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Background: The Molecular International Prognostic Scoring System (IPSS-M) has improved the prediction of clinical outcomes for myelodysplastic syndromes (MDS). The Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS), based on classical clinical parameters, has outperformed the IPSS, revised version (IPSS-R). For the first time, we validated the IPSS-M and other molecular prognostic models and compared them with the established IPSS-R and AIPSS-MDS models using data from South American patients., Methods: Molecular and clinical data from 145 patients with MDS and 37 patients with MDS/myeloproliferative neoplasms were retrospectively analyzed., Results: Prognostic power evaluation revealed that the IPSS-M (Harrell's concordance [C]-index: 0.75, area under the receiver operating characteristic curve [AUC]: 0.68) predicted overall survival better than the European MDS (EuroMDS; C-index: 0.72, AUC: 0.68) and Munich Leukemia Laboratory (MLL) (C-index: 0.70, AUC: 0.64) models. The IPSS-M prognostic discrimination was similar to that of the AIPSS-MDS model (C-index: 0.74, AUC: 0.66) and outperformed the IPSS-R model (C-index: 0.70, AUC: 0.61). Considering simplified low- and high-risk groups for clinical management, after restratifying from IPSS-R (57% and 32%, respectively, hazard ratio [HR]: 2.8; P =0.002) to IPSS-M, 12.6% of patients were upstaged, and 5% were downstaged (HR: 2.9; P =0.001). The AIPSS-MDS recategorized 51% of the low-risk cohort as high-risk, with no patients being downstaged (HR: 5.6; P <0.001), consistent with most patients requiring disease-modifying therapy., Conclusions: The IPSS-M and AIPSS-MDS models provide more accurate survival prognoses than the IPSS-R, EuroMDS, and MLL models. The AIPSS-MDS model is a valid option for assessing risks for all patients with MDS, especially in resource-limited centers where molecular testing is not currently a standard clinical practice.

Background: The postthrombotic syndrome (PTS) is a long-term complication of deep venous thrombosis (DVT). Increase knowledge on the PTS pathophysiology and novel biomarkers are needed in order to predict PTS development and to improve treatment results. The aim of this study was to analyze novel endothelium-biomarkers for PTS in patients with DVT out of the acute phase., Methods: A case-control study was conducted. Inclusion criteria were symptomatic and confirmed DVT patients treated with anticoagulants for at least 3 months. Villalta score was performed at the time of inclusion and used to diagnose and classify the severity of PTS. Plasma inter-cellular adhesion molecule 1 (ICAM-1), P-selectin, fractalkine and vascular endothelial growth factor (VEGF) were quantified using cytometric bead array. Endothelial progenitor cells (EPCs) and circulating endothelial cells (CEC) level were quantified by flow cytometry., Results: Thirty two patients and 61 controls were included. PTS patients showed higher levels of CEC (0.56/μl (0.34-1.5) vs. 0.20/μl (0.11-0.77); P  = 0.04) and EPC (0.75/μl (0.38-1.52) vs. 0.09/μl (0.05-0.82); P  = 0.0021) compared to no PTS patients. Patients with PTS had significantly higher levels of fractalkine (387.60 pg/ml (222.30-597.90) vs. 98.00 pg/ml (82.30-193.02); P  = 0.044) than patients without PTS. Fracktalkine levels showed a strong linear correlation with Villalta score, r  = 0.86, P  < 0.0001. No differences were observed in P-selectin, ICAM-1 and VEGF between studied groups., Conclusions: The formation and early resolution of DVT are characterized by inflammation and endothelial/platelet activation. We have identified possible novel biomarkers such as CEC, EPC and fractalkine for the development of PTS. These results suggest a possible role of these mediators in the maintenance and worsening of PTS turning them into potential therapeutic targets., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

We present the case of a 53-yr-old woman with an inherited bone marrow failure coexisting with uncommon extrahematological symptoms, such as cirrhosis and skin abnormalities. Whole-exome sequencing revealed a diagnosis of Shwachman-Diamond syndrome (SDS) with an atypical presentation. Unexpected was the age of disease expression, normally around the pediatric age, with a predominantly median survival age of 36 yr. To our knowledge, she was the first adult patient with a molecular diagnosis of Shwachman-Diamond in Uruguay. The patient was referred to our service when she was 43-yr-old with a history of bone marrow failure with anemia and thrombocytopenia. All secondary causes of pancytopenia were excluded. Bone marrow aspirate and biopsy specimens were hypocellular for the patient's age. Numerous dysplastic features were observed in the three lineages. She had a normal karyotype and normal chromosomal fragility. A diagnosis of low-risk hypoplastic MDS was made. Dermatological examination revealed reticulate skin pigmentation with hypopigmented macules involving the face, neck, and extremities; nail dystrophy; premature graying; and thin hair. Extrahematological manifestations were present (e.g., learning difficulties, short stature). Last, she was diagnosed with cryptogenic liver cirrhosis CHILD C. This rules out all other possible causes of chronic liver disease. This clinical presentation initially oriented the diagnosis toward telomeropathy, so we did a telomeropathy NGS panel that came up negative. Finally, we did an exome sequencing that confirmed the diagnosis of SDS. Using whole-exome sequencing, we were able to find two compound heterozygous mutations in the SBDS gene that were responsible for the phenotype of a patient that was undiagnosed for 10 years. An earlier genetic diagnosis could have influenced our patient's outcome., (© 2022 Spangenberg et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Endothelial progenitor cells (EPCs) are immature cells able to proliferate and contribute to endothelial repair, vascular homeostasis, neovascularization, and angiogenesis. It therefore seems likely that circulating EPCs have therapeutic potential in ischemic and vascular diseases. In this study we evaluated the efficiency of EPC mobilization and collection by large volume leukapheresis in subjects with hematological diseases, treated with plerixafor in association with G-CSF., Methods: Twenty-two patients with lymphoid malignancies underwent rHuG-CSF and plerixafor treatment followed by leukapheresis. Blood samples before and after treatment and apheresis liquid sample were taken and analyzed by flow cytometry in order to quantified EPC., Results: The percentage of CD34+ cells and EPCs among circulating total nuclear cells (TNCs) increased significantly by approximately 2-fold and 3-fold, respectively, after plerixafor treatment. Consequently, the absolute number of CD34+ cells and EPCs were increased 4-fold after plerixafor treatment. The median PB concentration of EPCs before and after treatment were 0.77/μL (0.31-2.15) and 3.41/μL (1.78-4.54), respectively, P < .0001. The total EPCs collected per patient were 3.3×10 7 (0.8×10 7 -6.8×10 7 )., Conclusion: We have shown that plerixafor in combination with G-CSF allows the mobilization and collection of large amounts of EPCs along with CD34+ cells in lymphoid neoplasm patients. The possibility to collect and to store these cells could represent a promising therapeutic tool for the treatment of ischemic complications without the need of in vitro expansion., (© 2022 Wiley Periodicals LLC.)

Myeloid Neoplasms with germline predisposition become part of 2016 World Health Organization (WHO) classification of hematological malignancies since 2016. CCAAT/enhancer binding protein-alpha ( CEBPA ) is a myeloid transcription factor located in chromosome 19q. Acute myeloid leukemia (AML) with biallelic mutations of CEBPA AML with recurrent genetic abnormalities according to WHO classification. The inheritance of a germline CEBPA mutation predisposes to the development of AML with autosomal dominant inheritance. Familial CEBPA AML share characteristics with somatic CEBPA AML. However, a higher relapse incidence is reported. We present the case of a 46-years-old male with family history of acute leukemia who was diagnosed with single mutated CEBPA acute myeloid leukemia. The same mutation was found in two of his siblings. The clinical suspicion and proper diagnosis of familial cases is necessary, especially when a related allogenic transplant is indicated in order to select an adequate donor., Competing Interests: Conflict of interest: The authors declare no potential conflict of interest., (©Copyright: the Author(s).)

The role of decentralized assessment of measurable residual disease (MRD) for risk stratification in acute myeloid leukemia (AML) remains largely unknown, and so it does which methodological aspects are critical to empower the evaluation of MRD with prognostic significance, particularly if using multiparameter flow cytometry (MFC). We analyzed 1076 AML patients in first remission after induction chemotherapy, in whom MRD was evaluated by MFC in local laboratories of 60 Hospitals participating in the PETHEMA registry. We also conducted a survey on technical aspects of MRD testing to determine the impact of methodological heterogeneity in the prognostic value of MFC. Our results confirmed the recommended cutoff of 0.1% to discriminate patients with significantly different cumulative-incidence of relapse (-CIR- HR:0.71, P < 0.001) and overall survival (HR: 0.73, P = 0.001), but uncovered the limited prognostic value of MFC based MRD in multivariate and recursive partitioning models including other clinical, genetic and treatment related factors. Virtually all aspects related with methodological, interpretation, and reporting of MFC based MRD testing impacted in its ability to discriminate patients with different CIR. Thus, this study demonstrated that "real-world" assessment of MRD using MFC is prognostic in patients at first remission, and urges greater standardization for improved risk-stratification toward clinical decisions in AML., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Cesarean section increases four times the risk of venous thromboembolism compared to vaginal delivery. The Royal College of Obstetricians and Gynecologists guidelines are used at our service. A written alert was designed to stratify patients at high, intermediate or low risk making a suggestion for thromboprophylaxis., Aim: To assess the compliance with the guidelines and to evaluate the impact of a written alert in the thromboprophylaxis compliance in women subjected to caesarean section., Patients and Methods: Review of medical records of 233 women aged 19 to 32 years, subjected to a caesarean section in a Gynecology Service, between 2016-2017., Results: Compliance with recommendations was observed in 29% of patients (68/233), 86% in the low-risk group, 26% in the intermediate risk group and 100% in the high risk group. In 41/233 (18%) of patients, a written alert was included in the medical record. Compliance with recommendations in the presence of the written alert was 61% (25/41 women) compared to 22% (43/192) in those lacking the alert (p < 0.01). In women whose emergency caesarean section was the only risk factor, the compliance with the recommendation was 8%, compared with 30% among those who had at least one thrombotic risk factor associated with caesarean section (p < 0.01)., Conclusions: In this cross-sectional study, we observed a low compliance with thromboprophylaxis guidelines in cesarean women. We observed that the use of a written alert improved the compliance with thromboprophylaxis.

Introduction: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematological diseases. In addition to defects in hematologic progenitor and stem cells, dysfunctions in the bone marrow microenvironment (BMM) participate in the MDS pathogenesis. Furthermore, the immune response is deregulated by the pro-inflammatory response prevailing in low-risk MDS, while immunosuppression predominates in high-risk MDS. Mesenchymal stromal cells (MSC), part of the BMM, are characterized by plastic adherent growth and multipotentiality. They exhibit immunomodulatory properties and sustain hematopoiesis. There is conflicting evidence regarding their status in MDS. The aim of this study was to characterize MDS-MSC and evaluate the effect of 5-Azacytidine., Methods: The MSC from MDS patients and controls were cultured and characterized according to the International Society of Cell Therapy recommendations. Immunomodulatory properties were assessed by studying the MSD cytokine production, using the cytometric bead array. We evaluated the effect of 5-Azacytidine on the MSC cytokine production., Results: We included 35 MDS patients and 22 controls. The MSC from patients and controls were cultured and characterized. The MSC from patients showed morphological differences, but there were no differences in immunophenotype or multipotentiality. The interleukin 6 (IL-6) was the main MSC secreted cytokine. The MDS-MSC produced higher levels of IL-6, IL-17, interferon gamma, or interferon γ (INF-γ), and tumor necrosis factor alpha (TNF-α). The in vitro 5-Azacytidine treatment induced a significant decrease in the IL-6 production by MDS-MSC., Conclusions: The MDS-MSC show an increased production of pro-inflammatory cytokines. The in vitro treatment with 5-Azacytidine lead to a significant reduction in the IL-6 production by the MDS-MSC, restoring the IL-6 levels to those found in controls. The MSC produced inflammatory cytokines involved in the MDS pathogenesis, representing a potential future therapeutic target. Moreover, 5-Azacytidine may have a stromal effect, modulating the immune response in MDS., (Copyright © 2020 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: Disorders of iron metabolism are very common pathological conditions. Iron deficiency, with or without anemia, is estimated to affect more than 2 billion people.The aim of this study was to determine the prevalence of iron deficiency and anemia and their predisposing factors in a group of premenopausal women, university students of the School of Medicine of the University of the Republic in Uruguay., Methods: An observational cross-sectional study was carried out, including women of reproductive age, university students of the Faculty of Medicine. They were interviewed in order to collect clinical data and monthly menstrual volume was recorded through a pictogram. A hemogram was performed and ferritin levels were determined., Results: 196 women aged from 18 to 37 years were included. The prevalence of iron deficiency was 8.7% (n = 17) and the prevalence of anemia was 2.1% (n = 4). The presence of iron deficiency was associated with a lower consumption of red meat (p = 0.024), a higher menstrual volume (p = 0.018) and a higher frequency of abnormal uterine bleeding (p = 0.019)., Conclusions: This study shows the high frequency of iron deficiency in healthy women in relation to abnormal uterine bleeding and low consumption of red meat, which raises the need to implement programs that promote educational measures in order to promote early consultation and avoid anemia and iron deficiency in these women of reproductive age., (Universidad Nacional de Córdoba.)

To evaluate cerebrospinal fluid (CSF) and peripheral blood (PB) Treg, TH17 cells, TH1, TH2 and related cytokines in the acute phase of aSAH we assessed TH17, TH1, TH2, T regulatory cells and neutrophils in 39 aneurysmal subarachnoid hemorrhage (aSAH) patients and 56 controls. PB TH17 cells and TH17/Treg ratio were higher in CSF and PB of aSAH patients. Serum and CSF IL-17A levels were increased in aSAH. Serum IL-17A levels were associated with vasospasm and ICU mortality. Study results support the role of TH17/IL17 axis in aSAH pathogenesis, turning it into a potential clinical biomarker and a novel target for research., (Copyright © 2020 Elsevier B.V. All rights reserved.)

: Venous thromboembolism remains as one of the leading causes of maternal death. Prevention of venous thromboembolism in the obstetric population is challenging as recommendations for prophylaxis have low grade of evidence. Risk factors and prophylaxis guidelines have been highlighted by Royal College of Obstetricians and Gynaecologists. In 2014, we developed a written alert following this guidelines to guide thromboprophylaxis. The aim of this study is to assess recommendations compliance. This study was conducted at University-Hospital in Uruguay from January 2014 to December 2016. A total of 1035 women were enrolled and stratified in high, intermediate or low risk based on Royal College of Obstetricians and Gynaecologists guidelines. Thromboprophylaxis was recommended for women at intermediate and high risk. Women were followed up to assess symptomatic thromboembolism or haemorrhagic complications. A total of 309 were pregnant and 731 puerperal. Median age was 24 (19-29) years old. Of them, 3.0% (n = 31) were at high risk and 35.4% (n = 366) at intermediate risk. All high-risk women received prophylaxis with low-molecular-weight heparin. Of the 366 intermediate-risk women, 52.7% received prophylaxis. Venous thromboembolism was developed in only one woman of the intermediate group, who had received prophylaxis. Bleeding complications were not observed. Awareness of the thrombotic risk, as conferred by an easy and suitable risk assessment, has the potential to improve venous thromboembolism prophylaxis in pregnant and puerperal women. We have a good guidelines compliance with the written alert in the high-risk women group. However, we have to improve low-molecular-weight heparin indication in intermediate-risk group, especially in postcaesarean women.

We have previously shown that Salmonella immunotherapy is effective to treat B-cell non-Hodgkin lymphoma (B-NHL) in mice. However, this model involves animals with high tumor burden, whereas in the clinics B-NHL patients are usually treated with chemotherapy (CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line therapy prior to immunotherapy. Recently, we have described a NHL-B preclinical model using CHOP chemotherapy to achieve MRD in immunocompetent animals that closely resemble patients' conditions. In this work, we assessed the efficacy of Salmonella immunotherapy in B-NHL-bearing mice undergoing chemotherapy. Salmonella administration significantly delayed tumor growth and prolonged survival of chemotherapy-treated NHL-bearing animals. Mice receiving the CHOP- Salmonella combined therapy showed increased numbers of tumor-infiltrating leukocytes and a different profile of cytokines and chemokines expressed in the tumor microenvironment. Further, Salmonella immunotherapy in CHOP-treated animals also enhanced NK cells cytotoxic activity as well as induced systemic lymphoma-specific humoral and cellular responses. Chemotherapy treatment profoundly impacted on the general health status of recipient animals, but those receiving Salmonella showed significantly better overall body condition. Altogether, the results clearly demonstrated that Salmonella immunotherapy could be safely used in individuals under CHOP treatment, resulting in a better prognosis. These results give strong support to consider Salmonella as a neoadjuvant therapy in a clinical setting.

Background: Non-Hodgkin lymphomas (NHL) are the most frequent hemato-oncological malignancies. Despite recent major advances in treatment, a substantial proportion of patients relapses highlighting the need for new therapeutic modalities. Promissory results obtained in pre-clinical studies are usually not translated when moving into clinical trials. Pre-clinical studies are mainly conducted in animals with high tumor burden; instead patients undergo chemotherapy as first line of treatment and most likely are under remission when immunotherapies are applied. Thus, an animal model that more closely resembles patients' conditions would be a valuable tool., Methods: BALB/c mice were injected subcutaneously with A20 lymphoma cells and after tumor development different doses of chemotherapy were assessed to find optimal conditions for minimal residual disease (MRD) establishment. Tumor growth and survival, as well as drugs side effects, were all evaluated. Complete lymphoma remission was monitored in vivo using positron emission tomography (PET), and the results were correlated with histology. Immunological status was assessed by splenocytes proliferation assays in NHL-complete remission mice and by analyzing tumor cell infiltrates and chemokines/cytokines gene expression in the tumor microenvironment of animals with residual lymphoma., Results: Two cycles of CHOP chemotherapy at days 25 and 35 post-tumor implantation induced complete remission for around 20 days. PET showed to be a suitable follow-up technique for MRD condition with 85.7 and 75% of sensibility and specificity respectively. Proliferative responses upon mitogen stimulation were similar in animals that received chemotherapy and wild type mice. Tumors from animals with residual lymphoma showed higher numbers of CD4 + and CD8 + and similar numbers of NK, neutrophils and Tregs infiltrating cells as compared with non-treated animals. Gene expression of several cytokines as well as an array of chemokines associated with migration of activated T cells to tumor sites was upregulated in the tumor microenvironment of animals that received chemotherapy treatment., Conclusions: We established a NHL-B pre-clinical model using standard chemotherapy to achieve MRD in immunocompetent animals. The MRD condition is maintained for approximately 20 days providing a therapeutic window of time where new immunotherapies can be tested in conditions closer to the clinics.

The frequency and profile of lymphocyte subsets within the culprit coronary artery were investigated in 33 patients with myocardial infarction and compared to their systemic circulating counterparts. T cell subsets including CD4(+)CD28null, activated and regulatory T-cells, TH1/TH2/TH17 phenotypes, NK and B-cells were studied in intracoronary (IC) and arterial peripheral blood (PB) samples. CD4(+)CD28null T-lymphocytes were significantly increased in IC compared to PB (3.7 vs. 2.9 %, p < 0.0001). Moreover, patients with more than 6 h of evolution of STEMI exhibited higher levels of CD4(+)CD28null T-cells suggesting that this subset may be associated with more intense myocardial damage. The rare NK subpopulation CD3(-)CD16(+)CD56(-) was also increased in IC samples (5.6 vs. 3.9 %, p = 0.006). CD4(+)CD28null T-cells and CD3(-)CD16(+)CD56(-) NK subpopulations were also associated with higher CK levels. Additionally, IFN-γ and IL10 were significantly higher in IC CD4(+) lymphocytes. Particular immune cell populations with a pro-inflammatory profile at the site of onset were increased relative to their circulating counterparts suggesting a pathophysiological role of these cells in plaque instability, thrombi and myocardial damage.

Background: There is growing evidence supporting the role of inflammation in aneurysmal subarachnoid hemorrhage (aSAH) pathophysiology and it is of great interest to elucidate which immune mechanisms are involved., Methods: 12 aSAH patients and 28 healthy controls were enrolled prospectively. We assessed leukocytes subpopulations and their activation status by flow cytometry in cerebrospinal fluid (CSF) and peripheral blood (PB) of SAH patients at the same time and in PB of controls., Results: Monocytes and neutrophils were activated in CSF of aSAH patients. The percentage of CD14(++)CD16(+) monocytes were higher in CSF than in PB of aSAH patients, and were also increased in PB of aSAH patients compared with controls. An enhanced expression of CD69 was shown in CSF neutrophils compared with PB in aSAH patients. PB of aSAH patients showed lower percentage of total lymphocytes compared with controls PB. Additionally, lymphocytes were activated in CSF and PB of aSAH patients. CD4(+) and CD8(+) T cells had a decreased expression on CD3 and higher levels of CD69 in CSF compared with PB in aSAH patients. Moreover, PB CD4(+) and CD8(+) T cells of aSAH patients were activated compared with controls. Additionally, CD28 expression was decreased on CSF T lymphocytes., Conclusions: Our data suggest an important recruitment of leukocytes to the site of injury in aSAH as well as an increased activation at this level. Overall, these results indicate that aSAH probably stimulates both the innate and adaptive immune responses.

Background: Febrile neutropenia is an important cause of mortality and morbidity in hematology-oncology patients undergoing chemotherapy. The management of febrile neutropenia is typically algorithm-driven. The aim of this study was to assess the results of a standardized protocol for the treatment of febrile neutropenia., Methods: A retrospective cohort study (2011-2012) was conducted of patients with high-risk neutropenia in a hematology-oncology service., Results: Forty-four episodes of 17 patients with a median age of 48 years (range: 18-78 years) were included. The incidence of febrile neutropenia was 61.4%. The presence of febrile neutropenia was associated with both the duration and severity of neutropenia. Microbiological agents were isolated from different sources in 59.3% of the episodes with bacteremia isolated from blood being the most prevalent (81.3%). Multiple drug-resistant gram-negative bacilli were isolated in 62.5% of all microbiologically documented infections. Treatment of 63% of the episodes in which the initial treatment was piperacillin/tazobactam needed to be escalated to meropenem. The mortality rate due to febrile neutropenia episodes was 18.5%., Conclusion: The high rate of gram-negative bacilli resistant to piperacillin/tazobactam (front-line antibiotics in our protocol) and the early need to escalate to carbapenems raises the question as to whether it is necessary to change the current protocol., (Copyright © 2014 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.)