Bone Marrow Radiation Dose Research Articles

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

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

Bone Marrow Toxicity and Tolerance of Sandwich Therapy for Advanced-Stage Endometrial Cancer: A Single-Institution Experience

<h3>Purpose/Objective(s)</h3> Adjuvant therapy for advanced-stage endometrial cancer (EC) involve chemotherapy (CT) and/or radiation therapy (RT). Institutional practices vary regarding the sequencing of these therapies. While recent trials favored concurrent chemoradiation followed by consolidating CT, there is no randomized comparison of efficacy between ‘sandwich' (ST) versus concurrent CT. Previous studies show BM dose is predictive of hematological toxicities (HT) in concurrent chemoradiation. In this study, we sought to determine whether bone marrow dose contributes to hematological toxicity in ST for treatment of advanced-stage EC. <h3>Materials/Methods</h3> Data for patients who received ST (CT with carboplatin/paclitaxel then 45 Gy external beam radiation therapy [EBRT] with/without paraaortic [PA] fields then additional CT) at a single academic institution for EC cases was abstracted. Full ST was defined as 3 CT cycles, then RT, followed by a final 3 CT cycles. Grade 3 (G3) higher hematologic toxicities (ANC <1000, Hgb <8.0, platelet count <50,000) were recorded for each patient based at the time of infusion or radiation therapy. T-test and Chi-square test were used as appropriate to determine association. <h3>Results</h3> 98 EC patients that underwent ST were included; 66.0% were stage IIIC. 84% of patients completed full ST, and 26.3% of cases experienced ≥1 treatment delay. Among cycle delays cases, 57.7% had ≥1 G3 hematologic toxicity: 10 neutropenia, 4 anemia, and 3 thrombocytopenia. HT rate was 49.0%: 34% neutropenia, 13% anemia, 12% thrombocytopenia. Frequency of cycle delay (31.3% vs. 21.6%) or ST non-completion (13.7% vs. 18.4%) were not significantly associated with HT presence (p>0.05, all). Significantly fewer patients who had HT both pre- and post-EBRT completed post-sandwich CT compared to toxicities occurring at other time intervals (Table). While patients with ≥2 HT during their treatment received a significant larger mean bone marrow radiation dose (69.0 vs 72.5%, p=0.037), overall dosimetric data were similar regardless of HT timing during treatment. PA boost did display more frequent HT following RT (21.1% vs. 51.7%, p = 0.033) but completed ST at similar rates (63.2% vs 36.8%, p=0.441). There was a 10% mortality rate; overall survival was similar despite presence of HT occurrence, or with HT requiring a cycle delay or cycle non-completion (p>0.05, all cases). <h3>Conclusion</h3> In our study, BM dose does matter in determining HT even in ST, but does not affect overall treatment completion. The treatment completion rate is comparable to those reported historically for CT only arm. Low rates of cycle interruption and similar overall survival point to a promising safety and efficacy profile with ST.

Correlation of Hematological Toxicity with the Bone Marrow Radiation Dose and Volume during Concurrent Chemo Radiation in Patients with Cervical Cancer

Aims &amp; Objective: Hematological toxicity is common in patients with cervical cancer treated with concurrent chemo radiotherapy (CT-RT), so the purpose is to assess this hematological toxicity and correlate the toxicity with the dose and volume of bone marrow included in the field of radiation. Materials &amp; Methods: Twenty five patients with histologically proven cervical cancer attending to our Cancer centre from July 2018-August 2019 were the subjects of this study. Patients were treated on 6 MV linear accelerator with a radical intent with concurrent chemotherapy using cisplatin 50 mg weekly. The planning CT was done for all the patients before the treatment and contouring of the pelvic bone marrow apart from other organs at risk was done. Hematological toxicity was assessed using RTOG common toxicity criteria weekly during and at 2 weeks after the completion of the treatment. Results: A total of 25 patients on CT-RT treatment were assessed. Sixteen patients were in locally advanced stage. The variation in HB, TLC, Platelets, and ANC counts from the baseline to 2 weeks after chemo radiotherapy were assessed. Grade II anemia was observed in 12 and Grade III in 2 patients. There were no toxicity as far as WBC and platelets were considered. There was also no correlation between the volume of bone marrow included in the field of irradiation and appearance of anemia. Conclusion: CT-RT for cervical cancer is safe and is associated with minimal hematological toxicity in the form of anemia. The toxicity is same for different volumes of bone marrow included in the field of irradiation with both 3DCRT as well as IMRT technique. The toxicity observed is probably contributed by Cisplatin.

Abstract PO-054: Correlation of hematological toxicity with the bone marrow radiation dose and volume during concurrent chemo radiation in patients with cervical cancer

Abstract Aims &amp; Objective: Hematological toxicity is common in patients with cervical cancer treated with concurrent chemo radiotherapy (CT-RT), so the purpose is to assess this hematological toxicity and correlate the toxicity with the dose and volume of bone marrow included in the field of radiation. Materials &amp; Methods: Twenty-five patients with histologically proven cervical cancer attending to our cancer center from July 2008-August 2009 were the subjects of this study. Patients were treated on 6 MV linear accelerator with a radical intent with concurrent chemotherapy using cisplatin 50 mg weekly. The planning CT was done for all the patients before the treatment and contouring of the pelvic bone marrow apart from other organs at risk was done. Hematological toxicity was assessed using RTOG common toxicity criteria weekly during and at 2 weeks after the completion of the treatment. Results: A total of 25 patients on CT-RT treatment were assessed. Sixteen patients were in locally advanced stage. The variation in HB, TLC, Platelets, and ANC counts from the baseline to 2 weeks after chemo radiotherapy were assessed. Grade II anemia was observed in 12 and Grade III in 2 patients. There were no toxicity as far as WBC and platelets were considered. There was also no correlation between the volume of bone marrow included in the field of irradiation and appearance of anemia. Conclusion: CT-RT for cervical cancer is safe and is associated with minimal hematological toxicity in the form of anemia. The toxicity is same for different volumes of bone marrow included in the field of irradiation with both conventional as well as 3DCRT technique. The toxicity observed is probably contributed by Cisplatin. Citation Format: Irappa Madabhavi, Ragavendra Sagar, Apurva Patel, Malay Sarkar. Correlation of hematological toxicity with the bone marrow radiation dose and volume during concurrent chemo radiation in patients with cervical cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-054.

Acute Haematological Variations in Patients Receiving Radiotherapy and its Correlation with Volume of the Bone Marrow and Radiation Dose

Purpose: Radiation treatment of all malignancies inevitably includes certain percentage of bone marrow in the site and volume of irradiation. The purpose is to study the magnitude of radiation induced early haematological toxicity in relation to the total dose and volume of the marrow in the field of irradiation. Materials &amp; Methods: A Prospective analysis was done in 60 patients treated with telecobalt. Haemoglobin, WBC and platelet counts were done before starting treatment and then weekly till the completion of treatment. The volume of bone marrow in the radiation fields was also recorded. Results: The haemoglobin percentage change between baseline and 5th week was 5.19%(p=0.026) and7.35% (p=0.049) in &lt;5%, 5-20% &amp;&gt;20% of bone marrow irradiated respectively. The percentage of change between baseline and 5th week total WBC count was 23.79% (p=0.000), 35.53% (p=0.006) and 27.90% (p=0.000) in &lt;5%, 5-20% &amp;&gt;20% of bone marrow irradiated respectively. The percentage change in platelets between baseline and 5th week of 22.14%, 24.66% &amp; 24.80% in patients with &lt;5%, 5-20% and &gt;20% of bone marrow irradiated respectively (overall p=0.000). Conclusion: The percentage of active bone marrow in the field of irradiation, dose per fraction and the total dose received are the best parameters for the study of haematological variations in patients being treated with radiotherapy. There is significant Haematological variations with decreasing trend in relation to volume of bone marrow irradiated and radiation dose.

Radiation dose from digital breast tomosynthesis screening – A comparison with full field digital mammography

ObjectivesTo compare Mean Glandular Dose (MGD) and effective dose from digital breast tomosynthesis (DBT) screening with that from full field digital mammography (FFDM) screening. MethodTo simulate compressed breasts, two Perspex-polyethylene breast phantoms were used, one phantom for compressed breast in craniocaudal and the other for compressed breast in mediolateral oblique. An adult ATOM dosimetry phantom was loaded with high sensitivity thermoluminescence dosimeters; the phantom was then positioned on Hologic Selenia Dimensions mammographic machine to imitate DBT and 4-view FFDM screening. Organ radiation doses were measured from 4-view DBT and 4-view FFDM (craniocaudal and mediolateral oblique views for each breast). Organ radiation doses were used to calculate effective dose from one screening session. ResultsMGD for DBT was 3.6 mGy; MGD for FFDM was 2.8 mGy. For DBT, other organs (e.g. thymus, lungs, salivary glands, thyroid, contralateral breast and bone marrow) radiation dose was also higher than for FFDM. The use of DBT for breast cancer screening increases the effective dose (E) of one screening session by 22%. E for DBT was 0.44 mSv; E for FFDM was 0.34 mSv. ConclusionThe use of DBT for breast cancer screening increases the radiation dose to screening clients.

Haematological toxicity in cancer cervix patients treated with concurrent chemoradiation by conventional technique- correlation with bone marrow radiation dose

Introduction: The standard of care for treatment of cancer cervix is concurrent chemoradiation followed by brachytherapy in the majority of cases. Conventional radiotherapy with chemotherapy causes haematological toxicities which may be related to radiation to pelvic bone marrow. The present study aims to study the haematological toxicities and correlate with the mean dose to the bone marrow. Material and Methods: Retrospective data of cancer patients treated in the institute in the year 2019 was retrieved. Haematological toxicities were analyzed in terms of CTCAE criteria. Mean dose to bone marrow was calculated after the delineation in the CT scan. The correlation between haematological toxicity and mean bone marrow was done using a paired t-test for statistical significance. Results: The data of 20 patients were retrieved. Anaemia Grade, I and Grade II-IV was seen in 65% and 35% respectively. Leukopenia Grade I and Grade II-IV were seen in 85% and 15% respectively and Lymphopenia Grade I and Grade II-Iv were seen in 55% and 45% respectively. The mean dose to bone marrow did not show any statistical significance with the severity of haematological toxicity. There was no Grade II-IV toxicity of neutropenia and thrombocytopenia. Conclusion: Conventional radiotherapy can safely be practice for patients with cancer cervix with acceptable haematological toxicities.

Cholecystokinin 2 Receptor Agonist 177Lu-PP-F11N for Radionuclide Therapy of Medullary Thyroid Carcinoma: Results of the Lumed Phase 0a Study.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog 177Lu-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH2 (177Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (∼80 μg) of 177Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of 177Lu-PP-F11N to assess safety. Results: In all patients, 177Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85-1.04), 0.42 (IQR: 0.25-1.01), 0.11 (IQR: 0.07-0.13), and 0.028 (IQR: 0.026-0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11-14.4) without SG and 13.0 (IQR: 10.2-18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14-4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion:177Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, 177Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of 177Lu-PP-F11N.

Correlation between pelvic bone marrow radiation dose and acute hematological toxicity in cervical cancer patients treated with concurrent chemoradiation.

PurposeTo evaluate the association between pelvic bone marrow (BM) dose volume parameters and probability of acute hematological toxicity (HT), a cohort of cervical cancer patients receiving definitive chemoradiation (CRT) was assessed.Materials and methodsMedical records of patients treated by CRT (45 Gy in 25 fractions, without dose constraints applied to the BM) were reviewed. Baseline and weekly hematological parameters were collected. BM was retrospectively delineated and divided into sub-sites: iliac crests, lower pelvis, lumbosacral region. BM volumes (V) receiving 5, 10, 20, 30, 40 Gy (V5, V10, V20, V30, V40, respectively) and mean dose (Dm) were calculated. Logistic regression was used to analyze associations between HT and dose-volume histograms parameters.Results114 patients were included. 75.4% were treated with 3D radiation therapy and 24.6% were receiving intensity modulated radiation therapy (IMRT). Neither age, chemotherapy regimen (cisplatin vs carboplatin), number of chemotherapy cycles, performance status, body mass index, or para-aortic irradiation were associated with HT. In univariate analysis, more frequent grade 3+ leukopenia was found in the IMRT group (odds ratio [OR]: 3.5; 95% CI, 1.4–9.1; p=0.007). In multivariate analysis, grade 4 HT was associated with lower pelvis V5>95% (OR 4.1; 95% CI, 1.6–14. p=0.02), lower pelvis V20>45% (OR 3.5; 95% CI, 1.1–13.4; p=0.05), total pelvic bone V20>65%, and iliac crests Dm >31 Gy (OR 4.5; 95% CI, 1.4–14.7; p=0.02).ConclusionThe following dose constraints could be proposed to decrease acute HT risk: lower pelvis V5<95%, lower pelvis V20≤45%, total pelvic bone V20<65%, and iliac crests Dm <31 Gy.

Total Body Quantification of Active Bone Marrow Response to Chemoradiation Therapy Using FLT PET Images in Pelvic Cancer Patients

To quantify bone marrow radiation dose response using total body bone marrow (TBBM) quantification analysis of sequentially obtained FLT PET images prior to, during, and after chemoradiation therapy in pelvic cancer patients. A total of 33 pelvic cancer patients were enrolled in IRB approved protocols to obtain FLT PET images prior to, during, and after chemoradiation therapy. Pre-therapy images were used as a control for pelvic bone marrow FLT uptake change. Time series FLT PET images were acquired after 1 week (5 fractions) and 2 weeks (10 fractions) during therapy and 30 days and 1 year after therapy was complete. Weekly low dose (20 mAs) attenuation correction CTs (AC CTs) were co-registered to the FLT PET images. All FLT images were resampled according to the voxel size of the AC CT. The region of interest (ROI) was defined as 5cm above the auditory canal to 10cm below the greater trochanter using a threshold value of 300 HU on each AC CT. The resampled FLT images were used to calculate the voxel by voxel FLT uptake value as a surrogate for marrow activity. A TBBM value was calculated by summing each FLT voxel value and normalizing by the number of voxels with the ROI. The results for each subject were averaged over each time point, but all subjects did not complete all time points. TBBM voxel by voxel analysis of bone marrow activity was calculated as a single normalized value for each time point with all available subject data sets: Week 0 (N = 33), Week 1 (N = 31), Week 2 (N = 28), 30 Day (N = 26), and 1 Year (N = 18). The average TBBM activity values using the 300 HU threshold were 1626 ± 434, 1438 ± 334, 1244 ± 294, 1644 ± 341, and 1613 ± 445 for Week 0, Week 1, Week 2, 30 Day, and 1 Year time points respectively. On average, Week 1 TBBM activity was 88% of Week 0 activity and Week 2 TBBM activity was 76% of Week 0 activity. TBBM recovered to within 1% of Week 0 activity 30 days and 1 year after therapy. TBBM variation was relatively high with a coefficient of variation (CV) of 27%, 23%, 24%, 21%, and 28% for Week 0, Week 1, Week 2, 30 Day and 1 Year time points respectively, which is likely due to individual patient variation. Other HU thresholds were used to identify bone, which results in higher or lower absolute values of TBBM activity. However, the relative change was within 1% and the CV was within 5%. This indicates that identifying the boney ROI for TBBM calculation is relatively insensitive to the HU threshold value even with a low quality, low dose CT. This study shows the potential of an image analysis tool that quantifies TBBM activity for pelvic cancer patients before, during, and after chemoradiation therapy. This metric accounts for both bone marrow depletion and compensatory effects. Correlating an individual patient TBBM value to systemic changes in CBCs could enable patient specific therapy that maximizes therapeutic effect while minimizing toxicity.

Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers

BackgroundChronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population.MethodsA detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively).ResultsMutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival.ConclusionsNo significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation.

PO-0815: Correlation between pelvic bone marrow radiation dose and hematologic toxicity in cervical cancer

PO-0815: Correlation between pelvic bone marrow radiation dose and hematologic toxicity in cervical cancer

Clinical characteristics of chronic lymphocytic leukemia occurring in chornobyl cleanup workers.

The recently demonstrated radiation-induction of chronic lymphocytic leukemia (CLL) raises the question as to whether the amount of radiation exposure influences any of the clinical characteristics of the disease. We evaluated the relationship between bone marrow radiation doses and clinical characteristics and survival of 79 CLL cases diagnosed during 1986-2006 in a cohort of 110 645 male workers who participated in the cleanup work of the Chornobyl nuclear accident in Ukraine in 1986. All diagnoses were confirmed by an independent International Hematology Panel. Patients were followed up to the date of death or end of follow-up on 31 October 2010. The median age at diagnosis was 57 years. Median bone marrow dose was 22.6 milligray (mGy) and was not associated with time between exposure and clinical diagnosis of CLL (latent period), age, peripheral blood lymphocyte count or clinical stage of disease in univariate and multivariate analyses. Latent period was significantly shorter among those older at first exposure, smokers and those with higher frequency of visits to the doctor prior to diagnosis. A significant increase in the risk of death with increasing radiation dose was observed (p = 0.03, hazard ratio = 2.38, 95% confidence interval: 1.11,5.08 comparing those with doses ≥22 mGy to doses <22 mGy). After adjustment for radiation dose, survival of CLL cases was significantly shorter among those with younger age at first exposure, higher peripheral blood lymphocyte count, more advanced clinical stage of disease and older age at diagnosis (all p < 0.05). This is the first study to examine association between bone marrow radiation doses from the Chornobyl accident and clinical manifestations of the CLL in Chornobyl cleanup workers. The current study provides new evidence on the association of radiation dose and younger age at first radiation exposure at Chornobyl with shorter survival after diagnosis. Future studies are necessary with more cases in order to improve the statistical power of these analyses and to determine their significance. Copyright © 2016 John Wiley & Sons, Ltd.

Non-radiation risk factors for leukemia: A case-control study among chornobyl cleanup workers in Ukraine

BackgroundOccupational and environmental exposure to chemicals such as benzene has been linked to increased risk of leukemia. Cigarette smoking and alcohol consumption have also been found to affect leukemia risk. Previous analyses in a large cohort of Chornobyl clean-up workers in Ukraine found significant radiation-related increased risk for all leukemia types. We investigated the potential for additional effects of occupational and lifestyle factors on leukemia risk in this radiation-exposed cohort. MethodsIn a case-control study of chronic lymphocytic and other leukemias among Chornobyl cleanup workers, we collected data on a range of non-radiation exposures. We evaluated these and other potential risk factors in analyses adjusting for estimated bone marrow radiation dose. We calculated Odds Ratios and 95% Confidence Intervals in relation to lifestyle factors and occupational hazards. ResultsAfter adjusting for radiation, we found no clear association of leukemia risk with smoking or alcohol but identified a two-fold elevated risk for non-CLL leukemia with occupational exposure to petroleum (OR=2.28; 95% Confidence Interval 1.13, 6.79). Risks were particularly high for myeloid leukemias. No associations with risk factors other than radiation were found for chronic lymphocytic leukemia. ConclusionsThese data – the first from a working population in Ukraine – add to evidence from several previous reports of excess leukemia morbidity in groups exposed environmentally or occupationally to petroleum or its products.

Quantifying murine bone marrow and blood radiation dose response following 18F-FDG PET with DNA damage biomarkers

The purpose of this study was to quantify the poorly understood radiation doses to murine bone marrow and blood from whole-body fluorine 18 (18F)-fluorodeoxyglucose (FDG) positron emission tomography (PET), by using specific biomarkers and comparing with whole body external low dose exposures. Groups of 3–5 mice were randomly assigned to 10 groups, each receiving either a different activity of 18F-FDG: 0–37MBq or whole body irradiated with corresponding doses of 0–300mGy X-rays. Blood samples were collected at 24h and at 43h for reticulocyte micronucleus assays and QPCR analysis of gene expression in peripheral blood leukocytes. Blood and bone marrow dose estimates were calculated from injected activities of 18F-FDG and were based on a recommended ICRP model. Doses to the bone marrow corresponding to 33.43mGy and above for internal 18F-FDG exposure and to 25mGy and above for external X-ray exposure, showed significant increases in radiation-induced MN-RET formation relative to controls (P<0.05). Regression analysis showed that both types of exposure produced a linear response with linear regression analysis giving R2 of 0.992 and 0.999 for respectively internal and external exposure. No significant difference between the two data sets was found with a P-value of 0.493. In vivo gene expression dose–responses at 24h for Bbc3 and Cdkn1 were similar for 18F-FDG and X-ray exposures, with significant modifications occurring for doses over 300mGy for Bbc3 and at the lower dose of 150mGy for Cdkn1a. Both leucocyte gene expression and quantification of MN-RET are highly sensitive biomarkers for reliable estimation of the low doses delivered in vivo to, respectively, blood and bone marrow, following 18F-FDG PET.

What radiation dose does the FISH translocation assay measure in cases of incorporated radionuclides for the Southern Urals populations?

The fluorescence in situ hybridisation (FISH) technique is now well established for retrospective dosimetry in cases of external radiation exposure that occurred many years ago. However, the question remains as to whether FISH provides valid estimates of cumulative red bone marrow radiation doses in cases of incorporation of radionuclides or combined external and internal exposures. This question has arisen in connection with the interpretation of results of dose assessments for epidemiological studies of plutonium workers at the Russian Mayak plant and of members of the public exposed to strontium radioisotopes and external radiation as a result of discharges from Mayak to the Techa River. Exposures to penetrating external radiation result in fairly uniform irradiation of body tissues, and hence similar doses to all tissues, for which FISH dosimetry can provide a reliable measure of this whole body dose. However, intakes of radionuclides into the body by inhalation or ingestion may result in retention in specific organs and tissues, so that the distribution of dose is highly heterogeneous. For radionuclides emitting short-range radiations (e.g. alpha particles), this heterogeneity can apply to dose delivery within tissues and between cells within tissues. In this paper, an attempt is made to address the question of what FISH measures in such circumstances by considering evidence regarding the origin and lifetime dynamics of lymphocyte subsets in the human body in relation to the localised delivery of dose from the internal emitters (90)Sr and (239)Pu, which are of particular interest for the Southern Urals Mayak and Techa River populations, and for which most evidence is available in these populations. It is concluded that the FISH translocation assay can be usefully applied for detecting internal and combined external gamma and internal doses from internally deposited (90)Sr, albeit with fairly large uncertainties. The same may be true of (239)Pu, as well as other radionuclides, although much work remains to be done to establish dose-response relationships.

Letter to the Editor: On the Radiation-Leukemia Dose-Response Relationship among Recovery Workers after the Chernobyl Accident

This letter to the Editor continues the topic of the Chernobyl accident and probable overestimation of its consequences started in the journal Dose-Response (Jaworowski 2010; Jargin 2011) within a broader perspective: the dose-response relationship after low-dose low-rate exposures to ionizing radiation. UNSCEAR (2000) Report concluded that no increased risk of leukemia related to ionizing radiation has been found among recovery operation workers (liquidators) after the Chernobyl accident. According to the UNSCEAR (2008) Report, recent studies suggest an increase in the incidence of leukemia among the liquidators; however, limitations of those studies include low statistical power, uncertainties in dose reconstructions, and internal inconsistencies that suggest potential biases and confounding factors; evidence of the leukemia incidence increase among liquidators thus being “far from conclusive”. An association between a radiation exposure and leukemia incidence among liquidators was reported recently (Ivanov et al. 2012; Zablotska et al. 2013). Participation rates were higher among “cases” than among controls (Zablotska et al. 2013), a phenomenon noticed also by other researchers (Cardis et al. 2005; Kesminiene et al. 2008), being probably caused by higher motivation of the cases. The patients knowing their doses were probably on average more interested in further medical examinations if a dose estimate had been relatively high. In the health care system of the former Soviet Union, thoroughness of an examination sometimes depended on a patient’s initiative. In other words, individuals with higher dose estimates were probably given on average more attention, and cared more about their health themselves. “The dose-dependent participation of self-reported pre-screening cases” was pointed out by Zablotska et al. (2011), which probably can occur in Chernobyl-related research of different kind. Therefore, a probability of discovering a disease without specific local symptoms such as leukemia must be higher in people with higher dose estimates. Therefore, one of the reasons why no statistically significant radiation risks were observed for chronic lymphatic leukemia (CLL) by Ivanov et al. (2012) seems to be clear: this leukemia type is often accompanied by lymphadenopathy therefore probably remaining less frequently undiagnosed in the general population.

PD-0604: Impact of bone marrow radiation dose on acute and late hematological toxicity in cervical cancer patients

PD-0604: Impact of bone marrow radiation dose on acute and late hematological toxicity in cervical cancer patients

Radiation and the risk of chronic lymphocytic and other leukemias among chornobyl cleanup workers.

Background: Risks of most types of leukemia from exposure to acute high doses of ionizing radiation are well known, but risks associated with protracted exposures, as well as associations between radiation and chronic lymphocytic leukemia (CLL), are not clear.Objectives: We estimated relative risks of CLL and non-CLL from protracted exposures to low-dose ionizing radiation.Methods: A nested case–control study was conducted in a cohort of 110,645 Ukrainian cleanup workers of the 1986 Chornobyl nuclear power plant accident. Cases of incident leukemia diagnosed in 1986–2006 were confirmed by a panel of expert hematologists/hematopathologists. Controls were matched to cases on place of residence and year of birth. We estimated individual bone marrow radiation doses by the Realistic Analytical Dose Reconstruction with Uncertainty Estimation (RADRUE) method. We then used a conditional logistic regression model to estimate excess relative risk of leukemia per gray (ERR/Gy) of radiation dose.Results: We found a significant linear dose response for all leukemia [137 cases, ERR/Gy = 1.26 (95% CI: 0.03, 3.58]. There were nonsignificant positive dose responses for both CLL and non-CLL (ERR/Gy = 0.76 and 1.87, respectively). In our primary analysis excluding 20 cases with direct in-person interviews < 2 years from start of chemotherapy with an anomalous finding of ERR/Gy = –0.47 (95% CI: < –0.47, 1.02), the ERR/Gy for the remaining 117 cases was 2.38 (95% CI: 0.49, 5.87). For CLL, the ERR/Gy was 2.58 (95% CI: 0.02, 8.43), and for non-CLL, ERR/Gy was 2.21 (95% CI: 0.05, 7.61). Altogether, 16% of leukemia cases (18% of CLL, 15% of non-CLL) were attributed to radiation exposure.Conclusions: Exposure to low doses and to low dose-rates of radiation from post-Chornobyl cleanup work was associated with a significant increase in risk of leukemia, which was statistically consistent with estimates for the Japanese atomic bomb survivors. Based on the primary analysis, we conclude that CLL and non-CLL are both radiosensitive.

TU-C-BRA-03: Dose-Mapping to Determine Anatomically Sensitive Bone Marrow Regions

Multiple studies have established associations between increased bone marrow (BM) radiation dose and hematologic toxicity, which is an important barrier to optimal delivery of chemoradiotherapy. Generalized linear toxicity models have been validated, using metrics derived from dose-volume histograms (DVHs), but these models are limited by low predictive power. One reason may be that DVH-based metrics disregard spatial information regarding the 3D BM dose distribution. For example, it is known that BM is comprised of subregions of heterogeneous functionality, which cannot be distinguished on traditional computed tomography (CT) simulation scans. BM-sparing radiation techniques could be optimized by specifically sparing functional BM subregions, but the precise location of active BM subregions and relationship between toxicity and radiation dose to these subregions remains unclear. We have analyzed two approaches to identifying critical BM subregions: (1) a “bottom-up” approach, using functional imaging to map hematopoietically active BM, and (2) a “top-down” approach, using deformable image registration and high dimensional data analysis to statistically map BM subregions in which radiation dose is associated with toxicity. An advantage of the latter approach is that if active BM exists in consistent locations within the pelvis, a class solution for active BM-sparing IMRT would be feasible, obviating the need for expensive functional imaging in every patient. Validation of the models and hypotheses underlying both approaches is still needed. This lecture will review the contemporary literature on BM-sparing radiotherapy techniques, particularly functional BM-sparing using the aforementioned approaches. Special attention will be given to toxicity modeling techniques that move beyond DVH-based metrics to capture information about the spatial relationship between BM dose and toxicity. Learning Objectives: 1. Understand techniques used to locate heterogeneously functioning subregions within an organ, particularly bone marrow 2. Understand techniques used to quantify and model relationships between hematologic toxicity and radiation dose to functional bone marrow 3. Critically evaluate strengths and limitations of existing approaches and literature pertaining to this subject matter