Anti-CD20 Therapy Acts via FcγRIIIA to Diminish Responsiveness of Human Natural Killer Cells

Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating FcγRIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies (mAb). In this study, we show that CD16 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK-activating receptors (including NKG2D, DNAM-1, NKp46, and 2B4). Similar effects were obtained from NK cells isolated from patients with chronic lymphocytic leukemia in an autologous setting. NK cells rendered hyporesponsive in this manner were deficient in the ability of these cross-tolerized receptors to phosphorylate effector signaling molecules critical for NK cytotoxicity, including SLP-76, PLCγ2, and Vav1. These effects were associated with long-lasting recruitment of the tyrosine phosphatase SHP-1 to the CD16 receptor complex. Notably, pharmacologic inhibition of SHP-1 with sodium stibogluconate counteracted CD20 mAb-induced NK hyporesponsiveness, unveiling an unrecognized role for CD16 as a bifunctional receptor capable of engendering long-lasting NK cell inhibitory signals. Our work defines a novel mechanism of immune exhaustion induced by CD20 mAb in human NK cells, with potentially negative implications in CD20 mAb-treated patients where NK cells are partly responsible for clinical efficacy. Cancer Res; 75(19); 1-12. ©2015 AACR

War and Food (In)security – A Lesson from the Russian-Ukrainian Conflict

The Russian invasion of Ukraine has implemented legitimate fears of a global crisis and further and inevitably aggravating existing food-security challenges. The international community is being called upon to take targeted action to address the rapidly-evolving, resultant scenarios, making it essential to go beyond immediate interim measures and to re-examine the agricultural and energy policies that underpin our global economy. This article, without any claim to exhaustiveness, examines the inevitable link between war and the dynamics related to food security. In the first instance, a theoretical-interpretative key of the logics of violent conflicts that generate a relevant impact on global food supplies and food (in)security is provided, within the broader framework of the dynamics related to the instability of international relations which hinder the supply of energy resources and determine the volatility of general price levels. In the concluding section, there is refl ection crossed reference to the ongoing Russia/Ukraine conflict as well as the devastating consequences on global food systems, already put under stress by the COVID-19 pandemic

Onset and Progression of Precancerous Lesions on Gastric Mucosa of Patients Treated for Gastric Lymphoma.

Background and Aims: Patients with primary gastric lymphoma are at an increased risk of developing gastric cancer. Data on gastric precancerous lesions development in these patients are scanty. We assessed gastric precancerous lesions in a cohort of patients with primary lymphoma. Methods: Data of patients with primary gastric lymphoma [mucosa-associated lymphoid tissue (MALT)- lymphoma or diffuse large B-cell lymphoma (DLBCL)] were analysed. Multiple (>10) biopsies were performed on gastric mucosa at each endoscopic control, beyond macroscopic lesions. Presence and distribution of intestinal metaplasia (IM) at baseline, the onset at follow-up, and progression through the stomach or transformation in the incomplete IM type were assessed. The onset of neoplastic lesions was recorded. Results: Data of 50 patients (mean age of 63.6 ± 10.7 years; M/F: 25/25), including 40 with MALT-lymphoma and 10 with DLBCL, with median follow-up of 30.5 months (range: 9-108) and a median of 6 endoscopic controls (range: 3-14) were evaluated. At entry, IM was present in 12 (24%), and it developed in other 22 (57.9%) patients at a median follow-up of 6 (range: 3-40) months. Overall, progression of IM was observed in 7 (21.2%) cases, including extension in the stomach (n=5) or transformation into the incomplete type (n=2). Low-grade dysplasia was detected in 4, and indefinite dysplasia in other 7 patients. In one patient, low-grade dysplasia had progressed to high-grade and gastric adenocarcinoma of the fundus. Conclusions: Our data found a frequent onset and rapid progression of precancerous lesions on gastric mucosa of lymphoma patients. This observation could explain the increased incidence of metachronous gastric cancer in these patients

Early progression as a predictor of survival in marginal zone lymphomas: An analysis from the FIL-NF10 study

Marginal zone lymphomas (MZLs) are indolent nonfollicular B-cell lymphomas (INFLs) and have heterogeneous clinical behavior. Recently, time to progression of disease at 24 months (POD24) was identified to stratify overall survival (OS) in follicular non-Hodgkin lymphoma and in INFL. Here, we examined the ability of POD24 to predict subsequent OS in a large, international cohort of MZL as part of the NF10 prospective international registry headed by Fondazione Italiana Linfomi (FIL). POD24 was only calculated for MZL patients requiring immediate therapy and was defined as experiencing lymphoma progression within 24 months from diagnosis. Among the 1325 patients enrolled in the NF10 study, we identified 321 patients with MZL for whom immediate therapy was planned right after lymphoma diagnosis. Overall, POD24 was confirmed in 59 patients (18%). Three-year OS for patients with POD24 was 53% with a hazard ratio of 19.5 (95% confidence interval, 8.4-45) compared with patients without POD24 (3-year OS, 95%). Association of POD24 with OS was confirmed for the subgroup of splenic and extranodal MZLs. Assessment of POD24 stratifies subsequent outcome inMZL and identifies a high-risk population

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

The Gaia mission

Gaia is a cornerstone mission in the science programme of the EuropeanSpace Agency (ESA). The spacecraft construction was approved in 2006, following a study in which the original interferometric concept was changed to a direct-imaging approach. Both the spacecraft and the payload were built by European industry. The involvement of the scientific community focusses on data processing for which the international Gaia Data Processing and Analysis Consortium (DPAC) was selected in 2007. Gaia was launched on 19 December 2013 and arrived at its operating point, the second Lagrange point of the Sun-Earth-Moon system, a few weeks later. The commissioning of the spacecraft and payload was completed on 19 July 2014. The nominal five-year mission started with four weeks of special, ecliptic-pole scanning and subsequently transferred into full-sky scanning mode. We recall the scientific goals of Gaia and give a description of the as-built spacecraft that is currently (mid-2016) being operated to achieve these goals. We pay special attention to the payload module, the performance of which is closely related to the scientific performance of the mission. We provide a summary of the commissioning activities and findings, followed by a description of the routine operational mode. We summarise scientific performance estimates on the basis of in-orbit operations. Several intermediate Gaia data releases are planned and the data can be retrieved from the Gaia Archive, which is available through the Gaia home page. http://www.cosmos.esa.int/gai

War and Food (In)security – A Lesson from the Russian-Ukrainian Conflict

The Russian invasion of Ukraine has implemented legitimate fears of a global crisis and further and inevitably aggravating existing food-security challenges. The international community is being called upon to take targeted action to address the rapidly-evolving, resultant scenarios, making it essential to go beyond immediate interim measures and to re-examine the agricultural and energy policies that underpin our global economy. This article, without any claim to exhaustiveness, examines the inevitable link between war and the dynamics related to food security. In the first instance, a theoretical-interpretative key of the logics of violent conflicts that generate a relevant impact on global food supplies and food (in)security is provided, within the broader framework of the dynamics related to the instability of international relations which hinder the supply of energy resources and determine the volatility of general price levels. In the concluding section, there is reflection crossed reference to the ongoing Russia/Ukraine conflict as well as the devastating consequences on global food systems, already put under stress by the COVID-19 pandemic