RILEVANZA CLINICO-BIOLOGICA DELLE REAZIONI AVVERSE INFUSIONALI AI FARMACI: IL CASO DELL’ANTICORPO MONOCLONALE RITUXIMAB

L'anticorpo monoclonale Rituximab, che identifica l'antigene target CD20, è oramai parte integrante del trattamento delle neoplasie ematologiche che esprimono il CD20 di superficie e, più di recente, si è dimostrato efficace anche nel trattamento delle patologie autoimmuni. Tuttavia, si possono verificare delle reazioni avverse alla infusione dell'anticorpo che, in alcuni casi, ne causano la definitiva sospensione della somministrazione privando il paziente, in tal modo, della opportunità di ricevere una molecola di straordinaria efficacia. In questo studio multicentrico sono stati valutati retrospettivamente 374 pazienti trattati con Rituximab somministrato per via endovenosa e il 23.5% di essi ha manifestato delle reazioni avverse infusionali. Nel complesso le reazioni avverse sono state osservate più frequentemente nei pazienti affetti da linfoma non-Hodgkin e leucemia linfatica cronica (25-35.9%), che nelle patologie autoimmuni (9.4-17.5%) (p < 0.0001). Una tossicità di grado 3-4 si è manifestata in 8 pazienti (2.1%), e in 4 di essi (1% di tutta la casistica) è stato necessario interrompere definitivamente la somministrazione dell'anticorpo. Sono stati identificati 3 gruppi di pazienti con differente rischio di sviluppare una reazione avversa alla infusione dell'anticorpo, utilizzando una heat-map predittiva, ottenuta dalla combinazione di 4 parametri (splenomegalia, storia di allergia, livelli di emoglobina circolante e sesso del paziente) selezionati attraverso una analisi multivariata. Il nostro modello, presentato in questo studio, potrebbe essere utile nell'identificare pazienti a più alto rischio di sviluppare una reazione avversa infusionale al rituximab e che, quindi, potrebbero giovarsi di terapie di prevenzione più appropriate, e pazienti a più basso rischio ai quali potrebbe essere risparmiata una terapia di "premedicazione" o potrebbe esserne somministrata una forma meno intensiva

Monoclonal B-cell lymphocytosis

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic hematologic condition defined by the presence of a small (<5 x 109/L) clonal B-cell population in the peripheral blood in the absence of lymph-node enlargement, cytopenias or autoimmune diseases. It is found in approximately 3-12% of normal persons depending on the accuracy of analytical techniques applied. According to the immunophenotypic profile of clonal B-cells, the majority of MBL cases (75%) are classified as chronic lymphocytic leukemia (CLL)-like. This form may progress into CLL at a rate of 1–2% per year. It is thought that CLL is always preceded by MBL. The remaining MBL cases are defined as atypical CLL-like (CD5+/CD20bright) and CD5- MBL. The MBL clone size is quite heterogenous. Accordingly, two forms of MBL are identified: i) high-count, or ‘clinical’ MBL, in which an evidence of lymphocytosis (<5 x 109/L clonal B-cells) is seen, and ii) a low-count MBL, in which a normal leukocyte count is found and that is identified only in population-screening studies. Both forms of MBL may carry the cytogenetic abnormalities that are the hallmark of CLL, including 13q-, 17p- and trisomy 12. Consistent with the indolent phenotype of this condition, genetic lesions, such as TP53, ATM, NOTCH1 and SF3B1 mutations, usually associated with high-risk CLL, are rarely seen. Overall, no prognostic indicator of evolution of MBL to overt CLL has been found at present time. However, taking into account this possibility, a clinical and lab monitoring (at least annually), is recommended

Cognitive Health of Nonagenarians in Southern Italy: A Descriptive Analysis from a Cross-Sectional, Home-Based Pilot Study of Exceptional Longevity (Cilento Initiative on Aging Outcomes Or CIAO).

Background: Nonagenarians and centenarians (NCs) are an extremely fragile population, particularly in regard to their physical and cognitive function. The aim of this study was to define the neurocognitive profiles among 29 NCs and their 49 younger cohabitants aged 50-75 years from The Cilento Initiative on Aging Outcomes (CIAO) Pilot study in the South of Italy that had provided initial hypotheses regarding positive psychological traits related to exceptional longevity. Methods: During the home visits, lifestyle information with specific questionnaires, functional autonomy and the neuropsychological Mini Mental Scale Examination (MMSE), and the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) scale were obtained by qualified study personnel. The total blood oxidative capacity was also determined by testing the reactive derivative of oxygen metabolites (d-ROM) and by the Biological Antioxidant Potential (BAP). In all individuals, the APOE genotype determination was also performed. Results: All the subjects in both groups showed high adherence to the Mediterranean Diet. None of the NCs had severe cognitive impairment, and a very low incidence of dementia was found. The data obtained on the Activities ed Instrumental Activities of Daily Living (ADL-IADL) scale showed that the majority of NCs (16/29) were autonomous in daily life activities. The comparative assessment of NCs and cohabitants showed no significant differences in the laboratory assessment of oxidative stress and APOE genotype. Conclusion: In the Cilento Region of Southern Italy, NCs seemed to have good cognitive status when compared to younger cohabitants aging 50-65 years without significant differences in oxidative stress markers or APOE genotype. These results might be related to optimal adherence to the Mediterranean diet, although other lifestyle factors and positive personality traits may also contribute to their healthy aging. Further studies on a larger population should be performed to confirm the results of this pilot study

CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential

AbstractOur interest in chronic lymphocytic leukemia (CLL) derives primarily from the exploitation of human diseases as strategic models for defining the in vivo biological roles of CD38. Using this model, we showed that CD38 triggers robust proliferation/survival signals modulated through the interactions with the CD31 ligand expressed by nurselike cells and by the stromal/endothelial components. By analyzing a cohort of 56 patients with clinically and molecularly characterized CLL, we show that (1) patients with CD38+/ZAP-70+ are characterized by enhanced migration toward Stromal derived factor-1α (SDF-1α)/CXCL12; (2) CD38 ligation leads to tyrosine phosphorylation of ZAP-70, showing that these markers are functionally linked; (3) ZAP-70 represents a limiting factor for the CD38 pathway in the CLL context, as shown by studying CD38-mediated signal transduction in 26 molecularly characterized patients; and (4) the CLL subgroup of patients defined on the basis of migratory potential is marked by a specific genetic signature, with a significant number of differentially expressed genes being involved in cell-cell interactions and movement. Altogether, the results of this work provide biological evidence for why the combined analysis of CD38 and ZAP-70 expression as determined in several clinical trials results in more dependable identification of patients with CLL who have aggressive disease

IGHV gene mutational status and 17p deletion are independent molecular predictors in a comprehensive clinical-biological prognostic model for overall survival prediction in chronic lymphocytic leukemia

Prognostic index for survival estimation by clinical-demographic variables were previously proposed in chronic lymphocytic leukemia (CLL) patients. Our objective was to test in a large retrospective cohort of CLL patients the prognostic power of biological and clinical-demographic variable in a comprehensive multivariate model. A new prognostic index was proposed

REGULATORY T-CELLS IN CHRONIC LYMPHOCYTIC LEUKEMIA

&lt;span style="font-family: Times New Roman; font-size: small;"&gt; &lt;/span&gt;&lt;p style="margin: 0cm 0cm 10pt; text-align: justify; line-height: 200%;" class="MsoNormal"&gt;&lt;span lang="EN-US" style="line-height: 200%; font-family: &amp;quot;Times New Roman&amp;quot;,&amp;quot;serif&amp;quot;; font-size: 12pt; mso-ansi-language: EN-US; mso-bidi-font-size: 11.0pt;"&gt;Regulatory T-cells (Tregs) constitute a small subset of cells that are actively involved in maintaining self-tolerance, in immune homeostasis and in antitumor immunity. They are thought to play a significant role in the progression of cancer and are generally increased in patient with chronic lymphocytic leukemia (CLL). Their number correlates with more aggressive disease status and is predictive of the time to treatment, as well. Moreover, it is now clear that dysregulation in Tregs cell frequency and/or function may result in a plethora of autoimmune diseases, including multiple sclerosis, type 1 diabetes mellitus, myasthenia gravis, systemic lupus erythematosis, autoimmune lymphoproliferative disorders, rheumatoid arthritis, and psoriasis. Efforts are made aiming to develop approaches to deplete Tregs or inhibit their function in either cancer and autoimmune disorders. &lt;/span&gt;&lt;/p&gt;&lt;span style="font-family: Times New Roman; font-size: small;"&gt; &lt;/span&gt

Fournier's Gangrene Complicating Hematologic Malignancies: Literature Review and Treatment Suggestions

Fournier’s gangrene (FG) is a rare but severe necrotizing fasciitis of the external genitalia that may complicate the clinical course of hematologic malignancies and sometimes may be the first sign of the disease. The clinical course of FG is very aggressive and the mortality is still high despite the improvement in its management. Early recognition of FG and prompt appropriate treatment with surgical debridement and administration of antibiotics are the cornerstone of the management of this very severe disease