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Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n = 11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m2, melphalan (MEL) 210 mg/m2, and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n = 10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p = 0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.

Fludarabine with intravenous busulfan (6.4 mg/kg; FB2) and fludarabine with intermediate-dose melphalan (140 mg/m2; FM140) are the most widely used reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation. FM140 generally has a lower relapse rate and higher non-relapse mortality (NRM), resulting in overall survival (OS) comparable to that seen with FB2. To evaluate the effect of reducing the melphalan dose, we retrospectively compared transplant outcomes in 156 patients who received FB2 (n = 103) or FM80 (n = 53) at our center (median age: 63 years; range 27–72 years). All patients received 4-Gy total body irradiation. Three-year OS, the cumulative incidence of relapse, and NRM were comparable between groups (FB2 vs. FM80, 58% vs. 47%, p = 0.24; 30% vs. 36%, p = 0.57; 17% vs. 21%, p = 0.44, respectively). There was no significant difference in the cumulative incidence of graft-versus-host disease (GVHD) at day 100, chronic GVHD at 3 years, or the 3-year GVHD-free/relapse-free survival rate. In the high-risk disease group, patients receiving FM80 tended to have lower 3-year OS (FB2 vs. FM80, 48% vs. 17%, p = 0.06). In summary, transplant outcomes following FB2 or FM80 were comparable except in patients with high-risk disease.

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6–97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5–33.0%) and 16.9% (95% CI: 11.4–23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3–69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.

Purpose Exposure to high doses of ionizing radiation can result in hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE). There is no radiation medical countermeasure approved by the U.S. Food and Drug Administration which can be used prior to radiation exposure to protect exposed individuals. Different formulations containing synthetic genistein (BIO 300) are being developed to counter the harmful effects of radiation exposure. Materials and methods We investigated the efficacy of a BIO 300 Oral Powder (OP) formulation as a prophylactic radiation medical countermeasure against a lethal dose of cobalt-60 gamma-radiation in CD2F1 male mice while comparing to other formulations of BIO 300 and Neulasta (PEGylated filgrastim), a standard of care drug for H-ARS. Results BIO 300 OP provided significant radioprotection against ionizing radiation in mice when administered twice per day for six days prior to total-body radiation exposure. Its radioprotective efficacy in the murine model was comparable to the efficacy of a single subcutaneous (sc) injection of Neulasta administered after total-body radiation exposure. Conclusions Our results demonstrate that BIO 300 OP, which can be administered orally, is a promising prophylactic radiation countermeasure for H-ARS.

Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41 years. The median total nucleated cell and total CD34+ cell doses in a UCB unit at cryopreservation were 2.5 × 107/kg and 0.7 × 105/kg, respectively. The median follow-up period for survivors was 47 months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34+ cell dose in an UCB unit (≥ 0.7 × 105/kg; hazard ratio, 0.57, P = 0.01) and total dose of TBI (4 Gy of TBI; hazard ratio, 0.32, P = 0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups.

Epstein–Barr virus (EBV) and cytomegalovirus (CMV) reactivations are common complications after allogeneic hematopoietic cell transplantation (allo-HCT), but data focusing on non–Hodgkin lymphoma (NHL) are limited. We retrospectively analyzed the prevalence of EBV and CMV reactivation post-allo-HCT and the impacts on transplant outcomes in 160 NHL patients. The 1-year incidences of EBV and CMV reactivation were 22.58% and 25.55%, respectively. Independent impactors for EBV reactivation were more than 6 lines of chemotherapy (P = 0.030), use of rituximab (P = 0.004), and neutrophil recovery within 30 days post-HCT (P = 0.022). For T-cell lymphoblastic lymphoma patients, the International Prognostic Index (IPI) (P = 0.015) and chronic GVHD (P = 0.001) increased the risk of CMV reactivation. CMV reactivation was independently related to a lower risk of relapse (P = 0.027) but higher transplant-related mortality (TRM) (P = 0.038). Although viral reactivation had no significant impact on overall survival (OS) in the whole cohort, it led to an inferior 2-year OS (67.6% versus 92.5%, P = 0.005) and TRM (20.1% versus 4.7%, P = 0.020) in recipients surviving for more than 180 days. We concluded that EBV and CMV reactivation post-allotransplant still deserved concern particularly in NHL patients with high-risk factors, since it is generally related to a deteriorated prognosis. Large-scale studies are warranted to validate our findings.

Patients with high-risk or relapsed aggressive B-cell lymphomas are characterized by poor prognosis. High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) can induce durable remissions in these patients and is potentially curative. Two hundred forty-seven patients with aggressive B-cell lymphomas treated with high-dose chemotherapy and ASCT, either as consolidation after first-line therapy or after salvage therapy for relapsed disease, between 2002 and 2019 at the University Hospital Muenster, were analyzed. The median follow-up of surviving patients was 36 months (range 0–163). Progression-free survival (PFS) and overall survival (OS) after 3 years was 63% and 68%, respectively. After ASCT, 28% of all patients experienced a relapse. The cumulative incidence of non-relapse mortality at day 100 after ASCT was 4%. Multivariate analysis identified remission status at ASCT, age at ASCT, and the numbers of infused CD34+ cells as independent prognostic factors for both PFS and OS. Patients with mantle cell lymphoma (MCL) or primary CNS lymphoma (PCNSL) treated with ASCT in first-line had a superior OS and PFS when compared to patients treated with ASCT in relapsed disease. For patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL), early relapse (

PURPOSE Total body irradiation (TBI) -induced hematopoietic system injury is mainly due to the failure of self-renewal and to the differentiation ability of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) after radiation exposure. The mouse parabiosis model is mainly used in the field of aging research to explore whether circulating factors in peripheral blood can improve the functions of aged tissues and organs. In this study, we generated a mouse model to verify whether non-irradiated peripheral circulation can improve the circulatory environment in irradiated mice and ameliorate TBI-induced hematopoietic system injury. MATERIALS AND METHODS Six- to eight-week-old male C57BL/6 mice were adjoined by a surgical operation. Four weeks later, one mouse in the pair was exposed to 8 Gy or 6 Gy X-ray, and B and T cells in the peripheral blood, bone marrow, spleen, mesenteric lymph nodes and thymus were then detected by flow cytometry. Hematopoietic stem/progenitor cells in bone marrow cells and their levels of ROS and apoptosis were also detected in this study. RESULTS The results showed decreased percentages of B and T lymphocytes in the peripheral blood, bone marrow (BM), spleen and mesenteric lymph nodes (MLNs) in the isotype irradiated mice. The proportions of CD4-positive, CD8-positive, and CD4 and CD8 double-negative cells were also increased, while the proportion of CD4 and CD8 double-positive cells in the irradiated thymus was decreased. Thus, all of the above lymphocyte injuries in the parabiosis model were improved to nearly the levels of the control. We further detected radiation-induced HSC and HPC injury; however, the reduced HSC and HPC numbers, ROS levels and apoptosis percentages were not ameliorated in the parabiotic irradiated mice. CONCLUSIONS Above all, our results showed that non-irradiated peripheral circulation can promote the recovery of TBI-induced lymphocyte injury, further indicating that the recovery of immune cells may play a very important role in the repair of TBI-induced damage.

The space radiation environment consists of multiple species of charged particles, including 28Si ions, that may impact brain function during and following missions. To develop biomarkers of the space radiation response, BALB/c and C3H female and male mice and their F2 hybrid progeny were irradiated with 28Si ions (350 MeV/n, 0.2 Gy) and tested for behavioral and cognitive performance 1, 6, and 12 months following irradiation. The plasma of the mice was collected for analysis of miRNA levels. Select pertinent brain regions were dissected for lipidomic analyses and analyses of levels of select biomarkers shown to be sensitive to effects of space radiation in previous studies. There were associations between lipids in select brain regions, plasma miRNA, and cognitive measures and behavioral following 28Si ion irradiation. Different but overlapping sets of miRNAs in plasma were found to be associated with cognitive measures and behavioral in sham and irradiated mice at the three time points. The radiation condition revealed pathways involved in neurodegenerative conditions and cancers. Levels of the dendritic marker MAP2 in the cortex were higher in irradiated than sham-irradiated mice at middle age, which might be part of a compensatory response. Relationships were also revealed with CD68 in miRNAs in an anatomical distinct fashion, suggesting that distinct miRNAs modulate neuroinflammation in different brain regions. The associations between lipids in selected brain regions, plasma miRNA, and behavioral and cognitive measures following 28Si ion irradiation could be used for the development of biomarker of the space radiation response.

Allogenic hematopoietic stem cell transplantation (allo‐HCT) is the standard treatment for acute myeloid leukemia (AML) in non‐complete remission (non‐CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non‐CR AML undergoing allo‐HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo‐HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266–0.554; p, Allogenic hematopoietic stem cell transplantation (allo‐HCT) is the standard treatment for acute myeloid leukemia (AML) in non‐complete remission (non‐CR); however, the prognosis is inconsistent. We developed and validated prognostic models (nomograms and web application) to predict the overall survival of patients with non‐CR AML undergoing allo‐HCT (cord blood transplantation, bone marrow transplantation and peripheral blood stem cell transplantation) using a large cohort. The web application is available at https://JSHCT‐AMLWG.shinyapps.io/Predict‐OS‐nonCR‐AML‐post‐HCT/.

To investigate the effect of acute graft-versus-host disease (aGVHD) mouse models established respectively by total body irradiation (TBI) and busulfan combined with cyclophosphamide (BU/CY) conditioning regimens after allogeneic hematopoietic stem cell transplantation (allo-HSCT).Bone marrow cells and splenic mononuclear cells were isolated respectively from femur, tibia, and spleen of C57BL/6 male mice (H-2Kb) which were selected as donors. After TBI pretreatment, BALB/c female mice (H-2Kd) were injected with donor bone marrow cells 1×10Both TBI and BU/CY as conditioning regimens can successfully establish stable mouse models of aGVHD after fully allo-HSCT and haploidentical HSCT for further research about mechanism of aGVHD. BU/CY conditioning regimen can more truly simulate physiological status in vivo of patients with chemotherapy based conditioning regimen, while TBI conditioning regimen shows significantly more typical aGVHD symptoms and easier to operate.TBI与BU/CY两种预处理方案建立急性移植物抗宿主病小鼠模型的比较.分别使用全身照射（TBI）与白消安联合环磷酰胺（BU/CY）两种预处理方案建立异基因造血干细胞移植后的急性移植物抗宿主病（aGVHD）小鼠模型，并探讨两种预处理方案建立aGVHD小鼠模型的效果.以C57BL/6雄性小鼠（H-2Kb）为供鼠，分离股骨、胫骨骨髓细胞及脾单个核细胞，使用TBI预处理BALB/c雌性小鼠（H-2Kd），同时使用BU/CY方案预处理CB6F1雌性小鼠（H-2Kd/b）后，两组小鼠经尾静脉分别注射供鼠骨髓细胞1×10两组小鼠移植后均出现精神萎靡、活动度下降、体重连续下降，以及不同程度的脱 毛、弓背体位、腹泻及肛门肿胀等aGVHD表现，所有小鼠在4周内全部死亡；流式细胞术检测结果显示，两组小鼠移植后均完全嵌合；病理检查显示，小鼠皮肤、肠道、肝脏、肺和脾等靶器官组织可见明显的aGVHD病理学改变。TBI组小鼠较BU/CY组小鼠表现出更为明显的体重下降、大面积脱毛及皮肤皱褶等典型体征，aGVHD评分显著高，两组比较差异有统计学意义（P0.05）.TBI与BU/CY两种预处理方案可成功构建稳定的完全异基因造血干细胞移植与半相合骨髓移植后aGVHD模型，采用BU/CY预处理方案可更真实地模拟目前临床上更为常用的化疗为主的预处理方案的患者体内的生理状态，而TBI预处理方案的小鼠具有更为典型的aGVHD表现，操作更为简便，两种方案均可为后续研究aGVHD发生相关机制提供可靠的临床前模型.

As the potential risk of radiation exposure is increasing, radioprotectors studies are gaining importance. In this study, novel hybrid compounds containing edaravone analogue and 3‐n‐butylphthalide ring‐opening derivatives were synthesized, and their radioprotective effects were evaluated. Among these, compound 10a displayed the highest radioprotective activity in IEC‐6 and HFL‐1 cells. Its oral administration increased the survival rates of irradiated mice and alleviated total body irradiation (TBI)‐induced hematopoietic damage by mitigating myelosuppression and improving hematopoietic stem/progenitor cell frequencies. Furthermore, 10a treatment prevented abdominal irradiation (ABI)‐induced structural damage to the small intestine. Experiment results demonstrated that 10a increased the number of Lgr5+ intestinal stem cells, lysozyme+ Paneth cells and Ki67+ transient amplifying cells, and reduced apoptosis of the intestinal epithelium cells in irradiated mice. Moreover, in vitro and in vivo studies demonstrated that the radioprotective activity of 10a is associated to the reduction of oxidative stress and the inhibition of DNA damage. Furthermore, compound 10a downregulated the expressions of p53, Bax, caspase‐9 and caspase‐3, and upregulated the expression of Bcl‐2, suggesting that it could prevent irradiation‐induced intestinal damage through the p53‐dependent apoptotic pathway. Collectively, these findings demonstrate that 10a is beneficial for the prevention of radiation damage and has the potential to be a radioprotector.

Advancements in hematopoietic cell transplantation (HCT) have led to increased survivorship rates in many childhood diseases. However, this growing group of long-term survivors face a myriad of late effects. There are currently limited guidelines for surveillance of gastrointestinal polyps for pediatric transplant patients. Here we describe 5 patients undergoing HCT with total body irradiation-based conditioning regimens for leukemia who developed symptomatic polyps a median of 4.5 (range: 0.75 to 5.75) years after HCT. Because of limited surveillance guidelines in children, we conclude that the development of new or progressive symptoms related to the gastrointestinal tract deserves prompt recognition and evaluation.

Acute radiation syndrome (ARS) due to whole body exposure (WBE) presents various clinical pictures, occasionally leading to fatal consequences. In this report, the literature providing details of the clinical course of severe ARS owing to WBE is reviewed and the lessons learned from recent accidents are discussed, to better prepare for another radiological event. Studies investigating radiological accidents that provided details of medical care for severe ARS were searched in official reports from the International Atomic Energy Agency and through the databases of PubMed, Medline, CiNii and Google Scholar and reviewed. Four fatal cases of severe ARS due to WBE in Soreq 1990 and Nesvizh 1992, and two cases in JCO Tokaimura 1999 were reviewed. A common set of medical interventions was carried out, that put a focus on medical management assuming the occurrence of hematopoietic disorders. However, clinicians were faced with a mixture of chronic hematological and non-hematological events including persistent gastrointestinal disorders, gradual and progressive skin disorders, liver and renal dysfunction and respiratory failure. Clinical pictures following high-dose WBE have become more complicated as treatment modalities improve. To address these issues, a concept of severe ARS due to WBE has been proposed with respect to radiation-induced multi-organ dysfunction syndrome (RI-MODS) and failure (RI-MOF). These patients need to be managed at institutions where multidisciplinary, resource-intensive therapy can be provided.

Metformin, a first-line oral drug for type II diabetes mellitus, not only reduces blood glucose levels, but also has many other biological effects. Recent studies have been conducted to determine the protective effect of metformin in irradiation injuries. However, the results are controversial and mainly focus on the time of metformin administration. In this study, we aimed to investigate the protective effect of metformin in BALB/c mice exposed to 6 Gy or 8 Gy of a 60Co source of γ-rays for total body irradiation (TBI). Survival outcomes were assessed following exposure to 8 Gy or 6 Gy TBI, and hematopoietic damage and intestinal injury were assessed after exposure to 6 Gy TBI. Metformin prolonged the survival of mice exposed to 8 Gy TBI and improved the survival rate of mice exposed to 6 Gy TBI only when administered before exposure to irradiation. Moreover, pretreatment with metformin reduced the frequency of micronuclei (MN) in the bone marrow of mice exposed to 6 Gy TBI. Pretreatment of metformin also protected the intestinal morphology of mice, reduced inflammatory response and decreased the number of apoptotic cells in intestine. In conclusion, we demonstrated that pretreatment with metformin could alleviate irradiation injury.

Reproductive toxicity is common after total body irradiation (TBI) and has major quality of life implications for patients. In that context, this is the first report of gonadal-sparing volumetric-modulated arc therapy (VMAT) TBI, successfully delivered in a boy and a girl with aplastic anemia. Both patients' VMAT TBI plans demonstrated improved gonadal sparing versus simulated conventional 2-dimensional (2D) approach (mean testes dose, 0.45 Gy VMAT vs 0.72 Gy 2D; mean ovary dose, 0.64 Gy VMAT vs 1.47 Gy 2D). Planning target volume coverage was also improved for both cases with the VMAT plan versus conventional 2D plan (2 Gy D90% vs 1.9 Gy D90%, respectively). Given these dosimetric advantages, the present study can serve as a proof-of-concept for further prospective studies evaluating this technique for wider applications in populations receiving TBI.

Ionizing radiation-induced intestinal injury is a catastrophic complication in patients receiving radiotherapy. Circulating exosomes from patients undergoing radiotherapy can mediate communication between cells and facilitate a variety of pathological processes in vivo, but its effects on ionizing radiation-induced intestinal damage are undetermined. In this study we investigated the roles of exosomes during total body irradiation (TBI)-induced intestinal injury in vivo and in vitro. We isolated exosomes from serum of donor mice 24 h after lethal dose (9 Gy) TBI (Exo-IR-24h), then intravenously injected the exosomes into receipt mice, and found that Exo-IR-24h injection not only exacerbated 9 Gy TBI-induced lethality and weight loss, but also promoted crypt-villus structural and functional injury of the small intestine in receipt mice. Moreover, Exo-IR-24h injection significantly enhanced the apoptosis and DNA damage of small intestine in receipt mice following TBI exposure. In murine intestinal epithelial MODE-K cells, treatment with Exo-IR-24h significantly promoted 4 Gy ionizing radiation-induced apoptosis, resulting in decreased cell vitality. We further demonstrated that Exo-IR-24h promoted the IR-induced injury in receipt mice partially through its DNA damage-promoting effects and attenuating Nrf2 antioxidant response in irradiated MODE-K cells. In addition, TBI-related miRNAs and their targets in the exosomes of mice were enriched functionally using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, injection of GW4869 (an inhibitor of exosome biogenesis and release, 1.25 mg·kg(−1)·d(−1), ip, for 5 consecutive days starting 3 days before radiation exposure) was able to rescue mice against 9 Gy TBI-induced lethality and intestinal damage. Collectively, this study reveals that exosomes are involved in TBI-induced intestinal injury in mice and provides a new target to protect patients against irradiation-induced intestinal injury during radiotherapy.

Amifostine has been the only small molecule radio-protector approved by FDA for decades; however, the serious adverse effects limit its clinical use. To address the toxicity issues and maintain the good potency, a series of modified small polycysteine peptides had been prepared. Among them, compound 5 exhibited the highest radio-protective efficacy, the same as amifostine, but much better safety profile. To confirm the correlation between the radiation-protective efficacy and the DNA binding capability, each of the enantiomers of the polycysteine peptides had been prepared. As a result, the l-configuration compounds had obviously higher efficacy than the corresponding d-configuration enantiomers; among them, compound 5 showed the highest DNA binding capability and radiation-protective efficacy. To our knowledge, this is the first study that has proved their correlations using direct comparison. Further exploration of the mechanism revealed that the ionizing radiation (IR) triggered ferroptosis inhibition by compound 5 could be one of the pathways for the protection effect, which was different from amifostine. In summary, the preliminary result showed that compound 5, a polycysteine as a new type of radio-protector, had been developed with good efficacy and safety profile. Further study of the compound for potential use is ongoing.

PURPOSE Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129 ). RESULTS Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

Introduction Immunotherapy (IT) and radiotherapy (RT) have improved overall survival in patients with melanoma with brain metastasis (MBM). We examined the real‐world survival impact of IT and RT combination and timing strategies. Materials and Methods From the facility‐based National Cancer Database (NCDB) data set, 3008 cases of MBM were identified between 2011 and 2015. Six treatment cohorts were identified: stereotactic radiosurgery (SRS) + IT, SRS alone, whole brain radiotherapy (WBRT) + IT, WBRT alone, IT alone, and none. Concurrent therapy was defined as IT given within 28 days before or after RT; nonconcurrent defined as IT administered within 28–90 days of RT. The co‐primary outcomes were propensity score‐adjusted overall survival by treatment regimen and overall survival by RT and IT timing. Results Median overall survival (mOS) was performed for each treatment category; SRS +IT 15.77 m; (95%CI 12.13–21.29), SRS alone (9.33 m; 95%CI: 8.0–11.3), IT alone (7.29 m; 95%CI: 5.35–12.91), WBRT +IT (4.89 m; 95%CI: 3.65–5.92), No RT or IT (3.29 m; 95%CI: 2.96–3.75), and WBRT alone (3.12 m; 95%CI 2.79–3.52). By propensity score matching, mOS for SRS +IT (15.5 m; 95%CI: 11.5–20.2) was greater than SRS alone (10.1 m; 95%CI: 8.4–11.8) (p = 0.010), and median survival for WBRT +IT (4.6 m; 95%CI: 3.4–5.6) was greater than WBRT alone (2.9 m; 95%CI: 2.5–3.5) (p, In our study of the National Cancer Data Base (NCBD), addition of immunotherapy to radiation therapy improves survival in patients with melanoma with brain metastases when added to SBRT or WBRT, with the best survival observed for IT with SBRT. Concurrrent versus Noncurrent immunotherapy combined with radiation had no significantly different survival.

Hematopoietic acute radiation syndrome (H-ARS) and delayed effects of acute radiation exposure (DEARE) are detrimental health effects that occur after exposure to high doses of ionizing radiation. BIO 300, a synthetic genistein nanosuspension, was previously proven safe and effective against H-ARS when administered (via the oral (po) or intramuscular (im) route) prior to exposure to lethal doses of total-body radiation. In this study, we evaluated the proteomic changes in serum of nonhuman primates (NHP) after administering BIO 300 by different routes (po and im). We utilized nanoflow-ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (NanoUPLC-MS/MS) methods for comprehensive global profiling and quantification of serum proteins. The results corroborate previous findings that suggest a very similar metabolic profile following both routes of drug administration. Furthermore, we observed minor alterations in protein levels, 2 hours after drug administration, which relates to the Cmax of BIO 300 for both routes of administration. Taken together, this assessment may provide an insight into the mechanism of radioprotection of BIO 300 and a reasonable illustration of the pharmacodynamics of this radiation countermeasure.

Aim: In this study, we aimed to determine possible mitigation of radiationinduced toxicities in the duodenum, jejunum and colon using post-exposure treatment with resveratrol and alpha-lipoic acid. Background: After the bone marrow, gastrointestinal system toxicity is the second critical cause of death following whole-body exposure to radiation. Its side effects reduce the quality of life of patients who have undergone radiotherapy. Resveratrol has an antioxidant effect and stimulates DNA damage responses (DDRs). Alpha-lipoic acid neutralizes free radicals via the recycling of ascorbic acid and alpha-tocopherol. Objective: This study is a pilot investigation of the mitigation of enteritis using resveratrol and alpha-lipoic acid following histopathological study. Methods: 60 male mice were randomly assigned to six groups; control, resveratrol treatment, alpha-lipoic acid treatment, whole-body irradiation, irradiation plus resveratrol, and irradiation plus alpha-lipoic acid. The mice were irradiated with a single dose of 7 Gy from a cobalt-60 gamma-ray source. Treatment with resveratrol or alpha-lipoic acid started 24 h after irradiation and continued for 4 weeks. All mice were sacrificed after 30 days for histopathological evaluation of radiation-induced toxicities in the duodenum, jejunum and colon. Results and Conclusion: Exposure to radiation caused mild to severe damages to vessels, goblet cells and villous. It also led to significant infiltration of macrophages and leukocytes, especially in the colon. Both resveratrol and alpha-lipoic acid were able to mitigate morphological changes. However, they could not mitigate vascular injury. Conclusion: Resveratrol and alpha-lipoic acid could mitigate radiation-induced injuries in the small and large intestine. A comparison between these agents showed that resveratrol may be a more effective mitigator compared to alpha-lipoic acid.

Varicella and zoster, produced by varicella-zoster virus (VZV), are associated with an increased risk of stroke that may be due to persistent inflammation and hypercoagulability. Because substance P is associated with inflammation, hypercoagulability, and atherosclerotic plaque rupture that may contribute to increased stroke risk after VZV infection, we measured serum substance P in simian varicella virus-infected rhesus macaques. We found significantly increased and persistent serum substance P concentrations during varicella and zoster compared with pre-inoculation, supporting the hypothesis that VZV-induced increases in serum substance P may contribute to increased stroke risk associated with VZV infection.

The aim of this work was to study the effect of proton pencil beam scanning in the Bragg peak in the dose range of 0.1-1.5 Gy on the induction of cytogenetic damage in the bone marrow, reactive oxygen species (ROS) production in whole blood, and the state of lymphoid organs after total body irradiation of mice. Irradiation was carried out in the Prometeus proton synchrotron (Protvino) in the Bragg peak with proton energy at the output of 90-116 MeV. It was found that, under irradiation of mice in the range of low and medium doses of proton pencil beam scanning in the Bragg peak, the relative biological effectiveness (RBE) according to the criterion of cytogenetic changes was 1.15. In addition, it was found that the pathophysiological effect on the lymphoid organs and the production of ROS by blood cells were different as compared with the effect of X-rays.

Purpose We aimed to predict and compare radiation-induced, organ-specific, secondary solid-tumor occurrence risks from conventional total body irradiation (TBI) and total marrow irradiation (TMI) for patients undergoing hematopoietic cell transplant. Methods and Materials We retrospectively selected 20 patients who received TMI treatments before hematopoietic cell transplant. Ten patients (5 men; 5 women) received 12 Gy to the skeletal bones, lymph nodes, and spleen, and the other 10 patients (5 men; 5 women) received an escalated dose of 20 Gy to the same targets and 12 Gy to the brain and liver. A conventional TBI treatment plan was generated for each patient with a prescription dose of 12 Gy, using anterior-posterior and posterior-anterior photon beams with lung shielding and a chest wall boost with electron beams. Secondary cancer risks were estimated using linear-exponential and plateau models for major organs. Results At the 12 Gy dose level, using the linear-exponential model, the total radiation-induced secondary solid-tumor risks for major organs were 159.3 ± 8.7 for men and 221.5 ± 14.4 for women per 10,000 people per year with the TMI plans, which is a reduction of 38.8% and 32.9%, respectively, compared with those with the TBI plans. At the 20 Gy dose level, the risks were 220.3 ± 8.3 for men and 298.5 ± 9.3 for women with the TMI plans, which is a reduction of 14.6% and 9.2%, respectively, compared with those with the 12 Gy TBI plans. Significant risk reductions were also found with the TMI plans using the plateau risk model. Conclusions At both the 12 Gy and 20 Gy prescription dose levels, a conditioning regimen using TMI could significantly lower overall radiation-induced secondary solid-tumor risks for major organs compared with a conditioning regimen with standard 12 Gy TBI. Clinical data from long-term follow-up studies are needed to verify the model predictions.

The radiological incidents and terrorism have demanded the need for the development of rapid, precise, and non-invasive technique for detection and quantification of exposed dose of radiation. Though radiation induced metabolic markers have been thoroughly investigated, but reproducibility still needs to be elucidated. The present study aims at assessing the reliability and reproducibility of markers using nuclear magnetic resonance (NMR) spectroscopy and further deriving a logistic regression model based on these markers. C57BL/6 male mice (8–10 weeks) whole body γ-irradiated and sham irradiated controls were used. Urine samples collected at 24 h post dose were investigated using high resolution NMR spectroscopy and the datasets were analyzed using multivariate analysis. Fifteen distinguishable metabolites and 3 metabolic pathways (TCA cycle, taurine and hypotaurine metabolism, primary bile acid biosynthesis) were found to be amended. ROC curve and logistic regression was used to establish a diagnostic model as Logit (p) = log (p/1 − p) = −0.498 + 13.771 (tau) − 3.412 (citrate) − 34.461 (α-KG) + 515.183 (fumarate) with a sensitivity and specificity of 1.00 and 0.964 respectively. The findings demonstrate the proof of concept and the potential of NMR based metabolomics to establish a prediction model that can be implemented as a promising mass screening tool during triage.