Explore the vast range of titles available.

IntroductionThe usage of a T-cell depleted, reduced intensity conditioning (RIC) approach to haematopoietic cell transplantation (HCT) in adult patients with acute lymphoblastic leukaemia (ALL) over 40 years of age and in first complete remission (CR) has resulted in encouraging rates of event-free and overall survival in a population of adults with high risk disease. However, relapse rates remain high—with disease progression being the major cause of treatment failure. Using different, more powerful conditioning approaches is the logical next step in examining the role of RIC allogeneic HCT in adult ALL.Methods and analysisThe ALL-RIC trial is a two-arm, phase II, multicentre, randomised clinical trial in adult patients with ALL in first or second CR, who are undergoing allogeneic HCT. Comparison of a novel RIC transplant conditioning regimen using reduced-dose total body irradiation (TBI), cyclophosphamide and alemtuzumab, is made against a standardised RIC approach using fludarabine, melphalan and alemtuzumab. The primary outcome of the study is disease-free survival at 3 years, defined as time from randomisation to the first of either relapse or death from any cause. Patients who are still alive and progression-free at the end of the trial will be censored at their last date known to be alive. Secondary outcomes include overall survival and non-relapse mortality.Ethics and disseminationThe protocol was approved by the East Midlands—Leicester Central Research Ethics committee (18/EM/0112). Initial approval was received on 12 June 2018. Current protocol version (V.6.0) approval obtained on 18 November 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) also approved all protocol versions. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications.Trial registration numberEudraCT Number: 2017-004800-23.ISRCTN99927695.

Background This study evaluated the effect of radiation dose rate in patients with hematolymphoid malignancies undergoing myeloablative conditioning with total body irradiation (TBI), for hematopoietic stem cell transplantation. Methods The incidence of pulmonary toxicity (PT) and treatment efficacy were compared between the conventional (≥ 6 cGy/min) and reduced dose rate (< 6 cGy/min). Seventy-seven patients receiving once-daily TBI between 2000 and 2016 were reviewed. We compared the cumulative rate of PT, overall survival (OS), relapse, and transplantation-related mortality (TRM) between conventional ( n  = 54) and reduced ( n  = 23) groups. Factors associated with PT were assessed in the presence of competing risks. Results The median follow-up time was 40.7 months, and PT occurred in 50 patients (64.9%). On multivariate analyses, the groups classified by the dose rate ( P  = 0.010), total dose ( P  = 0.025), and conditioning regimen ( P  = 0.029) were significant factors for the development of PT. OS was significantly reduced when PT occurred ( P  < 0.001). However, the OS, relapse, and TRM were not different between the two groups. Conclusions In summary, about two-thirds of the patients undergoing daily TBI experienced PT, which affected OS. Therefore, reducing the dose rate (less than 6 cGy/min) of TBI can decrease the risk of PT, without compromising the treatment efficacy.

Palifermin, a recombinant human keratinocyte growth factor, is commonly given to prevent mucositis following autologous transplantation. In the allogeneic hematopoietic stem cell transplant (allo-HSCT) setting, safety and efficacy data are limited. We conducted a retrospective study in 251 patients undergoing allo-HSCT, 154 of whom received peritransplant palifermin. In all patients, palifermin significantly decreased the mean number of days of total parenteral nutrition (TPN, 13 vs 16 days, P =0.006) and patient-controlled analgesia (PCA, 6 vs 10 days, P =0.023), as well as the length of initial hospital stay (LOS, 32 vs 37 days, P =0.014). However, the effect of palifermin was only significant in patients who received a TBI- but not BU-based chemotherapy conditioning regimen. In TBI recipients, palifermin decreased the mean number of days of TPN (13 vs 17 days, P <0.001) and PCA (7 vs 12 days, P =0.033), and the length of stay (32 vs 38 days, P =0.001). Palifermin did not affect GVHD, graft failure or relapse. Therefore, in the largest analysis with this patient population to date, we demonstrate that palifermin is safe in allo-HSCT patients, decreases TPN and PCA use and decreases LOS following TBI-based but not chemotherapy-based allo-HSCT.

Ina, Y., Tanooka, H., Yamada, T. and Sakai, K. Suppression of Thymic Lymphoma Induction by Life-Long Low-Dose-Rate Irradiation Accompanied by Immune Activation in C57BL/6 Mice. Radiat. Res. 163, 153–158 (2005). The induction of thymic lymphomas by whole-body X irradiation with four doses of 1.8 Gy (total dose: 7.2 Gy) in C57BL/6 mice was suppressed from a high frequency (90%) to 63% by preirradiation with 0.075 Gy X rays given 6 h before each 1.8-Gy irradiation. This level was further suppressed to 43% by continuous whole-body irradiation with 137Cs γ rays at a low dose rate of 1.2 mGy/h for 450 days, starting 35 days before the challenging irradiation. Continuous irradiation at 1.2 mGy/h resulting in a total dose of 7.2 Gy over 258 days yielded no thymic lymphomas, indicating that this low-dose-rate radiation does not induce these tumors. Further continuous irradiation up to 450 days (total dose: 12.6 Gy) produced no tumors. Continuously irradiated mice showed no loss of hair and a greater body weight than unirradiated controls. Immune activities of the mice, as measured by the numbers of CD4+ T cells, CD40+ B cells, and antibody-producing cells in the spleen after immunization with sheep red blood cells, were significantly increased by continuous 1.2-mGy/h irradiation alone. These results indicate the presence of an adaptive response in tumor induction, the involvement of radiation-induced immune activation in tumor suppression, and a large dose and dose-rate effectiveness factor (DDREF) for tumor induction with extremely low-dose-rate radiation.

To prevent ovarian dysfunction due to total body irradiation, we started ovarian shielding at our center (Saitama Medical Center, Jichi Medical University (SMC-JMU)) with a long source axis distance, which is different from the original method used at the University of Tokyo Hospital (UTH). We retrospectively analyzed the outcome of eight patients with a median age of 20.5 years from SMC-JMU and compared the results with the published data for eight patients with a median age of 22 years from UTH. The recovery of ovarian function was observed in five and six patients, respectively. The cumulative incidence of ovarian recovery, while treating relapse and death without ovarian recovery as competing risks, was 68.8 % at 2 years after transplantation in the total population, and there was no statistically significant difference between the two institutions ( p  = 0.85). Age and the history of previous chemotherapy did not affect the incidence of ovarian recovery. Two patients from each center had a relapse of leukemia. Overall, among the 11 patients who have survived without relapse, only one has not achieved ovarian recovery. In conclusion, ovarian shielding with both methods strongly protected ovarian function. However, we should continue to monitor the relapse rate among patients who undergo this procedure.

Purpose The ultra-high dose rate (UHDR) radiation shows promise in eradicating tumors while reducing normal tissue toxicities. However, the biological outcomes of UHDR are influenced by various factors, particularly the mean dose rate and instantaneous dose rate. Additionally, the UHDR response at large field sizes is lacking. This study aimed to explore the impact of different dose rate combinations on gastrointestinal biological outcomes following total-body irradiations (TBI) and to examine the involved molecular signaling pathways. Method Female C57BL6/J mice received 10 Gy TBI using three modes: ultra-high mean and ultra-high instantaneous dose rate irradiation (HH mode), low mean and ultra-high instantaneous dose rate irradiation (LH mode), and low mean and low instantaneous dose rate irradiation (LL mode). Mice were euthanized at 3 h and 48 h post irradiation to assess acute normal tissue damage and perform transcriptome sequencing. Furthermore, a subset of mice was monitored for 30 days to evaluate survival. Results We found that when the instantaneous dose rate is sufficiently high (> 10 5 Gy/s), both ultra-high or low mean dose rate irradiation reduced mice mortality, myelosuppression, DNA damage, and cell apoptosis. The survival probabilities 30 days after 10 Gy TBI were 4/7, 4/6, and 0/6 in the HH, LH, and LL groups, respectively. Myelosuppression was lower at 3 h and 48 h post HH and LH irradiations than LL irradiation. The better regulated inflammatory response was evident at 48 h post HH and LH irradiation compared to LL irradiation. Additionally, DNA damages and cell apoptosis in the intestinal tissue were significantly reduced after HH and LH irradiations compared to LL irradiation. Transcriptome sequencing of intestinal tissues revealed that HH irradiation activated immune response pathways and suppressed mitochondrial related pathways compared to LL irradiation. Conclusion Our findings underscore the pivotal role of instantaneous dose rate in reducing radiation damages. When the instantaneous dose rate is sufficiently high (> 10 5 Gy/s), both ultra-high or low mean dose rate irradiation (HH and LH mode) reduced mice mortality, myelosuppression, DNA damage, and cell apoptosis. Understanding these dose rate effects and biological responses are crucial for optimizing radiotherapy strategies and exploring the potential benefits of UHDR irradiation.

Many studies have demonstrated hydrogen’s therapeutic and preventive effects on various diseases. Its selective antioxidant properties against hydroxyl radicals, which are responsible for the indirect effects of ionizing radiation, may make it worthy of attention as a new radio-protector. We recently developed new hydrogen water that is more stable and has higher antioxidant activity by using ultra-fine bubbles. In this study, female C57BL/6J mice given ad libitum access to ultra-fine bubble hydrogen water (UBHW) were subjected to whole-body irradiation (WBI) with X-rays, and the radio-protective effect of UBHW was evaluated. WBI with 6.0 Gy (sub-lethal dose) resulted in a 30-day survival rate of 100% in UBHW-fed mice, compared with 37% in control mice. In the case of WBI with 6.5 Gy (lethal dose), while the control mice died out in about 3 weeks, the 30-day survival rate improved to 40% by UBHW due to the high scavenging activity of hydroxy radicals. Twenty-six serum proteins involved in inflammatory and immune responses were significantly identified in UBHW-fed mice by proteomics, and UBHW may enhance and regulate these functions, resulting in reduced damage in mice exposed to WBI. We conclude that UBHW has good potential in radio-protection, with evidence that warrants further research efforts in this field.

Narrow band ultraviolet B (NB UVB) radiation doses are administered during phototherapy for various dermatological ailments. Precise quantification of these doses is vital because the absorbed irradiation can cause adverse photochemical reactions which can lead to potential phototherapeutic side effects. The paper presents development of diacetylene based dosimeter for the determination of therapeutic NB UVB doses during phototherapy. The amide terminated diacetylene analogues have been synthesized by tailoring them with different functional groups. The synthesized diacetylene monomers have been introduced in a polyvinyl alcohol binder solution to obtain a film dosimeter. The influence of different headgroups on the colorimetric response to UV radiation has been studied. Among all the synthesized diacetylene analogues, the naphthylamine substituted diacetylene exhibited excellent color transition from white to blue color at 100 mJ cm −2 NB UVB radiation dose. The developed amide films can be easily pasted on multiple sites of the patient’s skin to monitor doses during phototherapy simultaneously at different anatomical regions. The digital image processing of the scanned images of the irradiated films facilitates rapid dose measurement which enables facile implementation of the developed film dosimeters and promising application in routine clinical dosimetry.

Should whole brain radiation therapy (WBRT) be used as the sole therapy in patients with newly-diagnosed, surgically accessible, single brain metastases, compared with WBRT plus surgical resection, and in what clinical settings? Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection; however, the recommendation does not apply to relatively radiosensitive tumors histologies (i.e., small cell lung cancer, leukemia, lymphoma, germ cell tumors and multiple myeloma). Recommendation Surgical resection plus WBRT versus WBRT alone Level 1 Class I evidence supports the use of surgical resection plus post-operative WBRT, as compared to WBRT alone, in patients with good performance status (functionally independent and spending less than 50% of time in bed) and limited extra-cranial disease. There is insufficient evidence to make a recommendation for patients with poor performance scores, advanced systemic disease, or multiple brain metastases. If WBRT is used, is there an optimal dosing/fractionation schedule? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Level 1 Class I evidence suggests that altered dose/fractionation schedules of WBRT do not result in significant differences in median survival, local control or neurocognitive outcomes when compared with “standard” WBRT dose/fractionation. (i.e., 30 Gy in 10 fractions or a biologically effective dose (BED) of 39 Gy10). If WBRT is used, what impact does tumor histopathology have on treatment outcomes? Target population This recommendation applies to adults with newly diagnosed brain metastases. Recommendation Given the extremely limited data available, there is insufficient evidence to support the choice of any particular dose/fractionation regimen based on histopathology. The following question is fully addressed in the surgery guideline paper within this series by Kalkanis et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of WBRT in the management of brain metastases, this recommendation has been included below. Does the addition of WBRT after surgical resection improve outcomes when compared with surgical resection alone? Target population This recommendation applies to adults with newly diagnosed single brain metastases amenable to surgical resection. Recommendation Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone.

Clonal hematopoiesis (CH) is prevalent in the elderly and associates with hematologic malignancy and cardiovascular disease. Although the risk of developing these diseases increases with radiation doses in atomic-bomb survivors, the causal relationship between radiation exposure and CH is unclear. This study investigated whether radiation exposure induces CH in mice 12–18 months after 3-Gy whole-body irradiation. We found radiation-associated increases in peripheral blood myeloid cells and red blood cell distribution width (RDW). Deep sequencing of bone marrow and non-hematopoietic tissue cells revealed recurrent somatic mutations specifically in the hematopoietic system in 11 of 12 irradiated mice but none in 6 non-irradiated mice. The irradiated mice possessed mutations with variant allele frequencies (VAFs) of > 0.02 on an average of 5.8 per mouse; mutations with VAFs of > 0.1 and/or deletion were prevalent. Examining hematopoietic stem/progenitor cells in two irradiated mice revealed several mutations co-existing in the same clones and multiple independent clones that deliver 60–80% of bone marrow nuclear cells. Our results indicate development of massive CH due to radiation exposure. Moreover, we have characterized mutations in radiation-induced CH.