Valutazione retrospettiva del ruolo del background genetico di fattori pro- ed anti- angiogenetici nel predire la risposta al trattamento con bevacizumab in pazienti con carcinoma mammario metastatico

Nel corso degli ultimi decenni gli avanzamenti nel campo della diagnostica precoce e dei trattamenti medici hanno sensibilmente ridotto la mortalità per carcinoma mammario. Tuttavia una parte delle pazienti sviluppa una malattia metastatica e la sopravvivenza mediana in queste pazienti è di 24-48 mesi. In considerazione dell’eterogeneità clinico-biologica non esiste un trattamento standard per la malattia metastatica e la scelta del clinico deve conformarsi sul singolo caso e su un’attenta valutazione del rapporto tra beneficio e tossicità dei trattamenti. La chemioterapia è il trattamento di scelta nella malattia ormonoresistente, con impegno viscerale o andamento rapidamento evolutivo e ad oggi disponiamo di numerosi farmaci attivi in questo setting. L’associazione di bevacizumab, anticorpo monoclonale umanizzato diretto contro il Vascular Endothelial Growth Factor (VEGF), mediatore chiave della neoangiogenesi tumorale, ad una chemioterapia di prima linea con taxani rappresenta una possibile opzione terapeutica nella malattia avanzata, sulla base dei risultati di studi clinic randomizzati. Tuttavia lo sviluppo di resistenza in una parte di pazienti, la disponibilità di numerosi farmaci attivi in questo setting e i costi del trattamento ne limitano talvolta l’impiego. L’identificazione di biomarcatori predittivi di efficacia in grado di selezionare i soggetti con minori o maggiori possibilità di beneficiare dell’inibizione di VEGF permetterebbe un’ottimizzazione del rapporto costo/efficacia dei trattamenti; ad oggi tuttavia non disponiamo di fattori predittivi di efficacia validati. Sulla base di lavori recenti è stato ipotizzato che specifici polimorfismi del gene VEGF e di altri geni coinvolti nell’angiogenesi possano condizionare l’efficacia del trattamento con bevacizumab. Nel nostro studio condotto grazie alla cooperazione di 8 U.O. di Oncologia Medica italiane è stato valutato retrospettivamente il significato predittivo/prognostico di alcuni polimorfismi germinali di VEGF, VEGFR2, IL-8, TSP-1, EPAS1 e HIF1α su una casistica di 111 pazienti con carcinoma mammario metastatico trattate in prima linea con l’associazione di paclitaxel e bevacizumab, a partire dal DNA estratto da sangue periferico. Si tratta di una popolazione femminile con le seguenti caratteristiche: età mediana 59 anni (range 32-81), performance status (PS) 0/1=100/11, recettori ormonali positivi/negativi=92/19, intervallo libero da malattia (DFI)12 mesi=30/81, mediana di sedi metastatiche=2 (range 1-6), malattia viscerale = 81 /scheletro o tessuti molli = 81/39. Ad un follow up di 17.4 mesi la PFS e la sopravvivenza globale (OS) mediane sono risultate di 11.6 e 32.4 mesi. Nesuno dei polimorfismi analizzati individualmente ha mostrato una significativa associazione con la PFS. L’analisi di interazione genetica ha mostrato come l’interazione tra due geni, IL-8 e VEGFR-2, identifichi un profilo genetico (56 pazienti) associato significativamente con la PFS, con una PFS mediana di 14.0 mesi (IC 95% 11.7-16.3) rispetto alla PFS mediana di 10.9 mesi (IC 95% 9.4-12.4) dei restanti pazienti (46 pazienti) [p=0.033, log rank test] [HR 0.63, IC95% 0.4-0.99, p =0.046, Cox-model]. In conclusione non un singolo polimorfismo bensì l’interazione tra polimorfismi di più geni potrebbe condizionare l’outcome di pazienti con carcinoma mammario metastatico trattati con bevacizumab; data la complessità del processo angiogenetico e dei meccanismi di regolazione dell’espressione genica, è ragionevole ipotizzare che combinazioni di diversi geni e polimorfismi, piuttosto che singoli polimorfismi, possano influenzare il fenotipo angiogenetico e la sensibilità a farmaci anti-VEGF come bevacizumab

Venetoclax in combination with hypomethylating agents in previously untreated patients with acute myeloid leukemia ineligible for intensive treatment: a real-life multicenter experience

The addition of venetoclax to hypomethylating agents (HMA-V) improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive treatment. The aim of our study was to confirm data reported in literature, in a real-life multicenter experience. We retrospectively evaluated 56 naive AML patients who received HMA-V at 8 different collaborating Hematology Units in the North-East of Italy, from September 2018 to October 2020. Patients received azacitidine or decitabine at standard dose, adding venetoclax starting from cycle 1-3. The median time-to-response was 2 cycles and composite complete remission rate (CCR) was 67.9%. Thirteen out of 38 responders (34.2%) relapsed, with a median response duration of 13.7 months. Transfusion independence (TI) was obtained in 27 (87.0%) and 28 (90.3%) out of 31 patients for red blood cells and platelets, respectively. Median OS was 12.3 months (95% CI, 8.1-16.5), and median PFS was 11.3 months (95% CI, 4.6-17.9). Cytogenetic risk was the only variable impacting on survival, while no differences were observed stratifying patients by age, bone marrow blasts, WHO classification or type of HMA. In conclusion, our real-life multicenter experience indicates that HMA-V treatment allows achieving good response rates in naive AML patients, ineligible for intensive chemotherapy

Impact of Beneficial Microorganisms on Strawberry Growth, Fruit Production, Nutritional Quality, and Volatilome

Arbuscular mycorrhizal fungi (AMF) colonize the roots of most terrestrial plant species, improving plant growth, nutrient uptake and biotic/abiotic stress resistance and tolerance. Similarly, plant growth promoting bacteria (PGPB) enhance plant fitness and production. In this study, three different AMF (Funneliformis mosseae, Septoglomus viscosum, and Rhizophagus irregularis) were used in combination with three different strains of Pseudomonas sp. (19Fv1t, 5Vm1K and Pf4) to inoculate plantlets of Fragaria × ananassa var. Eliana F1. The effects of the different fungus/bacterium combinations were assessed on plant growth parameters, fruit production and quality, including health-promoting compounds. Inoculated and uninoculated plants were maintained in a greenhouse for 4 months and irrigated with a nutrient solution at two different phosphate levels. The number of flowers and fruits were recorded weekly. At harvest, fresh and dry weights of roots and shoots, mycorrhizal colonization and concentration of leaf photosynthetic pigments were measured in each plant. The following fruit parameters were recorded: pH, titratable acids, concentration of organic acids, soluble sugars, ascorbic acids, and anthocyanidins; volatile and elemental composition were also evaluated. Data were statistically analyzed by ANOVA and PCA/PCA-DA. Mycorrhizal colonization was higher in plants inoculated with R. irregularis, followed by F. mosseae and S. viscosum. In general, AMF mostly affected the parameters associated with the vegetative portion of the plant, while PGPB were especially relevant for fruit yield and quality. The plant physiological status was differentially affected by inoculations, resulting in enhanced root and shoot biomass. Inoculation with Pf4 bacterial strain increased flower and fruit production per plant and malic acid content in fruits, while decreased the pH value, regardless of the used fungus. Inoculations affected fruit nutritional quality, increasing sugar and anthocyanin concentrations, and modulated pH, malic acid, volatile compounds and elements. In the present study, we show for the first time that strawberry fruit concentration of some elements and/or volatiles can be affected by the presence of specific beneficial soil microorganisms. In addition, our results indicated that it is possible to select the best plant-microorganism combination for field applications, and improving fruit production and quality, also in terms of health promoting properties

Severe asthma: One disease and multiple definitions

Introduction: There is, so far, no universal definition of severe asthma. This definition usually relies on: number of exacerbations, inhaled therapy, need for oral corticosteroids, and respiratory function. The use of such parameters varies in the different definitions used. Thus, according to the parameters chosen, each patient may result in having severe asthma or not. The aim of this study was to evaluate how the choice of a specific definition of severe asthma can change the allocation of patients. Methods: Data collected from the Severe Asthma Network Italy (SANI) registry were analyzed. All the patients included were then reclassified according to the definitions of U-BIOPRED, NICE, WHO, ATS/ERS, GINA, ENFUMOSA, and TENOR. Results: 540 patients, were extracted from the SANI database. We observed that 462 (86%) met the ATS/ERS criteria as well as the GINA criteria, 259 (48%) the U-Biopred, 222 (41%) the NICE, 125 (23%) the WHO, 313 (58%) the Enfumosa, and 251 (46%) the TENOR criteria. The mean eosinophil value were similar in the ATS/ERS, U-Biopred, and Enfumosa (528, 532 and 516 cells/mcl), higher in WHO and Tenor (567 and 570 cells/mcl) and much higher in the NICE classification (624 cells/mcl). Lung function tests resulted similarly in all groups, with WHO (67%) and ATS/ERS-GINA (73%), respectively, showing the lower and upper mean FEV1 values. Conclusions: The present observations clearly evidence the heterogeneity in the distribution of patients when different definitions of severe asthma are used. However, the recent definition of severe asthma, provided by the GINA document, is similar to that indicated in 2014 by ATS/ERS, allowing mirror reclassification of the patients examined. This lack of homogeneity could complicate the access to biological therapies. The definition provided by the GINA document, which reflects what suggested by ATS/ERS, could partially overcome the problem

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements