Exploring the prognostic role of complex karyotype in chronic lymphocytic leukaemia patients treated with venetoclax-based regimens.

Although the unfavourable prognostic role of complex karyotype (CK) in chronic lymphocytic leukaemia (CLL) patients treated with chemoimmunotherapy has been clarified, its impact on the outcome of patients being treated with novel targeted agents, and especially with venetoclax-based regimens, remains to be resolved. In fact, only few studies, utilizing data derived from clinical trials (e.g. MURANO, CLL14, GAIA-CLL13), specifically focus on this topic while real-word evidence is missing. In our real-life retrospective study conducted on 61 patients with CLL and treated with venetoclax-based regimens in any therapeutic line, we documented a remarkable lower progression-free survival in patients harbouring both CK and high CK, while overall response rate (including complete remissions and partial remissions) and overall survival are not affected by CK in our population.

Decoherence and Momentum Relaxation in Fermi-Polaron Rabi Dynamics: A Kinetic Equation Approach.

Despite the paradigmatic nature of the Fermi-polaron model, the theoretical description of its nonlinear dynamics poses challenges. Here, we apply a quantum kinetic theory of driven polarons to recent experiments with ultracold atoms, where Rabi oscillations between a Fermi-polaron state and a noninteracting level were reported. The resulting equations separate decoherence from momentum relaxation, with the corresponding rates showing a different dependence on microscopic scattering processes and quasiparticle properties. We describe both the polaron ground state and the excited repulsive-polaron state and we find a good quantitative agreement between our predictions and the available experimental data without any fitting parameter. Our approach not only takes into account collisional phenomena, but also it can be used to study the different roles played by decoherence and the collisional integral in the strongly interacting highly imbalanced mixture of Fermi gases.

Impact of the presence and number of chromosomal abnormalities on the clinical outcome in Waldenström Macroglobulinemia: a monocentric experience.

The prognostic and predictive role of specific gene mutations in Waldenström Macroglobulinemia (WM) is well-ascertained whereas the clinical impact of chromosome aberrations is far less known. Recent work has provided initial evidence for an adverse prognostic impact of some aberrations, such as del(6q), while other studies suggest a possible relationship between some clinical features (e.g. advanced age and/or inflammatory status) and specific cytogenetic abnormalities. To add to the still limited knowledge on WM cytogenetics and its clinical implications, we herein report our experience in a cohort of WM patients across 23 years. Based on our retrospective study, we found that abnormal karyotype was more represented in older patients and maintained a statistically significant independence from other molecular, clinical, and biological features related to WM. The presence and number of cytogenetic aberrations correlated with inferior overall and progression-free survival outcomes regardless of the type of single chromosome aberration. Our data suggests that the role of the altered karyotype deserves to be further clarified especially in elderly WM patients, in whom cytogenetic abnormalities and disease biology appear to be characterized by a higher degree of complexity.

Effective diffusion along the backbone of combs with finite-span 1D and 2D fingers.

Diffusion in complex heterogeneous media, such as biological tissues or porous materials, typically involves constrained displacements in tortuous structures and sticky environments. Therefore, diffusing particles experience both entropic (excluded-volume) forces and the presence of complex energy landscapes. In this situation, one may describe transport through an effective diffusion coefficient. In this paper, we examine comb structures with finite-length 1D and finite-area 2D fingers, which act as purely diffusive traps. We find that there exists a critical width of 2D fingers, above which the effective diffusion along the backbone is faster than for an equivalent arrangement of 1D fingers. Moreover, we show that the effective diffusion coefficient is described by a general analytical form for both 1D and 2D fingers, provided the correct scaling variable is identified as a function of the structural parameters. Interestingly, this formula corresponds to the well-known general situation of diffusion in a medium with fast reversible adsorption. Finally, we show that the same formula describes diffusion in the presence of dilute potential energy traps, e.g., through a landscape of square wells. While diffusion is ultimately always the result of microscopic interactions (with particles in the fluid, other solutes, and the environment), effective representations are often of great practical use. The results reported in this paper help clarify the microscopic origins and the applicability of global, integrated descriptions of diffusion in complex media.

Non-Fermi-Liquid Behavior from Cavity Electromagnetic Vacuum Fluctuations at the Superradiant Transition.

We study two-dimensional materials where electrons are coupled to the vacuum electromagnetic field of a cavity. We show that, at the onset of the superradiant phase transition towards a macroscopic photon occupation of the cavity, the critical electromagnetic fluctuations, consisting of photons strongly overdamped by their interaction with electrons, can in turn lead to the absence of electronic quasiparticles. Since transverse photons couple to the electronic current, the appearance of non-Fermi-Liquid behavior strongly depends on the lattice. In particular, we find that in a square lattice the phase space for electron-photon scattering is reduced in such a way to preserve the quasiparticles, while in a honeycomb lattice the latter are removed due to a nonanalytical frequency dependence of the damping ∝|ω|^{2/3}. Standard cavity probes could allow us to measure the characteristic frequency spectrum of the overdamped critical electromagnetic modes responsible for the non-Fermi-liquid behavior.

Peripheral neuropathy as clinical onset of monoclonal IgM/k-related amyloidosis.

AIM: Neuropathy is a frequent complication of Waldenström's macroglobulinemia (WM), the most common being a demyelinating polyneuropathy with anti-myelin associated glycoprotein (MAG) antibodies, but also cryoglobulins, vasculitis, neurolymphomatosis, and amyloidosis. We describe a patient with IgM/kappa WM who presented with a severe, not length-dependent, peripheral neuropathy as clinical onset of IgM/kappa-related amyloidosis. METHODS: A 69-year-old woman came to our attention for weight loss, gait imbalance and sensory loss at upper limbs. In her medical history, she was in hematological follow-up for WM, and had undergone left carpal tunnel release. At neurological evaluation she had weakness and loss of sensation at upper limbs up to the elbows, more at the left side, gait was unsteady with right foot drop. Hypotrophy and areflexia were present at four limbs. Sensory loss and vibration sense were dramatically reduced. She underwent extensive diagnostic workup. RESULTS: Laboratory workup revealed an IgM/kappa monoclonal paraprotein of 16 g/L and increased NT-proBNP; anti-MAG antibodies were absent. Bone marrow biopsy demonstrated a population of neoplastic B-lymphocytes. Total-body CT scan and echocardiogram were negative. Neurophysiology revealed a symmetric, no length dependent sensory-motor polyneuropathy Periumbilical fat biopsy was positive for amyloid. Sural nerve biopsy detected amyloid in the wall of an epineurial vein. CONCLUSIONS: This case report describes a rare and unusual manifestation of IgM-related AL amyloidosis in WM. The patient presented with a subacute clinically asymmetric neuropathy with no pain or dysautonomic features as clinical onset of IgM/kappa-related amyloidosis. Sural nerve biopsy was crucial for the diagnosis.

The complex karyotype landscape in chronic lymphocytic leukemia allows the refinement of the risk of Richter syndrome transformation.

Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with ≥5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter real-life retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, and TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q- /TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (P<0.0001). We herein demonstrate that CK landscape at CLL diagnosis allows the risk of RS transformation to be refined and we recapitulated clinico-biological variables into a prognostic model.

The physics of boundary conditions in reaction-diffusion problems.

The use of fully or partially absorbing boundary conditions for diffusion-based problems has become paradigmatic in physical chemistry and biochemistry to describe reactions occurring in solutions or in living media. However, as chemical states may indeed disappear, particles cannot, unless such degradation happens physically and should, thus, be accounted for explicitly. Here, we introduce a simple, yet general idea that allows one to derive the appropriate boundary conditions self-consistently from the chemical reaction scheme and the geometry of the physical reaction boundaries. As an illustration, we consider two paradigmatic examples, where the known results are recovered by taking specific physical limits. More generally, we demonstrate that our mathematical analysis delivers physical insight that cannot be accessed through standard treatments.

Long-Range Photon Fluctuations Enhance Photon-Mediated Electron Pairing and Superconductivity.

Recently, the possibility of inducing superconductivity for electrons in two-dimensional materials has been proposed via cavity-mediated pairing. The cavity-mediated electron-electron interactions are long range, which has two main effects: firstly, within the standard BCS-type pairing mediated by adiabatic photons, the superconducting critical temperature depends polynomially on the coupling strength, instead of the exponential dependence characterizing the phonon-mediated pairing; secondly, as we show here, the effect of photon fluctuations is significantly enhanced. These mediate novel non-BCS-type pairing processes, via nonadiabatic photons, which are not sensitive to the electron occupation but rather to the electron dispersion and lifetime at the Fermi surface. Therefore, while the leading temperature dependence of BCS pairing comes from the smoothening of the Fermi-Dirac distribution, the temperature dependence of the fluctuation-induced pairing comes from the electron lifetime. For realistic parameters, also including cavity loss, this results in a critical temperature which can be more than 1 order of magnitude larger than the BCS prediction. Moreover, a finite average number of photons (as can be achieved by incoherently pumping the cavity) adds to the fluctuations and leads to a further enhancement of the critical temperature.

Rabi Regime of Current Rectification in Solids.

We investigate rectified currents in response to oscillating electric fields in systems lacking inversion and time-reversal symmetries. These currents, in second-order perturbation theory, are inversely proportional to the relaxation rate, and, therefore, naively diverge in the ideal clean limit. Employing a combination of the nonequilibrium Green function technique and Floquet theory, we show that this is an artifact of perturbation theory, and that there is a well-defined periodic steady state akin to Rabi oscillations leading to finite rectified currents in the limit of weak coupling to a thermal bath. In this Rabi regime the rectified current scales as the square root of the radiation intensity, in contrast with the linear scaling of the perturbative regime, allowing us to readily diagnose it in experiments. More generally, our description provides a smooth interpolation from the ideal periodic Gibbs ensemble describing the Rabi oscillations of a closed system to the perturbative regime of rapid relaxation due to strong coupling to a thermal bath.

Effectiveness and Safety of Pixantrone for the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma in Every-Day Clinical Practice: The Italian Cohort of the PIXA Registry.

INTRODUCTION: Treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) represents a challenge for clinicians due to the lack of therapeutic options. DLBCL is not a rare disease in Italy. Pixantrone is an aza-anthracenedione, which, when compared to anthracyclines and anthracenediones, has a significantly reduced cardiotoxicity while maintaining good anti-tumor activity. However, the evidence on the use of pixantrone in the context of daily clinical practice is scarce. METHODS: We focused on the Italian patient subset of a larger European retrospective study (the PIXA Registry) to assess the efficacy and safety of pixantrone in a real-life DLBCL population. The molecular profile of the disease and its impact on drug efficacy were also assessed. RESULTS: Fifteen heavily pretreated DLBCL patients (13 males and 2 females) underwent treatment with pixantrone for a median of 2 cycles (range 1-6). Eight patients were bcl2 positive, 7 bcl6 positive, and 4 myc positive; 4 patients were diagnosed as double-hit, and 2 as triple-hit DLBCL. The overall response rate was 26.7% with a best response rate of 46.7%. Three patients had grade IV adverse events, which caused drug discontinuation. Four patients had 5 cases of grade III toxicities (1 thrombocytopenia, 1 stomatitis, and 3 neutropenia). One mild cardiac toxicity (sinus tachycardia for which no action was required) was possibly related to the study drug. CONCLUSION: Our data documented drug efficacy that is satisfactory for this high-risk subset of patients with an acceptable toxicity profile. Results indicate that pixantrone could be a significant treatment option in patients with R/R aggressive DLBCL treated in everyday clinical practice.

Targeting Protein Kinases in Blood Cancer: Focusing on CK1α and CK2.

Disturbance of protein kinase activity may result in dramatic consequences that often lead to cancer development and progression. In tumors of blood origin, both tyrosine kinases and serine/threonine kinases are altered by different types of mutations, critically regulating cancer hallmarks. CK1α and CK2 are highly conserved, ubiquitously expressed and constitutively active pleiotropic kinases, which participate in multiple biological processes. The involvement of these kinases in solid and blood cancers is well documented. CK1α and CK2 are overactive in multiple myeloma, leukemias and lymphomas. Intriguingly, they are not required to the same degree for the viability of normal cells, corroborating the idea of "druggable" kinases. Different to other kinases, mutations on the gene encoding CK1α and CK2 are rare or not reported. Actually, these two kinases are outside the paradigm of oncogene addiction, since cancer cells' dependency on these proteins resembles the phenomenon of "non-oncogene" addiction. In this review, we will summarize the general features of CK1α and CK2 and the most relevant oncogenic and stress-related signaling nodes, regulated by kinase phosphorylation, that may lead to tumor progression. Finally, we will report the current data, which support the positioning of these two kinases in the therapeutic scene of hematological cancers.

Interaction-Induced Transparency for Strong-Coupling Polaritons.

The propagation of light in strongly coupled atomic media takes place through the formation of polaritons-hybrid quasiparticles resulting from a superposition of an atomic and a photonic excitation. Here we consider the propagation under the condition of electromagnetically induced transparency and show that a novel many-body phenomenon can appear due to strong, dissipative interactions between the polaritons. Upon increasing the photon-pump strength, we find a first-order transition between an opaque phase with strongly broadened polaritons and a transparent phase where a long-lived polariton branch with highly tunable occupation emerges. Across this nonequilibrium phase transition, the transparency window is reconstructed via nonlinear interference effects induced by the dissipative polariton interactions. Our predictions are based on a systematic diagrammatic expansion of the nonequilibrium Dyson equations which can be controlled, even in the nonperturbative regime of large single-atom cooperativities, provided the polariton interactions are sufficiently long-ranged. Such a regime can be reached in photonic crystal waveguides thanks to the tunability of interactions, allowing us to observe the interaction-induced transparency transition even at low polariton densities.

Hierarchy of Relaxation Timescales in Local Random Liouvillians.

To characterize the generic behavior of open quantum systems, we consider random, purely dissipative Liouvillians with a notion of locality. We find that the positivity of the map implies a sharp separation of the relaxation timescales according to the locality of observables. Specifically, we analyze a spin-1/2 system of size ℓ with up to n-body Lindblad operators, which are n local in the complexity-theory sense. Without locality (n=ℓ), the complex Liouvillian spectrum densely covers a "lemon"-shaped support, in agreement with recent findings [S. Denisov et al., Phys. Rev. Lett. 123, 140403 (2019)PRLTAO0031-900710.1103/PhysRevLett.123.140403]. However, for local Liouvillians (n<ℓ), we find that the spectrum is composed of several dense clusters with random matrix spacing statistics, each featuring a lemon-shaped support wherein all eigenvectors correspond to n-body decay modes. This implies a hierarchy of relaxation timescales of n-body observables, which we verify to be robust in the thermodynamic limit. Our findings for n locality generalize immediately to the case of spatial locality, introducing further splitting of timescales due to the additional structure.

New responsibilities for aged kinases in B-lymphomas.

The knowledge accumulated over the last decade on B-cell-derived non-Hodgkin lymphoma (B-NHL) pathogenesis has led to the identification of several molecular abnormalities, opening new perspectives in the design of novel therapies. Indeed, drugs targeting specific biochemical pathways critical for B-NHL cell survival, proliferation, and fitness within the malignant microenvironment are now available to the clinician: the B-cell receptor signaling inhibitors of BTK, PI3Kδ, ζ, γ, and SYK or the pro-apoptotic BH3-mimetics are clear examples of it. Moreover, it is emerging that malignant B-cell growth is sustained not only by mutations in oncogenes/tumor suppressors but also by the "addiction" to nononcogene (ie, nonstructurally altered) molecules. In this regard, a consistent body of data has established that the Ser/Thr kinases CK1, CK2, and GSK3 are involved in malignant lymphocyte biology and act as pro-survival and signaling-boosting molecules, both in precursor and mature B-cell tumors. Currently, an experimental and clinical groundwork is available, upon which to design CK1-, CK2-, and GSK3-directed antilymphoma/leukemia therapies. In this review, we have examined the main features of CK1, CK2, and GSK3 kinases, summarized the data in B-NHL supporting them as suitable therapeutic targets, and proposed a perspective on potential future research development.

Ibrutinib in relapsed hairy cell leukemia variant: A case report and review of the literature.

Hairy cell leukemia variant (HCLv) is a provisional disease in the 2016 WHO classification of lymphomas, characterized by unfavorable prognosis and early relapse following conventional purine analog-based regimens. In this study, we report 2 patients with relapsed HCLv treated with ibrutinib. The first patient achieved a partial response following ibrutinib treatment and received the drug for 16 months, without severe adverse events. However, at disease progression venetoclax was not clinically active. The second patient discontinued the drug early due to intolerance. Ibrutinib was active in our patients with HCLv and deserve further investigations.

Primary pancreatic lymphoma: Clinical presentation, diagnosis, treatment, and outcome.

Primary pancreatic lymphoma (PPL) is a rare disease representing 0.1% of malignant lymphomas, which lacks well-defined diagnostic and therapeutic protocols. OBJECTIVES: To describe PPL clinical, diagnostic and histological characteristics, together with therapy and outcome, in a relatively large series of patients. METHODS: The study includes 39 PPL patients, aged ≥15 years, observed from January 2005 to December 2018, in 8 Italian Institutions. RESULTS: The main symptoms were abdominal pain (58%) and jaundice (47%). Lactate dehydrogenase serum levels were elevated in 43% of patients. Histological specimens were mostly obtained by percutaneous (41%) or endoscopic (36%) biopsy, with diffuse large B-cell lymphoma being the most frequent (69%) histological diagnosis. Chemotherapy was administered alone in 65% of patients, with radiotherapy in 17%, or after surgery in 9%. The 2-year overall survival (OS) was 62%, the 2-year progression-free survival (PFS) 44%. Debulking surgery (with or without chemotherapy) was associated with a significant worse OS. Three (9.4%) of 32 high-grade patients experienced a central nervous system (CNS) relapse. CONCLUSIONS: PPL is rare, often high-grade, with symptoms and localization similar to other pancreatic malignancies. Biopsy should be the preferred diagnostic method. High-grade PPL should undergo CNS prophylaxis.

Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies.

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P = .002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P = .028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

Polyethylene glycol crowding effect on hyaluronidase activity monitored by capillary electrophoresis.

To mimic the activity of hyaluronidase in natural environment, the hydrolysis of hyaluronic acid (HA) by hyaluronidase was investigated for the first time in the presence of crowding agents using capillary electrophoresis (CE) as a simple and reliable technique for conducting enzymatic assay. Polyethylene glycol (PEG) 6000 was selected as a model crowder and the hyaluronic acid degradation catalyzed by bovine testes hyaluronidase (BTH) was carried out at different PEG concentrations (0%, 10%, and 17%). After optimization of the CE analytical method and enzymatic assay, the degradation products were monitored at different HA concentrations. At 10% of PEG and 0.3 mg mL-1 of HA, the activity of the enzyme was significantly reduced showing inconvenient interactions of PEG with the hyaluronidase blocking the release of hydrolysis products. A similar reduction of hyaluronidase activity was observed at 1 mg mL-1 of HA due to the presumable formation of the BTH-substrate complex. The experimental curves obtained by CE also evidence that the overall kinetics are governed by the hydrolysis of hexasaccharide intermediates. Finally, the effect of PEG on hyaluronidase activity was evaluated in the presence of natural or synthetic inhibitors. Our results show a significant difference of the inhibitors' affinity toward hyaluronidase in the presence of PEG. Surprisingly, the presence of the crowding agent results in a loss of the inhibition effect of small polycyclic inhibitors, while larger charged inhibitors were less affected. In this work, CE analyses confirm the importance of mimicking the cellular environment for the discovery and development of reliable inhibitors. Graphical abstract.

Analysis and forecast of COVID-19 spreading in China, Italy and France.

In this note we analyze the temporal dynamics of the coronavirus disease 2019 outbreak in China, Italy and France in the time window 22 / 01 - 15 / 03 / 2020 . A first analysis of simple day-lag maps points to some universality in the epidemic spreading, suggesting that simple mean-field models can be meaningfully used to gather a quantitative picture of the epidemic spreading, and notably the height and time of the peak of confirmed infected individuals. The analysis of the same data within a simple susceptible-infected-recovered-deaths model indicates that the kinetic parameter that describes the rate of recovery seems to be the same, irrespective of the country, while the infection and death rates appear to be more variable. The model places the peak in Italy around March 21st 2020, with a peak number of infected individuals of about 26000 (not including recovered and dead) and a number of deaths at the end of the epidemics of about 18,000. Since the confirmed cases are believed to be between 10 and 20% of the real number of individuals who eventually get infected, the apparent mortality rate of COVID-19 falls between 4% and 8% in Italy, while it appears substantially lower, between 1% and 3% in China. Based on our calculations, we estimate that 2500 ventilation units should represent a fair figure for the peak requirement to be considered by health authorities in Italy for their strategic planning. Finally, a simulation of the effects of drastic containment measures on the outbreak in Italy indicates that a reduction of the infection rate indeed causes a quench of the epidemic peak. However, it is also seen that the infection rate needs to be cut down drastically and quickly to observe an appreciable decrease of the epidemic peak and mortality rate. This appears only possible through a concerted and disciplined, albeit painful, effort of the population as a whole.