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Abstract: Objective.: To evaluate long-term outcome, risk factors, and causes of death in stage I–IIIA endometrial carcinoma (EC) patients treated only with adjuvant vaginal brachytherapy (VB) and to clarify for which subgroups of patients it is safe to omit external-beam radiotherapy (EBRT). Methods.: Out of 224 EC patients receiving postoperative radiotherapy between 1990 and 2002, 138 had VB alone in curative intent (FIGO [2002]: 85%I, 12%II, 3%IIIA; 18 low risk [IA G1–2, IB G1], 103 intermediate risk [IB G2–3, IC G1–2, IIA–B G1–2], 17 high risk [IC G3, IIIA]). After surgery±lymphadenectomy, HDR-brachytherapy prescription (in 95.7% of patients) was 3×10 Gy to the surface or 3×5 Gy at 5 mm tissue depths. Results.: Median follow-up was 107 months (range 3–185). Three intermediate and 7 high risk-patients relapsed. The 10-year vaginal control was 99.2%, locoregional control was 95.2% (low/intermediate/high risk: 100%/98.9%/68.8%), and disease-free survival (DFS) was 91.7% (100%/96.8%/55.2%). Risk factors for poor DFS were lymphovascular space invasion, ≥50% myometrial invasion (univariate, p <0.05), pathological FIGO-stage, and grade 3 (uni-/multivariate, p <0.05). Leading causes of deaths (n =41) were cardiovascular disease (29%) and other malignancies (24%) ahead of EC (19.5%). The 10-year overall survival was 68.5% and the disease-specific survival was 92.4%. Thirty-five secondary tumors in 31 patients led to a higher actuarial death rate (10-year 9.9%, 15-year 17.7%) than EC (7.6%). Conclusions.: Restricting adjuvant therapy to VB alone seems to be safe in low and intermediate risk EC and can be recommended. As death rarely relates to early-stage EC, value of adjuvant therapy is probably better reflected by DFS rather than by overall survival. [Copyright &y& Elsevier]

Hypoxia is an important negative prognostic factor for radiation treatment of head and neck cancer. This study was performed to evaluate the feasibility of use of 18F-labelled fluoroazomycin arabinoside ([18F]FAZA) for clinical PET imaging of tumour hypoxia. Eleven patients (age 59.6 ± 9 years) with untreated advanced head and neck cancer were included. After injection of approximately 300 MBq of [18F]FAZA, a dynamic sequence up to 60 min was acquired on an ECAT HR+ PET scanner. In addition, approximately 2 and 4 h p.i., static whole-body PET ( n = 5) or PET/CT ( n = 6) imaging was performed. PET data were reconstructed iteratively (OSEM) and fused with CT images (either an external CT or the CT of integrated PET/CT). Standardised uptake values (SUVs) and tumour-to-muscle (T/M) ratios were calculated in tumour and normal tissues. Also, the tumour volume displaying a T/M ratio >1.5 was determined. Within the first 60 min of the dynamic sequence, the T/M ratio generally decreased, while generally increasing at later time points. At 2 h p.i., the tumour SUVmax and SUVmean were found to be 2.3 ± 0.5 (range 1.5–3.4) and 1.4 ± 0.3 (range 1.0–2.1), respectively. The mean T/M ratio at 2 h p.i. was 2.0 ± 0.3 (range 1.6–2.4). The tumour volume displaying a T/M ratio above 1.5 was highly variable. At 2 h p.i., [18F]FAZA organ distribution was determined as follows: kidney > gallbladder > liver > tumour > muscle > bone > brain > lung. [18F]FAZA PET imaging appears feasible in head and neck cancer patients, and the achieved image quality is adequate for clinical purposes. Based on our initial results, [18F]FAZA warrants further evaluation as a hypoxia PET tracer for imaging of cancer. [ABSTRACT FROM AUTHOR]

Abstract Neural tube defects (NTD) are likely to result from an interaction of several genes and environmental factors. Because periconceptional folate intake reduces the NTD risk in the fetus, and because mothers of children with NTD showed elevated plasma homocysteine levels, gene polymorphisms of the folate and homocysteine pathway, such as 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C arrow right T, MTHH 1298A arrow right C and cystathionine beta-synthase (CBS) 844ins68, have been implicated in the etiology of NTD. Several studies have demonstrated that these polymorphisms may indeed be associated with NTD in some populations. In order to evaluate the role of these polymorphisms and their interaction in NTD, we genotyped 417 individuals for case-control studies and 129 families for transmission disequilibrium tests. We are the first to present detailed data on MTHFR haploid genotypes in combination with CBS 844ins68. The MTHR risk genotype 677CT/1298AC, known to be associated with decreased enzyme activity and increased homocysteine, was found significantly more often in patients than in controls (P = 0.02). A CBS insertion allele in addition to MTHFR 677CT/ 1298AC heterozygosity or MTHFR 677TT/1298AA homozygosity did not result in an increased risk for NTD. This is in agreement with the recently reported homocysteine-lowering effect of the CBS 844ins68 allele in carriers of MTHFR variants. [ABSTRACT FROM AUTHOR]

In this study, we sought to determine the prognostic value of both the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC-STBSG) score and the histologic parameters viable tumor, coagulative necrosis, hyalinization/fibrosis, and infarction in patients (n=64) with localized, nonmetastatic high-grade soft-tissue sarcomas after preoperative radiomonotherapy. A standardized macroscopic workup for pretreated surgical specimen including evaluation of a whole section of high-grade soft tissue sarcomas in the largest diameter, was used. Association with overall survival and disease-free survival was assessed. Limb salvage could be accomplished in 98.4% of patients. Overall, 90.6% tumors had negative resection margins. The median postoperative tumor diameter was 9 cm. Undifferentiated pleomorphic sarcoma (42.2%) and myxofibrosarcoma (17.2%) were the most common diagnoses. In all, 9.4% of patients had local recurrence despite clear resection margins, and 50% had distant metastases. Morphologic mapping suggests an overall heterogenous intratumoral response to radiotherapy, with significant differences among histologic subtypes. Complete regression (0% vital tumor cells) was not seen. Categorizing the results according to the proposed EORTC-STBSG 5-tier response score, <1% viable tumor cells were seen in 3.1%, ≥1% to <10% viable tumor cells in 20.4%, ≥10% to <50% viable tumor cells in 35.9% and ≥50% viable tumor cells in 40.6% of cases. Mean values for viable tumor cells were 40% (range: 1% to 100%), coagulative necrosis 5% (0% to 60%), hyalinization/fibrosis 25% (0% to 90%) and infarction 15% (0% to 79%). Hyalinization/fibrosis was a significant independent prognostic factor for overall survival (hazard ratio=4.4; P =0.047), while the other histologic parameters including the EORTC-STBSG score were not prognostic., Competing Interests: Conflicts of Interest and Source of Funding: Part of this work was funded by the Wilhelm Sander Foundation (Projekt 2009.900.2). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Optimal doses for the treatment of adrenal metastases with stereotactic radiotherapy (SBRT) are unknown. We aimed to identify dose-volume cut-points associated with decreased local recurrence rates (LRR). A multicenter database of patients with adrenal metastases of any histology treated with SBRT (biologically effective dose, BED10 ≥50 Gy, ≤12 fractions) was analyzed. Details on dose-volume parameters were required (planning target volume: PTV-D98%, PTV-D50%, PTV-D2%; gross tumor volume: GTV-D50%, GTV-mean). Cut-points for LRR were optimized using the R maxstat package. One hundred and ninety-six patients with 218 lesions were included, the largest histopathological subgroup was adenocarcinoma (n = 101). Cut-point optimization resulted in significant cut-points for PTV-D50% (BED10: 73.2 Gy; P = .003), GTV-D50% (BED10: 74.2 Gy; P = .006), GTV-mean (BED10: 73.0 Gy; P = .007), and PTV-D2% (BED10: 78.0 Gy; P = .02) but not for the PTV-D98% (P = .06). Differences in LRR were clinically relevant (LRR ≥ doubled for cut-points that were not achieved). Further dose-escalation was not associated with further improved LRR. PTV-D50%, GTV-D50%, and GTV-mean cut-points were also associated with significantly improved LRR in the adenocarcinoma subgroup. Separate dose optimizations indicated a lower cut-point for the PTV-D50% (BED10: 69.1 Gy) in adenocarcinoma lesions, other values were similar (<2% difference). Associations of cut-points with overall survival (OS) and progression-free survival were not significant but durable freedom from local recurrence was associated with OS in a landmark model (P < .001). To achieve a significant improvement of LRR for adrenal SBRT, a moderate escalation of PTV-D50% BED10 >73.2 Gy (adenocarcinoma: 69.1 Gy) should be considered., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

To report outcome (freedom from local progression [FFLP], overall survival [OS] and toxicity) after stereotactic, palliative or highly conformal fractionated (>12) radiotherapy (SBRT, Pall-RT, 3DCRT/IMRT) for adrenal metastases in a retrospective multicenter cohort within the framework of the German Society for Radiation Oncology (DEGRO). Adrenal metastases treated with SBRT (≤12 fractions, biologically effective dose [BED10] ≥ 50 Gy), 3DCRT/IMRT (>12 fractions, BED10 ≥ 50 Gy) or Pall-RT (BED10 < 50 Gy) were eligible for this analysis. In addition to unadjusted FFLP (Kaplan-Meier/log-rank), we calculated the competing-risk-adjusted local recurrence rate (CRA-LRR). Three hundred twenty-six patients with 366 metastases were included by 21 centers (median follow-up: 11.7 months). Treatment was SBRT, 3DCRT/IMRT and Pall-RT in 260, 27 and 79 cases, respectively. Most frequent primary tumors were non-small-cell lung cancer (NSCLC; 52.5%), SCLC (16.3%) and melanoma (6.7%). Unadjusted FFLP was higher after SBRT vs Pall-RT (P = .026) while numerical differences in CRA-LRR between groups did not reach statistical significance (1-year CRA-LRR: 13.8%, 17.4% and 27.7%). OS was longer after SBRT vs other groups (P < .05) and increased in patients with locally controlled metastases in a landmark analysis (P < .0001). Toxicity was mostly mild; notably, four cases of adrenal insufficiency occurred, two of which were likely caused by immunotherapy or tumor progression. Radiotherapy for adrenal metastases was associated with a mild toxicity profile in all groups and a favorable 1-year CRA-LRR after SBRT or 3DCRT/IMRT. One-year FFLP was associated with longer OS. Dose-response analyses for the dataset are underway., (© 2021 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)

Purpose: Advanced Ewing sarcomas have poor prognosis. They are defined by early relapse (<24 months after diagnosis) and/or by metastasis to multiple bones or bone marrow (BM). We analyzed risk factors, toxicity and survival in advanced Ewing sarcoma patients treated with the MetaEICESS vs. EICESS92 protocols., Design: Of 44 patients, 18 patients were enrolled into two subsequent MetaEICESS protocols between 1992 and 2014, and compared to outcomes of 26 advanced Ewing sarcoma patients treated with EICESS 1992 between 1992 and 1996. MetaEICESS 1992 consisted of induction chemotherapy, whole body imaging directed radiotherapy to the primary tumor and metastases, tandem high-dose chemotherapy and autologous rescue. In MetaEICESS 2007 this treatment was complemented by allogeneic stem cell transplantation. EICESS 1992 comprised induction chemotherapy, local therapy to the primary tumor only followed by consolidation chemotherapy., Results: In MetaEICESS 8/18 patients survived in complete remission vs. 2/26 in EICESS 1992 (p<0.05). Survival did not differ between MetaEICESS 2007 and MetaEICESS 1992. Three MetaEICESS patients died of complications, all in MetaEICESS 1992. After exclusion of patients succumbing to treatment related complications (n=3), 7/10 patients survived without BM involvement, in contrast to 0/5 patients with BM involvement. This was confirmed in a multivariate analysis. There was no correlation between BM involvement and the number of metastases at diagnosis., Conclusion: The MetaEICESS protocols yield long-term disease-free survival in patients with advanced Ewing sarcoma. Allogeneic stem cell transplantation was not associated with increased death of complications. Bone marrow involvement is a risk factor distinct from multiple bone metastases.

Background: The aim of the trial is to demonstrate that with the use of modern IMRT/IGRT and reduction of safety margins postoperative wound complications can be reduced., Methods/ Design: The trial is designed as a prospective, monocentric clinical phase II trial. The treatment is performed with helical IMRT on the Tomotherapy HiArt System© or with RapidArc© IMRT as available. All treatments are performed with 6 MV photons and daily online CT-based IGRT. A dose of 50 Gy in 2 Gy single fractions (5 fractions per week) is prescribed. Restaging including MRI of the primary tumor site as well as CT of the thorax/abdomen is planned 4 weeks after RT. PET-examinations or any other imaging can be performed as required clinically. In cases of R1 resection, brachytherapy is anticipated in the 2nd postoperative week. Brachytherapy catheters are implanted into the tumor bed depending on the size and location of the lesion. Surgery is planned 5-6 weeks after completion of neoadjuvant RT. All patients are seen for a first follow-up visit 2 weeks after wound healing is completed, thereafter every 3 months during the first 2 years. The endpoints of the study are evaluated in detail during the first (2 weeks) and second (3 months) follow-up. Functional outcome and QOL are documented prior to treatment and at year 1 and 2. Treatment response and efficacy will be scored according to the RECIST 1.1 criteria. A total patient number of 50 with an expected 20% rate of wound complications were calculated for the study, which translates into a 95% confidence interval of 10.0-33.7% for wound complication rate in a binomial distribution., Discussion: The present study protocol prospectively evaluates the use of IMRT/IGRT for neoadjuvant RT in patients with soft tissue sarcomas of the extremity with the primary endpoint wound complications, which is the major concern with this treatment sequence. Besides complications rates, local control rates and survival rates, as well as QOL, functional outcome and treatment response parameters (imaging and pathology) are part of the protocol. The data of the present PREMISS study will enhance the current literature and support the hypothesis that neoadjuvant RT with IMRT/IGRT offers an excellent risk-benefit ratio in this patient population., Trial Registration: NCT01552239.

A technical set-up for irradiation of subcutaneous tumours in mice with nanosecond-pulsed proton beams or continuous proton beams is described and was successfully used in a first experiment to explore future potential of laser-driven particle beams, which are pulsed due to the acceleration process, for radiation therapy. The chosen concept uses a microbeam approach. By focusing the beam to approximately 100 × 100 μm(2), the necessary fluence of 10(9) protons per cm(2) to deliver a dose of 20 Gy with one-nanosecond shot in the Bragg peak of 23 MeV protons is achieved. Electrical and mechanical beam scanning combines rapid dose delivery with large scan ranges. Aluminium sheets one millimetre in front of the target are used as beam energy degrader, necessary for adjusting the depth-dose profile. The required procedures for treatment planning and dose verification are presented. In a first experiment, 24 tumours in mice were successfully irradiated with 23 MeV protons and a single dose of 20 Gy in pulsed or continuous mode with dose differences between both modes of 10%. So far, no significant difference in tumour growth delay was observed.

Purpose: In order to obtain more insight into heavy ion tumour therapy, some features of the underlying molecular mechanisms controlling the cellular response to high linear energy transfer (LET) radiation are currently analysed., Materials and Methods: We analysed the decay of the integrated fluorescence intensity of gamma-H2AX (phosphorylated histone H2AX) which is thought to reflect the repair kinetics of radiation-induced DNA double-strand breaks (DSB) using Laser-Scanning-Cytometry. Asynchronous human HeLa cells were irradiated with a single dose of either 1.89 Gy of 55 MeV carbon ions or 5 Gy of 70 kV X-rays., Results: Measurements of the gamma-H2AX-intensities from 15-60 min resulted in a 16 % decrease for carbon ions and in a 43 % decrease for X-rays. After 21 h, the decrease was 77 % for carbon ions and 85 % for X-rays. The corresponding time-effect relationship was fitted by a bi-exponential function showing a fast and a slow component with identical half-life values for both radiation qualities being 24 +/- 4 min and 13.9 +/- 0.7 h, respectively. Apparent differences in the kinetics following high and low LET irradiation could completely be attributed to quantitative differences in their contributions, with the slow component being responsible for 47 % of the repair after exposure to X-rays as compared to 80 % after carbon ion irradiation., Conclusion: gamma-H2AX loss kinetics follows a bi-exponential decline with two definite decay times independent of LET. The higher contribution of the slow component determined for carbon ion exposure is thought to reflect the increased amount of complex DSB induced by high LET radiation.

Purpose: To present a modification of a technique combining the advantages of brachytherapy for local radiation treatment and vacuum therapy for wound conditioning after resection of subfascial soft-tissue sarcomas (STS) of the extremities., Patients and Methods: Between January and May 2008, four patients with large (> 10 cm) subfascial STS of the thigh underwent marginal tumor excision followed by early postoperative HDR (high-dose-rate) brachytherapy (iridium-192) and vacuum therapy as part of their interdisciplinary treatment. The sponge of the vacuum system was used to stabilize brachytherapy applicators in parallel positions and to allow for a maximal wound contraction in the early postoperative phase, thus preventing seroma and deterioration of local dose distribution as optimized in computed tomography-(CT-)based three-dimensional conformal treatment planning. In three patients this was followed by external-beam radiotherapy. Acute wound complications and late effects according to LENT-SOMA after 4-8 months of follow-up were recorded., Results: The combination of vacuum and brachytherapy was applicable in all patients. CT scans from the 1st postoperative day showed the shrinkage of the sponge located in the tumor bed with the brachytherapy applicators in the intended position and easily visible. 15-18 Gy in fractions of 3 Gy bid prescribed to 5 mm tissue depth were applied over the next days with removal of the sponge and applicators on days 5-8. No early or late toxicity exceeding grade 2 was observed. The mean Enneking Score for functional outcome was 63% (perfect function = 100%)., Conclusion: The combination of vacuum and brachytherapy is applicable and safe in the treatment of large subfascial STS.

Background and Purpose: Laser accelerated radiotherapy is a prospect for cancer treatment with proton and/or carbon ion beams that is currently under fast development. In principal, ultra fast, high-energy laser pulses will lead to a "pulsed" delivery of the induced ion beam with pulse durations of 1ns and below, whereas conventional proton beams deriving from a cyclotron or synchrotron apply the dose within 100 ms ("continuous")., Materials and Methods: A simulation of both irradiation modes could be established at the Munich tandem accelerator with a 20MeV proton beam, and a wide-field fast scanning system was implemented that allowed for application of up to 5 Gy per tissue voxel in a single pulse. The relative biological effectiveness (RBE) of pulsed and continuous modes of irradiation with 20 MeV protons relative to the reference radiation 70 kV X-rays was examined in a human tissue model (3D human reconstructed skin, EpiDermFT) which preserves the three-dimensional geometric arrangement and communication of cells present in tissues in vivo. Using the induction of micronuclei (MN) in keratinocytes as the biological endpoint, the RBE was calculated as the ratio between the dose of 70 kV X-rays and 3 Gy of 20 MeV protons (pulsed or continuous) which produced equal response., Results: For pulsed and continuous 20 MV proton exposures of the human skin model, RBE values of 1.08+/-0.20 and 1.22+/-0.15 versus 70 kV X-rays were obtained in a first experiment and 1.00+/-0.14 and 1.13+/-0.14 in a second experiment during distinct beam access times, respectively. The approximately 10% difference in RBE between the respective irradiation modes in both experiments was associated with large uncertainties which were not statistically significant (p approximately 0.5)., Conclusion: These findings represent an important step on the way towards application of laser-accelerated protons for clinical radiotherapy. Further clinically relevant endpoints in normal and tumor tissue have to be evaluated., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We tested whether the chromosomal radiosensitivity of in vitro irradiated lymphocytes could be used to predict the risk of acute reactions after radiotherapy., Methods and Materials: Two prospective studies were performed: study A with 51 patients included different tumor sites and study B included 87 breast cancer patients. Acute reaction was assessed using the Radiation Therapy Oncology Group score. In both studies, patients were treated with curative radiotherapy, and the mean tumor dose applied was 55 Gy (40-65) +/- boost with 11 Gy (6-31) in study A and 50.4 Gy +/- boost with 10 Gy in study B. Individual radiosensitivity was determined with lymphocytes irradiated in vitro with X-ray doses of either 3 or 6 Gy and scoring the number of chromosomal deletions., Results: Acute reactions displayed a typical spectrum with 57% in study A and 53% in study B showing an acute reaction of Grade 2-3. Individual radiosensitivity in both studies was characterized by a substantial variation and the fraction of patients with Grade 2-3 reaction was found to increase with increasing individual radiosensitivity measured at 6 Gy (study A, p = 0.238; study B, p = 0.023). For study B, this fraction increased with breast volume, and the impact of individual radiosensitivity on acute reaction was especially pronounced (p = 0.00025) for lower breast volume. No such clear association with acute reaction was observed when individual radiosensitivity was assessed at 3 Gy., Conclusion: Individual radiosensitivity determined at 6 Gy seems to be a good predictor for risk of acute effects after curative radiotherapy.

Purpose: Integrin-linked kinase (ILK) mediates signals from beta integrins and links integrins to epidermal growth factor receptor (EGFR). Previous studies have identified an antisurvival effect of ILK in irradiated cells. The aim of this study was to evaluate the role of EGFR tyrosine kinase (tk) activity for ILK-mediated radiosensitization., Materials and Methods: Human FaDu squamous cell carcinoma (SCC) cells stably transfected with hyperactive ILK (ILK-hk) and ILK(fl/fl) and ILK(-/-) mouse fibroblasts were treated with the pharmacological EGFR-tk inhibitor BIBX1382BS without or in combination with single doses of X-rays. Clonogenic radiation survival, protein expression and phosphorylation (EGFR, v-akt murine thymoma viral oncogene homolog 1 (Akt), p42/44 mitogen-activated protein kinase), DNA-double strand break (DSB) repair measured by gammaH2AX foci, cell morphology and cell cycle distribution were examined., Results: Expression of ILK-hk or ILK(fl/fl) status resulted in significant radiosensitization relative to vector controls or ILK(-/-). Following BIBX1382BS, clonogenic survival of normal fibroblasts and vector controls remained unaffected while ILK-hk-related radiosensitization was significantly diminished. In contrast to BIBX1382BS, which did not affect DNA-DSB repair, ILK-hk-mediated radiosensitization was associated with reduced DNA-DSB repair. At 10 days after BIBX1382BS treatment, FaDu transfectants, in contrast to fibroblasts, showed reduced cell size, accumulation of G1 phase cells and reduced Akt-serine(S)473 phosphorylation., Conclusions: Our findings confirm ILK as a cell type-independent antisurvival factor in irradiated cells, which actions in terms of radiosensitization critically depend on proper EGFR-tk activity.

Purpose: To evaluate the role of hypoxia positron emission tomography (PET) using [18F]fluoroazomycin-arabinoside (FAZA) in head and neck cancer for radiation treatment planning using intensity-modulated radiotherapy and dose painting., Methods and Materials: Eighteen patients with advanced squamous cell head and neck cancer were included. Both FAZA-PET and axial CT were performed using mask fixation. The data were coregistered using software based on mutual information. Contours of tumor (primary gross tumor volume, GTV/CT-P) and lymph node metastases (GTV/CT-N) were outlined manually, and FAZA standardized uptake values (SUVs) were calculated automatically. The hypoxic subvolume (GTV/PET-FAZA) having at least 50% more FAZA uptake than background (mean SUV) neck muscle tissue was contoured automatically within GTV/CT-P (GTV/PET-FAZA-P) and GTV/CT-N (GTV/PET-FAZA-N)., Results: The median GTV/PET-FAZA-P was 4.6 mL, representing 10.8% (range, 0.7-52%) of the GTV/CT-P. The GTV/PET-FAZA-P failed to correlate significantly with the GTV/CT-P (p = 0.06). The median GTV/PET-FAZA-N was 4.1 mL, representing 8.3% (range, 2.2-51.3%) of the GTV/CT-N. It was significantly correlated with the GTV/PET-N (p = 0.006). The GTV/PET-FAZA-P was located in a single confluent area in 11 of 18 patients (61%) and was diffusely dispersed in the whole GTV/CT-P in 4 of 18 patients (22%), whereas no hypoxic areas were identified in 3 of 18 patients (17%). The GTV/PET-FAZA-N was outlined as a single confluent region in 7 of 18 patients (39%), in multiple diffuse hypoxic regions in 4 of 18 patients (22%), and was not delineated in 7 of 18 patients (39%)., Conclusion: This study demonstrates that FAZA-PET imaging could be used for a hypoxia-directed intensity-modulated radiotherapy approach in head and neck cancer.

Background and Purpose: Information on a patient's prognosis is important for the clinical decision-making process. This study explored the capacity of quantitative ultrasound imaging to increase prognostic information., Materials and Methods: High-resolution B-scan and colour-coded duplex-sonography of the neck was prospectively applied to 50 HNSCC-patients stage IVA-B 05/99-01/02 before definite radio-(chemo-)therapy. Every lymph node >1.5 cm was scored for the following Malignancy Criteria: Inhomogeneity, Surface-irregularity, Missing hilar sign, Spherical form, Matting, Aberrant intranodal vessels, Infiltration of surrounding tissue, Intranodal cystic necrosis., Results: Median Overall Survival (OS) was 1 year. High MMCC (Maximal Malignancy Criteria Count in a single node) predicted a poor outcome with a median OS of 8.1 months (MMCC=7-8, n=24) vs. 24.7 months for low MMCC (1-6, n=26, p=0.0004, logrank). Estimated 1- and 3-year-OS was 25% and 8% for high vs. 69% and 41% for low MMCC. Ten out of eleven living patients (follow-up 2.3-5.3 years) had a low MMCC. Of the clinical parameters determined, only pre-treatment hemoglobin levels <12 g/dl and treatment less radical than chemoradiation to 70 Gy predicted poor OS (univariate p=0.04 and 0.02, respectively). In multivariate Cox analysis, MMCC continued to significantly predict for OS (p=0.002) and Disease-Free Survival (p=0.002)., Conclusions: Quantification of nodal ultrasonography offers valuable prognostic information for the conservative management of HNSCC.

Tumor cells are efficiently killed after incubation with alpha-emitter immunoconjugates targeting tumor-specific antigens. Therefore, application of alpha-emitter immunoconjugates is a promising therapeutic option for treatment of carcinomas that are characterized by dissemination of single tumor cells in the peritoneum like ovarian cancer or gastric cancer. In diffuse-type gastric cancer, 10% of patients express mutant d9-E-cadherin on the surface of tumor cells that is targeted by the monoclonal antibody d9MAb. Coupling of the alpha-emitter (213)Bi to d9MAb provides an efficient tool to eliminate HSC45-M2 gastric cancer cells expressing d9-E-cadherin in vitro and in vivo. Elucidation of the molecular mechanisms triggered by alpha-emitters in tumor cells could help to improve strategies of alpha-emitter radioimmunotherapy. For that purpose, gene expression of (213)Bi-treated tumor cells was quantified using a real time quantitative-PCR low-density array covering 380 genes in combination with analysis of cell proliferation and the mode of cell death. We could show that (213)Bi-induced cell death was initiated by G(2) arrest; up-regulation of tumor necrosis factor (TNF), SPHK1, STAT5A, p21, MYT1, and SSTR3; and down-regulation of SPP1, CDC25 phosphatases, and of genes involved in chromosome segregation. Together with morphologic changes, these results suggest that (213)Bi activates death cascades different from apoptosis. Furthermore, (213)Bi-triggered up-regulation of SSTR3 could be exploited for improvement of the therapeutic regimen.

This paper presents methods and a clinical procedure for integrating B-mode ultrasound images tagged with position information with a planning computed tomography (CT) scan for radiotherapy. A workflow is described that allows the integration of these modalities into the clinic. A surface mapping approach provides a preregistration of the ultrasound image borders onto the patient's skin. Successively, a set of individual ultrasound images from a freehand sweep is chosen by the physician. These images are automatically registered with the planning CT scan using novel intensity-based methods. We put a particular focus on deriving an appropriate similarity measure based on the physical properties and artifacts of ultrasound. A combination of a weighted mutual information term, edge correlation, clamping to the skin surface, and occlusion detection is able to assess the alignment of structures in ultrasound images and information reconstructed from the CT data. We demonstrate the practicality of our methods on five patients with head and neck tumors and cervical lymph node metastases and provide a detailed report on the conducted experiments, including the setup, calibration, acquisition, and verification of our algorithms. The mean target registration error on nine data sets is 3.9 mm. Thus, the additional information about intranodal architecture and fulfillment of malignancy criteria derived from a high-resolution ultrasonography of lymph nodes can be localized and visualized in the CT scan coordinate space and is made available for further radiation treatment planning.

Unlabelled: We evaluated the predictive value of PET using the hypoxia tracer (18)F-fluoroazomycin arabinoside ((18)F-FAZA) for success of radiotherapy in combination with tirapazamine, a specific cytotoxin for hypoxic cells., Methods: Imaging was performed on EMT6 tumor-bearing nude mice before allocating mice into 4 groups: radiochemotherapy (RCT: 8 fractions of 4.5 Gy within 4 d combined with tirapazamine, 14 mg/kg), radiotherapy alone (RT), chemotherapy alone (tirapazamine) (CHT), or control. Treatment success was assessed by several tumor growth assays, including tumor growth time from 70 to 500 microL and absolute growth delay (aGD). The median pretreatment (18)F-FAZA tumor-to-background ratio served as a discriminator between "hypoxic" and "normoxic" tumors., Results: The mean tumor growth was significantly accelerated in hypoxic control tumors (growth time from 70 to 500 microL, 11.0 d) compared with normoxic control tumors (growth time from 70 to 500 microL, 15.6 d). Whereas RT delayed tumor growth regardless of the level of hypoxia, an additive beneficial therapeutic effect of tirapazamine to RT was observed only in hypoxic tumors (aGD, 12.9 d) but not in normoxic tumors (aGD, 6.0 d)., Conclusion: This study provides compelling evidence that hypoxia imaging using (18)F-FAZA PET is able to predict the success of RCT of tumor-bearing mice using the hypoxia-activated chemotherapeutic agent tirapazamine. Pretreatment (18)F-FAZA PET, therefore, offers a way for the individualization of tumor treatment involving radiation. The data suggest that by reserving hypoxia-directed therapy to tumors with high (18)F-FAZA uptake, improvement of the therapeutic ratio is possible, as the therapeutic effect of tirapazamine seems to be restricted to hypoxic tumors.

Purpose: Investigating tumor oxygenation in breast cancer with the Eppendorf device is hampered by the deep location and inadequate fixation of the tumor within the breast. In order to ensure the correct site of pO(2) measurements, guiding aids were introduced and the reliability of the refined method was evaluated., Material and Methods: For guidance of the needle electrode, a metal trocar was inserted up to the tumor rim. Its positioning and all transtumoral tracks of the needle electrode were monitored continuously by ultrasonography. Thus, 150 tumor measurements in 148 patients were evaluated. In a phantom, the possible influence of the metal trocar was assessed and the measurements of two histographs with five different needle electrodes were compared., Results: In 88% of measurements (132/150) complete or partial sonographic demarcation of the tumor was possible. 83.2% of the tracks (437/525) could be controlled by ultrasonography. Overall, in 60% of measurements (90/150) all values derived reliably from within the tumor. In vitro, an influence of the metal trocar on the measurements could be excluded. Differences between histographs were in accordance with tolerance limits., Conclusion: From theoretical considerations and the phantom experiments a significant negative impact of the technical modifications could be excluded. Instead, the method described here showed to be beneficial in measuring tumor oxygenation in breast tumors. The authors strongly advise to consider exclusively intratumoral pO(2) values as proven by ultrasonography for oxygenation profiling, as in 40% of all measurements the origin of single pO(2) values or tracks was questionable.

Today, most sarcoma patients can be spared an amputation through the use of adjuvant radiotherapy. Treatment by an experienced multidisciplinary team offers the best chance of achieving permanent tumor control. Histopathologically-free resection margins are of the greatest importance. The indication for radiotherapy is determined by the recurrence risk profile of the individual patient. In addition to the well-proven postoperative irradiation, neoadjuvant radiotherapy is also successful. In the event of an unfavorably sited tumor, intra-operative irradiation can be applied in combination with either form. Patients with large G3 tumors can be given adjuvant chemotherapy to reduce the risk of distant metastases. On account of its appreciable toxicity, however, it should be reserved for patients younger than 65 in a good state of health.

Freehand 3D ultrasound systems acquire sets of B-Mode ultrasound images tagged with position information obtained by a tracking device. For both further processing and clinical use of these ultrasound slice images scattered in space, it is often required to reconstruct them into 3D-rectilinear grid arrays. We propose new efficient methods for this so-called ultrasound spatial compounding using a backward-warping paradigm. They allow to establish 3D-volumes from any scattered freehand ultrasound data with superior quality / speed properties with respect to existing methods. In addition, arbitrary MPR slices can be reconstructed directly from the freehand ultrasound slice set, without the need of an extra volumetric reconstruction step. We qualitatively assess the reconstruction quality and quantitatively compare our compounding method to other algorithms using ultrasound data of the neck and liver. The usefulness of direct MPR reconstruction for multimodal image registration is demonstrated as well.

We present a framework for rigid registration of a set of B-mode ultrasound images to a CT scan in the context of Radiotherapy planning. Our main focus is on deriving an appropriate similarity measure based on the physical properties and artifacts of ultrasound. A combination of a weighted Mutual Information term, edge correlation, clamping to the skin surface and occlusion detection is able to assess the alignment of structures in ultrasound images and simulated slices generated from the CT data. Hence a set of ultrasound images, whose relative transformations are given by a magnetic tracking device, can be registered automatically to the CT scan. We validated our methods on neck data of patients with head and neck tumors and cervical lymph node metastases.

Background and Purpose: In radiotherapy of the breast following breast-conserving surgery, the adverse reaction predominantly found is confined to the skin. After phase II studies, Thêta-Cream, containing CM Glucan, Hydroxyprolisilan C und Matrixyl as active substances, was said to have prophylactic properties of preventing acute radiation side effects in skin tissue. In a prospective randomized study, Thêta-cream was compared with standard skin care using Bepanthol lotion., Patients and Methods: 20 breast cancer patients were randomly assigned to use Thêta-Cream or Bepanthol lotion during radiotherapy. At 0, 30, and 50 Gy, acute skin toxicity was scored with a modified RTOG scoring system. The patients' content with the skin care and the technical assistants' content with the skin marks were recorded., Results: For single aspects of toxicity and their sums in defined skin areas, no differences in median and range between study groups were found. The maximal toxicity anywhere in the breast averaged in a moderate erythema, mild elevation of skin temperature, no desquamation in both groups. Mild itchiness and sporadic efflorescences were more frequently seen with Thêta-Cream. According to a ranking of anonymized breast photos at 50 Gy by independent investigators, side effects were equal. Patients' content was high with both skin care regimens (1.25 on a scale from 0 to 10). With Thêta-Cream a trend toward worse skin marks was noted. Adverse events exclusively occurred in Thêta-Cream users: suspected allergic reaction once, and the necessity for resimulation twice., Conclusion: In direct comparison with dexpanthenol-containing lotion, no advantage for Thêta-Cream was found. Higher costs and problems with skin marks prevent a general recommendation.

Purpose: To investigate the relationship between late tissue response after radiotherapy, cellular sensitivity and DNA repair capacity measured in dermal fibroblasts and chromosomal aberrations measured in lymphocytes. The study was in particular designed to compare cellular parameters of patients with maximum differences in late tissue reactions., Materials and Methods: The study was performed with 16 pair-wise matched head and neck cancer patients 2-7 years after curative therapy exhibiting maximum differences (grade 1 vs. grade 3) in late normal tissue reactions. Clinical endpoints were fibrosis, telangiectasia, mucositis and xerostomia using the radiation therapy oncology group score. Patients with grade 3 reactions were tested for mutations in ataxia telangiectasia (AT), Nijmegen Breakage Syndrome (NBS), MRE11, RAD50 and DNA ligase IV genes by means of polymerase chain reaction-single-strand conformation polymorphism and sequencing analysis. Skin fibroblasts obtained from biopsies were used to determine the cellular sensitivity by colony formation and the induction and repair of DNA double-strand breaks (dsb) using constant-field gel electrophoresis. Lymphocytes were taken to measure chromosomal damage either in metaphase using conventional chromosome analysis or in G(0) using premature chromosome condensation (PCC)-technique., Results: Patients with extreme late reactions (grade 3) showed no evidence for an AT, NBS, MRE11 or RAD50 mutation. Studies with fibroblasts revealed that extreme late reactions were associated neither with a pronounced cellular radiosensitivity nor with a difference in dsb repair capacity. In contrast, there was a significant difference in chromosomal damage measured in lymphocytes. After in vitro irradiation with 6Gy, lymphocytes taken from overreacting patients showed on average a significantly higher number of lethal aberrations than lymphocytes isolated from patients with mild reactions (7.2+/-0.8 vs. 5.0+/-0.3). Similar differences were found for PCC fragments., Conclusion: This study suggests that lymphocytes are more promising than fibroblasts to predict patient's normal tissue response after radiotherapy.

Background: Refresher courses as presented at the annual DEGRO meeting are important parts in the continuous training of radiotherapists. For further quality improvement, knowledge about the participants' needs is essential., Methods: During the DEGRO meeting 10/2000 in Munich, participants of refresher courses were encouraged to grade the presentations with regard to six questions with marks from 1 ("very good") to 6 ("not acceptable"). Free comments were welcomed. The individual results were handed over to future organizing committees and the speakers themselves, cumulative results can be read up in the present note., Results: Approximately 1,000 participants of refresher courses filled in 381 questionnaires concerning 24 different training sessions. Altogether 48.5% of all answers said "very good", 31.7% "good" and 11.1% "satisfactory" (all worse marks together 3%, no statement in 5.7%). Free comments dealt mainly with handouts and a later starting time for the refresher courses than 7:30 a.m., Conclusion: Participants of the annual DEGRO meeting show a great amount of interest in refresher courses and seem to be quite content with the present findings. First steps are taken to get the proposals under way.