Marrow Transplantation Research Articles

Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease.

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme ( Hexb ). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To understand how a microglial gene is involved in maintaining neuronal homeostasis, we demonstrated that β-hexosaminidase is secreted by microglia and integrated into the neuronal lysosomal compartment. To assess therapeutic relevance, we treated SD mice with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaced Hexb -/- microglia with Hexb -sufficient cells. This intervention reversed apoptotic gene signatures, improved behavior, restored enzymatic activity and Hexb expression, ameliorated substrate accumulation, and normalized neuronal lysosomal phenotypes. These results underscore the critical role of myeloid-derived β- hexosaminidase in neuronal lysosomal function and establish microglial replacement as a potential LSD therapy.

Acquired Partial Lipodystrophy: Clinical Management in a Pregnant Patient.

Pregnancy represents an additional challenge to the complex clinical picture of lipodystrophy disorders, and the management of such conditions with related comorbidities has been underreported. This work aims to outline the risk associated with a pregnancy event for women dealing with acquired partial lipodystrophy and the need for diverse but specialized care. We report on the successful pregnancy outcome of a 28-year-old woman with an acquired partial form of lipodystrophy related to an allogenic bone marrow transplant that occurred at pediatric age. Although metabolic control was challenging, glucose levels progressively improved during the pregnancy, and triglycerides increased less than expected. The periodic monitoring of leptin levels showed a progressive increase with a peak in the third trimester (41.53 ng/mL), followed by a fast decline the day after giving birth, with a lower basal level than the prepregnancy period. However, preterm delivery occurred associated with cardiac complications in the mother. A total of 12 studies were retrieved concerning women aged 14 to 38 years with various lipodystrophy phenotypes. Diabetes and hypertriglyceridemia were the most common comorbidities. Most women had successful pregnancies despite gestational complications (including miscarriages), preterm and emergency deliveries, and newborns undergoing partum or postpartum transient or chronic complications. Lipodystrophy disorders expose both mothers and children to very high risk. Intensive monitoring and care of all potential clinical complications should be planned and carried out by a multidisciplinary team before, during, and after the pregnancy. Leptin secretion during pregnancy should be investigated more deeply in these patients.

Precision medicine results from equitable representation.

In this special issue of Bone Marrow Transplantation, investigators report the impact of IDH1 [1], IDH2 [2], and FLT3-TKD [3] measurable residual disease (MRD) pre-hematopoietic cell transplantation (HCT) in predicting relapse of acute myeloid leukemia (AML) in adults receiving allogeneic HCT. The patient population for these retrospective cohorts, reflecting clinical transplant practice patterns and research biobank participation, was 84-86% non-Hispanic White (NHW) in each study. In this commentary, we explore the implications of racial and ethnic disparities in access to both HCT and HCT-related research and propose strategies to promote representation in precision medicine, given the emerging impact of the field on HCT outcomes.

Latexin deficiency limits foam cell formation and ameliorates atherosclerosis by promoting macrophage phenotype differentiation

Latexin (LXN) is abundant in macrophages and plays critical roles in inflammation. Much is known about macrophages in atherosclerosis, the role of macrophage LXN in atherosclerosis has remained elusive. Here, the expression of LXN in human and mouse atherosclerotic lesions was examined by immunofluorescence and immunohistochemistry. LXN knockout and LXN/ApoE double-knockout mice were generated to evaluate the functions of LXN in atherosclerosis. Bone marrow transplantation (BMT) experimentation was carried out to determine whether macrophage LXN regulates atherosclerosis. We found that LXN is enriched in human and murine atherosclerotic lesions, mainly localized to macrophages. LXN deletion ameliorated atherosclerosis in ApoE-/- mice. BMT demonstrate that deletion of LXN in bone marrow protects ApoE-/- mice against atherosclerosis. Mechanistically, we found that LXN targets and inhibits JAK1 in macrophages. LXN deficiency stimulates the JAK1/STAT3/ABC transporter pathway, thereby enhancing the anti-inflammatory and anti-oxidant phenotype, cholesterol efflux, subsequently minimizing foam cell formation and atherosclerosis. Gene therapy by treatment of atherosclerotic mice with adeno-associated virus harbouring LXN-depleting shRNA attenuated the disease phenotype. In summary, our study provides new clues for the role of LXN in the pathological regulation of atherosclerosis, and determines that LXN is a target for preventing atherosclerosis, which may be a potential new anti-atherosclerosis therapeutic target.

Opportunistic Identification of Coronary Artery Calcium and Valve/Vascular Calcifications on Chest X-Ray: Improvements With Single-Exposure Dual-Energy Imaging.

Purpose: To evaluate whether single-exposure, dual-energy chest X-ray (DEX) improves visualization of coronary artery calcium (CAC) and valve/vascular calcifications compared to conventional X-ray. Materials and Methods: Sixty-one bone-marrow transplant patients (22- 79 years; median 61; IQR 15; w/m, 24/37), underwent single-exposure dual-energy X-ray (Reveal 35C, KA imaging) in pa and lateral projection, followed by a standard-of-care chest CT. Two DEX pairs (pa/lateral) were calculated: a composite image (COMP) and a bone image with soft-tissue subtraction (BI). The COMP pair was reviewed by 2 chest radiologists, assessing the presence/absence of CAC and valve/vascular calcifications on a confidence scale from -2 (confidently not present) to 2 (confidently present). Subsequently, the BI pair was revealed, and readers reevaluated both pairs (COMP and BI) jointly using the identical scale. CTCAC scores were categorized according to the CAC-DRS (0-3) and served as standard of reference, valve/vascular calcifications were categorized on CT as present or absent. Results: For detecting CAC on DEX in any CAC-DRS category (1-3), in category 2-3, in category 3, and for valve/vascular calcifications, the ROC-AUC (combined for both readers) for COMP images was 0.74 (CI: 0.64-0.84), 0.81 (CI: 0.68-0.94), 0.84 (CI: 0.69-0.98), and 0.90 (CI: 0.83-0.99), and for the BI images 0.91 (CI: 0.83-0.98), 0.94 (CI: 0.86- 1.00), 0.89 (CI: 0.77-1.00), and 0.98 (CI: 0.96-1.00), with P = .0003, P = .044, P = .42, and P = .55, respectively. The Intraclass-Correlation-Coefficient (ICC) for CAC on COMP/BI was 0.973/0.954, and for valve/vascular calcifications 0.971/0.965. Conclusion: Single-exposure, dual-energy acquisition improves diagnostic confidence for coronary artery calcium and valve/vascular calcification identification on chest X-rays.

Vitamin A to Keep GVHD Away: Single Oral High-Dose Vitamin A Before Bone Marrow Transplant Reduces Graft-Versus-Host Disease in Pediatric and Young Adult Patients

Vitamin A to Keep GVHD Away: Single Oral High-Dose Vitamin A Before Bone Marrow Transplant Reduces Graft-Versus-Host Disease in Pediatric and Young Adult Patients

Epstein-Barr Virus-Driven T-Cell Lymphoma with Haemophagocytic Lymphohistiocytosis: A Life-Threatening Disorder Extending Beyond Childhood.

EBV-associated T-cell lymphoma with haemophagocytic lymphohistiocytosis can affect not only children but also adolescents and young adults, highlighting the need for awareness of the high fatality risk.Early recognition of EBV-associated haemophagocytic lymphohistiocytosis (EBV-HLH) is crucial; when a patient presents with fever, pancytopaenia and hepatosplenomegaly.Future prospective studies are warranted to determine the treatment strategy and the optimal patient population that requires early bone marrow transplantation when initial treatment is inadequate.

Nutrition support pharmacy practices in hospitalized cancer patients admitted to bone marrow transplant units: A 3-year retrospective analysis of clinical nutrition support pharmacists’ interventions

Nutrition support pharmacy practices in hospitalized cancer patients admitted to bone marrow transplant units: A 3-year retrospective analysis of clinical nutrition support pharmacists’ interventions

Hoyeraal-Hreidarsson syndrome: a case report of dyskeratosis congenita with a novel PARN gene mutation

Introduction and importance: Dyskeratosis congenita (DC) is a rare multisystem disorder primarily characterized by bone marrow failure due to telomere shortening. Typical clinical features include oral leukoplakia, skin hyperpigmentation, and nail dystrophy, along with an increased risk of malignancies. Hoyeraal-Hreidarsson Syndrome (HH), a severe variant of DC, is associated with profound neurological and immunological complications, emphasizing the importance of early diagnosis and genetic evaluation to guide appropriate management. Case Presentation: We present a case of a 2-year-old girl diagnosed with Hoyeraal-Hreidarsson Syndrome, linked to a newly discovered mutation in the poly (A)-specific ribonuclease (PARN) gene. The patient exhibited intrauterine growth retardation (IUGR), congenital cytomegalovirus (CMV) infection, immunodeficiency, microcephaly, and cerebellar hypoplasia. Whole exome sequencing (WES) identified a novel mutation in the PARN gene. Clinical Discussion: Hoyeraal-Hreidarsson Syndrome, a severe form of DC, manifests with multisystem involvement and is genetically heterogeneous. Early genetic testing through techniques such as WES can aid in diagnosing rare syndromes like HH and guide treatment strategies, including bone marrow transplantation. Conclusion: This case underscores the importance of genetic evaluation in complex, rare syndromes like HH. Whole exome sequencing plays a crucial role in identifying pathogenic mutations and tailoring management. The patient’s prognosis is being closely monitored following bone marrow transplantation.

A 16-Year-Old Moroccan Child's Diffuse Bronchiectasis Exacerbation Revealed Deficient Expression of HLA Class II Molecules

Deficiency in HLA class II expression is an uncommon autosomal recessive immune deficiency associated with mutations in genes that regulate major histocompatibility complex class II (MHC II) expression. Despite being diagnosed during adolescence, our case is distinguished by a delayed diagnosis and a weak clinical presentation. We describe the medical history of a 16-year-old child who has been treated intermittently for constipation and meningitis since early childhood. The child also experienced alternating episodes of diarrhea and constipation. As a result of a bacterial exacerbation of diffuse bronchiectasis, the patient was hospitalized. Deficient expression of HLA class II molecules was confirmed by immune assessments. Favorable clinical development was achieved by starting antibiotic medication in conjunction with nutritional control. Bone marrow transplantation is the sole curative treatment available for this real-life Maghrebian illness.

DEVELOPMENT OF SYSTEMIC MASTOCYTOSIS AFTER BONE MARROW TRANSPLANTATION FOR AN ACUTE MYELOID LEUKEMIA: DONOR DERIVEN DISEASE OR SYSTEMIC MASTOCYTOSIS WITH AN ASSOCIATED MYELOID NEOPLASM

Abstract Introduction/Objective Systemic mastocytosis may have variable presentation ranging from an indolent disease to an aggressive form. Systemic mastocytosis with an associated myeloid neoplasm can occur simultaneously, or within an interval of a myeloid neoplasm and should meet the diagnostic criteria of both entities. Methods/Case Report Herein, we present a patient with history of acute myeloid leukemia with KMT2A(11q23) amplification who initially underwent an allogeneic hematopoietic stem cell transplantation from a matched sibling donor. One year later, the patient developed isolated central nervous system relapse, as well as evidence of molecular relapse in the bone marrow and underwent a second allogeneic transplantation, but this time, from a matched unrelated donor. The 100 days post second transplant bone marrow biopsy was negative for involvement by acute myeloid leukemia and the chimerism study revealed evidence of total engraftment with 100% donor cells. Additionally, Fluorescence in situ hybridization analysis detected no evidence of KMT2A amplification. However, morphologic examination of the bone marrow biopsy demonstrated involvement by systemic mastocytosis with multiple dense aggregates of CD117 and tryptase positive mast cells showing spindled cell morphology. Mast cells were positive for CD25 and demonstrated negative expression of CD2 and CD30. PCR analysis of the peripheral blood did not detect evidence of KIT mutation, but serum tryptase was elevated. Results (if a Case Study enter NA) NA Conclusion This case highlights a rare instance of systemic mastocytosis in the setting of remission from an acute myeloid leukemia in a post transplantation bone marrow and represents a diagnostic challenge. While development of systemic mastocytosis in a patient with prior history of an acute myeloid leukemia suggests the possibility of systemic mastocytosis with an associated myeloid neoplasm, some other features including the complete remission and total engraftment of the post transplantation bone marrow with 100% donor cells, raise the possibility of a donor driven disease.

Knowledge, attitude and acceptance regarding bone marrow transplantation in caregivers of beta-thalassemia major patients.

Knowledge, Attitude, and Acceptance regarding Bone marrow transplantation in caregivers of beta-thalassemia major patients. A cross-sectional study was conducted among the caregivers of pediatric patients with betathalassemia major in blood transfusion centres in Bangalore, India. Their knowledge, attitude, and acceptance regarding bone marrow transplantation were assessed using a validated questionnaire. The study aimed to identify factors that influence caregivers' decision about bone marrow transplantation. The knowledge, attitude, and acceptance of the caregivers towards bone marrow transplantation are shown to depend on gender, education and socio-economic status. The results of this study reveal that male caregivers generally exhibited higher levels of knowledge and had a better attitude towards it as compared to their female counterparts. Higher education and socio-economic status were associated with better knowledge, more favourable attitudes and a higher acceptance towards the procedure.

Novel machine learning technique further clarifies unrelated donor selection to optimize transplantation outcomes

AbstractWe investigated the impact of donor characteristics on outcomes in allogeneic hematopoietic cell transplantation (HCT) recipients using a novel machine learning approach, the Nonparametric Failure Time Bayesian Additive Regression Trees (NFT BART). NFT BART models were trained on data from 10 016 patients who underwent a first HLA-A, B, C, and DRB1 matched unrelated donor HCT between 2016 and 2019, reported to the Center for International Blood and Marrow Transplant Research, then validated on an independent cohort of 1802 patients. The NFT BART models were adjusted based on recipient, disease, and transplant variables. We defined a clinically meaningful impact on overall survival (OS) or event-free survival (EFS; survival without relapse, graft failure, or moderate to severe chronic graft-versus-host disease) as >1% difference in predicted outcome at 3 years. Characteristics with <1% impact (within a zone of indifference) were not considered to be clinically relevant. Donor cytomegalovirus, parity, HLA-DQB1, and HLA-DPB1 T-cell epitope matching fell within the zone of indifference. The only significant donor factor that associated with OS was age, in which, compared with 18-year-old donors, donors aged ≥31 years old were associated with lower OS. Both donor age (≤32 years) and use of a male donor, regardless of recipient sex, improved EFS. We, therefore, recommend selecting the earliest available donor within the 18 to 30 years age range for HCT to optimize OS. If several donors in the 18 to 30 years age range are available, a male donor may be chosen to optimize EFS.

Implementing a standardized workflow for early detection of steroid-induced hyperglycemia in allogeneic stem cell transplant recipients: A quality improvement project

BackgroundSteroid-induced hyperglycemia (SIH) worsens overall outcomes in the allo-SCT population. Currently, there is no standardized workflow for monitoring SIH. To address this need, a quality improvement (QI) initiative was implemented, as part of a Doctor of Nursing Practice project for the University of Kansas School of Nursing, to standardize glucose monitoring after the initiation of glucocorticoids (CGs) for the treatment of acute or chronic graft-versus-host-disease (GVHD). ObjectiveThis QI initiative aimed to decrease the median time to identification of SIH and the initiation of treatment in allo-SCT recipients on GCs for GVHD. Study DesignThe study took place at a large Midwestern blood and marrow transplant program. Patients diagnosed with acute or chronic GVHD and prescribed ≥0.5 mg kg-1/day prednisone equivalent (PE) steroids were requested to monitor postprandial blood glucose values for 14 days. A control group (retrospective chart review) was used for comparison. Time to the identification of SIH was compared between the two groups, as well as the time to treatment of hyperglycemia. ResultsOver 9 weeks, 19 patients enrolled in the QI initiative. The control group consisted of 21 patients. The median PE steroid dose was 1 mg kg-1/day in both groups (p = 0.8100). Eighteen of the 19 patients (95 %) had at least 1 blood glucose (BG) > 180 mg/dL and only 6 of 21 patients (29 %) had at least 1 BG > 180 mg/dL (p < 0.0001). The median time to a BG > 180 mg/dL was 1.5 days in the QI group and 7 days in the control group (p = 0.0232). The median time to insulin was 2 days in the QI group and 10 days in the control group (p = 0.0355). ConclusionThis project demonstrated that daily postprandial blood glucose monitoring is superior for the earlier identification and treatment of SIH when compared to monitoring at routine clinic visits alone.

Incremental eligibility criteria for the BMT CTN 1507 haploidentical trial for children with sickle cell disease

AbstractThe Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507 leadership and the data safety monitoring board (DSMB) established incremental entry criteria for children aged 5 to 14.99 years with sickle cell disease (SCD) enrolling in a phase 2 trial of HLA-haploidentical hematopoietic stem cell transplantation. First, the enrollment was limited to overt stroke in the first 10 participants (stage 4). Subsequently, the DSMB reviewed the interim results and expanded the eligibility to include children with silent cerebral infarcts or abnormal transcranial Doppler velocities with magnetic resonance angiography–defined cerebral vasculopathy (stage 3). A third cohort was enrolled after the DSMB reviewed the clinical outcomes in these cumulative initial enrollments (n = 18). Additions to the entry criteria included nonneurologic morbidities (stage 2). Eligibility criteria included the following: (1) life-threatening acute chest syndrome requiring exchange transfusion; (2) right heart catheterization confirmed pulmonary hypertension; (3) persistent systemic hypertension despite maximum medical therapy; (4) acute pain despite maximum medical therapy in the absence of psychosocial factors and unmanaged asthma after adjudication; or (5) 2 major priapism episodes in 12 months or 3 in 24 months. Children with SCD who did not meet the criteria for stages 4, 3, and 2 were not eligible. To our knowledge, for the first time, we introduce a staged strategy for eligibility in a curative therapy trial for children with SCD concordant with 45 Code of Federal Regulations § 46.405(b). The research governance–mandated eligibility strategy used within the BMT CTN 1507 phase 2 study may apply to future pediatric SCD curative therapy trials. This trial was registered at www.ClinicalTrials.gov as #NCT032635590.

Self-rated health is an independent predictor of subsequent late mortality after blood or marrow transplantation: A Blood or Marrow Transplant Survivor Study report.

The prevalence of suboptimal self-rated health (SRH) and its association with subsequent all-cause and cause-specific mortality after blood or marrow transplantation (BMT) were examined. Study participants were drawn from the multicenter Blood or Marrow Transplant Survivor Study, and included patients who were transplanted between 1974 and 2014 and had survived ≥2 years after BMT. Participants (aged ≥18 years) completed a survey at a median of 9 years from BMT, and were followed for a median of 5.6 years after survey completion. Survivors provided information on sociodemographic factors, chronic health conditions, health behaviors, and SRH (a single-item measure rated as excellent, very good, good, fair, or poor; excellent, very good, and good SRH were classified as good SRH, and fair and poor were classified as suboptimal SRH). The National Death Index Plus and Accurint databases and medical records provided vital status through December 2021. Of 3739 participants, 784 died after survey completion (21%). Overall, 879 BMT survivors (23.5%) reported suboptimal SRH. Pain, low socioeconomic status, psychological distress, lack of exercise, severe/life-threatening chronic health conditions, post-BMT relapse, obesity, smoking, and male sex were associated with suboptimal SRH. BMT survivors who reported suboptimal SRH had a 1.9-fold increased risk of all-cause mortality (95% confidence interval [CI],1.6-2.3), 1.8-fold increased risk of recurrence-related mortality (95% CI,1.4-2.5), and 1.9-fold increased risk of non-recurrence-related mortality (95% CI, 1.4-2.4) compared to those who reported good SRH. This single-item measure could help identify vulnerable subpopulations who could benefit from interventions to mitigate the risk for subsequent mortality.

Outcome of autologous bone marrow transplant in patients with relapsed and refractory diffuse large B-cell lymphoma in relation with prognostic factor: A single-center experience

Abstract: BACKGROUND Currently, about 50% of diffuse large B-cell lymphoma patients are relapsed following their complete response to first-line therapy. The treatment strategy for fit patients with relapsed refractory diffuse large B-cell lymphoma (R/R DLBCL) has been done with salvage therapy with non-cross resistant combination chemo-immunotherapy regimens followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT). OBJECTIVES: The aim of study was to evaluate the outcome of ASCT for R/R DLBCL in relation to certain prognostic parameters. PATIENTS, MATERIALS AND METHODS: This is retrospective study, conducted from May 2014 to December 2022, at Hematology and BMT Center of Medical City Complex in Baghdad. Thirty-six patients with R/R DLBCL were investigated pre- and post-ASCT; the recorded data included patient disease status pre-transplant, early mortality rate, and type of response at day 100 post-transplant and, survival rate, relapsed rate, and mortality at the end of the study were documented accordingly. RESULTS: The mean age of DLBCL patients in this study was 41.3 (14–65) years, post-ASCT at day 100; there were 33 (91.6%), 2 (5.5%), and 1 (2.7%) patients in complete remission, relapsed progressive disease, and death, respectively, At 3-year posttransplant, the overall survival (OS) was 71%, whereas the event-free survival (EFS) was 59%. According to disease status pre-ASCT, the OS was 62%, 80%, and 66% with P = 0.7, whereas the EFS was 66%, 60%, and 50% with P = 0.5 for CR, UCR, and PR, respectively. CONCLUSION: Iraqi bone marrow transplant center data showed acceptable OS and EFS results in the treatment of R/R DLBCL patients in areas where there is no more option in terms of better OS and EFS but with insignificant relation to the available prognostic factor.

Non-cryopreserved autologous peripheral blood stem cell transplantation for multiple myeloma and lymphoma in countries with limited resources: practice considerations from the Worldwide Network for Blood and Marrow Transplantation.

Autologous peripheral blood stem cell (PBSC) transplantation is a standard treatment of multiple myeloma (MM), Hodgkin lymphoma and various subtypes of non-Hodgkin lymphoma. Cryopreservation of hematopoietic stem cells is standard practice that allows time for delivery of conditioning regimen prior to cell infusion. The aim of this Worldwide Network for Blood & Marrow Transplantation (WBMT) work was to assess existing evidence on non-cryopreserved autologous transplants through a systematic review/meta-analysis, to study feasibility and safety of this approach. We searched PubMed, Web of Science and SCOPUS for studies that utilized non-cryopreserved autologous PBSC transplantation. Identified literature was reviewed for information on mobilization, apheresis, preservation and viability, conditioning regimen, engraftment, response, and survival. Results highlight collective experience from 19 transplant centers (1686 patients), that performed autologous transplants using non-cryopreserved PBSCs. The mean of infused CD34+ was 5.6 × 106/kg. Stem cell viability at transplantation was >90% in MM and >75% in lymphomas, after a storage time of 24-144 h at +4 °C. Mean time-to-neutrophil engraftment was 12 days and 15.3 days for platelets. Pooled proportion estimates of day 100 transplant-related mortality and graft failure were 1% and 0%, respectively. Non-cryopreservation of apheresed autologous PBSCs appears feasible and safe.

8265 Premature Ovarian Insufficiency in Pediatric Cancer Patients: a 10-Year Rady Children's Hospital Experience

Abstract Disclosure: M. Robinson: None. L. Meller: None. M.E. Patterson: None. Objective: To highlight the occurrence of premature ovarian insufficiency in cancer patients treated at a children’s hospital and to determine which patient characteristics or treatment modalities are associated with ovarian failure and subsequent recovery of ovarian function. Study design: A retrospective chart review. Setting: Rady Children’s Hospital San Diego. Subjects and Methods: Between August 2011 and August 2021, the cases of 36 patients with cancer and ovarian failure were reviewed. Data collected included type of cancer, age at diagnosis, types of chemotherapy used in treatment, whether a bone marrow transplant or radiation was part of the treatment plan, peak FSH value and age when this occurred, peak AMH value, whether GnRHa treatment was used, type of hormone replacement therapy used, and whether there was recovery of ovarian function. Results: The most common type of cancer identified in this group of patients was acute lymphoblastic leukemia (ALL) (13, 36.1%). The mean age of diagnosis was 8.5 ± 4.3 years and the mean age of peak FSH value was 12.6 ± 2.8 years. Nearly all patients (97.2%) were treated with alkylating agents as part of their chemotherapy regimen and 72.2% received some form of radiation. Most patients (26, 72.2%) also received some form of hormone therapy, most commonly transdermal hormone therapy (13, 36.1%) or oral contraceptive pill (10, 27.8%), and 15.8% of patients were treated with the GnRHa Lupron. Fertility planning was offered or discussed in 36.1% of patients. Ten patients (27.8%) were noted to have some degree of recovery in their ovarian function. Age at diagnosis and type of cancer treatment were significant predictors of recovery in multivariate regression modeling. Specifically, each year older in age was associated with a 30% decrease in odds of recovery (OR: 0.7, CI: 0.5-0.95, P = 0.035), and treatment with an alkylating agent without transplant was associated with a 3-fold increase in odds of recovery (OR: 3, CI:2.7-564, P = 0.007). Conclusion: This retrospective review demonstrates that, while uncommon, POI can occur in pediatric cancer survivors, emphasizing the importance of educating patients on the potential long-term effects of cancer treatment and routine surveillance for these complications. This study also confirmed that recovery of ovarian function is possible in these patients, especially when diagnosed at a younger age, so continued monitoring is essential. Presentation: 6/3/2024

Deletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury by reducing accumulation of reparative macrophage and production of HGF

BackgroundAcetaminophen (APAP)-induced liver injury is the most common cause of acute liver failure. Macrophages are key players in liver restoration following APAP-induced liver injury. Thromboxane A2 (TXA2) and its receptor, thromboxane prostanoid (TP) receptor, have been shown to be involved in tissue repair. However, whether TP signaling plays a role in liver repair after APAP hepatotoxicity by affecting macrophage function remains unclear.MethodsMale TP knockout (TP−/−) and C57BL/6 wild-type (WT) mice were treated with APAP (300 mg/kg). In addition, macrophage-specific TP-knockout (TP△mac) and control WT mice were treated with APAP. We explored changes in liver inflammation, liver repair, and macrophage accumulation in mice treated with APAP.ResultsCompared with WT mice, TP−/− mice showed aggravated liver injury as indicated by increased levels of alanine transaminase (ALT) and necrotic area as well as delayed liver repair as indicated by decreased expression of proliferating cell nuclear antigen (PCNA). Macrophage deletion exacerbated APAP-induced liver injury and impaired liver repair. Transplantation of TP-deficient bone marrow (BM) cells to WT or TP−/− mice aggravated APAP hepatotoxicity with suppressed accumulation of macrophages, while transplantation of WT-BM cells to WT or TP−/− mice attenuated APAP-induced liver injury with accumulation of macrophages in the injured regions. Macrophage-specific TP−/− mice exacerbated liver injury and delayed liver repair, which was associated with increased pro-inflammatory macrophages and decreased reparative macrophages and hepatocyte growth factor (HGF) expression. In vitro, TP signaling facilitated macrophage polarization to a reparative phenotype. Transfer of cultured BM-derived macrophages from control mice to macrophage-specific TP−/− mice attenuated APAP-induced liver injury and promoted liver repair. HGF treatment mitigated APAP-induced inflammation and promoted liver repair after APAP-induced liver injury.ConclusionsDeletion of TP signaling in macrophages delays liver repair following APAP-induced liver injury, which is associated with reduced accumulation of reparative macrophages and the hepatotrophic factor HGF. Specific activation of TP signaling in macrophages may be a potential therapeutic target for liver repair and regeneration after APAP hepatotoxicity.