Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

Beta-Blocker Use in Older Hospitalized Patients Affected by Heart Failure and Chronic Obstructive Pulmonary Disease: An Italian Survey From the REPOSI Register

Beta (β)-blockers (BB) are useful in reducing morbidity and mortality in patients with heart failure (HF) and concomitant chronic obstructive pulmonary disease (COPD). Nevertheless, the use of BBs could induce bronchoconstriction due to β2-blockade. For this reason, both the ESC and GOLD guidelines strongly suggest the use of selective β1-BB in patients with HF and COPD. However, low adherence to guidelines was observed in multiple clinical settings. The aim of the study was to investigate the BBs use in older patients affected by HF and COPD, recorded in the REPOSI register. Of 942 patients affected by HF, 47.1% were treated with BBs. The use of BBs was significantly lower in patients with HF and COPD than in patients affected by HF alone, both at admission and at discharge (admission, 36.9% vs. 51.3%; discharge, 38.0% vs. 51.7%). In addition, no further BB users were found at discharge. The probability to being treated with a BB was significantly lower in patients with HF also affected by COPD (adj. OR, 95% CI: 0.50, 0.37-0.67), while the diagnosis of COPD was not associated with the choice of selective β1-BB (adj. OR, 95% CI: 1.33, 0.76-2.34). Despite clear recommendations by clinical guidelines, a significant underuse of BBs was also observed after hospital discharge. In COPD affected patients, physicians unreasonably reject BBs use, rather than choosing a β1-BB. The expected improvement of the BB prescriptions after hospitalization was not observed. A multidisciplinary approach among hospital physicians, general practitioners, and pharmacologists should be carried out for better drug management and adherence to guideline recommendations

The role of small extracellular vesicles in the modulation of premetastatic niche and tumor microenvironment in pediatric lymphomas

I linfomi Non-Hodgkin (NHL) sono una serie di neoplasie che originano dal tessuto linfoide, in particolare da progenitori di cellule B o T. Le small-extracellular vesicles (S-EV), sono vescicole di piccole dimensioni racchiuse da un doppio strato fosfolipidico, potenzialmente rilasciate da qualsiasi tipo cellulare e ritrovate in ogni fluido corporeo. I microRNA (miRNAs) al loro interno, sono stati ampiamente studiati dato il loro ruolo fondamentale nella regolazione dell’espressione genica. Per quanto riguarda i linfomi però, molti di questi studi riguardano solo gli adulti; esistono quindi poche informazioni riguardo al loro ruolo nei linfomi pediatrici. Per questa ragione, lo scopo di questa ricerca è stato quello di caratterizzare il cargo delle S-EVs derivate dal plasma di pazienti pediatrici affetti da NHL. Innanzitutto, abbiamo dimostrato che il miR-26a-5p è il gene di riferimento migliore per la normalizzazione dei miRNAs nelle analisi di qPCR, nel contesto delle neoplasie onco-ematologiche pediatriche. Abbiamo poi caratterizzato, tramite small RNA-sequencing, il profilo dei miRNAs derivati dalle S-EVs del plasma di due diversi sottotipi di NHL pediatrici: il linfoma anaplastico a grandi cellule (ALCL), e lo stadio leucemico del linfoma di Burkitt, noto anche come leucemia linfoblastica acuta a cellule B mature (B-mALL). Per quanto riguarda le B-mALL abbiamo validato con qPCR la maggiore abbondanza dei miR-214-3p, miR-152-3p e miR-486-3p nelle S-EVs plasmatiche dei pazienti alla diagnosi. Il livello di questi miRNAs è significativamente più basso nelle S-EVs ottenute dal plasma di pazienti durante la chemioterapia. Questo risultato suggerisce che questi miRNAs siano validi biomarcatori tumorali della malattia. Inoltre, abbiamo dimostrato che le cellule tumorali e quelle del midollo osseo comunicano efficientemente tra di loro tramite S-EVs. Infatti, le cellule endoteliali aumentano il loro potenziale angiogenico quando trattate con S-EVs di cellule leucemiche. Le cellule mesenchimali stromali (MSCs) aumentando le loro capacità di migrazione, aumentano anche il loro differenziamento adipocitico e inibiscono quello osteoblastico dopo trattamento con S-EVs tumorali. Interessante notare che PTEN, un importante regolatore del differenziamento delle MSCs, può essere negativamente regolato dai miR-214-3p e miR-152-3p, risultati più abbondanti nelle S-EVs plasmatiche dei pazienti. Analizzando le vie di segnale inibite da PTEN abbiamo infatti riscontrato una maggiore fosforilazione di AKT e ERK in MSCs over-esprimenti i due miRNA, dimostrando un loro ruolo nella regolazione di questi pathways. Riassumendo, in questa parte dello studio si è dimostrato il ruolo del cargo di miRNAs delle S-EVs nel modificare le cellule del microambiente del midollo osseo, aprendo nuove prospettive terapeutiche nelle B-mALL. Anche negli ALCL si è rilevato un profilo peculiare di miRNA delle S-EVs plasmatiche rispetto ai controlli sani. In particolare, in questi pazienti abbiamo validato la maggiore espressione del miR-122-5p, un miRNA specifico del fegato, ipotizzando una sua origine non tumorale. Esiste inoltre una correlazione di questo miRNA con gli stadi tumorali avanzati e con funzioni epatiche alterate. Esperimenti in vitro hanno poi dimostrato che il miR-122-5p inibisce il consumo di glucosio nelle cellule stromali, aumentando così la disponibilità di questo metabolita nella nicchia, favorendo infine l’aggressività delle cellule tumorali. Inoltre, il miR-122-5p può aumentare la disseminazione del tumore in vivo. Nel complesso, alti livelli di miR-122-5p nelle S-EVs circolanti in pazienti con ALCL possono promuovere la disseminazione tumorale inducendo cambiamenti metabolici nella nicchia premetastatica. In conclusione, questi risultati supportano l’ipotesi di un possibile uso terapeutico di antagonisti del miR-122-5p per migliorare l’esito clinico dei pazienti affetti da ALCL.Non-Hodgkin lymphomas (NHL) are a series of malignant neoplasms originating from the lymphoid tissue and, in particular, tumor cells can derive from B or T cell progenitors. Small-extracellular vesicles (S-EVs) are lipid-bilayer enclosed vesicles that can be released by any cell type and found in all body fluids. S-EVs derived micro-RNAs (miRNAs) have generated great attention for their fundamental role in the regulation of gene expression and their aberrant expression in many tumors. Most of the studies about S-EVs miRNAs in lymphomas are focused on adults. Thus, so far, there is scarce information in the pediatric field. For these reasons the aim of this study was to characterize plasma S-EVs cargo in pediatric patients affected by NHL. Firstly, we demonstrated that miR-26a-5p is the most suitable reference gene for plasma S-EVs miRNA normalization in qPCR analysis, in the context of pediatric onco-hematological malignancies. Then, we profiled miRNAs cargo of plasma S-EVs in two different pediatric NHL subtypes, Anaplastic Large Cell Lymphoma (ALCL) and the leukemic stage of Burkitt Lymphoma also known as B-mature Cell Acute Lymphoblastic Leukemia (B-mALL). Differentially expressed miRNAs have been selected and validated, and their functional role in the biology of the tumor have been investigated. Small RNA sequencing data from plasma S-EVs showed a peculiar miRNA cargo in B-mALL compared to healthy donors (HD), revealing 40 small-RNAs significantly deregulated. We validated by qPCR the upregulation of miR-214-3p, miR-152-3p and miR-486-3p in patients’ S-EVs obtained at diagnosis; the significant decrease of these markers during chemotherapy suggests a tumor origin and corroborates their role as tumor biomarkers. Moreover, we demonstrated that leukemic cells and BM niche cells efficiently communicate between each other through S-EVs release and uptake, inducing modifications on target cells. We found an increased angiogenic potential of endothelial cells as a result of tumor-derived S-EVs treatment. Furthermore, mesenchymal stromal cells (MSCs) enhanced their migratory capacity after tumor-derived S-EVs treatment, approaching a cancer associated fibroblast phenotype. Recent evidence shows that leukemic cells can remodel BM niche also by blocking osteo-lineage development and inducing adipocyte formation. Interestingly, we confirm an increased adipogenesis and a decreased osteoblast formation in MSCs after tumor-derived S-EVs treatment. PTEN is an important regulator of MSCs differentiation; strikingly, miR-214-3p and miR-152-3p, upregulated in plasma S-EVs, negatively target PTEN. Interestingly, we found an increased activation of PTEN downstream pathways (enhanced phosphorylation of AKT and ERK) in MSCs overexpressing these two miRNAs. In summary, we demonstrated the potential role of S-EVs miRNAs cargo in modifying BM microenvironment, opening prospective for new targeted therapies in B-mALL. Small RNA sequencing of plasma S-EVs revealed a peculiar microRNA profile also in pediatric ALCL patients, when compared to HD. In particular, we validated the liver-specific miR-122-5p as more abundant in ALCL plasma S-EVs compared to HD, hyphotetizing a non- tumoral origin of this miRNA. We found that elevated levels of miR-122-5p correlate with advanced stage disease and impaired hepatic function in ALCL patients. In vitro experiments demonstrated that miR-122-5p inhibits glucose consumption in stromal cells, and the increased glucose availability enhances ALCL cell aggressiveness. Moreover, miR-122-5p promoted tumor dissemination in vivo. Overall, these data indicate that an increased level of miR-122-5p in circulating S-EVs of ALCL patients can promote cancer cells dissemination by inducing a metabolic change in the pre-metastatic niche. In conclusion, this finding sets the ground for investigating the clinical use of miR-122-5p antagonists in ALCL patients to potentially improve the clinical outcome

MiR-26a-5p as a Reference to Normalize MicroRNA qRT-PCR Levels in Plasma Exosomes of Pediatric Hematological Malignancies

Plasma exosomal microRNAs (miRNAs) are considered as valid circulating biomarkers for cancer diagnosis and prognosis. Quantitative real-time polymerase chain reaction (qRT-PCR), the most commonly used technique to assess circulating miRNA levels, requires a normalization step involving uniformly expressed endogenous miRNAs. However, there is still no consensus on reference miRNAs for plasma exosomal miRNA abundance normalization. In this study, we identified a panel of miRNAs with stable abundance by analyzing public plasma exosome RNA-seq data and selected miR-486-5p, miR-26a-5p, miR-423-5p and miR191-5p as candidate normalizers. Next, we tested the abundance variation of these miRNAs by qRT-PCR in plasma exosomes of healthy donors and pediatric patients with anaplastic large cell lymphoma, Burkitt lymphoma, Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia. MiR-486-5p and miR-26a-5p showed the most stable levels, both between healthy controls and patients and among the malignancies analyzed. In light of previous reports on miRNA stability in different exosome isolation methods, our data indicated that miR-26a-5p is a bona fide reference miRNA for qRT-PCR normalization to evaluate miRNA abundance from circulating plasma exosomes in studies of hematological malignancies

Increased Tenascin C, Osteopontin and HSP90 Levels in Plasmatic Small Extracellular Vesicles of Pediatric ALK-Positive Anaplastic Large Cell Lymphoma: New Prognostic Biomarkers?

Over the past 15 years, several biological and pathological characteristics proved their significance in pediatric anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALCL) prognostic stratification. However, the identification of new non-invasive disease biomarkers, relying on the most important disease mechanisms, is still necessary. In recent years, plasmatic circulating small extracellular vesicles (S-EVs) gathered great importance both as stable biomarker carriers and active players in tumorigenesis. In the present work, we performed a comprehensive study on the proteomic composition of plasmatic S-EVs of pediatric ALCL patients compared to healthy donors (HDs). By using a mass spectrometry-based proteomics approach, we identified 50 proteins significantly overrepresented in S-EVs of ALCL patients. Gene Ontology enrichment analysis disclosed cellular components and molecular functions connected with S-EV origin and vesicular trafficking, whereas cell adhesion, glycosaminoglycan metabolic process, extracellular matrix organization, collagen fibril organization and acute phase response were the most enriched biological processes. Of importance, consistently with the presence of nucleophosmin (NPM)-ALK fusion protein in ALCL cells, a topological enrichment analysis based on Reactome- and Kyoto Encyclopedia of Genes and Genomes (KEGG)-derived networks highlighted a dramatic increase in proteins of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway in ALCL S-EVs, which included heat shock protein 90-kDa isoform alpha 1 (HSP90AA1), osteopontin (SPP1/OPN) and tenascin C (TNC). These results were validated by Western blotting analysis on a panel of ALCL and HD cases. Further research is warranted to better define the role of these S-EV proteins as diagnostic and, possibly, prognostic parameters at diagnosis and for ALCL disease monitoring

An inherited gain‐of‐function risk allele in EPOR predisposes to familial JAK2 V617F myeloproliferative neoplasms

International audienceMyeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPORP488S ) in a large family diagnosed with JAK2V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPORP488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN

Prognostic Role of Minimal Disseminated Disease and NOTCH1/FBXW7 Mutational Status in Children with Lymphoblastic Lymphoma: The AIEOP Experience

NOTCH1/FBXW7 (N/F) mutational status at diagnosis is employed for T-cell lymphoblastic lymphoma (T-LBL) patients' stratification in the international protocol LBL 2018. Our aim was to validate the prognostic role of Minimal Disseminated Disease (MDD) alone and in combination with N/F mutational status in a large retrospective series of LBL pediatric patients. MDD was analyzed in 132 bone marrow and/or peripheral blood samples by flow cytometry. Mutations in N/F genes were analyzed on 58 T-LBL tumor biopsies. Using the previously established cut-off of 3%, the four-year progression-free survival (PFS) was 57% for stage I-III patients with MDD ≥ 3% versus 80% for patients with MDD inferior to cut-off (p = 0.068). We found a significant worsening in the four-year PFS for nonmutated (51 ± 12%) compared to mutated patients (100%, p = 0.0013). Combining MDD and N/F mutational status in a subgroup of available cases, we found a statistically significant difference in the four-year PFS for different risk groups (p = 0.0012). Overall, our results demonstrate that N/F mutational status has a more relevant prognostic value than MDD at diagnosis. However, the combination of N/F mutations with MDD analysis could identify patients with very aggressive disease, which might benefit from a more intensive treatment

Appropriateness of antiplatelet therapy for primary and secondary cardio- and cerebrovascular prevention in acutely hospitalized older people

Aims: Antiplatelet therapy is recommended for the secondary prevention of cardio- and cerebrovascular disease, but for primary prevention it is advised only in patients at very high risk. With this background, this study aims to assess the appropriateness of antiplatelet therapy in acutely hospitalized older people according to their risk profile. Methods: Data were obtained from the REPOSI register held in Italian and Spanish internal medicine and geriatric wards in 2012 and 2014. Hospitalized patients aged ≥65 assessable at discharge were selected. Appropriateness of the antiplatelet therapy was evaluated according to their primary or secondary cardiovascular prevention profiles. Results: Of 2535 enrolled patients, 2199 were assessable at discharge. Overall 959 (43.6%, 95% CI 41.5–45.7) were prescribed an antiplatelet drug, aspirin being the most frequently chosen. Among patients prescribed for primary prevention, just over half were inappropriately prescribed (52.1%), being mainly overprescribed (155/209 patients, 74.2%). On the other hand, there was also a high rate of inappropriate underprescription in the context of secondary prevention (222/726 patients, 30.6%, 95% CI 27.3–34.0%). Conclusions: This study carried out in acutely hospitalized older people shows a high degree of inappropriate prescription among patients prescribed with antiplatelets for primary prevention, mainly due to overprescription. Further, a large proportion of patients who had had overt cardio- or cerebrovascular disease were underprescribed, in spite of the established benefits of antiplatelet drugs in the context of secondary prevention