Functional changes of the gustatory organ caused by local radiation exposure during radiotherapy of the head-and-neck region.

PURPOSE: The aim of this prospective study was to investigate how often and at which dose levels gustatory disturbances appear during radiotherapy of the tongue and to which extent permanent gustatory deficiencies occur. PATIENTS AND METHODS: The study included 44 patients treated by definitive irradiation for malignant head-and-neck tumors. In 22 patients the posterior two thirds of the tongue (group 1), and in the other 22 patients the entire tongue (group 2) were exposed to radiation. The control group comprised 30 patients with non-small cell lung cancer receiving definitive radiation therapy (group 3). The dose distribution in the tongue area was calculated using CT-based three-dimensional planning. Before, during and after irradiation the gustatory function was determined by means of gustometry and correlated with the corresponding results of enoral inspection and the patients' subjective statements on gustatory function. RESULTS: The gustatory ability of the control group was not affected, whereas patients in the locally irradiated groups in parallel with enoral mucositis suffered from loss of gustatory function after a total dose of 20 Gy with a maximum between 40 and 60 Gy. Supportive measures had little influence on acute side effects. The gustatory disturbances regressed within 8 weeks after radiotherapy in patients with partial-tongue irradiation and almost completely after 6 months in patients with entire-tongue irradiation. CONCLUSION: The severity of gustatory disturbances and the longer recovery time in patients with entire-tongue irradiation suggest an influence of the volume exposed. Therefore, reduction of the highly exposed tongue volume by intensity-modulated radiotherapy opens up possibilities for a reduction of this undesirable side effect.

Estimation of cancer risks from radiotherapy of benign diseases.

BACKGROUND: The effective-dose method which was proposed by the ICRP (International Commission of Radiation Protection) for the estimation of risk to the general population from occupational or environmental, low-dose radiation exposure is not adequate for estimating the risk of cancer induction by radiotherapy of malignant or nonmalignant diseases. METHODS: The risk of cancer induction by radiotherapy of benign diseases should be based on epidemiologic data directly derived from follow-up studies of patients who had been given radiotherapy for nonmalignant diseases in the past. RESULTS: Risk factors were derived from epidemiologic studies of patients treated with irradiation for nonmalignant diseases to be used for selecting treatment options and optimizing treatment procedures. CONCLUSION: In most cases, cancer risks estimated by the effective-dose method may overestimate the true risks by one order of magnitude, yet in other cases even may underestimate it. The proposed method using organ-specific risk factors may be more suitable for treatment planning.

Low-dose X-irradiation of adjuvant-induced arthritis in rats. Efficacy of different fractionation schedules.

BACKGROUND AND PURPOSE: Low-dose radiotherapy is widely accepted as a very effective treatment option for inflammatory symptoms associated with painful degenerative joint disorders. Radiation doses and fractionation schedules in practical use are empirical and mainly based on clinical observations. Experimental data are rare. The efficacy of low-dose X-irradiation on adjuvant induced arthritis in rats using different fractionation schemes was investigated in vivo, in order to explore whether there is a dose and fractionation dependence. MATERIAL AND METHODS: Adjuvant arthritis in female Lewis rats (n = 128) was induced by intradermal injection of heat-inactivated Mycobacterium tuberculosis on day 0. Both arthritic hind paws were sham-irradiated (group 1: days 10-14; group 2: days 15-19; group 3: days 22-26) or X-irradiated with either 5 x 1.0 Gy (group 4: days 10-14; group 6: days 15-19; group 8: days 22-26; group 10: days 10, 12, 14, 16, and 18) or 5 x 0.5 Gy (group 5: days 10-14; group 7: days 15-19; group 9: days 22-26; group 11: days 10, 12, 14, 16, and 18; group 12: days 10-14 and 22-26). The clinical parameters arthritis score (AS), hind paw volume (HPV), and body weight were determined. RESULTS: A significant decrease of the clinical arthritis parameters was observed following 5 x 0.5 Gy or 5 x 1.0 Gy during the acute maximum of the inflammatory response (days 15-19). The most pronounced treatment effect was reached after two daily fractionated series of 5 x 0.5 Gy with an early treatment onset (days 10-14) and repetition in interval (days 22-26). After the application of 5 x 1.0 Gy on days 10-14 or in a protracted scheme (days 10, 12, 14, 16, and 18), only a nonsignificant positive trend could be detected. Daily fractionated X-irradiation in the chronic phase of adjuvant arthritis (days 22-26) did not show any positive clinical effect. CONCLUSION: Low-dose radiotherapy is able to prevent a full-blown arthritic reaction if given during the florid phase of adjuvant arthritis. Two series of 5 x 0.5 Gy with an early treatment onset (days 10-14) and repetition in interval (days 22-26) were the most effective treatment schedule in this experimental study.

Inhibition of the iNOS pathway in inflammatory macrophages by low-dose X-irradiation in vitro. Is there a time dependence?

BACKGROUND: Low radiation doses (< or = 1.25 Gy), if applied 6 h before or after stimulation, are known to inhibit the inducible nitric oxide synthase (iNOS) pathway in inflammatory macrophages in vitro. We therefore investigated the time dependence and the underlying molecular mechanism of this effect, since it may be involved in the clinically observed anti-inflammatory and analgesic efficacy of low-dose radiotherapy. MATERIAL AND METHODS: Metabolic activity, nitric oxide (NO) production, iNOS- and hemoxygenase 1-(HO-1-)protein and -mRNA expression by macrophages in vitro after stimulation with LPS/IFN-gamma (0.1 microg ml(-1)/100 U ml(-1)) were investigated. Irradiation was performed at 6, 4, 2 h before and 0, 2, 4, 6 h after stimulation with doses ranging from 0.3 to 10 Gy. For each group, three independent experiments were performed over a period of 30 h with sampling intervals of 3 h. RESULTS: In stimulated macrophages, metabolic activity was not affected by radiation doses up to 10 Gy. A dose-dependent modulation of the cumulative NO production was observed with significant inhibition by low radiation doses < or = 1.25 Gy) and return to control level and even higher concentrations by higher doses (< or = 5 Gy). The degree of inhibition did not show any significant time dependence within the experimental time window used. The iNOS-mRNA expression 3-18 h following stimulation and subsequent irradiation was not affected by doses < or = 1.25 Gy. The iNOS-protein expression 6-24 h following stimulation and subsequent irradiation was reduced by doses < or = 1.25 Gy. By contrast, neither HO-1-protein nor HO-1-mRNA expression at the same time points was influenced by these low doses. CONCLUSION: The inhibitory interference of low radiation doses with the iNOS pathway in inflammatory macrophages appears to be based on radiation effects on the translational and posttranslational control mechanisms of iNOS activity. However, contrary to our working hypothesis this is not related to radiation-induced induction of HO-1 expression and thereby increased degradation of heme which is essential for iNOS activity. Thus, other posttranslational modifications such as the proteasome degradation pathway might be involved.

[Functional and molecular aspects of anti-inflammatory effects of low-dose radiotherapy]. / Funktionelle und molekulare Aspekte der antiinflammatorischen Wirkung niedrig dosierter Radiotherapie.

PURPOSE: Low-dose radiotherapy (LD-RT) with single fractions between 0.1 and 1.0 Gy is known to exert an antiinflammatory effect. Although different mechanisms for the clinical efficiency were proposed, only few experimental data are still available. This paper focuses on functional and molecular aspects of LD-RT. METHODS AND RESULTS: The antiinflammatory efficiency of LD-RT in clinical studies could be confirmed in experimental models of osteoarthritis and rheumatoid arthritis. In a model of adjuvants arthritis, 5 x 1.0 Gy as well as 5 x 0.5 Gy, given at the maximum of the acute inflammation, could prevent clinically and histologically progression of the disease without affecting existing signs of inflammation. The effect of LD-RT on the adhesion of peripheral blood mononuclear cells (PBMC) and endothelial cells (EC) was analyzed in in-vitro assays. In the dose range between 0.3 and 0.7 Gy almost 4 hours after irradiation adherent cells reached a relative minimum of adhesion compared to unirradiated controls. In PBMC an discontinuous increase of apoptosis with a maximum between 0.3 and 0.5 Gy, the proteolytic shedding of L-selectin and an increased expression of the antiinflammatory cytokine interleukin 10 as well as downregulation of TNF alpha could be identified as potential mechanisms for the observed reduced adhesion. Conversely, reduced expression of E-selectin and an increased induction of transforming growth factor beta (TGF beta 1) with a maximum at 0.5 Gy could be observed in endothelial cells. Macrophages immigrating the site of inflammation are known to express inducible nitrix-oxide synthase (iNOS), which in turn mediates cytotoxic and immunmodulatory effects by producing nitric oxide (NO). LD-RT of stimulated macrophages within the dose range between 0.6 and 1.25 Gy reduced NO production and iNOS-protein expression without affecting iNOS-mRNA expression. CONCLUSION: Our experimental data have confirmed the antiinflammatory efficiency of LD-RT in vitro and in vivo, indicating effects on different cellular components and mechanisms of inflammation. The regulation of the adhesion between PBMC and endothelial cells and the effects on activated macrophages may mediate the antiinflammatory properties of LD-RT. Ongoing experiments will help to clarify the molecular mechanism.

Chromosomal aberration in peripheral lymphocytes and doses to the active bone marrow in radiotherapy of prostate cancer.

BACKGROUND AND PURPOSE: Radiotherapy plays an important role in the management of prostate cancer. Epidemiological data indicate a small but significant risk of radiation-induced leukemia after radiotherapy which might be related to the high mean bone marrow dose associated with radiotherapy of prostate cancer. The purpose of the study was to investigate the relation between the mean bone marrow dose and unstable chromosome aberrations in peripheral blood lymphocytes in patients undergoing conformal radiotherapy for prostate cancer as a possible indicator of risk. Endometrial cancer patients were also included for comparison. PATIENTS AND METHODS: Nine patients, six with prostate cancer (60-73 years old) and three with endometrial cancer (61-81 years old) treated with radiotherapy were included in the study. The non-bony spaces inside the pelvic bones were outlined on every CT slice using the treatment planning system and mean doses to the bone marrow calculated. Blood samples of the patients were obtained at different times before, during and at the end of treatment. Lymphocytes were cultured in the usual way and metaphases scored for dicentric aberrations. RESULTS: 46 samples from nine patients were obtained. The mean number of metaphases analyzed per sample was 180 with a range from 52 to 435. The mean bone marrow doses for prostate cancer patients ranged from 2.8 to 4.2 Gy and for endometrial cancer patients from 12.8 to 14.8 Gy. The aberration yield increased with the planning target volume and the mean bone marrow dose. CONCLUSION: The yield of dicentric aberrations for prostate cancer patients correlated closely with the mean bone marrow dose albeit the induction of dicentrics occurred in mature T lymphocytes most of which were probably in transit through the irradiated volumes. Therefore, the observed relationship between dicentrics and mean bone marrow doses are indirect.