Continous Treatment with Ibrutinib in 100 Untreated Patients with TP53 Disrupted Chronic Lymphocytic Leukemia. A Real-Life Campus CLL Study

Continous Treatment with Ibrutinib in 100 Untreated Patients with TP53 Disrupted Chronic Lymphocytic Leukemia. A Real-Life Campus CLL Stud

Interplay Between Age and Neuroinflammation in Multiple Sclerosis: Effects on Motor and Cognitive Functions

Aging is one of the main risk factors for the development of many neurodegenerative diseases. Emerging evidence has acknowledged neuroinflammation as potential trigger of the functional changes occurring during normal and pathological aging. Two main determinants have been recognized to cogently contribute to neuroinflammation in the aging brain, i.e., the systemic chronic low-grade inflammation and the decline in the regulation of adaptive and innate immune systems (immunosenescence, ISC). The persistence of the inflammatory status in the brain in turn may cause synaptopathy and synaptic plasticity impairments that underlie both motor and cognitive dysfunctions. Interestingly, such inflammation-dependent synaptic dysfunctions have been recently involved in the pathophysiology of multiple sclerosis (MS). MS is an autoimmune neurodegenerative disease, typically affecting young adults that cause an early and progressive deterioration of both cognitive and motor functions. Of note, recent controlled studies have clearly shown that age at onset modifies prognosis and exerts a significant effect on presenting phenotype, suggesting that aging is a significant factor associated to the clinical course of MS. Moreover, some lines of evidence point to the different impact of age on motor disability and cognitive deficits, being the former most affected than the latter. The precise contribution of aging-related factors to MS neurological disability and the underlying molecular and cellular mechanisms are still unclear. In the present review article, we first emphasize the importance of the neuroinflammatory dependent mechanisms, such as synaptopathy and synaptic plasticity impairments, suggesting their potential exacerbation or acceleration with advancing age in the MS disease. Lastly, we provide an overview of clinical and experimental studies highlighting the different impact of age on motor disability and cognitive decline in MS, raising challenging questions on the putative age-related mechanisms involved

Erythropoietin and chronic lymphocytic leukemia

Anemia is a frequent clinical feature with adverse prognostic effects in patients with chronic lymphocytic leukemia (CLL). It may complicate CLL at any time during the course of the disease. Different factors concur to the occurrence of anemia in CLL, as in other lymphoproliferative diseases: leukemic bone marrow infiltration, the myelosuppressive effect of chemotherapy and inhibiting cytokines, autoimmune phenomena, hypersplenism, a poor nutritional status that leads to folic acid, vitamin B12 and iron deficiency In addition, a defective endogenous erythropoietin (EPO) production has also been described in patients with lymphoproliferative diseases, The severity of anemia, which may be worsened by an impaired cardiopulmonary function, may profoundly compromise the patients' quality of life and, indirectly, the outcome of cancer bearing patients. Several Authors have reported the clinical activity of recombinant human (rHu)EPO in anemic patients with lymphoproliferative diseases, including CLL. Low serum EPO levels at baseline and EPO levels inappropriately low for the degree of anemia help to identify patients who are likely to respond to EPO. A clear dose-dependent response to EPO has been reported by different Authors and it has been suggested that 5,000 IU should be considered as an appropriate initial dose for the majority of patients. rHuEPO represents a potentially effective and safe therapy for the management of anemia associated with lymphoproliferative diseases. The reduction of red blood cell transfusion requirement, the improvement of quality of life through the remission of fatigue-related anemia are two important results that should be considered in the management of patients with CLL. In prospect, the availability of new rHuEPO molecules with a more prolonged half-life may open new therapeutic avenues

New developments in the diagnosis, prognosis and treatment of chronic lymphocytic leukemia

Purpose of review The remarkable progress witnessed over the past few years in the diagnosis, prognosis, and therapy of chronic lymphocytic leukemia has profoundly changed the clinical approach to this disease. This review focuses on the most recent advances in the diagnostic and prognostic examination of patients with chronic lymphocytic leukemia, with particular emphasis on their implications in clinical management, taking into account the broadening of the therapeutic possibilities available today. Recent findings Through the biologic improvements achieved during the past few years it is now possible to effectively stratify chronic lymphocytic leukemia patients prognostically at presentation on the basis of several laboratory parameters. Furthermore, the availability of purine analogs and monoclonal antibodies and the extension of autografting and allografting procedures have allowed the achievement of higher response rates, including molecular remissions. With the aim of investigating whether early and aggressive treatment intervention may improve the survival of patients with a poor prognosis, new therapeutic trials have been specifically designed. Summary A complete biologic and clinical examination now allows the establishment of a correct diagnostic characterization of patients with chronic; lymphocytic leukemia and to identify patients with early disease with a different prognostic likelihood. Multicenter prospective trials, in which the enrolled patients are stratified and treated according to their prognostic risk, will determine the best treatment for the different categories of patients. It is likely that in the near future each chronic lymphocytic leukemia patient can be offered a targeted treatment algorithm based on the clinical and biologic characteristics at presentation

Laquinimod ameliorates excitotoxic damage by regulating glutamate re-uptake

Abstract Background Laquinimod is an immunomodulatory drug under clinical investigation for the treatment of the progressive form of multiple sclerosis (MS) with both anti-inflammatory and neuroprotective effects. Excitotoxicity, a prominent pathophysiological feature of MS and of its animal model, experimental autoimmune encephalomyelitis (EAE), involves glutamate transporter (GluT) dysfunction in glial cells. The aim of this study was to assess whether laquinimod might exert direct neuroprotective effects by interfering with the mechanisms of excitotoxicity linked to GluT function impairments in EAE. Methods Osmotic minipumps allowing continuous intracerebroventricular (icv) infusion of laquinimod for 4 weeks were implanted into C57BL/6 mice before EAE induction. EAE cerebella were taken to perform western blot and qPCR experiments. For ex vivo experiments, EAE cerebellar slices were incubated with laquinimod before performing electrophysiology, western blot, and qPCR. Results In vivo treatment with laquinimod attenuated EAE clinical score at the peak of the disease, without remarkable effects on inflammatory markers. In vitro application of laquinimod to EAE cerebellar slices prevented EAE-linked glutamatergic alterations without mitigating astrogliosis and inflammation. Moreover, such treatment induced an increase of Slcla3 mRNA coding for the glial glutamate–aspartate transporter (GLAST) without affecting the protein content. Concomitantly, laquinimod significantly increased the levels of the glial glutamate transporter 1 (GLT-1) protein and pharmacological blockade of GLT-1 function fully abolished laquinimod anti-excitotoxic effect. Conclusions Overall, our results suggest that laquinimod protects against glutamate excitotoxicity of the cerebellum of EAE mice by bursting the expression of glial glutamate transporters, independently of its anti-inflammatory effects

Riattivazione dell’infezione cronica da virus dell’epatite C in pazienti affetti da malattie ematologiche maligne linfoidi o mieloidi riceventi chemioterapia e/o immunoterapia. Motivazione: Progetto fattibile, con buon razionale scientifico. Presumibili ricadute positive sulla cura dei pazienti

Razionale ed outcome scientifico del progetto L’organizzazione mondiale della sanità stima che nel mondo gli individui infetti da virus dell’epatite C (Hepatitis C Virus, HCV) siano >185 milioni (circa il 3% della popolazione mondiale); di questi, 130-170 milioni di individui sono cronicamente infetti e 350.000 morti avvengono ogni anno a causa di cirrosi e di carcinoma epatocellulare HCV correlato (1). In aggiunta a danni epatici, HCV contribuisce ad un ampio spettro di manifestazioni extraepatiche, quali l’insulino resistenza ed il diabete, la crioglobulinemia mista, la glomerulonefrite ed i linfomi B. La prevalenza di infezione da HCV oscilla tra 1.2% e 3.8% nelle varie regioni del mondo, essendo l’Italia una regione a prevalenza moderata (1.5%-3.5%) (1). La prevalenza stimata di HCV in pazienti con malattie onco-ematologiche è del 1.5% - 32 %, e rappresenta una prevalenza maggiore di quella osservata nella popolazione generale (2-5). Nei pazienti affetti da neoplasie ematologiche maligne l’infezione da HCV presenta aspetti peculiari: 1) L’infezione da HCV aggiunge notevole complessità alla gestione dei pazienti neoplastici per la mancanza di linee guida dedicate a questo gruppo di pazienti (6). 2) La maggior parte degli studi pubblicati ha analizzato l’associazione tra Linfoma non-Hodgkin ed infezione da HCV. Pochi studi sono stati condotti in pazienti con infezione da HCV affetti da altre malattie ematologiche maligne (2,5) 3) La definizione, il rischio e le conseguenze cliniche dell’esacerbazione acuta o della riattivazione di HCV in individui affetti da cancro e riceventi chemioterapia e/o immunoterapia rappresentano aspetti ancora oggi poco definiti rispetto al ruolo di HBV in tale contesto clinico (7-9). 4) Pazienti con malattie onco-ematologiche riceventi trapianto allogenico di cellule staminali (HSCT) hanno un elevato rischio di sviluppare fibrosi e cirrosi HCV correlate (10). 5) L’uso di rituximab nei pazienti onco-ematologici ed in particolare in quelli affetti da linfoma non-Hodgkin, è correlato con l’esacerbazione acuta (incremento di ALT > 3 volte) e la riattivazione di HCV (incremento della replicazione virale > 1 log10 IU/ml) (8,9). 6) La riattivazione di HCV potrebbe ridurre la sopravvivenza dei pazienti affetti da malattie onco-ematologiche per i seguenti motivi: per l’interruzione della chemioterapia anti-neoplastica, per l’impossibilità di usare chemioterapie salvavita e per le interazioni tra farmaci antineoplastici e farmaci anti HCV, quali interferon e ribavirina (6,11,12). 7) Recentemente è stato dimostrato che l’uso della terapia anti- HCV (interferon e ribavirina), nonostante gli effetti collaterali e le relative limitazioni, ha consentito due importanti risultati: a) prevenire la progressione della cirrosi e dello sviluppo dell’epatocarcinoma nei pazienti con cancro (13), b) essere associato ad una prolungata sopravvivenza dei pazienti HCV positivi affetti da linfoma non-Hodgkin (14). 8) Studi su l’efficacia di nuovi farmaci “direct-acting antiviral agents” per i pazienti affetti da malattie onco-ematologico sono necessari; potrebbe essere possibile curare nei prossimi 2-3 anni l'infezione da HCV con brevi periodi (<12 settimane) di terapia antivirale “interferon-free” somministrata durante o dopo la chemioterapia. La cooperazione tra ematologi, oncologi, infettivologi, gastroenterologi ed epatologi potrebbe consentire una gestione integrata multidisciplinare di un complesso problema clinico in assenza di linee guida dedicate a questa tipologia di pazienti. Alcuni aspetti dell’infezione da HCV osservati più frequentemente nei pazienti oncologici (6) rispetto a quelli senza cancro, sono: 1) frequenza di l’infezione occulta 2) rischio più elevato di sviluppare cirrosi 3) frequenza più elevata di progressione di fibrosi 4) possibilità di riattivazione di HCV 5) assenza di trattamento standard 6) prognosi virologica peggiore Fattore predisponente la progressione dell’infezione cronica da HCV negli individui immunocompetenti, ma non ancora estesamente valutato in individui con neoplasie ematologiche maligne è rappresentato dallo studio del genotipo. Uno studio multicentrico (15) ha mostrato che la distribuzione di genotipo 1, 2 e 3 di HCV differisce in relazione alla malattia oncologica nonostante i pazienti provengano dalla stessa area geografica e suggerisce un’associazione causa effetto per il genotipo 2 con l’insorgenza di linfoma non Hodgkin. Obiettivi/Endpoints principali di progetto: 1) valutare l'incidenza della riattivazione di HCV in pazienti con neoplasie ematologiche maligne linfoidi o mieloidi riceventi chemioterapia e/o immunoterapia. 2) valutare la relazione tra malattie ematologiche e l’esacerbazione acuta di infezione cronica da HCV, confrontando le caratteristiche cliniche dei pazienti con esacerbazione acuta vs quelli che non manifestano esacerbazione acuta. 3) valutare la riattivazione di HCV in funzione della tipologia di malattie ematologiche maligne ed in relazione ai tipi di chemioterapie 4) correlazione tra esacerbazione acuta di infezione cronica da HCV e riattivazione virale 5) valutazione dell’ esacerbazione acuta e la riattivazione di HCV in pazienti sieropositivi per HCV con HCV-RNA non determinabile

The prognostic value of CD38 expression in chronic lymphocytic leukaemia patients studied prospectively at diagnosis: a single institute experience

The purpose of this study was to assess in chronic lymphocytic leukaemia (CLL) patients the prevalence and clinical impact of CD38 expression, evaluated prospectively at disease presentation, and to verify whether this parameter changes over time. In 242 consecutive and untreated CLL patients, the percentage of CD38(+) cases, according to the 7%, 20% and 30% cut-off points, was 21%, 17% and 14%, respectively. Using the 7% threshold, CD38 positivity correlated with male sex, intermediate and high-risk (Rai I-IV) disease, lower Hb and platelet levels, and higher lymphocyte count. Furthermore, patients with a CD38 expression >= 7% showed a significantly lower 3-year probability of treatment-free survival (TFS) than CD38(-) patients (P = 7% identified a subgroup of patients with a significantly lower 3-year probability of TFS (P = 0.0005). Furthermore, this parameter did not change in 30 of 31 (97%) re-evaluated patients. In conclusion, this study indicates that, when tested at diagnosis and on fresh material, a CD38 expression >= 7% is an important parameter for the identification of early CLL patients with more aggressive disease and that its expression remains stable over time