CLAG combined with total body irradiation as intensive conditioning chemotherapy prior to allogeneic hematopoietic stem cell transplantation in patients with refractory or relapsed acute myeloid leukemia.

Refractory or relapsed acute myeloid leukemia (R/R AML) remains the major challenge of AML treatment. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only valid option to achieve cure, but the prognosis is still dismal. We conducted a retrospective analysis for the feasibility of CLAG regimens (cladribine, cytarabine, and granulocyte colony-stimulating factor) combined with total body irradiation (TBI) as new intensive conditioning chemotherapy prior to HSCT in R/R AML. A total of 70 patients, including 21 primary refractory and 49 relapsed AML, were analyzed. Forty-nine (70%) patients had extramedullary diseases, and 54 (77%) patients received haploidentical transplantation. Except for one who died before white blood cell engraftment, all of the 69 evaluable patients achieved measurable residual disease (MRD) negative complete remission. The 3-year overall survival (OS) and relapse-free survival (RFS) rates were 46.0% (95% confidence interval [CI], 33.5-57.7%) and 38.5% (95%CI, 26.8-50.0%). The 1-year cumulative incidences of relapse and non-relapse mortality (NRM) were 38.6% (95%CI, 27.3-49.3%) and 11.6% (95%CI: 5.4-20.3%), respectively. The presence of chronic graft-versus-host disease (cGVHD) showed a trend to be associated with a lower risk of relapse (P = 0.054) and extramedullary diseases with a higher risk of NRM (P = 0.074). Multivariate analyses identified low leukemia burden pre-HSCT (defined as bone marrow blasts ≤ 50%) and cGVHD as independent factors associated with favorable OS and RFS. In conclusion, intensive conditioning with CLAG regimens plus TBI may be an effective and well-tolerated choice for R/R AML patients undergoing allo-HSCT.

Late effects following HSCT for childhood ALL: A national single-center study using three different modalities of delivery of total body irradiation.

BACKGROUND: Total body irradiation (TBI) is a pivotal part of conditioning prior to hematopoietic stem cell transplantation (HSCT) for childhood acute lymphoblastic leukemia (ALL), yet evidence is sparse regarding the effect of TBI delivery techniques on acute and late toxicities. DESIGN: In a national cohort of pediatric HSCT-recipients, we compared three TBI schedules; 12 Gray (Gy) delivered as (i) 4 Gy daily fractions from 2008 to 2011 (n = 12); (ii) 2 Gy fractions twice daily with two-dimensional (2D) planning technology from 2012 to 2015 (n = 16); and (iii) 2 Gy twice daily with three-dimensional (3D) planning intensity-modulated radiotherapy (IMRT) from 2016 to 2020 (n = 14). RESULTS: The 5-year event-free survival was 75.0%, 81.3%, and 81.3% in Cohorts 1, 2, and 3, respectively. Acute toxicity assessed as maximum ferritin and C-reactive protein during the first 3 months post HSCT did not differ between cohorts, nor did the time to first hospital discharge (median 28, 32, and 31 days, p = .25). The incidences of acute graft-versus-host disease (GvHD) (66%, 56%, 71%) and chronic GvHD (25%, 31%, 14%) were comparable. Pulmonary function assessed by spirometry did not differ significantly. The 5-year cataract-free survival was 33.3%, 79%, and 100% in Cohorts 1, 2, and 3, respectively. We found a nonsignificant tendency toward more endocrinopathies in Cohort 1 compared to Cohorts 2 and 3. CONCLUSION: The change of modality did not result in more relapses. More fractionation led to improvement with a lower incidence of cataract and a tendency toward fewer endocrinopathies. The effect of 3D-planning-IMRT technology requires further evaluation in larger studies.

Dose to organs at risk for total body irradiation: Single-institution data using the modulated arc total body irradiation technique.

BACKGROUND: Organs at risk (OAR) dose reporting for total body irradiation (TBI) patients is limited, and standardly reported only as mean doses to the lungs and kidneys. Consequently, dose received and effects on other OAR remain unexplored. To remedy this gap, this study reports dose data on an extensive list of OAR for patients treated at a single institution using the modulated arc total body irradiation (MATBI) technique. METHOD: An audit was undertaken of all patients treated with MATBI between January 2015 and March 2021 who had completed their course of treatment. OAR were contoured on MATBI patient treatment plans, with 12 Gy in six fraction prescription. OAR dose statistics and dose volume histogram data are reported for the whole body, lungs, kidneys, bones, brain, lens, heart, liver and bowel bag. RESULTS: The OAR dose data for 29 patients are reported. Mean dose results are body 11.77 Gy, lungs 9.86 Gy, kidneys 11.84 Gy, bones 12.03 Gy, brain 12.12 Gy, right lens 12.31 Gy, left lens 12.64 Gy, heart 11.07 Gy, liver 11.81 Gy and bowel bag 12.06 Gy. Dose statistics at 1-Gy intervals of V6-V13 for lungs and V10-V13 for kidneys are also included. CONCLUSION: This is the first time an extensive list of OAR data has been reported for any TBI technique. Due to the paucity of reporting, this information could be used by centres implementing the MATBI technique, in addition to aiding comparison between TBI techniques, with the potential for greater understanding of the relationship between dose volume data and toxicity.

Postmortem pathologic findings in dogs that underwent total body irradiation and hematopoietic cell transplant: A case series of five dogs with B-cell multicentric lymphoma.

Alternative therapies that can help achieve complete remission in dogs with lymphoma include total body irradiation and hematopoietic cell transplant, though there are few reports describing successes and pathologic sequelae of these procedures. During a 10-year period, 94 dogs with multicentric lymphoma received a hematopoietic cell transplant following total body irradiation at North Carolina State University College of Veterinary Medicine. Seven of these 94 dogs (7%) died prior to discharge, five (5%) of which presented for postmortem examination. Of these dogs, four received an autologous hematopoietic cell transplant, while one received a haploidentical allogeneic hematopoietic cell transplant. All five dogs had bone marrow depletion with all hematopoietic lines affected. Three had systemic candidiasis, while two had bacterial infections. To the authors' knowledge, this is the first report to document pathologic findings and development of systemic mycoses in dogs post total-body irradiation therapy and hematopoietic cell transplant.

Total body irradiation delivered using a dedicated Co-60 TBI unit: Evaluation of dosimetric uniformity and dose verification.

This work presents the dosimetric characteristics of Total Body Irradiation (TBI) delivered using a dedicated Co-60 TBI unit. We demonstrate the ability to deliver a uniform dose to the entire patient without the need for a beam spoiler or patient-specific compensation. Full dose distributions are calculated using an in-house Monte Carlo treatment planning system, and cumulative dose distributions are created by deforming the dose distributions within two different patient orientations. Sample dose distributions and profiles are provided to illustrate the plan characteristics, and dose and DVH statistics are provided for a heterogeneous cohort of patients. The patient cohort includes adult and pediatric patients with a range of 132-198 cm in length and 16.5-37.5 cm in anterior-posterior thickness. With the exception of the lungs, a uniform dose of 12 Gy is delivered to the patient with nearly the entire volume receiving a dose within 10% of the prescription dose. Mean lung doses (MLDs) are maintained below the estimated threshold for radiation pneumonitis, with MLDs ranging from 7.3 to 9.3 Gy (estimated equivalent dose in 2 Gy fractions (EQD2 ) of 6.2-8.5 Gy). Dose uniformity is demonstrated across five anatomical locations within the patient for which mean doses are all within 3.1% of the prescription dose. In-vivo dosimetry demonstrates excellent agreement between measured and calculated doses, with 78% of measurements within ±5% of the calculated dose and 99% within ±10%. These results demonstrate a state-of-the-art TBI planning and delivery system using a dedicated TBI unit and hybrid in-house and commercial planning techniques which provide comprehensive dosimetric data for TBI treatment plans that are accurately verified using in-vivo dosimetry.

Total body irradiation: A transition from a Co-60 treatment unit to an IMRT lateral-field extended-SAD technique.

PURPOSE: The purpose of this work was to detail our center's experience in transitioning from a Co-60 treatment technique to an intensity modulated radiation therapy (IMRT) based lateral-field extended source-to-axis distance (e-SAD) technique for total body irradiation (TBI). MATERIALS AND METHODS: An existing beam model in RayStation v.10A was validated for the use of e-SAD TBI treatments. Data were acquired with an Elekta Synergy linear accelerator (LINAC) at an extended source-to-surface distance of 365 cm with an 18 MV beam. Beam model validation measurements included percentage depth dose (PDD), profile data, surface dose, build-up region and transmission measurements. End-to-end testing was carried out using an anthropomorphic phantom. Treatments were performed in a supine position in a whole-body Vac-Lok at an e-SAD of 400 cm with a beam spoiler 10 cm from the couch. Planning was achieved using IMRT, where multi-leaf collimators were used to modulate the beam and shield the organs at risk. Beam's eye view projection images were used for in-room patient positioning and in-vivo dosimetry was performed for every treatment. RESULTS: The percent difference between the measured and calculated PDD and profiles was less than 2% at all locations. Surface dose was 83.8% of the maximum dose with the beam spoiler at a 10 cm distance from the phantom. The largest percent difference between the treatment planning system (TPS) and measured data within the anthropomorphic phantom was approximately 2%. In-vivo dosimetry measurements yielded results within the 5% institutional threshold. CONCLUSION: In 2022, 17 patients were successfully treated using the new IMRT-based lateral-field e-SAD TBI technique. The resulting clinical plans respected the institutional standard. The commissioning process, as well as the treatment planning and delivery aspects were described in this work with the intention of supporting other clinics in implementing this treatment method.

A novel AP/PA total body irradiation technique using abutting IMRT fields at extended SSD.

PURPOSE: To develop a Total Body Irradiation (TBI) technique using IMRT at extended SSD that can be performed in any size Linac room. METHODS: Patients studied were placed on a platform close to the floor, directly under the gantry with cranial-caudal axis parallel to the gantry rotation plane and at SSD ∼200 cm. Two abutting fields with the same external isocenter at gantry angles of ±21˚, collimator angle of 90˚, and field size of 25 × 40 cm2 are employed for both supine and prone positions. An iterative optimization algorithm was developed to generate a uniform dose at the patient mid-plane with adequate shielding to critical organs such as lungs and kidneys. The technique was validated in both phantom and patient CT images for treatment planning, and dose measurement and QA were performed in phantom. RESULTS: A uniform dose distribution in the mid-plane within ±5% of the prescription dose was reached after a few iterations. This was confirmed with ion-chamber measurements in phantom. The mean dose to lungs and kidneys can be adjusted according to clinical requirements and can be as low as ∼25% of the prescription dose. For a typical prescription dose of 200 cGy/fraction, the total MU was ∼2400/1200 for the superior/inferior field. The overall treatment time for both supine/prone positions was ∼54 min to meet the maximum absorbed dose rate criteria of 15 cGy/min. IMRT QA with portal dosimetry shows excellent agreement. CONCLUSIONS: We have developed a promising TBI technique using abutting IMRT fields at extended SSD. The patient is in a comfortable recumbent position with good reproducibility and less motion during treatment. An additional benefit of this technique is that full 3D dose distribution is available from the TPS with a DVH summary for organs of interest. The technique allows precise sparing of lungs and kidneys and can be executed in any linac room.

Analysis of the Proteomic Profile in Serum of Irradiated Nonhuman Primates Treated with Ex-Rad, a Radiation Medical Countermeasure.

There are currently four radiation medical countermeasures that have been approved by the United States Food and Drug Administration to mitigate hematopoietic acute radiation syndrome, all of which are repurposed radiomitigators. The evaluation of additional candidate drugs that may also be helpful for use during a radiological/nuclear emergency is ongoing. A chlorobenzyl sulfone derivative (organosulfur compound) known as Ex-Rad, or ON01210, is one such candidate medical countermeasure, being a novel, small-molecule kinase inhibitor that has demonstrated efficacy in the murine model. In this study, nonhuman primates exposed to ionizing radiation were subsequently administered Ex-Rad as two treatment schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation) and the proteomic profiles of serum using a global molecular profiling approach were assessed. We observed that administration of Ex-Rad post-irradiation is capable of mitigating radiation-induced perturbations in protein abundance, particularly in restoring protein homeostasis, immune response, and mitigating hematopoietic damage, at least in part after acute exposure. Taken together, restoration of functionally significant pathway perturbations may serve to protect damage to vital organs and provide long-term survival benefits to the afflicted population.

Transcriptome profile changes in the jejunum of nonhuman primates exposed to supralethal dose of total- or partial-body radiation.

The risk of exposure of the general public or military personnel to high levels of ionizing radiation from nuclear weapons or radiological accidents is a dire national security matter. The development of advanced molecular biodosimetry methods, those that measure biological response, such as transcriptomics, to screen large populations of radiation-exposed victims is key to improving survival outcomes during radiological mass casualty scenarios. In this study, nonhuman primates were exposed to either 12.0 Gy cobalt-60 gamma (total-body irradiation, TBI) or X-ray (partial-body irradiation, PBI) 24 h after administration of a potential radiation medical countermeasure, gamma-tocotrienol (GT3). Changes in the jejunal transcriptomic profiles in GT3-treated and irradiated animals were compared to healthy controls to assess the extent of radiation damage. No major effect of GT3 on radiation-induced transcriptome at this radiation dose was identified. About 80% of the pathways with a known activation or repression state were commonly observed between both exposures. Several common pathways activated due to irradiation include FAK signaling, CREB signaling in the neurons, phagosome formation, and G-protein coupled signaling pathway. Sex-specific differences associated with excessive mortality among irradiated females were identified in this study, including Estrogen receptor signaling. Differential pathway activation was also identified across PBI and TBI, pointing towards altered molecular response for different degrees of bone marrow sparing and radiation doses. This study provides insight into radiation-induced changes in jejunal transcriptional profiles, supporting the investigation for the identification of biomarkers for radiation injury and countermeasure efficacy.

Phase I trial of myeloablative conditioning with 3-day total marrow and lymphoid irradiation for leukemia.

This prospective phase I trial aimed to determine the recommended dose of 3-day total marrow and lymphoid irradiation (TMLI) for a myeloablative conditioning regimen by increasing the dose per fraction. The primary end-point of this single-institution dose escalation study was the recommended TMLI dose based on the frequency of dose-limiting toxicity (DLT) ≤100 days posthematopoietic stem cell transplantation (HSCT); a 3 + 3 design was used to evaluate the safety of TMLI. Three dose levels of TMLI (14/16/18 Gy in six fractions over 3 days) were set. The treatment protocol began at 14 Gy. Dose-limiting toxicities were defined as grade 3 or 4 nonhematological toxicities. Nine patients, with a median age of 42 years (range, 35-48), eight with acute lymphoblastic leukemia and one with chronic myeloblastic leukemia, received TMLI followed by unrelated bone marrow transplant. The median follow-up period after HSCT was 575 days (range, 253-1037). Three patients were enrolled for each dose level. No patient showed DLT within 100 days of HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. All patients achieved neutrophil engraftment at a median of 19 days (range, 14-25). One-year overall and disease-free survival rates were 83.3% and 57.1%, respectively. Three patients experienced relapse, and no nonrelapse mortality was documented during the observation period. One patient died due to disease relapse 306 days post-HSCT. The recommended dose of 3-day TMLI was 18 Gy in six fractions. The efficacy evaluation of this regimen is currently being planned in a phase II study.

Assessment of Micronuclei Frequency in the Peripheral Blood of Adult and Pediatric Patients Receiving Fractionated Total Body Irradiation.

The cytokinesis-block micronucleus (CBMN) assay is an established method for assessing chromosome damage in human peripheral blood lymphocytes resulting from exposure to genotoxic agents such as ionizing radiation. The objective of this study was to measure cytogenetic DNA damage and hematology parameters in vivo based on MN frequency in peripheral blood lymphocytes (PBLs) from adult and pediatric leukemia patients undergoing hematopoietic stem cell transplantation preceded by total body irradiation (TBI) as part of the conditioning regimen. CBMN assay cultures were prepared from fresh blood samples collected before and at 4 and 24 h after the start of TBI, corresponding to doses of 1.25 Gy and 3.75 Gy, respectively. For both age groups, there was a significant increase in MN yields with increasing dose (p < 0.05) and dose-dependent decrease in the nuclear division index (NDI; p < 0.0001). In the pre-radiotherapy samples, there was a significantly higher NDI measured in the pediatric cohort compared to the adult due to an increase in the percentage of tri- and quadri-nucleated cells scored. Complete blood counts with differential recorded before and after TBI at the 24-h time point showed a rapid increase in neutrophil (p = 0.0001) and decrease in lymphocyte (p = 0.0006) counts, resulting in a highly elevated neutrophil-to-lymphocyte ratio (NLR) of 14.45 ± 1.85 after 3.75 Gy TBI (pre-exposure = 4.62 ± 0.49), indicating a strong systemic inflammatory response. Correlation of the hematological cell subset counts with cytogenetic damage, indicated that only the lymphocyte subset survival fraction (after TBI compared with before TBI) showed a negative correlation with increasing MN frequency from 0 to 1.25 Gy (r = -0.931; p = 0.007). Further, the data presented here indicate that the combination of CBMN assay endpoints (MN frequency and NDI values) and hematology parameters could be used to assess cytogenetic damage and early hematopoietic injury in the peripheral blood of leukemia patients, 24 h after TBI exposure.

Sex as a Factor in Murine Radiation Research: Implications for Countermeasure Development.

There is an increased threat of exposure to ionizing radiation; in the event of such exposure, the availability of medical countermeasures will be vital to ensure the protection of the population. Effective countermeasures should be efficacious across a varied population and most importantly amongst both males and females. Radiation research must be conducted in animal models which act as a surrogate for the human response. Here, we identify differences in survival in male and female C57BL/6 in both a total body irradiation (TBI) model using the Armed Forces Radiobiology Research Institute (AFRRI) 60Co source and a partial body irradiation (PBI) model using the AFRRI Linear Accelerator (LINAC) with 4 MV photons and 2.5% bone marrow shielding. In both models, we observed a higher degree of radioresistance in female animals and a corresponding radiosensitivity in males. One striking difference in male and female rodents is body size/weight and we investigated the role of pre-irradiation body weight on survivability for animals irradiated at the same dose of irradiation (8 Gy TBI, 14 Gy PBI). We found that weight does not influence survival in the TBI model and that heavier males but lighter females have increased survival in the PBI model. This incongruence in survival amongst the sexes should be taken into consideration in the course of developing radiation countermeasures for response to a mass casualty incident.

Effect of lethal total body irradiation on bone marrow chimerism, acute graft-versus-host disease, and tumor engraftment in mouse models: impact of different radiation techniques using low- and high-energy X-rays.

PURPOSE: Effects of X­ray energy levels used for myeloablative lethal total body irradiation (TBI) delivery prior to bone marrow transplantation (BMT) in preclinical mouse models were examined. MATERIALS AND METHODS: In mouse models, single-fraction myeloablative TBI at a lethal dose was delivered using two different X­ray devices, either low (160 kV cabinet irradiator) or high energy (6 MV linear accelerator), before semi-allogeneic hematopoietic stem-cell transplantation (HSCT) to ensure bone marrow (BM) chimerism, graft-versus-host disease (GVHD), and tumor engraftment. Recipient mice were clinically followed for 80 days after bone marrow transplantation (BMT). Flow cytometry was performed to assess donor chimerism and tumor engraftment in recipient mice. RESULTS: Both X­ray irradiation techniques delivered a 10 Gy single fraction of TBI, presented a lethal effect, and could allow near-complete early donor chimerism on day 13. However, low-energy irradiation increased T cells' alloreactivity compared to high-energy irradiation, leading to clinical consequences for GVHD and tumor engraftment outcomes. The alloreactive effect differences might be attributed to the distinction in inflammatory status of irradiated recipients at donor cell infusion (D0). Delaying donor cell administration (D1 after lethal TBI) attenuated T cells' alloreactivity and clinical outcomes in GVHD mouse models. CONCLUSION: Different X­ray irradiation modalities condition T cell alloreactivity in experimental semi-allogeneic BMT. Low-energy X­ray irradiator induces a post-TBI inflammatory burst and exacerbates alloreactive reactions. This technical and biological information should be considered in interpreting GVHD/ graft-versus-leukemia effect results in mice experimental models of BMT.

Analysis of long-term mortality after total body irradiation-based and melphalan-based chemotherapy conditioning for acute myeloid leukemia.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment option for selected patients with acute myeloid leukemia. Yet, the influence of total body irradiation (TBI)-based conditioning as compared to non-TBI-based conditioning on long-term mortality is unclear. We retrospectively evaluated outcomes after TBI-based (n = 91) and non-TBI-based conditioning (melphalan-based, n = 248) for 1st allo-HSCT patients transplanted at the University Hospital Regensburg between 1999 and 2020. TBI was performed with an average dose rate of 4 cGy/min. Median follow-up was 8.3 years (interquartile range, 4.8-12.9 years). Cumulative incidence rates of 5-year non-relapse mortality (NRM) were 17% (95% confidence interval, CI, 10-25) and 33% (95% CI, 27-40) after TBI- and non-TBI-based conditioning (P < 0.001). Five-year cumulative incidences of relapse (CIR) were 42% (95% CI, 32-52) and 29% (95% CI, 23-35) after TBI- and non-TBI-based conditioning (P = 0.030). The 5-year OS was 54% (95% CI, 43-64) and 55% (95% CI, 48-62) after TBI- and non-TBI-based conditioning. Both groups had similar 100-day acute graft-versus-host disease (aGVHD, 43% vs. 40%) and 5-year chronic GVHD (34% vs. 36%). The multivariable regression models found no associations of TBI with the outcomes NRM, CIR, PFS, OS, aGVHD, and cGVHD. TBI was no risk factor for NRM, even including mortality caused by secondary malignancies. NRM was influenced by patient age, advanced disease status, and the use of female donors for male recipients. TBI- and non-TBI-based conditioning appear to be equally effective and tolerable for AML patients eligible for 1st allo-HSCT.

Sequence matters: Total body irradiation (TBI)-based myeloablative conditioning with post-transplant cyclophosphamide may reduce the early nonrelapse mortality compared with pretransplant cyclophosphamide plus TBI.

OBJECTIVES: High-dose total body irradiation (TBI) is considered a cornerstone of myeloablative conditioning for allogeneic stem cell transplantation (allo-SCT). We retrospectively compared the main outcomes of an HLA matched or 1-allele mismatched related or unrelated allo-SCT in adult patients affected by acute leukemia (AL) or myelodysplastic syndromes (MDS). METHODS: Fifty-nine patients received cyclophosphamide (Cy)-TBI (13.5 Gy) and graft-versus-host disease (GVHD) prophylaxis with a calcineurin-inhibitor plus methrotrexate (CyTBI group) and 28 patients received fludarabine-TBI (8.8-13.5 Gy) and GVHD prophylaxis with PTCy and tacrolimus (FluTBI-PTCy group). RESULTS: Median follow-up for survivors was 82 and 22 months. The 12-month probability of overall survival and progression-free survival were similar (p = .18, p = .7). The incidence of Grades 2-4 and 3-4 acute GVHD, and the incidence of moderate-to-severe chronic GVHD were higher in the CyTBI group (p = .02, p < .01and p = .03). Nonrelapse mortality (NRM) at 12 months posttransplant was higher in the CyTBI group (p = 0.05), while the incidence of relapse was similar in both groups (p = 0.7). The number of GVHD-free and relapse-free patients without systemic immunosuppression (GRFS) at 1-year posttransplant was higher in the FluTBI-PTCy group (p = 0.01). CONCLUSIONS: The study confirms the safety and efficacy of a novel FluTBI-PTCy platform with reduced incidence of severe acute and chronic GVHD, and early improvement of NRM.

Improved organ sparing using auto-planned Stanford volumetric modulated arc therapy for total body irradiation technique.

PURPOSE/OBJECTIVES: To evaluate dosimetric differences between auto-planned volumetric modulated arc therapy (VMAT) total body irradiation (TBI) technique and two-dimensional radiotherapy using anterior-posterial/posterio-anterial beams (2D AP/PA) TBI technique. METHODS: Ten pediatric patients treated with VMAT-TBI on Varian c-arm linac were included in this study. VMAT-TBI plans were generated using our in-house developed and publicly shared auto-planning scripts. For each VMAT-TBI plan, a 2D AP/PA plan was created replicating the institution's clinical setup with the patient positioned at extended source to skin distance (SSD) with a compensator to account for differences in patient thickness, 50% transmission daily lung blocks, and electron chest wall boosts prescribed to 50% of the photon prescription. Clinically relevant metrics were analyzed and compared between the VMAT and 2D plans. RESULTS: All VMAT-TBI plans achieved planned target volume (PTV) D90% ≥ 100% of prescription. VMAT-TBI PTV D90% significantly increased (7.1% ± 2.9%, p < .001) compared to the 2D technique, whereas no differences were observed in global Dmax (p < .2) and PTV V110% (p < .4). Compared to the 2D plans, significant decreases in the Dmean to the lungs (-25.6% ± 11.5%, p < .001) and lungs-1 cm (-34.1% ± 10.1%, p < .001) were observed with the VMAT plans. The VMAT technique also enabled decrease of dose to other organs: kidneys Dmean (-32.5% ± 5.0%, p < .001) and lenses Dmax (-5.3% ± 8.1%, p = .03); and in addition, for 2 Gy prescription: testes/ovaries Dmean (-41.5% ± 11.5%, p < .001), brain Dmean (-22.6% ± 5.4%, p = .002), and thyroid Dmean (-18.2% ± 16.0%, p = .03). CONCLUSIONS: Superior lung sparing with improved target coverage and similar global Dmax were observed with the VMAT plans as compared to 2D plans. In addition, VMAT-TBI plans provided greater dose reductions in gonads, kidneys, brain, thyroid, and lenses.

Planning and dosimetric evaluation of three total body irradiation techniques: Standard SSD VMAT, Extended SSD VMAT and Extended SSD Field-in-Field.

The aim of this study was to dosimetrically compare three total body irradiation (TBI) techniques which can be delivered by a standard linear accelerator, and to deduce which one is preferable. Specifically, Extended Source to Surface Distance (SSD) Field-in-Field (FiF), Extended SSD Volumetric Modulated Arc Therapy (VMAT), and Standard SSD VMAT TBI techniques were dosimetrically evaluated. Percent depth dose and dose profile measurements were made under treatment conditions for each specified technique. After having generated treatment plans with a treatment planning system (TPS), dose homogeneity and critical organ doses were investigated on a Rando phantom using radiochromic films and optically stimulated luminescence dosimeters (OSLDs). TBI dose of 12 Gy in six fractions was prescribed for each technique. The gamma index (5%/5 mm) was used for the analysis of radiochromic films. Passing rates for Extended SSD FiF, Extended SSD VMAT and Standard SSD VMAT techniques were found to be 90%, 87% and 94%, respectively. OSLD measurements were within ± 5% agreement with TPS calculations for the first two techniques whereas the agreement was found to be within ± 3% for the Standard SSD VMAT technique. TPS calculations demonstrated that mean lung doses in the first two techniques were around 8.5 Gy while it was kept around 7 Gy in Standard SSD VMAT. It is concluded that Standard SSD VMAT is superior in sparing the lung tissue while all three TBI techniques are feasible in clinical practice with acceptable dose homogeneity. In the absence of VMAT-based treatment planning, Extended SSD FiF would be a reasonable choice compared to other conventional techniques.

Unique approaches for testicular shielding during total-body irradiation for pediatric patients.

Total-body irradiation (TBI) has been used as a part of the conditioning regimen for patients undergoing hematopoietic stem cell transplantation for certain nonmalignant conditions such as sickle cell disease. Although effective, TBI can cause lasting side effects for pediatric patients. One of these potential side effects includes oligospermia or even permanent azoospermia. Although many investigators have studied ways to shield the testicles during the TBI for nonmalignant conditions, there is no set standard. We describe the technical aspects of effective techniques to shield the testicles of male pediatric patients undergoing TBI. We verified that our techniques reduced the testicular dose by approximately 80%-85% of the TBI prescription dose in four male pediatric patients, keeping the dose well below the documented doses that can cause permanent infertility and hypogonadism.

Identifying serum miRNA biomarkers for radiation exposure in hematopoietic humanized NSG-SGM3 mice.

BACKGROUND: Humans are commonly exposed to ionizing radiation. The conventional approach for estimating radiation exposure is to integrate physical and clinical measurements for optimizing the dose calculation. However, these methods have several limitations. The present study attempted to identify candidate microRNA (miRNA) biomarkers for radiation exposure in a hematopoietic humanized NSGS (hu-NSGS) mouse model. METHODS: We grafted human CD34+ hematopoietic stem cells into NSG-SGM3 (NSGS) mice. The hu-NSGS mice underwent total body irradiation at doses of 2, 3, and 4 Gy. Tissues from the spleen, thymus, and lymph nodes of hu-NSGS mice were prepared to analyze levels of CD45+ and CD3+ T cells and CD 20+ B cells using flow cytometry and immunohistochemistry. Serum miRNAs were profiled using a digital multiplexed NanoString n-Counter. RESULTS: The expression of 45 miRNAs was upregulated/downregulated hu-NSGS mice. The miRNAs hsa-mir-188-5p, hsa-let-7a-5p, hsa-mir-612, hsa-mir-671-5p, and hsa-mir-675-5p were highly radiation-responsive in irradiated hu-NSGS mice. When compared with control mice, radiation-exposed mice exhibited significant upregulated of hsa-let-7a-5p expression and significant downregulation of hsa-mir-188-5p expression. CONCLUSIONS: Single miRNAs or combinations of hsa-mir-188-5p, hsa-let-7a-5p, hsa-mir-675-5p, hsa-mir-612, and hsa-mir-671-5p can be used as biomarkers for predicting the impact of radiation exposure. The current findings suggest the usefulness of hu-NSGS models for investigating radiation biomarkers.

Improved growth with growth hormone treatment in children after hematopoietic stem cell transplantation.

OBJECTIVE: Hematopoietic stem cell transplantation (HSCT) can be a curative treatment for malignant and nonmalignant diseases in children but is associated with significant late effects including growth failure. Growth hormone treatment (GHRx) is offered to improve growth, but limited data are available on its effect on adult height (AH). We aim to evaluate the effectiveness of GHRx. DESIGN: Single-center retrospective study. PATIENTS: Thirty-four patients who had received GHRx for ≥1 year were matched with two controls each, without GHRx, based on sex, indication for HSCT (malignancy, benign haematological disease or immunodeficiency), age at HSCT and conditioning with/without total body irradiation (TBI). All had reached AH. MEASUREMENTS: The primary outcome measure was the difference between AH and predicted AH (PAH) at start of GHRx or the equivalent age in controls (AH-PAH), calculated according to Bailey and Pinneau. RESULTS: GHRx was started at age 12.0 ± 2.6 years; median treatment duration was 3.8 years (range 1.7-9.2). AH-PAH standard deviation score (SDS) was significantly higher in growth hormone (GH) treated boys (-0.5 ± 0.7 SDS) than in controls (-1.5 ± 1.0 SDS, p < .001). Girls also had a higher AH-PAH after GHRx (+0.5 ± 0.6 SDS) compared to controls (-0.2 SDS ±0.7, p < .01). AH remained approximately 2 SDS below target height (TH) in treated and untreated individuals. Among GH-treated children, AH-PAH was higher in those who had received busulfan-based compared to TBI-based conditioning. CONCLUSION: GHRx had a significant positive effect on AH compared to PAH, although AH remained far below TH. Higher AH-PAH was observed in girls and in those conditioned without TBI.