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Background: South Asian gay, bisexual, and other men who have sex with men (GBM) in the United States have been persistently overlooked in HIV research and programming. To address this limitation, this article describes their HIV-related knowledge, risk perception, and minority stressors, with a focus on identifying variations between American-born individuals and immigrants., Methods: Participants were recruited from April-July 2022 through social media advertising and peer referral and surveyed about their sociodemographic and HIV-related behavioral characteristics. Previously validated scales were used to assess their HIV-related knowledge, risk perception, disclosure of sexual identity, experienced homophobia, and perceived racism within the sexual and gender minority community. Mann-Whitney-Wilcoxon tests were conducted to compare those born in the United States and those born abroad., Results: Of the 112 participants, 26 (23.21%) were American-born individuals and 86 (76.79%) were immigrants. Despite similar levels of sexual risk behaviors, such as having multiple male sex partners, engaging in condomless anal sex, and using alcohol or drugs immediately before or during sex, immigrants had lower levels of HIV-related knowledge ( p = .0480) and risk perception ( p = .0114) compared to American-born individuals. Immigrants were also less likely to have disclosed their sexual identity to family, friends, and society compared to American-born individuals ( p = .0004). No differences were identified with respect to experiences of homophobia ( p = .2303) or perceptions of racism ( p = .4011)., Conclusion: Comprehensive HIV prevention efforts that address the social and cultural norms of South Asian GBM in the United States are needed., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract: Serial cardiovascular magnetic resonance evaluation of children and young adults with SCD who underwent hematopoietic cell transplantation showed mean ECV, representing diffuse myocardial fibrosis, decreased 3.4% from baseline to 12 months posttransplantation. This trial was registered at www.clinicaltrials.gov as #NCT04362293., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

CCAAT/enhancer-binding protein α (C/EBPα), a key myeloid transcription factor, drives myeloid differentiation from blast cells by regulating the expression of granulocyte colony stimulating factor receptor and C/EBPε as required for promoting granulocyte differentiation. Here, we show that serine/threonine-protein kinase NLK, also known as Nemo-like kinase, physically associates with C/EBPα and phosphorylates it at multiple sites, including Ser21, Thr226, Thr230 and S234, leading to its ubiquitin-mediated degradation. Individual phospho-point mutants of C/EBPα could be phosphorylated by NLK, but a mutant with all phosphorylatable residues replaced by alanine resisted phosphorylation and degradation by NLK, as did the single point mutants. Furthermore, although ectopic expression of NLK enhanced phosphorylation of C/EBPα levels, it markedly inhibited total C/EBPα protein levels. Conversely, NLK depletion inhibited endogenous C/EBPα phosphorylation but enhanced its total protein levels in several acute myeloid leukemia (AML) cell lines and in peripheral blood mononuclear cells isolated from number of AML patient samples. Importantly, NLK depletion in peripheral blood mononuclear cells from primary AML patients not only restored C/EBPα protein levels, but also induced myeloid differentiation, suggesting that NLK could be therapeutically targeted to restore C/EBPα to resolve differentiation arrest in AML., (© 2024 Federation of European Biochemical Societies.)

Purpose: Seizures are a common clinical occurrence in high-grade glioma (HGG). While many studies have explored seizure incidence and prevalence in HGG, limited studies have examined the prognostic effect of seizures occurring in the post-diagnosis setting. This study aims to assess the impact of seizure presentation on HGG survival outcomes., Methods: Single-center retrospective review identified 950 patients with histologically-confirmed high-grade glioma. Seizure presentation was determined by clinical history and classified as early onset (occurring within 30 days of HGG presentation) or late onset (first seizure occurring after beginning HGG treatment). The primary outcome, hazard ratios for overall survival and progression-free survival, was assessed with multivariable Cox proportional-hazards models. IDH1 mutation status (assessed through immunohistochemistry) was only consistently available beginning in 2015; subgroup analyses were performed in the subset of patients with known IDH1 status., Results: Epileptic activity before (HR = 0.81, 95% CI = 0.68-0.96, P = 0.017) or after (HR = 0.74, 95% CI = 0.60-0.91, P = 0.005) HGG diagnosis associated with improved overall survival. Additionally, late seizure onset significantly associated with lower odds of achieving partial (OR = 0.25, 95% CI = 0.12-0.53, P = < 0.001) or complete (OR = 0.30, 95% CI = 0.18-0.50, P < 0.001) seizure control than patients with early seizure onset., Conclusions: Clinical seizures both at the time of diagnosis and later during the HGG treatment course are associated with improved overall survival. This association potentially persists for both IDH1-wildtype and IDH1-mutant patients, but further study is required., (© 2024. The Author(s).)

Competing Interests: AS has received consultant fees from Spotlight Therapeutics, Medexus, Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine. He is a medical monitor for a Resource for Clinical Investigations in Blood and Marrow Transplantation Conditioning SCID Infants Diagnosed Early clinical trial for which he receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. AS is the St Jude Children's Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to AS's institution. AS has no direct financial interest in these therapies. AS is supported by a grant (1U01HL163983) from the National Institutes of Health/National Heart, Lung, and Blood Institute. The content of this Comment is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. TDJ has participated as an advisory board member and received consulting fees from Bluebird Bio and Vertex Pharmaceuticals. She is a medical monitor for BMT CTN 2001 GRASP study for which she receives compensation. TDJ is the Stanford site principal investigator of clinical trials for genome editing sponsored by Beam Therapeutics (NCT04443907). TDJ has no direct financial interest in this therapy. We thank Keith A Laycock for scientific editing of the Comment. We also thank Jennifer Adair, Fred Hutch Cancer Center, Jane Hankins, St Jude Children's Research Hospital, and Zainab Garba-Sani, Stanford University and NHS England, for offering critical insights on the topic and reviewing an early draft of the manuscript.

Genetically modified cell therapies (GMCT), particularly immune effector cells (IEC) such as chimeric receptor antigen (CAR) T cells, have shown promise in curing cancer and rare diseases after a single treatment course. Following close behind CAR T approvals are GMCT based on hematopoietic stem cells, such as products developed for hemoglobinopathies and other disorders. Academically sponsored GMCT products, often developed in academic centers without industry involvement, face challenges in sustaining access after completion of early phase studies when there is no commercial partner invested in completing registration trials for marketing applications. The American Society for Transplantation and Cellular Therapy (ASTCT) formed a task force named ACT To Sustain (Adoptive Cell Therapy to Sustain) to address the "valley of death" of academic GMCT products. This paper presents the task force's findings and considerations regarding financial sustainability of academically sponsored GMCT products in the absence of commercial development. We outline case scenarios illustrating barriers to maintaining access to promising GMCT developed by academic centers. The paper also delves into the current state of GMCT development, commercialization, and reimbursement, citing examples of abandoned products, cost estimates associated with GMCT manufacturing and real-world use of cost recovery. We propose potential solutions to address the financial, regulatory, and logistical challenges associated with sustaining access to academically sponsored GMCT products and to ensure that products with promising results do not languish in a "valley of death" due to financial or implementational barriers. The suggestions include aligning US Food and Drug Administration (FDA) designations with benefit coverage, allowing for cost recovery of certain products as a covered benefit, and engaging with regulators and policy makers to discuss alternative pathways for academic centers to provide access. We stress the importance of sustainable access to GMCT and call for collaborative efforts to develop regulatory pathways that support access to academically sponsored GMCT products., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

The use of immunotherapies for the treatment of cancer in children, adolescents, and young adults has become common. As the use of immunotherapy has expanded, including in earlier lines of therapy, it has become evident that several aspects of how these immunotherapies impact longer-term outcomes among survivors are understudied. Traditional cancer therapies like alkylating and platin agents carry the greatest risk of infertility, but little is known about the impact of novel immunotherapies on fertility. This topic is of great interest to patients, patient advocates, and clinicians. In this article, we review immunotherapeutic agents used to treat childhood and young adult cancers and discuss potential mechanisms by which they may impact fertility based on the known interplay between the immune system and reproductive organs. We highlight the relative paucity of high-quality literature examining these late effects. We discuss interventions to optimize fertility preservation (FP) for our patients. Conducting longitudinal, collaborative, and prospective research on the fertility outcomes of pediatric and young adult patients with cancer who receive immunotherapy is critical to learn how to effectively counsel our patients on long-term fertility outcomes and indications for FP procedures. Collection of patient-level data will be necessary to draft evidence-based guidelines on which providers can make therapy recommendations., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Sickle cell disease (SCD) is a common, severe genetic blood disorder. Current pharmacotherapies are partially effective and allogeneic hematopoietic stem cell transplantation (HSCT) is associated with immune toxicities. Genome editing of patient hematopoietic stem cells (HSCs) to reactivate fetal hemoglobin (HbF) in erythroid progeny offers an alternative potentially curative approach to treat SCD. Although the FDA released guidelines for evaluating genome editing risks, it remains unclear how best to approach pre-clinical assessment of genome-edited cell products. Here we describe rigorous pre-clinical development of a therapeutic γ-globin gene promoter editing strategy that supported an investigational new drug (IND) application cleared by the FDA. We compared γ-globin promoter and BCL11A enhancer targets, identified a potent HbF-inducing lead candidate, and tested our approach in mobilized CD34 + HSPCs from SCD patients. We observed efficient editing, HbF induction to predicted therapeutic levels, and reduced sickling. With single-cell analyses, we defined the heterogeneity of HbF induction and HBG1/HBG2 transcription. With CHANGE-seq for sensitive and unbiased off-target discovery followed by targeted sequencing, we did not detect off-target activity in edited HSPCs. Our study provides a blueprint for translating new ex vivo HSC genome editing strategies towards clinical trials for treating SCD and other blood disorders., (Copyright © 2024. Published by Elsevier Inc.)

Background: Umbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients., Objective: To compare outcomes by social determinants of health., Study Design: We designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS)., Results: For 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults. Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes., Conclusions: OS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Abstract: There has been an increase in volume as well as an improvement in overall survival (OS) after hematopoietic cell transplantation (HCT) for hematologic disorders. It is unknown if these changes have affected racial/ethnic minorities equally. In this observational study from the Center for International Blood and Marrow Transplant Research of 79 904 autologous (auto) and 65 662 allogeneic (allo) HCTs, we examined the volume and rates of change of autoHCT and alloHCT over time and trends in OS in 4 racial/ethnic groups: non-Hispanic Whites (NHWs), non-Hispanic African Americans (NHAAs), and Hispanics across 5 2-year cohorts from 2009 to 2018. Rates of change were compared using Poisson model. Adjusted and unadjusted Cox proportional hazards models examined trends in mortality in the 4 racial/ethnic groups over 5 study time periods. The rates of increase in volume were significantly higher for Hispanics and NHAAs vs NHW for both autoHCT and alloHCT. Adjusted overall mortality after autoHCT was comparable across all racial/ethnic groups. NHAA adults (hazard ratio [HR] 1.13; 95% confidence interval [CI] 1.04-1.22; P = .004) and pediatric patients (HR 1.62; 95% CI 1.3-2.03; P < .001) had a higher risk of mortality after alloHCT than NHWs. Improvement in OS over time was seen in all 4 groups after both autoHCT and alloHCT. Our study shows the rate of change for the use of autoHCT and alloHCT is higher in NHAAs and Hispanics than in NHWs. Survival after autoHCT and alloHCT improved over time; however, NHAAs have worse OS after alloHCT, which has persisted. Continued efforts are needed to mitigate disparities for patients requiring alloHCT., (© 2024 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.)

Hydrocephalus is a known complication following surgical resection of a cerebral hemisphere for refractory epilepsy, yet the pathological mechanism remains poorly understood. We present a case of refractory aseptic inflammatory hydrocephalus following cerebral hemispherectomy surgery for refractory epilepsy treated with a combination of cerebral spinal fluid (CSF) diversion and immunosuppression via IL-1 receptor agonist, Anakinra. At 6 month follow up, the patient had returned to neurologic baseline, with improvement in school and physical therapy performance. Further investigation into the beneficial role of immunosuppressive therapy is needed to better understand the relationship between neuro-inflammation and improving outcomes following epilepsy surgery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Inc.)

Hemispherectomy is an effective procedure used in the treatment of drug-resistant hemispheric epilepsy, especially in the pediatric population. A number of resective and disconnective techniques are used, and selection of surgical strategy is paramount to achieving successful results. Notably, disconnective (or functional) hemispherotomy maximizes the benefits of safe, surgical disconnection while minimizing hemispheric tissue resection, thereby avoiding some of the perioperative factors contributing to morbidity in traditional anatomical hemispherectomy procedures. In this video, the authors outline the principal surgical steps of disconnective hemispherotomy and highlight important technical factors leading to optimal outcomes in patients with refractory, oftentimes catastrophic, hemispheric epilepsy. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2436., Competing Interests: Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication.The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this publication., (© 2024, The Authors.)

A pediatric patient with acute myeloid leukemia was referred to our institution for investigational therapy after disease relapse following a mismatched unrelated donor hematopoietic cell transplant (HCT). Prior to second HCT, the patient's serum was negative for antibodies to class I and class II HLA. Eight days after receiving a maternal donor haploidentical transplant, the patient became platelet refractory and highly sensitized to multiple class I HLA. Serum from the patient's mother was positive for the strongest antibodies present in the patient, suggesting the antibodies were donor-derived. Patient sera showed magnified and expanded sensitization over time in the context of 100% donor chimerism and despite undetectable circulating B cells. Escalating sensitization suggests active transfer of rituximab-resistant antibody-producing passenger lymphocytes from a haploidentical donor to a transplant recipient at the time of progenitor cell infusion. Evaluation of donor sensitization status may be a consideration prior to HLA mismatched HCT., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Akshay Sharma has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine. He is a medical monitor for the RCI BMT CSIDE clinical trial, for which receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. Dr. Sharma is the St. Jude Children’s Research Hospital site principal investigator for clinical trials of genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trials, which includes salary support paid to Dr Sharma’s institution. Dr Sharma has no direct financial interest in these therapies. Shane Cross has received consultant fees for Lexicomp (Wolters Kluwer). The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

There is lack of guidance for immune monitoring and infection prevention after administration of ex vivo genetically modified hematopoietic stem cell therapies (GMHSCT). We reviewed current infection prevention practices as reported by providers experienced with GMHSCTs across North America and Europe, and assessed potential immunologic compromise associated with the therapeutic process of GMHSCTs described to date. Based on these assessments, and with consensus from members of the International Society for Cell & Gene Therapy (ISCT) Stem Cell Engineering Committee, we propose risk-adapted recommendations for immune monitoring, infection surveillance and prophylaxis, and revaccination after receipt of GMHSCTs. Disease-specific and GMHSCT-specific considerations should guide decision making for each therapy., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Pneumocystis jirovecii pneumonia (PJP) in hematopoietic cell transplant (HCT) recipients can be prevented by efficient prophylaxis. We surveyed HCT centers in North America to assess their PJP prophylaxis practices. Most institutions used intravenous (IV) pentamidine (29.6%) or inhaled pentamidine (14.8%); 37% institutions changed from trimethoprim/sulfamethoxazole (TMP-SMX) to another medication after conditioning; and 44% administered no PJP prophylaxis during the pre-engraftment period. Most institutions avoided using TMP-SMX during the pre-engraftment period, mainly because of concerns about myelotoxicity, despite this being the preferred PJP prophylaxis agent. There is a need to evaluate the effects of TMP-SMX on engraftment., (© 2024 Wiley Periodicals LLC.)

Background: Relapse remains a challenge after transplantation in pediatric patients with hematological malignancies. Myeloablative regimens used for disease control are associated with acute and long-term adverse effects. We used a CD45RA-depleted haploidentical graft for adoptive transfer of memory T cells combined with NK-cell addback and hypothesized that maximizing the graft-versus-leukemia (GVL) effect might allow for reduction in intensity of conditioning regimen., Methods: In this phase II clinical trial (NCT01807611), 72 patients with hematological malignancies (complete remission (CR)1: 25, ≥ CR2: 28, refractory disease: 19) received haploidentical CD34 + enriched and CD45RA-depleted hematopoietic progenitor cell grafts followed by NK-cell infusion. Conditioning included fludarabine, thiotepa, melphalan, cyclophosphamide, total lymphoid irradiation, and graft-versus-host disease (GVHD) prophylaxis consisted of a short-course sirolimus or mycophenolate mofetil without serotherapy., Results: The 3-year overall survival (OS) and event-free-survival (EFS) for patients in CR1 were 92% (95% CI:72-98) and 88% (95% CI: 67-96); ≥ CR2 were 81% (95% CI: 61-92) and 68% (95% CI: 47-82) and refractory disease were 32% (95% CI: 11-54) and 20% (95% CI: 6-40). The 3-year EFS for all patients in morphological CR was 77% (95% CI: 64-87) with no difference amongst recipients with or without minimal residual disease (P = 0.2992). Immune reconstitution was rapid, with mean CD3 and CD4 T-cell counts of 410/μL and 140/μL at day + 30. Cumulative incidence of acute GVHD and chronic GVHD was 36% and 26% but most patients with acute GVHD recovered rapidly with therapy. Lower rates of grade III-IV acute GVHD were observed with NK-cell alloreactive donors (P = 0.004), and higher rates of moderate/severe chronic GVHD occurred with maternal donors (P = 0.035)., Conclusion: The combination of a CD45RA-depleted graft and NK-cell addback led to robust immune reconstitution maximizing the GVL effect and allowed for use of a submyeloablative, TBI-free conditioning regimen that was associated with excellent EFS resulting in promising long-term outcomes in this high-risk population. The trial is registered at ClinicalTrials.gov (NCT01807611)., (© 2024. The Author(s).)

Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in neurocognitive deficits. Hydroxyurea is the standard treatment for SCD; however, whether hydroxyurea influences such effects is unclear. A key area of SCD-associated neurocognitive impairment is working memory, which is implicated in other cognitive and academic skills. The neural correlates of working memory can be tested using n-back tasks. We analyzed functional magnetic resonance imaging (fMRI) data of patients with SCD (20 hydroxyurea-treated patients and 11 controls, aged 7-18 years) while they performed n-back tasks. Blood-oxygenation level-dependent (BOLD) signals were assessed during working memory processing at 2 time points: before hydroxyurea treatment and ~1 year after treatment was initiated. Neurocognitive measures were also assessed at both time points. Our results suggested that working memory was stable in the treated group. We observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- >0-back contrast. Searchlight-pattern classification of the 2 time points of the 2-back tasks identified greater changes in the pattern and magnitude of BOLD signals, especially in the posterior regions of the brain, in the control group than in the treated group. In the control group at 1-year follow-up, 2-back BOLD signals increased across time points in several clusters (e.g., right inferior temporal lobe, right angular gyrus). We hypothesize that these changes resulted from increased cognitive effort during working memory processing in the absence of hydroxyurea. In the treated group, 0- to 2-back BOLD signals in the right angular gyrus and left cuneus increased continuously with increasing working memory load, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. These findings suggest that hydroxyurea treatment helps maintain working memory function in SCD., Competing Interests: Dr. Akshay Sharma has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. Dr. Sharma is the St. Jude site principal investigator of clinical trials for genome editing for SCD sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to our institution. Dr. Sharma has no direct financial interest in these therapies. Dr. Andrew M. Heitzer has received consulting fees from Global Blood Therapeutics. Neither Dr. Sharma nor Dr. Heitzer is an employee of any commercial entity. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This does not alter our adherence to PLoS ONE policies on sharing data and materials., (Copyright: © 2024 Lai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Genetic manipulation of hematopoietic stem cells (HSCs) is being developed as a therapeutic strategy for several inherited disorders. This field is rapidly evolving with several novel tools and techniques being employed to achieve desired genetic changes. While commercial products are now available for sickle cell disease, transfusion-dependent β-thalassemia, metachromatic leukodystrophy and adrenoleukodystrophy, several challenges remain in patient selection, HSC mobilization and collection, genetic manipulation of stem cells, conditioning, hematologic recovery and post-transplant complications, financial issues, equity of access and institutional and global preparedness. In this report, we explore the current state of development of these therapies and provide a comprehensive assessment of the challenges these therapies face as well as potential solutions., Competing Interests: Declaration of competing interest Ashish Gupta is a site principal investigator at University of Minnesota for clinical trials in genome editing for sickle cell disease sponsored by Bluebird Bio (NCT04293185) and Beam Therapeutics (NCT05456880). He is also the site principal investigator at University of Minnesota for clinical trials in genome editing for Hurler syndrome (NCT06149403). He has received consultancy fees from Vertex Pharmaceuticals and is on speaker bureau for Emerging Therapies Solutions. He also has research funding from Jazz Pharmaceuticals for an investigator initiated trial. Akshay Sharma has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics and Editas Medicine. He is a medical monitor for an RCI BMT clinical trial for which he receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. Akshay Sharma is also the St. Jude Children's Research Hospital site principal investigator for clinical trials of genome editing for sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907) and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trials, which includes salary support paid to the investigator's institution. Akshay Sharma has no direct financial interest in these therapies. Jaap Jan Boelens has received consultant fees from Sanofi, Sobi, Merck, Immusoft and Smart Immune, is the MSKCC site PI for Novartis Pharmaceuticals (NCT04443907) and received research funding from Sanofi (for investigator-initiated research). Jaap Jan Boelens is also the chair of an independent data safety monitoring board (for bluebird bio gene therapy trials), for which he receives compensation (CRO; Advanced Clinical). Susan Prockop has received support for the conduct of clinical trials from AlloVir, Atara, and Jasper through Boston Children's Hospital. She has received an honorarium from Pierre Fabre and Regeneron and consults for CellEvolve, Smart Immune and Century. She has IP related to the implementation of third-party viral-specific T cells, with all rights assigned to Memorial Sloan Kettering Cancer Center. Chrystal U. Louis has equity in and is an employee of TScan Therapeutics. The other authors have nothing to disclose., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the volume of HCT performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long-term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and other underlying risk-factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and updated in 2012. To review contemporary literature and update the recommendations while considering the changing practice of HCT and cellular therapy, an international group of experts was again convened. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed but cGVHD management is not covered in detail. These guidelines emphasize special needs of patients with distinct underlying HCT indications or comorbidities (e.g., hemoglobinopathies, older adults) but do not replace more detailed group, disease, or condition specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings., (© 2024. The Author(s).)

Allogeneic hemopoietic cell transplantation remains the goal of therapy for high-risk acute myeloid leukemia (AML). However, treatment failure in the form of leukemia relapse or severe graft-versus-host disease remains a critical area of unmet need. Recently, significant progress has been made in the cell therapy-based interventions both before and after transplant. In this review, the Stem Cell Engineering Committee of the International Society for Cell and Gene Therapy summarizes the literature regarding the identification of high risk in AML, treatment approaches before transplant, optimal transplant platforms and measures that may be taken after transplant to ideally prevent, or, if need be, treat AML relapse. Although some strategies remain in the early phases of clinical investigation, they are built on progress in pre-clinical research and cellular engineering techniques that are already improving outcomes for children and adults with high-risk malignancies., (Copyright © 2023 International Society for Cell & Gene Therapy. All rights reserved.)

A shortage of transplant and cellular therapy (TCT) physicians is expected given the expansion of TCT indications and the scope of practice of TCT programs in recent years. American Society of Transplantation and Cellular Therapy (ASTCT) conducted a survey of early career transplant physicians and trainees to assess the factors that prompted them to pursue to career in TCT. This was a cross-sectional survey conducted via emails sent to the ASTCT membership. Fifty-nine respondents completed the survey. The vast majority of respondents decided to pursue a career in TCT during their hematology/oncology fellowship (41%), followed by during residency (25%) or medical school (18%), and a majority of them had some exposure to TCT in their clinical training already. The most common reason for choosing to specialize in TCT was interest in the clinical practice of TCT (81%) closely followed by the scientific allure of the field (75%). Most respondents were extremely committed to remaining in this field of practice. We found that those in the field report high levels of satisfaction despite factors that would otherwise predispose them to burnout. A systematic and sustained effort to promote trainee engagement that could result in improved recruitment and retention in the field of TCT is needed. Professional societies in partnership with educational institutions could conduct outreach and help attract trainees from diverse backgrounds., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Socioeconomic status (SES) and race/ethnicity have been associated with outcomes of allogeneic hematopoietic cell transplantation (allo-HCT). Certain aspects of GVHD management such as the need for long term care, prolonged immunosuppressive treatment, and need for close follow up for complications may exacerbate disparities. Adults (≥ 18 years) reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent a first alloHCT for acute leukemia, myelodysplastic syndrome, or myeloproliferative neoplasm between 2008 - 2018 were included. Endpoints for those developing GVHD included overall survival (OS), transplant related mortality (TRM), and disease relapse. Models were adjusted for patient and transplant related variables. A two-sided p-value < 0.01 was considered significant. Among the 14,825 allo-HCT recipients, 6,259 (42.2%) and 6,675 (45.0%) patients developed aGVHD and cGVHD, respectively. In patients with aGVHD, non-Hispanic Blacks had increased TRM (HR 1.50, 95% CI 1.24-1.83, p=0.0001) and overall mortality (HR 1.31, 1.14-1.50, p=0.0002) compared with non-Hispanic Whites, an association that disappeared when severity of aGVHD was included in the model. Lower SES was associated with increased risk of disease relapse (p=0.0016) but not OS or TRM. In patients who developed cGVHD, race and ethnicity were not associated with OS, TRM and disease relapse. However, the highest quartile of annual household income (≥ $80,000) had improved OS (HR 0.77, 0.69-0.85, p<0.0001) and reduced TRM (HR 0.86, 0.67-0.87, p<0.0001) compared with lowest quartile, adjusting for race and ethnicity. Race/ethnicity and SES are associated with outcomes after GVHD. Optimizing health care resources available to low SES patients and strategies to minimize the risk of severe GVHD in non-Hispanic Blacks may improve long-term outcomes., (Copyright © 2024 American Society of Hematology.)

Background: Exagamglogene autotemcel (exa-cel) is a nonviral cell therapy designed to reactivate fetal hemoglobin synthesis by means of ex vivo clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 gene editing of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) at the erythroid-specific enhancer region of BCL11A ., Methods: We conducted a phase 3, single-group, open-label study of exa-cel in patients 12 to 35 years of age with sickle cell disease who had had at least two severe vaso-occlusive crises in each of the 2 years before screening. CD34+ HSPCs were edited with the use of CRISPR-Cas9. Before the exa-cel infusion, patients underwent myeloablative conditioning with pharmacokinetically dose-adjusted busulfan. The primary end point was freedom from severe vaso-occlusive crises for at least 12 consecutive months. A key secondary end point was freedom from inpatient hospitalization for severe vaso-occlusive crises for at least 12 consecutive months. The safety of exa-cel was also assessed., Results: A total of 44 patients received exa-cel, and the median follow-up was 19.3 months (range, 0.8 to 48.1). Neutrophils and platelets engrafted in each patient. Of the 30 patients who had sufficient follow-up to be evaluated, 29 (97%; 95% confidence interval [CI], 83 to 100) were free from vaso-occlusive crises for at least 12 consecutive months, and all 30 (100%; 95% CI, 88 to 100) were free from hospitalizations for vaso-occlusive crises for at least 12 consecutive months (P<0.001 for both comparisons against the null hypothesis of a 50% response). The safety profile of exa-cel was generally consistent with that of myeloablative busulfan conditioning and autologous HSPC transplantation. No cancers occurred., Conclusions: Treatment with exa-cel eliminated vaso-occlusive crises in 97% of patients with sickle cell disease for a period of 12 months or more. (CLIMB SCD-121; ClinicalTrials.gov number, NCT03745287.)., (Copyright © 2024 Massachusetts Medical Society.)

Background and Aim: Sexed semen (SS), a reproductive biotechnology tool, can alter the sex ratio of offspring in bovines. This study elucidates a comparative analysis of estrus-related parameters influencing conception rate and pregnancy losses under field conditions between conventional and SS., Materials and Methods: In the present study, artificial insemination with (SS; n = 143) and conventional semen (CS; n = 143) was performed at spontaneous estrus, i.e., 16-18 h after the onset of estrus signs, to analyze their comparative evaluation in terms of conception rates in crossbred cows under field conditions. Different parameters such as age, parity, body condition score (BCS), estrus duration, inter-estrus interval (IEI), diameter of pre-ovulatory follicle (DPOF) at estrus, and cervical mucus properties (pH and spinnbarkeit [SBK]) were recorded for each cow., Results: The first insemination conception rates for sexed and conventional semen were 55.24% and 63.63% whereas the overall conception rates were 49.14% and 57.37% on days 35 and 75 post-insemination, respectively, with no significant difference (p > 0.05). Conception rates between sexed and CS inseminations were statistically significant (p < 0.01), whereas factors such as age, parity, BCS, DPOF, IEI), and SBK value exhibited no substantial variance (p > 0.05) for both types of semen straw., Conclusion: SS straws yielded a conception rate equivalent to CS straws, with estrus duration being the key factor affecting conception under field conditions., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Sharma, et al.)

Patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT) have a poor prognosis. Although proceeding to subsequent HCT can provide potential for long-term survival, there are limited data to guide which patients are most likely to benefit and which HCT strategies are best in this heavily pretreated population. The goals of this study were to describe the clinical outcomes of subsequent HCT in pediatric patients with relapsed hematologic malignancies in a cohort enriched for haploidentical donors, and to evaluate the associations of patient-, disease-, and treatment-related factors with survival. We retrospectively evaluated patients who underwent a subsequent HCT for management of post-HCT relapse at a single institution between 2000 and 2021. Among 106 patients who underwent a second allogeneic HCT, the 1-year event-free survival (EFS) was 34% and 1-year overall survival (OS) was 46%, with a 5-year EFS of 26% and 5-year OS of 31%. Only disease-related factors were associated with outcome after second HCT-specifically, the interval between HCTs and the presence or absence of active disease at the time of HCT. In this cohort, patient- and treatment-related factors were not associated with differences in EFS or OS. Patients undergoing a third or fourth HCT (n = 13) had comparable survival outcomes to those undergoing a second HCT. Our experience highlights that a subsequent HCT has curative potential for a subset of patients who relapse after HCT, including those who undergo a subsequent HCT from a haploidentical donor. Although relapse and treatment-related toxicities remain major challenges, our study indicates that achieving complete remission prior to subsequent HCTs has the potential to further improve outcomes., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: The risk of hydrocephalus following hemispherectomy for drug resistant epilepsy (DRE) remains high. Patients with pre-existing hydrocephalus pose a postoperative challenge, as maintaining existing shunt patency is necessary but lacks a clearly defined strategy. This study examines the incidence and predictors of shunt failure in pediatric hemispherectomy patients with pre-existing ventricular shunts., Methods: We performed a retrospective chart review at our center to identify pediatric patients diagnosed with DRE who were treated with ventricular shunt prior to their first hemispherectomy surgery. Demographic and perioperative data were obtained including shunt history, hydrocephalus etiology, epilepsy duration, surgical technique, and postoperative outcomes. Univariate analysis was performed using Fisher's exact test and Pearson correlation, with Bonferroni correction to a = 0.00625 and a = 0.01, respectively., Results: Five of nineteen (26.3%) patients identified with ventriculoperitoneal shunting prior to hemispherectomy experienced postoperative shunt malfunction. All 5 of these patients underwent at least 1 shunt revision prior to hemispherectomy, with a significant association between pre- and post-hemispherectomy shunt revisions. There was no significant association between post-hemispherectomy shunt failure and valve type, intraoperative shunt alteration, postoperative external ventricular drain placement, hemispherectomy revision, lateralization of shunt relative to resection, postoperative complications, or postoperative aseptic meningitis. There was no significant correlation between number of post-hemispherectomy shunt revisions and age at shunt placement, age at hemispherectomy, epilepsy duration, or shunt duration prior to hemispherectomy., Conclusions: Earlier shunt revision surgery may portend a subsequent need for shunt revision following hemispherectomy. These findings may guide neurosurgeons in counseling patients with pre-existing ventricular shunts prior to hemispherectomy surgery., (© 2024. The Author(s).)

Background and Objectives: We developed, tested, and validated a novel, noninvasive, Leksell G frame-based fiducial attachment, for use in stereotactic registration for stereoelectroencephalography (sEEG). Use of the device increased the number of fixed reference points available for registration, while obviating the need for additional scalp incisions. We report here on our experience and safety profile of using the device., Methods: We collected registration data using the fiducial device across 25 adult and pediatric patients with epilepsy consecutively undergoing robotic-guided sEEG for invasive epilepsy monitoring, treated between May 2022 and July 2023. ROSA One Brain was used for trajectory planning and electrode implantation. Postoperative clinical and radiographic data were computed and quantified, including mean registration error for all patients. Entry point, target point (TP), and angular errors were measured. Descriptive statistics and correlation coefficients for error were calculated., Results: Twenty-five patients underwent robotic-guided sEEG implantation (11 patients, bilateral; 10 patients, left unilateral; 4 patients, right). The mean number of electrodes per patient was 18 ± 3. The average mean registration error was 0.77 ± 0.11 mm. All patients were implanted with Ad-Tech depth electrodes. No clinically relevant complications were reported. Analysis of trajectory error was performed on 446 electrodes. The median entry point error was 1.03 mm (IQR 0.69-1.54). The median TP error was 2.26 mm (IQR 1.63-2.93). The mean angular error was 0.03 radians (IQR 0.02-0.05). There was no significant correlation between root mean square error and lead error. Root mean square error did not appreciably change over time, nor were there any significant changes in average angular, entry point, or TP error metrics., Conclusion: A novel, noninvasive, Leksell G frame-based fiducial attachment was developed, tested, and validated, facilitating O-arm-based stereotactic registration for sEEG. This simple innovation maintained an excellent accuracy and safety profile for sEEG procedures in epilepsy patients, with the added advantages of providing additional reference points for stereotactic registration, without requiring additional scalp incisions., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Poor-risk (PR) cytogenetic/molecular abnormalities generally direct pediatric patients with acute myeloid leukemia (AML) to allogeneic hematopoietic stem cell transplant (HSCT). We assessed the predictive value of cytogenetic risk classification at diagnosis with respect to post-HSCT outcomes in pediatric patients. Patients younger than 18 years at the time of their first allogeneic HSCT for AML in CR1 between 2005 and 2022 who were reported to the European Society for Blood and Marrow Transplantation registry were subgrouped into four categories. Of the 845 pediatric patients included in this study, 36% had an 11q23 abnormality, 24% had monosomy 7/del7q or monosomy 5/del5q, 24% had a complex or monosomal karyotype, and 16% had other PR cytogenetic abnormalities. In a multivariable model, 11q23 (hazard ratio [HR] = 0.66, P = 0.03) and other PR cytogenetic abnormalities (HR = 0.55, P = 0.02) were associated with significantly better overall survival when compared with monosomy 7/del7q or monosomy 5/del5q. Patients with other PR cytogenetic abnormalities had a lower risk of disease relapse after HSCT (HR = 0.49, P = 0.01) and, hence, better leukemia-free survival (HR = 0.55, P = 0.01). Therefore, we conclude that PR cytogenetic abnormalities at diagnosis predict overall survival after HSCT for AML in pediatric patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Chronic graft- versus -host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available.The purpose of this joint European Respiratory Society and European Society for Blood and Marrow Transplantation Task Force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine, methodology as well as patient advocates formulated eight PICO (Patient, Intervention, Comparison, Outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to develop recommendations.The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

We sought to perform a systematic review and individual participant data meta-analysis to identify predictors of treatment response following thalamic neuromodulation in pediatric patients with medically refractory epilepsy. Electronic databases (MEDLINE, Ovid, Embase, and Cochrane) were searched, with no language or data restriction, to identify studies reporting seizure outcomes in pediatric populations following deep brain stimulation (DBS) or responsive neurostimulation (RNS) implantation in thalamic nuclei. Studies featuring individual participant data of patients with primary or secondary generalized drug-resistant epilepsy were included. Response to therapy was defined as >50% reduction in seizure frequency from baseline. Of 417 citations, 21 articles reporting on 88 participants were eligible. Mean age at implantation was 13.07 ± 3.49 years. Fifty (57%) patients underwent DBS, and 38 (43%) RNS. Sixty (68%) patients were implanted in centromedian nucleus and 23 (26%) in anterior thalamic nucleus, and five (6%) had both targets implanted. Seventy-four (84%) patients were implanted bilaterally. The median time to last follow-up was 12 months (interquartile range = 6.75-26.25). Sixty-nine percent of patients achieved response to treatment. Age, target, modality, and laterality had no significant association with response in univariate logistic regression. Until thalamic neuromodulation gains widespread approval for use in pediatric patients, data on efficacy will continue to be limited to small retrospective cohorts and case series. The inherent bias of these studies can be overcome by using individual participant data. Thalamic neuromodulation appears to be a safe and effective treatment for epilepsy. Larger, prolonged prospective, multicenter studies are warranted to further evaluate the efficacy of DBS over RNS in this patient population where resection for curative intent is not a safe option., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Abstract: Allogeneic hematopoietic cell transplantation (HCT) can be complicated by life-threatening organ toxicity and infection necessitating intensive care. Epidemiologic data have been limited by single-center studies, poor database granularity, and a lack of long-term survivors. To identify contemporary trends in intensive care unit (ICU) use and long-term outcomes, we merged data from the Center for International Blood and Marrow Transplant Research and the Virtual Pediatric Systems databases. We identified 6995 pediatric patients with HCT aged ≤21 years who underwent first allogeneic HCT between 2008 and 2014 across 69 centers in the United States or Canada and followed patients until the year 2020. ICU admission was required for 1067 patients (8.3% by day +100, 12.8% by 1 year, and 15.3% by 5 years after HCT), and was linked to demographic background, pretransplant organ toxicity, allograft type and HLA-match, and the development of graft-versus-host disease or malignancy relapse. Survival to ICU discharge was 85.7%, but more than half of ICU survivors required ICU readmission, leading to 52.5% and 42.6% survival at 1- and 5-years post-ICU transfer, respectively. ICU survival was worse among patients with malignant disease, poor pretransplant organ function, and alloreactivity risk factors. Among 1-year HCT survivors, those who required ICU in the first year had 10% lower survival at 5 years and developed new dialysis-dependent renal failure at a greater rate (P<.001). Thus, although ICU management is common and survival to ICU discharge is high, ongoing complications necessitate recurrent ICU admission and lead to a poor 1-year outcome in select patients who are at high risk., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.)

Abstract: Serial prognostic evaluation after allogeneic hematopoietic cell transplantation (allo-HCT) might help identify patients at high risk of lethal organ dysfunction. Current prediction algorithms based on models that do not incorporate changes to patients' clinical condition after allo-HCT have limited predictive ability. We developed and validated a robust risk-prediction algorithm to predict short- and long-term survival after allo-HCT in pediatric patients that includes baseline biological variables and changes in the patients' clinical status after allo-HCT. The model was developed using clinical data from children and young adults treated at a single academic quaternary-care referral center. The model was created using a randomly split training data set (70% of the cohort), internally validated (remaining 30% of the cohort) and then externally validated on patient data from another tertiary-care referral center. Repeated clinical measurements performed from 30 days before allo-HCT to 30 days afterwards were extracted from the electronic medical record and incorporated into the model to predict survival at 100 days, 1 year, and 2 years after allo-HCT. Naïve-Bayes machine learning models incorporating longitudinal data were significantly better than models constructed from baseline variables alone at predicting whether patients would be alive or deceased at the given time points. This proof-of-concept study demonstrates that unlike traditional prognostic tools that use fixed variables for risk assessment, incorporating dynamic variability using clinical and laboratory data improves the prediction of mortality in patients undergoing allo-HCT., (© 2024 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 present research was carried out to assess the serum progesterone (P 4 ) concentration and uterine hemodynamics at estrus till ovulation in cyclic cows (N = 130) with healthy or diseased uterus. At estrus, 85 cows were diagnosed with clinical endometritis (CE; n = 44) and sub-clinical endometritis (SCE; n = 41); whereas, 45 cows being served as control namely no endometritis (NE; n = 45) were included in the study. Serum progesterone estimation at 12 - 14 and 40 hr after the onset of estrus and Doppler sonography of both middle uterine arteries were done to envisage the uterine hemodynamics and ovulation. The serum progesterone concentration was significantly higher at 12 - 14 hr after onset of estrus in CE and SCE cows. At 12 - 14 hr after onset of estrus, a cut-off value of ≥ 0.48 ng mL -1 P 4 was obtained, above which 22.72% CE, 26.82% SCE and only 8.88% NE cows failed to ovulate within 36 - 40 hr of estrus onset. Among the Doppler indices, pulsatility and resistance indices were significantly higher; whereas, volume and velocity indices were significantly lower in NE cows. In cows diagnosed with CE and SCE, a higher supra-basal P 4 concentration, and velocity and volume of blood flow to uterus at estrus negatively affected the duration to ovulation., Competing Interests: No conflict of interest was reported by the authors., (© 2024 Urmia University. All rights reserved.)

The study aimed to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and nonmalignant late effects (NM-LE) in 2-year disease-free adult survivors following hematopoietic cell transplantation (HCT) for a hematologic malignancy. To do so, we conducted a retrospective analysis of 3884 survivors of HCT for hematologic malignancy in the Center of International Blood and Marrow Transplant Research database. We conducted a landmark analysis at the 2-year post-transplantation date, comparing first SN and NM-LE in survivors with and without cGVHD. The cumulative incidence (CuI) of SN and NM-LE were estimated through 10 years post-HCT in both groups, with death or disease relapse as a competing risk. Cox proportional hazards models were used to evaluate the associations of cGVHD and its related characteristics with the development of SN and NM-LE. The estimated 10-year CuI of SN in patients with GVHD (n = 2669) and patients without cGVHD (n = 1215) was 15% (95% confidence interval [CI], 14% to 17%) versus 9% (7.2% to 11%) (P < .001). cGVHD by 2 years post-HCT was independently associated with SN (hazard ratio [HR], 1.94; 95% CI, 1.53 to 2.46; P < .0001) with a standardized incidence ratio of 3.2 (95% CI, 2.9 to 3.5; P < .0001). Increasing severity of cGVHD was associated with an increased risk of SN. The estimated 10-year CuI of first NM-LE in patients with and without cGVHD was 28 (95% CI, 26% to 30%) versus 13% (95% CI, 11% to 15%) (P < .001). cGVHD by 2 years post-HCT was independently associated with NM-LE (HR, 2.23; 95% CI, 1.81 to 2.76; P < .0001). Multivariate analysis of cGVHD-related factors showed that increasing severity of cGVHD, extensive grade, having both mucocutaneous and visceral involvement, and receiving cGVHD treatment for >12 months were associated with the greatest magnitude of risk for NM-LE. cGVHD was closely associated with both SN and NM-LE in adult survivors of HCT for hematologic malignancy. Patients identified as having more severe involvement and both mucocutaneous and visceral organ involvement may warrant enhanced monitoring and screening for SNs and NM-LEs. However, caution is warranted when interpreting these results, as patients with cGVHD may have more vigilant post-transplantation health care and surveillance for late effects., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Fungal infection (FI) after allogeneic hematopoietic cell transplantation (HCT) is associated with increased morbidity and mortality. Neutropenia, HLA mismatch, graft-versus-host disease (GVHD), and viral infections are risk factors for FI. The objectives of this Center for International Blood and Marrow Transplant Research registry study were to compare the incidence and density of FI occurring within 180 days after HCT in matched sibling (Sib) transplants with either calcineurin inhibitor (CNI)-based or post-transplantation cyclophosphamide (PTCy)-based GVHD prophylaxis and related haploidentical transplants receiving PTCy, and to examine the impact of FI by day 180 on transplantation outcomes., Methods: Patients who underwent their first HCT between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome and received a related haploidentical transplant with PTCy (HaploCy; n = 757) or a Sib transplant with PTCy (SibCy; n = 403) or CNI (SibCNI; n = 1605) were analyzed. The incidence of FI by day 180 post-HCT was calculated as cumulative incidence with death as the competing risk. The associations of FI with overall survival, transplant-related mortality, chronic GVHD, and relapse at 2 years post-HCT were examined in Cox proportional hazards regression models. Factors significantly associated with the outcome variable at a 1% level were kept in the final model., Results: By day 180 post-HCT, 56 (7%) HaploCy, 24 (6%), SibCy, and 59 (4%) SibCNI recipients developed ≥1 FI (P < .001). The cumulative incidence of yeast FI was 5.2% (99% confidence interval [CI], 3.3% to 7.3%) for HaploCy, 2.2% (99% CI, .7% to 4.5%) for SibCy, and 1.9% (99% CI, 1.1% to 2.9%) for SibCNI (P = .001), and that of mold FI was 2.9% (99% CI, 1.5% to 4.7%), 3.7% (99% CI, 91.7% to 6.6%), and 1.7% (99% CI, 1.0% to 2.6%), respectively (P = .040). FI was associated with an increased risk of death, with an adjusted hazard ratio (HR) of 4.06 (99% CI, 2.2 to 7.6) for HaploCy, 4.7 (99% CI, 2.0 to 11.0) for SibCy, and 3.4 (99% CI, 1.8 to 6.4) for SibCNI compared with SibCNI without FI (P < .0001 for all). Similar associations were noted for transplantation-related mortality. FI did not impact rates of relapse or chronic GVHD., Conclusions: Rates of FI by day 180 ranged between 1.9% and 5.2% for yeast FI and from 1.7% to 3.7% for mold FI across the 3 cohorts. The use of PTCy was associated with higher rates of yeast FI only in HaploHCT and with mold FI in both HaploHCT and SibHCT. The presence of FI by day 180 was associated with increased risk for overall mortality and transplant-related mortality at 2 years regardless of donor type or PTCy use. Although rates of FI were low with PTCy, FI is associated with an increased risk of death, underscoring the need for improved management strategies., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: Hemispherectomy surgery is an effective procedure for pediatric patients with intractable hemispheric epilepsy. Hydrocephalus is a well-documented complication of hemispherectomy contributing substantially to patient morbidity. Despite some clinical and operative factors demonstrating an association with hydrocephalus development, the true mechanism of disease is incompletely understood. The aim of this study was to investigate a range of clinical and surgical factors that may contribute to hydrocephalus to enhance understanding of the development of this complication and to aid the clinician in optimizing peri- and postoperative surgical management., Methods: A retrospective chart review was conducted on all pediatric patients younger than 21 years who underwent hemispherectomy surgery at the Cleveland Clinic between 2002 and 2016. Data collected for each patient included general demographic information, neurological and surgical history, surgical technique, pathological analysis, presence and duration of perioperative CSF diversion, CSF laboratory values obtained while an external ventricular drain (EVD) was in place, length of hospital stay, postoperative aseptic meningitis, and in-hospital surgical complications (including perioperative stroke, hematoma formation, wound breakdown, and/or infection). Outcomes data included hemispherectomy revision and Engel grade at last follow-up (based on the Engel Epilepsy Surgery Outcome Scale)., Results: Data were collected for 204 pediatric patients who underwent hemispherectomy at the authors' institution. Twenty-eight patients (14%) developed hydrocephalus requiring CSF diversion. Of these 28 patients, 13 patients (46%) presented with hydrocephalus during the postoperative period (within 90 days), while the remaining 15 patients (54%) presented later (beyond 90 days after surgery). Multivariate analysis revealed postoperative aseptic meningitis (OR 7.0, p = 0.001), anatomical hemispherectomy surgical technique (OR 16.3 for functional/disconnective hemispherectomy and OR 7.6 for modified anatomical, p = 0.004), male sex (OR 4.2, p = 0.012), and surgical complications (OR 3.8, p = 0.031) were associated with an increased risk of hydrocephalus development, while seizure freedom (OR 0.3, p = 0.038) was associated with a decreased risk of hydrocephalus., Conclusions: Hydrocephalus remains a prominent complication following hemispherectomy, presenting both in the postoperative period and months to years after surgery. Aseptic meningitis, anatomical hemispherectomy surgical technique, male sex, and surgical complications show an association with an increased rate of hydrocephalus development while seizure freedom postsurgery is associated with a decreased risk of subsequent hydrocephalus. These findings speak to the multifactorial nature of hydrocephalus development and should be considered in the management of pediatric patients undergoing hemispherectomy for medically intractable epilepsy.

Patient-reported outcomes (PROs) capture subjective social determinants of health (SDOHs), which can affect health outcomes through the stress response pathway. The conserved transcriptional response to adversity (CTRA) is a stress-mediated proinflammatory transcriptomic pattern that has been linked to adverse hematopoietic cell transplant (HCT) outcomes. This study examined the association of pretransplant CTRA with patient-reported SDOHs in allogeneic HCT recipients. In this cross-sectional study, pre-HCT SDOH-related PROs included the 36-Item Short Form Health Survey and the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT). CTRA was assessed by RNA sequencing of whole blood specimens, with mixed effects linear regression models relating CTRA expression to PRO scores while controlling for age, sex, race, disease, and performance status. Among 121 patients, the median age was 54 years, 42% were female, and 91% were White. CTRA was elevated in participants reporting lower scores on the FACT-BMT (P = .003), including the general (P = .003) and BMT-specific (P = .014) components. Effects were driven by the social well-being domain (P = .0001). This corresponded to an 8% to 15% difference in CTRA RNA expression across a 4 standard deviation range in patient-reported SDOHs. Ancillary bioinformatics analyses confirmed the association of well-being with reduced proinflammatory transcription pathway activity [cyclic AMP response element-binding protein, (CREB), NF-κB, and activating protein-1 (AP-1)]. In conclusion, HCT-treated patients who experience unfavorable social conditions show elevated CTRA expression in pretransplant blood samples. These data highlight the biologic sequelae of social well-being and community context and suggest a potential molecular mechanism for the impact of social gradients in HCT outcomes. Targeting this pathway could optimize outcomes in this high-risk population., (© 2023 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.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes., (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.)

Racial/ethnic minorities have demonstrated worse survival after allogeneic hematopoietic cell transplantation (HCT) compared to whites. Whether the racial disparity in HCT outcomes persists in long-term survivors and possibly may be even exacerbated in this population, which frequently transitions back from the transplant center to their local healthcare providers, is unknown. In the current study, we compared long-term outcomes among 1-year allogeneic HCT survivors by race/ethnicity and socioeconomic status (SES). The Center for International Blood and Marrow Transplant Research database was used to identify 5473 patients with acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, or myelodysplastic syndromes who underwent their first allogeneic HCT between 2007 and 2017 and were alive and in remission for at least 1 year after transplantation. The study was restricted to patients who underwent HCT in the United States. SES was defined using patient neighborhood poverty level estimated from the recipient's ZIP code of residence; a ZIP code with ≥20% of persons below the federal poverty level was considered a high poverty area. The primary outcome was to evaluate the associations of race/ethnicity and neighborhood poverty level with overall survival (OS), relapse, and nonrelapse mortality (NRM). Cox regression models were used to determine associations of ethnicity/race and SES with OS, relapse, and NRM. Standardized mortality ratios were calculated to compare mortality rates of the study patients and their general population peers matched on race/ethnicity, age, and sex. The study cohort was predominately non-Hispanic white (n = 4385) and also included non-Hispanic black (n = 338), Hispanic (n = 516), and Asian (n = 234) patients. Overall, 729 patients (13%) resided in high-poverty areas. Significantly larger proportions of non-Hispanic black (37%) and Hispanic (26%) patients lived in high-poverty areas compared to non-Hispanic whites (10%) and Asians (10%) (P < .01). Multivariable analysis revealed no significant associations between OS, PFS, relapse, or NRM and race/ethnicity or poverty level when adjusted for patient-, disease- and transplantation-related covariates. Our retrospective cohort registry study shows that among adult allogeneic HCT recipients who survived at least 1 year in remission, there were no associations between race/ethnicity, neighborhood poverty level, and long-term outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

(1) Background: The most significant cause of an unacceptable deviation from the planned dose during respiratory motion is the interplay effect. We examined the correlation between the magnitude of splenic motion and its impact on plan quality for total lymphoid irradiation (TLI); (2) Methods: Static and 4D CT images from ten patients were used for interplay effect simulations. Patients' original plans were optimized based on the average CT extracted from the 4D CT and planned with two posterior beams using scenario-based optimization (±3 mm of setup and ±3% of range uncertainty) and gradient matching at the level of mid-spleen. Dynamically accumulated 4D doses (interplay effect dose) were calculated based on the time-dependent delivery sequence of radiation fluence across all phases of the 4D CT. Dose volume parameters for each simulated treatment delivery were evaluated for plan quality; (3) Results: Peak-to-peak splenic motion (≤12 mm) was measured from the 4D CT of ten patients. Interplay effect simulations revealed that the ITV coverage of the spleen remained within the protocol tolerance for splenic motion, ≤8 mm. The D100% coverage for ITV spleen decreased from 95.0% (nominal plan) to 89.3% with 10 mm and 87.2% with 12 mm of splenic motion; (4) Conclusions: 4D plan evaluation and robust optimization may overcome problems associated with respiratory motion in proton TLI treatments. Patient-specific respiratory motion evaluations are essential to confirming adequate dosimetric coverage when proton therapy is utilized.

Diamond-Blackfan anemia (DBA) is one of the most common inherited causes of bone marrow failure in children. DBA typically presents with isolated erythroid hypoplasia and anemia in infants. Congenital anomalies are seen in 50% of the patients. Over time, many patients experience panhematopoietic defects resulting in immunodeficiency and multilineage hematopoietic cytopenias. Additionally, DBA is associated with increased risk of myelodysplastic syndrome, acute myeloid leukemia and solid organ cancers. As a prototypical ribosomopathy, DBA is caused by heterozygous loss-of-function mutations or deletions in over 20 ribosomal protein genes, with RPS19 being involved in 25% of patients. Corticosteroids are the only effective initial pharmacotherapy offered to transfusion-dependent patients aged 1 year or older. However, despite good initial response, only ~20-30% remain steroid-responsive while the majority of the remaining patients will require life-long red blood cell transfusions. Despite continuous chelation, iron overload and related toxicities pose a significant morbidity problem. Allogeneic hematopoietic cell transplantation (HCT) performed to completely replace the dysfunctional hematopoietic stem and progenitor cells is a curative option associated with potentially uncontrollable risks. Advances in HLA-typing, conditioning regimens, infection management, and graft-versus-host-disease prophylaxis have led to improved transplant outcomes in DBA patients, though survival is suboptimal for adolescents and adults with long transfusion-history and patients lacking well-matched donors. Additionally, many patients lack a suitable donor. To address this gap and to mitigate the risk of graft-versus-host disease, several groups are working towards developing autologous genetic therapies to provide another curative option for DBA patients across the whole age spectrum. In this review, we summarize the results of HCT studies and review advances and potential future directions in hematopoietic stem cell-based therapies for DBA., Competing Interests: AS has received consultant fees from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine; research funding from CRISPR Therapeutics; and honoraria from Vindico Medical Education. He is the St Jude Children’s Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals and CRISPR Therapeutics ClinicalTrials.gov NCT03745287, Novartis Pharmaceuticals NCT04443907, and Beam Therapeutics NCT05456880. The industry sponsors provide funding for the clinical trial, which includes salary support paid to his institution. AS has no direct financial interest in these therapies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bhoopalan, Suryaprakash, Sharma and Wlodarski.)

Background Aims: CD4 immune reconstitution (IR) after allogeneic hematopoietic cell transplant (allo-HCT) correlates with lower non-relapse mortality (NRM), but its impact on leukemia relapse remains less clear, especially in children. We studied the correlation between IR of lymphocyte subsets and HCT outcomes in a large cohort of children/young adults with hematological malignancies., Methods: We retrospectively analyzed CD4, CD8, B-cell and natural killer (NK) cell reconstitution in patients after first allo-HCT for a hematological malignancy at three large academic institutions (n = 503; period 2008-2019). We used Cox proportional hazard and Fine-Gray competing risk models, martingale residual plots and maximally selected log-rank statistics to assess the impact of IR on outcomes., Results: Achieving CD4 >50 and/or B cells >25 cells/μL before day 100 after allo-HCT was a predictor of lower NRM (CD4 IR: hazard ratio [HR] 0.26, 95% confidence interval [CI] 0.11-0.62, P = 0.002; CD4 and B cell IR: HR 0.06, 95% CI 0.03-0.16, P < 0.001), acute graft-versus-host disease (GVHD) (CD4 and B cell IR: HR 0.02, 95% CI 0.01-0.04, P < 0.001) and chronic GVHD (CD4 and B cell IR: HR 0.16, 95% CI 0.05-0.49, P = 0.001) in the full cohort, and of lower risk of relapse (CD4 and B cell IR: HR 0.24, 95% CI 0.06-0.92, P = 0.038) in the acute myeloid leukemia subgroup. No correlation between CD8 and NK-cell IR and relapse or NRM was found., Conclusions: CD4 and B-cell IR was associated with clinically significant lower NRM, GVHD and, in patients with acute myeloid leukemia, disease relapse. CD8 and NK-cell IR was neither associated with relapse nor NRM. If confirmed in other cohorts, these results can be easily implemented for risk stratification and clinical decision making., Competing Interests: Conflicts of Interest CL reports honoraria for a lecture from Genzyme and is on a Data Safety Monitoring Board of ExCellThera (related to this topic). SP reports support for the conduct of clinical trials: Jasper, Atara, AlloVir, Consulting/Advisory Board Participation CellEvolve, Smart Immune, Regeneron and IP related to VSTs licensed to Atara with all rights assigned to Memorial Sloan Kettering Cancer Center. AS has received consultant fee from Spotlight Therapeutics, Medexus Inc. and Vertex Pharmaceuticals. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. AS is the St. Jude Children's Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics, Novartis Pharmaceuticals and Beam Therapeutics. The industry sponsors provide funding for the clinical trial, which includes salary support paid to his institution. AS has no direct financial interest in these therapies. None of these conflicts are related to the work presented here. JJB reports honoraria from Avrobio, BlueRock, Bluebird Bio, Sanofi, Sobi, SmartImmune, Advanced Clinical consulting (not related to this topic). All other authors report no conflicts of interest., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

The liver is the primary organ for the metabolism of many chemotherapeutic agents. Treatment-induced liver injury is common in children undergoing cancer therapy. Hepatic injury occurs due to various mechanisms, including biochemical cytotoxicity, hepatic vascular injury, radiation-induced cytotoxicity, and direct hepatic injury through minimally invasive and invasive surgical treatments. Treatment-induced liver injury can be seen contemporaneous with therapy and months to years after therapy is complete. Patients can develop a combination of hepatic injuries manifesting during and after treatment. Acute toxic effects of cancer therapy in children include hepatitis, steatosis, steatohepatitis, cholestasis, hemosiderosis, and vascular injury. Longer-term effects of cancer therapy include hepatic fibrosis, chronic liver failure, and development of focal liver lesions. Quantitative imaging techniques can provide useful metrics for disease diagnosis and monitoring, especially in treatment-related diffuse liver injury such as hepatic steatosis and steatohepatitis, hepatic iron deposition, and hepatic fibrosis. Focal liver lesions, including those developing as a result of treatment-related vascular injury such as focal nodular hyperplasia-like lesions and hepatic perfusion anomalies, as well as hepatic infections occurring as a consequence of immune suppression, can be anxiety provoking and confused with recurrent malignancy or hepatic metastases, although there often are imaging features that help elucidate the correct diagnosis. Radiologic evaluation, in conjunction with clinical and biochemical screening, is integral to diagnosing and monitoring hepatic complications of cancer therapy in pediatric patients during therapy and after therapy completion for long-term surveillance. © RSNA, 2023 Quiz questions for this article are available in the supplemental material See the invited commentary by Ferraciolli and Gee in this issue.