Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients.

BACKGROUND: Stereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT). MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created. RESULTS: 36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT. CONCLUSION: Repeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Changes in the characteristics of patients treated for brain metastases with repeat stereotactic radiotherapy (SRT): a retrospective study of 184 patients.

PURPOSE: Brain metastases (BMs) are the leading cause of intracranial malignant neoplasms in adults. WHO, Karnofsky performance status (KPS), age, number of BMs, extracerebral progression (ECP), recursive partitioning analysis (RPA), diagnosis-specific graded prognostic assessment (Ds-GPA) are validated prognostic tools to help clinicians decide on treatment. No consensus exists for repeat stereotactic radiotherapy (SRT) for BMs. The aim of this study was to review the changes in patient characteristics treated with repeated SRTs. METHODS AND MATERIALS: The data of patients treated between 2010 and 2020 with at least two courses of SRT without previous whole brain radiotherapy (WBRT) were reviewed. Age, WHO, KPS, ECP, type of systemic treatment, number of BMs were recorded. RPA, Ds-GPA and brain metastasis velocity (BMV) were calculated. RESULTS: 184 patients were treated for 915 BMs and received two to six SRTs for local or distant brain recurrence. The median number of BMs treated per SRT was 1 (range: 1-6), for a median of 4 BMs treated during all sessions (range: 2-19). WHO, Ds-GPA and RPA were stable between each session of SRT, whereas KPS was significantly better in SRT1 than in the following SRT. The number of BMs was not significantly different between each SRT, but there was a tendency for more BM at SRT1 (p = 0.06). At SRT1, patients had largest BM and undergo more surgery than during the following SRT (p < 0.001). 6.5%, 37.5% and 56% of patients were classified as high, intermediate, and low BMV, respectively, at the last SRT session. There was almost perfect concordance between the BMV-grade calculated at the last SRT session and at SRT2 (r = 0.89; p < 0.001). CONCLUSION: Repeated SRT doesn't lead to a marked alteration in the general condition, KPS was maintained at over 70% for more than 95% of patients during all SRTs. Long survival can be expected, especially in low-grade BMV patients. WBRT shouldn't be aborted, especially for patients developing more than twelve BMs annually.

Radionecrosis after repeated courses of radiotherapy under stereotactic conditions for brain metastases: Analysis of clinical and dosimetric data from a retrospective cohort of 184 patients.

PURPOSE: Between 10 and 40% of patients with cancer will develop one or more brain metastases (BMs). Stereotactic radiotherapy (SRT) is part of the therapeutic arsenal for the treatment of de novo or recurrent BM. Its main interest is to delay whole brain radiation therapy (WBRT), which may cause cognitive toxicity. However, SRT is not exempt from long-term toxicity, and the most widely known SRT is radionecrosis (RN). The objective of this study was to analyze the occurrence of RN per BM and per patient. MATERIAL AND METHODS: Between 2010 and 2020, data from 184 patients treated for 915 BMs by two to six SRT sessions for local or distant brain recurrence without previous or intercurrent WBRT were retrospectively reviewed. RN was examined on trimestral follow-up MRI and potentially confirmed by surgery or nuclear medicine. For each BM and SRT session plan, summation V12Gy, V14Gy, V21Gy and V23Gy isodoses were collected. Volumes of intersections were created between the 12Gy isodose at the first SRT and the 18Gy isodose of the following SRT (V18-12Gy). RESULTS: At the end of follow-up, 23.0% of patients presented RN, and 6.3% of BM presented RN. Median follow-up of BM was 13.3 months (95%CI 18.3-20.8). The median interval between BM irradiation and RN was 8.7 months (95% CI 9.2-14.7). Six-, 12- and 24-month RN-free survival rates per BM were 75%, 54% and 29%, respectively. The median RN-free survival per patient was 15.3 months (95% CI 13.6-18.1). In multivariate analysis, the occurrence of RN per BM was statistically associated with local reirradiation (P<0.001) and the number of SRTs (P<0.001). In univariate analysis, the occurrence of RN per patient was statistically associated with the sum of all V18-12Gy (P=0.02). No statistical association was found in multivariate analysis. A sum of all V18-12Gy of less than 1.5ml was associated with a 14.6% risk of RN, compared with 35.6% when the sum of all V18-12Gy was superior to 1.5ml. The sum of all V18-12Gy larger than 1.5ml was associated with a 74% specificity and 53% sensitivity of RN (P<0.001). CONCLUSION: Based on these results, a small number of BMs show RN during repeated SRT for local or distant recurrent BMs. Local reirradiation was the most predictive factor of brain RN. A V18-12Gy larger than 7.6ml in the case of local reirradiation or larger than 1.5ml in proximity reirradiation were prognostic factors of RN. The more BM patients need radiation therapy, and the longer they survive after irradiation, the higher their individual risk of developing RN.

[Repeated irradiation of brain metastases under stereotactic conditions: A review of the literature]. / Irradiations répétées de métastases cérébrales en conditions stéréotaxiques : revue de la littérature.

Stereotactic radiotherapy has become a standard in the management of patients with brain metastases; its main interest is to differ whole brain radiotherapy, provider of neurocognitive toxicity and to increase the rate of local control. The repetition of radiotherapy sessions under stereotactic conditions is not codified, neither on the number of technically and clinically possible sessions, nor on the maximum total number or volume of metastases to be treated. The purpose of this review is to analyse the data in the literature concerning repeated irradiations under stereotactic conditions. The second reirradiation in stereotactic condition shows satisfactory results in terms of overall survival, local control, and toxicity. However, we lack data for patients receiving more than two sessions of SRS as well as to define dose constraints to reirradiated healthy tissues. Prospective trials are still needed to validate the management of recurrent brain metastases after initial SRS.

[Overall survival and survival without local recurrence in case of radiotherapy of the tumor bed of ductal carcinomas in situ of the breast: Review of the literature]. / Survie globale et sans récidive locale en cas de radiothérapie du lit tumoral des carcinomes canalaires in situ du sein : revue de la littérature.

INTRODUCTION: Carcinomas in situ represent more than 15 to 20% of breast cancers. Radiotherapy of whole breast is part of the therapeutic standard and follows surgery. However, the indication of tumor bed irradiation is still controversial and heterogeneous according to international practice even though it is a very frequent clinical situation. The aim of this study is to define the indications of tumor bed irradiation in the context of ductal carcinomas in situ and to discuss accelerated partial irradiation of the breast. METHOD: The selected papers were published between 2015 and 2020 and included as MeSH terms "ductal carcinoma in situ" and "boost" for the analysis of tumor bed irradiation, and "ductal carcinoma in situ" and "accelerated partial breast irradiation" for the analysis of accelerated partial irradiation. RESULTS: Boost was more often performed when risk factors for local recurrence were present, such as age less than 40 or 50 years old, clinical mode of detection, tumor size greater than 15 to 20mm, high nuclear grade, presence of necrosis, positive or insufficient surgical margins, associated atypical hyperplastic lesions, and lobular carcinoma in situ. Accelerated partial irradiation is an option for favorable or intermediate prognosis CCIS, further studies involving more patients are required. CONCLUSION: Radiotherapy of the mammary gland in the context of DCIS has shown its effectiveness in terms of local and locoregional control of the disease, thus reducing in situ and infiltrating recurrences. However, the indication of operating bed irradiation is still debated, and the practice is very heterogeneous depending on the country. Another possible alternative for patients with a favorable prognosis and a small tumor bed volume would be IPA.

[Pelvic irradiation and hematopoietic toxicity: A review of the literature]. / Irradiation pelvienne et toxicité hématopoïétique : revue de la littérature.

Pelvic bone marrow is the site of nearly 50% of total hematopoiesis. Radiation therapy of pelvic lymph node areas, and cancers located near the bony structures of the pelvis, exposes to hematological toxicity in the range of 30 to 70%. This toxicity depends on many factors, including the presence or absence of concomitant chemotherapy and its type, the volume of irradiated bone, the received doses, or the initial hematopoietic reserve. Intensity modulated radiation therapy allows the optimisation of dose deposit on at risk organs while providing optimal coverage of target volumes. However, this suggests that dose constraints should be known precisely to limit the incidence of radiation side effects. This literature review focuses firstly on pelvic lymph node areas and bony volumes nearby, then on the effects of irradiation on bone marrow and the current dosimetric constraints resulting from it, and finally on hematological toxicities by carcinologic location and progress in reducing these toxicities.

Dosimetric comparison of mono-isocentric and multi-isocentric plans for oligobrain metastases: A single institutional experience.

PUPOSE: To compare dosimetric plans for the treatments of oligobrains metastases (2-6) using mono-isocentric arc therapy and multi-isocentric volumetric modulated arc therapy (VMAT). MATERIAL AND METHODS: A total of sixteen patients with multiple brain metastases were selected. Prescription dose was between 24 and 15Gy depending on the tumor size. For every patient,arctherapy and VMAT plans were generated respectively, with Elements Multiple Brain Mets SRS version 2.0 (BrainLab) and Eclipse SRS Treatment Planning Systeme version 15.5. The conformity index (CI), homogeinity index (HI), gradient index (GI), dose volume histogram for each organs at risk, total Monitor Units were evaluated. RESULTS: For coverage of the PTV, mono-isocentric plans showed a better CI and a better GI than multi-isocentric plans, respectively CI of 1.18±0.11 vs 1.41±0.20 (P<0.01), and GI of 3.55±0.59 vs 4.03±1.20 (P<0.01). Homogeneity index was not better with mono-isocentric plans, with respectively HI 24.32±3.87 vs 14.05±4.46 (P=1). For organs at risk, there were no statistical differences between mono and multi-isocentric plans for both eyes, both lenses, both optic nerves, chiasma, brainstem, and hippocampi.V12Gy and V10Gy of normal brain were statistically lower with mono-isocentric plans than with multi-isocentric plans, respectivellyV12Gy of 3.06Gy 95%CI [2.25;3.86]vs 5.18Gy 95%CI [3.43;6.93] (P<0,01) and V10Gy 4.66Gy 95%CI [3.33;5.98] vs7.30Gy 95%CI [4.73;9.87] (P<0.03). Total number of MU was significantly lower with mono-isocentric plans than with multi-isocentric plans, respectively 6668±1463 vs 12403±4941 (P<0.01), then treatment time was lower with mono-isocentric plans. CONCLUSION: Mono-isocentric plans had a better conformity index and gradient index than multi-isocentric plans for the treatment of multiple brain metastases. Moreover, mono-isocentric techniques gave fewer doses to normal brain and used less monitor units than multi-isocentric techniques.

[Hypofractioned radiotherapy in elderly patient with glioblastoma]. / Radiothérapie hypofractionnée dans le glioblastome de la personne âgée.

Glioblastoma is the most frequent primary brain tumor, with more than half of all patients being at least 65 years old. The treatment of the elderly in this pathology represents therefore a considerable challenge for oncologists and radiation therapists. However, in most clinical trials, age is a non-eligible criterial. In the last ten years, geriatric therapeutic trials have been multiplied. The treatment of glioblastoma consists of adjuvant chemoradiotherapy. In elderly patients, the evaluation of performans status and the molecular characteristics of the tumor are important factors in order to propose the appropriate treatment in terms of efficacy and toxicity.

Serological abnormalities induced by engraftment of viable motheaten hematopoietic cells in nude beige recipients.

C57BL/6J (B6) mice homozygous for the viable motheaten (mev) mutation are short-lived and display severe immunodeficiency, autoimmunity and inflammatory disease. B6 mice doubly homozygous for the nude (nu) and beige (bg) mutations (nubg mice) are also short-lived and immunodeficient. Nevertheless, grafts of mev lympho-hematopoietic cells increased life expectancy of nubg recipients. Such [mev --> nubg] chimeras did not develop any mev-like inflammatory pathology but showed autoimmunity features, particularly hyperglobulinemia which, unlike the mev one, was due to IgG rather than IgM. Serological studies of [mev IgHb --> nubg Igha] chimeras surprisingly revealed the exclusive host B-cell origin of the IgG2a overproduced by these chimeras. Yet, about half of such chimera serum IgM being IgMb, mev B cells had actually engrafted the nubg hosts. Together with the lack of transfer of the inflammatory pathology, this suggests that a non-mev environment might succeed acting as a regulator of some mev-induced dysfunctions.

The viable motheaten (mev) mouse--a new model for arthritis.

Homozygous mev mice are first identified at the age of 3-4 days by focal depigmentation of the skin, followed by patchy absence of hair and by necrotic lesions on paws, tail and ears. Of particular interest are the inflammatory reactions in the paws of these animals which consist mainly of polymorphonuclear and mononuclear cell infiltration in the subcutaneous tissue extending to the periosteum and joint, resulting in focal destructive arthritis and osteomylitis. These lesions are to some extent reminiscent of an acute form of rheumatoid-like arthritis. Since mev mice are sterile, a limited number of symptomatic offspring can be obtained by cross-breeding their heterozygous siblings which are phenotypically not distinguishable from mice lacking this mutation. In order to produce a sufficient number of diseased animals for performing pharmacological studies, we have established a model by transferring this disease in lethally irradiated, 8- to 10-week-old syngeneic mice which were grafted with mev spleen cells. Such reconstituted recipients develop first inflammatory symptoms of the paws 2 to 3 weeks after cell transfer. The arthritic inflammation finally affects all paws and toes by 30 to 50 days. This procedure increased the number of mev-like mice expressing arthritis, allowing assessment of the effects of standard reference drugs used in the therapy of rheumatoid arthritis (RA). The immunosuppressants cyclosporin and rapamycin and the steroid dexamethasone at therapeutic concentrations exert a strong inhibitory effect on the development of arthritis in this novel model. In contrast, the non-steroidal anti-inflammatory drug phenylbutazone shows only a moderate effect. These results indicate the particular sensitivity of this model for efficacy of potentially new therapeutic but non-cytostatic compounds for clinical use.

Lack of transfer of lpr-type abnormalities (lymphoproliferation or lymphoid aplasia) in double congenic nude beige mice engrafted with lpr haematopoietic cells.

The aetiology of the autoimmune and lymphoproliferative syndrome caused by the murine lpr (lymphoproliferation) mutation was studied by the adoptive transfer methodology using non-irradiated athymic and natural killer (NK)-deficient C57BL/6 nude beige mice (B6 nubg) as recipients. The [lpr-->nubg] chimeras did not display the severe lymphoid organ aplasia shown by irradiated non-lpr recipients of lpr haematopoietic cells. However, nor did they either express the typical lpr phenotype features (hyperglobulinaemia, autoimmunity and lymphoid hyperplasia). Nevertheless, engraftment of lpr cells in the nubg recipients was shown by their much increased survival, the recovery of T-cell mitogen responsiveness in the spleen, and the presence of T-dependent immunoglobulin isotypes in their serum. The host of donor origin of serum immunoglobulin was studied by measuring IgG2a allotypes in the serum of [lpr-->nubg] chimeras made with different lgh-congenic mice. Interestingly, several months after grafting, the serum IgG2a was found to be mainly of lpr graft origin, suggesting that only lpr B cells could function in such chimeras. In conclusion, a lpr spleen cell graft reconstituted non-irradiated nubg recipients and induced neither a typical lpr syndrome nor a lpr-type graft-versus-host (GVH)-like disease. These features of the lpr syndrome are at variance with those of the phenotypically similar gld syndrome, since this mutation allows the transfer of a generalized lymphadenopathy disease by grafting gld spleen cells in nubg or irradiated recipients. Unlike the gld syndrome, the lpr gene might not only affect haematopoietic cells but also cells of the environment, which would interact in the same impaired process.

Modulation of adoptively transferred viable motheaten pathology in sublethally irradiated normal recipient mice by normal hematopoietic cells.

"Adoptive mev" chimeras were created by grafting hematopoietic cells (HC) from B6 viable motheaten (mev) mice into bg or wild sublethally irradiated (SI) mice: the chimeras developed mev-type symptoms such as paw inflammation and necrosis, lung damage, thymus atrophy, and high serological IgM concentration and autoantibody levels as well as rapid death. The phenotype of adoptive mev mice could be obtained even after two to three successive passages into SI mice (Kuntz et al., 1991. Immunology 73, 356). In the present study, mixed HC transfer experiments showed that bg or wild HC could not prevent or delay neither the serological symptoms nor the pathology conferred by cotransferred mev HC. Nevertheless, when cotransferred with adoptive mev chimera HC, bg or wild HC could block the development of the pathology and the morbidity, although only delayed the emergence of the serological abnormalities. This shows that the differentiation of mev HC in a bg or wild normal-type environment does not allow the maintenance of all mev HC-dependent abnormalities.

Adoptive transfer of viable motheaten pathology in sublethally irradiated beige recipient mice.

B6 viable motheaten (mev) mice are short-living autoimmune and immunodeficient mice. Most of the mev pathology is transferable into the B6 beige (bg) irradiated mouse by injection of mev haematopoietic cells. Indeed there is a rapid establishment of lung damage, thymus aplasia, inflammation and necrosis of peripheral joints, an increase of serological IgM concentrations and autoantibody levels as well as a rapid death. This mev-type pathology can be again obtained by transferring haematopoietic cells of these [mev----bg] chimeras into other irradiated bg mice, although the appearance of these serological and phenotypical symptoms seems to be more and more delayed when doing cascade transfers.

Immunoglobulin isotypes of C57BL/6 nu/nu, lpr/lpr mice. Lack of direct intrinsic effect of the lpr gene on B cell hyperactivity.

The absolute concentrations of mouse immunoglobulin (Ig) heavy chain isotypes were determined by specific ELISAs in the serum of C57BL/6 (B6) mice doubly homozygous at the nude (nu) and the lymphoproliferation (lpr) locus (B6 nu, lpr mice), and compared with normal B6 nu mice. The distribution and the absolute concentrations of all Ig isotypes were found to be very similar in B6 nu, lpr and B6 nu mice, for both sexes and with similar increases in titers with ageing. Thus, the major part of the severe autoimmunity and hyperglobulinemia characteristic of the lpr syndrome of euthymic B6 lpr mice, including their elevated titers of thymus-independent IgM and IgG3 isotypes, is abrogated by the nude mutation, an effect of which is the lack of thymus differentiation. Though a postulated intrinsic activity of the lpr gene directly on B cell hyperactivity cannot be discarded, its expression would then require the presence of either the thymus or of T cells or of other cells or factors whose expression is also abrogated by the homozygosity at the nude locus.

Adoptive transfer of viable motheaten (mev) humoral autoimmunity: IgM to IgG switch of the hyperglobulinaemia in nude, beige recipient mice.

Homozygous C57BL/6 nude, beige mice (B6 nu,bg) were used as recipients for the transfer of lymphoid cells from autoimmune homozygous B6 'viable motheaten' mice (B6 mev) and from either normal B6 mice (B6 wild) or B6 bg mice as controls. Surprisingly, the mev cell grafts prolonged survival of these short-living doubly immunodeficient recipients. Although the [mev----nu,bg] chimeras did not develop the mev external necrosis phenotype, they showed a hyperglobulinaemia and a significant increase of their anti-single-stranded DNA (ssDNA) antibody titres, compared to control chimeras ([bg----nu,bg] and [wild----nu,bg]). However, this hyperglobulinaemia was quite different from the mev-type hyperglobulinaemia, with poor contribution of the IgM isotype. Moreover, the anti-ssDNA antibodies were more distributed among the various Ig classes than the anti-ssDNA antibodies of the mev homozygous mice. Though the adoptive transfer of some mev-type humoral autoimmunity symptoms were achieved in this chimera model, the recipient mice did not suffer from the several other features of the mev syndrom, such as the severe pathology and the extremely high IgM serological levels.

Adoptive transfer of viable motheaten humoral autoimmunity in cyclophosphamide-immunodepressed beige recipient mice.

Cyclophosphamide-pretreated homozygous C57BL/6 beige mice (B6 bg) were used as recipients for the transfer of lymphoid cells either of short-living autoimmune homozygous B6 'viable motheaten' mice (B6 mev) or of normal B6 mice (B6+) or B6 bg mice as controls. The grafts had no incidence on the survival of the recipients, whatever protocol used. The [mev----bg] chimeras did not develop the mev external phenotype, but there was a transfer of humoral autoimmunity. Compared to control Compared to control chimeras ([bg----bg] and [+----bg]), recipients of mev cells always showed an increase in anti-single-stranded DNA (ssDNA) antibody titres, reaching 2/3 of the mev ones 40 weeks after the cell transfers. Moreover, the anti-ssDNA were mainly of IgM class, correlating with the higher total IgM level found in [mev----bg] chimeras, thus reflecting the serological phenotype of the mev homozygous mice. Though the adoptive transfer of some mev-type humoral autoimmunity symptoms was clearly achieved in this chimera model, the recipient mice did not suffer from the several other features of the mev syndrome, such as the hyperglobulinemia and the severe pathology. This indicates that microenvironmental influences act in concert with B cells to produce pathology in mev mice.

Serum concentrations of IgM, IgG1, IgG2b, IgG3 and IgA in C57BL/6 mice and their congenics at the lpr (lymphoproliferation) locus.

The serum concentrations of IgM, IgG1, IgG2b, IgG3 and IgA were determined in mice of C57BL/6 background, from weaning to one year of age, by quantitative isotype-specific, indirect double sandwich enzyme-linked immunosorbent assays (ELISAs). Only limited data could be obtained for the IgG2a isotype in the present study. The mean serum Ig levels found for 6-month-old B6 mice were 0.22 mg/ml for IgM, 0.28 mg/ml for IgG1, 1.22 mg/ml for IgG2b, 0.18 mg/ml for IgG3, 0.075 mg/ml for IgA and about 0.7 mg/ml for IgG2a. In comparison with mice of the wild strain, C57BL/6 mice homozygous at the lpr (lymphoproliferation) locus showed very high increases in serum Ig levels when older than 20 weeks. With 6-month-old B6 lpr mice, increases in concentration were found for all tested heavy chain isotypes: 6 to 6.5-fold for IgA (0.45 mg/ml) and IgG1 (1.82 mg/ml), 9-fold for IgG3 (1.6 mg/ml), 11 to 11.5-fold for IgM (2.44 mg/ml) and IgG2b (13.8 mg/ml) and about 8-fold for IgG2a (5.5 mg/ml). Therefore homozygosity at the lpr locus provides the conditions for generalized, poly-isotypic rather than isotype-specific restricted Ig enhancement. This observation may be more compatible with hyperinducibility of all B-cell subclasses than with excessive production of T-cell-derived factors whose activity would be expected to be restricted to some T-dependent subclasses, and at least to affect IgM-committed B cells to a lesser extent than other B-cell classes.

Radiation therapy of spontaneous autoimmunity: a review of mouse models.

The classical types of generalized autoimmune disease in man are systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Several murine strains which develop SLE and sometimes RA-like diseases are now available. They should help in the understanding of the etiopathology of SLE and RA. Basically two main therapeutic strategies which use solely irradiation have been tried; one being sublethal whole-body irradiation (WBI) and the other fractionated total lymphoid irradiation (TLI). Other protocols which combine lethal WBI and stem cell transplantation have often been attempted. It was regularly found that the bone marrow transplant (BMT) dictates the immune status of the recipient. This paper reviews the data published about NZB, NZB/W, BXSB and MRL mice in this context.