Immunoglobulin light chain mutational status refines IGHV prognostic value in identifying chronic lymphocytic leukemia patients with early treatment requirement.

The mutational status of immunoglobulin (IG) light chain genes in chronic lymphocytic leukemia (CLL) and its clinical impact have not been extensively studied. To assess their prognostic significance, the IG light chain gene repertoire in CLL patients has been evaluated using a training-validation approach. In the training cohort (N = 573 CLL), 92.

The macroecology of Mesozoic dinosaurs.

Dinosaurs thrived for over 160 million years in Mesozoic ecosystems, displaying diverse ecological and evolutionary adaptations. Their ecology was shaped by large-scale climatic and biogeographic changes, calling for a 'deep-time' macroecological investigation. These factors include temperature fluctuations and the break up of Pangaea, influencing species richness, ecological diversity and biogeographic history.

A brief review of non-avian dinosaur biogeography: state-of-the-art and prospectus.

Dinosaurs potentially originated in the mid-palaeolatitudes of Gondwana 245-235 million years ago (Ma) and may have been restricted to cooler, humid areas by low-latitude arid zones until climatic amelioration made northern dispersals feasible 215 Ma. However, this scenario is challenged by new Carnian Laurasian fossils and evidence that even the earliest dinosaurs had adaptations for arid conditions. After becoming globally distributed in the Early-Middle Jurassic (200-160 Ma), dinosaurs experienced vicariance driven by Pangaean fragmentation.

Cranial anatomy of Acynodon adriaticus and extreme durophagous adaptations in Eusuchia (Reptilia: Crocodylomorpha).

Acynodon adriaticus, a small eusuchian from the Late Cretaceous of Italy, is known for its well-preserved cranial and postcranial material. Despite its excellent preservation, many details remain hidden due to the physical overlap between the elements and matrix obliteration. We used Micro-CT scans to reveal previously overlooked anatomical features and describe in detail the cranial and dental anatomy of this taxon, shedding new light on its palaeoecology.

The VLA-4 integrin is constitutively active in circulating chronic lymphocytic leukemia cells via BCR autonomous signaling: a novel anchor-independent mechanism exploiting soluble blood-borne ligands.

In chronic lymphocytic leukemia (CLL), survival of neoplastic cells depends on microenvironmental signals at lymphoid sites where the crosstalk between the integrin VLA-4 (CD49d/CD29), expressed in ~40% of CLL, and the B-cell receptor (BCR) occurs. Here, BCR engagement inside-out activates VLA-4, thus enhancing VLA-4-mediated adhesion of CLL cells, which in turn obtain pro-survival signals from the surrounding microenvironment. We report that the BCR is also able to effectively inside-out activate the VLA-4 integrin in circulating CD49d-expressing CLL cells through an autonomous antigen-independent BCR signaling.

Exposure to obinutuzumab does not affect outcomes of SARS-CoV-2 infection in vaccinated patients with newly diagnosed advanced-stage follicular lymphoma.

URBAN is a multicentric, ambispective study evaluating the effectiveness and safety of obinutuzumab-based immuno-chemotherapy and maintenance in patients with untreated advanced follicular lymphoma (FL). The study began before the COVID-19 emergency declaration in Italy. It is currently ongoing for follow-up, and the enrolment timeline encompassed different stages of the pandemic, various vaccination roll-out phases and prevalence of SARS-CoV-2 variants.

Early reappearance of intraclonal proliferative subpopulations in ibrutinib-resistant chronic lymphocytic leukemia.

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4/CD5 proliferative fraction (PF), its correlation with therapeutic outcome and emergence of ibrutinib resistance. By longitudinal tracking, the PF, initially suppressed by ibrutinib, reappeared upon early disease progression, without association with lymphocyte count or serum beta-2-microglobulin.

End of induction [F]FDG PET is prognostic for progression-free survival and overall survival in follicular lymphoma patients enrolled in the FOLL12 trial.

Purpose: To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [F]FDG PET (PET) in follicular lymphoma patients.

Methods: Adult patients with untreated grade 1-3a FL/ stage II-IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post-induction management (experimental arm). Baseline and EOI PET were mandatory for the study.

Early Jurassic origin of avian endothermy and thermophysiological diversity in dinosaurs.

A fundamental question in dinosaur evolution is how they adapted to long-term climatic shifts during the Mesozoic and when they developed environmentally independent, avian-style acclimatization, becoming endothermic. The ability of warm-blooded dinosaurs to flourish in harsher environments, including cold, high-latitude regions, raises intriguing questions about the origins of key innovations shared with modern birds, indicating that the development of homeothermy (keeping constant body temperature) and endothermy (generating body heat) played a crucial role in their ecological diversification. Despite substantial evidence across scientific disciplines (anatomy, reproduction, energetics, biomechanics, osteohistology, palaeobiogeography, geochemistry, and soft tissues), a consensus on dinosaur thermophysiology remains elusive.

Monocyte-to-platelets ratio (MPR) at diagnosis is associated with inferior progression-free survival in patients with mantle cell lymphoma: a multi-center real-life survey.

Mantle cell lymphoma (MCL) pathogenesis is strongly related to the role of the tumor immune microenvironment (TIME) in which MCL cells proliferate. TIME cells can produce growth signals influencing MCL cells' survival and exert an antitumoral immune response suppression. The activity of TIME cells might be mirrored by some ratios of peripheral blood cell subpopulations, such as the monocyte-to-platelet ratio (MPR).

Innovative Combinations, Cellular Therapies and Bispecific Antibodies for Chronic Lymphocytic Leukemia: A Narrative Review.

In the last few years, several agents targeting molecules that sustain the survival and the proliferation of chronic lymphocytic leukemia (CLL) cells have become clinically available. Most of these drugs target surface proteins, such as CD19 or CD20, via monoclonal or bispecific monoclonal antibodies (BsAbs), CAR T cells, intracellular proteins like BTK by using covalent or non-covalent inhibitors or BCL2 with first or second generation BH3-mimetics. Since the management of CLL is evolving quickly, in this review we highlighted the most important innovative treatments including novel double and triple combination therapies, CAR T cells and BsAbs for CLL.

Real-World Outcome of Treatment with Single-Agent Ibrutinib in Italian Patients with Chronic Lymphocytic Leukemia: Final Results of the EVIdeNCE Study.

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, = 118), 2L ( = 127) and ≥3L ( = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.

NFKBIE mutations are selected by the tumor microenvironment and contribute to immune escape in chronic lymphocytic leukemia.

Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL.

Baseline IgM Amounts Can Identify Patients with Poor Outcomes: Results from a Real-Life Single-Center Study on Classical Hodgkin Lymphoma.

Hodgkin Lymphoma (HL) is characterized by an inflammatory background in which the reactive myeloid cells may exert an immune-suppressive effect related to the progression of the disease. Immunoglobulin M is the first antibody isotype produced during an immune response, which also plays an immunoregulatory role. Therefore, we investigated if, as a surrogate of defective B cell function, it could have any clinical impact on prognosis.

Ibrutinib as first line therapy in chronic lymphocytic leukemia patients over 80 years old: A retrospective real-life multicenter Italian cohort.

Although chronic lymphocytic leukemia (CLL) predominantly affects the elderly, limited data exists about the outcomes of over 80-year-old patients, usually underrepresented in clinical trials. We conducted a multicenter study enrolling 79 consecutive CLL patients ≥80 years at the time of frontline therapy, all treated with ibrutinib. Nearly 48% of cases exhibited unmutated IGHV genes, 32% 17p deletion, and 39.

Patients' preferences for chronic lymphocytic leukemia treatment: The CHOICE study.

Chronic lymphocytic leukemia (CLL) therapies differ in efficacy, side effects, route, frequency, and duration of administration. We assessed patient preferences for treatment attributes and evaluated associations with disease stage, treatment line, and socio-demographic characteristics in a cross sectional, observational study conducted at 16 Italian hematology centers. Study visits occurred between February and July 2020; 401 adult patients with CLL (201 Watch and Wait (W&W), 200 treated) participated in a discrete choice experiment (DCE), composed of 8 choices between pairs of treatment profiles with different levels of 5 attributes of currently available CLL treatments (length of response, route and duration of administration, risk of side effects including diarrhea, infections, or organ damage).

Efficacy and safety of tixagevimab-cilgavimab versus SARS-CoV-2 breakthrough infection in the hematological conditions.

Background: Managing SARS-CoV-2 infection in frail and immunosuppressed patients still represents an open challenge, but, starting from the phase 3 PROVENT study, prophylaxis with tixagevimab-cilgavimab has improved the approach in this category of patients, guaranteeing a better outcome and inferior mortality. Real-life data in a heterogeneous cohort are few.

Methods: The aim of this study is to evaluate the benefit of prophylaxis with tixagevimab-cilgavimab in a cohort of 202 patients affected by different hematological diseases (lymphoproliferative, myeloproliferative, autoimmune, patients recently receiving a bone marrow transplant), active (with ongoing treatment), or in watch-and-wait strategy, followed in our center, during a median follow-up of 249 (45-325) days.

100 million years of turtle paleoniche dynamics enable the prediction of latitudinal range shifts in a warming world.

Past responses to environmental change provide vital baseline data for estimating the potential resilience of extant taxa to future change. Here, we investigate the latitudinal range contraction that terrestrial and freshwater turtles (Testudinata) experienced from the Late Cretaceous to the Paleogene (100.5-23.

Shifts in food webs and niche stability shaped survivorship and extinction at the end-Cretaceous.

It has long been debated why groups such as non-avian dinosaurs became extinct whereas mammals and other lineages survived the Cretaceous/Paleogene mass extinction 66 million years ago. We used Markov networks, ecological niche partitioning, and Earth System models to reconstruct North American food webs and simulate ecospace occupancy before and after the extinction event. We find a shift in latest Cretaceous dinosaur faunas, as medium-sized species counterbalanced a loss of megaherbivores, but dinosaur niches were otherwise stable and static, potentially contributing to their demise.