Factor-α (TNFα), oxLDL, and high-sensitivity C-reactive protein (hs-CRP) plasma levels were measured at diagnosis and during treatment, with the aim to investigate changes in the inflammatory status favoring AOEs of each patient. Clinical and biochemical pro-atherothrombotic profiles and the 10-year SCORE chart were also evaluated. We showed a pro-inflammatory/pro-oxidative milieu increasing along treatment with nilotinib compared with imatinib or dasatinib, as demonstrated by higher hs-CRP and oxLDL levels and increased IL6/IL10 and TNFα/IL10 ratios only in nilotinib cohort. After median follow-up of 23.3 months starting from TKI, 10/186 patients (5.4%) suffered an AOE. Approximately 5/10 (50%) AOEs occurred during nilotinib treatment despite a lower 10-year SCORE and a lower median age in this subgroup. A longer follow-up is needed to further confirm the active role of nilotinib in AOEs pathogenesis.

Abstract A case of an early‐relapsed high‐risk T‐ALL with high BCL‐2 expression on leukemic blasts was successfully treated with decitabine and venetoclax, achieving a CR. We suggest decitabine and venetoclax should be synergistic in BCL2‐positive ALL.

The paper aims to investigate the possibilities of using the panorama-based VR to survey data related to that set of activities for planning and management of urban areas, belonging to the Smart Cities strategies. The core of our workflow is to facilitate the visualization of the data produced by the infrastructures of the Smart Cities. A graphical interface based on spherical panoramas, instead of complex three-dimensional could help the user/citizen of the city to better know the operation related to control units spread in the urban area. From a methodological point of view three different kind of spherical panorama acquisition has been tested and compared in order to identify a semi-automatic procedure for locating homologous points on two or more spherical images starting from a point cloud obtained from the same images. The points thus identified allow to quickly identify the same hot-spot on multiple images simultaneously. The comparison shows how all three systems have proved to be useful for the purposes of the research but only one has proved to be reliable from a geometric point of view to identify the locators useful for the construction of the virtual tour.

Multiple myeloma survival has significantly improved in recent years, due to novel agents that are available for treatment. The anti-CD38 monoclonal antibody Daratumumab is particularly efficient for patients with relapse/refractory disease, and many studies have shown its unprecedented efficacy also as a first treatment. However, to avoid the incidence of infusion reactions, long infusion schedules of 8 h at first dose and 4 h in the following doses are required, which can reduce the compliance of patients and health care professionals. A reduced infusion time of 90 min has been reported previously, but data are missing on the prolonged safety of this over time as well as the efficacy of this approach. In this work, we investigate the safety of 484 rapid Daratumumab infusions given early after the second dose over a 22 months period in 39 myeloma patients.

Background: Several cardiopulmonary exercise test (CPET) parameters (peak VO2, PetCO2 and VE/VCO2) emerged as tools for the prediction of pulmonary arterial hypertension (PAH). Less is known on ventilatory power (VP) in patients with suspect PAH. Aim: To ascertain possible correlations between VP derived at CPET and hemodynamic parameters at right heart catheterization (RHC) indicative of PH. Methods: Forty-seven consecutive outpatients with suspect of PAH were assessed by CPET and RHC; VP was defined as peak SBP divided by the minute ventilation-CO2 production slope at CPET and Diastolic Pressure Gradient (DPG), Trans-pulmonary Pressure Gradient (TPG), mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) at RHC were also assessed and compared with VP. Results: VP values were inversely related to mPAP (r −0.427, p 0.003), DPG (r −0.36, p 0.019), TPG (r: −0.43, p 0.004), and PVR (r −0.52, p 0.001). Correlations remained significant even after correction at multivariate analysis for age and gender. VP values below median identified subjects with mPAP ≥ 25 mmHg with an odds ratio of 4.5 (95% confidence interval 1.05–19.36, p

The heterogeneity of the formats and standards of clinical data, which includes both structured, semi-structured, and unstructured data, in addition to the sensitive information contained in them, require the definition of specific approaches that are able to implement methodologies that can permit the extraction of valuable information buried under such data. Although many challenges and issues that have not been fully addressed still exist when this information must be processed and used for further purposes, the most recent techniques based on machine learning and big data analytics can support the information extraction process for the secondary use of clinical data. In particular, these techniques can facilitate the transformation of heterogeneous data into a common standard format. Moreover, they can also be exploited to define anonymization or pseudonymization approaches, respecting the privacy requirements stated in the General Data Protection Regulation, Health Insurance Portability and Accountability Act and other national and regional laws. In fact, compliance with these laws requires that only de-identified clinical and personal data can be processed for secondary analyses, in particular when data is shared or exchanged across different institutions. This work proposes a modular architecture capable of collecting clinical data from heterogeneous sources and transforming them into useful data for secondary uses, such as research, governance, and medical education purposes. The proposed architecture is able to exploit appropriate modules and algorithms, carry out transformations (pseudonymization and standardization) required to use data for the second purposes, as well as provide efficient tools to facilitate the retrieval and analysis processes. Preliminary experimental tests show good accuracy in terms of quantitative evaluations.

Background: We have designed a prospective study aiming to monitor the immune response in 178 health care workers six months after BNT162b2 mRNA vaccination. Methods: The humoral immune response of all subjects was evaluated by chemiluminescence (CMIA); in 60 serum samples, a live virus-based neutralization assay was also tested. Moreover, 6 months after vaccination, B- and T-cell subsets from 20 subjects were observed by FACS analysis after restimulation with the trimeric SARS-CoV-2 Spike protein as an antigen, thus mimicking reinfection in vitro. Results: A significant decrease of circulating IgG levels and neutralizing antibodies over time were observed. Moreover, six months after vaccination, a variable T-cell immune response after in vitro antigen stimulation of PBMC was observed. On the contrary, the analysis of B-cell response showed a shift from unswitched to switched memory B-cells and an increase of Th17 cells. Conclusions: Although the variability of the CD4+ and CD8+ immune response and an antibody decline was observed among vaccinated subjects, the increase of switched memory B-cells and Th17 cells, correlating with the presence of neutralizing antibodies, opened the debate on the correct timing of vaccination.

Immunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile subjects, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients and the impact of ruxolitinib treatment are still too fragmented to support an informed decision on a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second mRNA SARS-CoV-2 vaccine dose, but the response has a slower kinetics compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD binding inhibition activity of spike-specific antibodies was also observed, especially in ruxolitinib-treated patients. Our results, showing slow kinetics of antibody responses in MF patients following vaccination with mRNA SARS-CoV-2 vaccines, support the need for a third vaccine dose.