Total Body Irradiation Research Articles

Enhanced Costimulation Blockade With αCD154, αCD2, and αCD28 to Promote Heart Allograft Tolerance in Nonhuman Primates.

Long-term renal allograft acceptance has been achieved in macaques using a transient mixed hematopoetic chimerism protocol, but similar regimens have proven unsuccessful in heart allograft recipients unless a kidney transplant was performed simultaneously. Here, we test whether a modified protocol based on targeting CD154, CD2, and CD28 is sufficient to prolong heart allograft acceptance or promote the expansion of regulatory T cells. Eight macaques underwent heterotopic allo-heart transplantation from major histocompatibility complex-mismatched donors. Induction treatment for donor bone marrow transplantation (BMT) was administered after a 4-mo delay period under TNX-1500 monotherapy. The BMT induction regimen comprised 1 (group 1, G1; n = 3) or 2 (group 2, G2; n = 5) doses of total body irradiation, thymic irradiation, and antithymocyte globulin, followed by 2 (G1) or 5 (G2) weekly doses of αCD2 and 5 weekly treatments with αCD28 and TNX-1500. During the delay period, 1 G1 graft was rejected and 2 (1 in each group) exhibited moderate rejection on protocol biopsy before BMT. Lymphocyte chimerism was seen in 3 of 5 G2 animals and in 1 of 2 G1 recipients. One G1 graft was rejected despite chimerism, whereas the other recipient succumbed to anti-cytomegalovirus treatment. Two G2 monkeys succumbed due to infection (cytomegalovirus, bacteremia) post-BMT and 3 due to posttransplantation lymphoproliferative disease. Intensive costimulation pathway blockade with αCD2, αCD154, and αCD28 promotes lymphocyte chimerism at the cost of high incidence of posttransplantation lymphoproliferative disease and opportunistic infections, preventing assessment of the effectiveness of the regimen to promote alloimmune tolerance.

Impact of Underlying Disease and Total Body Irradiation on the Incidence of Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation.

Multiple factors have been described to influence the risk of acute or chronic graft-versus-host disease (aGVHD or cGVHD) after allogeneic hematopoietic cell transplantation (HCT), including underlying chronic myeloid leukemia (CML) and high-dose total body irradiation (TBI). However, the impact of the underlying disease or low-dose TBI on the risk of GVHD in the modern era has not been determined. To determine risk factors for GVHD in the modern era in the setting of antithymocyte globulin (ATG)-based GVHD prophylaxis. This retrospective study included 1219 patients with hematologic malignancy who underwent first peripheral blood allogeneic HCT using myeloablative fludarabine and busulfan conditioning ± low-dose total body irradiation, along with ATG, cyclosporine, and methotrexate as GVHD prophylaxis. The adjusted cumulative incidence of GVHD was compared between patient subgroups using multivariable competing risks regression. When disregarding the underlying disease, risk factors for grade 2-4 aGVHD were donor type other than matched sibling donor (non-MSD) and lack of low-dose TBI (non-TBI). Risk factors for grade 3-4 aGVHD were non-MSD, non-TBI, and CMV donor negative/recipient positive serostatus (D-R+). Risk factors for moderate-severe cGVHD were ≤9/10 HLA match, nonmale/male, and non-TBI. In models including the underlying disease, additional significant risk factors were chronic lymphocytic leukemia (CLL) for grade 2 to 4 aGVHD (sub-hazard ratio over acute myeloid leukemia [SHR] 3.16, 95% CI 1.97-5.08, P < .001); CLL and acute lymphoblastic leukemia (ALL) for grade 3-4 aGVHD (SHR for CLL 3.54, 95% CI 1.54-8.17, P = .003 and SHR for ALL 2.26, 95% CI 1.26-4.04, P = .006); and myelofibrosis (MF) for moderate-severe cGVHD (SHR 2.14, 95 CI 1.34-3.41, P = .001). In the modern era when using ATG for GVHD prophylaxis, newly identified risk factors include CLL and non-TBI for grade 2-4 aGVHD; CLL, ALL, and non-TBI for grade 3-4 aGVHD; and MF and non-TBI for moderate-severe cGVHD. These findings, if confirmed in a separate cohort, should be taken into consideration when tailoring the prophylaxis of and monitoring for GVHD.

Synergistic effect of inulin hydrogels on multi-strain probiotics for prevention of ionizing radiation-induced injury.

Prebiotics and probiotics are applied against multiple diseases including ionizing radiation-induced injury but their functions are not revealed enough. Here, we used a prebiotic, inulin hydrogels (IGs) to load multi-strain probiotics (MSPs) for protecting them from the gastrointestinal environment and improving their colonization in the gut; more importantly, they showed the synergistic effect against ionizing radiation-induced injury. Probiotics were embedded in a great number of channels of the IGs and used IGs as food. The MSP was composed of Clostridium butyricum (Cb), Bifidobacterium adolescentis (Ba), and Akkermansia muciniphila (Akk), which separately mainly produced butyl acid, acetic acid and lactic acid, and stimulated mucin proteins. Although the MSP showed higher effect against mouse radiation enteritis than the single probiotics and the similar effect to IGs, the IG/MSP-based synbiotic had the highest protection and improved many factors close to the normal levels, including animal physical activity, enteric barrier function, occludin and ZO-1 expressions, injury extension, the levels of pro-inflammatory factors (IL-6, TNF-α), gut microbiota, and short-chained fatty acids. Moreover, the synbiotic had strong protection against whole-body irradiation with high blood cell numbers, hemopoietic system recovery, and high levels of IL-3 and IL-10. IGs greatly synergized probiotics against ionizing radiation-induced injury.

Comparison between different reduced intensity conditioning regimens in AML/MDS patients in a Latin American center of adult stem cell transplantation

ABSTRACT Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for several hematological diseases. Prospective and retrospective studies have associated myeloablative conditioning regimens with increased non-relapse mortality and less intense regimens with disease relapse, leading to similar overall survival rates. Objectives: Analyze the experience with the different RIC schemes in patients transplanted for AML/MDS in our program. Methods: We retrospectively analyzed our program's reduced-intensity conditioning regimens (RIC) between 2012 and 2022 in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Results: During this period, 450 allogeneic stem cell transplantations were performed, of which 52 patients were treated with RIC for AML, mostly in men. The 3-year overall survival/progression-free survival rates were 52/53%, 51/57%, and 57/55% in the fludarabine-reduced intensity with total-body irradiation, Melphalan, and Busulfan, respectively (p = 0.89). The composite incidences of aGVHD III-IV, cGVHD, and admission to the critical patient unit were 21%, 25%, and 30%, respectively, without statistically significant differences according to the type of conditioning, but with a trend of greater ICU admission in patients who used melphalan-based conditioning. Conclusion: Our study found no differences in overall survival, progression-free survival, and complications between the most commonly used reduced-intensity conditioning regimens.

Pharmacokinetic and Metabolomic Studies with BBT-059 in Nonhuman Primates Exposed to Total-Body Gamma Radiation.

BBT-059 is a long-acting PEGylated interleukin-11 analog that has been shown to have hematopoiesis-promoting and anti-apoptotic attributes, and is being studied as a radiation countermeasure for the hematopoietic acute radiation syndrome (H-ARS). This potential countermeasure has been demonstrated to enhance survival in irradiated mice. To investigate the toxicity and safety profile of this agent, 14 nonhuman primates (NHPs, rhesus macaques) were administered two different doses of BBT-059 subcutaneously 24 h after 4 Gy total-body irradiation and were monitored for the next 60 days postirradiation. Blood samples were investigated for the pharmacokinetics and pharmacodynamics of this agent and its effects on complete blood counts, cytokines, vital signs, and for metabolomic studies. No adverse effects were observed in either treatment group. Radiation-induced metabolomic dysregulation was observed in both treatment groups, and BBT-059 afforded some short-term radiomitigation. A few pathways were commonly dysregulated by radiation exposure including the steroid hormone biosynthesis pathway, fatty acid activation, and glycerophospholipid metabolism. Notably, radiation-induced dysregulation to the linoleate metabolism pathway was significantly mitigated by either dose of BBT-059. In brief, this study suggests that BBT-059 has a good safety profile in irradiated NHPs and that its development as a medical countermeasure for U.S. Food and Drug Administration approval for human use should be continued.

Efficacy and safety of low-dose TBI combined MAC regimen for HSCT in high-risk AML patients with active disease

Background The management of high-risk acute myeloid leukaemia (AML) remains challenging, highlighting the need for innovative conditioning strategies beyond current regimens. Methods In the present single-arm study, a FACT regimen comprised of low-dose total body irradiation (TBI) with fludarabine, cytarabine and cyclophosphamide was employed to treat cytogenetically high-risk AML patients exhibiting pre-transplant active disease. This clinical trial is registered in the Chinese Clinical Trial Registry with the registration number ChiCTR2000035111. Results In this study, 21 high-risk AML patients with pre-transplant disease statuses including primary induction failure, relapse and measurable residual disease positivity, were enrolled to undergo FACT conditioning. The FACT group demonstrated a 1-year non-relapse mortality (NRM) rate of 9.5%, indicating a similar level of safety and tolerability among the conditioning regimens. The estimated cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) at one year was 30.7%. Additionally, the cumulative incidence of chronic GVHD was 36.0% at one year and increased to 43.0% at two years. Conclusions The FACT regimen is an effective myeloablative conditioning (MAC) strategy for high-risk AML patients, potentially reducing relapse risk without increasing NRM, warranting further research.

Etoricoxib–NLC Mitigates Radiation-Induced Ovarian Damage in Rats: Insights into Pro-Inflammatory Cytokines, Antioxidant Activity, and Hormonal Responses

Radiotherapy is a critical treatment for cancer but poses significant risks to ovarian tissue, particularly in young females, leading to premature ovarian failure (POF). This study examines the therapeutic potential of etoricoxib nanostructured lipid carriers (ETO-NLC) in mitigating radiation-induced ovarian damage in female Wistar rats. Twenty-four female rats were randomly assigned to four groups: a control group receiving normal saline, a group exposed to a single dose of whole-body gamma radiation (6 Gy), a group treated with etoricoxib (10 mg/kg) post-radiation, and a group treated with ETO-NLC for 14 days following radiation. Histopathological evaluations and oxidative stress biomarker assessments were conducted, including ELISAs for reactive oxygen species (ROS), pro-inflammatory cytokines (IL-1β, TNF-α), and signaling molecules (PI3K, AKT, P38MAPK, AMH). Serum levels of estrogen, FSH, and LH were measured, and gene expression analysis for TGF-β and Nrf2 was performed using qRT-PCR. The findings indicate that ETO-NLC has the potential to ameliorate the harmful effects of ovarian damage induced by γ-radiation. These therapeutic effects were achieved through the modulation of oxidative stress, inflammation, augmentation of antioxidant defenses (including Nrf2 activation), support for cell survival pathways (via PI3K/Akt signaling), regulation of MAPK, mitigation of fibrosis (TGF-β), and preservation of ovarian reserve (as evidenced by AMH, FSH/LH, and estrogen levels). ETO-NLC shows promise as an effective strategy for attenuating radiation-induced ovarian damage, highlighting the need for further research to enhance therapeutic interventions aimed at preserving ovarian function during cancer treatment.

The inhibitory impact of various total body irradiation doses on the hematopoietic system of mice

Irradiation with X-rays has been widely utilized in the clinical treatment of solid tumors and certain hematopoietic malignancies. However, this method fails to completely distinguish between malignant and normal cells. Prolonged or repeated exposure to radiation, whether due to occupational hazards or therapeutical interventions, can cause damage to normal tissues, particularly impacting the hematopoietic system. Therefore, it is important to investigate the effects of total body irradiation on the hematopoietic system of mice and to compare the inhibitory effects of various doses of irradiation on this system. In this study, we primarily employed flow cytometry to analyze mature lineage cells in the peripheral blood, as well as immature hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and spleen. Additionally, we evaluated the multilineage differentiation capacity of HSPCs through colony-forming cell assays. Our results indicated that peripheral B and T cells demonstrated increased sensitivity to irradiation, with significant cell death observed 1-day post-irradiation. Common lymphoid progenitor cells exhibited greater radiotolerance compared to other progenitor cell types, enabling them to maintain a certain population even at elevated doses. Moreover, notable differences were observed between intramedullary and extramedullary hematopoietic stem cells and common lymphoid progenitor cells regarding the extent of damage and recovery rate following irradiation. The multilineage differentiation capacity of HSPCs was also compromised during radiation exposure. In conclusion, different types of mature blood cells, along with immature HSPCs, exhibited varying degrees of sensitivity and tolerance to irradiation, resulting in distinct alterations in cell percentages and numbers.

Subsequent Thyroid Carcinomas in Children and Adolescents Registered in the German MET Consortium (1997-2023).

Introduction: Among childhood cancer survivors, the cumulative incidence rate of differentiated thyroid carcinomas (DTCs) is estimated to be 8-11%. Although the association of DTC with prior radiotherapy is well-studied, the association with chemotherapy remains less understood. Most studies focused on young adults, leaving a knowledge gap on subsequent DTC occurring in childhood and adolescence. Methods: In this retrospective cohort study, we analyzed DTCs in children and adolescents under 18 years of age who were registered with the national multicenter Malignant Endocrine Tumor studies in Germany (1997-2023). We compared patients with first primary DTC to those with subsequent DTC that developed after a history of childhood cancer or hematopoietic stem cell transplantation (HSCT). In the subsequent DTC subgroup, we compared DTCs following chemotherapy only to those following chemo- and radiotherapy. Results: Of 505 patients with DTCs, 66 (13.1%) (38 male, 28 female) were subsequent DTCs. The median age at subsequent DTC diagnosis was 12.7 years (range, 5.1-17.9), with a median latency of 7.3 years (range, 2.2-15.6) from the first malignancy or HSCT. The 5-year overall survival (OS) and thyroid-related adverse event-free survival (EFS) estimates from the diagnoses of a subsequent DTC were 100.0% and 82.5%, respectively. Prior treatment included chemotherapy in 64 patients, with 18 receiving chemotherapy alone. In all, 46 subsequent DTC patients had a history of external radiotherapy, including 2 treated with radiotherapy only and 14 with total body irradiation. Two patients received 131I-metaiodobenzylguanidine treatment. Subsequent DTCs versus first DTCs were smaller in size but more frequently multifocal. Subsequent DTCs following chemotherapy only, compared with chemo- and radiotherapy, developed after a shorter latency (median 6.2 vs. 7.8 years), and were larger (median 1.86 vs. 1.18 cm). Patients with subsequent DTCs following chemotherapy only were younger at diagnosis (median 11.5 vs. 13.7 years). No differences were observed for OS and EFS. Conclusions: Presenting features of subsequent DTCs differ from primary counterparts, although the prognosis is not significantly different. Subsequent DTCs following chemotherapy only versus chemo- and radiotherapy DTCs were larger and diagnosed in younger patients after a shorter latency. More research is needed to identify risk factors and mechanisms potentially contributing to thyroid tumorigenesis post-chemotherapy.

Incidence of and Risk Factors for Cutaneous Malignant Neoplasms After Blood or Marrow Transplant

Cutaneous malignant neoplasms are the most common subsequent neoplasm after blood or marrow transplant (BMT), but a full assessment among survivors is lacking. To identify risk factors for subsequent cutaneous malignant neoplasms using the BMT Survivor Study (BMTSS). This retrospective cohort study included patients who underwent transplant from 1974 to 2014 at City of Hope, University of Minnesota, or University of Alabama at Birmingham and survived 2 years or longer, as well as a comparison cohort of siblings. Both groups completed the BMTSS survey. Data analysis took place from October 2022 to October 2024. Demographics, pre-BMT and BMT-related therapeutic exposures, chronic graft-vs-host disease (cGVHD), and posttransplant immunosuppression. Incident cutaneous malignant neoplasms (basal cell carcinoma [BCC], squamous cell carcinoma [SCC], and melanoma) after BMT. Exposures were evaluated for association with subsequent neoplasms using proportional subdistribution hazards models (reported as subdistribution hazard ratio [SHR] and 95% CI). Among the 3880 BMT survivors (median [range] age at BMT, 44.0 [0-78.0] years; 2165 [55.8%] male; 190 [4.9%] Black, 468 [12.1%] Hispanic, 2897 [74.7%] non-Hispanic White, and 325 [8.4%] of other race [including Asian and Pacific Islander] and multiracial) who were followed up for a median (range) of 9.5 (2.0-46.0) years, 605 developed 778 distinct cutaneous neoplasms (BCC, 321; SCC, 231; melanoma, 78; and unknown type, 148). The 30-year cumulative incidence of any cutaneous malignant neoplasm was 27.4% (BCC, 18.0%; SCC, 9.8%; and melanoma, 3.7%). Seventy-year cumulative probabilities of BCC, SCC, and melanoma were considerably higher in BMT survivors than siblings (18.1% vs 8.2%, 14.7% vs 4.2%, and 4.2% vs 2.4%, respectively). Among BMT survivors, risk factors for subsequent cutaneous malignant neoplasms included age of 50 years and older at BMT (BCC: SHR, 1.76; 95% CI, 1.36-2.29; SCC: SHR, 3.37; 95% CI, 2.41-4.72), male sex (BCC: SHR, 1.39; 95% CI, 1.10-1.75; SCC: SHR, 1.85; 95% CI, 1.39-2.45), pre-BMT monoclonal antibody exposure (BCC: SHR, 1.71; 95% CI, 1.27-2.31), allogeneic BMT with cGVHD (BCC: SHR, 1.48; 95% CI, 1.06-2.08; SCC: SHR, 2.61; 95% CI, 1.68-4.04 [reference: autologous BMT]), post-BMT immunosuppression (BCC: SHR, 1.63; 95% CI, 1.24-2.14; SCC: SHR, 1.48; 95% CI, 1.09-2.02; melanoma: SHR, 1.90; 95% CI, 1.16-3.12), and transplant at City of Hope (BCC: SHR, 3.55; 95% CI, 2.58-4.89; SCC: SHR, 3.57; 95% CI, 2.34-5.47 [reference: University of Minnesota]) or University of Alabama at Birmingham (BCC: SHR, 2.35; 95% CI, 1.35-4.23; SCC: SHR, 2.63; 95% CI, 1.36-5.08 [reference: University of Minnesota]). Race and ethnicity other than non-Hispanic White were protective for BCC (Black: no cases; Hispanic: SHR, 0.27; 95% CI, 0.16-0.44; other race and multiracial: SHR, 0.26; 95% CI, 0.14-0.50 [reference: non-Hispanic White]) and SCC (Black: SHR, 0.17; 95% CI, 0.04-0.67; Hispanic: SHR, 0.28; 95% CI, 0.16-0.50; other race and multiracial: SHR, 0.13; 95% CI, 0.05-0.37 [reference: non-Hispanic White]). Total body irradiation was associated with BCC risk among those younger than 50 years at BMT (SHR, 1.92; 95% CI, 1.27-2.92). In this cohort study, the high risk of cutaneous malignant neoplasms and malignant-specific risk factors suggest a need for personalized patient counseling and posttransplant dermatologic surveillance.

Biphasic Effect of Thyroid Hormone on Megakaryopoiesis and Platelet Production.

Background: Abnormal platelet counts are frequently observed in patients with thyroid dysfunction; however, the direct impact of thyroid hormones on thrombopoiesis remains largely undefined. Methods: This study elucidates the dose-response effect of the thyroid hormone triiodothyronine (T3) on megakaryocyte (MK) development and thrombopoiesis using both a murine model of hyperthyroidism/hypothyroidism and in vitro cultures of human cord blood CD34+ cell-derived MKs. After the application of inhibitors to MKs, the examination of total and phosphorylated protein levels of the phosphoinositide 3-kinase (PI3K)/AKT pathway was utilized to assess the specific mechanisms of T3 action. The use of autophagy dual-staining lentivirus and transmission electron microscopy was employed to evaluate the impact of T3 on the autophagy flux in MKs. Mouse whole-body irradiation and bone marrow transplantation models are applied to assess the influence of T3 on the recovery of MKs/platelets invivo. Results: We found that physiological or slightly elevated thyroid hormone levels are essential for sustaining MK development and thrombopoiesis, primarily through the TRα-PI3K/AKT signaling pathway. In contrast, supraphysiological thyroid hormone concentrations induce MK apoptosis via excessive autophagy, thereby reducing platelet production. Conclusions: Here, we present evidence that the thyroid hormone influences MK development and platelet production in a concentration-dependent manner, exhibiting a dualistic role. Our discoveries shed new light on the intricate relationship between thyroid hormones and platelet formation, offering novel perspectives on the pathophysiological consequences of thyroid disorders.

Combined CAR-T/HSCT approach in a patient with refractory acute lymphoblastic leukemia and cystic fibrosis.

The association of acute lymphoblastic leukaemia (ALL) and cystic fibrosis (CF) is rare. We present the case of a paediatric patient affected by CF and refractory B-cell precursor (BCP) ALL, who was treated with combined chimeric antigen receptor T-cells (CAR-T) and allogeneic haematopoietic stem cell transplantation (HSCT). Autologous-CD19 targeting CAR-T allowed to achieve molecular remission and spare chemo-related toxicity. As B-cell aplasia was not achieved, the patient underwent HSCT after total body irradiation (TBI)-based conditioning. The course after HSCT was complicated by veno-occlusive disease, status epileptic and pulmonary invasive fungal infection which showed progressive radiological worsening despite aggressive treatment. Five months after HSCT a left upper lobe lobectomy was successfully performed. Thirteen months after HSCT the patient is in complete disease remission with normal lung function. CAR-T cell therapy bridge-to-HSCT may be an effective approach in paediatric refractory ALL in the context of multiple comorbidities as observed in CF.

Radiation-Resistant Bacteria Deinococcus radiodurans-Derived Extracellular Vesicles as Potential Radioprotectors.

The increasing use of radiation presents a risk of radiation exposure, making the development of radioprotectors necessary. In the previous study, it is investigated that Deinococcus radiodurans (R1-EVs) exert the antioxidative properties. However, the radioprotective activity of R1-EVs remains unclear. In the present study, the protective effects of R1-EVs against total body irradiation (TBI)-induced acute radiation syndrome (ARS) are investigated. To assess R1-EVs' radioprotective efficacy, ARS is induced in mice with 8 Gy of TBI, and protection against hematopoietic (H)- and gastrointestinal (GI)-ARS is evaluated. The survival rate of irradiated mice group decreases substantially after irradiation. In contrast, pretreatment with R1-EVs increases the survival rates of the mice. The administration of R1-EVs provides effective protection against radiation-induced death of bone marrow cells and splenocytes by scavenging reactive oxygen species (ROS). Additionally, R1-EVs protect both intestinal stem and epithelial cells from radiation-induced apoptosis. R1-EVs stimulate the production of short-chain fatty acids in the gastrointestinal tract, suppress proinflammatory cytokines, and increase regulatory T cells in pretreated mice versus the irradiation-only group. Proteomic analysis shows that the R1-EV proteome is significantly enriched with proteins involved in oxidative stress response. These findings highlight R1-EVs as potent radioprotectors with applications against radiation damage and ROS-mediated diseases.

Long-Term Outcomes of Reduced-Toxicity Conditioning Using 8-Gray Total Body Irradiation, Fludarabine, and Cyclophosphamide in Children, Adolescents, and Young Adults With Hematological Malignancies.

Recent studies have indicated that total body irradiation (TBI)-based reduced-toxicity conditioning (RTC) may be a potential treatment modality, especially in adults with leukemia. However, its efficacy and safety in children with hematological malignancies remain unclear. To investigate the long-term outcomes and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) using an 8-Gray (Gy) TBI/fludarabine (FLU)/cyclophosphamide (CY) RTC in children with hematological malignancies. We included 66 consecutive patients with leukemia, lymphoma, or myelodysplastic syndrome in this retrospective cohort study. Participants were < 25years old and received an 8-Gy TBI/FLU/CY RTC regimen followed by the first allo-HSCT at Shinshu University Hospital between March 2004 and March 2021. The 5-year overall and relapse-free survival probabilities were 88.2% and 76.5%, respectively, in the lymphoid malignancy group. The myeloid malignancy group had probabilities of 72.4% and 58.6%, respectively. The 5-year cumulative incidences of relapse and non-relapse mortality were 20.6% and 2.9%, respectively, in the lymphoid malignancy group. These incidences were 37.9% and 3.4%, respectively, in the myeloid malignancy group. All patients had engraftment without early relapse and none developed grade 5 regimen-related toxicity within 28days after allo-HSCT. Nonetheless, two patients had congenital abnormalities caused by chromosomal aberrations and died without relapse. 8-Gy TBI/FLU/CY RTC was safe in children with hematological malignancies, regardless of the donor source. However, safety concerns were noted in cases of chromosomal aberration-induced congenital abnormalities. Additionally, patients in the lymphoid and myeloid malignancy groups had favorable prognoses.

BCL11A+58/+55 enhancer-editing facilitates HSPC engraftment and HbF induction in rhesus macaques conditioned with a CD45 antibody-drug conjugate.

Editing the+58 region of the BCL11A erythroid enhancer has shown promise in treating β-globin disorders. To address variations in fetal hemoglobin (HbF) response, we investigated editing both+58 and+55 enhancers. Rhesus macaques transplanted with edited hematopoietic stem/progenitor cells (HSPCs) following busulfan conditioning exhibited durable, high-level (∼90%) editing frequencies post transplantation with sustained HbF reactivation over 4 years, without hematological perturbations. HbF levels were further boosted by stress erythropoiesis or hydroxyurea. Bone marrow analysis revealed that gene edits were predominantly programmed deletions, programmed inversions, and short indels, each disrupting the enhancer core TGN7-9WGATAR half E-box/GATA binding motifs. Nonprogrammed long deletions were disfavored in engrafting cells. CD45 antibody-drug conjugate (ADC) conditioning achieved comparable engraftment and HbF reactivation, whereas lentiviral vector tracking showed polyclonal reconstitution with dynamics similar to animals conditioned with total body irradiation (TBI) or busulfan. Joining CD45-ADC conditioning with combined enhancer editing presents an effective strategy for β-hemoglobinopathies, enabling durable HbF reactivation without chemotherapy.

Efficacy and Safety of Total Body Irradiation versus Chemotherapy Conditioning for Hematopoietic Stem Cell Transplant in Adult Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Efficacy and Safety of Total Body Irradiation versus Chemotherapy Conditioning for Hematopoietic Stem Cell Transplant in Adult Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Clinical use of Gafchromic EBT4 film for in vivo dosimetry for total body irradiation.

In vivo dosimetry is a common requirement to validate dose accuracy/uniformity in total body irradiation (TBI). Several detectors can be used for in vivo dosimetry, including thermoluminescent dosimeters (TLDs), diodes, ion chambers, optically stimulated luminescent dosimeters (OSLDs), and film. TLDs are well established for use in vivo but required expertise and clinical system availability may make them impractical for multifractionated TBI. OSLDs offer quick readout, but recalls have restricted their use. The purpose of this work was to validate the newly available Gafchromic EBT4 film for TBI in vivo dosimetry. Film calibration curves were created under standard conditions (6MV/15MV, 1.5/3.0cm depth, 100cm source-to-surface distance (SSD), 10 × 10 cm2 field), and films were scanned at several time points (0.5-24h) to determine the shortest development time that yielded accurate dose measurements. 4 × 4 cm2 films were placed under 1.5cm thick bolus on the anterior and posterior sides of a solid water phantom to measure entrance and exit dose under TBI conditions (∼600cm SSD, 39.5 × 39.5 cm2 field, 6 MV/15 MV). These measurements were compared to ion chamber and diode readings for validation. Film measurements were also compared to OSLD measurements for three TBI patients. The shortest development time that resulted in accurate dosimetry and allowed for adequate physician review time was 4h (±4% dose accuracy). Film entrance and exit dose measurements were within±3.8% of ion chamber and diode readings for 6MV and 15MV beams. Patient film measurements were within ∼±5% for the majority of anatomical measurement locations; however, film and OSLD readings for some anatomic locations deviated by>10%. These results indicate that EBT4 film can be utilized for accurate in vivo dosimetry for TBI patients and shows good agreement with diode and ion chamber measurements. Further investigation into film and OSLD differences was not possible due to OSLD recalls.

Dosimetric comparison between volumetric modulated arc therapy on truebeam and halcyon of boost plan for total body irradiation

Dosimetric comparison between volumetric modulated arc therapy on truebeam and halcyon of boost plan for total body irradiation

Transcriptome of the murine duodenum during recovery after a lethal dose of total body irradiation.

In the aftermath of 9/11, the radiobiology community sought novel radiation mitigators capable of preventing death when administered 24 hours or later after exposure to lethal ionizing radiation. The survival and expansion of normal stem cells are crucial for restoring tissue integrity in time to prevent mortality. While FDA-approved drugs for acute radiation syndrome primarily target the hematopoietic system, restoring the integrity of the intestinal lining is equally important for survival. However, the radiation response of the intestinal stem cell (ISC) population and its niche environment is not as well understood as that of the bone marrow. The aim of this study was to explore early transcriptomic changes in the small intestine after a lethal dose of total body irradiation (TBI), and during subsequent recovery. C3H/Sed/Kam mice were irradiated with a TBI dose of 16 Gy, the published LD 70/10 . The compound 1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP) was administered 24 hours post-irradiation. RNAs from the proximal duodenum were extracted at 28, 72, and 96 hours post-irradiation and subjected to RNA-sequencing. Differentially expressed genes were analyzed using gene-set enrichment analysis. Radiation induced significant transcriptomic changes known to precede the death of lymphatic endothelial and epithelial cells. Upregulation of Lgr5+ ISC gene signature was observed during recovery. NSPP treatment further amplified the activation of ISC-associated genes and other regenerative markers. Notably, gene Psrc1 showed strong activation throughout the recovery process, highlighting its potential role in this regenerative response. These findings suggest additional points of intervention for radiation mitigation in the intestines beyond targeting programmed cell death.

Optimized scintillation imaging in low dose rate and bright room light conditions

Objective. To develop a robust method for non-contact surface dosimetry during Total Body Irradiation (TBI) that uses an optimally paired choice of scintillator material with camera photocathode and can work insensitively to the normal ambient room lighting conditions (∼500 Lux).Approach. This goal was approached by assessing the emission contrast of scintillator signal to background room ratio (SBR) detected by the camera, in the challening conditions of low dose rate TBI with high room lights. A total of 9 fast-response scintillators, 3 wavelength shifters, and 2 camera photocathodes were systematically tested to determine the optimal combination. The effects of room lights on the scintillator signal and the background signal were assessed to avoid signal saturation while retaining accurate dose measurement. A bandpass wavelength filter was then applied to reduce the effects on room lights and scintillator signal.Main Results. One scintillator (EJ262) combined with a blue-green sensitive photocathode camera and a 500 nm band pass filter produced the greatest available scintillator SBR of 95 with maximal room lights on. The caveat is that this design rejects all patient Cherenkov light, which can be useful for visualizing the patient treatment. Another option which retained the Cherenkov signal but produced less available scintillator signal was found with another scintillator (EJ-260) and a red photocathode camera with SBR of 35, but a narrow bandpass filter is required to make it work in ambient room lights, which addition will also remove most of the Cherenkov signal.Significance. Non-contact scintillator imaging can be used for surface dosimetry in TBI with appropriate pairing of scintillator emission spectrum and camera photocathode sensitivity or optical filtering range.