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.

Assessment of lung doses in patients undergoing total body irradiation for haematological malignancies with and without lung shielding.

INTRODUCTION: Total body irradiation (TBI) practices vary considerably amongst centres, and the risk of treatment related toxicities remains unclear. We report lung doses for 142 TBI patients who underwent either standing TBI with lung shield blocks or lying TBI without blocks. METHODS: Lung doses were calculated for 142 TBI patients treated between June 2016 and June 2021. Patients were planned using Eclipse (Varian Medical Systems) using AAA_15.6.06 for photon dose calculations and EMC_15.6.06 for electron chest wall boost fields. Mean and maximum lung doses were calculated. RESULTS: Thirty-seven patients (26.2%) were treated standing using lung shielding blocks with 104 (73.8%) treated lying down. Lowest relative mean lung doses were achieved using lung shielding blocks in standing TBI, reducing the mean lung doses to 75.2% of prescription (9.9 Gy), ±4.1% (range 68.6-84.1%) for a prescribed dose of 13.2 Gy in 11 fractions, including contributions from electron chest wall boost fields, compared to 12 Gy in 6 fraction lying TBI receiving 101.6% mean lung dose (12.2 Gy) ±2.4% (range 95.2-109.5%) (P ≪ 0.05). Patients treated lying down with 2 Gy single fraction received the highest relative mean lung dose on average, with 108.4% (2.2 Gy) ±2.6% of prescription (range 103.2-114.4%). CONCLUSION: Lung doses have been reported for 142 TBI patients using the lying and standing techniques described herein. Lung shielding blocks significantly reduced mean lung doses despite the addition of electron boost fields to the chest wall.

Whole body potassium as a biomarker for potassium uptake using a mouse model.

Potassium is known for its effect on modifiable chronic diseases like hypertension, cardiac disease, diabetes (type-2), and bone health. In this study, a new method, neutron generator based neutron activation analysis (NAA), was utilized to measure potassium (K) in mouse carcasses. A DD110 neutron generator based NAA assembly was used for irradiation.Thirty-two postmortem mice (n= 16 males and 16 females, average weight [Formula: see text] and [Formula: see text] g) were employed for this study. Soft-tissue equivalent mouse phantoms were prepared for the calibration. All mice were irradiated for 10 minutes, and the gamma spectrum with 42K was collected using a high efficiency, high purity germanium (HPGe) detector. A lead shielding assembly was designed and developed around the HPGe detector to obtain an improved detection limit. Each mouse sample was irradiated and measured twice to reduce uncertainty. The average potassium concentration was found to be significantly higher in males [Formula: see text] compared to females [Formula: see text]. We also observed a significant correlation between potassium concentration and the weight of the mice. The detection limit for potassium quantification with the NAA system was 46 ppm. The radiation dose to the mouse was approximately 56 [Formula: see text] mSv for 10-min irradiation. In conclusion, this method is suitable for estimating individual potassium concentration in small animals. The direct evaluation of total body potassium in small animals provides a new way to estimate potassium uptake in animal models. This method can be adapted later to quantify potassium in the human hand and small animals in vivo. When used in vivo, it is also expected to be a valuable tool for longitudinal assessment, kinetics, and health outcomes.

Assessment of Nuclear and Mitochondrial DNA, Expression of Mitochondria-Related Genes in Different Brain Regions in Rats after Whole-Body X-ray Irradiation.

Studies of molecular changes occurred in various brain regions after whole-body irradiation showed a significant increase in terms of the importance in gaining insight into how to slow down or prevent the development of long-term side effects such as carcinogenesis, cognitive impairment and other pathologies. We have analyzed nDNA damage and repair, changes in mitochondrial DNA (mtDNA) copy number and in the level of mtDNA heteroplasmy, and also examined changes in the expression of genes involved in the regulation of mitochondrial biogenesis and dynamics in three areas of the rat brain (hippocampus, cortex and cerebellum) after whole-body X-ray irradiation. Long amplicon quantitative polymerase chain reaction (LA-QPCR) was used to detect nDNA and mtDNA damage. The level of mtDNA heteroplasmy was estimated using Surveyor nuclease technology. The mtDNA copy numbers and expression levels of a number of genes were determined by real-time PCR. The results showed that the repair of nDNA damage in the rat brain regions occurs slowly within 24 h; in the hippocampus, this process runs much slower. The number of mtDNA copies in three regions of the rat brain increases with a simultaneous increase in mtDNA heteroplasmy. However, in the hippocampus, the copy number of mutant mtDNAs increases significantly by the time point of 24 h after radiation exposure. Our analysis shows that in the brain regions of irradiated rats, there is a decrease in the expression of genes (ND2, CytB, ATP5O) involved in ATP synthesis, although by the same time point after irradiation, an increase in transcripts of genes regulating mitochondrial biogenesis is observed. On the other hand, analysis of genes that control the dynamics of mitochondria (Mfn1, Fis1) revealed that sharp decrease in gene expression level occurred, only in the hippocampus. Consequently, the structural and functional characteristics of the hippocampus of rats exposed to whole-body radiation can be different, most significantly from those of the other brain regions.

Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis from 3 phase-II clinical trials.

BACKGROUND: Standard-dose (36-Gy) total skin electron beam therapy (TSEBT) is a highly effective treatment in mycosis fungoides. However, the regimen is time-intensive and may be associated with significant toxicity. OBJECTIVE: We sought to evaluate the efficacy and tolerability associated with low-dose (12-Gy) TSEBT. METHODS: Data from 3 clinical trials using low-dose (12-Gy) TSEBT were pooled. In all trials, TSEBT-naïve patients with stage IB to IIIA mycosis fungoides were treated with TSEBT (12 Gy, 1 Gy per fraction over 3 weeks). The primary end point was clinical response rate. Secondary end points included time to response and duration of clinical benefit. RESULTS: In all, 33 patients enrolled. Eighteen were male; stages were 22 IB, 2 IIA, 7 IIB, and 2 IIIA. Overall response rate was 88% (29/33), including 9 patients with complete response. Median time to response was 7.6 weeks (3-12.4 weeks). Median duration of clinical benefit was 70.7 weeks (95% confidence interval 41.8-133.8 weeks). Toxicities from TSEBT were mild and reversible. LIMITATIONS: Conclusions are limited because of the small number of patients. CONCLUSIONS: Low-dose TSEBT provides reliable and rapid reduction of disease burden in patients with mycosis fungoides, which could be administered safely multiple times during the course of a patient's disease with acceptable toxicity profile.

Stochastic modeling of stress erythropoiesis using a two-type age-dependent branching process with immigration.

The erythroid lineage is a particularly sensitive target of radiation injury. We model the dynamics of immature (BFU-E) and mature (CFU-E) erythroid progenitors, which have markedly different kinetics of recovery, following sublethal total body irradiation using a two-type reducible age-dependent branching process with immigration. Properties of the expectation and variance of the frequencies of both types of progenitors are presented. Their explicit expressions are derived when the process is Markovian, and their asymptotic behavior is identified in the age-dependent (non-Markovian) case. Analysis of experimental data on the kinetics of BFU-E and CFU-E reveals that the probability of self-renewal increases transiently for both cell types following sublethal irradiation. In addition, the probability of self-renewal increased more for CFU-E than for BFU-E. The strategy adopted by the erythroid lineage ensures replenishment of the BFU-E compartment while optimizing the rate of CFU-E recovery. Finally, our analysis also indicates that radiation exposure causes a delay in BFU-E recovery consistent with injury to the hematopoietic stem/progenitor cell compartment that give rise to BFU-E. Erythroid progenitor self-renewal is thus an integral component of the recovery of the erythron in response to stress.

Application of multivariate modeling for radiation injury assessment: a proof of concept.

Multivariate radiation injury estimation algorithms were formulated for estimating severe hematopoietic acute radiation syndrome (H-ARS) injury (i.e., response category three or RC3) in a rhesus monkey total-body irradiation (TBI) model. Classical CBC and serum chemistry blood parameters were examined prior to irradiation (d 0) and on d 7, 10, 14, 21, and 25 after irradiation involving 24 nonhuman primates (NHP) (Macaca mulatta) given 6.5-Gy (60)Co Υ-rays (0.4 Gy min(-1)) TBI. A correlation matrix was formulated with the RC3 severity level designated as the "dependent variable" and independent variables down selected based on their radioresponsiveness and relatively low multicollinearity using stepwise-linear regression analyses. Final candidate independent variables included CBC counts (absolute number of neutrophils, lymphocytes, and platelets) in formulating the "CBC" RC3 estimation algorithm. Additionally, the formulation of a diagnostic CBC and serum chemistry "CBC-SCHEM" RC3 algorithm expanded upon the CBC algorithm model with the addition of hematocrit and the serum enzyme levels of aspartate aminotransferase, creatine kinase, and lactate dehydrogenase. Both algorithms estimated RC3 with over 90% predictive power. Only the CBC-SCHEM RC3 algorithm, however, met the critical three assumptions of linear least squares demonstrating slightly greater precision for radiation injury estimation, but with significantly decreased prediction error indicating increased statistical robustness.

Protein biomarkers for enhancement of radiation dose and injury assessment in nonhuman primate total-body irradiation model.

Development and validation of early-response radiation injury biomarkers are critical for effective triage and medical management of irradiated individuals. Plasma protein and haematological profiles were evaluated using multivariate linear-regression analysis to provide dose-response calibration curves for photon-radiation dose assessment in 30 rhesus macaques total-body-irradiated to 1-8.5 Gy with (60)Co gamma rays (0.55 Gy min(-1)). Equations for radiation dose received were established based on different combinations of protein biomarkers [i.e. C-reactive protein (CRP), serum amyloid A (SAA), interleukin 6 (IL-6) and Flt3 Ligand (Flt3L)] at samples collection time-points 6 h, 1, 2, 3, 4 and 7 d post-total-body irradiation. Dynamic changes in the levels of CRP, SAA, IL-6 and Flt3L may function as prognostic indicators of the time course and severity of acute radiation sickness (ARS). The combination of protein biomarkers provides greater accuracy for early radiation assessment than any one biomarker alone.

Early-response biomarkers for assessment of radiation exposure in a mouse total-body irradiation model.

Nuclear accidents or terrorist attacks could expose large numbers of people to ionizing radiation. Early biomarkers of radiation injury will be critical for triage, treatment, and follow-up of such individuals. The authors evaluated the utility of multiple blood biomarkers for early-response assessment of radiation exposure using a murine (CD2F1, males) total-body irradiation (TBI) model exposed to 6°Co γ rays (0.6 Gy min⁻¹) over a broad dose range (0-14 Gy) and timepoints (4 h-5 d). Results demonstrate: 1) dose-dependent changes in hematopoietic cytokines: Flt-3 ligand (Flt3L), interleukin 6 (IL-6), granulocyte colony stimulating factor (G-CSF), thrombopoietin (TPO), erythropoietin (EPO), and acute phase protein serum amyloid A (SAA); 2) dose-dependent changes in blood cell counts: lymphocytes, neutrophils, platelets, and ratio of neutrophils to lymphocytes; 3) protein results coupled with peripheral blood cell counts established very successful separation of groups irradiated to different doses; and 4) enhanced separation of dose was observed as the number of biomarkers increased. Results show that the dynamic changes in the levels of SAA, IL-6, G-CSF, and Flt3L reflect the time course and severity of acute radiation syndrome (ARS) and may function as prognostic indicators of ARS outcome. These results also demonstrate proof-in-concept that plasma proteins show promise as a complimentary approach to conventional biodosimetry for early assessment of radiation exposures and, coupled with peripheral blood cell counts, provide early diagnostic information to manage radiation casualty incidents effectively, closing a gap in capabilities to rapidly and effectively assess radiation exposure early, especially needed in case of a mass-casualty radiological incident.

Lifetime increased cancer risk in mice following exposure to clinical proton beam-generated neutrons.

PURPOSE: To evaluate the life span and risk of cancer following whole-body exposure of mice to neutrons generated by a passively scattered clinical spread-out Bragg peak (SOBP) proton beam. METHODS AND MATERIALS: Three hundred young adult female FVB/N mice, 152 test and 148 control, were entered into the experiment. Mice were placed in an annular cassette around a cylindrical phantom, which was positioned lateral to the mid-SOBP of a 165-MeV, clinical proton beam. The average distance from the edge of the mid-SOBP to the conscious active mice was 21.5 cm. The phantom was irradiated with once-daily fractions of 25 Gy, 4 days per week, for 6 weeks. The age at death and cause of death (ie, cancer and type vs noncancer causes) were assessed over the life span of the mice. RESULTS: Exposure of mice to a dose of 600 Gy of proton beam-generated neutrons, reduced the median life span of the mice by 4.2% (Kaplan-Meier cumulative survival, P=.053). The relative risk of death from cancer in neutron exposed versus control mice was 1.40 for cancer of all types (P=.0006) and 1.22 for solid cancers (P=.09). For a typical 60 Gy dose of clinical protons, the observed 22% increased risk of solid cancer would be expected to decrease by a factor of 10. CONCLUSIONS: Exposure of mice to neutrons generated by a proton dose that exceeds a typical course of radiation therapy by a factor of 10, resulted in a statistically significant increase in the background incidence of leukemia and a marginally significant increase in solid cancer. The results indicate that the risk of out-of-field second solid cancers from SOBP proton-generated neutrons and typical treatment schedules, is 6 to 10 times less than is suggested by current neutron risk estimates.

[Assessment of the therapeutic possibilities of systemic radiotherapy as a component of combined treatment for advanced ovarian carcinoma].

The new technology of combined treatment for patients with ovarian carcinoma of III-IV stages and its relapse is presented. The essentially new component is systemic radiotherapy in nontumoricidal doses. It is used with both traditional surgical and chemotherapeutic components. Systemic radiotherapy is carried out in a form of subtotal body irradiation in two dose-time options with total dose of 1 Gy and 9 Gy. The choice of radiation option is carried out taking into account the initial somatic resource of patients estimated by the condition of lymphopoiesis. The use of systemic radiotherapy in combined treatment of advanced ovarian carcinoma allowed to achieve the significant increase of 3-, 5-year survival in patients as compared to traditional chemo-surgical method. Indirect mechanism of nontumoricidal systemic radiotherapy is to be considered as a vital way for tumor control.

Assessment of genotoxic and cytotoxic hazards in brain and bone marrow cells of newborn rats exposed to extremely low-frequency magnetic field.

The present study aimed to evaluate the association between whole body exposure to extremely low frequency magnetic field (ELF-MF) and genotoxic , cytotoxic hazards in brain and bone marrow cells of newborn rats. Newborn rats (10 days after delivery) were exposed continuously to 50 Hz, 0.5 mT for 30 days. The control group was treated as the exposed one with the sole difference that the rats were not exposed to magnetic field. Comet assay was used to quantify the level of DNA damage in isolated brain cells. Also bone marrow cells were flushed out to assess micronucleus induction and mitotic index. Spectrophotometric methods were used to measure the level of malondialdehyde (MDA) and the activity of glutathione (GSH) and superoxide dismutase (SOD). The results showed a significant increase in the mean tail moment indicating DNA damage in exposed group (P < 0.01, 0.001, 0.0001). Moreover ELF-MF exposure induced a significant (P < 0.01, 0.001) four folds increase in the induction of micronucleus and about three folds increase in mitotic index (P < 0.0001). Additionally newborn rats exposed to ELF-MF showed significant higher levels of MDA and SOD (P < 0.05). Meanwhile ELF-MF failed to alter the activity of GSH. In conclusion, the present study suggests an association between DNA damage and ELF-MF exposure in newborn rats.

Oral mucositis: etiology, and clinical and pharmaceutical management.

Oral mucosal damage is one of the common and worst side effects of radiotherapy and chemotherapy treatment for cancer. With prevalence between 10% and 100%, depending on the cytotoxic and/or radiotherapy regimen and patient-associated variables, this morbid condition represents a significant problem in oncology. This article addresses oral mucositis and discusses its prevalence, risk factors, clinical and economical impacts, etiology, and clinical management in view of the most recent evidence. Despite clear progress and the development of clinical guidelines on this topic, what we currently have to offer to patients to manage mucositis and oropharyngeal pain is still inadequate. This article offers two compounded preparations supported by evidence-based data to treat oral mucositis. Expansion of the knowledge of the pathogenesis of mucositis as well as a better insight into individual risk factors will provide opportunities to improve management strategies.

Assessment of total- and partial-body irradiation in a baboon model: preliminary results of a kinetic study including clinical, physical, and biological parameters.

This biodosimetry study used irradiated baboons to investigate the efficacy of a kinetic multiparameter (clinical, physical, and biological) approach for discriminating partial-body irradiation (PBI) and total-body irradiation (TBI). Animals were unilaterally (front) exposed to 60Co gamma rays (8 to 32 cGy min) using either TBI or vertical left hemi-body irradiation (HBI), as follows: 2.5 Gy TBI (n = 2), 5 Gy TBI (n = 2), 5 Gy HBI (n = 2), and 10 Gy HBI (n = 2). Midline tissue doses were measured at the anterior iliac crest level with an ionization chamber, and body dosimetry was performed using thermoluminescent dosimeters. Blood samples were collected before exposure and from 1 h until 200 d after irradiation. Clinical status, complete blood cell count, biochemical parameters, and cytogenetic analysis were evaluated. The partial least square discriminant analysis chosen for statistical analysis showed that the four groups of irradiated baboons were clearly separated. However, the dicentric chromosome assay may not distinguish HBI from TBI in confounding situations where equivalent whole-body doses are similar and the time of exposure is sufficient for peripheral blood lymphocyte homogenization. Interestingly, as bone marrow shielding in HBI animals prevented aplasia from happening, hematologic parameters such as the platelet count and Flt-3 ligand level helped to distinguish HBI and TBI. Moreover, the ratio of neutrophil to lymphocyte counts, creatine kinase, and citrulline levels may be discriminating biomarkers of dose or injury. Both early and delayed clinical signs and bioindicators appear to be useful for assessment of heterogeneous irradiation.

Changes in serum 25-hydroxyvitamin D and cholecalciferol after one whole-body exposure in a commercial tanning bed: a randomized study.

We wanted to evaluate the cutaneous synthesis of 25OHD and cholecalciferol after one whole-body exposure to ultraviolet radiation type B (UVB) in a randomized setup. Healthy volunteers were randomized to one whole-body exposure in a commercial tanning bed with UVB emission (UVB/UVA ratio 1.8-2.0%) or an identical placebo tanning bed without UVB. The output in the 280-320 nm range was 450 µW/cm². Blood samples were analyzed for 25OHD and cholecalciferol at baseline and during 7 days after treatment. We included 20 volunteers, 11 to UVB and 9 to placebo treatment. During the first 6 h, no significant differences in 25OHD between the groups were found. At the end of the study, we found a mean increase of 25OHD in the UVB group of 4.5 nmol/l (SD 7 nmol/l) compared to a decline of -1.2 nmol/l (SD 7 nmol/l) in the placebo group (p = 0.1). A linear mixed model yielded an increase of 25OHD in the UVB group of 1.0 nmol/l per 24 h (p < 0.01). For cholecalciferol, we found a near significant increase of 1 pmol/l per hour in the UVB group compared to the placebo group during the first 6 h (p = 0.052). One tanning bed session had significant, but modest impact on the level of 25OHD during 7 days after exposure to UVB.

Longitudinal assessment of hematopoietic stem cell transplantation and hyposalivation.

Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study determined stimulated whole-saliva flow rates in HSCT recipients in comparison with a healthy control group. Stimulated whole-saliva flow rates of 228 allogeneic HSCT recipients (134 males, 94 females; mean age, 43 yrs) were examined pre-HSCT and 6, 12, and 24 months post-HSCT. Healthy individuals (n = 144; 69 males, 75 females; mean age, 46 yrs) served as the control group. Stimulated saliva flow rates (mL/min) were measured and analyzed statistically, stratifying for hematological diagnoses and conditioning therapy. Hyposalivation (≤ 0.7 mL/min) was found in 40% (p < 0.00001), 53% (p < 0.00001), 31% (p < 0.01), and 26% (n.s.) of the recipients pre-HSCT, and 6, 12, and 24 months post-HSCT, respectively, whereas 16% of the control individuals had hyposalivation. Severe hyposalivation (≤ 0.3 mL/min) was found in 11%, 18%, 4%, and 4% of the recipients pre-HSCT, and 6, 12, and 24 months post-HSCT, respectively. Additionally, conditioning regimen and sex had an impact on saliva flow. In conclusion, hyposalivation was observed to be a common but generally reversible complication among HSCT recipients.

Severe pulmonary toxicity after myeloablative conditioning using total body irradiation: an assessment of risk factors.

PURPOSE: To assess factors associated with severe pulmonary toxicity after myeloablative conditioning using total body irradiation (TBI) followed by allogeneic stem cell transplantation. METHODS AND MATERIALS: A total of 101 adult patients who underwent TBI-based myeloablative conditioning for hematologic malignancies at Duke University between 1998 and 2008 were reviewed. TBI was combined with high-dose cyclophosphamide, melphalan, fludarabine, or etoposide, depending on the underlying disease. Acute pulmonary toxicity, occurring within 90 days of transplantation, was scored using Common Terminology Criteria for Adverse Events version 3.0. Actuarial overall survival and the cumulative incidence of acute pulmonary toxicity were calculated via the Kaplan-Meier method and compared using a log-rank test. A binary logistic regression analysis was performed to assess factors independently associated with acute severe pulmonary toxicity. RESULTS: The 90-day actuarial risk of developing severe (Grade 3-5) pulmonary toxicity was 33%. Actuarial survival at 90 days was 49% in patients with severe pulmonary toxicity vs. 94% in patients without (p < 0.001). On multivariate analysis, the number of prior chemotherapy regimens was the only factor independently associated with development of severe pulmonary toxicity (odds ratio, 2.7 per regimen). CONCLUSIONS: Severe acute pulmonary toxicity is prevalent after TBI-based myeloablative conditioning regimens, occurring in approximately 33% of patients. The number of prior chemotherapy regimens appears to be an important risk factor.

Acute radiation syndrome: assessment and management.

Primary care physicians may be unprepared to diagnose and treat rare, yet potentially fatal, illnesses such as acute radiation syndrome (ARS). ARS, also known as radiation sickness, is caused by exposure to a high dose of penetrating, ionizing radiation over a short period of time. The time to onset of ARS is dependent on the dose received, but even at the lowest doses capable of causing illness, this will occur within a matter of hours to days. This article describes the clinical manifestations of ARS, provides guidelines for assessing its severity, and makes recommendations for managing ARS victims.

Prospective assessment of bone turnover and clinical bone diseases after allogeneic hematopoietic stem-cell transplantation.

BACKGROUND: Bone complications after hematopoietic stem-cell transplantation (HSCT) are relatively frequent. Evaluation of biomarkers of bone turnover and dual energy x-ray absorptiometry (DEXA) are not known in this context. METHODS: We prospectively evaluated bone mineral density, biomarkers of bone turnover, and the cumulative incidence of bone complications after allogeneic HSCT. One hundred forty-six patients were included. Bone mineral density was measured by DEXA 2-month and 1-year post-HSCT. The markers of bone turnover were serum C-telopeptide (C-TP), 5 tartrate-resistant acid phosphatase (bone resorption), and osteocalcin (bone formation) determined pre-HSCT and 2 months and 1 year thereafter. Potential association between osteoporosis at 2 months, osteoporotic fracture or avascular necrosis and, individual patient's characteristics and biologic markers were tested. RESULTS: C-TP was high before and 2 months after transplant. At 2 months, DEXA detected osteoporosis in more than half the patients tested. Male sex, median age less than or equal to 15 years, and abnormal C-TP before HSCT were risk factors significantly associated with osteoporosis. Three-year cumulative incidences of fractures and avascular necrosis were 8% and 11%, respectively. Children were at higher risk of fracture, whereas corticosteroid treatment duration was a significant risk factor for developing a clinical bone complication post-HSCT. Bone complications and osteoporosis are frequent after HSCT. Bone biologic markers and DEXA showed that subclinical bone abnormalities appeared early post-HSCT. CONCLUSION: The risk factors, age, gender, and C-TP easily available at the time of transplantation were identified. Biphosphonates should probably be given to patients with those risk factors.

Multiple blood-proteins approach for early-response exposure assessment using an in vivo murine radiation model.

PURPOSE: The aim was to evaluate the utility of multiple blood-protein biomarkers for early-response assessment of radiation exposure using a murine radiation model system. MATERIAL AND METHODS: BALB/c male mice (8-10 weeks old) were exposed to whole-body 60Co gamma-rays (10 cGy min(-1)) over a broad dose range (0-7 Gy). Blood protein biomarkers (i.e., Growth Arrest and DNA Damage Inducible Gene 45 or GADD45alpha, interleukin 6 or IL-6, and serum amyloid A or SAA) were measured by enzyme linked immunosorbent assay (ELISA) at 4, 24, 48, and 72 h after total-body irradiation (TBI). RESULTS: Time- and dose-dependent increases in the protein targets were observed. The use of multiple protein targets was evaluated using multiple linear regression analysis to provide dose-response calibration curves for dose assessment. Multivariate discriminant analysis demonstrated enhanced dose-dependent separation of irradiated animals from control as the number of biomarkers increased. CONCLUSIONS: Results from this study represent a proof-of-concept for multiple blood-proteins biodosimetry approach. It was demonstrated for the first time that protein expression profile could be developed not only to assess radiation exposure in male BALB/c mice but also to distinguish the level of radiation exposure, ranging from 1-7 Gy.