Anemia and iron in internal medicine: an Italian survey and a review on iron intravenous therapy in medical patients

In Italy, Internal Medicine Units hospitalize approximately 1,300,000 patients, often elderly and comorbid. The prevalent diagnoses are respiratory diseases, heart failure, or pneumonia. As a matter of fact, anemia is probably underestimated in the compilation of the official discharge forms (SDO) according to ICD-9 diagnostic codes. We promoted a survey among the Members the Italian Scientific Society of Internal Medicine (FADOI) with the aim to investigate the prevalence of anemia and iron deficiency, over than certain aspects related to the therapeutic management of patients with anemia. Furthermore, we performed a review summarizing current evidence for iron intravenous therapy in these patients. According to the survey, anemia is present in around half of the patients hospitalized in Internal Medicine, and about a quarter of them shows iron metabolism alterations. In the evaluation of iron metabolism, the dosage of ferritin is the most requested exam, whereas transferrin saturation is less considered. By focusing on some categories of patients, the awareness of the usefulness of intravenous iron therapy in patients with heart failure seems to be sufficiently common (76% of physicians), while it seems lower (60%) in the management of patients with chronic kidney disease (CKD) and anemia. Finally, more than 75% of the physicians answered that, in their hospital, there are few outpatients' offices or diagnostic pathways dedicated to patients with anemia. Anemia due to absolute or functional iron deficiency is particularly prevalent in Internal Medicine inpatients. For this reason, an accurate evaluation of iron profile and an adequate iron therapy is mandatory in these patients. Recent studies show that, in patients with heart failure, intravenous iron therapy is an effective way of improving patients' health, regardless of the presence of anemia. Similarly, iron therapy results fundamental to optimize erythropoiesis-stimulating agent efficacy in patients with chronic renal failure. In the next future, other therapeutic aspects of intravenous iron therapy will be probably clarified by several interesting ongoing studies focused on these patients

Complexity in hospital internal medicine departments: What are we talking about?

Internal medicine (IM) patients are mostly elderly, with multiple complex co-morbidities, usually chronic. The complexity of these patients involves the intricate entanglement of two or more systems (e.g. body and disease, family-socio-economic and environmental status, coordination of care and therapies) and this requires comprehensive, multi-dimensional assessment (MDA). Despite attempts to improve management of chronic conditions, and the availability of several MDA tools, defining the complex patient is still problematic. The complex profile of our patients can only be described through the best assessment tools designed to identify their characteristics. In order to do this, the Federation of Associations of Hospital Doctors on Internal Medicine FADOI has created its own vision of IM. This involves understanding the different needs of the patient, and analyzing diseases clusters and the possible relationships between them. By exploring the real complexity of our patients and selecting their real needs, we can exercise holistic, anthropological and appropriate choices for their treatment and care. A simpler assessment approach must be adopted for our complex patients, and alternative tools should be used to improve clinical evaluation and prognostic stratification in a hierarchical selection of priorities. Further investigation of complex patients admitted to IM wards is needed

Optimization of RAASi Therapy with New Potassium Binders for Patients with Heart Failure and Hyperkalemia: Rapid Review and Meta-Analysis

(1) Background: The objective of this rapid review is to assess whether new potassium binders (NPBs) could enable the optimization of RAASi therapy more than usual care or placebo in patients with or at risk of heart failure and hyperkalemia. (2) Methods: We searched for RCTs that included patients with or at risk of hyperkalemia and patients treated with Patiromer or sodium zirconium cyclosilicate (ZSC). The comparators were placebo, usual care, and potassium binders with different doses or different treatment protocols. We searched the Cochrane CENTRAL, MEDLINE, and ClinicalTrials.gov databases. The risk of bias was assessed using the Cochrane risk of bias tool for RCTs. Data were pooled using the random effects model, and the fixed effects model was used for sensitivity analysis. (3) Results: We included 12 studies with 2800 enrolled patients. Only three of these trials (412 patients) were included in the meta-analysis. NPBs seemed to have an effect on the optimization of MRA therapy, with an RR (95% CI) of 1.24 (1.09, 1.42) (moderate certainty evidence); Patiromer seemed to have an effect on MRA optimization, with an RR (95% CI) or 1.25 (1.08, 1.45) (high certainty evidence). ZSC seemed to have no effect on enabling MRA therapy, with an RR (95% CI) of 1.19 (0.89, 1.59) (low certainty evidence). The AEs in HF patients with hyperkalemia treated with Patiromer were GI disorders and hypomagnesemia. ZSC The AEs included chronic cardiac failure, hypokalemia, and edema. (4) Conclusions: This meta-analysis included three studies with a small number of patients and a short follow-up period (1–3 months). The evidence of the effect of NPBs on MRA optimization had a moderate certainty for imprecision. Data on the effect on MRA optimization and less severe AEs in long-term treatment seem to suggest the use of Patiromer for the optimization of MRA therapy in patients with or at risk of heart failure and hyperkalemia. Future adequately powered RCTs are needed to assess the benefits and potential harms of potassium binders

Rhabdomyosarcoma Cells Produce Their Own Extracellular Matrix With Minimal Involvement of Cancer-Associated Fibroblasts: A Preliminary Study

Background: The interplay between neoplastic cells and surrounding extracellular matrix (ECM) is one of the determinant elements for cancer growth. The remodeling of the ECM by cancer-associated fibroblasts (CAFs) shapes tumor microenvironment by depositing and digesting ECM proteins, hence promoting tumor growth and invasion. While for epithelial tumors CAFs are well characterized, little is known about the stroma composition of mesenchymal cancers, such as in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma during childhood and adolescence. The aim of this work is to identify the importance of CAFs in specifying RMS microenvironment and the role of these stromal cells in RMS growth. Methods: We assessed in two dimensional (2D) and three dimensional (3D) systems the attraction between RMS cells and fibroblasts using epithelial colon cancer cell line as control. CAFs were studied in a xenogeneic mouse model of both tumor types and characterized in terms of fibroblast activation protein (FAP), mouse PDGFR expression, metalloproteases activation, and ECM gene and protein expression profiling. Results: In 2D model, the rate of interaction between stromal and malignant cells was significantly lower in RMS with respect to colon cancer. Particularly, in 3D system, RMS spheroids tended to dismantle the compact aggregate when grown on the layer of stromal cells. In vivo, despite the well-formed tumor mass, murine CAFs were found in low percentage in RMS xenogeneic samples. Conclusions: Our findings support the evidence that, differently from epithelial cancers, RMS cells are directly involved in their own ECM remodeling, and less dependent on CAFs support for cancer cell growth

Angiotensin II Promotes SARS-CoV-2 Infection via Upregulation of ACE2 in Human Bronchial Cells

Blockers of the renin‐angiotensin system (RAS) have been reported to increase the angiotensin converting enzyme (ACE)2, the cellular receptor of SARS‐CoV‐2, and thus the risk and course of COVID‐19. Therefore, we investigated if angiotensin (Ang) II and RAS blockers affected ACE2 expression and SARS‐CoV‐2 infectivity in human epithelial bronchial Calu‐3 cells. By infectivity and spike‐mediated cell–cell fusion assays, we showed that Ang II acting on the angiotensin type 1 receptor markedly increased ACE2 at mRNA and protein levels, resulting in enhanced SARS‐CoV‐ 2 cell entry. These effects were abolished by irbesartan and not affected by the blockade of ACE‐1‐ mediated Ang II formation with ramipril, and of ACE2‐ mediated Ang II conversion into Ang 1‐7 with MLN‐4760. Thus, enhanced Ang II production in patients with an activated RAS might expose to a greater spread of COVID‐19 infection in lung cells. The protective action of Angiotensin type 1 receptor antagonists (ARBs) documented in these studies provides a mechanistic explanation for the lack of worse outcomes in high‐risk COVID‐19 patients on RAS blockers

PANCREATIC CANCER (PaCa)-DERIVED SOLUBLE MEDIATORS INDUCE DENDRITIC CELLS (DC) TO ACQUIRE AN IMMUNESUPPRESSIVE PHENOTYPE BY DOWNREGULATING CTLA4

Objective: An altered function of lymphocytes, DC and immature myeloid cells appears to be an hallmark of tumor-mediated immune suppression and the two inhibitory co-stimulatory receptors PDL-1 and CTLA4 might have a role in this context. The aim of the present in vitro study was to assess whether PaCa cells cross-talk with normal mononuclear circulating cells (PBMC) causing them to acquire an immunesuppressive phenotype and to evaluate whether PDL1 and CTLA4 are involved. Methods: PBMC from blood donors were cultured for 4 days in Control (CTL) and in the PaCa cancer cell line Capan1 conditioned media (CM). Lymphocytes subsets (CD4+, CD8+, CD4+CD25+) and CD33+ immature myeloid cells subsets (CD14+/-; HLA-DR+/-) expressing or not PDL1 and/or CTLA4 were analysed by flow cytometry. To assess immunesuppressive function, myeloid cells were FACS sorted and co-coltured with allogenic total T lymphocytes in 1:20 and 1:40 ratio. Total T lymphocytes proliferation was determined by 3HThymidine uptake. Results: Capan1 CM caused an expansion of CD4+CD25+ (p=0.01) and a reduction of CD33+CD14- HLA-DR+ (p=0.03) cells. In this latter cellular subset, CM caused also an increase of PDL1 (p=0.046) and a decrease of CTLA4 (p=0.05) positive cells. FACS sorted CTL and CM CD33+CD14-HLA-DR+ cells did not significantly affect the proliferation of allogenic total T lymphocytes at 1:20 (p=0,54) or at 1:40 ratio (p=0,81). The CD33+CD14-HLA-DR+ PDL-1+ cells did not significantly modify allogenic T cells proliferation with respect to PDL- cells (p=0,11), while those cells which were CTLA4 negative caused a significant inhibition of T cell proliferation in comparison of CTLA4 positive cells (p=0,008). Conclusions: PaCa-derived soluble factors induce the expansion of the inhibitory lymphocytes subset CD4+CD25+ and a reduction of the immature CD33+CD14-DR+ dendritic cells. The tumor associated reduced expression of the inhibitory molecule CTLA4 in this cell population was demonstrated to characterize an immunosuppressive phenotype and this study suggests to take care in the use of anti-CTLA4 therapies