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Bruton's tyrosine kinase (BTK) inhibitors, such as ibrutinib, acalabrutinib, and zanubrutinib, are commonly used to treat chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, and mantle cell lymphoma. These inhibitors can cause cutaneous adverse events, including ecchymoses, skin infections, and hair and nail changes. Edema, or swelling, has been reported in 5-29% of patients treated with BTK inhibitors, but it has not been well classified. This article presents two cases of persistent upper extremity edema in patients on BTK inhibitor therapy and discusses the possible mechanisms and management of this side effect. [Extracted from the article]

This article focuses on the personal identities of a group of "Palestinian refugee" women. Here the quotation marks are very important since this article, based on an intersectional analysis, reveals how the spectrum of these women's identities ranges from identities imposed upon them to others that they negotiate or claim fervently. This article highlights this complexity that is punctuated by various "vectors of power" related to law, politics, religion, and the nation. [ABSTRACT FROM AUTHOR]

Immunosuppressive ability in human MSC donors has been shown to be variable and may be a limiting factor in MSC therapeutic efficacy in vivo. The importance of cytokine activation of mesenchymal stromal cells (MSCs) to facilitate their immunosuppressive function is well established. This study sought to further understand the interactions between MSCs and the commonly used calcineurin inhibitor cyclosporine A (CsA). The existing literature regarding approaches that use MSCs and cyclosporine are conflicting regarding the effect of CsA on MSC potency and function. Here, we clearly demonstrate that when added at the same time as MSCs, CsA negatively affects MSC suppression of T cell proliferation. However, licencing MSCs with IFNγ before addition of CsA protects MSCs from this negative effect. Notably, adding CsA to MSCs after IFNγ pre-stimulation enhances MSC production of IDO. Mechanistically, we identified that CsA reduces SOCS1 expression to facilitate enhanced IDO production in IFNγ pre-stimulated MSCs. Importantly, CsA exposure to IFNγ pre-stimulated MSC before administration, significantly enhanced the potency of MSCs in a human relevant humanised mouse model of acute Graft versus Host Disease. In summary, this study identified a novel licencing strategy to enhance MSC potency in vitro and in vivo. [ABSTRACT FROM AUTHOR]

• Child criminal exploitation (CCE) is a rising concern across several jurisdictions. • Crossover children in child protection and youth justice systems face high CCE risk. • Crossover children are subject to CCE by strangers, partners, and family members. • Those in residential care or with neurodisability may face heightened CCE risk. • CCE of crossover children may be enabled by sexual exploitation and substance abuse. While at higher risk, child protection-involved youth are the subject of negligible research focusing on the criminal exploitation of children by adults. This exploratory study examines criminal exploitation of 'crossover' children, those traversing the child protection and youth justice systems, in Victoria Australia. It examines the relationships, processes, and criminal activity related to child criminal exploitation amongst crossover children, and canvasses current legal and welfare responses to this phenomenon. Twenty-five interview and focus group consultations were undertaken with 87 child welfare, legal, justice, and education key stakeholders. Examples of child criminal exploitation were also identified from a case file audit crossover children (n = 300) appearing before three children's courts. Child criminal exploitation emerged as an issue in fifty percent (n = 12/25) of interview and focus group consultations. Participants regularly described this exploitation of crossover children by strangers, 'romantic' partners, and family members. Children in residential care and those with neurodisability were identified as vulnerable subgroups, with sexual exploitation and substance abuse operating as key facilitators of criminal exploitation. Legal and welfare responses included the use of intervention orders against exploiters, alongside child protection and secure welfare interventions with children. Child criminal exploitation is an identified concern for child protection-involved youth and other children who appear before criminal courts in the study jurisdiction. Findings demonstrate a need for a clear conceptualisation of child criminal exploitation, both locally and globally, that captures the scope of this phenomenon. Evidence-supported frameworks for identifying, preventing, and responding to child criminal exploitation are required to minimise detrimental legal and developmental impacts on children. [ABSTRACT FROM AUTHOR]

• Therapy-related AML with the t(8;16) is uncommon and associated with a poor prognosis. • Hematopoietic allogeneic stem cell transplantation remains the only curative option. • KAT6A-CREBBP transcript identification is necessary for measurable residual disease. • RT-qPCR monitoring confirms the efficacy of allogeneic stem cell transplantation. • In t(8;16) AML, measurable residual disease peri-transplant may influence prognosis. [ABSTRACT FROM AUTHOR]

Abstract: Concurrent Bruton tyrosine kinase and BCL2 inhibition has not yet been investigated in Waldenström macroglobulinemia (WM). We performed an investigator-initiated trial of ibrutinib and venetoclax in symptomatic treatment-naïve patients with MYD88-mutated WM. Patients received ibrutinib 420 mg once daily (cycle 1), followed by a ramp-up of venetoclax to 400 mg daily (cycle 2). The combination was then administered for 22 additional 4-week cycles. The attainment of very good partial response (VGPR) was the primary end point. Forty-five patients were enrolled in this study. The median baseline characteristics were as follows: age 67 years, serum IgM 43 g/L, and hemoglobin 102 g/L. Seventeen patients (38%) carried CXCR4 mutations. Nineteen patients (42%) achieved VGPR. Grade 3 or higher adverse events included neutropenia (38%), mucositis (9%), and tumor lysis syndrome (7%). Atrial fibrillation occurred in 3 (9%), and ventricular arrhythmia in 4 (9%) patients that included 2 grade 5 events. With a median follow-up of 24.4 months, the 24-month progression-free survival (PFS) and overall survival (OS) rates were 76% and 96%, respectively, and were not impacted by CXCR4 mutations. The median time on therapy was 10.2 months, and the median time after the end of therapy (EOT) was 13.3 months. Eleven of the 12 progression events occurred after EOT, and the 12-month PFS rates after EOT were 79%; 93% if VGPR was attained, and 69% for other patients (P = .12). Ibrutinib and venetoclax induced high VGPR rates and durable responses after EOT, although they were associated with a higher-than-expected rate of ventricular arrhythmia in patients with WM, leading to early study treatment termination. This trial was registered at www.clinicaltrials.gov as #NCT04273139., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Food allergy is considered a precursor to asthma in the context of the atopic march, but the relationship between infant food allergy phenotypes and lung function and asthma in childhood is unclear. We aimed to examine the association between food sensitisation and challenge-confirmed food allergy in infancy, as well as persistent and resolved food allergy up to age 6 years, and the risk of lung function deficits and asthma at age 6 years., Methods: The longitudinal, population-based HealthNuts cohort study in Melbourne, VIC, Australia, recruited 5276 infants children aged 1 year who attended council-run immunisation sessions between Sept 28, 2007, and Aug 5, 2011. At age 1 year, all children completed skin prick testing to four food allergens (egg, peanut, sesame, and either shrimp or cow's milk) and an oral food challenge (egg, peanut, and sesame) at the Royal Children's Hospital in Melbourne. Parents completed questionnaires about their infant's allergy history, demographic characteristics, and environmental exposures. At age 6 years, children were invited for a health assessment that included skin prick testing for ten foods (milk, egg, peanut, wheat, sesame, soy, shrimp, cashew, almond, and hazelnut) and eight aeroallergens (alternaria, cladasporum, house dust mite, cat hair, dog hair, bermuda grass, rye grass, and birch mix), oral food challenges, and lung function testing by spirometry. Questionnaires completed by parents (different to those completed at age 1 year) captured the child's allergy and respiratory history and demographics. We investigated associations between food allergy phenotypes (food-sensitised tolerance or food allergy; and ever, transient, persistent, or late-onset food allergy), lung function spirometry measures (forced expiratory volume in 1 sec [FEV 1 ] and forced vital capacity [FVC] z-scores, FEV 1 /FVC ratio, forced expiratory flow at 25% and 75% of the pulmonary volume [FEF 25-75% ], and bronchodilator responsiveness), and asthma using regression methods. Only children with complete data on the exposure, outcome, and confounders were included in models. Infants without food sensitisation or food allergy at age 1 year and 6 years served as the reference group., Findings: Of 5276 participants, 3233 completed the health assessment at age 6 years and were included in this analysis. Food allergy, but not food-sensitised tolerance, at age 1 year was associated with reduced FEV 1 and FVC (aβ -0·19 [95% CI -0·32 to -0·06] and -0·17 [-0·31 to -0·04], respectively) at age 6 years. Transient egg allergy was associated with reduced FEV 1 and FVC compared with never having egg allergy (-0·18 [95% CI -0·33 to -0·03] and -0·15 [-0·31 to 0·00], respectively), whereas persistent egg allergy was not (FEV 1 -0·09 [-0·48 to 0·31]; FVC -0·20 [-0·62 to 0·21]). Transient peanut allergy was associated with reduced FEV 1 and FVC (FEV 1 aβ -0·37 [-0·79 to 0·04] and FVC aβ -0·55 [-0·98 to -0·12]), in addition to persistent peanut allergy (FEV 1 aβ -0·30 [-0·54 to -0·06] and FVC aβ-0·30 [-0·55 to -0·05]), and late-onset peanut allergy (FEV 1 aβ -0·62 [-1·06 to -0·18] and FVC aβ-0·49 [-0·96 to -0·03]). Estimates suggested that food-sensitised tolerance and food allergy were associated with reduced FEF 25-75% , although some estimates were imprecise. Food allergy phenotypes were not associated with an FEV 1 /FVC ratio. Late-onset peanut allergy was the only allergy phenotype that was possibly associated with increased risk of bronchodilator responsiveness (2·95 [95% CI 0·77 to 11·38]). 430 (13·7%) of 3135 children were diagnosed with asthma before age 6 years (95% CI 12·5-15·0). Both food-sensitised tolerance and food allergy at age 1 year were associated with increased asthma risk at age 6 years (adjusted odds ratio 1·97 [95% CI 1·23 to 3·15] and 3·69 [2·81 to 4·85], respectively). Persistent and late-onset peanut allergy were associated with higher asthma risk (3·87 [2·39 to 6·26] and 5·06 [2·15 to 11·90], respectively)., Interpretation: Food allergy in infancy, whether it resolves or not, is associated with lung function deficits and asthma at age 6 years. Follow-up studies of interventions to prevent food allergy present an opportunity to examine whether preventing these food allergies improves respiratory health., Funding: National Health & Medical Research Council of Australia, Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government's Operational Infrastructure Support Program., Competing Interests: Declaration of interests MLKT has received research funding from Prota Therapeutics, is an employee of Prota Therapeutics, has received consultancy fees from Pfizer, and is an inventor on patents owned by MCRI “A method for of inducing tolerance to an allergen” and “Allergy Treatment”. KPP is Chair of the scientific advisory board for AllergyPal; has received research grants from DBV Technologies, Novartis, Aravax, and Siolta; and consultant fees from Aravax, outside of the submitted work, paid to their institution. SCD, CJL, and AJL received investigator-initiated grants from GSK for unrelated work. AJL, SCD, and JJK have received grant funding from Sanofi Regeneron for unrelated research. AJL has received in kind contributions of study intervention (EpiCeram) from Primus Pharmaceuticals for unrelated research. RLP receives honoraria for editorial involvement with the journal Paediatric Allergy and Immunology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

This study presents findings from a qualitative study conducted in two relatively remote, primarily rural regions of the Canadian province of Quebec whose resource-based economic structures exacerbate inequalities between men and women. The purpose of this study was to understand how violence and homelessness intertwine in women's life courses in such regions. On the basis of past research showing that gender socialization around traditional roles and conservative values is particularly tenacious in non-urban areas, we conducted life-course interviews with 22 women in 13 different towns and villages of these two regions. Our content analysis of these interviews showed that specific social responses have forced women to maintain relationships with their aggressors or with people who have protected them, thus relegating these women's lives to the private sphere while reducing their opportunities for social participation in the public sphere. These social responses, together with women's economic and social disadvantages in these regions, were also the main factors that explain homelessness experienced by the participants in this study. Our analysis of these responses illustrates the patriarchal social structure of power in these regions, which is perpetuated in the interpersonal, institutional, and representational dimensions and keeps women in precarious, subordinate social positions, while ostracizing or punishing women who try to resist.

The SRC family kinase (SFK) HCK is transcriptionally upregulated and activated by mutated MYD88 (MYD88Mut), a key adaptor for Toll-receptor signaling. HCK activates BTK, AKT, and ERK in MYD88Mut lymphomas. SYK, a B-cell receptor (BCR) component, is activated in MYD88Mut lymphoma cells. Although the SFK LYN serves as a trigger for SYK activation in MYD88Mut ABC DLBCL cells, LYN activity is muted in MYD88Mut Waldenstrom macroglobulinemia (WM) cells. We therefore investigated a role for HCK in mediating SYK activation. Overexpression of wild-type (WT) (HCKWT) or gatekeeper mutated (HCKThr333Met) HCK in MYD88Mut lymphoma cells triggered SYK activation. Conversely, HCK knockdown reduced p-SYK in MYD88Mut lymphoma cells. Coimmunoprecipitation experiments showed that HCK was complexed with p-SYK in MYD88Mut BCWM.1 and TMD8 cells, but not in MYD88 WT Ramos cells. Rescue experiments in MYD88Mut lymphoma cells expressing HCKThr333Met led to persistent HCK and SYK activation and resistance to the HCK inhibitor A419259. Treatment of primary MYD88Mut WM cells with A419259 reduced p-HCK and p-SYK expression. Taken together, our findings show that SYK is activated by HCK in MYD88Mut B-cell lymphomas cells, broaden the prosurvival signaling generated by aberrant HCK expression in response to MYD88Mut, and help define HCK as an important therapeutic target in MYD88Mut B-cell lymphomas., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The hematopoietic cell kinase (HCK) regulates BTK activation and represents a potential therapeutic target in Waldenstrom macroglobulinemia (WM). We investigated dasatinib, a potent HCK inhibitor, in patients with WM progressing on ibrutinib. Study treatment consisted of dasatinib administered at 100 mg by mouth once daily in four-week cycles for up to 24 cycles. This study was registered under ClinicalTrials.Gov ID NCT04115059. Three participants were enrolled and received at least one cycle of dasatinib. The best response was stable disease. Two patients received 5 months and one patient received 1 month of therapy. The dose of dasatinib was decreased in one participant due to volume overload. Based on the lack of responses observed, the study was terminated. Dasatinib might not be effective in patients with WM progressing on ibrutinib., Competing Interests: Jorge J. Castillo received research funds and/or honoraria from Abbvie, AstraZeneca, Beigene, Casma, Cellectar, Janssen, Pharmacyclics, Polyneuron, Roche and TG Therapeutics. Shayna Sarosiek received research funds and/or honoraria Acrotech Biopharma, ADC Therapeutics and BeiGene from Steven P. Treon received research funds and/or honoraria from Abbvie, Beigene, BMS, Pharmacyclics and X4., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Ibrutinib is highly active and produces long-term responses in patients with Waldenström macroglobulinemia (WM), but acquired resistance can occur with prolonged treatment. We therefore evaluated the natural history and treatment outcomes in 51 WM patients with acquired resistance to ibrutinib monotherapy. The median time between ibrutinib initiation and discontinuation was 2 years (range, 0.4-6.5 years). Following discontinuation of ibrutinib, a rapid increase in serum immunoglobulin M level was observed in 60% (29/48) of evaluable patients, of whom ten acutely developed symptomatic hyperviscosity. Forty-eight patients (94%) received salvage therapy after ibrutinib. The median time to salvage therapy after ibrutinib cessation was 18 days (95% confidence interval [CI]: 13-27). The overall and major response rates to salvage therapy were 56% and 44%, respectively, and the median duration of response was 48 months (95% CI: 34-not reached). Quadruple-class (rituximab, alkylator, proteasome inhibitor, ibrutinib) exposed disease (odds ratio [OR] 0.20, 95% CI: 0.05-0.73) and salvage therapy ≤7 days after discontinuing ibrutinib (OR 4.12, 95% CI: 1.07- 18.9) were identified as independent predictors of a response to salvage therapy. The 5-year overall survival (OS) following discontinuation of ibrutinib was 44% (95% CI: 26-75). Response to salvage therapy was associated with better OS after ibrutinib (hazard ratio 0.08, 95% CI: 0.02-0.38). TP53 mutations were associated with shorter OS, while acquired BTK C481S mutations had no impact. Our findings reveal that continuation of ibrutinib until subsequent treatment is associated with improved disease control and clinical outcomes.

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Although the association between child sexual abuse (CSA) and homelessness among women is well documented, few studies have investigated this topic from a feminist standpoint, examining the impact of sociocultural factors such as rape culture. Based on a qualitative life course approach, individual interviews were conducted with 21 women who experienced both CSA and homelessness. Participants were between 29 to 60 years old ( M = 45 years of age). Analyses revealed that CSA disclosure experiences were characterized by victim-blaming and disbelief. Women's traumatic experiences were further aggravated by these types of reactions. Finally, CSA and negative social reactions to women's disclosures of CSA were perceived as the onset of social exclusion, which lead to their homelessness. This study shows how traumatic CSA experiences and negative social reactions to their disclosure can both contribute to social exclusion and isolation, and to homelessness through the internalization of rape myths. These findings support the importance of focusing on CSA prevention to reduce social exclusion and homelessness.

Herein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate., (© 2021. The Author(s).)

Background: Bone marrow has been shown to be superior to peripheral blood, as a stem cell source, in young patients (<20 years of age) with acquired aplastic anemia undergoing a matched sibling transplant. The aim of this study was to test whether this currently also holds true for older patients with acquired aplastic anemia., Design and Methods: We analyzed 1886 patients with acquired aplastic anemia who received a first transplant from a human leukocyte antigen identical sibling between 1999 and 2009, with either bone marrow (n=1163) or peripheral blood (n=723) as the source of stem cells., Results: In multivariate Cox analysis negative predictors for survival were: patient's age over 20 years (RR 2.0, P<0.0001), an interval between diagnosis and transplantation of more than 114 days (RR 1.3, P=0.006), no anti-thymocyte globulin in the conditioning (RR 1.6, P=0.0001), a conditioning regimen other than cyclophosphamide (RR=1.3, P=0.008) and the use of peripheral blood as the source of stem cells (RR 1.6, P<0.00001). The survival advantage for recipients of bone marrow rather than peripheral blood was statistically significant in patients aged 1-19 years (90% versus 76% P<0.00001) as well as in patients aged over 20 years (74% versus 64%, P=0.001). The advantage for recipients of bone marrow over peripheral blood was maintained above the age of 50 years (69% versus 39%, P=0.01). Acute and chronic graft-versus-host disease were more frequent in peripheral blood transplants. Major causes of death were graft-versus-host disease (2% versus 6% in bone marrow and peripheral blood recipients, respectively), infections (6% versus 13%), and graft rejection (1.5% versus 2.5%)., Conclusions: This study shows that bone marrow should be the preferred stem cell source for matched sibling transplants in acquired aplastic anemia, in patients of all age groups.