[en] Stereotactic-Radio-Surgery (SRS) using Conformal-Arc-Therapy (CAT) is a well established irradiation technique for treatment of intracranial targets. Although small safety margins are required because of very high accuracy of patient positioning and exact online localisation, there are still disadvantages like long treatment time, high number of monitor units (MU) and covering of noncircular targets. This planning study analysed whether Rapid Arc (RA) with stereotactic localisation for single-fraction SRS can solve these problems. Ten consecutive patients were treated with Linac-based SRS. Eight patients had one or more brain metastases. The other patients presented a symptomatic vestibularis schwannoma and an atypic meningeoma. For all patients, two plans (CAT/RA) were calculated and analysed. Conformity was higher for RA with additional larger low-dose areas. Furthermore, RA reduced the number of MU and the treatment time for all patients. Dose to organs at risk were equal or slightly higher using RA in comparison to CAT. RA provides a new alternative for single-fraction SRS irradiation combining advantages of short treatment time with lower number of MU and better conformity in addition to accuracy of stereotactic localisation in selected cases with uncomplicated clinical realization

[en] Purpose: to analyze different control-system limitations on the measured dose distributions in low-dose regions of simplified intensity fields with an electronic portal imaging device to ascertain the optimal settings for the control-system limitations in the planning system. Material and methods: the authors created one field with an ''optimal fluence'' of intensity 1.0 (full dose) and one field with intensity 0.0 (no dose) in the central part of the field. The influence of different dose rates (DRs) and maximum leaf speeds (LS) on the calculated and measured dose and dose profiles were analyzed. Results: good agreement between calculated and measured dose in the case of a field of intensity 1.0 was found. For the field with intensity 0.0, the measured dose was 20-60% lower than the dose calculated by the ''actual fluence''. The results were found dependent on the DR and LS. Conclusion: The overestimation in regions of optimal intensity 0.0 by the planning system cannot be resolved by the user. Taking the measured dose in the region of desired intensity 1.0 and other technical limitations (like beam hold interrupts or spikes in the cross and longitudinal profiles) into consideration, the application of an LS of 2.5 cm/s and a DR of 500 MU/min is recommended in order to minimize radiation dose applied to organs at risk, which are located in regions of low intensity, like, for example, the spinal cord. (orig.)

[en] Purpose: to evaluate prostate volume changes during external-beam irradiation in consequence of high-dose-rate (HDR) brachytherapy in prostate cancer treatment. Patients and methods: 20 patients who underwent radiotherapy for prostate cancer were included in this prospective evaluation. All patients had a computed tomography (CT) scan for planning of the external-beam irradiation and additional scans after each HDR brachytherapy. For the planning target volume (PTV), a safety margin of 10 mm was added to the clinical target volume (CTV) in each direction. The prostate volume measured in the planning CT was compared with the prostate volumes measured after HDR brachytherapy and, subsequently, the change of prostate volume was calculated. Volume changes which resulted in differences of the prostate radius of > 5 mm for the CTV were defined as a reason for a new treatment-planning procedure for the patient. Results: taking all patients together, prostate volumes before HDR, 1 day and 4-6 days after the first HDR treatment, as well as 1 day and 4-6 days after the second HDR treatment were in median 37.7 cm³, 37.6 cm³, 38.2 cm³, 39.3 cm³, and 40.5 cm³, respectively. In none of the patient, a volume change resulted in a change of the prostate radius of > 5 mm for the CTV. Prerequisite for this calculation was the simplification of the complex prostate geometry to a sphere. No new treatment-planning procedure was necessary during external-beam radiotherapy. Conclusion: HDR brachytherapy does change the prostate volume. Under the condition of a 10-mm safety margin in each direction added to the CTV for the PTV, no new treatment-planning procedure was necessary after HDR brachytherapy. There is no need for CT scans at regular intervals during external-beam radiotherapy. (orig.)

[en] To evaluate gold marker displacement due to needle insertion during HDR-brachytherapy for therapy of prostate cancer. 18 patients entered into this prospective evaluation. Three gold markers were implanted into the prostate during the first HDR-brachytherapy procedure after the irradiation was administered. Three days after marker implantation all patients had a CT-scan for planning purpose of the percutaneous irradiation. Marker localization was defined on the digitally-reconstructed-radiographs (DRR) for daily (VMAT technique) or weekly (IMRT) set-up error correction. Percutaneous therapy started one week after first HDR-brachytherapy. After the second HDR-brachytherapy, two weeks after first HDR-brachtherapy, a cone-beam CT-scan was done to evaluate marker displacement due to needle insertion. In case of marker displacement, the actual positions of the gold markers were adjusted on the DRR. The value of the gold marker displacement due to the second HDR-brachytherapy was analyzed in all patients and for each gold marker by comparison of the marker positions in the prostate after soft tissue registration of the prostate of the CT-scans prior the first and second HDR-brachytherapy. The maximum deviation was 5 mm, 7 mm and 12 mm for the anterior-posterior, lateral and superior-inferior direction. At least one marker in each patient showed a significant displacement and therefore new marker positions were adjusted on the DRRs for the ongoing percutaneous therapy. Needle insertion in the prostate due to HDR-brachytherapy can lead to gold marker displacements. Therefore, it is necessary to verify the actual position of markers after the second HDR-brachytherapy. In case of significant deviations, a new DRR with the adjusted marker positions should be generated for precise positioning during the ongoing percutaneous irradiation

[en] The Physikalisch-Technische Bundesanstalt has established a secondary standard measurement system for the dose to water, D _W, based on alanine/ESR (Anton et al 2013 Phys. Med. Biol . 58 3259–82). The aim of this study was to test the established measurement system for the out-of-field measurements of inpatients with breast cancer. A set of five alanine pellets were affixed to the skin of each patient at the contra lateral breast beginning at the sternum and extending over the mammilla to the distal surface. During 28 fractions with 2.2 Gy per fraction, the accumulated dose was measured in four patients. A cone beam computer tomography (CBCT) scan was generated for setup purposes before every treatment. The reference CT dataset was registered rigidly and deformably to the CBCT dataset for 28 fractions. To take the actual alanine pellet position into account, the dose distribution was calculated for every fraction using the Acuros XB algorithm. The results of the ESR measurements were compared to the calculated doses. The maximum dose measured at the sternum was 19.9 Gy  ±  0.4 Gy, decreasing to 6.8 Gy  ±  0.2 Gy at the mammilla and 4.5 Gy  ±  0.1 Gy at the distal surface of the contra lateral breast. The absolute differences between the calculated and measured doses ranged from  −1.9 Gy to 0.9 Gy. No systematic error could be seen. It was possible to achieve a combined standard uncertainty of 1.63% for D _W  =  5 Gy for the measured dose. The alanine/ESR method is feasible for in vivo measurements. (paper)

[en] Superior treatment response and survival for patients with human papilloma virus (HPV)-positive head and neck cancer (HNSCC) are documented in clinical studies. However, the relevance of high-grade acute organ toxicity (HGAOT), which has also been correlated with improved prognosis, has attracted scant attention in HPV-positive HNSCC patients. Hence we tested the hypothesis that both parameters, HPV and HGAOT, are positive prognostic factors in patients with HNSCC treated with definite radiotherapy (RT) or radiochemotherapy (RCT). Pretreatment tumor tissue and clinical records were available from 233 patients receiving definite RT (62 patients) or RCT (171 patients). HPV infection was analysed by means of HPV DNA detection or p16^INK4A expression; HGAOT was defined as the occurrence of acute organ toxicity >grade 2 according to the Common Toxicity Criteria. Both variables were correlated with overall survival (OS) using Cox proportional hazards regression. Positivity for HPV DNA (44 samples, 18.9 %) and p16^INK4A expression (102 samples, 43.8 %) were significantly correlated (p < 0.01), and HGAOT occurred in 77 (33 %) patients. Overall, the 5-year OS was 23 %; stratified for p16^INK4A expression and HGAOT, OS rates were 47 %, 42 %, 20 % and 10 % for patients with p16^INK4A expression and HGAOT, patients with HGAOT only, patients with p16^INK4A expression only, and patients without p16^INK4A expression or HGAOT, respectively. After multivariate testing p16^INK4A expression (p = 0.003) and HGAOT (p < 0.001) were significantly associated with OS. P16^INK4A expression and HGAOT are independent prognostic factors for OS of patients with HNSCC, whereas p16^INK4A expression is particularly important for patients without HGAOT. (orig.)

[en] Purpose: Hepatocyte transplantation is strongly considered to be a promising option to correct chronic liver failure through repopulation of the diseased organ. We already reported on extensive liver repopulation by hepatocytes transplanted into rats preconditioned with 25-Gy single dose selective external beam irradiation (IR). Herein, we tested lower radiation doses and fractionated protocols, which would be applicable in clinical use. Methods and Material: Livers of dipeptidylpeptidase IV (DPPIV)-deficient rats were preconditioned with partial liver external beam single dose IR at 25 Gy, 8 Gy, or 5 Gy, or fractionated IR at 5 x 5 Gy or 5 x 2 Gy. Four days after completion of IR, a partial hepatectomy (PH) was performed to resect the untreated liver section. Subsequently, 12 million wild-type (DPPIV⁺) hepatocytes were transplanted via the spleen into the recipient livers. The degree of donor cell integration and liver repopulation was studied 16 weeks after transplantation by means of immunofluorescence and DPPIV-luminescence assay. Results: Donor hepatocyte integration and liver repopulation were more effective in the irradiated livers following pretreatment with the IR doses 1 x 25 Gy and 5 x 5 Gy (formation of large DPPIV-positive cell clusters) than single-dose irradiation at 8 Gy or 5 Gy (DPPIV-positive clusters noticeably smaller and less frequent). Quantitative analysis of extracted DPPIV revealed signals exceeding the control level in all transplanted animals treated with IR and PH. Compared with the standard treatment of 1 x 25 Gy, fractionation with 5 x 5 Gy was equally efficacious, the Mann-Whitney U test disclosing no statistically significant difference (p = 0.146). The lower doses of 1 x 5 Gy, 1 x 8 Gy, and 5 x 2 Gy were significantly less effective with p < 0.05. Conclusion: This study suggests that fractionated radiotherapy in combination with PH is a conceivable pretreatment approach to prime the host liver for hepatocyte transplantation, thus bringing the experimental model a step closer to clinical application.

[en] Chemoradiotherapy (CRT) represents a standard treatment for many human cancers, frequently combined with radical surgical resection. However, a considerable percentage of primary cancers are at least partially resistant to CRT, which represents a substantial clinical problem, because it exposes cancer patients to the potential side effects of both irradiation and chemotherapy. It is therefore exceedingly important to determine the molecular characteristics underlying CRT-resistance and to identify novel molecular targets that can be manipulated to re-sensitize resistant tumors to CRT. In this review, we highlight much of the recent evidence suggesting that the signal transducer and activator of transcription 3 (STAT3) plays a prominent role in mediating CRT-resistance, and we outline why inhibition of STAT3 holds great promise for future multimodal treatment concepts in oncology

[en] Background and purpose: KRAS and BRAF are mutated in 35% and 10% of colorectal cancers, respectively. However, data specifically for locally advanced rectal cancers are scarce, and the frequency of KRAS mutations in codons 61 and 146 remains to be established. Materials and methods: DNA was isolated from pre-therapeutic biopsies of 94 patients who were treated within two phase-III clinical trials receiving preoperative chemoradiotherapy. Mutation status of KRAS exons 1-3 and BRAF exon 15 was established using the ABI PRISM Big Dye Sequencing Kit and subsequently correlated with clinical parameters. Results: Overall, KRAS was mutated in 45 patients (48%). Twenty-nine mutations (64%) were located in codon 12, 10 mutations (22%) in codon 13, and 3 mutations (7%) in codons 61 and 146. No V600E BRAF mutation was detected. The presence of KRAS mutations was correlated neither with tumor response or lymph node status after preoperative chemoradiotherapy nor with overall survival or disease-free survival. When KRAS exon 1 mutations were separated based on the amino-acid exchange, we again failed to detect significant correlations (p = 0.052). However, G12V mutations appeared to be associated with higher rates of tumor regression than G13D mutations (p = 0.012). Conclusion: We are the first to report the mutation status of KRAS and BRAF in pre-therapeutic biopsies from locally advanced rectal cancers. The high number of KRAS mutations in codons 61 and 146 emphasizes the importance to expand current mutation analyses, whereas BRAF mutations are not relevant for rectal carcinogenesis. Although the KRAS mutation status was not correlated with response, the subtle difference between G12V and G13D mutations warrants analysis of a larger patient population.

[en] Background and purpose: Preoperative chemoradiotherapy (CRT) represents the standard treatment for locally advanced rectal cancer. Tumor response and progression vary considerably. MicroRNAs represent master regulators of gene expression, and may therefore contribute to this diversity. Material and methods: Genome-wide microRNA (miRNA) profiling was performed for 12 colorectal cancer (CRC) cell lines and an individual in vitro signature of chemoradiosensitivity was established. Functional relevance of selected miRNAs was established by transfecting miRNA-mimics into SW480 and SW837 cells. The prognostic value of selected miRNAs was assessed in 128 pretherapeutic patient biopsies. Results: Thirty-six miRNAs were identified to significantly correlate with sensitivity to CRT (Q < 0.05) including miR-320a and other miRNAs involved in the MAPK-, TGF- and Wnt-pathway. Transfection of selected miRNAs (let-7g, miR-132, miR-224, miR-320a) each induced a shift of sensitivity. High expression of let-7g was associated with a good prognosis in rectal cancer patients (P = 0.03). Conclusions: This is the first report of a miRNA expression signature for in vitro chemoradiosensitivity of CRC cell lines. Many of the identified miRNAs have not been linked to the response to CRT and may represent potential molecular targets to sensitize resistant cancers. If further validated, let7g expression may serve as predictive biomarker