Dose-Volume Parameters of Spared Magnetic Resonance Imaging-Defined Active Bone Marrow Predict Hematologic Toxicity in Pelvic Malignancies Patients Undergoing Radiotherapy: A Cohort Study.

Background: The objective of this investigation is to evaluate the superiority of dose-volume parameters relying on magnetic resonance imaging (MRI)-defined active bone marrow (ABM) over those based on total bone marrow (TBM) contoured via CT in the prediction of hematologic toxicity (HT) occurrence among patients with pelvic malignancies undergoing radiotherapy. Methods: The clinical data of 116 patients with pelvic malignancies treated with pelvic radiotherapy were analyzed retrospectively. The ABM areas on T1-weighted MRI were contoured. The statistical significance between TBM and ABM dose-volume measures was assessed through the utilization of either Student's t-test or Wilcoxon signed rank test. Logistic and linear regression models were employed to analyze the correlation between dose-volume parameters (V5-V50) and HT occurrence in pelvic ABM and TBM. Receiver operating characteristic (ROC) curves were used to compare predictors of HT2+. Results: There were significant differences in dosimetric parameters between ABM and TBM. Logistic regression analysis showed that ABM V5, ABM V10, ABM V15, ABM V20, and TBM V5 were significantly associated with the occurrence of HT2+ in pelvic malignancies. Linear regression analysis showed that ABM V5, ABM V10, and ABM V15 were significantly associated with white blood cell (WBC), absolute neutrophil count (ANC), hemoglobin (Hb), and lymphocyte (Lym) nadir. ABM V5, ABM V10, ABM V15, and ABM V30 were predictive of HT2+. Conclusions: More accurate prediction of HT in patients receiving pelvic radiotherapy may be achieved by relying on dose-volume parameters of MRI-based ABM. Further prospective studies are needed to confirm this.

Effects of bone marrow sparing radiotherapy on acute hematologic toxicity for patients with locoregionally advanced cervical cancer: a prospective phase II randomized controlled study.

OBJECTIVE: To evaluate effects of bone marrow sparing (BMS) radiotherapy on decreasing the incidence of acute hematologic toxicity (HT) for locoregionally advanced cervical cancer (LACC) patients treated by pelvic irradiation. MATERIALS AND METHODS: LACC patients were recruited prospectively from May 2021 to May 2022 at a single center and were evenly randomized into the BMS group and the control group. All patients received pelvic irradiation with concurrent cisplatin (40 mg/m2 weekly), followed by brachytherapy and BM V40 < 25% in the BMS group was additionally prescribed. Acute HT was assessed weekly. Binary logistic regression model and receiver operating characteristic (ROC) curve were used for predictive value analysis. The trial was registered with Chinese clinical trial registry (ChiCTR2200066485). RESULTS: A total of 242 patients were included in the analysis. Baseline demographic, disease and treatment characteristics were balanced between the two groups. In the intention-to-treat population, BMS was associated with a lower incidence of grade ≥ 2 and grade ≥ 3 acute HT, leukopenia and neutropenia s(72.70% v 90.90%, P < 0.001*; 16.50% vs. 65.30%, P < 0.001*; 66.10% vs. 85.10%, P = 0.001*; 13.20% vs. 54.50%, P < 0.001*; 37.20% vs. 66.10%, P < 0.001*; 10.70% vs. 43.80%, P < 0.001*). BMS also resulted in decreased dose delivered to the organs at risk (OARs) including rectum, bladder and left and right femoral head. Univariate and multivariate analyses showed that BM V40 was an independent risk factor for grade ≥ 3 acute HT (odds ratio [OR] = 2.734, 95% confidence interval [CI] = 1.959-3.815, P < 0.001*). Cutoff value was 25.036% and area under the curve (AUC) was 0.786. The nomogram was constructed, which was rigorously evaluated and internally cross-validated, showing good predictive performance. CONCLUSIONS: Receiving BMS pelvic irradiation could reduce the incidence of acute HT in LACC patients, and BM V40 < 25% may be a significant factor in reducing the risks of acute HT.

Thrombopoietin mimetic stimulates bone marrow vascular and stromal niches to mitigate acute radiation syndrome.

BACKGROUND: Acute radiation syndrome (ARS) manifests after exposure to high doses of radiation in the instances of radiologic accidents or incidents. Facilitating regeneration of the bone marrow (BM), namely the hematopoietic stem and progenitor cells (HSPCs), is key in mitigating ARS and multi-organ failure. JNJ-26366821, a PEGylated thrombopoietin mimetic (TPOm) peptide, has been shown as an effective medical countermeasure (MCM) to treat hematopoietic-ARS (H-ARS) in mice. However, the activity of TPOm on regulating BM vascular and stromal niches to support HSPC regeneration has yet to be elucidated. METHODS: C57BL/6J mice (9-14 weeks old) received sublethal or lethal total body irradiation (TBI), a model for H-ARS, by 137Cs or X-rays. At 24 h post-irradiation, mice were subcutaneously injected with a single dose of TPOm (0.3 mg/kg or 1.0 mg/kg) or PBS (vehicle). At homeostasis and on days 4, 7, 10, 14, 18, and 21 post-TBI with and without TPOm treatment, BM was harvested for histology, BM flow cytometry of HSPCs, endothelial (EC) and mesenchymal stromal cells (MSC), and whole-mount confocal microscopy. For survival, irradiated mice were monitored and weighed for 30 days. Lastly, BM triple negative cells (TNC; CD45-, TER-119-, CD31-) were sorted for single-cell RNA-sequencing to examine transcriptomics after TBI with or without TPOm treatment. RESULTS: At homeostasis, TPOm expanded the number of circulating platelets and HSPCs, ECs, and MSCs in the BM. Following sublethal TBI, TPOm improved BM architecture and promoted recovery of HSPCs, ECs, and MSCs. Furthermore, TPOm elevated VEGF-C levels in normal and irradiated mice. Following lethal irradiation, mice improved body weight recovery and 30-day survival when treated with TPOm after 137Cs and X-ray exposure. Additionally, TPOm reduced vascular dilation and permeability. Finally, single-cell RNA-seq analysis indicated that TPOm increased the expression of collagens in MSCs to enhance their interaction with other progenitors in BM and upregulated the regeneration pathway in MSCs. CONCLUSIONS: TPOm interacts with BM vascular and stromal niches to locally support hematopoietic reconstitution and systemically improve survival in mice after TBI. Therefore, this work warrants the development of TPOm as a potent radiation MCM for the treatment of ARS.

Assessment of lymph node area coverage with total marrow irradiation and implementation of total marrow and lymphoid irradiation using automated deep learning-based segmentation.

BACKGROUND: Total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) have the advantages. However, delineating target lesions according to TMI and TMLI plans is labor-intensive and time-consuming. In addition, although the delineation of target lesions between TMI and TMLI differs, the clinical distinction is not clear, and the lymph node (LN) area coverage during TMI remains uncertain. Accordingly, this study calculates the LN area coverage according to the TMI plan. Further, a deep learning-based model for delineating LN areas is trained and evaluated. METHODS: Whole-body regional LN areas were manually contoured in patients treated according to a TMI plan. The dose coverage of the delineated LN areas in the TMI plan was estimated. To train the deep learning model for automatic segmentation, additional whole-body computed tomography data were obtained from other patients. The patients and data were divided into training/validation and test groups and models were developed using the "nnU-NET" framework. The trained models were evaluated using Dice similarity coefficient (DSC), precision, recall, and Hausdorff distance 95 (HD95). The time required to contour and trim predicted results manually using the deep learning model was measured and compared. RESULTS: The dose coverage for LN areas by TMI plan had V100% (the percentage of volume receiving 100% of the prescribed dose), V95%, and V90% median values of 46.0%, 62.1%, and 73.5%, respectively. The lowest V100% values were identified in the inguinal (14.7%), external iliac (21.8%), and para-aortic (42.8%) LNs. The median values of DSC, precision, recall, and HD95 of the trained model were 0.79, 0.83, 0.76, and 2.63, respectively. The time for manual contouring and simply modified predicted contouring were statistically significantly different. CONCLUSIONS: The dose coverage in the inguinal, external iliac, and para-aortic LN areas was suboptimal when treatment is administered according to the TMI plan. This research demonstrates that the automatic delineation of LN areas using deep learning can facilitate the implementation of TMLI.

SPECT/CT Image-Derived Absorbed Dose to Red Marrow Correlates with Hematologic Toxicity in Patients Treated with [177Lu]Lu-DOTATATE.

Hematologic toxicity, although often transient, is the most common limiting adverse effect during somatostatin peptide receptor radionuclide therapy. This study investigated the association between Monte Carlo-derived absorbed dose to the red marrow (RM) and hematologic toxicity in patients being treated for their neuroendocrine tumors. Methods: Twenty patients each receiving 4 treatment cycles of [177Lu]Lu-DOTATATE were included. Multiple-time-point 177Lu SPECT/CT imaging-based RM dosimetry was performed using an artificial intelligence-driven workflow to segment vertebral spongiosa within the field of view (FOV). This workflow was coupled with an in-house macroscale/microscale Monte Carlo code that incorporates a spongiosa microstructure model. Absorbed dose estimates to RM in lumbar and thoracic vertebrae within the FOV, considered as representations of the whole-body RM absorbed dose, were correlated with hematologic toxicity markers at about 8 wk after each cycle and at 3- and 6-mo follow-up after completion of all cycles. Results: The median of absorbed dose to RM in lumbar and thoracic vertebrae within the FOV (D median,vertebrae) ranged from 0.019 to 0.11 Gy/GBq. The median of cumulative absorbed dose across all 4 cycles was 1.3 Gy (range, 0.6-2.5 Gy). Hematologic toxicity was generally mild, with no grade 2 or higher toxicity for platelets, neutrophils, or hemoglobin. However, there was a decline in blood counts over time, with a fractional value relative to baseline at 6 mo of 74%, 97%, 57%, and 97%, for platelets, neutrophils, lymphocytes, and hemoglobin, respectively. Statistically significant correlations were found between a subset of hematologic toxicity markers and RM absorbed doses, both during treatment and at 3- and 6-mo follow-up. This included a correlation between the platelet count relative to baseline at 6-mo follow up: D median,vertebrae (r = -0.64, P = 0.015), D median,lumbar (r = -0.72, P = 0.0038), D median,thoracic (r = -0.58, P = 0.029), and D average,vertebrae (r = -0.66, P = 0.010), where D median,lumbar and D median,thoracic are median absorbed dose to the RM in the lumbar and thoracic vertebrae, respectively, within the FOV and D average,vertebrae is the mass-weighted average absorbed dose of all vertebrae. Conclusion: This study found a significant correlation between image-derived absorbed dose to the RM and hematologic toxicity, including a relative reduction of platelets at 6-mo follow up. These findings indicate that absorbed dose to the RM can potentially be used to understand and manage hematologic toxicity in peptide receptor radionuclide therapy.

Dosimetric impact of bone marrow sparing for robustly optimized IMPT for locally advanced cervical cancer.

BACKGROUND AND PURPOSE: To investigate the trade-off between bone marrow sparing (BMS) and dose to organs at risk (OARs) for intensity modulated proton therapy (IMPT) for women with locally advanced cervical cancer (LACC). MATERIALS AND METHODS: Twenty LACC patients were retrospectively included. IMPT plans were created for each patient using automated treatment planning. These plans progressively reduced bone marrow mean doses by steps of 1 GyRBE, while constraining target coverage and conformality. The relation between bone marrow dose and bladder, small bowel, rectum, and sigmoid doses was evaluated. RESULTS: A total of 140 IMPT plans were created. Plans without BMS had an average [range] bone marrow mean dose of 17.3 [14.7-21.6] GyRBE , which reduced to 12.0 [10.0-14.0] GyRBE with maximum BMS. The mean OAR dose [range] increased modestly for 1 GyRBE BMS: 0.2 [0.0 - 0.6] GyRBE for bladder, 0.3 [-0.2 - 0.7] GyRBE for rectum, 0.4 [0.1 - 0.8] GyRBE for small bowel, and 0.2 [-0.2 - 0.4] GyRBE for sigmoid. Moreover, for maximum BMS, mean OAR doses [range] escalated by 3.3 [0.1 - 6.7] GyRBE for bladder, 5.8 [1.8 - 12.4] GyRBE for rectum, 3.9 [1.6 - 5.9] GyRBE for small bowel, and 2.7 [0.6 - 5.9] GyRBE for sigmoid. CONCLUSION: Achieving 1 GyRBE BMS for IMPT is feasible for LACC patients with limited dosimetric impact on other OARs. While further bone marrow dose reduction is possible for some patients, it may increase OAR doses substantially for others. Hence, we recommend a personalized approach when introducing BMS into clinical IMPT treatment planning to carefully assess individual patient benefits and risks.

Pelvic bone marrow dose-volume predictors of late lymphopenia following pelvic lymph node radiation therapy for prostate cancer.

BACKGROUND AND PURPOSE: Given the substantial lack of knowledge, we aimed to assess clinical/dosimetry predictors of late hematological toxicity on patients undergoing pelvic-nodes irradiation (PNI) for prostate cancer (PCa) within a prospective multi-institute study. MATERIALS AND METHODS: Clinical/dosimetry/blood test data were prospectively collected including lymphocytes count (ALC) at baseline, mid/end-PNI, 3/6 months and every 6 months up to 5-year after PNI. DVHs of the Body, ileum (BMILEUM), lumbosacral spine (BMLS), lower pelvis (BMPELVIS), and whole pelvis (BMTOT) were extracted. Current analysis focused on 2-year CTCAEv4.03 Grade ≥ 2 (G2+) lymphopenia (ALC < 800/µL). DVH parameters that better discriminate patients with/without toxicity were first identified. After data pre-processing to limit overfitting, a multi-variable logistic regression model combining DVH and clinical information was identified and internally validated by bootstrap. RESULTS: Complete data of 499 patients were available: 46 patients (9.2 %) experienced late G2+ lymphopenia. DVH parameters of BMLS/BMPELVIS/BMTOT and Body were associated to increased G2+ lymphopenia. The variables retained in the resulting model were ALC at baseline [HR = 0.997, 95 %CI 0.996-0.998, p < 0.0001], smoke (yes/no) [HR = 2.9, 95 %CI 1.25-6.76, p = 0.013] and BMLS-V ≥ 24 Gy (cc) [HR = 1.006, 95 %CI 1.002-1.011, p = 0.003]. When acute G3+ lymphopenia (yes/no) was considered, it was retained in the model [HR = 4.517, 95 %CI 1.954-10.441, p = 0.0004]. Performances of the models were relatively high (AUC = 0.87/0.88) and confirmed by validation. CONCLUSIONS: Two-year lymphopenia after PNI for PCa is largely modulated by baseline ALC, with an independent role of acute G3+ lymphopenia. BMLS-V24 was the best dosimetry predictor: constraints for BMTOT (V10Gy < 1520 cc, V20Gy < 1250 cc, V30Gy < 850 cc), and BMLS (V24y < 307 cc) were suggested to potentially reduce the risk.

Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding.

Introduction: Mouse models of radiation injury are critical to the development of medical countermeasures (MCMs) against radiation. Now that MCMs against hematopoietic acute radiation syndrome (H-ARS) have achieved regulatory approval, attention is shifting to develop MCMs against the adverse effects of gastrointestinal acute radiation syndrome (GI-ARS) and delayed effects of acute radiation exposure (DEARE). The C57L/J mouse model of partial body irradiation (PBI) with 2.5% bone marrow shielding (BM2.5) is being leveraged to examine both GI-ARS and DEARE effects. Within days of PBI, mice may develop H- and GI-ARS followed several months later by DEARE as a multi-organ injury, which typically involves the lung and kidney (L- and K-DEARE, respectively). The objective of this manuscript is to describe the dose response relationship and progression of radiation injury in the C57L/J mouse and to evaluate its suitability for use in DEARE MCM testing. Materials and methods: In two separate studies conducted over 2 years, male and female C57L/J mice were exposed to PBI BM2.5 with one hindlimb shielded from radiation, representing ~2.5% bone marrow shielding/sparing. Mice were X-ray irradiated at doses ranging from 9 to 13 Gy at 10 to 12 weeks of age for the purposes of assessing ARS survival at 30 days and DEARE survival at 182 days post-irradiation. Clinical indicators of ARS and DEARE were determined by clinical observations, body weights, hematology, clinical chemistry, magnetic resonance imaging (MRI) of lung, and histopathology of selected tissues. Results: C57L/J mice developed canonical ARS responses of hematopoietic atrophy and gastrointestinal injury resulting in dose dependent mortality at doses ≥11 Gy between 1- and 15-days post-irradiation. In animals that survived ARS, DEARE associated mortality occurred in dose dependent fashion at ≥9 Gy for both sexes between 60- and 159-days post-irradiation with histopathology examinations indicating lung injury as the primary cause of death in moribund animals. Conclusion: The PBI BM2.5 C57L/J mouse model reliably produced known H- and GI-ARS effects at doses greater than those resulting in DEARE effects. Because of this, the C57L/J mouse can be used to test MCMs against L-DEARE injury, while avoiding ARS associated mortality.

The prevention effect of pulsed electromagnetic fields treatment on senile osteoporosis in vivo via improving the inflammatory bone microenvironment.

This study aimed to assess PEMF in a rat model of senile osteoporosis and its relationship with NLRP3-mediated low-grade inflammation in the bone marrow microenvironment. A total of 24 Sprague Dawley (SD) rats were included in this study. Sixteen of them were 24-month natural-aged male SD rats, which were randomly distributed into the Aged group and the PEMF group (n = 8 per group). The remaining 8 3-month -old rats were used as the Young positive control group (n = 8). Rats in the PEMF group received 12 weeks of PEMF with 40 min/day, five days per week, while the other rats received placebo PEMF intervention. Bone mineral density/microarchitecture, serum levels of CTX-1 and P1CP, and NLRP3-related signaling genes and proteins in rat bone marrow were then analyzed. The 12-week of PEMF showed significant mitigation of aging-induced bone loss and bone microarchitecture deterioration, i.e. PEMF increased the bone mineral density of the proximal femur and L5 vertebral body and improved parameters of the proximal tibia and L4 vertebral body. Further analysis showed that PEMF reversed aging-induced bone turnover, specifically, decreased serum CTX-1 and elevated serum P1CP. Furthermore, PEMF also dramatically inhibited NLRP3-mediated low-grade inflammation in the bone marrow, i.e. PEMF inhibited the levels of NLRP3, proCaspase1, cleaved Caspase1, IL-1ß, and GSDMD-N. The study demonstrated that PEMF could mitigate the aging-induced bone loss and reverses the deterioration of bone microarchitecture probably through inhibiting NLRP3-mediated low-grade chronic inflammation to improve the inflammatory bone microenvironment in aged rats.

Sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production.

To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2-8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G-CSF-inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario.

Comparative Analysis of VMAT and IMRT Techniques: Evaluation of Dose Constraints and Bone Marrow Sparing in Cervical Cancer Patients Undergoing Chemoradiotherapy.

BACKGROUND: Carcinoma of the cervix is a globally significant cause of morbidity and mortality among women. Concurrent chemoradiotherapy, a standard approach for locally advanced cervical cancer, invariably involves pelvic irradiation. Although this strategy is effective, it inevitably affects the pelvic bone marrow, a crucial hematopoietic site, and leads to hematological toxicity The potential of IMRT to spare bone marrow in pelvic irradiation settings has been an area of significant interest, with the aim to mitigate the hematological toxicity associated with pelvic radiotherapy. Radiotherapy techniques have evolved in terms of conformity and normal tissue sparing. Our study intends to explore the use of BM sparing techniques among patients of carcinoma cervix. PATIENTS AND METHODS: Twenty patients of carcinoma cervix FIGO Stage IIIB treated with concurrent chemoradiotherapy were selected for this study. The external contour of bones was delineated on planning CT as a surrogate for BM. We generated three plans on a single patient:1. without BM as the dose constraint, namely N-IMRT plan; 2. with BM constraint, namely BMS-IMRT plan; 3. VMAT plan in which BM constraint was given. The dose volume histogram (DVH) for planning target volume (PTV) and organs at risk (OAR) were analyzed. BM parameters: V10, V20, V30, V40, mean, maximum and minimum dose were compared.  Results: PTV coverage was comparable in all techniques. VMAT plans resulted in superior BM sparing compared with N-IMRT plan (P-<0.001) and BMS-IMRT plan (P-<0.001, 0.021 and 0.001 respectively for V20, V30 and V40). VMAT plans had better CI compared with BMS-IMRT (P-0.002) and N-IMRT (P-0.001) plans. CONCLUSION: Our study adds to the growing evidence that VMAT might be the preferred technique for patients with carcinoma of the cervix undergoing concurrent chemoradiotherapy, as it provides comparable target coverage and better sparing of bone marrow compared to IMRT.

Modulation of Hematopoietic Injury by a Promising Radioprotector, Gamma-Tocotrienol, in Rhesus Macaques Exposed to Partial-Body Radiation.

Currently, no radioprotectors have been approved to mitigate hematopoietic injury after exposure to ionizing radiation. Acute ionizing radiation results in damage to both hematopoietic and immune system cells. Pre-exposure prophylactic agents are needed for first responders and military personnel. In this study, the ability of gamma-tocotrienol (GT3), a promising radioprotector and antioxidant, to ameliorate partial-body radiation-induced damage to the hematopoietic compartment was evaluated in a nonhuman primate (NHP) model. A total of 15 rhesus NHPs were divided into two groups, and were administered either GT3 or vehicle 24 h prior to 4 or 5.8 Gy partial-body irradiation (PBI), with 5% bone marrow (BM) sparing. Each group consisted of four NHPs, apart from the vehicle-treated group exposed to 5.8 Gy, which had only three NHPs. BM samples were collected 8 days prior to irradiation in addition to 2, 7, 14, and 30 days postirradiation. To assess the clonogenic ability of hematopoietic stem and progenitor cells (HSPCs), colony forming unit (CFU) assays were performed, and lymphoid cells were immunophenotyped using flow cytometry. As a result of GT3 treatment, an increase in HSPC function was evident by an increased recovery of CFU-granulocyte macrophages (CFU-GM). Additionally, GT3 treatment was shown to increase the percentage of CD34+ cells, including T and NK-cell subsets. Our data further affirm GT3's role in hematopoietic recovery and suggest the need for its further development as a prophylactic radiation medical countermeasure.

Iron Deposition in the Bone Marrow and Spleen of Nonhuman Primates with Acute Radiation Syndrome.

The risk of exposure to high levels of ionizing radiation from nuclear weapons or radiological accidents is an increasing world concern. Partial- or total-body exposure to high doses of radiation is potentially lethal through the induction of acute radiation syndrome (ARS). Hematopoietic cells are sensitive to radiation exposure; white blood cells primarily undergo apoptosis while red blood cells (RBCs) undergo hemolysis. Several laboratories demonstrated that the rapid hemolysis of RBCs results in the release of acellular iron into the blood. We recently demonstrated using a murine model of ARS after total-body irradiation (TBI) and the loss of RBCs, iron accumulated in the bone marrow and spleen, notably between 4-21 days postirradiation. Here, we investigated iron accumulation in the bone marrow and spleens from TBI nonhuman primates (NHPs) using histological stains. We observed trends in increased intracellular and extracellular brown pigmentation in the bone marrow after various doses of radiation, especially after 4-15 days postirradiation, but these differences did not reach significance. We observed a significant increase in Prussian blue-staining intracellular iron deposition in the spleen 13-15 days after 5.8-8.5 Gy of TBI. We observed trends of increased iron in the spleen after 30-60 days postirradiation, with varying doses of radiation, but these differences did not reach significance. The NHP model of ARS confirms our earlier findings in the murine model, showing iron deposition in the bone marrow and spleen after TBI.

Feasibility study of total marrow lymphoid irradiation with volumetric modulated arc therapy: clinical implementation in a tertiary care center.

PURPOSE: Total marrow lymphoid irradiation (TMLI) with volumetric modulated arc therapy (VMAT) is challenging due to large treatment fields with multiple isocenters, field matching at junctions, and targets being surrounded by many organs at risk. This study aimed to describe our methodology for safe dose escalation and accurate dose delivery of TMLI treatment with the VMAT technique based on early experience at our center. MATERIALS AND METHODS: Computed tomography (CT) scans were acquired in head-first supine and feet-first supine orientations for each patient with an overlap at mid-thigh. VMAT plans were generated for 20 patients on the head-first CT images with either three or four isocenters in the Eclipse treatment planning system (Varian Medical Systems Inc., Palo Alto, CA) and the treatment was delivered in a Clinac 2100 C/D linear accelerator (Varian Medical Systems Inc., Palo Alto, CA). RESULTS: Five patients were treated with a prescription dose of 13.5 Gy in 9 fractions and 15 patients were treated with an escalated dose of 15 Gy in 10 fractions. The mean doses to 95% of the clinical target volume (CTV) and planning target volume (PTV) were 14.3 ± 0.3 Gy and 13.6 ± 0.7 Gy for the prescription doses of 15 Gy, and 13 ± 0.2 Gy and 12.3 ± 0.3 Gy for the prescription doses of 13.5 Gy, respectively. Mean dose to the lung in both schedules was 8.7 ± 0.6 Gy. The overall time taken to execute the treatment plans was approximately 2 h for the first fraction and 1.5 h for subsequent fractions. The average in-room time of 15.5 h per patient over 5 days leads to potential changes in the regular treatment schedules for other patients. CONCLUSION: This feasibility study highlights the methodology adopted for safe implementation of TMLI with the VMAT technique at our institution. Escalation of dose to the target with adequate coverage and sparing of critical structures was achieved with the adopted treatment technique. Clinical implementation of this methodology at our center could serve as a practical guide to start the VMAT-based TMLI program safely by others who are keen to start this service.

Differential Response of Pelvic Bone Marrow Fluorodeoxyglucose Uptake in Patients Receiving Concurrent Chemoradiotherapy.

AIMS: Irradiation of pelvic bone marrow (PBM) at the level of the typical low dose bath of intensity-modulated radiotherapy delivery (10-20 Gy) is associated with an increased risk of haematological toxicity, particularly when combined with concurrent chemotherapy. Although sparing of the whole of the PBM at a 10-20 Gy dose level is unachievable, it is known that PBM is divided into haematopoietically active and inactive regions that are identifiable based on the threshold uptake of [18F]-fluorodeoxyglucose (FDG) seen on positron emission tomography-computed tomography (PET-CT). In published studies to date, the definition of active PBM widely used is that of a standardised uptake value (SUV) greater than the mean SUV of the whole PBM prior to the start of chemoradiation. These studies include those looking at developing an atlas-based approach to contouring active PBM. Using baseline and mid-treatment FDG PET scans acquired as part of a prospective clinical trial we sought to determine the suitability of the current definition of active bone marrow as representative of differential underlying cell physiology. MATERIALS AND METHODS: Active and inactive PBM were contoured on baseline PET-CT and using deformable registration mapped onto mid-treatment PET-CT. Volumes were cropped to exclude definitive bone, voxel SUV extracted and the change between scans calculated. Change was compared using Mann-Whitney U testing. RESULTS: Active and inactive PBM were shown to respond differentially to concurrent chemoradiotherapy. The median absolute response of active PBM for all patients was -0.25 g/ml, whereas the median inactive PBM response was -0.02 g/ml. Significantly, the inactive PBM median absolute response was shown to be near zero with a relatively unskewed distribution (0.12). CONCLUSIONS: These results would support the definition of active PBM as FDG uptake greater than the mean of the whole structure as being representative of underlying cell physiology. This work would support the development of atlas-based approaches published in the literature to contour active PBM based on the current definition as being suitable.

Modern Radiation for Hematologic Stem Cell Transplantation: Total Marrow and Lymphoid Irradiation or Intensity-Modulated Radiation Therapy Total Body Irradiation.

The development of large-field intensity-modulated radiation therapy (IMRT) has enabled the implementation of total marrow irradiation (TMI), total marrow and lymphoid irradiation (TMLI), and IMRT total body irradiation (TBI). IMRT TBI limits doses to organs at risk, primarily the lungs and in some cases the kidneys and lenses, which may mitigate complications. TMI/TMLI allows for dose escalation above TBI radiation therapy doses to malignant sites while still sparing organs at risk. Although still sparingly used, these techniques have established feasibility and demonstrated promise in reducing the adverse effects of TBI while maintaining and potentially improving survival outcomes.

Impact of the Extremities Positioning on the Set-Up Reproducibility for the Total Marrow Irradiation Treatment.

Total marrow (lymph node) irradiation (TMI/TMLI) delivery requires more time than standard radiotherapy treatments. The patient's extremities, through the joints, can experience large movements. The reproducibility of TMI/TMLI patients' extremities was evaluated to find the best positioning and reduce unwanted movements. Eighty TMI/TMLI patients were selected (2013-2022). During treatment, a cone-beam computed tomography (CBCT) was performed for each isocenter to reposition the patient. CBCT-CT pairs were evaluated considering: (i) online vector shift (OVS) that matched the two series; (ii) residual vector shift (RVS) to reposition the patient's extremities; (iii) qualitative agreement (range 1-5). Patients were subdivided into (i) arms either leaning on the frame or above the body; (ii) with or without a personal cushion for foot positioning. The Mann-Whitney test was considered (p < 0.05 significant). Six-hundred-twenty-nine CBCTs were analyzed. The median OVS was 4.0 mm, with only 1.6% of cases ranked < 3, and 24% of RVS > 10 mm. Arms leaning on the frame had significantly smaller RVS than above the body (median: 8.0 mm/6.0 mm, p < 0.05). Using a personal cushion for the feet significantly improved the RVS than without cushions (median: 8.5 mm/1.8 mm, p < 0.01). The role and experience of the radiotherapy team are fundamental to optimizing the TMI/TMLI patient setup.

Total marrow lymphoid irradiation and cyclophosphamide is associated with low toxicity and good outcomes in patients undergoing hematopoietic stem cell transplantation for acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crises - A phase I study.

INTRODUCTION: Total marrow lymphoid irradiation (TMLI) can deliver higher doses of irradiation without increasing toxicity compared to Total body irradiation (TBI). METHODS: Twenty adult patients undergoing hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia with lymphoid blast crises (CML-LBC) received TMLI and cyclophosphamide for conditioning. Ten patients each received 13.5 or 15 Gy of TMLI. The graft source was peripheral blood stem cells in all, and donors included matched related (n = 15), haplo-identical (n = 3) or matched unrelated donors (n = 2). RESULTS: The median cell dose infused was 9 × 106 CD34/kg (range 4.8-12.4). Engraftment occurred in all (100%) at a median of 15 days (range: 14-17). Toxicity was low with hemorrhagic cystitis seen in two but no sinusoidal obstruction syndrome. Acute GVHD occurred in 40% while chronic GVHD was seen in 70.5%. Viral infections were seen in 55% while blood stream bacterial infections occurred in 20% and invasive fungal disease (IFD) in 10%. The Day 100 non-relapse mortality (NRM) was 10%. At a median follow up of 25 months (range 2-48), two patients have relapsed. Overall survival at 2 years is 80% while the disease-free survival is 75%. CONCLUSIONS: The combination of TMLI and cyclophosphamide for myeloablative conditioning is associated with low toxicity and favorable early outcomes in patients undergoing HSCT for ALL and CML-LBC.

The impact of bone marrow irradiation dose on acute haematologic toxicity in cervical cancer patients treated with concurrent chemoradiotherapy.

OBJECTIVE: To evaluate the impact of bone marrow (BM) irradiation dose on acute haematologic toxicity (HT) in concurrent chemoradiotherapy for cervical cancer. METHODS: Sixty-nine patients with cervical cancer treated with curative or postoperative adjuvant therapy received weekly cisplatin concurrent chemotherapy (CCT) and intensity-modulated radiation therapy (IMRT). The whole pelvic bone marrow (PBM) was delineated and divided into three subsites: ilium (IL), lower pelvis (LP), and lumbosacral spine (LS). Associations between clinical variables, dose volume of BM, including PBM, IL, LP, and LS in the form of x-Vy (volume receiving y Gy for x), and blood cell count nadir were tested using linear regression models. Receiver operating characteristic (ROC) curve analysis was further used to analyse the cutoff values of the variables with p < 0.05 in the multivariate analysis. RESULTS: In 69 patients, the haemoglobin nadir was positive correlated with baseline haemoglobin (p < 0.001), negative correlated with relative LP-V10 (p = 0.005), relative LP-V25 (p = 0.002), relative LP-V50 (p = 0.007), relative LP-mean (p = 0.003), absolute LP-V15 (p = 0.049), absolute LP-V25 (p = 0.004) and absolute LP-V30 (p = 0.009). The platelet nadir was positive correlated with baseline platelets (p = 0.048) and negative correlated with relative LP-V40 (p = 0.028), but there was no significant variable in absolute radiation volume by multivariate analysis. No variables related to the neutrophil nadir were found, and the 69 patients were divided into group A (43 cases) receiving 3-4 cycles of CCT and group B (26 cases) receiving 5-6 cycles of CCT. In group A, the relative IL-V15 (p = 0.014), the relative IL-V50 (p = 0.010) and the absolute LP-V50 (p = 0.011) were negative correlated with the neutrophil nadir. No significant variable was found in group B. No significant variables related to the lymphocyte nadir were found, and the neutrophil-to-lymphocyte ratio (NLR) was analysed. Age (p < 0.05), relative LP-V15 (p = 0.037) and absolute PBM-mean (p < 0.001) were found to be negative related to NLR. CONCLUSION: The dosimetric parameters of relative irradiated volume of BM have more statistically significant datas on acute HT than absolute irradiated volume. The nadir of haemoglobin and platelets and the vertice of NLR were more affected by the irradiation dose to LP, while neutrophils were more affected by the dose to IL. Acute HT was negative related to both low-dose irradiation (V10-30) and high-dose irradiation (V40, V50). For more than 4 cycles of CCT, the effect of BM irradiation on the neutrophils nadir was masked by chemotherapy.

Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome.

Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.