Total-body irradiation with 25-MV photons in advanced non-Hodgkin's lymphoma and chronic lymphocytic leukemia. Preliminary results and complications.

Patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma were treated with total-body irradiation (TBI). One group was treated after chemotherapy failed, while the other group received TBI initially. TBI was ineffective against CLL after chemotherapy failed. All patients with lymphocytic lymphoma who initially responded to chemotherapy but later relapsed were helped by TBI, as were 88% of patients with previously untreated lymphocytic lymphomas.     

Radiation dose as a factor in host preparation for bone marrow transplantation across different genetic barriers.

Engraftment of donor bone marrow in relation to total body irradiation (TBI) dose was studied in syngeneic (B6----B6), MHC-compatible (BALB.B----B6) and MHC-incompatible allogeneic (BALB/c----B6) murine bone marrow transplantation (BMT) models. For each BMT combination radiation dose-response curves were obtained from stable long-term bone-marrow chimerism using Gpi-1 phenotyping and this was compared with the growth of exogenous CFU-S. Syngeneic engraftment required the lowest TBI doses limited to ablation of host haemopoietic stem cells. Resistance against H-2-compatible allogeneic engraftment was evident at low radiation doses (less than 5.5 Gy) but at 6 Gy and above the level of chimerism was comparable to syngeneic transplants, which indicated effective immunosuppression. Higher TBI doses were needed for engraftment as the immunological barrier was increased using fully H-2-incompatible allogeneic transplants. The high TBI dose (9.5 Gy) needed for suppression of spleen endocolonies in the CFU-S assay meant that rejection of exogenous bone marrow was evident only across the larger immunological barriers. When the fully allogeneic combination was reversed (B6----BALB/c) both CFU-S and chimerism data showed less rejection. The steep dose-response relationships show how engraftment is critically dependent on TBI dose, as well as the genetic disparity between donor and host.     

Total-body irradiation in advanced lymphosarcoma.

Thirty patients with stage III and IV non-Hodgkin's lymphoma were treated by total-body irradiation (TBI). Eleven patients had previously received local radiotherapy or chemotherapy. Toxicity was confined to haematological depression. Complete remission of disease was achieved in 14 patients. Non-leukaemic patients who had received no previous treatment reacted best to TBI (ten complete remissions in 13 patients). We consider TBI a helpful treatment in non-leukaemic patients with advanced lymphosarcoma.     

Can [18F]fluorodeoxyglucose positron emission tomography imaging complement biopsy results from the iliac crest for the detection of bone marrow involvement in patients with malignant lymphoma?

OBJECTIVES: To assess the usefulness of [18F]fluorodeoxyglucose positron emission tomography in the detection of bone marrow involvement in malignant lymphoma, and its impact in clinical management. METHODS: One hundred and six consecutive patients with a confirmed diagnosis of lymphoma, referred for staging or restaging of Hodgkin's lymphoma (n=18) or non-Hodgkin's lymphoma (n=88), were reviewed retrospectively. A positron emission tomography scan and bone marrow biopsy of the iliac crest were performed in all patients. The assessment of bone marrow involvement by lymphoma was confirmed by histology and/or progression of bone marrow lesions in clinical follow-up. RESULTS: In 28 of 106 patients, bone marrow involvement was found. Positron emission tomography was more sensitive (86%) than bone marrow biopsy (57%). Positron emission tomography and bone marrow biopsy were concordant by positive correlation in 12 of 28 cases (43%) and by negative correlation in 77 of 78 cases (99%). Ten cases of non-Hodgkin's lymphoma and two cases of Hodgkin's lymphoma with positive positron emission tomography results and an initial negative bone marrow biopsy showed clinical progression of the bone marrow lesions and/or subsequent positive histology. These were considered as false-negative results for bone marrow biopsy. In seven of the 12 positive cases with negative bone marrow biopsy, positron emission tomography uptake distant from the site of the biopsy was seen. In four cases of follicular lymphoma, the bone marrow biopsy was positive and the positron emission tomography scan was normal. CONCLUSIONS: Positron emission tomography and bone marrow biopsy are complementary in assessing the presence of bone marrow involvement in patients with malignant lymphoma. In our series, positron emission tomography was more sensitive than bone marrow biopsy in Hodgkin's and non-Hodgkin's lymphoma, except in follicular lymphoma.     

Enhanced oxidative damage induced by total body irradiation in mice fed a low protein diet

PURPOSE: To examine the influence of the level of dietary protein on oxidative damage to lipid and protein in the liver and on chromosomal damage in the bone marrow after total body irradiation (TBI). MATERIALS AND METHODS: Male mice were fed a low (7%), basal (20%) or high (33%) protein diet for 3 weeks, and then received TBI at a dose of 0, 0.5 or 1 Gy. Chromosomal damage in the bone marrow was evaluated by determining the proportion of micronucleated reticulocytes in peripheral blood. Oxidative damage in the liver and plasma, and chromosomal damage in the bone marrow were evaluated on day 2 after TBI. RESULTS: The levels of lipid peroxides and protein carbonyls in the liver, lipid peroxides in the plasma, and chromosomal damage in the bone marrow, did not differ among the groups that did not receive TBI. However, the oxidative damage to lipid and protein in the liver, and the level of lipid peroxides in the plasma were increased by TBI only in the low protein group. Chromosomal damage in the bone marrow was increased by TBI in a dose-dependent manner, and the damage was consistently higher in the low protein group than in the basal and high protein groups. In the low protein group, a greater decrease of the relative spleen weight by TBI was also observed. The concentrations of antioxidants (vitamin C, E and GSH) in the liver were lower, and the concentration of non-heme iron in the liver was higher in the low protein group than in the basal and high protein groups. The TBI-induced increase in the level of plasma iron was greater in the low protein group. CONCLUSIONS: Mice fed a low protein diet became susceptible to TBI-induced oxidative damage, and a decrease in antioxidants and an increase in iron are involved in the mechanism of this susceptibility.     

血小板源性生长因子促进移植真皮多能干细胞向全身照射大鼠骨髓的分布

目的 观察血小板源性生长因子-AA(PDGF-AA)处理能否增加真皮多能干细胞(dMSCs)向全身照射(TBI)大鼠骨髓的分布.方法 分离雄性大鼠dMSCs,向第3代dMSCs中加入10μg/L PDGF-AA,继续培养2 h后,Western blot检测dMSCs中tenascin-C的表达,Transwell小室观察dMSCs的迁移能力,并收集细胞静脉移植到雌性全身照射大鼠体内,伤后2周采用针对Y染色体的实时定量PCR法检测骨髓中dMSCs含量.以未处理的dMSCs作为对照.结果 与未处理的dMSCs相比,PDGF-AA处理可上调dMSCs中tenascin-C的表达,在骨髓提取液的趋化下迁移到Transwell小室下层的细胞多,移植后分布到骨髓的dMSCs数量为(1.79±0.13)×105个,明显高于未处理的(1.24±0.09)×105个(t=8.833,P＜0.01).结论 移植前用PDGF-AA处理dMSCs可增强其迁移能力,并可增加其向全身照射大鼠骨髓的分布.

Abstract：

Objective To observe whether dermal multipotent stem cells (dMSCs) treated with platelet-derived growth factor-AA ( PDGF-AA )could distribute more frequently to the bone marrow in rats of total body irradiation (TBI).Methods Male dMSCs were isolated and 10 μg/L PDGF-AA was added to the culture medium and further cultured for 2 h.Then the expression of tenascin-C were examined by Western blot, and the migration ability of dMSCs was assessed in transwell chamber.The pre-treated dMSCs were transplanted by tail vein injection into female rats administered with total body irradiation, and 2 weeks after transplantation, real-time PCR was employed to measure the amount of dMSCs in bone marrow.Non-treated dMSCs served as control.Results PDGF-AA treatment increased the expression of tenascin-C in dMSCs, made (1.79 ± 0.13) × 105 cells migrate to the lower chamber under the effect of bone marrow extract, and distributed to bone marrow in TBI rats, significantly more than ( 1.24 ± 0.09) ×105 in non-treated dMSCs (t = 8.833, P ＜ 0.0l ).Conclusions PDGF-AA treatment could enhance the migration ability of dMSCs and increase the amount of dMSCs in bone marrow of TBI rats after transplantation.     

Enhanced oxidative damage induced by total body irradiation in mice fed a low protein diet

Purpose : To examine the influence of the level of dietary protein on oxidative damage to lipid and protein in the liver and on chromosomal damage in the bone marrow after total body irradiation (TBI). Materials and methods : Male mice were fed a low (7%), basal (20%) or high (33%) protein diet for 3 weeks, and then received TBI at a dose of 0, 0.5 or 1 Gy. Chromosomal damage in the bone marrow was evaluated by determining the proportion of micronucleated reticulocytes in peripheral blood. Oxidative damage in the liver and plasma, and chromosomal damage in the bone marrow were evaluated on day 2 after TBI. Results : The levels of lipid peroxides and protein carbonyls in the liver, lipid peroxides in the plasma, and chromosomal damage in the bone marrow, did not differ among the groups that did not receive TBI. However, the oxidative damage to lipid and protein in the liver, and the level of lipid peroxides in the plasma were increased by TBI only in the low protein group. Chromosomal damage in the bone marrow was increased by TBI in a dose-dependent manner, and the damage was consistently higher in the low protein group than in the basal and high protein groups. In the low protein group, a greater decrease of the relative spleen weight by TBI was also observed. The concentrations of antioxidants (vitamin C, E and GSH) in the liver were lower, and the concentration of non-heme iron in the liver was higher in the low protein group than in the basal and high protein groups. The TBI-induced increase in the level of plasma iron was greater in the low protein group. Conclusions : Mice fed a low protein diet became susceptible to TBI-induced oxidative damage, and a decrease in antioxidants and an increase in iron are involved in the mechanism of this susceptibility.     

Total body irradiation in Essen--dosimetry and physical treatment planning

Since 1975, in Essen 109 patients received total body irradiation (TBI) prior to bone marrow transplantation. About 80 patients were treated by bilateral 5.7 MeV photon beams. Three new TBI techniques were developed providing precise, homogeneous, reliable and reasonable a. p./p. a. TBI for adults and children. Systematic TBI dosimetry and the beam-zone method enable for individual treatment planning.     

Vulnerability of folate in plasma and bone marrow to total body irradiation in mice

PURPOSE: To examine how folate status in a body is influenced by oxidative stress. MATERIAL AND METHODS: Mice were given total body irradiation (TBI) by X-ray, and changes in the concentration of folate were compared to those in vitamins C and E. RESULTS: In a time-dependent study, folate in plasma and bone marrow decreased from 5 h until 120 h post-TBI at 3 Gy. Folate in plasma and bone marrow decreased in a dose-dependent manner at 24 h. Marked decreases of vitamins C and E were also detected in bone marrow, but not in plasma even at 10 Gy of TBI. The susceptibility of plasma folate by irradiation was confirmed by an in vitro exposure study. Neither vitamins C and E nor folate were decreased in the liver by TBI. CONCLUSION: It is suggested that folate is vulnerable to oxidative stress, and folate may need to be evaluated, particularly for TBI or radiotherapy.     

N-草酰基-D-苯丙氨酸对小鼠造血系统辐射损伤的防护作用

目的:研究N-草酰基-D-苯丙氨酸（NOFD）对小鼠造血系统辐射损伤的防护作用。方法:将18只6 ~ 8周龄的健康C57BL/6J雄性小鼠按区组随机法分为3组：对照组、4 Gy γ射线全身照射组（简称照射组）和4 Gy γ射线全身照射+ 5 mg/kg NOFD组（简称照射给药组）,每组6只。照射给药组于照射前2、16...     

Total-Body Irradiation—Role and Indications

BACKGROUND AND PURPOSE: Total-body irradiation (TBI) is a key part of the conditioning regimen before hematopoietic stem cell transplantation (HSCT). The exact role of TBI as part of the conditioning regimen is largely unclear. In order to determine the relevance of TBI, the status of TBI utilization was analyzed on the basis of a nationwide registry. MATERIAL AND METHODS: 14,371 patients (1998-2002) documented in the German Stem Cell Transplantation Registry (DRST) were analyzed regarding TBI utilization prior to autologous or allogeneic transplantation, underlying disorder, type of donor, stem cell source, and size of the treatment center. RESULTS: For autologous HSCT approximately 10% of the patients (873/8,167) received TBI, with chronic lymphocytic leukemia (CLL, approximately 80%, 171/214) and low-grade non-Hodgkin's lymphoma (l-NHL, approximately 35%, 330/929) being the most important disorders. In the allogeneic setting 50% of the patients (2,399/4,904) received TBI, with acute lymphocytic leukemia (ALL, 85%, 794/930), acute myeloid leukemia (AML, 45%, 662/1,487) and chronic myeloid leukemia (CML, 49%, 561/1,156) being the key indications. The type of donor, stem cell source and center size did not strongly influence the use of TBI. CONCLUSION: TBI has only a limited role for the conditioning prior to autologous HCST. For allogeneic HSCT TBI is widely accepted with no major changes over the observation time. The use of TBI is generally accepted for ALL, whereas approximately half of the patients with CML or AML received TBI. Although a considerably large database was analyzed, no clear determinants for the use of TBI could be distinguished.     

Radiation protocols determine acute graft-versus-host disease incidence after allogeneic bone marrow transplantation in murine models

PURPOSE: Effects of radiation sources used for total body irradiation (TBI) on Graft-versus-Host Disease (GvHD) induction were examined. MATERIALS AND METHODS: In a T cell receptor (TCR) transgenic mouse model, single fraction TBI was performed with different radiation devices ((60)Cobalt; (137)Cesium; 6 MV linear accelerator), dose rates (0.85; 1.5; 2.9; 5 Gy/min) and total doses before allogeneic bone marrow transplantation (BMT). Recipients were observed for 120 days. Different tissues were examined histologically. RESULTS: Acute GvHD was induced by a dose rate of 0.85 Gy/min ((60)Cobalt) and a total dose of 9 Gy and injection of 5 x 10(5) lymph node cells plus 5 x 10(6) bone marrow cells. Similar results were obtained using 6 MV linear accelerator- (linac-) photons with a dose rate of 1.5 Gy/min and 0.85 Gy/min, a total dose of 9.5 Gy and injection of same cell numbers. TBI with (137)Cesium (dose rate: 2.5 Gy/min) did not lead reproducibly to lethal acute GvHD. CONCLUSIONS: Experimental TBI in murine models may induce different immunological responses, depending on total energy, total single dose and dose rate. GvHD might also be induced by TBI with low dose rates.     

5-甲氧基色胺-α-硫辛酸盐对6.0 Gy受照小鼠造血系统的辐射防护作用

目的 探讨新化合物5-甲氧基色胺-α-硫辛酸盐（MLA）对亚致死剂量受照小鼠造血系统损伤的辐射防护作用。方法 将15只C57BL/6小鼠完全随机分为对照组、照射组和照射+MLA组。对照组接受假照射（0 Gy）,其余两组进行6.0 Gy全身137Cs γ射线照射。照射后2 h将照射+MLA组小鼠按10 mg/kg灌胃给药,持续给药3 d。待照射后30 d处死小鼠,取外周血和单侧骨髓细胞进行计数,检测骨髓细胞克隆形成能力、造血细胞活性氧以及烟酰胺腺嘌呤二核苷磷酸氧化酶4（NOX4）的表达。结果 与对照组比较,照射组小鼠骨髓有核细胞计数、粒细胞-单核细胞集落生成数量（CFU-GM）均明显下降（t=9.304、7.493,均P＜0.05）;骨髓细胞活性氧水平和NOX4表达显著升高（t=14.74、53.12,均P＜0.05）,且差异有统计学意义。与照射组相比,照射+ＭＬＡ组小鼠外周血WBC、CFU-GM显著升高（t=4.858、3.947,均P＜0.05）;骨髓细胞活性氧水平和NOX4表达显著下降（t=11.21、33.93,均P＜0.05）,且差异有统计学意义。结论 ＭＬＡ对辐射引起的造血系统损伤有一定的防护作用。     

Compromising Effect of Low Dose-rate Total Body Irradiation on Allogeneic Bone Marrow Engraftment

The protraction of total body irradiation (TBI) to a continuous low dose-rate has been investigated for its effect on donor marrow engraftment in murine bone marrow transplant (BMT) models of varying histocompatibility. Three different BMT combinations were used: syngeneic [B6-Gpi-1^a → B6-Gpi-1^b], H-2 compatible allogeneic [BALB.B (H-2^b) → B6 (H-2^b)] and H-2 mismatched allogeneic [BALB/c (H-2^d) → B6 (H-2^b)]. TBI was delivered over a range of doses at either a high (HDR, 40 cGy/min) or low (LDR, 2 cGy/min) dose rate followed by infusion of 10⁷ bone marrow cells from syngeneic or allogeneic donors. The level of donor (Gpi-1^a) engraftment was determined from blood Gpi-typing at different times after TBI and BMT. Radiation dose–response relationships corresponding to long-term haemopoietic engraftment at 20 weeks showed a dose-sparing effect of LDR that became more prominent with increasing genetic disparity between donor and host. For fully allogeneic (H-2 incompatible) BMT, a dose as high as 16 Gy LDR was still not sufficient for achieving chimerism in all recipients. In many cases allogeneic BMT gave transient blood chimerism enabling the recipient to survive the acute effects of high dose TBI with full long-term repopulation from surviving stem cells of the host. Radiation cell survival curves were obtained for the frequency of alloreactive precursors of proliferating T-lymphocytes (pPTL) remaining in the spleen at 1 day after TBI. A radiation dose-sparing effect of LDR was also found for pPTL depletion. These data suggest that radiation damage repair during LDR irradiation in an immunocyte target cell population is mainly responsible for enhanced graft rejection thus rendering protracted TBI less effective for application in clinical allogeneic BMT.     

造血干细胞移植治疗飞行人员急性白血病（摘要）

目的采用造血干细胞移植治疗4例空军飞行人员急性白血病,其中3例为急性非淋巴细胞性白血病,1例为急性淋巴细胞性白血病。方法自1993～2003年4例急性白血病飞行员接受造血干细胞移植治疗,3例接受自体外周血干细胞或自体骨髓移植,预处理方案为环磷酰胺（CY）／全身照射（TBI）,1例接受半相合异基因骨髓移植,预处理方案为CY／TBI／阿糖胞苷/噻替哌。     

Prospective study of bone marrow infiltration in aggressive lymphoma by three independent methods: whole-body MRI, PET/CT and bone marrow biopsy

PURPOSE: Initial lymphoma staging requires bone marrow assessment in aggressive lymphomas. Bone marrow lymphoma infiltration is routinely assessed by bone marrow biopsy (BMB), considered as the "gold standard". The aim of this study was to compare the performance of BMB, whole-body MRI and PET/CT for evaluation of BM infiltration. METHODS: Patients with newly diagnosed aggressive lymphoma were evaluated by BMB, MRI and PET/CT. Two radiologists, two nuclear medicine physicians and one pathologist independently assessed the results of the three modalities. Bone was considered as involved if BM was positive or if PET/CT or MRI was positive and if there was a resolution of the abnormal image shown on PET/CT or MRI halfway or at the end of therapy. RESULTS: Both MRI and PET/CT detected bone marrow lesions in the 9/43 patients, but two patients with multiple lesions had more lesions detected by PET/CT compared to MRI. Among these nine patients, two with an iliac crest lesion detected by both MRI and PET/CT had bone marrow involvement with large-cell lymphoma on histological examination. The other seven patients had focal MRI and PET/CT lesions in areas other than the iliac crest, where the blind BMB was done. The other patients had bone marrow without large-cell lymphoma involvement. In all cases, after lymphoma therapy bone marrow involvement regressed on histological examination, PET and MRI. CONCLUSION: These preliminary results suggest that non-invasive morphological procedures could be superior to BMB for bone marrow assessment in aggressive lymphomas. Ongoing study is underway to validate these results.     

The effect of small radiation doses: desoxyribonucleic acid (DNA) synthesis and DNA repair by the thymus, spleen and bone marrow cells of rats following fractionated whole-body X-ray irradiation

After three to seven days following to fractionated total body X-ray irradiation (TBI) (four exposures with doses of 0.3 to 5.0 cGy per fraction at intervals of 24 hours), a maximum 50 percent stimulation of the semiconservative DNA synthesis (SDS) of spleen cells was measured in vitro. This was not dependent of the fact if an acute high-dose (400 and/or 800 cGy) unique irradiation was applied after the fractionated TBI at the moment of stimulation. A significant increase of 3H-thymidine incorporation into the DNA of bone marrow and thymus cells was only found when doses of 1.25 cGy per fraction had been used. After fractionated TBI with doses of greater than or equal to 5 cGy per fraction, an increase of DNA synthesis resistant to hydroxyurea ("unprogrammed" DNA synthesis, UDS) was demonstrated in spleen cells. The UV-stimulated UDS decreased proportionately. The sedimentation of thymus, spleen, and bone marrow nucleoids in a neutral saccharose gradient gave no evidence of an increased DNA repair capacity after fractionated TBI. Whereas the SDS stimulation by fractionated TBI with small doses can be explained by a modified proliferation behavior of exposed cells, the UDS behavior of spleen cells after considerably higher radiation doses suggests regenerative processes correlated with an increased number of cells resistant to hydroxyurea and cells presenting an UV repair deficiency. These findings can be considered to be a further proof of the assumed immune-stimulating effect of small radiation doses.     

Imaging findings of a primary bladder maltoma

Secondary involvement of the urinary bladder in non-Hodgkin's lymphoma is relatively common; however, primary malignant lymphoma of this organ is extremely rare. The most common type of primary bladder lymphoma is a low-grade B-cell mucosa-associated lymphoid tissue (MALT) lymphoma. We report here on the imaging findings of a primary bladder lymphoma with bone marrow infiltration.     

In vivo ESR dosimetry in total body irradiation

Total body irradiation (TBI) using high doses (about 10 Gy) with photons in the range between 1 and 10 MV combined with intensive chemotherapy has been used successfully in treatment of acute and chronic leukemia before bone marrow transplantation. One of the principal international guidelines in TBI is to use in vivo dosimetry in order to compare the prescribed dose with that absorbed. The use of in vivo dosimetry is also useful as a retrospective evaluation of any deviation from the prescribed dose greater than +/- 5% for relevant parts of the body, especially in the lung and in other organs at risk. In this paper, Electron Spin Resonance (ESR), using alanine dosimeters, is demonstrated to be a powerful tool for absorbed dose evaluation in TBI by detection of free radicals produced in alanine by ionizing radiation. In this study, we present the results obtained using ESR dosimetry in eleven patients undergoing TBI. The major advantages appear to be: 1. the ESR signal in alanine dosimetry is stable for years without fading: 2. the detection of the ESR signal does not destroy the information and so enables a retrospective judgment of the TBI plan adopted.     

Effect of radiation therapy on thoracic and lumbar bone marrow: evaluation with MR imaging

Bone marrow suppression is often the limiting factor in the use of radiation therapy. In order to determine if MR imaging can be used to quantify bone marrow changes, we performed a serial prospective study of patients with lung cancer (six cases) and lymphoma (six cases). Quantitative and qualitative assessments of T1-weighted sagittal images, 750/33 (TR/TE), obtained at 0.6 T before, during, and after radiotherapy showed increased signal intensity in the radiated portions of the spine. These changes appeared as early as 2 weeks after the beginning of radiation, continued to increase until a maximum value was attained, and then persisted during the follow-up period of 2 years. A significantly higher (p less than .04) ratio of pretreatment to maximum posttreatment signal intensity was seen in patients with lymphoma than in those with lung cancer, and pretreatment values in patients with lymphoma were significantly lower (p less than .01). The lower pretreatment values found in the patients with lymphoma may have been due to the smaller amount of yellow marrow in these patients, who were significantly younger (33 vs 62 years). The higher ratio of pre- and posttreatment signal intensity may have been related to the larger amount of hematopoietic marrow available to undergo fatty replacement. The persistence of elevated signal intensity for as long as 2 years after radiation suggests an endpoint in the process of marrow conversion, but not reversal in the form of regeneration of hematopoietic bone marrow. Quantitative MR evaluation of bone marrow may be of considerable value as a noninvasive means of monitoring the effects of radiotherapy.