CD34+CD19-CD22+ B-cell progenitors may underlie phenotypic escape in patients treated with CD19-directed therapies.

CD19-directed immunotherapies have revolutionized the treatment of advanced B-cell acute lymphoblastic leukemia (B-ALL). Despite initial impressive rates of complete remission (CR) many patients ultimately relapse. Patients with B-ALL successfully treated with CD19-directed T cells eventually relapse, which, coupled with the early onset of CD22 expression during B-cell development, suggests that preexisting CD34+CD22+CD19- (pre)-leukemic cells represent an "early progenitor origin-related" mechanism underlying phenotypic escape to CD19-directed immunotherapies. We demonstrate that CD22 expression precedes CD19 expression during B-cell development. CD34+CD19-CD22+ cells are found in diagnostic and relapsed bone marrow samples of ∼70% of patients with B-ALL, and their frequency increases twofold in patients with B-ALL in CR after CD19 CAR T-cell therapy. The median of CD34+CD19-CD22+ cells before treatment was threefold higher in patients in whom B-ALL relapsed after CD19-directed immunotherapy (median follow-up, 24 months). Fluorescence in situ hybridization analysis in flow-sorted cell populations and xenograft modeling revealed that CD34+CD19-CD22+ cells harbor the genetic abnormalities present at diagnosis and initiate leukemogenesis in vivo. Our data suggest that preleukemic CD34+CD19-CD22+ progenitors underlie phenotypic escape after CD19-directed immunotherapies and reinforce ongoing clinical studies aimed at CD19/CD22 dual targeting as a strategy for reducing CD19- relapses. The implementation of CD34/CD19/CD22 immunophenotyping in clinical laboratories for initial diagnosis and subsequent monitoring of patients with B-ALL during CD19-targeted therapy is encouraged.

Development of an in-house bone marrow collection kit: The Catalan bone marrow transplantation group experience.

BACKGROUND AND OBJECTIVES: Bone marrow (BM) harvesting is one of the essential sources of stem cells for haematopoietic stem cell transplantation. In 2019, commercial BM collection kits became unavailable in Europe. Consequently, we created an in-house BM collection kit as an alternative. MATERIALS AND METHODS: We compared two groups of BM collections. The first collections were taken using an in-house kit from June 2022 through February 2023 and the second with a commercial kit from February 2021 through May 2022. These all took place at seven collection centres (CC). We analysed the harvest quality (cell blood count, CD34+ cells, viability, potency and sterility), the incidents occurring with each kit and the time to neutrophil and platelet engraftment in recipients. RESULTS: A total of 23 donors underwent BM harvesting with the in-house kit and 23 with the commercial one. Both cohorts were comparable regarding donor characteristics, CC and time to procedure. No statistical differences were found in harvest quality between the in-house and commercial kits. A new transfusion set was required in three BM harvests (13%) with the in-house kit because of filter clogging. The median time to neutrophil and platelet engraftment was 21 days for both cohorts and 29 days (in-house) and 33 days (commercial), p = 0.284, respectively. CONCLUSION: The in-house BM collection kit offers a real approach to solve the diminished supply of commercial kits. A higher risk of filter clogging was observed compared with commercial kits due to the lack of 850 and 500 µm filters.

The role of women's traditional gender beliefs in depression, intimate partner violence and stress: insights from a Spanish abbreviated multicultural measure.

BACKGROUND: Research on traditional gender beliefs has highlighted their psychological impact and social implications for women. The purpose of this study was twofold. First, we aimed to adapt and validate the Spanish version of the Multicultural O'Kelly Women's Beliefs Scale. Next, we explored its sources of validity evidence in relation to intimate partner violence, stress, and depression. Based on the Rational Emotive Behavior Therapy framework, traditional gender beliefs were expected to be associated with higher levels of intimate partner violence, stress and depression. We also expected to obtain a psychometrically-sound factor structure of the Multicultural O'Kelly Women's Beliefs Scale. METHODS: A sample of Spanish women (N = 322) completed the Multicultural O'Kelly Women's Beliefs Scale, the Beck's Depression Inventory II, the Modified Conflict Tactics Scale, and the Stress Perceived Scale. To test the psychometric properties of the Multicultural O'Kelly Women's Beliefs Scale we implemented exploratory and confirmatory factor analyses and an analysis of the area under the curve. RESULTS: Regarding the psychometric properties of the scale, statistical analysis revealed a one-factor dimensionality (Global traditionalism) and supported a reduction of items in the original instrument. The abbreviated version (eight items) obtained the best fit indices. Considering the association between traditional gender beliefs and psychological outcomes, we found that traditional gender beliefs were associated with increased severity of stress, depressive symptoms and reciprocal verbal aggression. CONCLUSION: The Spanish adaptation of the Multicultural O'Kelly Women's Beliefs Scale provided a very short, psychometrically robust and clinically relevant measure of traditional gender beliefs. In addition to the association between traditional gender beliefs and mental health outcomes, an important finding was the relationship between traditional gender beliefs and intimate partner violence. Our scale might be used in clinical settings by helping women to identify their traditional gender beliefs and replace them by healthy and goal-oriented beliefs, which would also contribute in achieving a more egalitarian society.

What is going on between defibrotide and endothelial cells? Snapshots reveal the hot spots of their romance.

Defibrotide (DF) has received European Medicines Agency authorization to treat sinusoidal obstruction syndrome, an early complication after hematopoietic cell transplantation. DF has a recognized role as an endothelial protective agent, although its precise mechanism of action remains to be elucidated. The aim of the present study was to investigate the interaction of DF with endothelial cells (ECs). A human hepatic EC line was exposed to different DF concentrations, previously labeled. Using inhibitory assays and flow cytometry techniques along with confocal microscopy, we explored: DF-EC interaction, endocytic pathways, and internalization kinetics. Moreover, we evaluated the potential role of adenosine receptors in DF-EC interaction and if DF effects on endothelium were dependent of its internalization. Confocal microscopy showed interaction of DF with EC membranes followed by internalization, though DF did not reach the cell nucleus even after 24 hours. Flow cytometry revealed concentration, temperature, and time dependent uptake of DF in 2 EC models but not in other cell types. Moreover, inhibitory assays indicated that entrance of DF into ECs occurs primarily through macropinocytosis. Our experimental approach did not show any evidence of the involvement of adenosine receptors in DF-EC interaction. The antiinflammatory and antioxidant properties of DF seem to be caused by the interaction of the drug with the cell membrane. Our findings contribute to a better understanding of the precise mechanisms of action of DF as a therapeutic and potential preventive agent on the endothelial damage underlying different pathologic situations.

Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT.

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray.

Pharmaceutical interventions in the emergency department: cost-effectiveness and cost-benefit analysis.

OBJECTIVE: It has been shown that pharmacists, as members of multidisciplinary patient care teams, can decrease the number of medicine errors. The objective of the present study was to analyse pharmaceutical interventions (PI) in emergency departments, to assess their clinical relevance, the cost-effectiveness and the potential economic benefits. METHODS: We designed a 5-month observational prospective study of PI in the emergency department (ED) of a 330-bed hospital in Spain. We analysed PI made by a pharmacist during a period of 3 hours a day from Monday to Friday in the ED, and classified detected medication errors according to their relevance and severity using the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) severity index, and whether or not the drug involved was on the High-Alert Medications Institute for Safe Medication Practices (ISMP) list. We used statistical analysis to study the relationship between the relevance of PI and age, gender, the number of interventions per patient, and whether or not the drug was on the High-Alert Medications ISMP list. We also estimated the incremental cost incurred for each PI (cost-effectiveness) and the potential economic benefits (cost-benefit). RESULTS: A total of 529 interventions for 390 patients (median age 72.7±8.6 years, 53.1% women) were performed during the study period, representing 1.4 interventions per patient with an acceptance rate of 84.9%. Of all potential medication errors, 112 (21.2%) were related to drugs on the High-Alert Medications ISMP list, and using the NCC MERP severity index, we found that 150 (28.3%) of those errors could cause harm. We also found a relationship between patients on high-risk medications according to the ISMP and the relevance of PI. Finally, this study showed an incremental cost for each PI of 20.23 Euros and a cost-benefit ratio of 3.46 Euros per intervention. CONCLUSION: These results show that clinical pharmacist can positively identify and reduce medication errors and costs associated, considering the number of interventions observed and those of clinical relevance. Based on these results, drug safety therapy in the ED can be improved by the revision of prescriptions by a clinical pharmacist.

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML.

Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.

Rational Emotive Behavioural Therapy: The Evolution of a Revolution: Interview With Dr. Debbie Joffe Ellis, Work Partner and Wife of Dr. Albert Ellis, the Creator of REBT.

Recognized as one of the most influential thinkers and psychologists, Albert Ellis PhD (1913-2007) revolutionized Psychology when he created the first cognitive psychotherapy, Rational Emotive Behavioral Therapy. After he passed away, Dr. Debbie Joffe Ellis continues spreading his legacy around the world. Psychologist, lecturer, writer, trainer, she dedicates her life to disseminate REBT and extend it through different statements, from the social to the educational, from the academic to the clinical. In this interview, she goes through her own history and her husband's one, bringing us closer to understanding Albert Ellis as the leading figure in his field, and the oneness they experienced through their professional and personal relationship.

[Following breast cancer surgery, which treatments are necessary?]. / Después de la cirugía de cáncer de mama. Qué cuidados se precisan?

This essay received first prize in the Third Nursing Conferences organized by the Sanitary Consortium of the Alt Penedés County in Catalonia. In a very clear, simple way, this essay deals with those questions which most concern women who have undergone an axillary extirpation. The authors describe their everyday experiences in health education for women who have undergone this surgery.