Titers of IgG and IgA against SARS-CoV-2 proteins and their association with symptoms in mild COVID-19 infection.

Humoral immunity in COVID-19 includes antibodies (Abs) targeting spike (S) and nucleocapsid (N) SARS-CoV-2 proteins. Antibody levels are known to correlate with disease severity, but titers are poorly reported in mild or asymptomatic cases. Here, we analyzed the titers of IgA and IgG against SARS-CoV-2 proteins in samples from 200 unvaccinated Hospital Workers (HWs) with mild COVID-19 at two time points after infection. We analyzed the relationship between Ab titers and patient characteristics, clinical features, and evolution over time. Significant differences in IgG and IgA titers against N, S1 and S2 proteins were found when samples were segregated according to time T1 after infection, seroprevalence at T1, sex and age of HWs and symptoms at infection. We found that IgM + samples had higher titers of IgG against N antigen and IgA against S1 and S2 antigens than IgM - samples. There were significant correlations between anti-S1 and S2 Abs. Interestingly, IgM + patients with dyspnea had lower titers of IgG and IgA against N, S1 and S2 than those without dyspnea. Comparing T1 and T2, we found that IgA against N, S1 and S2 but only IgG against certain Ag decreased significantly. In conclusion, an association was established between Ab titers and the development of infection symptoms.

Cemented vs cementless stems for revision arthroplasties due to Vancouver B2 periprosthetic hip fracture.

PURPOSE: According to Vancouver classification, B2 type fractures are most often treated with removal of the loose stem and implantation of a long stem that bypasses the fracture site. However, there is a controversy about the stem fixation that should be used: cemented or cementless. Hence, this study aims to compare cemented and cementless stems in prosthetic revision due to Vancouver B2 (VB2) periprosthetic hip fracture. METHODS: A retrospective study was done including all the patients treated with stem exchange due to VB2 periprosthetic hip fracture in a tertiary hospital between 2015 and 2022. Patients were divided into two groups according to the stem fixation used: cemented or cementless. Functional outcomes, hospital stay, surgical time, complication rate, and mortality were compared between the two groups of patients. RESULTS: Of the 30 included patients, 13 (43.4%) were treated with cementless stems and 17 (56.7%) with cemented stems. There were no statistically significant differences in age, gender, anesthesia risk scale (ASA) or functional capacity prior to the intervention. Patients treated with cementless stems had a higher complication and reintervention rate than those treated with cemented stems: 62 and 45% versus 34 and 6% (p = 0.035; p = 0.010), respectively. Furthermore, in the group of cementless stems a higher proportion of non-union was found (53.8% vs. 17.6%; p = 0.037). Also, the hospital stay (33 vs. 24 days; p = 0.037) and the time to full weight-bearing (21 days vs. 9 days; p < 0.001) were longer in the cementless stem group. CONCLUSION: Cemented fixation in stem revision due to Vancouver B2 periprosthetic hip fracture could be an optimal option with faster recovery which could decrease the rate of complications and reintervention, without compromising the fracture healing and patient mortality. Thus, this option can be considered when an anatomical reduction can be obtained, especially in elderly patients with multiple comorbidities in which a less aggressive surgical option should be considered.

Vancouver B2 periprosthetic hip fractures treatment: fix or replace? A retrospective study comparing both techniques.

INTRODUCTION: Vancouver B2 periprosthetic hip fractures involve stem stability and they have been classically treated with revision surgery. Crucial factors such as age, clinical comorbidities and functional status are often neglected. The current study aims to compare clinical outcomes between patients treated with open reduction and internal fixation (ORIF) or femoral stem exchange. METHODS: This is a retrospective study that includes all Vancouver B2 periprosthetic hip fractures in a tertiary referral hospital from 2016 to 2020. Patients were divided into two groups: Group 1. Patients treated with an ORIF and Group 2. Patients treated with stem replacement. The outcomes that were compared between groups included demographic data, functional capacity, complications and mortality. RESULTS: 29 periprosthetic Vancouver B2 fractures were finally analyzed. 11 (37.9%) were treated with ORIF (Group 1) and 18 (62.1%) by stem replacement (Group 2). Surgery time (143 vs. 160 min), hemoglobin drop (1.8 vs. 2.5 g/dL) and hospital stance (25.5 vs. 29.6 days) were shorter in Group 1. According to complications, 18.2% of patients in the ORIF group had orthopedic complications compared with 44.4% in the revision group. In the revision group, 3 cases needed a two-stage revision and one of these revisions ended up with a resection arthroplasty (Girdlestone). The first-year mortality rate was 27% in Group 1 and 11% in Group 2. DISCUSSION: ORIF treatment seems to be a less aggressive and complex procedure which can lead to a faster general recovery. Revision surgery can imply a higher risk of orthopedic complications which can be severe and may require further aggressive solutions. The ORIF group mortality was similar to the proximal femur fracture rate (20-30%). In conclusion, ORIF treatment seems to be a good option especially in fragile patients with low functional demand when anatomical reduction is possible.

Machine Learning Improves Risk Stratification in Myelodysplastic Neoplasms: An Analysis of the Spanish Group of Myelodysplastic Syndromes.

Myelodysplastic neoplasms (MDS) are a heterogeneous group of hematological stem cell disorders characterized by dysplasia, cytopenias, and increased risk of acute leukemia. As prognosis differs widely between patients, and treatment options vary from observation to allogeneic stem cell transplantation, accurate and precise disease risk prognostication is critical for decision making. With this aim, we retrieved registry data from MDS patients from 90 Spanish institutions. A total of 7202 patients were included, which were divided into a training (80%) and a test (20%) set. A machine learning technique (random survival forests) was used to model overall survival (OS) and leukemia-free survival (LFS). The optimal model was based on 8 variables (age, gender, hemoglobin, leukocyte count, platelet count, neutrophil percentage, bone marrow blast, and cytogenetic risk group). This model achieved high accuracy in predicting OS (c-indexes; 0.759 and 0.776) and LFS (c-indexes; 0.812 and 0.845). Importantly, the model was superior to the revised International Prognostic Scoring System (IPSS-R) and the age-adjusted IPSS-R. This difference persisted in different age ranges and in all evaluated disease subgroups. Finally, we validated our results in an external cohort, confirming the superiority of the Artificial Intelligence Prognostic Scoring System for MDS (AIPSS-MDS) over the IPSS-R, and achieving a similar performance as the molecular IPSS. In conclusion, the AIPSS-MDS score is a new prognostic model based exclusively on traditional clinical, hematological, and cytogenetic variables. AIPSS-MDS has a high prognostic accuracy in predicting survival in MDS patients, outperforming other well-established risk-scoring systems.

Survival improvement of patients with FLT3 mutated acute myeloid leukemia: results from a prospective 9 years cohort.

Midostaurin added to intensive chemotherapy is the standard of care for acute myeloid leukemia (AML) with FLT3 mutations (FLT3mut). We analyzed the impact of midostaurin in 227 FLT3mut-AML patients included in the AML-12 prospective trial for fit patients ≤70 years (#NCT04687098). Patients were divided into an early (2012-2015) and late (2016-2020) cohorts. They were uniformly treated except for the addition of midostaurin in 71% of late group patients. No differences were observed in response rates or the number of allotransplants between groups. Outcome was improved in the late period: 2-year relapse incidence decreased from 42% vs 29% in early vs late group (p = 0.024) and 2-year overall survival (OS) improved from 47% vs 61% (p = 0.042), respectively. The effect of midostaurin was evident in NPM1mut patients (n = 151), with 2-yr OS of 72% (exposed) vs 50% (naive) patients (p = 0.011) and mitigated FLT3-ITD allelic ratio prognostic value: 2-yr OS with midostaurin was 85% and 58% in low and high ratio patients (p = 0.049) vs 67% and 39% in naive patients (p = 0.005). In the wild-type NPM1 subset (n = 75), we did not observe significant differences between both study periods. In conclusion, this study highlights the improved outcome of FLT3mut AML fit patients with the incorporation of midostaurin.

Prognostic impact of DNMT3A mutation in acute myeloid leukemia with mutated NPM1.

The negative prognostic impact of internal tandem duplication of FLT3 (FLT3-ITD) in patients with acute myeloid leukemia with mutated NPM1 (AML-NPM1) is restricted to those with a higher FLT3-ITD allelic ratio (FLT3high; ≥0.5) and considered negligible in those with a wild-type (FLT3WT)/low ITD ratio (FLT3low). Because the comutation of DNMT3A (DNMT3Amut) has been suggested to negatively influence prognosis in AML-NPM1, we analyzed the impact of DNMT3Amut in FLT3-ITD subsets (absent, low, and high ratios). A total of 164 patients diagnosed with AML-NPM1 included in 2 consecutive CETLAM protocols and with DNMT3A and FLT3 status available were studied. Overall, DNMT3Amut status did not have a prognostic impact, with comparable overall survival (P = .2). Prognostic stratification established by FLT3-ITD (FLT3WT = FLT3low > FLT3high) was independent of DNMT3Amut status. Measurable residual disease (MRD) based on NPM1 quantitative polymerase chain reaction was available for 94 patients. DNMT3Amut was associated with a higher number of mutated NPM1 transcripts after induction (P = .012) and first consolidation (C1; P < .001). All DNMT3Amut patients were MRD+ after C1 (P < .001) and exhibited significant MRD persistence after C2 and C3 (MRD+ vs MRD-; P = .027 and P = .001, respectively). Finally, DNMT3Amut patients exhibited a trend toward greater risk of molecular relapse (P = .054). In conclusion, DNMT3Amut did not modify the overall prognosis exerted by FLT3-ITD in AML-NPM1 despite delayed MRD clearance, possibly because of MRD-driven preemptive intervention.

European LeukemiaNet 2017 risk stratification for acute myeloid leukemia: validation in a risk-adapted protocol.

The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and postremission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the Cooperativo Para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, whereas it recommends allogeneic stem cell transplantation (alloSCT) as a postremission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%), and 245 (36%) patients allocated to the favorable-, intermediate-, and adverse-risk group, respectively. The 2- and 5-year overall survival (OS) rates were 77% and 70% for favorable-risk patients, 52% and 46% for intermediate-risk patients, and 33% and 23% for adverse-risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype, and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol based on alloSCT after remission for nonfavorable ELN subgroups and identifies a genetic subset with a very poor outcome that warrants investigation of novel strategies.

Many signs, one mutation: Early onset of de novo GATA2 deficiency syndrome. A case report.

We report a case with a broad spectrum of symptoms, related to GATA2 deficiency syndrome, which emerged as early as at 6 months of age. They ranged from lymphedema, deafness to myelodysplastic syndrome (MDS).

Bone marrow fibrosis, sequence variant of asxl1, and Sjögren syndrome: A case report.

Only proven pathogenic mutations associated with myeloid neoplasms are key to establish the clonal nature of the bone marrow fibrosis. In cases with genetic variants of uncertain meaning, the clinical picture may be required to rule out secondary causes.

Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease.

In the European LeukemiaNet favourable risk category, allogeneic haematopoietic stem cell transplantation (alloSCT) is not indicated in first complete remission for patients with acute myeloid leukaemia (AML) with NPM1 mutations (ELNfav NPM1 AML), although a proportion of these patients will relapse. Given the prognostic importance of measurable residual disease (MRD), CETLAM-12 considered a pre-emptive intervention in patients with molecular failure (MF). We analyzed 110 ELNfav NPM1 AML patients achieving complete remission (CR) after induction chemotherapy. Two-year cumulative incidence of relapse (CIR), overall survival (OS) and leukaemia-free survival (LFS) were 17%, 81·5% and 82%, respectively. Forty-six patients required additional therapy for MF (n = 33) or haematological relapse (HemR; n = 13), resulting in a molecular LFS (molLFS) and a cumulative incidence of MF at two years of 61% and 38% respectively. Two-year OS for these 46 patients was 66%, with a different outcome between patients with MF (86%) and HemR (42%) (P = 0·002). Quantitative NPM1 detection at different timepoints was predictive of molLFS; an MRD ratio (NPM1mut/ABL1 × 100) cut-off of 0·05 after first consolidation identified two cohorts with a two-year molLFS of 77% and 40% for patients below and above 0·05, respectively. In conclusion, MRD-based pre-emptive intervention resulted in a favourable outcome for ELNfav NPM1 AML patients.

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants.

The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

Ultrastructural, cytogenetic, and molecular findings in mast cell leukemia: Case report.

We report a de novo aleukemic form of MCL with a complex monosomic karyotype with LOH for multiple chromosomes and TP53 mutation. Additionally, whereas D816V KIT was not found, the c-Kit transmembrane domain p.M541L variant was detected which is the most common SNP of KIT gene in humans with controversial pathogenic role. In these cases, it is crucial to perform a rapid broad molecular study for an accurate diagnosis which could help to initiate targeted therapy.

Bone marrow WT1 levels in patients with myeloid neoplasms treated with 5-azacytidine: Identification of responding patients.

INTRODUCTION: Increased levels of Wilms' tumor (WT1) mRNA have been used to establish risk categories in patients with acute myeloid leukemia (AML). Raised values of WT1 have been associated with progression in myelodysplastic syndrome (MDS). METHODS: We retrospectively analyzed the available bone marrow (BM) samples from 115 patients with myeloid neoplasms obtained before and during treatment with 5-azacytidine. A threshold of 100 copies in BM was used to define risk groups: group 1: patients with WT1 levels always below < 100 copies; group 2: cases with initial WT1 levels greater than 100 copies but with a conversion to sustained levels below 100; and group 3: cases with follow-up WT1 levels greater than 100. RESULTS: Twenty patients were included in group 1, 17 in group 2, and 78 in group 3. Survival analysis showed statistically significant differences in terms of OS between groups (p: 0.016). Patients in group 2 showed the best 5-year overall survival (OS). In multivariate analysis, only the cytogenetic risk category and receiving an allogeneic hematopoietic stem cell transplantation (HCT) independently predicted the survival. CONCLUSIONS: Further studies are needed to assess whether BM WT1 levels could be useful to predict the survival of patients with myeloid neoplasms treated with 5-azacytidine.

ClonoSEQ assay for the detection of lymphoid malignancies.

Introduction: Immunoglobulin rearrangement studies by molecular methods are routinely used to detect clonality and to follow up patients with lymphoid malignancies. The design of a next-generation sequencing (NGS) panel using a comprehensive pool of primers, the establishment of a straightforward analytical protocol, a bioinformatic pipeline and the availability of the results of clinical studies have allowed the Clonoseq platform to be licensed as the first assay to measure minimal residual disease (MRD) both in acute lymphoblastic leukemia (ALL) and in multiple myeloma (MM). Areas covered: An extensive literature review (Pubmed search) on the applicability of the high-throughput sequencing (HTS) approach in lymphoid malignancies was conducted. This review discusses recent data in the field and compares this emerging molecular technique with standardized technologies. Expert Opinion: Real-time quantitative (RQ)-PCR and multiparametric flow cytometry (MPFC) are still the gold standard methods of minimal residual disease assessment. New HTS methods as Clonoseq show a high concordance with the above-mentioned techniques and at the same time it provides potential advantages to detect clonal changes. Clonoseq could be helpful to optimize risk-stratification and adjusting treatments in lymphoid malignancies. Moreover, HTS could also be applied to the detection of circulating tumor DNA (ctDNA) on the plasma in lymphomas.