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Purpose: To evaluate the safety of subretinal injection of cord blood platelet-rich plasma (CB-PRP) and its possible effect in eyes affected by geographic atrophy (GA) associated with dry age-related macular degeneration (d-AMD). Design: Interventional, open-label study started in January 2021 with follow-up at 12 months (the Si.Cord Study). This study was a single-center, nonrandomized, sequential-assigned clinical trial conducted in Rome, Italy, at Fondazione Policlinico Universitario Agostino Gemelli IRCCS (ClinicalTrials.gov NCT04636853). Participants: Thirteen patients (26 eyes) with bilateral d-AMD-related GA were enrolled. One eye from each patient (with more advanced GA) underwent CB-PRP treatment, and the fellow eye was considered the control. All patients participated in follow-up at 12 months. Intervention: All 13 eyes received 23-gauge (G) vitrectomy and subretinal injection of CB-PRP using a 41-gauge needle. Main Outcomes and Measures: Best-corrected visual acuity (BCVA) with ETDRS letters, central macular thickness using OCT, and atrophic area measured on en face OCT images were assessed at baseline, 1, 3, 6, and 12 months. Results: The BCVA in the treated group was 34.46 ± 20.8 ETDRS at baseline, 40.84 ± 20.52 at 1 month, 40.07 ± 20.34 at 3 months, 39.38 ± 19.84 at 6 months, and 35.84 ± 18.38 at 12 months. In the untreated group, the BCVA was 53 ± 21.1 ETDRS letters at baseline, 51.54 ± 20.99 at 1 month, 46.62 ± 19.47 at 3 months, 46.85 ± 18.58 at 6 months, and 43.92 ± 17.97 at 12 months (2-way analysis of variance: interaction of treatment by eye or time, P = 0.084). Central macular thickness did not show a significant intereye difference at 12 months (P = 0.97). The atrophic geographic areas tended to increase in both treated and fellow eyes at 12 months (P < 0.0001). No inflammatory reaction, endophthalmitis, retinal detachment, uveitis, or other complications due to the subretinal injection of CB-PRP were observed during the follow-up. Conclusions: Subretinal injection of CB-PRP could be safely used for d-AMD in its GA form. Despite its safety, a larger cohort of patients, and probably a new way of administration, will be needed to understand whether the CB-PRP could have a role in the GA treatment. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Abstract Background Extremely low gestational age neonates (ELGANs, i.e., neonates born before 28 weeks of gestation) are at high risk of developing retinopathy of prematurity (ROP), with potential long-life visual impairment. Due to concomitant anemia, ELGANs need repeated red blood cell (RBC) transfusions. These produce a progressive replacement of fetal hemoglobin (HbF) by adult hemoglobin (HbA). Furthermore, a close association exists between low levels of HbF and severe ROP, suggesting that a perturbation of the HbF-mediated oxygen release may derange retinal angiogenesis and promote ROP. Methods/design BORN (umBilical blOod to tRansfuse preterm Neonates) is a multicenter double-blinded randomized controlled trial in ELGANs, to assess the effect of allogeneic cord blood RBC transfusions (CB-RBCs) on severe ROP development. Recruitment, consent, and randomization take place at 10 neonatology intensive care units (NICUs) of 8 Italian tertiary hospitals. ELGANs with gestational age at birth comprised between 24+0 and 27+6 weeks are randomly allocated into two groups: (1) standard RBC transfusions (adult-RBCs) (control arm) and (2) CB-RBCs (intervention arm). In case of transfusion need, enrolled patients receive transfusions according to the allocation arm, unless an ABO/RhD CB-RBC is unavailable. Nine Italian public CB banks cooperate to make available a suitable amount of CB-RBC units for all participating NICUs. The primary outcome is the incidence of severe ROP (stage 3 or higher) at discharge or 40 weeks of postmenstrual age, which occurs first. Discussion BORN is a groundbreaking trial, pioneering a new transfusion approach dedicated to ELGANs at high risk for severe ROP. In previous non-randomized trials, this transfusion approach was proven feasible and able to prevent the HbF decrease in patients requiring multiple transfusions. Should the BORN trial confirm the efficacy of CB-RBCs in reducing ROP severity, this transfusion strategy would become the preferential blood product to be used in severely preterm neonates. Trial registration ClinicalTrials.gov NCT05100212. Registered on October 29, 2021

Patients affected by transfusion-dependent β-thalassemia are prone to developing several clinical complications, mostly related to the iron overload. We report the case of a patient affected by transfusion-dependent β-thalassemia (TDT) developing acute promyelocytic leukemia (APL). In our case, the therapeutic management was significantly complicated not only by myocardial dysfunction, but also by the occurrence of the differentiation syndrome following all-trans retinoic acid (ATRA) administration. We carried out a careful revision of the current literature on the occurrence of hematological malignancies in β-thalassemia patients to investigate the major complications so far described. APL occurrence in β-thalassemia patients has been very rarely reported, and our experience suggests that TDT patients suffering pre-existing comorbidities may develop a potentially fatal complication during ATRA therapy.

Repeated red blood cell (RBC) transfusions are thought to increase the risk for retinopathy of prematurity (ROP), likely due to a critical fetal hemoglobin (HbF) reduction. In this study, we investigated if the postmenstrual age (PMA) of neonates at transfusion influences the risk for ROP. We estimated the cumulative transfusion-free survival (TFS) in a series of 100 preterm neonates receiving one or more RBC units. TFS was calculated by censoring patients at first transfusion and expressing the time between birth and transfusion as either PMA or postnatal day. Then, we investigated if TFS predicted the occurrence of severe ROP, defined as ROP stage 3 or higher. We found that neonates with severe ROP displayed a significantly shorter TFS expressed according to their PMA (p = 0.001), with similar TFS according to postnatal days. At receiver operating characteristic (ROC) curve analysis, receiving an RBC unit before week 28 of PMA predicted severe ROP with a sensitivity of 64% and a specificity of 78%. In addition, receiving a second RBC unit before the PMA of 29 weeks predicted severe ROP with a sensitivity of 75% and a specificity of 69%. At multivariate analysis, PMA at the second transfusion was even more informative than at first transfusion and outperformed all other variables in predicting severe ROP, with an odds ratio of 4.554 (95% CI 1.332–15.573, p = 0.016). Since HbF decrease is greater after multiple RBC transfusions, it is conceivable that neonates receiving more than one unit before the PMA of 29 weeks may be exposed to a greater disturbance of retinal vascularization. Any strategy aimed at preventing the critical HbF decrease at this low age might potentially reduce the risk for severe ROP.

Background. The impact of ABO incompatibility (ABO-I) on hematopoietic stem cell transplant outcomes is still debated. Methods. We retrospectively investigated 432 consecutive transplants performed at our center (2012–2020). All patients but 6 were affected by hematologic malignancies. The effect of different ABO match combinations on engraftment rate, transfusion support, acute and chronic graft-versus-host disease incidences, nonrelapse mortality (NRM), disease-free survival, and overall survival was assessed in univariate and multivariate analysis. Significance was set at P

Defibrotide (DFB) effects on different endothelial cell pathways have been investigated focusing on a limited number of genes or molecules. This study explored the modulation of the gene expression profile of steady-state or lipopolysaccharide (LPS)-activated endothelial cells, following the DFB exposure. Starting from differentially regulated gene expression datasets, we utilized the Ingenuity Pathway Analysis (IPA) to infer novel information about the activity of this drug. We found that effects elicited by LPS deeply differ depending on cells were exposed to DFB and LPS at the same time, or if the DFB priming occurs before the LPS exposure. Only in the second case, we observed a significant down-regulation of various pathways activated by LPS. In IPA, the pathways most affected by DFB were leukocyte migration and activation, vasculogenesis, and inflammatory response. Furthermore, the activity of DFB seemed to be associated with the modulation of six key genes, including matrix-metalloproteinases 2 and 9, thrombin receptor, sphingosine-kinase1, alpha subunit of collagen XVIII, and endothelial-protein C receptor. Overall, our findings support a role for DFB in a wide range of diseases associated with an exaggerated inflammatory response of endothelial cells.

High End-Surgery Arterial Lactate Concentration (ES-ALC) predicts poor outcome after hepatectomy. The aim of this study was to identify intraoperative hemodynamic parameters predicting high ES-ALC during elective liver resection. Patients who underwent liver resection between 2017 and 2018, under FloTrac/EV1000TM hemodynamic monitoring, were included. The ES-ALC cutoff best predicting severe postoperative complications was identified. Association between high ES-ALC and preoperative and intraoperative variables was assessed. 108 patients were included; 90-day mortality was 0.9% and severe morbidity 14.8%. ES-ALC cutoff best discriminating severe complications was 5.05 mmol/L. Patients with ES-ALC > 5.0 mmol/L had a relative risk of severe complications of 2.8% (p = 0.004). High ES-ALC patients had longer surgery and ischemia duration, larger blood losses and higher requirements of fluids and blood transfusions. During surgery, hemoglobin concentration and oxygen delivery (DO2) decreased more significantly in patients with high ES-ALC, although they had similar values of stroke volume and cardiac output to those of other patients. At multivariate analysis, surgery duration and lowest recorded DO2 value were the strongest predictors of high ES-ALC. ES-ALC > 5.0 mmol/L in elective liver resection predicts postoperative morbidity and is essentially driven by the impaired DO2. Timely correction of blood losses might prevent the ES-ALC increase.

Abstract Objectives The primary objective is to demonstrate that COVID-19 convalescent plasma (CCP) prevents progression to severe pneumonia in elderly COVID-19 pneumonia patients with chronic comorbidities. Secondary objectives are to demonstrate that CCP decreases the viral load in nasopharyngeal swabs and increases the anti-SARS-CoV-2 antibody titre in recipients. Trial design This is a randomized, open-label, parallel group, phase II/III study with a superiority framework. The trial starts with a screening phase II designed with two-tailed alpha=0.2. In case of positive results, the trial will proceed in a formally comparative phase III (alpha=0.05). Participants Adult patients with confirmed or suspected COVID-19 who are at risk according to CDC definition are eligible. Inclusion criteria are all the following: age ≥ 65; pneumonia at CT scan; PaO2/FiO2 ≥300 mmHg; presence of one or more comorbidities; signed informed consent. Exclusion criteria are one of the following: age < 65; PaO2/FiO2 < 300 mmHg; pending cardiopulmonary arrest; refusal to blood product transfusions; severe IgA deficiency; any life-threatening comorbidity or any other medical condition which, in the opinion of the investigator, makes the patient unsuitable for inclusion. The trial is being conducted at three reference COVID-19 centres in the middle of Italy. Intervention and comparator Intervention: COVID-19 Convalescent Plasma (CCP) in addition to standard therapy. Patients receive three doses (200 ml/day on 3 consecutive days) of ABO matched CCP. Comparator: Standard therapy Main outcomes A. Primary outcome for Phase II: Proportion of patients without progression in severity of pulmonary disease, defined as worsening of 2 points in the ordinal scale of WHO by day 14. B. Primary outcome for Phase III: Proportion of patients without progression in severity of pulmonary disease, defined as worsening of 2 points in the ordinal scale of WHO by day 14. Secondary outcomes for Phase III: Decreased viral load on nasopharyngeal swab at days 6, 9 and 14; Decreased viremia at days 6 and 9; Increased antibody titer against SARS-CoV2 at days 30 and 60; Proportion of patients with negative of SARS-CoV2 nasopharyngeal swab at day 30; Length of hospital stay; Mortality rate at day 28; Total plasma related adverse event (day 60); Total non-plasma related adverse events (day 60); Severe adverse events (SAE) (day 60). Randomisation Treatment allocation is randomized with a ratio 1:1 in both phase II and phase III. Randomization sequences will be generated at Fondazione Policlinico Gemelli IRCCS through the RedCap web application. Randomized stratification is performed according to age (under/over 80 years), and sex. Blinding (masking) None, this is an open-label trial. Numbers to be randomised (sample size) Phase II: 114 patients (57 per arm). Phase III: 182 patients (91 per arm) Trial Status The trial recruitment started on May 27, 2020. The anticipated date of recruitment completion is April 30, 2021. The protocol version is 2 (May 10, 2020). Trial registration The trial has been registered on ClinicalTrials.gov (May 5, 2020). The Identifier number is NCT04374526 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

It is still under debate whether granulocyte transfusions (GTs) substantially increase survival in patients with febrile neutropenia. We retrospectively examined data relative to 96 patients with hematological malignancies receiving 491 GTs during 114 infectious episodes (IE). Patients were grouped according to the median doses of granulocytes transfused during the infectious episode (low-dose group: 3.0x108 cells/Kg). The impact of clinical, microbiological and GT-related variables on the infection-related mortality (IRM) was investigated. The IRM was not influenced by the number of GTs or by the total amount of granulocytes received, whereas a dose-related effect of the median dose received for IE was detected at univariate analysis (IRM of 18.4% in the standard-dose group, 44.4% in the low-dose group and 48.4% in the high-dose group, p = 0.040) and confirmed at multivariate analysis (OR 3.7, IC 95% 1.5-8.9; 0.004 for patients not receiving standard doses of GTs). Moreover, patients receiving GTs at doses lower or greater than standard had increased risk for subsequent ICU admission and reduced overall survival. The dose-related effect of GTs was confirmed in bacterial but not in fungal infections. Preliminary findings obtained from a subgroup of patients candidate to GTs revealed that levels of inflammatory response mediators increase in a dose-related manner after GTs, providing a possible explanation for the detrimental effect exerted by high-dose transfusions. GTs can constitute a valuable tool to improve the outcome of infections in neutropenic patients, provided that adequate recipient-tailored doses are supplied. Further investigations of the immunomodulatory effects of GTs are recommended.