Sodium-glucose cotransporter 2 inhibitors and the cancer patient: from diabetes to cardioprotection and beyond.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class initially designed and approved for treatment of diabetes mellitus, have been shown to exert pleiotropic metabolic and direct cardioprotective and nephroprotective effects that extend beyond their glucose-lowering action. These properties prompted their use in two frequently intertwined conditions, heart failure and chronic kidney disease. Their unique mechanism of action makes SGLT2i an attractive option also to lower the rate of cardiac events and improve overall survival of oncological patients with preexisting cardiovascular risk and/or candidate to receive cardiotoxic therapies. This review will cover biological foundations and clinical evidence for SGLT2i modulating myocardial function and metabolism, with a focus on their possible use as cardioprotective agents in the cardio-oncology settings. Furthermore, we will explore recently emerged SGLT2i effects on hematopoiesis and immune system, carrying the potential of attenuating tumor growth and chemotherapy-induced cytopenias.

Impact of Covid 19 pandemic on hematopoietic stem cell transplantation activities: Report from a single center.

The current COVID-19 pandemic has placed unprecedented stress on the healthcare system, including HSCT. Several international organizations have created guidelines for managing different aspects of HSCT in the context of the pandemic. Comparing 2019 and 2020, our transplant center performed the same number of transplants. In both periods, transplants were mainly for patients with acute leukemia; thus, the urgency criteria was respected in light of pandemic restraints. Transplants by sibling donors and cord blood units remained the same, while transplants by unrelated donors were increased, in particular from European registries, and transplants by haploidentical donors were decreased. This change was made in light of the necessity of cryopreserving all apheresis products. We decided against cryopreserving bone marrow products due to the greater risk of drastic reduction in CD34 + cell count during the process. For urgent cases with only a haploidentical donor available, we opted for the use of PBSC following stimulation with G-CSF. GvHD prophylaxis was performed with PTCY on days + 3 + 5, cyclosporine with tapering from day + 100, and mycophenolic acid until day + 90 post-HSCT. Post-transplant outcomes such as graft failure, sepsis, and GVHD were not affected by the changes implemented. As a result of logistic difficulties, we halted our Car-T program from the start of the lockdown in March 2020 until September 2020. In accord with international guidelines, we were able to continue our HSCT program in the order to ensure a lifesaving treatment for patients with hematologic diseases for whom this procedure cannot be postponed.

Viscoelastic versus conventional coagulation tests to reduce blood product transfusion in patients undergoing liver transplantation: A systematic review and meta-analysis.

BACKGROUND: Recent literature suggests viscoelastic test (VET)-guided transfusion management could be associated with reduced blood product administration in patients undergoing liver transplantation. OBJECTIVES: To assess the effectiveness of coagulation management guided by VETs compared with conventional coagulation tests (CCTs) in reducing blood product transfusion in patients undergoing liver transplantation. DESIGN: Systematic review and meta-analysis of randomised (RCTs) and nonrandomised clinical trials performed according to PRISMA guidelines. The protocol was previously published (PROSPERO: CRD42021230213). DATA SOURCES: The Cochrane Central Library, PubMed/MEDLINE, Embase and the Transfusion Evidence Library were searched up to 30 th January 2022. ELIGIBILITY CRITERIA: Setting: operating room. Patients: liver transplantation recipients. Intervention: use of VETs versus CCTs. Main outcome measures: the primary outcome was the mean number of transfused units for each blood product including red blood cells (RBCs), fresh frozen plasma (FFP), platelets (PLTs) and cryoprecipitate. Secondary outcomes included mortality rate, intensive care unit (ICU) and hospital length of stay (LOS). RESULTS: Seventeen studies ( n  = 5345 patients), 15 observational and two RCTs, were included in this review. There was a mean difference reduction in RBCs [mean difference: -1.40, 95% confidence interval (95% CI), -1.87 to -0.92; P  < 0.001, I2  = 61%) and FFP units (mean difference: -2.98, 95% CI, -4.61 to -1.35; P  =  < 0.001; I2  = 98%) transfused in the VETs group compared with the CCTs one. A greater amount of cryoprecipitate was administered in the VETs group (mean difference: 2.71, 95% CI, 0.84 to 4.58; P  = 0.005; I2  = 91%). There was no significant difference in the mean number of PLT units, mortality, hospital and ICU-LOS. CONCLUSION: Our meta-analysis demonstrated that VETs implementation was associated with reduced RBC and FFP consumption in liver transplantation patients without effects on mortality and hospital and ICU-LOS. The certainty of evidence ranged from moderate to very low. Further well conducted RCTs are needed to improve the certainty of evidence.

Validation plan of bone marrow collection, processing and distribution using the failure mode and effect analysis methodology: a technical report.

BACKGROUND AIMS: Bone marrow (BM) is commonly used in the pediatric and adult setting as a source of hematopoietic stem cells (HSCs). The standards of the Joint Accreditation Committee of the International Society for Cell & Gene Therapy & European Society for Blood and Marrow Transplantation (JACIE) include specific requirements regarding BM collection, processing and distribution. To run this process, each transplant team develops a series of JACIE-compliant procedures, customizing them with regard to local settings and paths. Moreover, JACIE standards require that transplant teams validate and periodically revise their procedures to keep the entire process under control. In this article, the authors describe the methodology adopted in our center to fulfill the aforementioned JACIE requirements. METHODS: The authors developed a validation plan based on the failure mode and effect analysis (FMEA) methodology. According to the FMEA approach, the authors carefully revised activities and procedures connected to BM collection, processing and distribution at our institution. The entire process was initially divided into five main phases (assessment of donor eligibility, perioperative autologous blood donation, preparation of BM collection kit, BM harvesting and BM processing and distribution), comprising 17 subphases and 22 activities. RESULTS: For each activity, one or more failure modes were identified, for a total of 28 failure modes, and a risk priority number (RPN) was then assigned to each failure mode. Although many procedures were validated, others were subjected to substantial changes according to the RPN rating. Moreover, specific indicators were identified for subsequent monitoring to contain the risk of failure of steps emerging as critical at FMEA. CONCLUSIONS: This is the first study describing use of the FMEA methodology within an HSC transplant program. Shaping the risk analysis based on local experience may be a trustworthy tool for identifying critical issues, directing strict monitoring of critical steps or even amending connected procedures. Overall, the FMEA approach enabled the authors to improve our process, checking its consistency over time.

Protective effect of SARS-CoV-2 preventive measures against ESKAPE and Escherichia coli infections.

BACKGROUND/OBJECTIVES: We investigated whether behavioral precautions adopted during Coronavirus disease (COVID-19) pandemic also influenced the spreading and multidrug resistance (MDR) of ESKAPEEc (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii [AB], Pseudomonas aeruginosa, Enterobacter spp and Escherichia Coli, [EC]) among Intensive Care Unit (ICU) patients. SUBJECTS/METHODS: We performed a single-center retrospective study in adult patients admitted to our COVID-19-free surgical ICU. Only patients staying in ICU for more than 48 hours were included. The ESKAPEEc infections recorded during the COVID-19 period (June 1, 2020 - February 28, 2021) and in the corresponding pre-pandemic period (June 1, 2019 - February 28, 2020) were compared. An interrupted time series analysis was performed to rule out possible confounders. RESULTS: Overall, 173 patients in the COVID-19 period and 132 in the pre-COVID-19 period were investigated. The ESKAPEEc infections were documented in 23 (13.3%) and 35 (26.5%) patients in the pandemic and the pre-pandemic periods, respectively (p = 0.005). Demographics, diagnosis, comorbidities, type of surgery, Simplified Acute Physiology Score II, length of mechanical ventilation, hospital and ICU length of stay, ICU death rate, and 28-day hospital mortality were similar in the two groups. In comparison with the pre-pandemic period, no AB was recorded during COVID-19 period, (p = 0.017), while extended-spectrum beta-lactamase-producing EC infections significantly decreased (p = 0.017). Overall, the ESKAPEEc isolates during pandemic less frequently exhibited multidrug-resistant (p = 0.014). CONCLUSIONS: These findings suggest that a robust adherence to hygiene measures together with human contact restrictions in a COVID-19 free ICU might also restrain the transmission of ESKAPEEc pathogens.

Coronavirus disease 2019 pandemic and allogeneic hematopoietic stem cell transplantation: a single center reappraisal.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has deeply modified the complex logistical process underlying allogeneic hematopoietic stem cell transplant practices. AIM: In light of these changes, the authors compared data relative to allogeneic transplants carried out from 2018 at their center before (n = 167) and during the pandemic (n = 45). METHODS: The authors examined patient characteristics, donor and graft types, cell doses and main transplant outcomes. Moreover, the authors evaluated the rise of costs attributable to additional COVID-19-related procedures as well as the risk of adverse events these procedures conveyed to grafts or recipients. RESULTS: Overall, the number of transplants did not decrease during the pandemic, whereas patients at high relapse risk were prioritized. Transplants were mainly from matched unrelated donors, with a significant decrease in haploidentical related donors. Moreover, the use of bone marrow as a graft for haploidentical transplant was almost abandoned. Cryopreservation was introduced for all related and unrelated apheresis products, with a median storage time of 20 days. Notably, transplant outcomes (engraftment, acute graft-versus-host disease and non-relapse mortality) with cryopreserved products were comparable to those with fresh products. CONCLUSIONS: Considering that the emergency situation may persist for months, cryopreserving allogeneic grafts can offer a lifesaving opportunity for patients whose allogeneic transplant cannot be postponed until after the end of the COVID-19 pandemic.

Allogeneic cord blood transfusions prevent fetal haemoglobin depletion in preterm neonates. Results of the CB-TrIP study.

Repeated red blood cell (RBC) transfusions in preterm neonates are associated with poor outcome and increased risk for prematurity-associated diseases. RBC transfusions cause the progressive replacement of fetal haemoglobin (HbF) by adult haemoglobin (HbA). We monitored HbF levels in 25 preterm neonates until 36 weeks of post-menstrual age (PMA); patients received RBC units from allogeneic cord blood (cord-RBCs) or from adult donors (adult-RBCs), depending on whether cord-RBCs were available. Primary outcome was HbF level at PMA of 32 weeks. Twenty-three neonates survived until this age: 14 received no transfusions, two only cord-RBCs, three only adult-RBCs and four both RBC types. HbF levels in neonates transfused with cord-RBCs were significantly higher than in neonates receiving adult-RBCs (P < 0·0001) or both RBC types (P < 0·0001). Superimposable results were obtained at PMA of 36 weeks. Every adult-RBCs transfusion increased the risk for an HbF in the lowest quartile by about 10-fold, whereas this effect was not evident if combined adult- and cord-RBCs were evaluated. Overall, these data show that transfusing cord-RBCs can limit the HbF depletion caused by conventional RBC transfusions. Transfusing cord blood warrants investigation in randomised trials as a strategy to mitigate the severity of retinopathy of prematurity (NCT03764813).

Bone marrow haploidentical transplant with post-transplantation cyclophosphamide: does graft cell content have an impact on main clinical outcomes?

We analyzed data relative to cell content in 88 consecutive patients receiving HLA haploidentical bone marrow (BM) transplants with post-transplantation cyclophosphamide (PT-CY). Median age was 54.5 (range, 17-72); diagnoses were acute leukemia (n = 46), lymphoproliferative disorders (n = 24), myelofibrosis (n = 11) and myelodysplastic syndromes (n = 5). Total nucleated cell (TNC) and CD34+, CD3+, CD4+ and CD8+ cell doses were stratified as higher than first, second and third quartile and the dose effect on various clinical outcomes was assessed. Median time to engraftment was 17 days for neutrophils and 24 days for platelets. To receive a dose of TNC ≥3.2 x 106/kg or CD34+ cells ≥2.7 x 106/kg significantly shortened the time to neutrophil and platelet engraftment and reduced the blood product requirements in the 30-day period after transplantation. Overall, TNC and CD34+ cell doses had no effect on acute graft-versus-host disease (GVHD) incidence, whereas patients receiving higher CD3+ and CD8+ cell doses seemed to have less chronic GVHD. No effect on non-relapse mortality, progression-free survival and overall survival was observed at different cell dose thresholds. These data suggest that in HLA haploidentical BM transplant with PT-CY, appropriate cell doses are relevant to the engraftment. The association between low CD3+/CD8+ cells and chronic GVHD deserves further investigation.

Infectious complications in neonatal transfusion: Narrative review and personal contribution.

Neonates and prematures are among the most transfused categories of patients. Adverse reactions due to transfusions, such as transfusion-transmitted infections, can affect the rest of their lives. In this systematic review, we revised the literature concerning transfusion-transmitted infection in neonates. We reported case-reports and case-series previously published and we integrated these data with our experience at local neonatal intensive care unit. Moreover, we illustrated strategies for mitigating transfusion-transmitted infections, including donor selection and testing, pathogen inactivation technologies and combined approaches, as for Cytomegalovirus infection, integrating leukoreduction and identification of seronegative donors.

Umbilical cord blood: Current uses for transfusion and regenerative medicine.

The past 20 years of experience with umbilical cord blood transplantation have demonstrated that cord blood is effective in the treatment of a spectrum of diseases, including hematological malignancies, bone marrow failure, hemoglobinopathies, and inborn errors of metabolism. However, only a few number of umbilical cord blood units collected have a cell content adequate for an allogenic hematopoietic stem cell transplantation. In the meanwhile, there is an increasing interest in exploiting cord blood derivatives in different fields. In this review, we will summarize the most recent updates on clinical applications of umbilical cord blood platelet derivatives for regenerative medicine, and we will revise the literature concerning the use of umbilical cord blood for autologous or allogeneic transfusion purposes. The methodological aspect and the biological characteristics of these products also will be discussed.

Preoperative autologous blood donation in adult bone marrow donors: reappraisal of a single-centre experience.

To avoid risk for allogeneic transfusions in healthy bone marrow (BM) donors, 1-2 preoperative autologous blood donations (PAD) are usually collected before the BM harvest. We analysed the haematological parameters in BM donors before and after the harvest, to assess the efficacy of this practice in limiting the postharvest anaemia. Overall, 102 consecutive donors underwent BM harvest preceded by one (26 cases) or two PAD (76 cases), which were infused during BM collection. We analysed the parameters related to donors, PAD timing and BM graft characteristics. PAD induced a significant decrease in Hb (from 14·6 g/dl, IQ range 13·3-15·5 to12·9 g/dl, IQ range 11·8-13·9; P < 0·0001) in all donors, with a median Hb loss at day -1 of 10·9% (IQ range 6·8-14·2). The PAD-related Hb decrease was independent of sex or number of PAD, and was inversely related to the time elapsed from first or last PAD. In comparison with values recorded at day-1, BM harvest produced an additional Hb decrease, accounting for a median Hb loss of 18·9% (IQ range 14·9-24·4). Overall, in comparison with pre-PAD values, Hb levels at day +1 were reduced of 28·9% (IQ range 23·6-32·2), independently if donors had 1 or 2 PAD reinfused. In conclusion, these data show that two PAD do not carry any advantage over one PAD. An eventual benefit of PAD can be achieved only if an adequate interval between PAD and BM harvest elapses. Prospective randomized studies could be worth to establish if any role for PAD does exist in BM donors.

Umbilical cord blood as a source for red-blood-cell transfusion in neonatology: a systematic review.

The prevention and treatment of anaemia in newborn patients made tremendous progress in the last decades. However, red-blood-cell (RBC) transfusions remain unavoidable in many neonates candidate to surgery and especially in preterm infants. In particular, anaemia occurring in neonates born at extremely low gestational age is actually severe and frequently requires transfusions. Several approaches have been explored to prevent or even to reduce the threshold and the frequency of RBC transfusions. Among these, umbilical cord blood (UCB) collection and processing to obtain RBC components for autologous or allogeneic transfusion have been extensively investigated. In this systematic review, we revised the literature concerning the use of UCB for either autologous or allogeneic transfusion purposes and we illustrated the rationale for a transfusion therapy tailored to extremely preterm neonates, based on RBC concentrates from allogeneic UCB donations.

Red Cell Alloantibody Screening: Comparative Analysis of Three Different Technologies.

BACKGROUND: The detection of irregular antibody is a critical issue in the management of red blood cell transfusion according to the Type & Screen (T&S) practice. In order to implement the T&S procedure at our blood bank, we compared three different automated analyzers based on column agglutination technique (CAT) or solid phase red cell adherence assay (SPACA) methods. METHODS: Pre-transfusion antibody screening was performed in 986 patients candidate to elective surgery at low risk for red blood cell transfusion. We tested the following kits: the three-cell panel micro-CAT system ID-DiaCell I-II-III (DiaMed), the four-cell panel solid-phase system Capture-R Ready Screen-4 (Immucor), and the four-cell panel micro-CAT system Serascan Diana-4 (Grifols). Positive results were further investigated using corresponding identification panels, and discrepant results were investigated with all the antibody identification systems. RESULTS: Among 986 samples, we observed 967 concordant negative results (98.1%), 8 concordant positive results (0.8% of cases), and 11 discrepant results (1.1%). Among discrepant samples, an alloantibody could been identified in two patents (anti-M, detected by Serascan Diana-4 and ID-DiaCell I, II, III; anti-Kpa, detected by Capture-R Ready Screen-4 and Serascan Diana-4). CONCLUSION: Among the evaluated technologies, the four-cell panel micro-CAT system displayed the highest sensitivity and specificity with an optimal negative predictive value. These features might be relevant to the routine implementation of the T&S transfusion strategy.

Granulocyte Transfusions: A Critical Reappraisal.

Granulocyte transfusions (GTs) are seldom used as a life-saving therapy for neutropenic patients with severe infections. Despite compelling evidence of GT efficacy in retrospective and prospective case series, no study has been successful in demonstrating a definite advantage for recipients in controlled clinical trials. This review critically revises some aspects emerging from past experience that might have weakened the evidence of GT benefits. Some specific issues relevant to the efficacy of this therapeutic approach, such as primary infection, delivered doses and schedules, and immunologic effects of GTs, are discussed. Importantly, the awareness of biologic effects accompanying the transfusion of neutrophils might support their use at standardized doses and may definitely convey significant advantages to the recipient patients.

Effects of exposure to gradient magnetic fields emitted by nuclear magnetic resonance devices on clonogenic potential and proliferation of human hematopoietic stem cells.

This study investigates effects of gradient magnetic fields (GMFs) emitted by magnetic resonance imaging (MRI) devices on hematopoietic stem cells. Field measurements were performed to assess exposure to GMFs of staff working at 1.5 T and 3 T MRI units. Then an exposure system reproducing measured signals was realized to expose in vitro CD34+ cells to GMFs (1.5 T-protocol and 3 T-protocol). CD34+ cells were obtained by Fluorescence Activated Cell Sorting from six blood donors and three MRI-exposed workers. Blood donor CD34+ cells were exposed in vitro for 72 h to 1.5 T or 3 T-protocol and to sham procedure. Cells were then cultured and evaluated in colony forming unit (CFU)-assay up to 4 weeks after exposure. Results showed that in vitro GMF exposure did not affect cell proliferation but instead induced expansion of erythroid and monocytes progenitors soon after exposure and for the subsequent 3 weeks. No decrease of other clonogenic cell output (i.e., CFU-granulocyte/erythroid/macrophage/megakaryocyte and CFU-granulocyte/macrophage) was noticed, nor exposed CD34+ cells underwent the premature exhaustion of their clonogenic potential compared to sham-exposed controls. On the other hand, pilot experiments showed that CD34+ cells exposed in vivo to GMFs (i.e., samples from MRI workers) behaved in culture similarly to sham-exposed CD34+ cells, suggesting that other cells and/or microenvironment factors might prevent GMF effects on hematopoietic stem cells in vivo. Accordingly, GMFs did not affect the clonogenic potential of umbilical cord blood CD34+ cells exposed in vitro together with the whole mononuclear cell fraction.

Blood and endothelial cells: together through thick and thin.

In this issue of Blood, Rosti and colleagues report that in JAK2V617F positive patients with myelofibrosis (MF), a proportion of endothelial cells (ECs) from spleen tissues and splenic vein harbored this mutation.

In vitro cardiomyocyte differentiation of umbilical cord blood cells: crucial role for c-kit(+) cells.

BACKGROUND AIMS: Although bone marrow c-kit(+) progenitor cells support myocardial regeneration, the cardiomyocyte differentiation potential of umbilical cord blood (UCB) c-kit(+) cells is unknown. METHODS: UCB mononuclear cells (MNCs) and c-kit(+) cells purified by use of immunomagnetic beads were used. Cardiomyocyte differentiation was induced with (i) α-minimum essential medium (MEM) with cyclosporine A, (ii) α-MEM with bone morphogenic protein 4 (BMP-4) and transforming growth factor-ß (TGF-ß) or (iii) MEM with dexamethasone. The expression of cardiac markers (GATA4, GATA6, ß-myosin heavy chain, α-sarcomeric actin and cardiac Troponin T) was investigated, and whole-cell current and voltage-clamp recordings were performed. RESULTS: Although c-kit(+) cells revealed an immature gene profile, with high expression of CD34, CD133, aldehyde dehydrogenase-A1 and c-myc RNAs, purified c-kit(+) cells did not succeed in differentiating into cardiomyocyte-like cells in culture. In contrast, MNCs (either in α-MEM plus cyclosporine A or in α-MEM plus BMP-4 and TGF-ß) produced large, adherent cells expressing several cardiac genes and exhibiting an excitable phenotype. Cardiomyocyte-like cell formation was prevented by removing the c-kit(+) cell fraction from MNCs. Furthermore, after co-culturing carboxyfluorescein diacetate succynimidyl ester (CFSE)-tracked c-kit(+) cells together with c-kit(-) cells, we found that cardiac Troponin T--expressing cells were also CFSE(+). CONCLUSIONS: We show that UCB contains progenitors endowed with differentiation potential into cardiomyocytes: these cells reside in the c-kit(+) fraction and require the presence of abundant accessory cells to accomplish the differentiation. These preliminary observations provide the basis for consider the storage of autologous UCB in patients with prenatal diagnosis of congenital heart diseases potentially amenable by myocardial regenerative approaches.

Weak D Type 4.2.2 (DAR1.2) in an African child: Serology and molecular characterization.

The weak D phenotype is represented by a group of RHD genotypes that code for alterated RhD proteins associated with a reduced RhD expression on red blood cell. By routine serology, some partial D variants are likely to be missed. In this report we describe the case of a three-year-old Black African child with a "unclear" reaction with monoclonal anti-D. We analyzed the blood sample of the child with different methods to conclude that it is a case of DAR 1.2 (weak D 4.2.2) and that it must be transfused with D negative erithrocytes.

Does "more" necessarily mean "better"?

In this issue of Blood, Leon and colleagues describe the effects of romiplostim, athrombopoietin (Tpo) mimetic peptide, in the mouse model of inherited platelet dysfunction because of mutation of the myosin 9 gene.1