Bone Marrow Volume Research Articles

A Systems-Level Analysis of 2-[18F]FDG PET in Pigs Reveals Complex Skeletal Metabolism Networks in vivo which are altered with Osteomyelitis

Our understanding of complex tissue interactions at a systems level remains rudimentary, limiting our ability to dissect mechanisms underlying diseases and develop novel therapeutics. Skeletal research has focused on the pathogenicity of obesity and diabetes mellitus on the skeleton; however, it has been recently revealed that the skeleton is not merely an endocrine target but also a secretory organ, modulating systemic energy homeostasis1,2. We recently discovered that different bones within the murine skeleton have a unique glucose metabolism and form a complex metabolic network3. Thus, we hypothesised that different bones within the porcine skeleton would have unique molecular signatures and form a distinct metabolic network, and these networks would be altered by osteomyelitis, an inflammatory condition of the bone. Five healthy mini and three Danish Landrace-Yorkshire pigs (inoculated with S. aureus to induce osteomyelitis) underwent static 2-[18F]FDG PET/CT and were analysed to measure bone and bone marrow adipose tissue (BMAT) glucose metabolism. Analyze was used for image analysis and processing. Bone and bone marrow volumes of interest were segmented in CT images using Hounsfield Unit (HU) > 300 (bone) and HU -200 to 115 (BMAT; Fig1). PET images were used to extract average standard uptake values. Network analysis was performed using Graphia. Osteomyelitis pigs had a lower bone density and increased BMAT volume compared to healthy controls. There was an increased incorporation of 2-[18F]FDG into the bone and BMAT of osteomyelitis pigs. Similar to what has previously been observed in the mouse3 and human4, there was an increased incorporation of 2-[18F]FDG in the axial skeleton compared to the appendicular skeleton. Network analysis indicated a shift in bone metabolic profiles between healthy and osteomyelitis pigs. Please click on the 'PDF' for the full abstract!

Dose-Response Relationships Between Radiation Exposure, Bone Marrow Function as Measured by 18F-Fluorothymidine Positron Emission Tomography, and Lymphocyte Counts During Chemoradiation for Non-Small Cell Lung Cancer

Purpose18F-Fluorothymidine(FLT)-PET enables sensitive imaging of bone marrow (BM) proliferation. Sequential FLT-PET/CT scans before and during chemoradiation (CRT) for non-small cell lung cancer (NSCLC) were repurposed to investigate dose-response effects of radiation on BM proliferation. Methods and materialsTwenty-six NSCLC patients underwent platinum-based CRT to 60Gy in 30 fractions with FLT-PET/CT scans at baseline, week 2 (20Gy) and week 4 (40Gy). FLT uptake in BM was isolated using Medical Image Merge software. Week 2 and week 4 FLT-PET BM scans were fused with contemporaneous radiation isodose distributions. Relationships between radiation dose and FLT BM uptake (SUVmax and visual parameters) were analyzed using generalized-linear and restricted cubic-spline models. Percentage volumes of total BM without appreciable FLT uptake (“ablated”) on week 2 and week 4 FLT-PET scans were calculated by comparisons with baseline scans. ResultsThoracic FLT uptake was ablated in BM regions exposed to cumulative radiation doses ≥3Gy by week 2. In all cases BM FLT SUVmax declined rapidly as radiation dose increased. BM proliferation significantly decreased by more than 95% after ≥3-4Gy at 2 weeks and ≥4-5Gy at 4 weeks. The ablated BM volume increased from week 2 to week 4 as BM in the penumbra accumulated radiation dose. Median percentage of total BM ablated was 13.1% (range 5.6-20.3) at 2 weeks and 15.7% (range 9.2 - 24.1) at 4 weeks. Mean lymphocyte counts fell from baseline of 2.01×109/L to 0.77 week 2, and 0.60 week 4. Lymphocyte decline strongly correlated with percentage of total BM ablated by week 4 (y=-46 -1.64 x, R2adj = 0.34, p=0.001). ConclusionsBM ablation associated with low dose-radiation exposure during CRT correlated significantly with lower week 4 lymphocyte counts. BM is a potential organ-at-risk and reducing the BM volume exposed to ≥3Gy may help preserve lymphocytes essential for effective adjuvant immunotherapy.

Acute hematologic toxicity prediction using dosimetric and radiomics features in patients with cervical cancer: does the treatment regimen matter?

Acute hematologic toxicity (HT) is a prevalent adverse tissue reaction observed in cervical cancer patients undergoing chemoradiotherapy (CRT), which may lead to various negative effects such as compromised therapeutic efficacy and prolonged treatment duration. Accurate prediction of HT occurrence prior to CRT remains challenging. A discovery dataset comprising 478 continuous cervical cancer patients (140 HT patients) and a validation dataset consisting of 205 patients (52 HT patients) were retrospectively enrolled. Both datasets were categorized into the CRT group and radiotherapy (RT)-alone group based on the treatment regimen, i.e., whether chemotherapy was administered within the focused RT duration. Radiomics features were derived by contouring three regions of interest (ROIs)-bone marrow (BM), femoral head (FH), and clinical target volume (CTV)-on the treatment planning CT images before RT. A comprehensive model combining the radiomics features as well as the demographic, clinical, and dosimetric features was constructed to classify patients exhibiting acute HT symptoms in the CRT group, RT group, and combination group. Furthermore, the time-to-event analysis of the discriminative ROI was performed on all patients with acute HT to understand the HT temporal progression. Among three ROIs, BM exhibited the best performance in classifying acute HT, which was verified across all patient groups in both discovery and validation datasets. Among different patient groups in the discovery dataset, acute HT was more precisely predicted in the CRT group [area under the curve (AUC) = 0.779, 95% CI: 0.657-0.874] than that in the RT-alone (AUC = 0.686, 95% CI: 0.529-0.817) or combination group (AUC = 0.748, 95% CI: 0.655-0.827). The predictive results in the validation dataset similarly coincided with those in the discovery dataset: CRT group (AUC = 0.802, 95% CI: 0.669-0.914), RT-alone group (AUC = 0.737, 95% CI: 0.612-0.862), and combination group (AUC = 0.793, 95% CI: 0.713-0.874). In addition, distinct feature sets were adopted for different patient groups. Moreover, the predicted HT risk of BM was also indicative of the HT temporal progression. HT prediction in cervical patients is dependent on both the treatment regimen and ROI selection, and BM is closely related to the occurrence and progression of HT, especially for CRT patients.

Bone marrow adipocytes and lung cancer bone metastasis: unraveling the role of adipokines in the tumor microenvironment.

Bone is a common site of metastasis for lung cancer. The "seed and soil" hypothesis suggests that the bone marrow microenvironment ("soil") may provide a conducive survival environment for metastasizing tumor cells ("seeds"). The bone marrow microenvironment, comprising a complex array of cells, includes bone marrow adipocytes (BMAs), which constitute about 70% of the adult bone marrow volume and may play a significant role in tumor bone metastasis. BMAs can directly provide energy for tumor cells, promoting their proliferation and migration. Furthermore, BMAs participate in the tumor microenvironment's osteogenesis regulation, osteoclast(OC) regulation, and immune response through the secretion of adipokines, cytokines, and inflammatory factors. However, the precise mechanisms of BMAs in lung cancer bone metastasis remain largely unclear. This review primarily explores the role of BMAs and their secreted adipokines (leptin, adiponectin, Nesfatin-1, Resistin, chemerin, visfatin) in lung cancer bone metastasis, aiming to provide new insights into the mechanisms and clinical treatment of lung cancer bone metastasis.

Retrospective cohort study for thrombocytopenia during concurrent chemoradiotherapy for rectal cancer.

The aim of this article was to establish the clinical prognostic models and identify the predictive radiation dosimetric parameters for thrombocytopenia during concurrent chemoradiotherapy for rectal cancer. In this retrospective cohort study, patients with rectal adenocarcinoma undergoing concurrent long-term chemoradiotherapy were included. The primary outcome of interest was grade 2 or higher (2+) thrombocytopenia (platelet(PLT) count <75,000/μL). Secondary outcomes included: grade 1 or higher thrombocytopenia (PLT count<100,000/μL) and the PLT count during chemoradiotherapy and its nadir. The risk prediction model was developed by logistic regression to identify clinical predictors of 2+ thrombocytopenia. Univariate linear regression models were used to test correlations between radiation dosimetric parameters and the absolute PLT count at nadirs. This retrospective cohort comprised 238 patients. Fifty-four (22.6%) patients developed thrombocytopenia during concurrent chemoradiotherapy, while 15 (6.3%) patients developed 2+ thrombocytopenia. Four independently associated risk factors, including age, Alb level, PLT count, and chemotherapy regimen, were included in the final model and used to form a 2+ thrombocytopenia probability estimation nomogram. The C-index was 0.87 (95% CI: 0.78-0.96). The calibration plot showed a moderate agreement, and the Brier score was 0.047 (95% CI: 0.025-0.070). The total absolute volume of bone marrow irradiated by 5 Gy, 10 Gy and 15 Gy of radiation (BM-V5ab, BM-V10ab, BM-V15ab), calculated by the volume of bone marrow multiplied by the corresponding Vx, were identified as new predictors. The nadir of PLT was found to be negatively correlated with BM-V5ab (β = -0.062, P =0.030), BM-V10ab (β = -0.065, P =0.030) and BM-V15ab (β = -0.064, P =0.042). The occurrence of 2+ thrombocytopenia during concurrent chemoradiotherapy for rectal cancer can be predicted by the patient's baseline status and chemoradiotherapy regimen, and low dose irradiation of bone marrow can affect the level of platelets during the treatment.

Dynamics and predictors of hematologic toxicity during cranio-spinal irradiation.

Craniospinal irradiation (CSI) is a complex radiotherapy (RT) technique required for treating specific brain tumors and some hematologic malignancies. With large volumes of hematogenous bone marrow (BM) being irradiated, CSI could cause acute hematologic toxicity, leading to treatment interruptions or severe complications. We report on the dynamics and dose/volume predictors of hematologic toxicity during CSI. Pediatric patients (≤ 18years) undergoing CSI in a tertiary cancer center were included. Medical records were retrospectively reviewed for clinical data and blood parameters were collected at baseline and weekly, until four weeks after the end of RT. The BM substructures were contoured, and dose-volume parameters were extracted. We used Wilcoxon rank-sum test to compare quantitative data, Chi square test for qualitative data and receiver operating characteristics (ROC) curves for dose/volume thresholds. Fifty-one patients were included. Severe toxicities (grade 3-4) were recorded as follows: 2% anemia, 8% thrombocytopenia, 25% leukopenia, 24% neutropenia. Ninety-eight percent of patients had lymphopenia (grade 1-4) at some point. Twenty-nine percent required granulocyte-colony stimulating factor, 50% had an infection and 8% required a blood transfusion. Dmean > 3.6 Gy and V15 Gy > 10.6% for Pelvic Bones were associated with a higher risk of developing any ≥ G3 toxicities. Dmean > 30-35 Gy to the thoracic and lumbar spine was predictive for G3-4 anemia and thrombocytopenia, and Cervical Spine Dmean > 30 Gy was associated with ≥ G3 neutropenia. CSI was well tolerated, without life-threatening complications in our cohort, but hematologic toxicity was frequent, with severity increasing with higher mean doses delivered to the hematogenous BM and larger volumes of BM receiving 30-35 Gy.

HISTOMORPHOMETRIC ASSESSMENT OF CHANGES THE STRUCTURAL COMPONENTS OF THE BONE IN RATS WITH CHRONIC CHOLESTASIS WITH CORRECTION OF THE COMPLEX FROM HEPATOPROTECTOR AND SORBENT

Problem. The disruption of the gastric duct in cholestasis causes insufficient absorption in the small intestine of macro- and microelements and fat-rich vitamins (A, D, E, K), which are necessary for healthy processes, and remodeling of bone tissue. To reduce pathological changes in bone tissue diseases of the hepatobiliary system in rats statement in cholestasis, need a comprehensive approach [6]. In the core of the preventive complex one can see a hepatoprotector, which, due to its main components (lecithin, quercetin), possesses the liver protecting properties, as well as has anti-inflammatory and bile-diluting effects, and a sorbent. Aim. To conduct a histomorphometric research of the femur in rats with chronic cholestasis and evaluate the effectiveness of the prophylactic complex. Methods. The follow-up study was carried out on male rats, divided into three groups: 1st group – intact, 2nd group – rats with simulated chronic cholestasis, 3rd group – rats, who, in parallel with the development of chronic cholestasis pathology, carried out prevention. Cholestasis in rats was modeled by ligation of the biliary duct under thiopental anesthesia [9]. A hepatoprotector at a dose of 500 mg/kg and a sorbent at a dose of 1 g/kg were administered to group 3 of the animals once over a period of 4 months. Histological analysis and photography of sections of the stegnus cyst were carried out using an additional light microscope and a camera for an Olympus LC30 microscope (Japan). Morphometric studies of rat femur were carried out using the following parameters: volume (%) of the articular epiphyseal cartilage, volume (%) of the cartilage, volume (%) of the cerebrum and the number of osteoblasts per the particular area. The main results. Certain histological changes in the epiphysis of the femoral bone were found in rats with chronic cholestasis, namely, noticeable delamination of the periosteum was noted. In the deep layers of the cartilage, a decrease in the number of isogenic groups was noted, in addition, they contained a smaller number of chondrocytes. Desolation of individual lacunae, a decrease in the number of osteoblasts, and thinning of bone trabeculae were also observed, indicating certain pathological changes in bone tissue. Analysis of the morphometric parameters of the femur in rats with chronic cholestasis revealed a decrease in the specific volume of the cartilage of the articular surfaces by 25.8%, a decrease in the specific volume of the bone marrow and the number of osteoblasts by 14.4% and 39.4%, respectively, and as well as an increase of 33.1% in the specific volume of bone beams in relation to the control group. The introduction of the prophylactic complex contributed to a significant increase in the specific volume of the cartilage of the articular surfaces – by 17.2%, the specific volume of bone marrow by 42.9%, the average number of osteoblasts by 34.9%, and a decrease in the specific volume of bone beams by 31 .7% relative to the group of animals with chronic cholestasis. That is, the use of a prophylactic complex, which consisted of a hepatoprotector and a sorbent, effectively eliminated pathological changes in bone tissue that arose against the background of the development of chronic cholestasis. Conclusions. The formation of chronic cholestasis leads to pathological changes in the cartilaginous tissue of the epiphysis of the femur of the animals under study, and it itself changes the volume of cartilage of the subglobular surfaces and causes destruction of the main components in bone tissue (reduces the volume of bone marrow and the number of osteoblasts at the background of the growth the volume of bone beams). The effectiveness of prophylactic in the elimination of pathological changes in bone tissue at the background of chronic cholestasis has manifested itself as a hepatoprotective, antioxidant, anti-inflammatory and anti-inflammatory hepatoprotector and those combined with a sorbent.

TNC/Kg and CD34+/Kg Cell Dose Impact on Patient Engraftment after Allogeneic Transplant with Conventional Bone Marrow; Better Predictability of Graft Content Needed

Introduction: Bone marrow (BM) harvested from a related (RD) or unrelated donor (URD) remains a viable graft source for patients (pts) receiving an allogeneic hematopoietic stem cell transplant (allo-HCT). However guidance on minimum TNC/kg &amp; CD34+/kg thresholds to optimize engraftment &amp; a method to best predict graft content are needed. Methods: All BM products (prdcts) harvested between 1/1/2016 to 6/30/2023 for adult &amp; pediatric (ped) pts were studied (n= 261). Pt, donor, &amp; BM prdct characteristics were collected. For each BM prdct, pre-processing (pre-proc) data was obtained to determine a median pre-proc TNC, TNC/mL, CD34+/mL, and CD34+/TNC % of all BM prdcts &amp; infused TNC &amp; CD34+ content was also recorded. Pt neutrophil (Neutr) &amp; platelet (Plt) engraftment data was collected with Neutr engraftment defined as the first of 3 consecutive days of an absolute neutr count ≥ 500 x 10^3/μl. Plt engraftment was defined as ≥ 20K/μl plts &amp; transfusion independence for ≥ 7 days. Univariable &amp; multivariable analyses (MVAs) using the Fine and Gray model were performed to assess impact of infused TNC/kg (MVA1), CD34+/kg (MVA2), and CD34+/TNC % (MVA3) of conventional BM prdcts on Neutr (n eval pts = 239) &amp; Plt engraftment (n eval pts = 238). The National Marrow Donor Program's (NMDP) provided estimate for median TNC/mL of BM (0.183 x 10^8) was used w/ donor weight (wt), the NMDP maximum (max) allowable amount of BM (20mL per donor kg), &amp; a standard max BM volume request (1500mL) to calculate an expected pre-proc TNC for all BM prdcts. The expected TNC for small ped pts was limited to (15 * pt wt) to ensure a TNC/kg cell dose of ≤ 15 x 10^8. An expected pre-proc CD34+ for each BM prdct was then calculated by expected TNC x CD34+/TNC % of all BM prdcts on study. An expectation accuracy (EA) % for both TNC &amp; CD34+ was calculated for each BM prdct (expected / actual pre-proc values observed by our center). TNC &amp; CD34+ EA % of BM prdcts collected by other domestic &amp; international centers were analyzed. Results: 261 BM prdcts from 259 donors for 258 pts were studied. The BM prdcts had the following pre-proc medians: TNC/mL of 0.136 x 10^8, CD34+/mL of 0.124 x 10^6, &amp; CD34+/TNC % of 0.96. MSKCC harvested 141 (54%) of the BM prdcts and the rest were facilitated by the NMDP: 71 (27%) from 26 domestic centers and 49 (19%) from 28 international centers. The cumulative incidence of Neutr engraftment was 96% (95% CI 92, 98%) by days +30 and +100 after allo-HCT and for Plts it was 48% (95% CI 42,54%) and 91% (95% CI 87,94%) respectively. Table 1 shows the MVA results testing TNC/kg (MVA1), CD34+/kg (MVA2), CD34+/TNC % (MVA3) &amp; engraftment after allo-HCT w/ conventional BM, indicating Neutr &amp; Plt engraftment is impacted by TNC/kg and CD34+/kg cell dose but not by CD34+/TNC %. In all 3 MVA models, associations were observed for pt diagnosis [SAA w/ better Plt engraftment vs. ref grp], donor type (≤ 7/8 URD or haploidentical RD w/ worse Neutr &amp; Plt engraftment vs. ref grp), donor ABO incompatibility (Minor w/ better Plt engraftment vs. ref grp), and infusion type [cryopreserved (cryo'ed)/thawed w/ worse Neutr engraftment vs. fresh]. The expectation accuracy (EA) analysis (Wilcoxon rank-sum test) of pre-proc TNC &amp; CD34+ is seen in Table 2. The median expected pre-proc TNC (274) &amp; CD34+ (264) of BM prdcts received from domestic centers &amp; international centers were the same. However BM prdcts from international centers had a lower median actual pre-proc TNC (192) &amp; CD34+ (162), a lower median TNC EA of 74% (vs. 89% for dom centers, p=0.008), &amp; a lower median CD34+ EA of 63% (vs. 93% for dom centers, p&amp;lt;0.001). All BM prdcts combined (n = 120) had a median TNC EA of 83% &amp; a median CD34+ EA of 76%. Conclusions: This large analysis suggests BM products with a TNC/kg &amp;gt; 2.0 x 10^8 and a CD34+/kg &amp;gt; 2.0 x10^6 were associated with better Neutr &amp; Plt engraftment, as was allo-HCT with an HLA-matched donor. Cryo'ed products were associated with worse Neutr but not Plt engraftment, while SAA &amp; having a BM graft from a donor with a minor ABO incompatibility were associated with better Plt engraftment. The expectation accuracy analysis suggests BM graft content is often not meeting expectations, highlighting a need for updated guidance on expectations of BM graft content. An update to NMDP's guidance on estimated TNC/mL of BM or analysis and provision of additional data (e.g., median pre-proc CD34+/mL or CD34+/TNC %) could allow centers to better anticipate TNC &amp; CD34+ BM graft content and help guide donor &amp; graft selection.

MRI Reliably Captures Bone Marrow Metrics in Myelofibrosis

Purpose Biopsy remains the clinical standard for evaluating bone marrow of patients with myelofibrosis (MF). However, randomly sampling a small volume of bone marrow, typically from the ilium, fails to capture heterogeneity of disease across anatomic sites. The invasive, painful nature of the procedure limits patient acceptance of repeated biopsies to monitor disease status and response to therapy. Here, we present a non-invasive, MRI technique for evaluating bone marrow in MF. Participants and Methods We analyzed bone marrow of 66 study participants (45 with MF; 15 with essential thrombocytosis or polycythemia vera; and 6 healthy controls). We assessed participant bone marrow across three anatomic sites (vertebral bodies, ilium, and femoral heads), using three quantitative MRI sequences: proton density fat fraction (PDFF) for fat content; apparent diffusion coefficient (ADC) for cellular effect on water mobility; and magnetization transfer (MT) for macromolecular structure and fiber deposition. We correlated these MRI metrics with patient prognosis (dynamic international prognostic scoring system; DIPSS) and iliac biopsy data for cellularity and fibrosis (MF grade). Results Participants with MF had elevated MT ratio (MTR) and ADC and lower PDFF compared to healthy participants. Non-MF MPN participants demonstrated the same trend, though to a lesser extent. Individual MRI metrics correlated strongly across anatomic sites (r pearson from 0.57 to 0.89, p-value &amp;lt; 0.01), with notable heterogeneity both within and among different regions. DIPSS risk groups had limited correlation with MRI metrics. To understand to what extent quantitative MRI biomarkers identify fibrotic marrow, we developed a multivariate logistic regression model to stratify the 45 participants with MF by early fibrosis (MF grades 0-1) and overt fibrosis (MF grades 2-3). Of the seven total anatomy-MRI metric combinations, three had the greatest contributions toward grading marrow fibrosis: PDFF in the vertebral bodies and ilium along with ADC in the ilium. We developed the logistic regression model to predict early and overt fibrosis with these three parameters using a 70%/30% train/test split with 5-fold cross validation. Based on this model, quantitative MRI metrics are associated with the severity of fibrosis in the bone marrow (test set performance: accuracy = 84.6%, sensitivity to predict overt fibrosis = 88.9%, specificity = 75%, area under the receiver operator curve = 0.94). Conclusion Quantitative bone marrow MRI reliably captures relevant metrics of MF bone marrow, including cellularity and fat replacement by fibrosis, and may be useful in clinical drug trials and patient management for MF.

Lymphocyte recovery from radiation-induced lymphopenia in locally advanced esophageal squamous cell carcinoma: correlations with prognosis and lymphocyte-related organs

BackgroundLimited studies explored the relationship between lymphocyte recovery after definitive concurrent chemoradiotherapy (dCCRT) and prognosis in esophageal squamous cell carcinoma (ESCC).MethodsESCC patients with obtainable absolute lymphocyte counts (ALCs) at 6 months after dCCRT were screened from prospective trials. Patients were divided into groups according to the grade of ALC nadir during radiotherapy (G4 or G1–3) and lymphocyte recovery status, which was assessed by lymphocyte recovery index (LRI), calculated as the ratio of post- to pre-treatment lymphocyte counts. Cox analysis was conducted to evaluate the prognostic significance of lymphocyte recovery status. Irradiated relative volumes of the bone marrow (BM) and spleen and effective dose to immune cells (EDIC) were collected to identify their impacts on lymphocyte recovery status by logistic analysis.Results232 patients were enrolled. In 69 patients with G4 ALC nadir (group A and B) and 163 patients with G1–3 ALC nadir (group C and D) during dCCRT, 27 (group A) and 67 (group C) patients showed an insufficient level of lymphocyte recovery (LRI < 60%), and 42 (group B) and 96 (group D) patients showed a satisfactory level of lymphocyte recovery (LRI ≥ 60%). Cox multivariable analysis revealed that inadequate lymphocyte recovery was significantly associated with worse overall survival (HR, 2.80 and 1.70) and local recurrence-free survival (HR, 2.82 and 1.60) both in group A vs group B and group C vs group D. Logistic analysis identified BM V5 (OR 4.24 and 2.29) as an independent predictor of inadequate lymphocyte recovery from G4 or G1–3 ALC nadir, respectively.ConclusionsInsufficient lymphocyte recovery might serve as a valuable prognostic factor, regardless of whether patients experienced G4 or G1–3 ALC nadir during radiotherapy. Additionally, it was observed that a larger relative volume of BM receiving ≥ 5 Gy was correlated with a higher risk of insufficient lymphocyte recovery.

A Dosimetric Correlation Between Radiation Dose to Bone and Reduction of Hemoglobin Levels After Radiation Therapy for Prostate Cancer

The aim of this work was to investigate the correlation between dose to pelvic bone marrow and anemia when treating prostate cancer (PC) with definitive radiation. Patients were selected from a prospective institutional database of patients with PC treated between 2008 and 2021. Pelvic bone (L3/L4 interface through ischial tuberosities) was contoured, and the dose to this structure was calculated. Doses were converted to 2-Gy equivalent doses using an α/β of 10. Exploratory analysis suggested dichotomizing into low-volume exposures of ≤1000 cc (LVE) and high-volume exposures of >1000 cc (HVE). Nonparametric kernel regressions were performed evaluating the effects of time, dose, and androgen deprivation therapy use on hemoglobin (Hgb) values. Reoptimization of plans was performed to evaluate the feasibility of adjusting significant dose levels. A total of 203 patients were included in the final analysis. Median baseline Hgb was 14.9 g/dL (interquartile range, 14.1-15.6). Patients with bone marrow HVE ≥15 Gy were found to have significantly lower predicted Hgb levels compared with those with LVE at day 90: 12.8 g/dL (95% CI, 12.4-13.3) versus 14.5 g/dL (95% CI, 14.0-14.9), respectively (P < .05). When normalizing starting Hgb levels, HVE patients still had significantly lower predicted Hgb levels than LVE at day 90: 86.1% (95% CI, 83.2%-89.7%) versus 96.2% (95% CI, 92.4%-100%), respectively. Reoptimizing 20 plans with high volume of bone marrow receiving 15 Gy resulted in a mean reduction from 1422 cc to 997 cc without compromise of other organs at risk or target coverage. Patients with >1000 cc of bone marrow receiving ≥15 Gy had significantly lower predicted Hgb levels than those with ≤1000 cc. Reoptimization of plans demonstrated that this dose constraint is achievable without impairing plan quality. This dose constraint can be considered to limit acute marrow toxicity in patients with PC.

Less Irradiation to Lymphocyte-Related Organs Reduced the Risk of G4 Lymphopenia in Esophageal Cancer: Re-Analysis of Prospective Trials.

This study aimed to explore the relationship between irradiation of lymphocyte-related organs at risk (LOARs) and lymphopenia during definitive concurrent chemoradiotherapy (dCCRT) for esophageal squamous cell carcinoma (ESCC). Cases of ESCC patients who received dCCRT from 2 prospective clinical trials were identified. To find its correlation with survival outcomes, grades of absolute lymphocyte counts (ALCs) nadir during radiotherapy were recorded following COX analysis. Associations of lymphocytes at nadir and dosimetric parameters including relative volumes of spleen and bone marrow receiving 0.5, 1, 2, 3, 5, 10, 20, 30, and 50Gy (V0.5, V1, V2, V3, V5, V10, V20, V30, and V50), and effective dose to circulating immune cells (EDIC) were examined by logistic risk regression analysis. The cutoffs of dosimetric parameters were determined by the receiver operating characteristic curve (ROC). A total of 556 patients were included. The incidences of grades 0, 1, 2, 3, and 4 (G4) lymphopenia during dCCRT were 0.2%, 0.5%, 9.7%, 59.7%, and 29.8%, respectively. Their median overall survival (OS) and progression-free survival (PFS) time were 50.2 and 24.3 months, respectively; the incidence of local recurrence and distant metastasis were 36.6% and 31.8%, respectively. Patients once suffering from G4 nadir during radiotherapy had unfavorable OS (HR, 1.28; P = .044) and a higher incidence of distant metastasis (HR, 1.52; P = .013). Furthermore, patients with EDIC ≤8.3Gy plus spleen V0.5 ≤11.1% and bone marrow V10 ≤33.2% were strongly associated with lower risk of G4 nadir (OR, 0.41; P = .004), better OS (HR, 0.71; P = .011) and lower risk of distant metastasis (HR, 0.56; P = .002). Smaller relative volumes of spleen V0.5 and bone marrow V10 plus lower EDIC were jointly prone to reduce the incidence of G4 nadir during definitive concurrent chemoradiotherapy. This modified therapeutic strategy could be a significant prognostic factor for survival outcomes in ESCC.

BONE MARROW VOLUME IRRADIATED AND RISK OF CYTOPENIAS IN AGGRESSIVE B‐CELL LYMPHOMA PATIENTS BRIDGED WITH RADIATION THERAPY FOR CART CELL THERAPY

Introduction: Patients (pts) with aggressive B cell lymphomas undergoing anti-CD19-directed chimeric antigen receptor T cell therapy (CART) can benefit from bridging radiation therapy (bRT) as immune priming. Previously, by measuring the bone marrow (BM) volume irradiated in multiple myeloma pts, we established that RT does not adversely affect stem cell collection.1 Here, we examined the impact of irradiated BM distribution on the risk of acute cytopenias after bRT prior to CART. Methods: We retrospectively reviewed adults with DLBCL between 2017 and 2022 who received bRT prior to CART, which included axicabtagene ciloleucel, tisagenlecleucel, or lisocabtagene maraleucel. Clinical characteristics, labs, and response were extracted. RT plans were reviewed; % BM irradiated was calculated as described previously with published estimates of skeletal BM distribution.2 Progression free survival (PFS), disease specific survival (DSS) and overall survival (OS) were modeled using the Kaplan-Meier method. Binary logistic regression and Mann-Whitney U correlated RT distribution with cytopenias (anemia, thrombocytopenia, and neutropenia per CTCAE v4.03). Results: Fifty-one pts received bRT, of which 13 (25.5%) had bulky disease (≥10 cm). Majority received bRT alone; 16 (31.4%) were additionally bridged with systemic therapy. The median bRT was 30 Gy (range: 4–48 Gy) and 26 pts (51%) pts received ≥30 Gy. Thirty-one pts (61%) received bRT comprehensively to all disease sites. The incidence of ≥Grade 3 cytopenias in timepoints following bRT are shown below. The median cumulative % of BM irradiated was 5.05% (range: 0%–50%). Nine pts (18%) received bRT encompassing ≥15% of the BM, for whom there was no increased incidence of ≥Grade 3 cytopenias overall (as well as specifically anemia, thrombocytopenia, and neutropenia) at any timepoint (all p > 0.2). Receipt of RT comprehensively to all disease sites, or bridging with both RT + systemic therapy, or delivery of ≥30 Gy bRT did not correlate with the incidence of ≥Grade 3 cytopenias at any timepoint. Regarding outcomes, 26 pts (51%) had CR at 30 days post-CART. Sixteen had PR (31.4%), and 9 pts (17.6%) had PD or SD. The OS/PFS were 84% (71–92)/78% (64–87) at 1 year, and 59% (44–71)/57% (42–70) at 2 years. Twenty-seven pts (52.9%) remain alive at last follow-up, 19 (70.4%) of whom have no evidence of disease. Conclusions: bRT is not associated with increased incidence of cytopenias, even for doses ≥30 Gy, when encompassing ≥15% of the BM, or when pts are treated comprehensively to all disease sites. While bRT can be delivered safely, we still urge careful field design to ensure minimum BM is treated to incorporate into pre-CART regimens. Keywords: aggressive B-cell non-Hodgkin lymphoma, cellular therapies, radiation therapy Conflicts of interests pertinent to the abstract R. E. Steiner Research funding from Seagen, BMS, GSK and Rafael pharmaceuticals.

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

ObjectiveTo evaluate the impact of bone marrow (BM) irradiation dose on acute haematologic toxicity (HT) in concurrent chemoradiotherapy for cervical cancer.MethodsSixty-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.ResultsIn 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.ConclusionThe 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.

Clinical study of acute toxicity of pelvic bone marrow-sparing intensity-modulated radiotherapy for cervical cancer.

To compare the dose volume of the target area and the toxicity of pelvic bone marrow-sparing intensity-modulated radiotherapy (PBMS-IMRT) with routine IMRT in patients undergoing radiochemotherapy for cervical cancer. Forty patients with indications for adjuvant radiochemotherapy after cervical cancer surgery were selected and randomly divided into IMRT (n = 20) and PBMS-IMRT (n = 20) groups to observe and record the toxicity and its severity in the blood, gastrointestinal tract, and genitourinary system. There was no significant difference in the target area conformity index (CI) or homogeneity index (HI) between the two groups (p > 0.05). The pelvic bone V10-V50 in the PBMS-IMRT group were lower than those in the IMRT group (p < 0.05), and there was lower hematological toxicity (p < 0.05) and fewer delays or interruptions in chemotherapy and/or radiotherapy (p < 0.05) in the PBMS-IMRT group. The toxicity to the gastrointestinal and genitourinary systems in the two groups was not significantly different (p > 0.05). PBMS-IMRT significantly reduced the dose volume of the pelvic bone marrow, thereby reducing the incidence of bone marrow suppression. However, it had no significant impact on the gastrointestinal or genitourinary systems.

TGFβ1+CCR5+ neutrophil subset increases in bone marrow and causes age-related osteoporosis in male mice

TGFβ1 induces age-related bone loss by promoting degradation of TNF receptor-associated factor 3 (TRAF3), levels of which decrease in murine and human bone during aging. We report that a subset of neutrophils (TGFβ1+CCR5+) is the major source of TGFβ1 in murine bone. Their numbers are increased in bone marrow (BM) of aged wild-type mice and adult mice with TRAF3 conditionally deleted in mesenchymal progenitor cells (MPCs), associated with increased expression in BM of the chemokine, CCL5, suggesting that TRAF3 in MPCs limits TGFβ1+CCR5+ neutrophil numbers in BM of young mice. During aging, TGFβ1-induced TRAF3 degradation in MPCs promotes NF-κB-mediated expression of CCL5 by MPCs, associated with higher TGFβ1+CCR5+ neutrophil numbers in BM where they induce bone loss. TGFβ1+CCR5+ neutrophils decreased bone mass in male mice. The FDA-approved CCR5 antagonist, maraviroc, reduced TGFβ1+CCR5+ neutrophil numbers in BM and increased bone mass in aged mice. 15-mon-old mice with TGFβRII specifically deleted in MPCs had lower numbers of TGFβ1+CCR5+ neutrophils in BM and higher bone volume than wild-type littermates. We propose that pharmacologic reduction of TGFβ1+CCR5+ neutrophil numbers in BM could treat or prevent age-related osteoporosis.

Automated shape-independent assessment of the spatial distribution of proton density fat fraction in vertebral bone marrow

This work proposes a method for automatic standardized assessment of bone marrow volume and spatial distribution of the proton density fat fraction (PDFF) in vertebral bodies. Intra- and interindividual variability in size and shape of vertebral bodies is a challenge for comparable interindividual evaluation and monitoring of changes in the composition and distribution of bone marrow due to aging and/or intervention. Based on deep learning image segmentation, bone marrow PDFF of single vertebral bodies is mapped to a cylindrical template and corrected for the inclination with respect to the horizontal plane. The proposed technique was applied and tested in a cohort of 60 healthy (30 males, 30 females) individuals. Obtained bone marrow volumes and mean PDFF values are comparable to former manual and (semi-)automatic approaches. Moreover, the proposed method allows shape-independent characterization of the spatial PDFF distribution inside vertebral bodies.

The effect of radiotherapy time and dose on acute hematologic toxicity during concurrent postoperative chemoradiotherapy for early high-risk cervical cancer.

Objective: This study aims to analyze the characteristics and factors that influence acute hematological toxicity (HT) during concurrent chemoradiotherapy (CCRT) for cervical cancer, as well as to provide reference data for clinical practice. Methods: Patients with FIGO IB1-IIA2 cervical cancer who underwent CCRT from May 2018 to August 2020 were included in this study retrospectively. All patients had received external beam radiation therapy and platinum-based concurrent chemotherapy. HT was assessed according to CTCAE 5.0. The pelvic bone marrow was redrawn on the original CT images and divided into four parts: the whole pelvic bone marrow (WP-BM), iliac bone marrow (IL-BM), lower pelvic bone marrow (LP-BM), and lumbosacral bone marrow (LS-BM). The radiation dose and volume of each part of the pelvic bone marrow were recalculated in a new plan created using the original planning parameters. The corresponding dose-volume histogram (DVH) was generated to obtain the bone marrow volumes receiving 10Gy, 20Gy, 30Gy, 40Gy, 45Gy, and 50Gy. Results: In 112 patients, the incidences of grade 2 or higher leukopenia, anemia, thrombocytopenia, and neutropenia were 49.1%, 2.7%, 1.8%, and 20.5%, respectively. Leukopenia was linked to LS-V20 (r = -0.310; P = 0.006) and radiotherapy treatment lengths (days) (r = -0.416; P = 0.013). Anemia was associated with WP-V30, WP-V40, WP-V45, WP-V50, IL-V20, IL-V40, ILV45, IL-V50, LP-V30, LP-V40, LP-V45, and LP-V50 (P <0.05). Thrombocytopenia (r = -0.304, P = 0.007) and neutropenia (r = -0.368, P = 0.009) was associated only with the length of radiotherapy treatment (day). Multiple regression analysis showed that only anemia was negatively correlated with WP-V30, IL-V40, and LP-V40 (P <0.05). Conclusions: Acute HT during CCRT in early-stage high-risk cervical cancer may be related to the duration of radiotherapy and the volume of different radiotherapy doses received at different parts in the pelvic bone marrow.

A Dosimetric Analysis of Modified Volumetric Modulated Arc Therapy for Bone Marrow Sparing Radiotherapy in Cervical Cancer-An alternative Approach to Conventional VMAT

External beam radiotherapy remains the primary treatment modality in cervical cancer. Nowadays Intensity Modulated Radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) are increasingly being used to reduce normal tissue toxicity. The drawback of conventional VMAT is that a considerable volume of pelvic bone marrow receives a low dose. We analyzed whether there was a way to reduce the volume of the low dose regions of bone marrow, and assessed the potential benefit of conventional-4Arc (C-4Arc VMAT), and Modified-4Arc (M-4Arc VMAT) over the conventional 2 ARC VMAT. Twelve clinically proven locally advanced cervical cancer patients treated with concurrent chemo-radiotherapy by Conventional VMAT (RapidArc) in dual rotation mode (C-2Arc VMAT) were selected for this study.C-4Arc VMAT and M-4Arc VMAT dose plans were generated for these twelve patients and these three different types of plans were evaluated for the quality and compared dosimetrically. M-4Arc VMAT designs exhibited a greater bone marrow sparing when compared with conventional VMATs with respect to volume receiving 5Gy to 35Gy without compromising PTV dose coverage. M-4Arc VMAT plans, the bone marrow volume receiving 30 Gy (V30Gy),40Gy (V40Gy), and mean doses were lower than the C- 4 Arc plan and a similar result was observed for V50(Gy) also when comparing with the standard 2 Arc plan. In modified VMAT plans, the rectum and bladder dose volumes were lower than standard VMAT. Similarly, the bowel bag V35(Gy), V40(Gy), V50(Gy), mean doses. The right and left femoral head doses were reduced significantly when compared to conventional VMAT plans. The M-4Arc VMAT plans are better than the C-2Arc and C-4Arc VMAT plans for reducing the dose to bone marrow by limiting the MLC field width travel.

EVALUATION OF PREDICTABILITY OF BONE MARROW CELL CELLULARITY FROM RELATED AND UNRELATED DONORS

Introduction: For successful hematopoietic stem cell transplantation, a minimum number of total nucleated cells should be obtained (TNC) during the bone marrow (BM) harvest procedure. Objectives: Evaluate the predictability of the BM TNC collected from an interim sample collected during the procedure and the factors related to high-cellular harvest. Methodology: This is a retrospective observational study including BM donors and recipient from 2017 to 2019. The final TNC was based on an interim quantification of TNC and was compared with the actual final TNC obtained. Results: 81 donors were included and interim TNC of 53 donors were available. Based on linear regression, a significant correlation was found between the volume of BM collected and the interim and final TNC (n=53; R2=0.83; P&lt;0.001). The relationship between donor and recipient weight significantly influenced the collection yield. There was also a positive correlation between the volume of BM collected and the interim and final count of TNC (n=53; r=0.88; p&lt;0.001). The difference in donor and recipient weight also had a positive correlation (p&lt;0.02). Conclusion: Our results showed that interim TNC quantification can help to achieve a better performance during the procedure, allowing real-time re-estimation of the volume needed to be harvested.