Relative biological effectiveness of low-energy X-rays (25 kV) in mutant p53 cancer cells.

Low-energy X-rays as used in radiation therapy and diagnostics such as mammography are associated with a certain risk of promoting tumour development, especially in patients with mutations in cancer-related genes like TP53. The present study therefore addressed the relative biological effectiveness (RBE) of low-energy X-rays for two human adenocarcinoma cell lines of the breast (MDA-MB-468) and pancreas (BxPC-3) with a mutation in the TP53 gene. Clonogenic survival and cytogenetic changes in terms of micronuclei (MN) formation were determined following irradiation with 25 kV X-rays and 200 kV reference irradiation in the dose range of 1-8 Gy. Except the frequency of MN-containing binucleated cells (BNC) (BNC + MN/BNC) in breast cancer cells yielding an RBE between 0.6 and 0.8, both cell lines displayed dose-dependent variations of RBE values between 1 and 2 for all biological end points (cell survival, (BNC + MN/BNC), MN/BNC, MN/(BNC + MN)) with increased effectiveness of 25 kV irradiation in pancreatic compared to breast cancer cells. The results confirm previous findings indicating increased effectiveness of low-energy X-rays and underline the necessity of careful risk estimation for cancer screening programmes.

Effect of irradiation on the expression of E-cadherin and ß-catenin in early and late radiation sequelae of the urinary bladder and its modulation by NF-κB inhibitor thalidomide.

PURPOSE: In a previous study we have shown in a mouse model that administration of nuclear factor-kappa B (NF-κB) inhibitor thalidomide has promising therapeutic effects on early radiation cystitis (ERC) and late radiation sequelae (LRS) of the urinary bladder. The aim of this study was to evaluate in the same mice the effect of thalidomide on adherens junction (AJ) proteins in ERC and LRS. METHODS: Urothelial expressions of E­cadherin and ß­catenin were assessed by immunohistochemistry in formalin-fixed paraffin-embedded (FFPE) bladder specimens over 360 days post single-dose irradiation on day 0. First, the effect of irradiation on AJ expression and then effects of thalidomide on irradiation-induced AJ alterations were assessed using three different treatment times. RESULTS: Irradiation provoked a biphasic upregulation of E­cadherin and ß­catenin in the early phase. After a mild decrease of E­cadherin and a pronounced decrease of ß­catenin at the end of the early phase, both increased again in the late phase. Early administration of thalidomide (day 1-15) resulted in a steeper rise in the first days, an extended and increased expression at the end of the early phase and a higher expression of ß­catenin alone at the beginning of the late phase. CONCLUSION: Upregulation of AJ proteins is an attempt to compensate irradiation-induced impairment of urothelial barrier function. Early administration of thalidomide improves these compensatory mechanisms by inhibiting NF-κB signaling and its interfering effects.

Results of a randomized controlled phase III trial: efficacy of polyphenol-containing cystus® tea mouthwash solution for the reduction of mucositis in head and neck cancer patients undergoing external beam radiotherapy.

PURPOSE: To determine the effect of Cystus® tea (Naturprodukte Dr. Pandalis GmbH & Co. KG) as mouthwash compared to sage tea on oral mucositis in patients undergoing radio(chemo)therapy for head and neck cancer. METHODS: In this randomized, prospective phase III study, 60 head and neck cancer patients with primary or postoperative radio(chemo)therapy were included between 04/2012 and 06/2014. They received either sage or Cystus® tea for daily mouthwash under therapy. Mucositis was scored twice a week following the Radiation Therapy Oncology Group and the European Organization for Research and Treatment Cancer (RTOG/EORTC) scoring system. Dental parameters were also recorded. Statistical evaluation of the primary endpoint was performed using t­test and log rank test. RESULTS: Data from 57 patients could be evaluated. Patient characteristics showed no significant difference between the two groups (n = 27 sage; n = 30 Cystus®). A total of 55 patients received the prescribed dose (60-66 Gy postoperative; 70-76.8 Gy primary). Mucositis grade 3 was observed in 23 patients (n = 11 sage; n = 12 Cystus®) and occurred between day 16 and 50 after start of therapy. There was no significant difference between the two groups in latency (p = 0.75) and frequency (p = 0.85) of the occurrence of mucositis grade 3. The self-assessment of the oral mucosa and the tolerability of the tea also showed no significant differences. Occurrence of dental pathologies appeared to increase over time after radiotherapy. CONCLUSION: Cystus® and sage tea have a similar effect on the occurrence of radiation-induced mucositis regarding latency and incidence. Cystus® tea mouthwash solution is tolerated well and can be applied in addition to intensive oral care and hygiene along with the application of fluorides.

Modulation of radiation-induced oral mucositis (mouse) by dermatan sulfate: effects on differentiation processes.

PURPOSE: During head and neck cancer radiotherapy, oral mucositis is the most frequent early side effect. Systemic dermatan sulfate (DS) administration has been shown to significantly decrease oral mucosal radiation reactions during daily fractionated irradiation (IR) in an established mouse model. The aim of this study was to investigate the mechanism of the oral epithelial differentiation process, during IR alone and in combination with DS treatment in the same mouse model. METHODS: Fractionated IR 5â€¯× 3 Gy/week was given to the snouts of mice over two weeks, either alone (IR) or in combination with daily DS treatment of 4 mg/kg (IR + DS). Groups of mice (n = 3) were sacrificed every second day over the course of 14 days in both experimental arms. Their tongue was excised and subjected to immunohistochemical processing. RESULTS: In the p16 analysis as a proliferation marker, the difference between IR alone and IR + DS in the germinal (proliferation) layer was not significant, not stimulating the proliferation process. For the p21 analysis as a differentiation marker on the functional (differentiation) layer, the difference between IR alone and IR + DS arms was significant, indicating that DS inhibited the differentiation process. In the cytokeratin (CK) analysis as the indicator of cellular skeletal integrity, the percentage of antibody-positive cells was above the normal level in both experimental arms and significantly superior in the IR + DS arm. CONCLUSION: The mucosal protective activity of DS, instead of stimulating proliferation, is based on prevention of cell loss by a combination of effects leading to the inhibition of cellular differentiation and an increase in the expression of epithelial mechanical strength between intercellular mechanical junctions.

Phantom design and dosimetric characterization for multiple simultaneous cell irradiations with active pencil beam scanning.

A new phantom was designed for in vitro studies on cell lines in horizontal particle beams. The phantom enables simultaneous irradiation at multiple positions along the beam path. The main purpose of this study was the detailed dosimetric characterization of the phantom which consists of various heterogeneous structures. The dosimetric measurements described here were performed under non-reference conditions. The experiment involved a CT scan of the phantom, dose calculations performed with the treatment planning system (TPS) RayStation employing both the Pencil Beam (PB) and Monte Carlo (MC) algorithms, and proton beam delivery. Two treatment plans reflecting the typical target location for head and neck cancer and prostate cancer treatment were created. Absorbed dose to water and dose homogeneity were experimentally assessed within the phantom along the Bragg curve with ionization chambers (ICs) and EBT3 films. LETd distributions were obtained from the TPS. Measured depth dose distributions were in good agreement with the Monte Carlo-based TPS data. Absorbed dose calculated with the PB algorithm was 4% higher than the absorbed dose measured with ICs at the deepest measurement point along the spread-out Bragg peak. Results of experiments using melanoma (SKMel) cell line are also presented. The study suggested a pronounced correlation between the relative biological effectiveness (RBE) and LETd, where higher LETd leads to elevated cell death and cell inactivation. Obtained RBE values ranged from 1.4 to 1.8 at the survival level of 10% (RBE10). It is concluded that dosimetric characterization of a phantom before its use for RBE experiments is essential, since a high dosimetric accuracy contributes to reliable RBE data and allows for a clearer differentiation between physical and biological uncertainties.

Postoperative radiotherapy for prostate cancer : Morbidity of local-only or local-plus-pelvic radiotherapy.

PURPOSE: The aim of this work was to characterise actuarial incidence and prevalence of early and late side effects of local versus pelvic three-dimensional conformal postoperative radiotherapy for prostate cancer. MATERIALS AND METHODS: Based on a risk-adapted protocol, 575 patients received either local (n = 447) or local-plus-pelvic (n = 128) radiotherapy. Gastrointestinal (GI) and genitourinary (GU) side effects (≥grade 2 RTOG/EORTC criteria) were prospectively assessed. Maximum morbidity, actuarial incidence rate, and prevalence rates were compared between the two groups. RESULTS: For local radiotherapy, median follow-up was 68 months, and the mean dose was 66.7 Gy. In pelvic radiotherapy, the median follow-up was 49 months, and the mean local and pelvic doses were 66.9 and 48.3 Gy respectively. Early GI side effects ≥ G2 were detected in 26% and 42% of patients respectively (p < 0.001). Late GI adverse events were detected in 14% in both groups (p = 0.77). The 5­year actuarial incidence rates were 14% and 14%, while the prevalence rates were 2% and 0% respectively. Early GU ≥ G2 side effects were detected in 15% and 16% (p = 0.96), while late GU morbidity was detected in 18% and 24% (p = 0.001). The 5­year actuarial incidence rates were 16% and 35% (p = 0.001), while the respective prevalence rates were 6% and 8%. CONCLUSIONS: Despite the low prevalence of side effects, postoperative pelvic radiotherapy results in significant increases in the actuarial incidence of early GI and late GU morbidity using a conventional 4­field box radiotherapy technique. Advanced treatment techniques like intensity-modulated radiotherapy (IMRT) or volumetric modulated arc radiotherapy (VMAT) should therefore be considered in pelvic radiotherapy to potentially reduce these side effects.

Protective effects of systemic dermatan sulfate treatment in a preclinical model of radiation-induced oral mucositis.

PURPOSE: Oral mucositis is a frequent, dose-limiting side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is based on multiple tissue changes, which could offer targets for a biologically tailored treatment. The potential of dermatan sulfate (DS) to modulate radiation-induced oral mucositis was tested in an established preclinical mucositis model. METHODS: Irradiation was either applied alone or in combination with daily DS treatment (4 mg/kg, subcutaneously) over varying time intervals. Irradiation comprised single dose irradiation with graded doses to the lower tongue surface or daily fractionated irradiation of the whole tongue. Fractionation protocols (5â€¯× 3 Gy/week) over one (days 0-4) or two weeks (days 0-4, 7-11) were terminated by an additional local single dose irradiation to a defined treatment field on the lower tongue surface to induce the mucosal radiation response. The additional single dose irradiation (top-up) on day 7 (after one week of fractionation) or day 14 (after 2 weeks of fractionation) comprised graded doses in order to generate full dose-effect curves. Ulceration of the epithelium of the lower tongue, corresponding to confluent mucositis, was analysed as clinically relevant endpoint. Additionally, the time course parameters, latent time and ulcer duration were analysed. RESULTS: DS treatment significantly reduced the incidence of ulcerations. DS application over longer time intervals resulted in a more pronounced reduction of ulcer frequency, increased latent times and reduced ulcer duration. CONCLUSION: DS has a significant mucositis-ameliorating activity with pronounced effects on mucositis frequency as well as on time course parameters.

Systemic administration of heparin ameliorates radiation-induced oral mucositis-preclinical studies in mice.

PURPOSE: The present study investigates the impact of systemic application of heparins on the manifestation of radiation-induced oral mucositis in a well-established mouse model. MATERIALS AND METHODS: Male C3H/Neu mice were irradiated with either single-dose or fractionated irradiation protocols with 5â€¯× 3 Gy/week, given over one (days 0-4) or two (days 0-4, 7-11) weeks. All fractionation protocols were concluded by a local test irradiation (day 7/14) using graded doses to generate complete dose-effect curves. Daily doses of unfractionated or low molecular weight heparin (40 or 200 I.U./mouse, respectively) were applied subcutaneously over varying time intervals. The incidence and the time course of mucosal ulceration, corresponding to confluent mucositis in patients (RTOG/EORTC grade 3), were analysed as clinically relevant endpoints. RESULTS: Systemic application of heparins significantly increased the iso-effective doses for the induction of mucosal ulceration, particularly in combination with fractionated irradiation protocols. Moreover, a tentative prolongation of the latent time and a pronounced reduction of the ulcer duration were observed. CONCLUSION: These data provide the first evidence for a protective and/or mitigative effect of heparins for radiation-induced oral mucositis. Further studies are ongoing investigating the underlying mechanism.

Upregulated epithelial junction expression represents a novel parameter of the epithelial radiation response to fractionated irradiation in oral mucosa.

PURPOSE: During head and neck cancer treatment, the radiation response of the oral mucosa represents a frequent early side effect. Besides radiation-induced inhibition of proliferation, various other cellular responses occur. The radiation response of adherens and tight junction proteins was so far mostly investigated with large single-dose irradiation protocols, in vivo and in vitro. Therefore, the current study was initiated to investigate the impact of daily fractionated irradiation on the expression of adherens and tight junction proteins in vivo. MATERIALS AND METHODS: Fractionation with 5â€¯× 3 Gy/week (days 0-4, 7-11) was given to the snouts of mice. Groups of 5 animals per day were euthanized every second day between day 0 (unirradiated controls) and day 14, and their tongues subjected to histological processing. Adherens junction marker (ß-catenin and E­cadherin) and tight junction marker (claudin-1 and occludin) expression was analysed in the oral mucosa of unirradiated controls and during two weeks of fractionated irradiation. RESULTS: Adherens as well as tight junction marker proteins were rapidly and consistently upregulated in both the germinal as well as the functional layer of the oral mucosa. This represents a previously unknown parameter of the epithelial radiation response to clinically relevant fractionation protocols. CONCLUSION: Fractionated irradiation significantly enhanced the expression of all proteins investigated. This study revealed a new parameter of the epithelial radiation response to fractionated irradiation.

Heart irradiation reduces microvascular density and accumulation of HSPA1 in mice.

PURPOSE: Improvement of radiotherapy techniques reduces the exposure of normal tissues to ionizing radiation. However, the risk of radiation-related late effects remains elevated. In the present study, we investigated long-term effects of radiation on heart muscle morphology. MATERIALS AND METHODS: We established a mouse model to study microvascular density (MVD), deposition of collagen fibers, and changes in accumulation of heat shock 70 kDa protein 1 (HSPA1) in irradiated heart tissue. Hearts of C57BL/6 mice received a single dose of X­ray radiation in the range 0.2-16 Gy. Analyses were performed 20, 40, and 60 weeks after irradiation. RESULTS: Reduction in MD was revealed as a long-term effect observed 20-60 weeks after irradiation. Moreover, a significant and dose-dependent increase in accumulation of HSPA1, both cytoplasmic and nuclear, was observed in heart tissues collected 20 weeks after irradiation. We also noticed an increase in collagen deposition in hearts treated with higher doses. CONCLUSIONS: This study shows that some changes induced by radiation in the heart tissue, such as reduction in microvessel density, increase in collagen deposition, and accumulation of HSPA1, are observed as long-term effects which might be associated with late radiation cardiotoxicity.

Long-term effects of low-dose mouse liver irradiation involve ultrastructural and biochemical changes in hepatocytes that depend on lipid metabolism.

The aim of the study was to investigate long-term effects of radiation on the (ultra)structure and function of the liver in mice. The experiments were conducted on wild-type C57BL/6J and apolipoprotein E knock-out (ApoE-/-) male mice which received a single dose (2 or 8 Gy) of X-rays to the heart with simultaneous exposure of liver to low doses (no more than 30 and 120 mGy, respectively). Livers were collected for analysis 60 weeks after irradiation and used for morphological, ultrastructural, and biochemical studies. The results show increased damage to mitochondrial ultrastructure and lipid deposition in hepatocytes of irradiated animals as compared to non-irradiated controls. Stronger radiation-related effects were noted in ApoE-/- mice than wild-type animals. In contrast, radiation-related changes in the activity of lysosomal hydrolases, including acid phosphatase, ß-glucuronidase, N-acetyl-ß-D-hexosaminidase, ß-galactosidase, and α-glucosidase, were observed in wild type but not in ApoE-deficient mice, which together with ultrastructural picture suggests a higher activity of autophagy in ApoE-proficient animals. Irradiation caused a reduction of plasma markers of liver damage in wild-type mice, while an increased level of hepatic lipase was observed in plasma of ApoE-deficient mice, which collectively indicates a higher resistance of hepatocytes from ApoE-proficient animals to radiation-mediated damage. In conclusion, liver dysfunctions were observed as late effects of irradiation with an apparent association with malfunction of lipid metabolism.

Radioprotective Effects of Dermatan Sulfate in a Preclinical Model of Oral Mucositis-Targeting Inflammation, Hypoxia and Junction Proteins without Stimulating Proliferation.

Oral mucositis is the most frequently occurring early side effect of head-and-neck cancer radiotherapy. Systemic dermatan sulfate (DS) treatment revealed a significant radioprotective potential in a preclinical model of oral mucositis. This study was initiated to elucidate the mechanistic effects of DS in the same model. Irradiation comprised daily fractionated irradiation (5 × 3 Gy/week) over two weeks, either alone (IR) or in combination with daily dermatan sulfate treatment of 4 mg/kg (IR + DS). Groups of mice (n = 5) were sacrificed every second day over the course of 14 days in both experimental arms, their tongues excised and evaluated. The response to irradiation with and without DS was analyzed on a morphological (cell numbers, epithelial thickness) as well as on a functional (proliferation and expression of inflammation, hypoxia and epithelial junction markers) level. The mucoprotective activity of DS can be attributed to a combination of various effects, comprising increased expression of epithelial junctions, reduced inflammation and reduced hypoxia. No DS-mediated effect on proliferation was observed. DS demonstrated a significant mucositis-ameliorating activity and could provide a promising strategy for mucositis treatment, based on targeting specific, radiation-induced, mucositis-associated signaling without stimulating proliferation.

Early inflammatory changes in radiation-induced oral mucositis : Effect of pentoxifylline in a mouse model.

PURPOSE: Early inflammation is a major factor of mucosal reactions to radiotherapy. Pentoxifylline administration resulted in a significant amelioration of radiation-induced oral mucositis in the mouse tongue model. The underlying mechanisms may be related to the immunomodulatory properties of the drug. The present study hence focuses on the manifestation of early inflammatory changes in mouse tongue during daily fractionated irradiation and their potential modulation by pentoxifylline. MATERIALS AND METHODS: Daily fractionated irradiation with 5 fractions of 3 Gy/week (days 0-4, 7-11) was given to the snouts of mice. Groups of 3 animals per day were euthanized every second day between day 0 and 14. Pentoxifylline (15 mg/kg, s. c.) was administered daily from day 5 to the day before sacrifice. The expression of the inflammatory proteins TNFα, NF-κB, and IL-1ß were analysed. RESULTS: Fractionated irradiation increased the expression of all inflammatory markers. Pentoxifylline significantly reduced the expression of TNFα and IL-1ß, but not NF-κB. CONCLUSION: Early inflammation, as indicated by the expression of the inflammatory markers TNFα, NF-κB, and IL-1ß, is an essential component of early radiogenic oral mucositis. Pentoxifylline differentially modulated the expression of different inflammatory markers. The mucoprotective effect of pentoxifylline does not appear to be based on modulation of NF-κB-associated inflammation.

Modulation of radiation-induced oral mucositis by thalidomide : Preclinical studies.

PURPOSE: Oral mucositis is a common, dose-limiting early side effect of radio(chemo)therapy for head-and-neck tumors. The epithelial radiation response is accompanied by changes in the inflammatory signaling cascades mediated by the transcription factor nuclear factor-kappa B (NF-κB). The present study was initiated to determine the effect of the NF-κB inhibitor thalidomide on the clinical manifestation of oral mucositis in the established mouse tongue model. MATERIALS AND METHODS: Treatment protocols comprised single dose irradiation and daily fractionated irradiation (5  fractions of 3 Gy/week) over 1 (days 0-4) or 2 weeks (days 0-4, 7-11), alone or in combination with daily thalidomide application (100 mg/kg intraperitoneally) over varying time intervals. Fractionation protocols were terminated by graded local radiation doses (day 7/14) to generate full dose-effect curves. Tongue epithelial ulcerations, corresponding to confluent mucositis, served as the clinically relevant endpoint. RESULTS: Thalidomide application did not show a significant radioprotective potential when administered in combination with single dose irradiation. Thalidomide in combination with one week of fractionated irradiation significantly increased the isoeffective top-up doses. Similar results were observed during two weeks of fractionated irradiation in all but one experiment. CONCLUSION: Thalidomide treatment demonstrated a significant mucositis-ameliorating effect during fractionated irradiation, which is likely to result from NF-κB inhibition. However, further mechanistic studies are required to define the underlying mechanisms of the observed mucoprotective effect.

Modulation of radiation-induced oral mucositis by pentoxifylline: preclinical studies.

BACKGROUND AND PURPOSE: Oral mucositis is a frequent early side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is accompanied by inflammatory reactions; their interaction with epithelial processes remains unclear. The aim of the present study was to investigate the effect of pentoxifylline (PTX) on the oral mucosal radiation response in the mouse tongue model. MATERIALS AND METHODS: Irradiation comprised fractionation (5 fractions of 3 Gy/week) over 1 (days 0-4) or 2 weeks (days 0-4, 7-11), followed by graded local top-up doses (day 7/14), in order to generate complete dose-effect curves. PTX (15 mg/kg subcutaneously) was applied once daily over varying time intervals. Ulceration of mouse tongue epithelium, corresponding to confluent mucositis, was analyzed as the clinically relevant endpoint. RESULTS: With fractionated irradiation over 1 week, PTX administration significantly reduced the incidence of mucosal reactions when initiated before (day-5) the onset of fractionation; a trend was observed for start of PTX treatment on day 0. Similarly, PTX treatment combined with 2 weeks of fractionation had a significant effect on ulcer incidence in all but one experiment. This clearly illustrates the potential of PTX to ameliorate oral mucositis during daily fractionated irradiation. CONCLUSION: PTX resulted in a significant reduction of oral mucositis during fractionated irradiation, which may be attributed to stimulation of mucosal repopulation processes. The biological basis of this effect, however, needs to be clarified in further, detailed mechanistic studies.

8-prenylnaringenin and tamoxifen inhibit the shedding of irradiated epithelial cells and increase the latency period of radiation-induced oral mucositis : cell culture and murine model.

PURPOSE: The major component in the pathogenesis of oral radiation-induced mucositis is progressive epithelial hypoplasia and eventual ulceration. Irradiation inhibits cell proliferation, while cell loss at the surface continues. We conceived to slow down this desquamation by increasing intercellular adhesion, regulated by the E-cadherin/catenin complex. We investigated if 8-prenylnaringenin (8-PN) or tamoxifen (TAM) decrease the shedding of irradiated human buccal epithelial cells in vitro and thus delay the ulcerative phase of radiation-induced mucositis in vivo. MATERIALS AND METHODS: In vitro, aggregates of buccal epithelial cells were irradiated and cultured in suspension for 11 days. 8-PN or TAM were investigated regarding their effect on cell shedding. In vivo, the lower tongue surface of mice was irradiated with graded single doses of 25 kV X-rays. The incidence, latency, and duration of the resulting mucosal ulcerations were analyzed after topical treatment with 8-PN, TAM or solvent. RESULTS: 8-PN or TAM prevented the volume reduction of the irradiated cell aggregates during the incubation period. This was the result of a higher residual cell number in the treated versus the untreated irradiated aggregates. In vivo, topical treatment with 8-PN or TAM significantly increased the latency of mucositis from 10.9 to 12.1 and 12.4 days respectively, while the ulcer incidence was unchanged. CONCLUSION: 8-PN and TAM prevent volume reduction of irradiated cell aggregates in suspension culture. In the tongues of mice, these compounds increase the latency period. This suggests a role for these compounds for the amelioration of radiation-induced mucositis in the treatment of head and neck tumors.

Health related quality of life and patient reported symptoms before and during definitive radio(chemo)therapy using image-guided adaptive brachytherapy for locally advanced cervical cancer and early recovery - a mono-institutional prospective study.

OBJECTIVE: To evaluate health-related quality of life (HR-QoL) and patient reported symptoms (PRS) before, during and early after treatment with external-beam radiotherapy (EBRT), chemotherapy and image-guided adaptive brachytherapy (IGABT) for locally advanced cervical cancer. METHODS: In fifty consecutive patients, HR-QoL and PRS were prospectively assessed with the EORTC-QLQ-C30+CX24 questionnaire prior to and during treatment, one week after IGABT and three months thereafter. HR-QoL was compared to an age-matched, female normative reference population. Prevalence rates of individual PRS are presented and defined as "substantial", if reported as "quite a bit" or "very much". RESULTS: Global health status and physical and role functioning show a highly significant decline during treatment (p≤0.001), before returning to near the baseline levels three months after end of treatment. Compared to the reference population, the global health status and emotional and role functioning remain impaired. The most frequently reported substantial PRS during active treatment are: fatigue (78%), diarrhea (68%), urinary frequency (60%) and nausea (54%); these recover to some degree three months after end of treatment. However, fatigue remains increased (50%) and an onset of hot flashes (44%), sexual worries (38%) and limb edema (22%) is observed. CONCLUSIONS: Several impairments in HR-QoL and PRS were found during definitive radio(chemo)therapy with IGABT, with different patterns of progress over time and signs of recovery three months thereafter, although some aspects of functional HR-QoL remain impaired. These findings support a comprehensive patients' counseling on what to expect and how to organize professional, social and family life and plan additional support during this period.

Application of organ tolerance dose-constraints in clinical studies in radiation oncology.

In modern radiation oncology, tolerance dose-constraints for organs at risk (OAR) must be considered for treatment planning, but particularly in order to design clinical studies. Tolerance dose tables, however, only address one aspect of the therapeutic ratio of any clinical study, i.e., the limitation of adverse events, but not the desired potential improvement in the tumor effect of a novel treatment strategy. A sensible application of "tolerance doses" in a clinical situation requires consideration of various critical aspects addressed here: definition of tolerance dose, specification of an endpoint/symptom, consideration of radiation quality and irradiation protocol, exposed volume and dose distribution, and patient-related factors of radiosensitivity. The currently most comprehensive estimates of OAR radiation tolerance are in the QUANTEC compilations (2010). However, these tolerance dose values must only be regarded as a rough orientation and cannot answer the relevant question for the patients, i.e., if the study can achieve a therapeutic advantage; this can obviously be answered only by the final scientific analysis of the study results. Despite all limitations, the design of clinical studies should currently refer to the QUANTEC values for appreciation of the risk of complications, if needed supplemented by one's own data or further information from the literature. The implementation of a consensus on the safety interests of the patients and on an application and approval process committed to progress in medicine, with transparent quality-assuring requirements with regard to the structural safeguarding of the study activities, plays a central role in clinical research in radiation oncology.

Modification of radiation-induced oral mucositis (mouse) by adult stem cell therapy: single-dose irradiation.

Early oral mucositis occurs in response to accidental upper partial body exposure as well as to radiotherapy in the head-and-neck region. This study was initiated to define the potential of mobilization of endogenous bone marrow (BM) stem cells by rHuG-CSF or of bone marrow transplantation (BMT) to reduce the effect of single-dose irradiation on mouse oral epithelium. A 3 × 3 mm(2) area of the lower tongue surface of mice was irradiated with graded single doses (day 0). Mucosal ulceration was used as the endpoint for dose-response analyses. Stem cells were mobilized by rHuG-CSF (8 times/4 days), timed to achieve a maximum of circulating stem cells on days 0, +1, +4, +8 or +10. Alternatively, syngeneic BM was transplanted on these days. The ED(50) (dose at which ulceration is expected in 50 % of the animals) for irradiation alone was 11.9 ± 3.4 Gy. Mobilization of stem cells with a maximum of circulating stem cells on days +4, +8 or +10 significantly increased the ED(50) to 25.5 ± 10.1, 23.5 ± 10.1 and 26.5 ± 13.0 Gy. In contrast, a maximum of circulating stem cells on day 0 or day +1 had no effect. BMT did not result in a significant change in isoeffective doses in any of the protocols. In conclusion, the response of oral mucosal epithelium to a single-radiation exposure can be significantly reduced by post-exposure mobilization, but not by transplantation, of BM stem cells.

Magnetic resonance imaging for assessment of parametrial tumour spread and regression patterns in adaptive cervix cancer radiotherapy.

PURPOSE: To investigate the impact of magnetic resonance imaging (MRI)-morphologic differences in parametrial infiltration on tumour response during primary radiochemotherapy in cervical cancer. MATERIAL AND METHODS: Eighty-five consecutive cervical cancer patients with FIGO stages IIB (n = 59) and IIIB (n = 26), treated by external beam radiotherapy (± chemotherapy) and image-guided adaptive brachytherapy, underwent T2-weighted MRI at the time of diagnosis and at the time of brachytherapy. MRI patterns of parametrial tumour infiltration at the time of diagnosis were assessed with regard to predominant morphology and maximum extent of parametrial tumour infiltration and were stratified into five tumour groups (TG): 1) expansive with spiculae; 2) expansive with spiculae and infiltrating parts; 3) infiltrative into the inner third of the parametrial space (PM); 4) infiltrative into the middle third of the PM; and 5) infiltrative into the outer third of the PM. MRI at the time of brachytherapy was used for identifying presence (residual vs. no residual disease) and signal intensity (high vs. intermediate) of residual disease within the PM. Left and right PM of each patient were evaluated separately at both time points. The impact of the TG on tumour remission status within the PM was analysed using χ(2)-test and logistic regression analysis. RESULTS: In total, 170 PM were analysed. The TG 1, 2, 3, 4, 5 were present in 12%, 11%, 35%, 25% and 12% of the cases, respectively. Five percent of the PM were tumour-free. Residual tumour in the PM was identified in 19%, 68%, 88%, 90% and 85% of the PM for the TG 1, 2, 3, 4, and 5, respectively. The TG 3-5 had significantly higher rates of residual tumour in the PM in comparison to TG 1 + 2 (88% vs. 43%, p < 0.01). CONCLUSION: MRI-morphologic features of PM infiltration appear to allow for prediction of tumour response during external beam radiotherapy and chemotherapy. A predominantly infiltrative tumour spread at the time of diagnosis resulted in a significantly higher rate of residual tumour in the PM at the time of brachytherapy in comparison to a predominantly expansive tumour spread.