Hematopoietic cell infusion for the treatment of nuclear disaster victims: New data from the Chernobyl accident

Purpose:?To present previously unavailable data on the use of stem cell administration to aid recovery of victims of the Chernobyl disaster. On 26 April 1986, an accident at Unit 4 of the Chernobyl Nuclear Power Plant took place during the planned test of one of the safety systems. The diagnosis of acute radiation syndrome (ARS) was confirmed in 134 individuals exposed to high levels of radiation. There were nine patients heretofore unreported in the scientific literature who underwent intraosseous injections of allogeneic bone marrow cells in Kyiv.

Conclusions:?Transplantation was associated with significantly shortened time to recovery of granulocyte and platelet counts in these patients. While current guidelines would certainly include the use of cytokines, these data provide an indication of the effectiveness of stem cell transplant to treat victims of radiation exposure.     

Modelling hematological parameters after total body irradiation

Abstract

Purpose: The time- and dose-dependent reconstitution of hematopoiesis after radiation exposure is strongly related to the stem cell population and can be used to predict hematological parameters. These parameters allow further insight into the hematopoietic system and might lead to the development of novel stem cell transplantation models.

Materials and methods: CD4-/- C57Bl/6 mice, transgenic for human CD4 and HLA-DR3, were irradiated in a single (3, 6, 8 and 12 Gy) and fractionated (6 × 1 Gy, 6 × 1.5 Gy, 6 × 2 Gy; twice daily) dose regimen. Blood was analyzed weekly for red blood cells (RBC), hemoglobin concentration (Hb), hematocrit (HCT) and white blood cells (WBC). Organ and tissue damage after irradiation were examined by histopathology.

Results: The recovery curves for RBC, Hb, HCT and WBC showed the same velocity (< 1 week) for all radiation doses (3–12 Gy) starting at different, dose-dependent times. The only dose-dependent parameter was defined by the beginning of the recovery process (dose-dependent shift) and higher doses were related to a later recovery of the hematopoietic system. The RBC, Hb and HCT recovery was followed by a saturation curve reaching a final concentration independent of the radiation dose. Histological analysis of the bone marrow in the single dose cohort showed a dose-dependent reduction of the cellularity in the bone marrow cavities. The fractioned radiation dose cohort resulted in a regeneration of all bone marrow cavities.

Conclusion: Specific functions were developed to describe the reconstitution of hematological parameters after total body irradiation.     

南京“5.7”192Ir源放射事故患者造血系统的改变

目的 通过对南京¹⁹²Ir源放射事故中患者的血液系统进行观察研究,探讨造血系统损伤规律,为核与辐射事故医学应急的救治和随访提供临床资料和积累经验。方法 应用血细胞分析仪动态观察患者的白细胞计数、淋巴细胞计数、血小板计数及血红蛋白值的变化,取其双侧髂骨骨髓涂片观察骨髓象的改变,采用PCR-以测序为基础的分型技术(PCR-SBT)方法检测融合基因突变情况;分别采用流式细胞术和放射免疫分析法测定T淋巴细胞亚群百分率和血清免疫球蛋白(IgA、IgG、IgM)、补体(C3、C4)含量,评价细胞免疫和体液免疫功能。结果 患者骨髓造血轻度障碍,予以粒细胞集落刺激因子(G-CSF)治疗后,短时间内恢复正常,受照后约40 d进入恢复期;受照侧骨髓增生低下;融合基因检测未检测到突变;局部感染导致淋巴细胞计数及免疫功能下降。结论 轻度骨髓型急性放射病造血系统损伤较小,病程分期不明显,造血功能恢复较快,尚未造成免疫抑制,但局部感染可导致免疫功能下降。临床医生需注意全身治疗与局部治疗的统一。     

Data Bank and Consulting System for Medical Management of Patiens with Acute Radiation Sickness

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异基因外周血造血干细胞移植治疗极重度骨髓型和肠型急性放射病的临床报告

目的 探讨异基因外周血造血干细胞移植在肠型和极重度骨髓型放射病救治中的作用和地位.方法 山东"10·21" 60Co 辐射事故中2例病人受到意外照射,病例A受照射剂量20～25Gy,诊断为"肠型放射病",病例B受照射剂量9～15Gy,诊断为"极重度骨髓型放射病".经联合环磷酰胺、抗淋巴细胞球蛋白和氟达拉滨预处理,2例分别行HLA半相合及全相合外周血造血干细胞移植.采用环孢霉素A和骁悉方案(病例A加用CD25单抗和供者间充质干细胞)预防移植物抗宿主病(GVHD).结果 2例均移植成功,供体完全存活,移植后9～11天白细胞开始恢复,2周后白细胞恢复正常、骨髓造血重建成功.2例均未发生移植排斥和GVHD.病例A照射后33天死于败血症和多器官功能衰竭.病例B照射后75天死于心衰为主的多器官功能衰竭.结论 HLA相合及半相合外周血造血干细胞移植救治极重度骨髓型和肠型急性放射病是完全可能和可行的,联合免疫抑制剂预处理对促进供体稳定植入是必要的,环孢霉素A、骁悉和CD25单抗及供者间充质干细胞对预防GVHD有重要作用.     

武汉"921113"放射事故四例急性放射病人的临床报告

目的为了总结临床经验，本文作者报告一起６０Ｃｏγ射线事故引起４人受照的剂量估算、临床经过和诊断治疗。方法剂量估算是采用现场模拟试验和手表红宝石热释光测量，外周血染色体畸变率、微核率分析方法。临床诊断根据患者受照剂量，临床表现和实验室结果进行综合分析，治疗上在对症治疗和综合治疗的基础上，应用了美国生产的ＧＭ－ＣＳＦ。结果１例中度（偏重）骨髓型急性放射病，１例中度骨髓型急性放射病，１例轻度骨髓型急性放射病。１例过量照射。４例病人经过６２～６８天住院积极治疗，病情好转，取得了良好的治疗效果。结论从医疗实践中我们着重总结以下几点：①及时、正确地早期诊断；②根据国家标准的治疗原则积极治疗；③ＧＭ－ＣＳＦ使用时注意选择时机和注意使用方法，才能取得良好的疗效     

一例极重度骨髓型急性放射病的临床救治

目的通过对山东济宁“10．21”^60Co源辐射事故病例B的诊治经过的回顾，积累资料，总结经验。方法剂量估算采用染色体畸变及微核分析、物理模拟、电子自旋共振（ESR）测量并结合尸检病理。临床诊断根据受照剂量、临床过程及实验室结果进行综合分析。治疗上给予全环境保护，HLA相合的异基因外周血造血干细胞移植（PBSCT），积极抗感染及对症支持洽疗，维护脏器功能。结果病例B诊断为极重度骨髓型急性放射病，受照后7d进行了HLA完全相合的PBSCT，移植后9d三系造血逐步恢复，并获持续稳定的完全供者型植入，无移植排斥及移植物抗宿主病（GVHD）发生。由于病人的放射损伤继续发展，并逐渐发生严重肺部混合感染，心功能不全，照后45d行气管切开、呼吸机辅助呼吸，75d发生多脏器功能衰竭死亡。结论极重度骨髓型放射病应尽早分类诊断及实施全环境保护，可经异基因PBSCT使造血重建，为延长存活奠定基础。需加强抗感染及多脏器维护；促进免疫重建及组织损伤修复是今后极重度骨髓型急性放射损伤研究的难点及重点。     

河南“4.26”60Co源辐射事故3例中重度骨髓型急性放射病临床报告

目的：通过对^60Co源事故3种例中重度骨髓型急性放射病（ARS）患者的剂量估算,临床经过和诊治方法的总结,以积累临床资料,方法：依据受照剂量,临床表现,实验实检测结果进行综合分析,以明确诊断,治疗上经全环境保护隔离,在有指征对症治疗的基础上,应用了造血生长因子,结果：3例病人经过83d住治疗,达到临床治愈,结论：正确的早期分类诊断和初期的积极治疗有利于安全度过极期,女病人如正逢病程极期来月预雄性激素以改变经期,可避免大出血,适时足量应用粒－巨噬细胞集落刺激因子（GM－CSF）有助造血功能恢复。     

rhGM-CSF、rhEPO在3例急性放射病患者救治中的应用

目的 观察rhGM-CSF、rhEPO在3例急性放射病(ARS)救治中的疗效。方法 一例重度ARS患者使用了rhGM-CSF和rhEPO,另两例中度ARS患者仅用rhGMCSF.3例患者均在照后10d、79d检测血清GM-CSF、EPO浓度。结果 使用rhGMCSF后,外周血白细胞下降速度慢,低值持续时间短,回升速度快,骨髓恢复时间提前。使用rhEPO的患者,外周血网织红细胞为0的持续时间明显缩短,骨髓红系增殖池比例增加。3位患者照后10d血清GM-CSF、EPO浓度明显升高,并与受照剂量及骨髓损伤程度相关。结论 rhGM-CSF、rhEPO的应用促进了3例ARS患者造血功能恢复。     

四例骨髓型急性放射病患者受照后12年医学随访观察

目的 通过对1999年河南省发生的“4.26”60Co源辐射事故所致的4名骨髓型急性放射病患者受照后12年医学随访观察,探讨电离辐射远后效应,为核事故医学应急的救治和随访提供临床资料和积累经验.方法 采用“一对一”和“多对一”的方式采集病史,观察和记录“梅”、“旺”、“天”、“民”4名患者的临床症状和体征.实验室及器械检查包括血细胞分析、肝肾功能、甲状腺功能、体液免疫、性激素水平、肿瘤标志物及眼科检查、甲状腺彩超、腹部B超、心电图及胸部X片检查,评价其全身情况.辐射遗传学分析包括外周血淋巴细胞染色体畸变分析和微核分析.应用实时荧光定量PCR法,检测其外周血GADD45和nm23-H1基因的mRNA表达,与健康对照人群相比较.采用卡特尔16种个性因素测验(16PF)、抑郁自评量表(SDS)、焦虑自评量表(SAS),对4名患者实施心理测评.结果 4名患者受照后12年造血免疫功能基本恢复正常.“天”乙肝两对半的检查结果中,表面抗原(HBsAg)及核心抗体(HBcAb)为阳性,乙肝病毒复制转为慢性期,传染性弱.4人眼晶状体均有不同程度的混浊性改变,“梅”受照后3年即发生放射性白内障.“梅”、“天”、“民”性激素水平仍有异常.外周血淋巴细胞染色体畸变分析可见少许断片和双着丝粒,但易位率仍较高.分子生物标志物外周血GADD45和nm23-H1基因mRNA定量分析较正常对照组差异无统计学意义.心理测评发现,“梅”重度抑郁、焦虑,其余3人存在紧张、焦虑、恐慌情绪.结论 对4名骨髓型急性放射病患者进行了较为系统的医学随访观察和心理测评,为类似病例的临床救治和随访提供资料.     

Chromosome Aberrations Induced in Human Lymphocytes by An X-radiation Accident: Results of A 4-year Postirradiation Analysis

Summary

After occupational and medical radiation exposures structural chromosome aberrations may be induced in the lymphocytes of the irradiated persons. Many authors have estimated the radiation dose from the yields of dicentric aberrations. We analysed the influence on the dicentric yield of increasing time intervals between irradiation and blood sampling from a person involved in an X-radiation accident (radiography). During a 4-year follow-up we observed an approximately 7-fold decline of the dicentric yield up to the 25th month and thereafter an almost constant value. Since the decline did not commence until around the 10th month after the exposure, an exponential decrease of dicentric yield with time should be considered with reservation in this study, although it cannot be entirely ruled out. We conclude that in ‘biological dosimetry’ blood should be sampled as early as possible after the exposure. Furthermore, computation of ‘half-times’ of lymphocytes to allow for a delay in blood sampling seems uncertain after partial body exposures to high doses. Therefore in such cases dose estimates obtained 1 or more years after irradiation should be considered as minimum values.     

Accelerated hematopoietic recovery with angiotensin-(1–7) after total body radiation

Purpose: Angiotensin (1–7) [A(1–7)] is a component of the renin angiotensin system (RAS) that stimulates hematopoietic recovery after myelosuppression. In a Phase I/IIa clinical trial, thrombocytopenia after chemotherapy was reduced by A(1–7). In this study, the ability of A(1–7) to improve recovery after total body irradiation (TBI) is shown with specific attention to radiation-induced hematopoietic injury.

Materials and methods: Mice were exposed to TBI (doses of 2–7 Gray [Gy]) of cesium 137 gamma rays, followed by treatment with A(1–7), typical doses were 100–1000 μg/kg given once or once daily for a specified number of days depending on the study. Animals are injected subcutaneously via the nape of the neck with 0.1 ml drug in saline. The recovery of blood and bone marrow cells was determined. Effects of TBI and A(1–7) on survival and bleeding time was also evaluated.

Results: Daily administration of A(1–7) after radiation exposure improved survival (from 60% to 92–97%) and reduced bleeding time at day 30 after TBI. Further, A(1–7) increased early mixed progenitors (3- to 5-fold), megakaryocyte (2- to 3-fold), myeloid (3- to 6-fold) and erythroid (2- to 5-fold) progenitors in the bone marrow and reduced radiation-induced thrombocytopenia (RIT) (up to 2-fold). Reduction in the number of treatments to 3 per week also improved bone marrow recovery and reduced RIT. As emergency responder and healthcare systems in case of nuclear accident or/and terrorist attack may be overwhelmed, the consequence of delayed initiation of treatment was ascertained. Treatment with A(1–7) can be delayed up to 5 days and still be effective in the reduction of RIT or acceleration of bone marrow recovery.

Conclusions: The data presented in this paper indicate that A(1–7) reduces the consequences of critical radiation exposure and can be initiated well after initial exposure with maximal effects on early responding hematopoietic progenitors when treatment is initiated 2 days after exposure and 5 days after exposure for the later responding progenitors and reduced thrombocytopenia. There was some effect of A(1–7) even when given days after radiation exposure.     

Investigating chromosome damage using fluorescent in situ hybridization to identify biomarkers of radiosensitivity in prostate cancer patients

Abstract

Purpose: In order to evaluate fluorescent in situ hybridization (FISH) as a method for predicting radiosensitivity, this study examined the incidence of translocations, after exposure to in vitro radiation, in both normally responding patients and those exhibiting severe late effects after radiotherapy treatment.

Materials and methods: Patients were selected from a randomized trial for intermediate-risk prostate cancer. Of the patients entered on trial with mature follow-up, 3% developed grade 3 late proctitis. Blood samples were taken from this radiosensitive cohort along with matched control patients with no late proctitis. Whole blood samples were exposed to 0 or 4 Gy and cultured according to the recommended methods. Colour junctions were evaluated in the resulting metaphases and scored according to the Protocol for Aberration Identification and Nomenclature Terminology (PAINT) system.

Results: Both groups were statistically similar at 0 Gy. After 4 Gy in vitro radiation, the radiosensitive group had significantly higher rates of chromosome damage in the number of colour junctions per cell (p = 0.002), the number of deletions per cell (p = 0.01) and the number of dicentrics per cell (p = 0.005).

Conclusions: These results indicate that the analysis of translocations using FISH after in vitro irradiation correlates with clinical response to radiation. This cytogenetic assay should be considered as a potential predictor of radiosensitivity.     

Biological dose estimation for two severely exposed patients in a radiation accident in Shandong Jining,China, in 2004

Purpose:?To estimate the biological doses for two severely exposed subjects (A and B) in a radiation accident in Shandong Jining, China in 2004.

Materials and methods:?Conventional chromosome aberration analysis and cytokinesis-block micronuclei (CBMN) assay were performed in peripheral blood and bone marrow samples on two subjects after the accident. A new dose-effect curve and the nuclear division index (NDI) obtained from in vitro irradiation experiments using high dose of ⁶⁰Co γ-rays were used to estimate the exposed doses.

Results:?No metaphases or binucleated cells were observed in the peripheral blood cultures from either of the subjects. However, metaphases and binucleated cells were obtained from both subjects after bone marrow cultures. Both dicentric/ring and micronuclei yields were very high. The dose estimated for A and B were 20.0 Gy and 8.8 Gy, respectively, by dicentric/ring scoring, similar to the data by combination of the CBMN and NDI (CBMN?+?NDI) assay. The estimated doses by the two methods were in accordance with the clinical symptoms.

Conclusion:?The new curve, together with the CBMN?+?NDI assay, are reliable for estimating higher doses of irradiation. In future radiation accidents, the accuracy and significance of these methods can be further tested.     

Early GLS changes detection after chemoradiation in locally advanced non-small cell lung cancer (NSCLC)

Purpose

Chemoradiation is the standard treatment in patients with locally advanced non-small-cell lung cancer (LA-NSCLC), and thanks to the recent combination with immunotherapy, median survival has unexpectedly improved. This study aims to evaluate early changes in cardiac function after chemoradiotherapy (CRT) in LA-NSCLC by multimodal use of advanced imaging techniques.

Materials and methods

This is a prospective, observational cohort study. At the beginning of combined treatment, screening tests including blood samples, electrocardiogram (ECG), echocardiographic examination (TTE), and cardiac magnetic resonance were performed in all patients with LA-NSCLC. ECG and cardiac marker assays were performed weekly during treatment. ECG and TTE were performed at month 1 (M1) and month 3 (M3) after the end of CRT.

Results

This preliminary analysis included thirty-four patients with a mean age of 69.5 years. The median follow-up was 27.8 months. 62% of patients were in stage IIIA. Radiation therapy was delivered with a median total dose of 60 Gy with conventional fractionation. All patients were treated with concurrent CRT, and 65% of cases were platinum-based therapy. Global longitudinal strain (GLS) and ejection fraction (EF) progressively decreased from baseline to M1 and M3. There was a strong correlation between GLS and EF reduction (at M1: p?=?0.034; at M3: p?=?0.018). Cardiac arrhythmias occurred in eight patients (23.5%) at a mean follow-up of 15.8 months after CRT.

Conclusions

Reduction in GLS is an early sign occurring after the end of CRT for LA-NSCLC. Future studies are needed to identify variables that can increase the risk of cardiac events in this patient population to implement adequate damage prevention strategies.

     

造血干细胞移植中预先全身照射对全身及造血系统的影响及并发症治疗

目的 探讨全身照射联合高剂量化疗对造血干细胞移植患者全身和造血系统影响的特点和治疗,为急性放射病的诊治提供临床经验。方法 回顾分析64例接受造血干细胞移植患者,系统观察急性照射及大剂量化疗后患者血液学改变及临床不良反应,并分析其骨髓重建特点。结果 移植相关病死率3.12%。移植后随访9～72个月 (中位随访时间26个月)。1、3、5年生存率分别为(95.8±3.3)%, (89.8±4.7)%和(81.7±6.9)%。全身照射联合高剂量化疗后,所有患者均出现了血液学不良反应,以白细胞及血小板下降最为明显,白细胞总数最低值为(0.18±0.13) ×10⁹个/L,血小板最低值为(14.48±8.85)×10⁹个/L;在造血干细胞支持及粒细胞集落刺激因子(G-CSF)应用后,均可恢复。此外患者不同程度出现消化道反应、感染、肝功能受损及出血等不良反应,经相关治疗后好转。结论以TBI联合高剂量化疗为预处理,随后进行造血干细胞移植,患者恶性血液系统疾病治疗效果好,并且其临床情况在一定程度上模拟了急性放射病的临床过程,为急性放射病的救治提供了一定的临床经验。     

10例 60 Co源辐射事故受照者眼晶状体的随访观察

目的 观察 ⁶⁰Co源辐射事故对受照者眼晶状体的远后效应。方法 对河南省1986年至2000年期间发生的4起⁶⁰Co源辐射事故共10例受照者进行眼晶状体远期医学观察。用复方托吡卡胺充分散瞳后在裂隙灯下检查眼晶状体,记录病变特征。结果 开封事故中"亮"、新乡事故中"梅"分别于照后2、3年出现典型放射性白内障;许昌事故中"许",照后6年出现典型放射性白内障;开封事故中"燕"、郑州事故中"杰"、新乡事故中"天"、"勇"、"义"照后随访观察仅出现双眼晶状体后囊下少量点状、颗粒状浑浊等放射性白内障的初期改变,未观察到典型放射性白内障的形态特点;新乡事故中"旺"、"民"则未观察到晶状体后囊下的浑浊。结论 眼晶状体是辐射事故受照者远期随访观察应重点关注的靶器官。电离辐射致眼晶状体浑浊的发展程度与照射剂量密切相关。     

Are thyroid cancer patients sensitive to ionising radiation?

Abstract

Purpose: To determine the ionising radiation sensitivity of peripheral blood lymphocytes in a group of differentiated thyroid cancer (DTC) patients.

Material and methods: A total of 53 thyroid cancer patients (26 women and 27 men) and 50 donors (23 women and 27 men) were included in the study. The cytokinesis-block micronucleus assay (CBMN) in G0 peripheral blood lymphocytes was carried out using the cytochalasin B technique. Four cultures were established per each donor, two were irradiated with 0.5 Gy 137Cs g-rays, while the other two remained untreated.

Results: No significant differences were observed in the frequency of binucleated cells with micronuclei (BNMN) between patients and controls, for both spontaneous and after the irradiation frequencies. Nevertheless, a positive and significant correlation was found between the frequencies of both spontaneous and after irradiation DNA damage, for control and patient groups.

Conclusions: We have found that DTC patients do not present particular sensitivity to ionising radiation when an in vitro treatment is performed in G0 stage of the cell cycle, but this result does not discard the hypothesis about an increased sensitivity in other stages of the cell cycle in DTC patients.     

Mechanism of hypocoagulability in proton-irradiated ferrets

Abstract

Purpose: To determine the mechanism of proton radiation- induced coagulopathy.

Material and methods: Ferrets were exposed to either solar particle event (SPE)-like proton radiation at a predetermined dose rate of 0.5 Gray (Gy) per hour (h) for a total dose of 0 or 1 Gy. Blood was collected pre- and post-irradiation for a complete blood cell count or a soluble fibrin concentration analysis, to determine whether coagulation activation had occurred. Tissue was stained with an anti-fibrinogen antibody to confirm the presence of fibrin in blood vessels.

Results: SPE-like proton radiation exposure resulted in coagulation cascade activation, as determined by increased soluble fibrin concentration in blood from 0.7–2.4 at 3 h, and 9.9 soluble fibrin units (p < 0.05) at 24 h post-irradiation and fibrin clots in blood vessels of livers, lungs and kidneys from irradiated ferrets. In combination with this increase in fibrin clots, ferrets had increased prothrombin time and partial thromboplastin time values post-irradiation, which are representative of the extrinsic/intrinsic coagulation pathways. Platelet counts remained at pre-irradiation values over the course of 7 days, indicating that the observed effects were not platelet-related, but instead likely to be due to radiation-induced effects on secondary hemostasis. White blood cell (WBC) counts were reduced in a statistically significant manner from 24 h through the course of the seven-day experiment.

Conclusions: SPE-like proton radiation results in significant decreases in all WBC counts as well as activates secondary hemostasis; together, these data suggest severe risks to astronaut health from exposure to SPE radiation.     

“6.25”60Co源辐射事故病人照后2.5年远后效应随访观察

探讨“６．２５”６０Ｃｏ源辐射事故所致５名骨髓型急性放射病患者的远后效应。方法照后２．５年对患者临床表现、造血功能、免疫功能、神经系统、生殖功能、眼晶体及某些癌基因进行检查。结果发现患者在上述诸方面存在不同程度辐射损伤。结论研究结果不仅为患者的医疗保健提供了依据，而且为急性放射病远后效应积累宝贵资料