ECLIM-SEHOP: how to develop a platform to conduct academic trials for childhood cancer.

INTRODUCTION: ECLIM-SEHOP platform was created in 2017. Its main objective is to establish the infrastructure to allow Spanish participation into international academic collaborative clinical trials, observational studies, and registries in pediatric oncology. The aim of this manuscript is to describe the activity conducted by ECLIM-SEHOP since its creation. METHODS: The platform's database was queried to provide an overview of the studies integrally and partially supported by the organization. Data on trial recruitment and set-up/conduct metrics since its creation until November 2023 were extracted. RESULTS: ECLIM-SEHOP has supported 47 studies: 29 clinical trials and 18 observational studies/registries that have recruited a total of 5250 patients. Integral support has been given to 25 studies: 16 trials recruiting 584 patients and nine observational studies/registries recruiting 278 patients. The trials include front-line studies for leukemia, lymphoma, brain and solid extracranial tumors, and other key transversal topics such as off-label use of targeted therapies and survivorship. The mean time from regulatory authority submission to first patient recruited was 12.2 months and from first international site open to first Spanish site open was 31.3 months. DISCUSSION: ECLIM-SEHOP platform has remarkably improved the availability and accessibility of international academic clinical trials and has facilitated the centralization of resources in childhood cancer treatment. Despite the progressive improvement on clinical trial set-up metrics, timings should still be improved. The program has contributed to leveling survival rates in Spain with those of other European countries that presented major differences in the past.

Corrigendum: Impact of disease burden and late loss of B cell aplasia on the risk of relapse after CD19 chimeric antigen receptor T Cell (Tisagenlecleucel) infusion in pediatric and young adult patients with relapse/refractory acute lymphoblastic leukemia: role of B-cell monitoring.

[This corrects the article DOI: 10.3389/fimmu.2023.1280580.].

Immune cell kinetics and antibody response in COVID-19 patients with low-count monoclonal B-cell lymphocytosis.

Low-count monoclonal B-cell lymphocytosis (MBLlo ) has been associated with an underlying immunodeficiency and has recently emerged as a new risk factor for severe COVID-19. Here, we investigated the kinetics of immune cell and antibody responses in blood during COVID-19 of MBLlo versus non-MBL patients. For this study, we analyzed the kinetics of immune cells in blood of 336 COVID-19 patients (74 MBLlo and 262 non-MBL), who had not been vaccinated against SARS-CoV-2, over a period of 43 weeks since the onset of infection, using high-sensitivity flow cytometry. Plasma levels of anti-SARS-CoV-2 antibodies were measured in parallel by ELISA. Overall, early after the onset of symptoms, MBLlo COVID-19 patients showed increased neutrophil, monocyte, and particularly, plasma cell (PC) counts, whereas eosinophil, dendritic cell, basophil, and lymphocyte counts were markedly decreased in blood of a variable percentage of samples, and with a tendency toward normal levels from week +5 of infection onward. Compared with non-MBL patients, MBLlo COVID-19 patients presented higher neutrophil counts, together with decreased pre-GC B-cell, dendritic cell, and innate-like T-cell counts. Higher PC levels, together with a delayed PC peak and greater plasma levels of anti-SARS-CoV-2-specific antibodies (at week +2 to week +4) were also observed in MBLlo patients. In summary, MBLlo COVID-19 patients share immune profiles previously described for patients with severe SARS-CoV-2 infection, associated with a delayed but more pronounced PC and antibody humoral response once compared with non-MBL patients.

Role of urine culture in paediatric patients with cancer with fever and neutropenia: a prospective observational study.

OBJECTIVE: To evaluate the need for routine urine studies in children with febrile neutropenia with cancer. DESIGN: A prospective, observational study was conducted in two hospitals between November 2019 and October 2021. PATIENTS: We recruited 205 patients in total. MAIN OUTCOME MEASURES: The primary outcome was presence of positive urine culture (UC). Urinary tract infection (UTI) was defined as urinary signs/symptoms and positive UC with or without pyuria. A descriptive analysis of data is provided.We conducted a prospective study of paediatric patients with cancer with urinary continence. Data were analysed using descriptive statistics. The diagnostic performance of urinalysis was calculated using positive UC as the gold standard. RESULTS: Positive UC was found in 7 of the 205 patients (3.4%; 95% CI 1.4% to 6.9%), 2 presenting urinary symptoms. UTI prevalence was 1.0% (95% CI 0.1% to 3.5%). A 23.8% prevalence of positive UC was found in patients with urinary symptoms and/or history of urinary tract disease (95% CI 8.2% to 47.2%) as compared with 1.1% of those without symptoms or history (95% CI 0.1% to 3.9%) (p<0.001). The sensitivity, specificity, negative predictive value, and area under the curve for urinalysis were 16.7% (95% CI 3.0% to 56.4%), 98.4% (95% CI 95.3% to 99.4%), 97.3% (95% CI 93.9% to 98.9%), and 0.65 (95% CI 0.51 to 0.79), respectively. CONCLUSIONS: UTI is an infrequent cause of infection in these patients. Urinalysis is indicated only in children with febrile neutropenia with urinary signs/symptoms and in asymptomatic patients with a history of urinary tract disease or unknown history. When urine is collected, UC should be requested regardless of the result of the urinalysis.

Impact of disease burden and late loss of B cell aplasia on the risk of relapse after CD19 chimeric antigen receptor T Cell (Tisagenlecleucel) infusion in pediatric and young adult patients with relapse/refractory acute lymphoblastic leukemia: role of B-cell monitoring.

Introduction: Loss of B-cell aplasia (BCA) is a well-known marker of functional loss of CD19 CAR-T. Most relapses and loss of BCA occur in the first months after CD19 CAR-T infusion. In addition, high tumor burden (HTB) has shown to have a strong impact on relapse, especially in CD19-negative. However, little is known about the impact of late loss of BCA or the relationship between BCA and pre-infusion tumor burden in patients infused with tisagenlecleucel for relapsed/refractory B-cell acute lymphoblastic leukemia. Therefore, the optimal management of patients with loss of BCA is yet to be defined. Methods: We conducted a Spanish, multicentre, retrospective study in patients infused with tisagenlecleucel after marketing authorization. A total of 73 consecutively treated patients were evaluated. Results: Prior to infusion, 39 patients had HTB (≥ 5% bone marrow blasts) whereas 34 had a low tumor burden (LTB) (<5% blasts). Complete remission was achieved in 90.4% of patients, of whom 59% relapsed. HTB was associated with inferior outcomes, with a 12-month EFS of 19.3% compared to 67.2% in patients with LTB (p<0.001) with a median follow-up of 13.5 months (95% CI 12.4 - 16.2). In the HTB subgroup relapses were mainly CD19-negative (72%) whereas in the LTB subgroup they were mainly CD19-positive (71%) (p=0.017). In the LTB group, all CD19-positive relapses were preceded by loss of BCA whereas only 57% (4/7) of HTB patients experienced CD19-positive relapse. We found a positive correlation between loss of BCA and CD19-positive relapse (R-squared: 74) which persisted beyond six months post-infusion. We also explored B-cell recovery over time using two different definitions of loss of BCA and found a few discrepancies. Interestingly, transient immature B-cell recovery followed by BCA was observed in two pediatric patients. In conclusion, HTB has an unfavorable impact on EFS and allo-SCT might be considered in all patients with HTB, regardless of BCA. In patients with LTB, loss of BCA preceded all CD19-positive relapses. CD19-positive relapse was also frequent in patients who lost BCA beyond six months post-infusion. Therefore, these patients are still at significant risk for relapse and close MRD monitoring and/or therapeutic interventions should be considered.

Tisagenlecleucel therapy for relapsed or refractory B-cell acute lymphoblastic leukaemia in infants and children younger than 3 years of age at screening: an international, multicentre, retrospective cohort study.

BACKGROUND: Children aged younger than 3 years were excluded from the ELIANA phase 2 trial of tisagenlecleucel in children with acute lymphoblastic leukaemia. The feasibility, safety, and activity of tisagenlecleucel have not been defined in this group, the majority of whom have high-risk (KMT2A-rearranged) infant acute lymphoblastic leukaemia and historically poor outcomes despite intensification of chemotherapy, and for whom novel therapies are urgently needed. We aimed to provide real-world outcome analysis of the feasibility, activity, and safety of tisagenlecleucel in younger children and infants with acute lymphoblastic leukaemia. METHODS: We did an international, multicentre, retrospective cohort study at 15 hospitals across ten countries in Europe. Eligible patients were children aged younger than 3 years at screening between Sept 1, 2018, and Sept 1, 2021, who were screened for tisagenlecleucel therapy for relapsed or refractory B-cell precursor acute lymphoblastic leukaemia according to licensed indications. Patients received a single intravenous infusion of tisagenlecleucel. We tracked chimeric antigen receptor T-cell therapy outcomes using a standardised data reporting form. Overall survival, event-free survival, stringent event-free survival, B-cell aplasia, and toxicity were assessed in all patients who received a tisagenlecleucel infusion. FINDINGS: 38 eligible patients were screened, of whom 35 (92%) received a tisagenlecleucel infusion. 29 (76%) of 38 patients had KMT2A-rearranged acute lymphoblastic leukaemia, and 25 (66%) had relapsed after previous allogeneic haematopoietic stem-cell transplantation (HSCT). Patients had previously received a median of 2 lines (IQR 2-3) of (non-HSCT) therapy. Seven (18%) of 38 patients had received inotuzumab and 14 (37%) had received blinatumomab. After a median of 14 months (IQR 9-21) of follow-up, overall survival at 12 months after tisagenlecleucel infusion was 84% (64-93; five patients had died), event-free survival was 69% (47-83; nine events), and stringent event-free survival was 41% (23-58; 18 events). The probability of ongoing B-cell aplasia was 70% (95% CI 46-84; seven events) at 12 months. Adverse events included cytokine release syndrome, which occurred at any grade in 21 (60%) of 35 patients and at grade 3 or worse in five (14%), and neurotoxicity at any grade in nine (26%), none of which were severe. Measurable residual disease-negative complete response with or without haematological recovery occurred in 24 (86%) of 28 patients who had measurable disease. INTERPRETATION: These data suggest that tisagenlecleucel has antitumour activity and has an acceptable safety profile for young children and infants with B-cell precursor acute lymphoblastic leukaemia. FUNDING: None.

Safety and Acceptance of COVID-19 Vaccination After Multisystem Inflammatory Syndrome in Children (MIS-C) in Spain.

In this cohort of 42 adolescents with a previous multisystem inflammatory syndrome (MIS-C) diagnosis, 32 (76.2%) were vaccinated with COVID-19 vaccines, with a low incidence of relevant adverse events. More importantly, no new MIS-C or myocarditis occurred after a median of 10 weeks (range 5.3-19.7) post-vaccination.

Comparison of pneumonia features in children caused by SARS-CoV-2 and other viral respiratory pathogens.

BACKGROUND: Pneumonia is a frequent manifestation of coronavirus disease 2019 (COVID-19) in hospitalized children. METHODS: The study involved 80 hospitals in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spanish Pediatric National Cohort. Participants were children <18 years, hospitalized with SARS-CoV-2 community-acquired pneumonia (CAP). We compared the clinical and radiological characteristics of SARS-CoV-2-associated CAP with CAP due to other viral etiologies from ValsDance (retrospective) cohort. RESULTS: In total, 151 children with SARS-CoV-2-associated CAP and 138 with other viral CAP were included. Main clinical features of SARS-CoV-2-associated CAP were cough, fever, or dyspnea. Lymphopenia was found in 43% patients and 15% required admission to the pediatric intensive care unit (PICU). Chest X-ray revealed condensation (42%) and other infiltrates (58%). Compared with CAP from other viral pathogens, COVID-19 patients were older, with lower C-reactive protein (CRP) levels, less wheezing, and greater need of mechanical ventilation (MV). There were no differences in the use of continuous positive airway pressure (CPAP) or HVF, or PICU admission between groups. CONCLUSION: SARS-CoV-2-associated CAP in children presents differently to other virus-associated CAP: children are older and rarely have wheezing or high CRP levels; they need less oxygen but more CPAP or MV. However, several features overlap and differentiating the etiology may be difficult. The overall prognosis is good.

How we treat HR-positive, HER2-negative early breast cancer.

The present goal of therapy for early HR+/HER2- breast cancer (BC) is to optimize disease-free survival (DFS) and overall survival (OS) rates with the currently available therapies while avoiding any relevant long-term sequalae. Local therapies have evolved toward less aggressive techniques (i.e. breast-preserving surgery, sentinel lymph node biopsy and intraoperative radiotherapy), which significantly reduce the long-term sequalae observed with more radical treatments. Endocrine therapy (ET) is still the cornerstone of adjuvant treatment because it significantly reduces BC relapse and mortality. Adjuvant chemotherapy is today recommended only for a particular subset of patients with a high risk of recurrence with ET alone, identified through genomic assays, age and/or disease stage. Bisphosphonates reduce the risk of bone metastasis and produce a slight although statistically significant improvement in survival in postmenopausal women. The CDK 4/6 inhibitor abemaciclib has been recently approved by the US FDA for patients at high risk of relapse.

The goal of therapy for patients diagnosed with early HR+/HER2- breast cancer (BC) is to maximize survival rates while maintaining the quality of life and avoiding long-term sequalae. Local therapies have evolved toward less aggressive techniques, which significantly reduce the long-term sequalae observed with more radical approaches. Endocrine therapy (ET) remains as the cornerstone of adjuvant treatment because it significantly reduces BC relapse and mortality. Adjuvant chemotherapy is, however, recommended only for a particular subset of patients with a high-risk of recurrence with ET alone, identified through genomic assays together with clinical variables such as age and/or axillary involvement. Additionally, bisphosphonates reduce the risk of bone metastasis with a slight improvement in survival in postmenopausal women. The CDK 4/6 inhibitor abemaciclib has been recently approved by the US FDA for patients at high risk of relapse.

[Pericardial and myocardial involvement after SARS-CoV-2 infection: a cross-sectional descriptive study in healthcare workers]. / Afección pericárdica y miocárdica tras infección por SARS-CoV-2: estudio descriptivo transversal en trabajadores sanitarios.

Introduction and objectives: The cardiac sequelae of SARS-CoV-2 infection are still poorly documented. We conducted a cross-sectional study in healthcare workers to report evidence of pericardial and myocardial involvement after SARS-CoV-2 infection. Methods: We studied 139 healthcare workers with confirmed past SARS-CoV-2 infection. Participants underwent clinical assessment, electrocardiography, and laboratory tests, including immune cell profiling and cardiac magnetic resonance (CMR). Clinically suspected pericarditis was diagnosed when classic criteria were present and clinically suspected myocarditis was based on the combination of at least 2 CMR criteria. Results: Median age was 52 (41-57) years, 71.9% were women, and 16.5% were previously hospitalized for COVID-19 pneumonia. On examination (10.4 [9.3-11.0] weeks after infection-like symptoms), participants showed hemodynamic stability. Chest pain, dyspnea or palpitations were present in 41.7% participants, electrocardiographic abnormalities in 49.6%, NT-proBNP elevation in 7.9%, troponin in 0.7%, and CMR abnormalities in 60.4%. A total of 30.9% participants met criteria for either pericarditis and/or myocarditis: isolated pericarditis was diagnosed in 5.8%, myopericarditis in 7.9%, and isolated myocarditis in 17.3%. Most participants (73.2%) showed altered immune cell counts in blood, particularly decreased eosinophil (27.3%; P < .001) and increased cytotoxic T cell numbers (17.3%; P < .001). Clinically suspected pericarditis was associated (P < .005) with particularly elevated cytotoxic T cells and decreased eosinophil counts, while participants diagnosed with clinically suspected myopericarditis or myocarditis had lower (P < .05) neutrophil counts, natural killer-cells, and plasma cells. Conclusions: Pericardial and myocardial involvement with clinical stability are frequent after SARS-CoV-2 infection and are associated with specific immune cell profiles.Full English text available from:www.revespcardiol.org/en.

Clinical spectrum of COVID-19 and risk factors associated with severity in Spanish children.

We aimed to identify the spectrum of disease in children with COVID-19, and the risk factors for admission in paediatric intensive care units (PICUs). We conducted a multicentre, prospective study of children with SARS-CoV-2 infection in 76 Spanish hospitals. We included children with COVID-19 or multi-inflammatory syndrome (MIS-C) younger than 18 years old, attended during the first year of the pandemic. We enrolled 1200 children. A total of 666 (55.5%) were hospitalised, and 123 (18.4%) required admission to PICU. Most frequent major clinical syndromes in the cohort were mild syndrome (including upper respiratory tract infection and flu-like syndrome, skin or mucosae problems and asymptomatic), 44.8%; bronchopulmonary syndrome (including pneumonia, bronchitis and asthma flare), 18.5%; fever without a source, 16.2%; MIS-C, 10.6%; and gastrointestinal syndrome, 10%. In hospitalised children, the proportions were 28.5%, 25.7%, 16.5%, 19.1% and 10.2%, respectively. Risk factors associated with PICU admission were age in months (OR: 1.007; 95% CI 1.004 to 1.01), MIS-C (OR: 14.4, 95% CI 8.9 to 23.8), chronic cardiac disease (OR: 4.8, 95% CI 1.8 to 13), asthma or recurrent wheezing (OR: 2.5, 95% CI 1.2 to 5.2) and after excluding MIS-C patients, moderate/severe liver disease (OR: 8.6, 95% CI 1.6 to 47.6). However, asthmatic children were admitted into the PICU due to MIS-C or pneumonia, not due to asthma flare.Conclusion: Hospitalised children with COVID-19 usually present as one of five major clinical phenotypes of decreasing severity. Risk factors for PICU include MIS-C, elevation of inflammation biomarkers, asthma, moderate or severe liver disease and cardiac disease. What is Known: • All studies suggest that children are less susceptible to serious SARS-CoV-2 infection when compared to adults. Most studies describe symptoms at presentation. However, it remains unclear how these symptoms group together into clinically identifiable syndromes and the severity associated with them. What is New: • We have gathered the primary diagnoses into five major syndromes of decreasing severity: MIS-C, bronchopulmonary syndrome, gastrointestinal syndrome, fever without a source and mild syndrome. Classification of the children in one of the syndromes is unique and helps to assess the risk of critical illness and to define the spectrum of the disease instead of just describing symptoms and signs.

Dynamics of Reverse Transcription-Polymerase Chain Reaction and Serologic Test Results in Children with SARS-CoV-2 Infection.

OBJECTIVES: To determine the time to reverse transcription-polymerase chain reaction (RT-PCR) negativity after the first positive RT-PCR test, factors associated with longer time to RT-PCR negativity, proportion of children seroconverting after proven severe acute respiratory syndrome coronavirus 2 infection, and factors associated with the lack of seroconversion. STUDY DESIGN: The Epidemiological Study of Coronavirus in Children of the Spanish Society of Pediatrics is a multicenter study conducted in Spanish children to assess the characteristics of coronavirus disease 2019. In a subset of patients, 3 serial RT-PCR tests on nasopharyngeal swab specimens were performed after the first RT-PCR test, and immunoglobulin G serology for severe acute respiratory syndrome coronavirus 2 antibodies was performed in the acute and follow-up (<14 and ≥14 days after diagnosis) phase. RESULTS: In total, 324 patients were included in the study. The median time to RT-PCR negativity was 17 days (IQR, 8-29 days), and 35% of patients remained positive more than 4 weeks after the first RT-PCR test. The probability of RT-PCR negativity did not differ across groups defined by sex, disease severity, immunosuppressive drugs, or clinical phenotype. Globally, 24% of children failed to seroconvert after infection. Seroconversion was associated with hospitalization, persistence of RT-PCR positivity, and days of fever. CONCLUSIONS: Time to RT-PCR negativity was long, regardless of the severity of symptoms or other patient features. This finding should be considered when interpreting RT-PCR results in a child with symptoms, especially those with mild symptoms. Seroprevalence and postimmunization studies should consider that 11 in 4 infected children fail to seroconvert.

Palliative home-based care to pediatric cancer patients: characteristics and healthcare delivered.

OBJECTIVES: Cancer patients constitute an important group in pediatric palliative care. Though the patients' home is the preferred place of care, little is known about the characteristics of patients attended by units that provide home assistance. Our objective is to describe the characteristics of cancer patients and healthcare delivered by a pediatric palliative care unit with a home hospitalization program. METHODS: Retrospective study based on clinical records of deceased patients attended by the pediatric palliative care unit of Madrid over 10 years. Data collected included general characteristics, type of cancer, whether they received home assistance, place of death, healthcare delivered (hospitalizations, devices, oncological treatments…), and symptom prevalence. RESULTS: After excluding 47 patients, the clinical records of 144 patients were analyzed. The median age at referral was 9.4 years (IQR: 5.6-14.1), 61.2% were males; 44.2% had solid non-CNS tumors, 35.4% CNS tumors, and 20.4% hematological malignancies; 137 received home care with 89 not requiring further hospital admissions and 70.1% dying at home. The median follow-up time was 1.6 months (IQR: 0.5-2.9). The most used devices were venous ports (71.4%) and oxygen (49.4%); 53.5% of the patients received oncological support therapies. The most common symptoms were pain (91.8%) dyspnea (49.0%) and fatigue (46.9%). CONCLUSIONS: Home assistance was provided in a high number of patients, with a large proportion needing one or no hospital admissions and 70.1% of them dying at home. Further studies characterizing these patients and the factors which promote early access to palliative care are needed.

Pericardial and myocardial involvement after SARS-CoV-2 infection: a cross-sectional descriptive study in healthcare workers.

INTRODUCTION AND OBJECTIVES: The cardiac sequelae of SARS-CoV-2 infection are still poorly documented. We conducted a cross-sectional study in healthcare workers to report evidence of pericardial and myocardial involvement after SARS-CoV-2 infection. METHODS: We studied 139 healthcare workers with confirmed past SARS-CoV-2 infection. Participants underwent clinical assessment, electrocardiography, and laboratory tests, including immune cell profiling and cardiac magnetic resonance (CMR). Clinically suspected pericarditis was diagnosed when classic criteria were present and clinically suspected myocarditis was based on the combination of at least 2 CMR criteria. RESULTS: Median age was 52 (41-57) years, 71.9% were women, and 16.5% were previously hospitalized for COVID-19 pneumonia. On examination (10.4 [9.3-11.0] weeks after infection-like symptoms), participants showed hemodynamic stability. Chest pain, dyspnea or palpitations were present in 41.7% participants, electrocardiographic abnormalities in 49.6%, NT-proBNP elevation in 7.9%, troponin in 0.7%, and CMR abnormalities in 60.4%. A total of 30.9% participants met criteria for either pericarditis and/or myocarditis: isolated pericarditis was diagnosed in 5.8%, myopericarditis in 7.9%, and isolated myocarditis in 17.3%. Most participants (73.2%) showed altered immune cell counts in blood, particularly decreased eosinophil (27.3%; P<.001) and increased cytotoxic T cell numbers (17.3%; P <.001). Clinically suspected pericarditis was associated (P <.005) with particularly elevated cytotoxic T cells and decreased eosinophil counts, while participants diagnosed with clinically suspected myopericarditis or myocarditis had lower (P <.05) neutrophil counts, natural killer-cells, and plasma cells. CONCLUSIONS: Pericardial and myocardial involvement with clinical stability are frequent after SARS-CoV-2 infection and are associated with specific immune cell profiles.

Age- and Sex-Matched Normal Leukocyte Subset Ranges in the General Population Defined with the EuroFlow Lymphocyte Screening Tube (LST) for Monoclonal B-Cell Lymphocytosis (MBL) vs. Non-MBL Subjects.

Reference ranges of blood-circulating leukocyte populations by, e.g., age and sex, are required for monitoring immune-cell kinetics. Most previous reports in which flow cytometry has been used to define the reference ranges for leukocyte counts included a limited number of donors and/or cell populations and/or did not consider age and sex simultaneously. Moreover, other factors not previously considered in the definition of normal ranges, such as the presence of chronic-lymphocytic-leukemia (CLL)-like low-count monoclonal B-cell lymphocytosis (MBLlo), might also be associated with an altered distribution of leukocytes in blood in association with an immunodeficiency and increased risk of infection and cancer. Here, we established reference cell-count ranges for the major populations of leukocytes in blood of non-MBL and MBLlo adult Caucasians matched by age and sex using the EuroFlow Lymphocyte Screening Tube (LST). A total of 706 Caucasian adult donors­622 non-MBL and 84 MBLlo­were recruited from the general population. Among non-MBL donors, the total leukocyte, neutrophil, basophil dendritic cell and monocyte counts remained stable through adulthood, while the absolute numbers of T- and B-cell populations and plasma cells decreased with age. The number of eosinophils and NK-cell increased over time, with clear differences according to sex for certain age ranges. In MBLlo subjects, few differences in the absolute cell counts by age (vs. non-MBL) were observed, and MBLlo men and women showed similar trends to non-MBL subjects except for the B-cell count drop observed in >70 y-men, which was more pronounced in MBLlo vs. non-MBL controls. Building robust age- and sex-matched reference ranges for the most relevant immune-cell populations in the blood of non-MBL donors is essential to appropriately identify an altered immune status in different clinical settings and highlight the altered immune-cell profiles of MBLlo subjects.

The Hydropathy Index of the HCDR3 Region of the B-Cell Receptor Identifies Two Subgroups of IGHV-Mutated Chronic Lymphocytic Leukemia Patients With Distinct Outcome.

The HCDR3 sequences of the B-cell receptor (BCR) undergo constraints in length, amino acid use, and charge during maturation of B-cell precursors and after antigen encounter, leading to BCR and antibodies with high affinity to specific antigens. Chronic lymphocytic leukemia consists of an expansion of B-cells with a mixed immature and "antigen-experienced" phenotype, with either a mutated (M-CLL) or unmutated (U-CLL) tumor BCR, associated with distinct patient outcomes. Here, we investigated the hydropathy index of the BCR of 138 CLL patients and its association with the IGHV mutational status and patient outcome. Overall, two clearly distinct subgroups of M-CLL patients emerged, based on a neutral (mean hydropathy index of -0.1) vs. negatively charged BCR (mean hydropathy index of -1.1) with molecular features closer to those of B-cell precursors and peripheral/mature B-cells, respectively. Despite that M-CLL with neutral HCDR3 did not show traits associated with a mature B-cell repertoire, important differences in IGHV gene usage of tumor cells and patient outcome were observed in this subgroup of patients once compared to both U-CLL and M-CLL with negatively charged HCDR3 sequences. Compared to M-CLL with negatively charged HCDR3 sequences, M-CLL with neutral HCDR3 sequences showed predominance of men, more advanced stages of the disease, and a greater frequency of genetic alterations-e.g., del(17p)-together with a higher rate of disease progression and shorter time to therapy (TTT), independently of other prognostic factors. Our data suggest that the hydropathy index of the HCDR3 sequences of CLL cells allows the identification of a subgroup of M-CLL with intermediate prognostic features between U-CLL and the more favorable subgroup of M-CLL with a negatively charged BCR.

Comparison of clinical outcomes between unrelated single umbilical cord blood and "ex-vivo" T-cell depleted haploidentical transplantation in children with hematological malignancies.

BACKGROUND: Over the last two decades, umbilical cord blood (UCB) and haploidentical transplantation (HaploHSCT) have emerged as alternative sources of hematopoietic stem cell for allogeneic transplantation. There are few retrospective studies and no prospective studies comparing both types of alternative transplantation in pediatric patients. RESULTS: We analyzed the data of 134 children with hematological malignancies who received a hematopoietic stem cell transplantation from a single umbilical cord blood (UCB) (n = 42) or an "ex-vivo" T-cell depleted transplant from a haploidentical-related donor (HaploHSCT) (n = 92) between 1996 and 2014. Hematological recovery was faster after HaploHSCT than the UCB transplant group (median times to neutrophil and platelet recovery: 13 vs. 16 days, 10 vs. 57 days, respectively) (P < 0.001). The HaploHSCT group had a significantly early immune reconstitution based on NK and CD8 + T cells compared with the UCB group. However, after the first year post-transplantation, HaploHSCT had a lower number of CD4 + T and B lymphocytes compared with the UCB transplant recipients. The cumulative incidence of TRM was 29±8% in the HaploHSCT group versus 40±5% in the UCB group. Relapse incidence was 21±7% in the HaploHSCT group and 19±8% in the UCB group. Probability of DFS was 58±8% in the HaploHSCT group versus 40±9% in the UCB group (P = 0.051). CONCLUSIONS: TCD haploidentical transplant is associated with advantages in terms of engraftment and early immune reconstitution kinetics. TCD haploidentical transplant was associated with lower incidence of infectious and non-infectious complications, especially in the early phases of the transplant compared with UCB transplant recipients. However, there are no advantages in transplant outcomes compared with UCB transplant.

A Bayesian Model to Predict COVID-19 Severity in Children.

BACKGROUND: We aimed to identify risk factors causing critical disease in hospitalized children with COVID-19 and to build a predictive model to anticipate the probability of need for critical care. METHODS: We conducted a multicenter, prospective study of children with SARS-CoV-2 infection in 52 Spanish hospitals. The primary outcome was the need for critical care. We used a multivariable Bayesian model to estimate the probability of needing critical care. RESULTS: The study enrolled 350 children from March 12, 2020, to July 1, 2020: 292 (83.4%) and 214 (73.7%) were considered to have relevant COVID-19, of whom 24.2% required critical care. Four major clinical syndromes of decreasing severity were identified: multi-inflammatory syndrome (MIS-C) (17.3%), bronchopulmonary (51.4%), gastrointestinal (11.6%), and mild syndrome (19.6%). Main risk factors were high C-reactive protein and creatinine concentration, lymphopenia, low platelets, anemia, tachycardia, age, neutrophilia, leukocytosis, and low oxygen saturation. These risk factors increased the risk of critical disease depending on the syndrome: the more severe the syndrome, the more risk the factors conferred. Based on our findings, we developed an online risk prediction tool (https://rserver.h12o.es/pediatria/EPICOAPP/, username: user, password: 0000). CONCLUSIONS: Risk factors for severe COVID-19 include inflammation, cytopenia, age, comorbidities, and organ dysfunction. The more severe the syndrome, the more the risk factor increases the risk of critical illness. Risk of severe disease can be predicted with a Bayesian model.

Activity of docetaxel, carboplatin, and doxorubicin in patient-derived triple-negative breast cancer xenografts.

Triple-negative breast cancer (TNBC) is highly responsive to neoadjuvant polychemotherapy regimens including anthracyclines, taxanes, and, more recently, carboplatin. However, there is inadequate information on the individual contribution of each of these agents to the global activity of the combinations, and the use of combinations of up to four of these drugs is associated with relevant toxicity. Identifying single-drug activity in the clinical neoadjuvant setting is challenging. We developed patient-derived xenografts (PDXs) from several chemotherapy-naïve TNBC samples to assess the antitumor activity of single drugs and combinations of drugs. PDXs were established from chemotherapy-naïve TNBC samples. Nine TNBC PDX models (all of which corresponded to a basal-like phenotype according to the PAM50 classifier) were treated with carboplatin, docetaxel, and doxorubicin and the combination of docetaxel and carboplatin. Only one of nine PDX models showed sensitivity to doxorubicin, while eight of nine PDX models showed sensitivity to docetaxel and carboplatin as single agents. The 3 PDX models derived from patients with gBRCA-1 or gPALB2 mutations were very sensitive to carboplatin single agent. All 6 PDX models from patients without hereditary germ-line mutations showed increased sensitivity to the combination of docetaxel and carboplatin. In the present study, docetaxel and carboplatin single agents were active drugs against basal-like TNBC, while doxorubicin monotherapy showed low activity. The combination of docetaxel and carboplatin was more effective than the drugs used as single agents, except in the PDX from patients with gBRCA1/PALB2 mutations.