The radiobiological basis of total body irradiation

Total body irradiation (TBI) is an all-pervasive systemic treatment modality which is well suited to the sterilization of small numbers of widely dispersed radiosensitive cells. This makes it attractive for the treatment of leukaemia or lymphoma in remission. It is unlikely that hypoxia or repopulation will be a problem in TBI treatment of leukaemia, and clonal resistance to radiation occurs less readily than to drugs. Leukaemic cells are often radiosensitive with poor repair capacities but considerable variation is seen in laboratory studies and leukaemias may be highly individual. It is possible that programmed cell death (apoptosis) contributes to leukaemic cell killing and variability of apoptosis may give rise to biological individuality. Molecular methodologies may now be used to monitor leukaemic cell populations and may enable semi-quantitative predictive assays of radiosensitivity. When the malignant cell population is not uniformly distributed throughout the body, as in lymphoma, non-uniform TBI is appropriate, e.g. by addition of local boosts or by the combination of TBI with radiolabelled antibody treatment. Major side-effects mostly relate to critical organs with late-responding characteristics (low alpha/beta ratio, high sensitivity to fraction size or dose rate). The radiobiological basis of developmental effects in children is not well understood. In future, improved selectivity of TBI may come from molecular biological strategies to sensitize malignant cells and to protect normal tissues.     

Successful pregnancy after conditioning with cyclophosphamide and fractionated total body irradiation

We report the case of a 24-year-old man who received high-dose cyclophosphamide (CY) 120 mg/kg over 2 days and twice daily fractionated total body irradiation (TBI) over 3 days(1,320 cGy) prior to allogeneic bone marrow transplantation. Seven and one-half years later he fathered a normal child who has developed normally so far.     

Induction of hepatocyte growth factor in the liver, kidney and lung following total body irradiation in rat

Hepatocyte growth factor (HGF) has been shown to have a pleiotropic function to act as a potent organotropic factor in the regeneration of injury in various organs, including the liver, kidney and lung. To examine the involvement of HGF in radiation injury, the authors analysed the changes in HGF mRNA and HGF protein levels in the rat organs (liver, lung, kidney) and plasma following 6 Gy of total body irradiation. Expression of HGF mRNA in the liver and kidney increased 6-48 h after total body irradiation and returned to previous values 1 week later. HGF protein levels in lung and liver showed 1.3-2-fold elevations 1-2 weeks after irradiation (P < 0.05). HGF levels in plasma stayed at undetectable levels up to 1 month after total body irradiation. The labelling index determined 2 weeks and 1 month after total body irradiation indicated no enhancement of regeneration. Thus, total body irradiation induced transient HGF elevation in these organs without enhancement of regeneration.     

Safety and cost-effectiveness of outpatient total body irradiation in pediatric patients undergoing stem cell transplantation

Political changes in Poland in 1989 initiated a transition period for country's economy into a free market. This new situation prompted the pharmaceutical sector to apply for marketing authorization of a huge number of drugs. Subsequently, the availability, supply and variety of drugs was changing to resemble the one existing on the European Union market. We have analyzed the pattern of adverse drug reactions reported in Poland during the past 10 years. Subsequently we compared our data for years 1991-1995 with the reports received by the Belgian National Center for Monitoring of Adverse Drug Reactions over period 1990-1994. It was found that the number of reports increased in parallel with the number of drugs available. Also the variety of reported reactions was greater. Spontaneous reporting by individual physicians increased and the number of reports from the pharmaceutical inspection diminished. Comparison with the patterns of reporting in Belgium showed the range of drugs included in the reports to be similar in both countries during the studied period. In conclusion: we found that the increase in range and availability of drugs changed substantially the patterns of reporting of adverse drug reactions in Poland. It became similar to that observed in EU countries.     

Discrimination of human tumor radioresponsiveness using low-dose rate irradiation

PURPOSE: Evaluation of the theoretical and practical value of using low-dose rate (LDR) irradiation to increase the resolution of radiosensitivity testing of primary human tumors using clonogenic assays. METHODS AND MATERIALS: Fourteen human tumor cell lines were assessed for surviving fraction at 2-8 Gy (SF2-SF8) using low-dose rate irradiation and a clonogenic assay. Further data were collected from the literature for 64 low-dose rate irradiation survival curves from human tumor cell lines. The data were grouped into five different radioresponsiveness categories (A-E). An analysis was made of the ability of the graded survival levels to discriminate between the different radioresponse groups and compared with previous analyses for high-dose rate SF2. Fifteen human cervical carcinoma specimens were analysed for SF2 and SF3.5 following high- and low-dose rate irradiation. RESULTS: Low-dose rate irradiation increased the spread of tumor cell line radiosensitivity data and the ability to discriminate between radioresponse groups was greater at low than at high-dose rates. Using low-dose rate irradiation on primary tumor specimens and a soft agar clonogenic assay decreased the success rate in obtaining data. The latter dropped from 70% for high-dose rate SF2 to 51% for low-dose rate SF3.5. CONCLUSIONS: The work on cell lines illustrates that low-dose rate irradiation does improve the ability of clonogenic radiosensitivity measurements to discriminate between tumors of different radioresponsiveness groups. However, using low-dose rate irradiation on primary human tumors with a soft agar clonogenic assay was not practical because of reducing the success rate for obtaining data for radiosensitivity measurements.     

Radiobiological modeling of combined targeted 131I therapy and total body irradiation for treatment of disseminated tumors of differing radiosensitivity

PURPOSE: A model is presented for calculating combinations of targeted 131I and total body irradiation, followed by bone marrow rescue, in the treatment of tumors of different radiosensitivity. The model is used to evaluate the role of the total body irradiation component in the optimal combination regime as a function of the radiosensitivity of the tumor cells. METHODS AND MATERIALS: A microdosimetric model was used to calculate absorbed dose in small tumors and micrometastases when uniformly targeted by the radionuclide 131I. Cell kill was calculated from absorbed dose using an extended version of the linear quadratic model. The addition of varying total doses of total body irradiation, assuming 2 Gy fractions, was also calculated using the linear quadratic model. The net cell kill from combined modality (targeted 131I and total body irradiation) was computed for varying proportions of the two components, for a range of tumor sizes, restricting the total radiation dose to within tolerance for a full-course TBI regime (approximately 14 Gy total) in all cases. The calculations were repeated for a range of presumed tumor uptakes of the targeting agent and for a range of tumor radiosensitivities, typical of those reported for tumor cells of differing type in culture. Optimal regimes were identified as those predicted to yield a high probable tumor cure rate (evaluated using a Poisson statistical model) for all tumor sizes. RESULTS: The analysis supports earlier model studies which predicted that systemic combination treatment with targeted 131I and total body irradiation would be superior to either component used alone. The intrinsic tumor radiosensitivity is found to be a factor which influences the optimal combination of the 131I and external beam total body irradiation components. The total body irradiation component is greater in optimal regimes treating radio-resistant than radiosensitive tumors. However, an obligatory total body irradiation component is also predicted for more radiosensitive tumors; the analysis suggests that the total body irradiation component should in no circumstances be less than 2 x 2 Gy, whilst practical arguments exist in favor of higher doses. CONCLUSION: Total body irradiation is an obligatory component for effective systemic treatment of disseminated malignant tumors to which 131I can be selectively targeted. Clinical studies applying this strategy to the treatment of neuroblastoma by 131I targeted by meta-iodo-benguanidine (mIBG), total body irradiation and bone marrow rescue are now in progress.     

Total body irradiation with translation method

METHOD: An extended coverage bladder (ECB) G-suit was evaluated on the DCIEM centrifuge against the current service G-suit (CSU-15/P) in two separate series of experiments. The ECB G-suit covered approximately 85% of the lower body measuring from the umbilicus and all five bladders completely encircled each leg and the lower trunk. The CSU-15/P G-suit covered approximately 30% of the lower body and its five bladders were located only over the frontal aspect of each leg and the lower trunk. The first series of experiments involved five subjects from the highly experienced DCIEM A-team. A standard gradual onset rate (GOR) run was used and suit testing order was counterbalanced across subjects. RESULTS: The test condition G-tolerances are listed as mean +/- SEM; relaxed uninflated tolerances were 4.0 +/- 0.14 for the CSU-15/P suit vs. 4.1 +/- 0.09 for the ECB suit (ns, single tailed, paired t-test) while relaxed inflated tolerances were 4.7 +/- 0.19 for the CSU-15/P suit and 5.5 +/- 0.37 for the ECB suit (p = 0.02, single tailed, paired t-test). The straining tolerances were 8.1 +/- 0.44 for the CSU-15/P suit and 9.0 +/- 0.56 for the ECB suit (p = 0.01, single tailed, paired t-test). The second series involved nine subjects for the following three G-suit conditions; CSU-15/P, ECB with inflation limiters, and ECB with inflation limiters and foot bladders. Relaxed uninflated tolerances were 4.0 +/- 0.13, 4.0 +/- 0.08, and 3.9 +/- 0.10 (ns) while straining inflated tolerances were 9.4 +/- 0.48, 10.1 +/- 0.38 and 10.6 +/- 0.42, respectively (p = 0.01 between all three straining conditions, ANOVA with Scheffé F-test). The ECB G-suit with inflation limiters eliminated abdominal pain and discomfort. CONCLUSION: The ECB G-suit provides improved G-tolerance for both inflated relaxed and straining exposures. Foot bladders eliminated high Gz foot pain and improved straining G-tolerance by about half a Gz. The efficacy of ECB G-suits should be evaluated when used in conjunction with positive pressure breathing. While the ultimate G-suit has yet to be conceived and will no doubt be part of an integrated life support system, ECB G-suits are a step in the right direction in the evolution of life support garmentry.     

Ovarian recovery after total body irradiation and allogeneic bone marrow transplantation: long-term follow up of 79 females

Seventy-nine females undergoing allogeneic BMT following conditioning with total body irradiation (TBI), were prospectively followed between March 1983 and March 1992 with regular gynaecological examinations, including plasma levels of luteinising hormone (LH), follicle stimulating hormone (FSH), 17-beta oestradiol (E2) and pelvic ultrasonography. The end-points of this study were the following: (1) early and late effects of TBI on ovarian function, (2) compliance and results of hormonal replacement therapy (HRT), and (3) predictive events for ovarian recovery. During the first year post-BMT most adult women complained of vasomotor and/or genitourinary tract symptoms. These were associated with decreased E2 and increased LH-FSH plasma levels and a deterioration in their sexual life (94% of sexually active women). Forty-nine adult females were selected to receive systemic hormonal replacement therapy (HRT), consisting of cyclic transdermal oestrogens plus medroxyprogesterone acetate (MPA) or cyclic oral therapy with low doses of conjugated oestrogens and MPA: these patients were selected on the basis of age (< 45 years), absence of medical contraindications or subjective refusal. Compliance and tolerability were overall good: most women (65%) never stopped HRT; this was discontinued in 14 patients for medical reasons and in 3 because of refusal. Forty-three females completed 6 months of HRT: vasomotor symptoms disappeared in 91% of 58 women who previously referred these symptoms. Improvement of genitourinary symptoms was seen both with local and systemic hormonal therapy. However sexual symptoms were reduced in 21 of 26 women (81%) given HRT compared with 8 of 19 (42%) women given local treatment (p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired androgen production in female adolescents and young adults after total body irradiation prior to BMT in childhood

Prognostic value of cellular DNA content was evaluated in 189 children with acute lymphoblastic leukemia. Treatment outcome of the three different DNA index (DI) groups (Group A, DI = 1.0 vs. Group B, DI 1.01-1.15 vs. Group C, DI > or = 1.16) was compared between the two treatment risk groups (standard-risk and high-risk groups) stratified by the initial leukocyte count and age. In the standard-risk group, these groups had 10-year event free survival (EFS) rate (SE) of 62% (6%), 40% (21%) and 87% (6%), respectively (p < 0.05). In the high risk group, they had 10-year EFS rate of 30% (5%), 33% (27%) and 60% (19%), respectively (p < 0.01). Use of the DI, leukocyte count and age may be sufficient to distinguish the patients with an extremely low risk of failing to the standard ALL therapy from the patients with a relatively high-risk of treatment failure.     

Isolated testicular relapse after bone marrow transplant with total body irradiation and testicular boost in acute lymphoblastic leukemia

A case of fixed drug eruption due to rifampin in a leprosy patient is described. Fixed drug eruption due to rifampin with the classical residual hyperpigmentation has not been described before.     

Bioimpedance spectroscopy technique: intra-, extracellular, and total body water

The purpose of this study was to test the validity of a multiple frequency bioimpedance spectroscopy (BIS) technique that estimates extracellular fluid volume (ECV), intracellular fluid volume (ICV), and total body water (TBW). Thirteen healthy males (mean +/- SD: age, 23 +/- 3 yr; body mass, 80.6 +/- 14.7 kg) had their TBW and ECV measured by ingesting dilution tracers (7.27 g deuterium oxide, 1.70 g sodium bromide; blood samples at 0 and 4 h). ICV was calculated as TBW minus ECV. Impedance was measured (50-500 kHz) at rest, on a nonconducting surface, with a BIS analyzer. Electrode placement, posture, exercise, food/fluid intake, and ambient temperature were controlled. Dilution measures (TBW, 51.00 +/- 9.30; ECV, 19.88 +/- 3.14; ICV, 31.12 +/- 6.80 L) and BIS volumes (TBW, 50.03 +/- 7.67; ECV, 20.95 +/- 3.33; ICV, 29.04 +/- 4.51 L) were significantly different for ECV (P < 0.01) and ICV (P < 0.05); some individual differences were large. The correlation coefficients of dilution versus BIS volumes (r = 0.93 to 0.96) were significant at P < 0.0001; SEEs were: TBW, 2.23 L; ECV, 1.26 L; and ICV, 1.71 L. We concluded that BIS is valid for between-subject comparisons of body fluid compartments, is appropriate in clinical settings where change in ECV/ICV ratio is important, and should be used by comparing the required level of accuracy to the inherent technique error/variance.