Refractory and 17p-deleted chronic lymphocytic leukemia: improving survival with pathway inhibitors and allogeneic stem cell transplantation.

ABSTRACT Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients

Case report: Cytopenias in VEXAS syndrome - a WHO 2022 based approach in a single-center cohort

VEXAS syndrome is an acquired autoinflammatory disease characterized in most cases by cytopenias and macrocytic anemia. Dyshematopoiesis is a frequent finding in chronic inflammatory conditions and therefore, cytopenias are not easily classified in VEXAS patients. Here we report a series of 7 patients affected by VEXAS associated cytopenias, treated at our center. The use of NGS, together with morphological assays, integrated with the WHO 2022 criteria, allowed to identify three subsets of VEXAS associated cytopenias: ICUS (idiopathic cytopenia of uncertain significance), CCUS (clonal cytopenia of uncertain significance) at high risk of clonal evolution, and MDS. This approach could help to better understand the nature of VEXAS associated cytopenias and to guide the use of specific targeted treatments in order to achieve long lasting responses

EHA evaluation of the ESMO-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies

Objective Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. Results In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. Conclusions Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials

EHA evaluation of the ESMO—Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) for haematological malignancies

Objective: Value frameworks in oncology have not been validated for the assessment of treatments in haematological malignancies, but to avoid overlaps and duplications it appears reasonable to build up experience on existing value frameworks, such as the European Society for Medical Oncology—Magnitude of Clinical Benefit Scale (ESMO-MCBS). Methods: Here we present the results of the first feasibility testing of the ESMO-MCBS v1.1 for haematological malignancies based on the grading of 80 contemporary studies for acute leukaemia, chronic leukaemia, lymphoma, myeloma and myelodysplastic syndromes. The aims were (1) to evaluate the scorability of data, (2) to evaluate the reasonableness of the generated grades for clinical benefit using the current version and (3) to identify shortcomings in the ESMO-MCBS v1.1 that require amendments to improve the efficacy and validity of the scale in grading new treatments in the management of haematological malignancies. Results: In general, the ESMO-MCBS v1.1 was found to be widely applicable to studies in haematological malignancies, generating scores that were judged as reasonable by European Hematology Association (EHA) experts. A small number of studies could either not be graded or were not appropriately graded. The reasons, related to the differences between haematological and solid tumour malignancies, are identified and described. Conclusions: Based on the findings of this study, ESMO and EHA are committed to develop a version of the ESMO-MCBS that is validated for haematological malignancies. This development process will incorporate all of the usual stringencies for accountability of reasonableness that have characterised the development of the ESMO-MCBS including field testing, statistical modelling, evaluation for reasonableness and openness to appeal and revision. Applying such a scale will support future public policy decision-making regarding the value of new treatments for haematological malignancies and will provide insights that could be helpful in the design of future clinical trials

Computational analysis of the evolutionarily conserved Missing In Metastasis/Metastasis Suppressor 1 gene predicts novel interactions, regulatory regions and transcriptional control

Missing in Metastasis (MIM), or Metastasis Suppressor 1 (MTSS1), is a highly conserved protein, which links the plasma membrane to the actin cytoskeleton. MIM has been implicated in various cancers, however, its modes of action remain largely enigmatic. Here, we performed an extensive in silico characterisation of MIM to gain better understanding of its function. We detected previously unappreciated functional motifs including adaptor protein (AP) complex interaction site and a C-helix, pointing to a role in endocytosis and regulation of actin dynamics, respectively. We also identified new functional regions, characterised with phosphorylation sites or distinct hydrophilic properties. Strong negative selection during evolution, yielding high conservation of MIM, has been combined with positive selection at key sites. Interestingly, our analysis of intra-molecular co-evolution revealed potential regulatory hotspots that coincided with reduced potentially\ua0pathogenic polymorphisms. We explored databases for the mutations and expression levels of MIM in cancer. Experimentally, we focused on chronic lymphocytic leukaemia (CLL), where MIM showed high overall expression, however, downregulation on poor prognosis samples. Finally, we propose strong conservation of MTSS1 also on the transcriptional level and predict novel transcriptional regulators. Our data highlight important targets for future studies on the role of MIM in different tissues and cancers

Atlante della vegetazione ripariale e sommersa della Riserva Naturale Regionale Lago di Vico

Il Lago di Vico è uno dei laghi vulcanici con il miglior stato di conservazione dell'Italia centrale ed uno dei bacini più studiati a livello europeo: è oggetto di indagini sin dagli anni '60, da parte di istituti di ricerca italiani e stranieri. Sebbene la crescente antropizzazione dell'area abbia comportato importanti mutamenti soprattutto nell'uso del suolo della caldera, con conseguenze sullo stato trofico del lago, Vico rappresenta ancora un'importante area di studio per analizzare le dinamiche della vegetazione acquatica e ripariale. In questo scenario, il ruolo dell'area protetta è quello di conservare gli ecosistemi presenti e per questo scopo si ritiene indispensabile promuovere la ricerca di base, indirizzandola in particolare verso studi che forniscano indicazioni gestionali il più possibile univoche e concrete. Lo studio della vegetazione acquatica è di importanza cruciale, non solo perché coinvolge direttamente habitat tutelati a livello comunitario, dove svernano migliaia di uccelli, ma anche perché la vegetazione rappresenta un ottimo indicatore ambientale: essa fornisce informazioni sullo stato di conservazione dell'intero ecosistema e può essere studiata tramite indagini relativamente semplici, che non necessitano di esami di laboratorio o di strumentazioni complesse, quindi con un rapporto ottimale costi-benefici. Questo studio, che nasce grazie alla collaborazione con l'Agenzia Regionale per i Parchi, rappresenta un aggiornamento delle ricerche sulla vegetazione della caldera effettuate alla fine degli anni '80 e un approfondimento delle conoscenze sulla vegetazione sommersa. Il confronto con i dati pregressi ha confermato alcune tendenze negative in atto già 30 anni fa, ossia un progressivo impoverimento floristico e una riduzione dell'estensione della vegetazione sommersa, ma allo stesso tempo lo studio ha fornito alcune sorprese positive, come nel caso di Nitellopsis obtusa, una macroalga molto diffusa a Vico di cui è stato possibile documentare la riproduzione sessuata per la prima volta in Europa. Le ricerche svolte hanno permesso anche di verificare concretamente gli effetti di un importante intervento di gestione finalizzato alla regolazione del livello del lago e realizzato dalla Riserva: il ripristino della chiusa farnesiana sull'emissario artificiale Rio Vicano. Si ipotizzava da tempo l'importanza di mantenere un alto livello delle acque del lago e gli studi per il piano di gestione confermavano questa idea. Nel 2009, a seguito delle abbondanti precipitazioni invernali e dell'entrata in funzione della chiusa, il livello del lago si è mantenuto alto e le approfondite ricerche in campo, in corso dal 2007, hanno permesso di monitorare puntualmente le modificazioni della vegetazione: alcune specie rare (Ranunculus baudotii, Juncus bufonius) scomparse o sull'orlo dell'estinzione locale sono tornate a vegetare con buone popolazioni in aree dove erano assenti negli anni precedenti. Questo studio ha così dimostrato in modo univoco l'importanza di mantenere un alto livello delle acque del Lago di Vico e ha permesso di chiudere il cerchio virtuoso di conoscenza-gestione-monitoraggio, che rappresenta uno dei paradigmi della conservazione e sicuramente un aspetto di eccellenza per un'area protetta

Attività antiaggregante di polipeptidi isolati dal veleno di vipere in diverse specie animali

Lo scopo della presente ricerca è stato quello di valutare la capacità di inibizione dell'aggregazione piastrinica di tre disintegrine (echistatina, kistrina e flavoridina) su PRP ottenuto da differenti specie animali (cavallo, bovino e bufalo) I risultati hanno evidenziato che tali molecole inibiscono l'aggregazione piastrinica in tutte e tre le specie a concentrazioni nanomolari. Sono state comunque osservate differenze nell'attività di inibizione dell'aggregazione in funzione della specie animale considerata. Tali risultati evidenziano che la differente attività osservata potrebbe essere ascritta non solo al RGD motif ma alla presenza di altri siti per il riconoscimento da parte delle integrine presenti sulle piastrine