Total Body Irradiation Research Articles

Abstract P013: Low-dose radiation acts as a promising preconditioning regimen for dendritic cell vaccines

Abstract Background: While anti-tumor immunity can be improved with dendritic cell vaccines, it is not fully known what approved preconditioning agents, if any, improve dendritic cell vaccine-induced antitumor T-cell response and tumor elimination. We explored the effect of whole-body and tumor-directed low-dose radiation (LD RT), cyclophosphamide, and paclitaxel as preconditioning regiments for antigen-loaded dendritic cell vaccine-induced antitumor T-cell response. Methods: Syngeneic KP tumors were engineered with ovalbumin and injected subcutaneously into the flank of wild-type B6 mice. Preconditioning regiments of LD RT (2 Gy to the whole body), cyclophosphamide (250mg/kg), LD RT (2 Gy to the whole body) + cyclophosphamide (250mg/kg), paclitaxel (20mg/kg), or nothing (control) were given on day 4. Bone marrow dendritic cells (DCs) were electroporated with ovalbumin protein, and then one million cells were injected i.v. on days 5 and 8. Blood collection was done, and ovalbumin-specific T-cell populations were examined by tetramer staining for SIINFEKL-specific TCR over time. Tumor size was measured over time, and survival data was analyzed accordingly. Results: The usage of cyclophosphamide and paclitaxel resulted in a higher tumor burden than the no preconditioning group, which indicated that lymphodepletion chemotherapy should be avoided during dendritic cell vaccines, unlike in other cellular therapies such as CAR T-cells. Whole-body LD RT performed significantly better than the control group in both tumor burden and survival, which led to further examination of LD RT and the potential difference in whole-body and tumor-specific LD RT as a preconditioning regimen. There was a significant difference in the percentage of SIINFEKL tetramer+ T-cells amongst all CD8+ cells when LD RT was administered compared to other preconditioning regimens. Furthermore, whole-body LD RT produced a significantly higher percentage of SIINFEKL tetramer+ T-cells than tumor-directed LD RT. The overall survival rate and tumor burden of subjects receiving whole-body or tumor LD RT significantly improved compared to all other groups. Interestingly, intergroup comparisons of tumor growth and survival rates between the whole-body and tumor LD-RT groups had no significant difference. Conclusions: Here, we find that LD-RT is the most effective preconditioning regimen before dendritic cell vaccination for inducing an antitumor T-cell response and achieving tumor control over time. LD RT provides a promising method to supplement dendritic cell vaccination to potentially improve patient outcomes. However, further study of the differences in whole-body and tumor-specific LD RT is necessary to determine the most ideal preconditioning regimen for dendritic cell vaccination. Citation Format: Eric Kwon, Shelby Namen, Solomon Kang, Colin Wiloughby, Kevin Zhang, Gaurav Pandey, Carl J. DeSelm.Low-dose radiation acts as a promising preconditioning regimen for dendritic cell vaccines.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P013

Abstract IA07: Improving CAR T cell therapy efficacy in hematologic malignancies with low-dose total body irradiation

Abstract Chimeric Antigen Receptor (CAR) T cell therapy represents a significant advance in the treatment of hematologic malignancies, as demonstrated by the high response rates and improved survival in diseases such as acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Diffuse large cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL). The FDA has approved several CAR T cell therapies, including some approaches targeting CD19 (CART19) for adult and pediatric patients with B-cell malignancies. Response rates for CD19 CART therapy have been quite promising, reaching 80% overall response and 60% complete response; however, relapses are observed at an estimate of 30-40% within the first year. Thus, finding clinically translatable approaches to improve response rates for patients receiving CART19 therapies, such as the potential of LD-TBI, is critical. Multiple mechanisms of CAR T cell therapy resistance include limited persistence of the CAR T cell product upon infusion, CAR T cell exhaustion, and reduced or complete loss of target expression. Here, we will describe the significant role of radiation therapy, particularly low-dose total body irradiation (LD-TBI), in enhancing the long-term response of CAR T cell therapy. LD-TBI can modulate antigen stability, augment the expression of death receptors in tumor cells, and improve the persistence of CAR T cells. Moreover, LD-TBI also enhances lymphodepletion and the trafficking of CAR T cells to the tumor-infiltrated organs. As a result, LD-TBI significantly prolongs the survival of mice bearing lymphoma or B-ALL in combination with anti-CD19 CAR T cells, thereby improving patient outcomes and offering a promising future for cancer treatment. Citation Format: Monica L. Guzman. Improving CAR T cell therapy efficacy in hematologic malignancies with low-dose total body irradiation. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr IA07

Diabetes Risk After Treatment for Childhood and Young Adult Cancer.

Diabetes is a potential late consequence of childhood and young adult cancer (CYAC) treatment. Causative treatments associated with diabetes have been identified in retrospective cohort studies but have not been validated in population-based cohorts. Our aim was to define the extent of diabetes risk and explore contributory factors for its development in survivors of CYAC in the United Kingdom. Cancer registration data (n = 4,238) were linked to electronic health care databases to identify cases of diabetes through clinical coding or HbA1c values. Total effect of prespecified treatment exposures on diabetes risk was estimated using flexible parametric modeling and standardized cause-specific cumulative incidence functions (CIFs). After median follow-up of 14.4 years, 163 individuals (3.8%) were identified with diabetes. Total body irradiation (TBI) increases diabetes risk over time, with a 40-year CIF reaching 21.0% (95% CI 13.8-31.9) compared with 8.4% (95% CI 6.1-11.5) without TBI. Survivors treated with corticosteroids had a 7.7% increased risk at 40 years after cancer diagnosis. Hematopoietic stem cell transplant (HSCT) survivors had markedly higher risk, with a 40-year CIF of 19.6% (95% CI 13.4-28.6) versus 8.2% (95% CI 6.0-11.3) for patients who had not undergone HSCT. Among patients who received allogeneic HSCT, the 40-year CIF of diabetes was 25.7% (95% CI 17.4-38.0), compared with 7.9% (95% CI 3.3-19.1) in patients who received autologous transplants. This evaluation of a hospital-based cohort of patients with CYAC identifies these patients' increased long-term risk of developing diabetes and how this varies temporally according to treatment modalities. Notable contrasts in risk by treatment were detected as early as 10 years after cancer diagnosis. Findings should inform the development of risk-stratified evidence-based screening.

A Comparison of Planned Dose in TBI VMAT Treatment with Dosimetry Using Portal Dosimetry® and IBA MatriXX®

Bone Marrow Transplant (BMT) is an essential therapeutic intervention in the treatment of diseases such as leukemia and lymphoma, where Total Body Irradiation (TBI) plays a crucial role by eradicating residual diseases and inducing immunosuppression, thus facilitating cell transplantation and reducing the risk of graft rejection. Traditionally, TBI has used large radiation fields, which can lead to significant toxicities in organs at risk (OARs) due to challenges in dose optimization. Volumetric Modulated Arc Therapy (VMAT) emerges as a promising technique, offering advantages such as the use of smaller treatment spaces and reduced doses to OARs, which may improve patient quality of life and reduce treatment costs. This study evaluates the effectiveness of VMAT in TBI by comparing the planned dose with the dose measured by quality control systems, such as the MatriXX FFF from IBA and the Portal Dosimetry from the VitalBeam linear accelerator, demonstrating that VMAT is a viable and effective alternative with the potential to optimize therapeutic outcomes in BMT.

Increased Non-Relapse Mortality in Older People With Allogeneic Hematopoietic Stem Cell Transplantation Using Fludarabine and Myeloablative Dose of Busulfan-Based Regimen.

Fludarabine and myeloablative busulfan (FluBu4) in allogeneic hematopoietic stem cell transplantation (HSCT) for older people have not been adequately examined. This retrospective study analyzed data from a large-scale, nationwide database in Japan. Adult patients (> 15 years old, y/o) who received their first HSCT with FluBu4 for hematological malignancies were included. They were categorized into the younger (< 60 y/o, N = 1295) and the older group (≥ 60 y/o, N = 993). The 3-year overall survival (OS) rate after HSCT was significantly worse in the older group than in the other (p < 0.01, 39.9% vs. 48.5%). The 3-year non-relapse mortality (NRM) was significantly higher in the older group than in the other (p < 0.01, 30.9% vs. 23.0%), and the 3-year cumulative incidence of relapse was comparable between them. According to the multivariate analysis, age ≥ 60 years was significantly associated with poor OS and high NRM. In a subgroup analysis of the older group, the use of additional chemotherapeutic drugs to FluBu4 was significantly associated with poor OS and high NRM. Total body irradiation was significantly associated with high NRM and 1-year incidence of sinusoidal obstruction syndrome but not with OS. Thus, FluBu4 should be used with caution in older people.

Cardiovascular Complications of Immune Effector Cell Therapies in Pediatric Hematological and Solid Tumors.

Immune effector cell (IEC) therapies, including chimeric antigen receptor (CAR)-modified T-cell therapy, have shown efficacy in pediatric B-cell acute lymphoblastic leukemia (B-ALL) and are being investigated for other malignancies. A common toxicity associated with IEC therapy is cytokine release syndrome (CRS), which can lead to cardiovascular decompensation due to systemic inflammation. Data are limited regarding cardiovascular adverse effects in children. This study aims to describe the cardiovascular adverse effect profile of IEC therapies in pediatric patients with hematologic and solid tumor malignancies. We retrospectively reviewed patients who received IECs directed towards various targets in patients with hematologic, solid, and brain tumor malignancies from January 2014 to June 2023 at Texas Children's Hospital. The primary end point was hypotension requiring vasoactive support and/or heart failure within 30 days of infusion. A total of 203 patients met inclusion criteria. Pretreatment echocardiogram was available for 142 (70%) pediatric patients, of whom 140 (96%) had normal baseline systolic function. Hypotension requiring vasoactive support occurred in 26 (13%) patients. Hematologic malignancy indications (p = 0.002), total body irradiation (TBI) (p = 0.002), and allogenic hematopoietic stem cell transplants (HCT) (p = 0.035) were associated with increased risk of hypotension requiring vasoactive support. Follow-up echocardiograms were available for 14 patients who met the primary end point, and all showed return to baseline within 6 months. Significant hemodynamic compromise occurred in a minority of patients treated with IEC therapies. All experiencing cardiac dysfunction had recovery of function, and there was no cardiovascular-related mortality.

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.

Donor Type Does Not Impact Late Graft Failure Following Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis.

Post-transplant cyclophosphamide (PTCy) is a commonly used graft-vs-host disease (GVHD) prophylaxis, particularly in the setting of haploidentical (haplo) hematopoietic cell transplantation (HCT). The rate of graft failure has been reported to be as high as 12% to 20% in haplo-HCT recipients using PTCy. The objective of this study was to determine whether donor type influenced the risk of late graft failure following reduced-intensity conditioning (RIC) HCT using PTCy-based GVHD prophylaxis. A retrospective cohort analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database among adult patients who underwent first RIC haplo or 8/8 matched unrelated donor (MUD) HCT between 2011 and 2018 for acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS) with PTCy GVHD prophylaxis. The primary outcome was incidence of late graft failure, defined as secondary graft loss in the absence of relapse or poor graft function requiring a cellular therapy intervention. A total of 1336 patients met the eligibility criteria (1151 haplo, 185 MUD). Patients in the MUD group were older (65 vs. 61 years), less ethnically diverse (95% vs. 72% White), received fewer bone marrow grafts (45% vs. 16%), and had younger donors (median age, 28 vs. 37 years old). Conditioning regimens were predominately fludarabine, cyclophosphamide, and total body irradiation (TBI; 87% haplo and 38% MUD). At 2 years, the adjusted probabilities of late graft failure for the haplo group was 6.5% (95% confidence interval [CI], 5.2-8.0) versus 5.9% (95% CI, 2.7%-10.9%) for the MUD group (P = .79). Multivariate analysis for risk factors associated with late graft failure found associations with a diagnosis of MDS (HR, 1.98; 95% CI, 1.22-3.20; P = .005), and earlier year of HCT (2015-2018 vs. 2011-2014; HR, 0.39; 95% CI, 0.24-0.64; P = .0002). A post-hoc sensitivity analysis was performed to evaluate the effect of donor age and use of peripheral blood stem cell (PBSC) grafts. Graft failure did not differ between haplo and MUD HCT (HR, 1.19; P = .67) when adjusted for donor age nor when restricted to PBSC grafts only (HR, 0.85; P = .70). In this registry-based analysis of patients undergoing RIC HCT for AML, ALL, or MDS using GVHD prophylaxis with PTCy, there was no significant difference in late graft failure rates between haplo and MUD donors. Overall rates of late graft failure were high.

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.

Distinct Urinary Metabolite Signatures Mirror In Vivo Oxidative Stress-Related Radiation Responses in Mice.

Exposure to ionizing radiation disrupts metabolic pathways and causes oxidative stress, which can lead to organ damage. In this study, urinary metabolites from mice exposed to high-dose and low-dose whole-body irradiation (WBI HDR, WBI LDR) or partial-body irradiation (PBI BM2.5) were analyzed using targeted and untargeted metabolomics approaches. Significant metabolic changes particularly in oxidative stress pathways were observed on Day 2 post-radiation. By Day 30, the WBI HDR group showed persistent metabolic dysregulation, while the WBI LDR and PBI BM2.5 groups were similar to control mice. Machine learning models identified metabolites that were predictive of the type of radiation exposure with high accuracy, highlighting their potential use as biomarkers for radiation damage and oxidative stress.

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.