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In order to evaluate the predictive value of positron emission tomography–computed tomography (PET/CT) in discriminating the presence of a Richter’s syndrome (RS) or a second malignancy (SM), as well as to evaluate its prognostic value in patients with chronic lymphocytic leukemia (CLL), we retrospectively analyzed the data of 90 patients who, in the suspicion of a RS or a SM, underwent PET/CT followed by the biopsy of the involved tissue. The median maximum Standardized Uptake Value (SUV max ) in the presence of a CLL/small lymphocytic lymphoma, a diffuse large B-cell lymphoma (DLBCL), a Hodgkin lymphoma (HL), a SM were 3.5, 14.6, 7.0 and 6.3, respectively ( P ⩽0.0001). A SUV max cutoff value ⩾5 showed a sensitivity, specificity, positive and negative predictive values of 88.2, 71.2, 51.3 and 94%, respectively, for the presence of a more aggressive disease (DLBCL, HL and SM). A SUV max ⩾5 identified also a subset of treatment naive patients with an inferior progression-free survival ( P =0.011) and overall survival ( P =0.067). These findings suggest that PET/CT may helpfully integrate the biologically-based prognostic stratification of CLL. Prospective clinical trials including larger cohorts of patients are needed to conclusively define the role and prognostic impact of PET/CT in the routine management of CLL patients.

Recognition of biased immunoglobulin variable (IgV) gene usage in B-cell chronic lymphocytic leukemia (B-CLL) may yield insight into leukemogenesis and may help to refine prognostic categories. We explored Ig variable heavy (V H ) and light (V L ) chain gene usage in highly stable and indolent B-CLL ( n =25) who never required treatment over 10 or more years. We observed an unexpectedly high usage of mutated V H 3-72 (6/25; 24.0%), a gene that was otherwise rare in B-CLL (7/805; 0.87%; P <0.01), including mutated cases (6/432; 1.39%; P <0.01) and was exceptional among indolent (1/230, 0.435%; P <0.01), and aggressive B-cell lymphomas (0/105; P <0.01). Three of six V H 3-72 B-CLL cases utilized the same V L V κ 4-1 gene. Two V H 3-72 B-CLL cases had highly homologous V H complementarity determining regions 3 (CDR3s), encoding Cys-XXXX-Cys domains, and utilized V κ 4-1 genes with homologous IgV L CDR3s. An identical threonine to isoleucine change at codon 84 of V H 3-72 framework region 3 (FR3) recurred in four cases of highly stable V H 3-72 B-CLL. This mutation is expected to cause a conformational change of FR3 proximal to CDR3 that might critically affect high-affinity antigen binding. B-cell receptors encoded by V H 3-72 may identify a specific B-CLL group and be implicated in leukemogenesis through an antigen-driven expansion of B cells.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m 2 ) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57–84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0–95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9–68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ⩾3 neutropenia was observed in 61.7% of patients; however, grade ⩾3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.

BackgroundErythrocytes (RBCs) are highly sensitive cells constantly exposed to several stress stimuli including inflammatory mediators. Despite the absence of nuclei and the lack of crucial elements in the machinery of apoptosis, they have developed a rapid self-destruction process called eryptosis. During this process the externalization of phosphatidylserine (PS) activates the correct elimination of erythrocytes by phagocytes preventing inflammation and intravascular hemolysis. It has been recently demonstrated that PS-exposing erythrocytes are able to adhere to endothelial cells causing an impairment of circulation,1 suggesting a possible involvement of eryptosis in the increased risk of thrombotic episodes typical of antiphospholipid syndrome (APS).ObjectivesEnhanced eryptosis is known to contribute to several pathological conditions but the role of this process in APS has not been investigated yet. For this reason, we evaluated the effect of antibodies (Abs) purified from APS patients and healthy subjects positive for antiphospolipid antibodies without clinical manifestations (aPL carriers) on eryptosis activation. Moreover, spontaneous eryptosis levels in APS, aPL carriers, autoimmune haemolytic anaemia (AIHA) and healthy donors (HD) were analyzed.Methods30 patients with primary APS (M/F 7/23, mean age 50.5±8.2 years), 17 aPL carriers (M/F 4/13, mean age 48.6±8.3 years) were recruited after written informed consent. Moreover 13 AIHA patients and 17 HD were also enrolled as positive and negative control group respectively. Ammonium sulfate precipitation is used to purify Abs from sera of APS and aPL carriers subjects. RBCs, isolated from whole blood by centrifugation, were incubated with APS and aPL carriers Abs at concentration of 20ug/mL and after 4 hours the percentage of annexin V-positive cells (PS-exposing cells) was analyzed by flow cytometry. The same technique was used to estimate spontaneous eryptosis levels in all cohorts studied.ResultsIn vitro Abs from APS induced eryptosis in RBCs isolated from HD after 4 hours of culture compared to untreated and RBCs stimulated with Intravenous Immunoglobulins (IVIG), both p= 0.02. On the contrary, Abs from aPL carriers had no effect on the percentage of PS-exposing RBCs (figure 1). Ex vivo, APS patients showed higher levels of spontaneous eryptosis compared to HD (p=0.001). As expected, eryptosis was upregulated in AIHA patients compared to all populations studied (p<0.0001). Interestingly, the percentage of annexin V- positive RBCs was lower in aPL carriers respect to APS patients (p=0.001). No significant correlation between eryptosis and clinical parameters was found.Abstract AB0163 – Figure 1ConclusionsIn this study we demonstrated a new aspect of APS pathogenesis based on the capacity of Abs isolated from APS patients, and not those from aPL carriers, to stimulate eryptosis suggesting a possible contribution of this process in APS clinical manifestations.Reference[1] Borst O, Abed M, Alesutan I, et al. Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX. Am J Physiol Cell Physiol 2012;302:C644–51.Disclosure of InterestNone declared

B cell chronic lymphocytic leukaemia (CLL) shows evidence of familial aggregation, but the inherited basis is poorly understood. Mutations in the ATM gene have been demonstrated in CLL. This, coupled with a possibly increased risk of leukaemia in relatives of patients with Ataxia Telangiectasia, led us to question whether the ATM gene is involved in familial cases of CLL. To examine this proposition we typed five markers on chromosome 11q in 24 CLL families. No evidence for linkage between CLL and ATM in the 24 families studied and the best estimates of the proportion of sibling pairs that share no, one or both haplotypes at ATM were not different from their null expectations. This would imply that ATM is unlikely to make a significant contribution to the three-fold increase in risk of CLL seen in relatives of patients.

BackgroundErythrocytes (RBCs) hold a crucial role in hemostasis and their integrity is influenced by different stimuli including circulating inflammatory mediators. Even though RBCs do not have nuclei and mitochondria, they have developed a process allowing them to undergo a rapid self-destruction named eryptosis. The exact mechanism of erythrocytes cell death is not fully clarified yet but it seems to involve Ca2+ and ceramide formation, leading to cell shrinkage and externalization of phosphatidylserine (PS) (1). Interaction between platelets and erythrocytes could participate in an increasing risk of thrombotic episodes typical of several diseases including antiphospholipid syndrome (APS). In fact, not only signals triggering eryptosis are involved in thrombosis activation, but also recent studies have demonstrated how PS-exposing erythrocytes are able to adhere to the vascular wall causing an impairment of circulation (2,3).ObjectivesEnhanced eryptosis is known to contribute to several pathological conditions (1) but the involvement of this process in APS has not been investigated yet. For this reason the aim of the study was to evaluate eryptosis levels in APS, healthy subjects positive for antiphospolipid antibodies without clinical manifestations (aPL carriers), autoimmune haemolytic anaemia (AIHA) and healthy donors (HD).Methods27 patients with primary APS (M/F 5/22, mean age 51.1±7.6 years), 14 aPL carriers (M/F 3/11, mean age 48.9±8.4 years) were recruited after written informed consent. Moreover 10 AIHA patients and 12 HD were also enrolled as positive and negative control group respectively. RBCs were isolated from whole blood after centrifugation and eryptosis levels were analysed by flow cytometry, evaluating the percentage of annexin V-positive cells (PS-exposing cells). Flow cytometry was also use to estimated cellular volume from forward scatter (FSC).ResultsAPS patients showed higher levels of eryptosis compared to HD (p=0.01). Interestingly, the percentage of annexin V-positive RBCs was lower in aPL carriers respect to APS patients (p=0.001). Moreover, an inverse correlation between RBCs volume and eryptosis was found in APS patients (r=-0.4, p=0.03). No clinical correlation between eryptosis and clinical manifestations were noticed. As expected, eryptosis was upregulated in AIHA patients compared to all populations studied (p<0.0001).ConclusionsOur study provides for the first time evidence of eryptosis enhancement in APS patients suggesting a possible contribution of RBCs apoptosis in the pathogenesis of the disease.References Lang E, Lang F. Triggers, inhibitors, mechanisms, and significance of eryptosis: the suicidal erythrocyte death. Biomed Res Int. 2015;2015:513518.Borst O, Abed M, Alesutan I, Towhid ST, Qadri SM, Foller M, Gawaz M, Lang F. Dynamic adhesion of eryptotic erythrocytes to endothelial cells via CXCL16/SR-PSOX. Am J Physiol Cell Physiol. 2012;302:C644-C651.Pretorius E, du Plooy JN, Bester J. A Comprehensive Review on Eryptosis. Cell Physiol Biochem. 2016;39:1977–2000. Disclosure of InterestNone declared