Late-responding Tissues Research Articles

Characterizing Proton-Induced Biological Effects in a Mouse Spinal Cord Model: A Comparison of Bragg Peak and Entrance Beam Response in Single and Fractionated Exposures

Proton relative biological effectiveness (RBE) is a dynamic variable influenced by factors like linear energy transfer (LET), dose, tissue type, and biological endpoint. The standard fixed proton RBE of 1.1, currently used in clinical planning, may not accurately represent the true biological effects of proton therapy (PT) in all cases. This uncertainty can contribute to radiation-induced normal tissue toxicity in patients. In late-responding tissues such as the spinal cord, toxicity can cause devastating complications. This study investigated spinal cord tolerance in mice subjected to proton irradiation and characterized the influence of fractionation on proton- induced myelopathy at entrance (ENT) and Bragg peak (BP) positions. Cervical spinal cords of 8-week-old C57BL/6J female mice were irradiated with single- or multi-fractions (18x) using lateral opposed radiation fields at 1 of 2 positions along the Bragg curve: ENT (dose-mean LET = 1.2 keV/μm) and BP (LET = 6.9 keV/μm). Mice were monitored over 1 year for changes in weight, mobility, and general health, with radiation-induced myelopathy as the primary biological endpoint. Calculations of the RBE of the ENT and BP curve (RBEENT/BP) were performed. Single-fraction RBEENT/BP for 50% effect probability (tolerance dose (TD50), grade II paresis, determined using log-logistic model fitting) was 1.10 ± 0.06 (95% CI) and for multifraction treatments it was 1.19 ± 0.05 (95% CI). Higher incidence and faster onset of paralysis were seen in mice treated at the BP compared with ENT. The findings challenge the universally fixed RBE value in PT, indicating up to a 25% mouse spinal cord RBEENT/BP variation for multifraction treatments. These results highlight the importance of considering fractionation in determining RBE for PT. Robust characterization of proton-induced toxicity, aided by in vivo models, is paramount for refining clinical decision-making and mitigating potential patient side effects.

Radioadapted Response Early Effects and Late Effects on Survival of White Blood Cells in Mice (Mus musculus L) Post C0-60 Gamma Radiation

Aims: Determine the radioadapted response to the early and late effects of white blood cells in mice after Co-60 gamma radiation. Furthermore, the effect of the radioadapted early and late effects of the radioresponse with the interval dose adaptation (DA) with the challenge dose (DC) to the white blood cells of mice, as well as the survival rate of mice white blood cells after gamma Co-60 radiation through the radio-adapted response of the early effect and the late effect.
 Place and Duration of Study: The Radioteraphy Installation in Prof. I.G.N.G. NGOERAH Hospital, between from August to October 2022.
 Methodology: This research used a low-dose method (adapted-DA dose) and at certain time intervals was continued with a larger dose (dose challenge-DC) in mice with six treatments and one as a control. From each treatment, mice's white blood cells were taken to determine the number of leukocytes and their components. Through the number of leukocytes, it is possible to analyze the radio-adaptated response to the early effect and the late effect, so that thesurvival rate of whiteblood cells inmice after gamma Co-60 radiation can be determined.
 Results: The results of research on the survival of leukocyte cells, neutrophils, and lymphocyte cell components show early-responding tissue and late-responding tissue. As for cell survival, other componentssuch asmonocytes, eosinophils, andbasophils did not respond in the same way after gamma Co-60 radiation. In general, giving a time delay to the challenge dose for all radiation dose treatments gives a fast response (early effect) to cell survival within a few days after radiation, then with time the full response that occurs is a slow (late effect). The longer the delay in giving the challenge dose, the slower the response will fully occur in the tissue after gamma Co-60 radiation. The cell survival curve also shows that the α/β ratio for the early effect is 3 and for the late effect is 10, which is an illustration of the early effect on radiation, with a linear shape of the cell death curve indicating that tissue is more sensitive to changes in radiation dose and has a greater α/β ratio. When compared to the tissue with a late effect on radiation, the tissue has a smaller α/β ratio indicating that the tissue is less sensitive to changes in the timing of the challenge dose.
 Conclusion: Radioadapted response to the survival of leukocytes, neutrophils cell components, and lymphocytes have shown early responding tissue and late responding tissue after gamma Co-60 radiation. By giving a time lag for the challenge dose, an early response to cell survival occurs for only a few days, then with time, fully the response that occurs is late responding.

Stereotactic Body Radiation Therapy in Prostate Cancer: Where Do We Stand?

Stereotactic body radiotherapy (SBRT) is an important option for prostate cancer treatment. It involves the delivery of a high dose of radiation to the malignant tissue without affecting the neighboring healthy tissue to achieve a high therapeutic index. As the cells of prostate cancer are radiobiologically similar to a late-responding tissue with a low 𝛼/𝛽 ratio, the dose escalation approach has a better disease control probability than conventional dose fractionation. Therefore, considering the availability of intensity-modulated RT and possibility of dose escalation (>70 Gy), ultrahypofractionated SBRT is now being recommended in select patients with prostate cancers of low and intermediate risk. Although adverse events following SBRT are a concern, acute toxicity can be limited to a certain extent by adjusting the overall length of treatment time by spacing out RT over multiple fractions. Modern radiation planning and delivery methods used in conjunction with cutting-edge imaging techniques have led to the increased adoption of SBRT in prostate cancer. Thus, from a practical standpoint, it is noninvasive and effective for treating prostate cancer, leading to increased access and higher patient satisfaction.

Role of upper abdominal reirradiation for gastrointestinal malignancies: asystematic review of cumulative dose, toxicity, and outcomes on behalf of the Re-Irradiation Working Group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

Abdominal recurrences of gastrointestinal malignancies are common. Evidence in clinical studies has shown that re-irradiation (Re-I) is tolerable and efficient in different tumor locations. In contrast, little clinical data are available on normal long-term Re‑I tolerance doses. Asystematic review of upper abdominal Re‑I was performed with the aim of exploring the cumulative dose, toxicity, and outcomes. Acomputerized search was undertaken in MEDLINE, EMBASE, OVID, and the Cochrane database. Only studies reporting toxicity and/or outcomes were taken into consideration. To improve the comparability of the different Re‑I regimens and assess the relationship between Radiotherapy (RT) dose and toxicity, the equivalent dose in 2‑Gy fractions was calculated according to the linear quadratic model. Sixteen studies met the inclusion criteria, with the total patients numbering 408. Median follow-up Re‑I ranged from 5.9 to 45months. The median time elapsed since previous RT treatment was 15months (2-162months). Re‑I prescription doses were variable (22.5 Gy in 3fractions to 126.5 Gy with 125I). Cumulative doses calculated for acute- and late-responding tissues ranged from 67.25 to 136 Gy and 30.3 to 188.38 Gy, respectively. Comprehensively, the pooled ≥G3 toxicity was 12% (95%CI: 7.6-19%). The overall 1‑year survival and local recurrence-free survival rates were 53.7% (95%CI: 45.6-63.2%) and 66.5% (95% CI: 58.7-75.4%), respectively. Pain improvement was reported in 66.9% of patients. Due to limited evidence as aresult of the retrospective design of the majority of the studies, our review suggests that upper abdominal Re‑I is effective in terms of local control and palliation, with amoderate rate of severe toxicities.

Uncertainties in the relative biological effectiveness of therapeutic proton beams associated with bias towards high doses per fraction in radiobiological experiments

Most data supporting the widely accepted relative biological effectiveness (RBE) value of 1.1 for therapeutic proton beams are from radiobiological experiments with relatively high doses per fraction. The purpose of this study was to estimate bias in RBE that differences in dose levels between these experiments and proton radiotherapy treatments may cause. The linear quadratic model was applied to calculate, using prior experimental data, RBE variations with dose and a/b ratio for doses delivered in a standard fractionation regimen. The results suggest that the RBE measured at relatively high doses per fraction typical for a radiobiological experiment underestimates the RBE of proton radiotherapy with a standard fractionation. The bias increases with decreasing radiation dose and decreasing a/b ratio, suggesting that, if differences in dose levels are not accounted for, there may be a large underestimation of biological effects in late-responding tissues exposed to low doses of radiation.

Optimization of radiation dosing schedules for proneural glioblastoma.

Glioblastomas are the most aggressive primary brain tumor. Despite treatment with surgery, radiation and chemotherapy, these tumors remain uncurable and few significant increases in survival have been observed over the last half-century. We recently employed a combined theoretical and experimental approach to predict the effectiveness of radiation administration schedules, identifying two schedules that led to superior survival in a mouse model of the disease (Leder et al., Cell 156(3):603-616, 2014). Here we extended this approach to consider fractionated schedules to best minimize toxicity arising in early- and late-responding tissues. To this end, we decomposed the problem into two separate solvable optimization tasks: (i) optimization of the amount of radiation per dose, and (ii) optimization of the amount of time that passes between radiation doses. To ensure clinical applicability, we then considered the impact of clinical operating hours by incorporating time constraints consistent with operational schedules of the radiology clinic. We found that there was no significant loss incurred by restricting dosage to an 8:00 a.m. to 5:00 p.m. window. Our flexible approach is also applicable to other tumor types treated with radiotherapy.

Radiobiological intercomparison of the 160 MeV and 230 MeV proton therapy beams at the Harvard Cyclotron Laboratory and at Massachusetts General Hospital.

The purpose of this study was to determine the relative biological effectiveness (RBE) along the axis of two range-modulated proton beams (160 and 230 MeV). Both the depth and the dose dependence of RBE were investigated. Chinese hamster V79-WNRE cells, suspended in medium containing gelatin and cooled to 2 °C, were used to obtain complete survival curves at multiple positions throughout the entrance and 10 cm spread-out Bragg peak (SOBP). Simultaneous measurements of the survival response to (60)Co gamma rays served as the reference data for the proton RBE determinations. For both beams the RBE increased significantly with depth in the 10 cm SOBP, particularly in the distal half of the SOBP, then rose even more sharply at the distal edge, the most distal position measured. At a 4 Gy dose of gamma radiation (S = 0.34) the average RBE values for the entrance, proximal half, distal half and distal edge were 1.07 ± 0.01, 1.10 ± 0.01, 1.17 ± 0.01 and 1.21 ± 0.01, respectively, and essentially the same for both beams. At a 2 Gy dose of gamma radiation (S = 0.71) the average RBE values rose to 1.13 ± 0.03, 1.15 ± 0.02, 1.26 ± 0.02 and 1.30 ± 0.02, respectively, for the same four regions of the SOBP. The difference between the 4 Gy and 2 Gy RBE values reflects the dose dependence of RBE as measured in these V79-WNRE cells, which have a low α/β value, as do other widely used cell lines that also show dose-dependent RBE values. Late-responding tissues are also characterized by low α/β values, so it is possible that these cell lines may be predictive for the response of such tissues (e.g., spinal cord, optic nerve, kidney, liver, lung). However, in the very small number of studies of late-responding tissues performed to date there appears to be no evidence of an increased RBE for protons at low doses. Similarly, RBE measurements using early responding in vivo systems (mostly mouse jejunum, an early-responding tissue which has a large α/β ∼ 10 Gy) have generally shown little or no detectable dose dependence. It is useful to compare the RBE values reported here to the commonly used generic clinical RBE of 1.1, which assumes no dependence on depth or on dose. Our proximal RBEs obviously avoid the depth-related increase in RBE and for doses of 4 Gy or more, the low-dose increase in RBE is also minimized, as shown in this article. Thus the proximal RBE at a 4 Gy dose of 1.10 ± 0.01, quoted above, represents an interesting point of congruence with the clinical RBE for conditions where it could reasonably be expected in the measurements reported here. The depth dependence of RBE reported here is consistent with the majority of measurements, both in vitro and in vivo, by other investigators. The dose dependence of RBE, on the other hand, is tissue specific but has not yet been demonstrated for protons by RBE values in late-responding normal tissue systems. This indicates a need for additional RBE determination as function of dose, especially in late-responding tissues.

Effect of variable dose rate on biologically effective dose

Purpose: To investigate the effect of variable dose rate on biologically effective dose (BED).Materials and methods: By using the linear-quadratic (LQ) model with bi-exponential repair, we analytically determine the time-dependent dose rate which minimizes the effective protraction factor (Geff) and BED under the condition of fixed fraction time and dose per fraction. Because normal tissue complication probability (NTCP) monotonically decreases with decreasing BED, the dose rate also minimizes NTCP.Results: The dependences of Geff , BED and NTCP on fraction time were determined for different radiobiological parameters and two different dose rates: constant dose rate R0 and varying dose rate .Conclusion: The results of this study indicate that under certain conditions the reduction in BED for late-responding tissues due to increased fraction time can be significantly greater than the reduction in BED for tumors. Our analysis also indicates that dose rate optimization can be radiobiologically beneficial because of the resulting decrease in NTCP.

PO-0898: Extending RI-MODS: sensitivity of late-responding tissues to secondary insult following radiation

PO-0898: Extending RI-MODS: sensitivity of late-responding tissues to secondary insult following radiation

Chronic oxidative stress after irradiation: An unproven hypothesis

Injury and organ failure after irradiation of late-responding tissues is a substantial problem in radiation oncology and a major threat after accidental or belligerent exposures. The mechanisms of injury may include death of clonogens, vascular injury, activation of cytokine networks, and/or chronic oxidative stress. Knowledge of mechanisms may guide optimal use of mitigators. The hypothesis of chronic oxidative stress as a mechanism for late radiation injury has received much attention. We review herein the published evidence for chronic oxidative stress in vivo, and for use of antioxidants as mitigators of normal tissue radiation injury. We conclude that there is only indirect evidence for chronic oxidative stress after irradiation, and there are only limited published reports of mitigation by antioxidants. We did not find a differentiation of persistent markers of oxidative stress from an ongoing production of oxygen radicals. It is thus unproven that chronic oxidative stress plays a major role in causing radiation injury and organ failure in late-responding tissues. Further investigation is justified, to identify chronic oxidative stress and to identify optimal mitigators of radiation injury.

Accumulation of DNA Double-Strand Breaks in Normal Tissues After Fractionated Irradiation

There is increasing evidence that genetic factors regulating the recognition and/or repair of DNA double-strand breaks (DSBs) are responsible for differences in radiosensitivity among patients. Genetically defined DSB repair capacities are supposed to determine patients' individual susceptibility to develop adverse normal tissue reactions after radiotherapy. In a preclinical murine model, we analyzed the impact of different DSB repair capacities on the cumulative DNA damage in normal tissues during the course of fractionated irradiation. Different strains of mice with defined genetic backgrounds (SCID(-/-) homozygous, ATM(-/-) homozygous, ATM(+/-)heterozygous, and ATM(+/+)wild-type mice) were subjected to single (2 Gy) or fractionated irradiation (5 x 2 Gy). By enumerating gammaH2AX foci, the formation and rejoining of DSBs were analyzed in organs representative of both early-responding (small intestine) and late-responding tissues (lung, kidney, and heart). In repair-deficient SCID(-/-) and ATM(-/-)homozygous mice, large proportions of radiation-induced DSBs remained unrepaired after each fraction, leading to the pronounced accumulation of residual DNA damage after fractionated irradiation, similarly visible in early- and late-responding tissues. The slight DSB repair impairment of ATM(+/-)heterozygous mice was not detectable after single-dose irradiation but resulted in a significant increase in unrepaired DSBs during the fractionated irradiation scheme. Radiation-induced DSBs accumulate similarly in acute- and late-responding tissues during fractionated irradiation, whereas the whole extent of residual DNA damage depends decisively on the underlying genetically defined DSB repair capacity. Moreover, our data indicate that even minor impairments in DSB repair lead to exceeding DNA damage accumulation during fractionated irradiation and thus may have a significant impact on normal tissue responses in clinical radiotherapy.

Intrinsic radiosensitivity and repair of sublethal radiation-induced damage in canine osteosarcoma cell lines

To characterize the radiosensitivity and capacity for sublethal damage repair (SLDR) of radiation-induced injury in 4 canine osteosarcoma cell lines. 4 canine osteosarcoma cell lines (HMPOS, POS, COS 31, and D17). A clonogenic colony-forming assay was used to evaluate the cell lines' intrinsic radiosensitivities and SLDR capacities. Dose-response curves for the cell lines were generated by fitting the surviving fractions after radiation doses of 0 (control cells), 1, 2, 3, 6, and 9 Gy to a linear quadratic model. To evaluate SLDR, cell lines were exposed to 2 doses of 3 Gy (split-dose experiments) at an interval of 0 (single 6-Gy dose), 2, 4, 6, or 24 hours, after which the surviving fractions were assessed. Mean surviving fraction did not differ significantly among the 4 cell lines at the radiation doses tested. Mean surviving fraction at 2 Gy was high (0.62), and the alpha/beta ratios (predictor of tissue sensitivity to radiation therapy) for the cell lines were low (mean ratio, 3.47). The split-dose experiments revealed a 2.8- to 3.9-fold increase in cell survival when the radiation doses were applied at an interval of 24 hours, compared with cell survival after radiation doses were applied consecutively (0-hour interval). Results indicated that these canine osteosarcoma cell lines are fairly radioresistant; alpha/beta ratios were similar to those of nonneoplastic, late-responding tissues. Future clinical investigations should involve increasing the fraction size in a manner that maximizes tumor killing without adverse effects on the nonneoplastic surrounding tissues.

Hypofractionation in radiotherapy

Major changes in cancer radiotherapy have followed a greater understanding of the biological effects of radiation on tumours and normal tissues. Clinical radiotherapy is today a solid body of knowledge with well defined scientific foundations. Key concepts in current radiobiology include lethal and sublethal injuries, dose-effect coefficients, alpha/beta ratios, acute and late response, biologically equivalent dose, fraction dose, irradiation time and tumour regeneration between others. Effects of irradiation time and dose per fraction on tumours versus normal tissues are of special importance. Dose per fraction must be considered for analysis of effects in normal late-responding tissues. In contrast, both dose per fraction and irradiation time influence the response to radiation of malignant tumours and acute-responding tissues. Finally, the ability to quantify relationships between radiation dose and biological effect has been of particular value in the development of radiotherapy. This is illustrated by the growing use of high doses per fraction for the treatment of some cancers.

Linac radiosurgery as a tool in neurosurgery

Deinsberger and Tidstrand review the current treatment of different malignant and benign diseases by radiosurgery. The authors focus on an adjunct role of radiosurgery, although this method represents an appropriate treatment modality in its own right. Some radiobiological considerations should be added concerning linac radiosurgery as well as gamma knife radiosurgery. In particular, the mature neuron cells are considered the most radioresistant cells in the central nervous system, due to their postmitotic status. The proliferating glial and endothelial cells are more radiosensitive. They act like the connective tissue, to feed and stabilise the neurons. Damage to these cells will consecutively damage the nerve tissue. Already 1 day after high-dose irradiation, dose-dependent extravasation of serum proteins occurs as a sign of the disrupted blood–brain barrier. This damage increases for a few more days and in the course of the next few weeks it fades away to the normal condition. Two to 3 months after irradiation, reversible demyelinisation can occur as a subacute reaction. Dose-dependently, these demyelinated plaques can become confluent. In addition, capillary damage occurs. Later on, the neuron and glial cells and the vessels become further alterated. Increasing gliosis and demyelination are associated with vascular changes. Consecutively, a progressive vasogenic oedema results. After all, the oedema causes a further exacerbation of cell nutrition, thus closing a vicious circle. To understand the clinical implications for the efficacy and toxicity of radiosurgery, one must take into account the difference between earlyand late-responding tissues. According to the linear-quadratic model, a single dose of 20 Gy corresponds to about 50 Gy for early-responding and about 90–100 Gy for late-responding tissues. The target may be earlyor late-responding, whereas the surrounding nerval structures (brain, cranial nerves) always are late-responding. Arteriovenous malformations (AVM) appear also to be late-responding. This means that reactions following irradiation depend very strongly on the applied single dose. For these lesions, no therapeutic gain for fractionation is expected. However, by analogy with surgical treatment, it is assumed that no angiographically visible AVM after radiosurgery means no risk of bleeding. This analogy may not be appropriate as the mechanism of radiation induced blood vessel obliteration is an occlusion of vessels remaining in situ. Radiosurgery is not without complications, as the aim of high dose irradiation is to cause late normal tissue damage to the blood vessels. AVM are often embedded in normal functioning brain, which is also responsible for treatment toxicity as it receives the full radiosurgery dose. Circumscribed radionecroses or leukoencephalopathies following a conventional fractionated irradiation are a typical late effect which can be seen after 9–36 months. After radiosurgery, a manifestation of a necrosis is possible within only a few weeks. The risk of development of this adverse reaction strongly correlates with the volume of irradiated brain and the received dose. In particular, the brain volume irradiated with more than 10 Gy is a predictive parameter. The sensitivity of the optic apparatus seems to be relatively high. Applying 10–22 Gy leads to a complication rate of 20%. The authors supposed the radiosensitivity of the oligodendroglial tissue building the myelin sheath of the optic nerves to be the cause. Existing injury of the visual system increases the sensitivity to radiosurgery with reduced tolerance. The tolerance dose for a single fraction for the optic system is considered 8 Gy. The main acute reactions after radiosurgery with a frequency of 0–7% are headache, nausea and vomiting, and seizures. Usually, these symptoms decline within a few hours. Probability and extent of these effects depend on lesion size and localisation as well as duration of treatment. Headache can develop due to the fixation of the stereotactic headring on the skull. Symptoms will increase This commentary refers to the article http://dx.doi.org/10.1007/ s10143-005-0376-7

Concurrent Radiation Chemotherapy for Locally Advanced Head and Neck Carcinoma: Are We Addressing Burning Subjects?

Improving the outcome for patients with locally advanced head and neck carcinomas (HNC) by rational modification of radiation fractionation regimens or combinations of radiation with chemotherapy has been the subject of intensive clinical investigations for more than three decades. The two prototypes of biologically sound-altered radiation fractionation regimens are hyperfractionation and accelerated fractionation. Hyperfractionation was based on preferential sparing of late-responding tissues when the radiation dose per fraction is reduced. Accelerated fractionation regimens emerged through the recognition that tumor clonogen proliferation occurring during radiotherapy has a detrimental effect on outcome. Results of large randomized trials addressing the optimization of radiation fractionation collectively show that a number of biologically sound altered fractionation schedules improve the locoregional (LR) control rate on the order of 10% to 15%, but have only a modest impact on overall survival. Although several altered fractionation regimens consistently induce more severe acute mucositis than standard 7-week radiotherapy, the general consensus is that late toxicities are not appreciably increased. Scores of clinical trials testing combined-modality therapy have also been published. Meta-analyses of studies completed before 1995 reveal that cytotoxic agents given before or after surgery or radiation do not significantly improve the therapeutic outcome over LR treatment alone. In contrast, chemotherapy given concurrently with radiation improves 2and 5-year overall survival rates by 8%. Although a variety of cytotoxic agents have been studied, cisplatin is the most extensively investigated, and will be the emphasis of this commentary. The data from four recent trials using standard radiation fractionation, with or without high-dose single-agent cisplatin given every 3 weeks, in the treatment of locally advanced non-nasopharyngeal HNC have been reported in the last 2 years. All four trials showed that the combined regimen was superior to radiation therapy alone in LR control or organ preservation; two trials also showed improvement in overall survival. A common finding, however, is that 100 mg/m of cisplatin given every 3 weeks during the course of radiotherapy substantially increases the severity of mucositis, apparently more so than altered fractionation regimens without chemotherapy. In addition, cisplatin induces systemic toxicity requiring intensive premedication and supportive care. Unfortunately, recording and reporting of the late morbidity of combined radiation-chemotherapy have not been sufficiently consistent and systematic. A thorough report of the long-term results of a French cooperative group (French Head and Neck Oncology and Radiotherapy Group [GORTEC]) trial revealed that the late complication rate of the combination of radiation with concurrent carboplatin and fluorouracil was significantly higher than that of radiation alone. Due to a lack of adequate reporting, there is controversy as to whether the late toxicity of the combination of standard radiation with 100 mg/m of cisplatin every 3 weeks might also be higher than radiation alone. Hopefully, longer and more complete follow-up data on late morbidities will be reported in the future. Although the collective data are strong in establishing the superiority of the combination of radiation with concurrent chemotherapy relative to standard radiation fractionation alone in the management of locally advanced HNC, there is variability of clinical trials in patient selection and regimens, leading to continuing debate as to which combined regimen should be considered standard. Furthermore, many questions remain to be answered, including whether the cisplatin dose can be altered to reduce acute JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 22 NUMBER 23 DECEMBER 1 2004

Expression of type II iodothyronine deiodinase marks the time that a tissue responds to thyroid hormone-induced metamorphosis in Xenopus laevis

The thyroid gland synthesizes thyroxine (T4), which passes through the larval tadpole's circulatory system. The enzyme type II iodothyronine deiodinase (D2) converts thyroxine (T4) to the active hormone 3,5,3′-triiodothyronine (T3) in peripheral tissues. An early response to thyroid hormone (TH) in the Xenopus laevis tadpole is the stimulation of cell division in cells that line the brain ventricles, the lumen of the spinal cord, and the limb buds. These cells express constitutively high levels of D2 mRNA. Exogenous T4 induces early DNA synthesis in brain, spinal cord, and limb buds as efficiently as T3. The deiodinase inhibitor iopanoic acid blocks T4- but not T3-induced cell division. At metamorphic climax, both TH-induced cell division and D2 expression decrease in the brain. Then D2 expression appears in late-responding tissues including the anterior pituitary, the intestine, and the tail where cell division is reduced or absent. Therefore, constitutive expression of D2 occurs in the earliest target tissues of TH that will grow and differentiate, while TH-induced expression of D2 takes place in late-responding tissues that will remodel or die. This pattern of constitutive and induced D2 expression contributes to the timing of metamorphic changes in these tissues.

Dose-effect relationship for cataract induction after single-dose total body irradiation and bone marrow transplantation for acute leukemia

Purpose : To determine a dose-effect relationship for cataract induction, the tissue-specific parameter, α/β, and the rate of repair of sublethal damage, μ value, in the linear-quadratic formula have to be known. To obtain these parameters for the human eye lens, a large series of patients treated with different doses and dose rates is required. The data of patients with acute leukemia treated with single-dose total body irradiation (STBI) and bone marrow transplantation (BMT) collected by the European Group for Blood and Marrow Transplantation were analyzed. Methods and Materials : The data of 495 patients who underwent BMT for acute leukemia, who had STBI as part of their conditioning regimen, were analyzed using the linear-quadratic concept. The end point was the incidence of cataract formation after BMT. Of the analyzed patients, 175 were registered as having cataracts. Biologic effective doses (BEDs) for different sets of values for α/β and μ were calculated for each patient. With Cox regression analysis, using the overall chi-square test as the parameter evaluating the goodness of fit, α/β and μ values were found. Risk factors for cataract induction were the BED of the applied TBI regimen, allogeneic BMT, steroid therapy for >14 weeks, and heparin administration. To avoid the influence of steroid therapy and heparin on cataract induction, patients who received steroid or heparin treatment were excluded, leaving only the BED as a risk factor. Next, the most likely set of α/β and μ values was obtained. With this set, the cataract-free survival rates were calculated for specific BED intervals, according to the Kaplan-Meier method. From these calculations, cataract incidences were obtained as function of the BED at 120 months after STBI. Results : The use of BED instead of the TBI dose enabled the incidence of cataract formation to be predicted in a reasonably consistent way. With Cox regression analysis for all STBI data, a maximal chi-square value was obtained for α/β = 1.75 Gy and μ = 0.75 h −1. When Cox regression analysis was applied for patients who had no steroid treatment after BMT, a maximal chi-square value was obtained for α/β = 1 Gy and μ = 0.6 h −1. Cox regression analysis was repeated using the data of patients who had not received posttransplant steroid treatment and also no heparin administration; we found α/β = 0.75 Gy and μ = 0.65 h −1. An increased cataract incidence was observed after steroid treatment of >14 weeks and heparin administration. Conclusion : The α/β value of 0.75 Gy and a μ value of 0.65 h −1 found for the eye lens are characteristic for late-responding tissues. The incidence of cataract formation can now be quantified, taking into account the values calculated for α/β and μ, TBI dose, and dose rate. Also, the reduction in cataract incidence as a result of lens dose reduction by eye shielding can be estimated.

Experimental radiotherapy of late-responding tissues--recent advances and future development.

Experimental radiotherapy of late-responding tissues--recent advances and future development.

Proton relative biological effectiveness (RBE) for survival in mice after thoracic irradiation with fractionated doses

Purpose: This study aims at providing relative biological effectiveness (RBE) data under reference conditions accounting for the determination of the “clinical RBE” of protons. Methods and Materials: RBE (ref. 60Co γ-rays) of the 200 MeV clinical proton beam produced at the National Accelerator Centre (South Africa) was determined for lung tolerance assessed by survival after selective irradiation of the thorax in mice. Irradiations were performed in 1, 3, or 10 fractions separated by 12 h. Proton irradiations were performed at the middle of a 7-cm spread out Bragg peak (SOBP). Control γ irradiations were randomized with proton irradiations and performed simultaneously. A total of 1008 mice was used, of which 96 were assessed for histopathology. Results: RBEs derived from LD50 ratios were found not to vary significantly with fractionation (corresponding dose range, ∼2–20 Gy). They, however, tend to increase with time and reach (mean of the RBEs for 1, 3 and 10 fractions) 1.00, 1.08, 1.14, and 1.25 for LD50 at 180, 210, 240, and 270 days, respectively (confidence interval approximately 20%). α/β ratios for protons and γ are very similar and average 2.3 (0.6–4.8) for the different endpoints. Additional irradiations in 10 fractions at the end of the SOBP were found slightly more effective (∼6%) than at the middle of the SOBP. A control experiment for intestinal crypt regeneration in mice was randomized with the lung experiment and yielded an RBE of 1.14 ± 0.03, i.e., the same value as obtained previously, which vouches for the reliability of the experimental procedure. Conclusion: There is no need to raise the clinical RBE of protons in consideration of the late tolerance of healthy tissues in the extent that RBE for lung tolerance was found not to vary with fractionation nor to differ significantly from those of the majority of early- and late-responding tissues.

Biological Aspects of Conformal Therapy

Both conformal and intensity-modulated radiation therapy have great potential to further increase tumor control rates and decrease morbidity. A homogeneous escalation of 'biological' dose within a tumor should increase the likelihood of local cure, especially within the mid-range (e.g. 15% to 80%) of tumor control rates, and conversely, a lower control rate should follow a homogeneously reduced dose. However, when the dose to critical normal tissues is tightly constrained, the dose distributions within the treatment volume may necessarily be heterogeneous, and the effect on tumor control probability will depend upon the magnitude of over- or underdosage, and on the proportions of the tumor clonogen population receiving higher or lower than the nominal dose. Dose-volume histograms provide a measure of heterogeneity of dose within the planned treatment volume, but tumor control probability is also influenced by other variables, e.g. inherent tumor clonogen radiosensitivity and growth rates during a course of treatment, alpha/beta ratios, oxygenation and clonogen density throughout the target volume. Heterogeneity in these factors introduces heterogeneity in tumor responses and a less steep change in tumor control probability with change in dose, reducing the gains or losses that would be predicted to result from heterogeneity of dose. Similarly, modeling the effect of inhomogeneous dose distributions on estimates of probability of complications in normal tissues is hindered by uncertainty of estimates for alpha/beta ratios, especially for late-responding tissues, and lack of data on volume effects. Although the effects of dose inhomogeneity cannot be presented with sufficiently reliable quantitation to be directly applicable to dose prescriptions in radiation therapy, the relative influences of heterogeneities in dose and volume can be modeled to provide a framework for clinical decision-making. The magnitude of a dose reduction is the major determinant of decline in tumor control probability. A large dose reduction to even a small volume of tumor can profoundly decrease tumor control probability. Conversely, the most rapid improvement in tumor control probability occurs the closer to 100% the amount of tumor exposed to an increased dose. Escalation of dose is of little value unless it is distributed through most of the tumor: even very large increases in dose to small volumes are of little benefit.