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  • 1
    Abstract: BACKGROUND AND PURPOSE: This review aims to provide a comprehensive overview of the literature and elucidate open questions for future clinical trials concerning diagnostics and treatment modalities for cervical cancer of unknown primary (CUP). METHODS: A literature search for head and neck CUP was performed with focus on diagnostics and therapies as well as molecular markers. RESULTS: High level evidence on CUP is limited. However, it seems that a consensus exists regarding the optimal diagnostic procedures. The correct implementation of biomarkers for patient stratification and treatment remains unclear. An even greater dispute dominates about the ideal treatment with publications ranging from sole surgery to surgery with postoperative bilateral radiotherapy with inclusion of the mucosa and concomitant chemotherapy. CONCLUSIONS: Cervical CUP represents a very heterogeneous malignant disease. On this account many aspects concerning treatment optimization remain unclear, despite a considerable number of publications in the past. Future research in form of prospective randomized trials is needed in order to better define patient stratification criteria and enable tailored treatment.
    Type of Publication: Journal article published
    PubMed ID: 28486947
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  • 2
    Keywords: EXPRESSION ; IN-VIVO ; PATHWAY ; LUNG-CANCER ; ACTIVATION ; RADIATION-THERAPY ; chemotherapy ; SQUAMOUS-CELL CARCINOMA ; CISPLATIN ; tumor microenvironment ; HIF-1 ; GLUCOSE-METABOLISM ; UNFAVORABLE PROGNOSIS ; HUMAN TUMOR XENOGRAFT ; HIF-1-ALPHA ; Local tumor control ; Fractionated radiation ; HIF pathway inhibition ; INDUCIBLE FACTOR-1-ALPHA
    Abstract: BACKGROUND: The transcription factor hypoxia-inducible factor-1 (HIF-1) pathway plays an important role in tumor response to cytotoxic treatments. We investigated the effects of a novel small molecule inhibitor of mitochondrial complex I and hypoxia-induced HIF-1 activity BAY-87-2243, on tumor microenvironment and response of human squamous cell carcinoma (hSCC) to clinically relevant fractionated radiotherapy (RT) with and without concomitant chemotherapy. METHODS: When UT-SCC-5 hSCC xenografts in nude mice reached 6 mm in diameter BAY-87-2243 or carrier was administered before and/or during RT or radiochemotherapy with concomitant cisplatin (RCT). Local tumor control was evaluated 150 days after irradiation and the doses to control 50% of tumors (TCD50) were compared between treatment arms. Tumors were excised at different time points during BAY-87-2243 or carrier treatment for western blot and immunohistological investigations. RESULTS: BAY-87-2243 markedly decreased nuclear HIF-1alpha expression and pimonidazole hypoxic fraction already after 3 days of drug treatment. BAY-87-2243 prior to RT significantly reduced TCD50 from 123 to 100 Gy (p=0.037). Additional BAY-87-2243 application during RT did not decrease TCD50. BAY-87-2243 before and during radiochemotherapy did not improve local tumor control. CONCLUSIONS: Pronounced reduction of tumor hypoxia by application of BAY-87-2243 prior to RT improved local tumor control. The results demonstrate that radiosensitizing effect importantly depends on treatment schedule. The data support further investigations of HIF-1 pathway inhibitors for radiotherapy and of predictive tests to select patients who will benefit from this combined treatment.
    Type of Publication: Journal article published
    PubMed ID: 25234922
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  • 3
    Keywords: APOPTOSIS ; EXPRESSION ; IN-VITRO ; IRRADIATION ; radiotherapy ; THERAPY ; TISSUE ; p53 ; sensitivity ; CANCER-THERAPY ; HISTONE DEACETYLASE INHIBITORS ; STRAND BREAKS ; HISTONE DEACETYLASE INHIBITION ; SUBEROYLANILIDE HYDROXAMIC ACID ; H2AX PHOSPHORYLATION ; heavy ion radiotherapy ; GAMMA-H2AX FOCI ; Infantile sarcoma ; RADIATION RESPONSE ; SAHA
    Abstract: Introduction: The pan-HDAC inhibitor (HDACI) suberoylanilide hydroxamic acid (SAHA) has previously shown to be a radio-sensitizer to conventional photon radiotherapy (XRT) in pediatric sarcoma cell lines. Here, we investigate its effect on the response of two sarcoma cell lines and a normal tissue cell line to heavy ion irradiation (HIT). Materials and methods: Clonogenic assays after different doses of heavy ions were performed. DNA damage and repair were evaluated by measuring gamma H2AX via flow-cytometry. Apoptosis and cell cycle analysis were also measured via flow cytometry. Protein expression of repair proteins, p53 and p21 were measured using immunoblot analysis. Changes of nuclear architecture after treatment with SAHA and HIT were observed in one of the sarcoma cell lines via light microscopy after staining towards chromatin and gamma H2AX. Results: Corresponding with previously reported photon data, SAHA lead to an increase of sensitivity to heavy ions along with an increase of DSB and apoptosis in the two sarcoma cell lines. In contrast, in the osteoblast cell line (hFOB 1.19), the combination of SAHA and HIT showed a significant radio-protective effect. Laser scanning microscopy revealed no significant morphologic changes after HIT compared to the combined treatment with SAHA. Immunoblot analysis revealed no significant up or down regulation of p53. However, p21 was significantly increased by SAHA and combination treatment as compared to HIT only in the two sarcoma cell lines - again in contrast to the osteoblast cell line. Changes in the repair kinetics of DSB p53-independent apoptosis with p21 involvement may be part of the underlying mechanisms for radio-sensitization by SAHA. Conclusion: Our in vitro data suggest an increase of the therapeutic ratio by the combination of SAHA with HIT in infantile sarcoma cell lines
    Type of Publication: Journal article published
    PubMed ID: 21933400
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  • 4
    Keywords: REGISTRATION ; CANCER-PATIENTS ; GUIDANCE ; Image-guided radiotherapy ; PAROTID-GLANDS ; SETUP ERRORS
    Abstract: BACKGROUND: To evaluate the impact of image-guided radiation therapy (IGRT) versus non-image-guided radiation therapy (non-IGRT) on the dose to the clinical target volume (CTV) and the cervical spinal cord during fractionated intensity-modulated radiation therapy (IMRT) for head-and-neck cancer (HNC) patients. MATERIAL AND METHODS: For detailed investigation, 4 exemplary patients with daily control-CT scans (total 118 CT scans) were analyzed. For the IGRT approach a target point correction (TPC) derived from a rigid registration focused to the high-dose region was used. In the non-IGRT setting, instead of a TPC, an additional cohort-based safety margin was applied. The dose distributions of the CTV and spinal cord were calculated on each control-CT and the resulting dose volume histograms (DVHs) were compared with the planned ones fraction by fraction. The D50 and D98 values for the CTV and the D5 values of the spinal cord were additionally reported. RESULTS: In general, the D50 and D98 histograms show no remarkable difference between both strategies. Yet, our detailed analysis also reveals differences in individual dose coverage worth inspection. Using IGRT, the D5 histograms show that the spinal cord less frequently receives a higher dose than planned compared to the non-IGRT setting. This effect is even more pronounced when looking at the curve progressions of the respective DVHs. CONCLUSIONS: Both approaches are equally effective in maintaining CTV coverage. However, IGRT is beneficial in spinal cord sparing. The use of an additional margin in the non-IGRT approach frequently results in a higher dose to the spinal cord than originally planned. This implies that a margin reduction combined with an IGRT correction helps to maintain spinal cord dose sparing best as possible. Yet, a detailed analysis of the dosimetric consequences dependent on the used strategy is required, to detect single fractions with unacceptable dosimetric deviations.
    Type of Publication: Journal article published
    PubMed ID: 22873744
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  • 5
    Keywords: APOPTOSIS ; CANCER ; carcinoma ; PROTEIN ; CELL-CYCLE ; TYPE-16 ; DNA-DAMAGE ; E6 ; WILD-TYPE P53 ; HELA-CELLS
    Abstract: BACKGROUND: Clinical studies have demonstrated that HPV induced tumors constitute a specific subclass of cancer with a better response to radiation treatment. The purpose of this study was to investigate meaning of viral E2-gene for radiosensitivity. METHODS: W12 cells contain episomal HPV 16 genomes, whereas S12 cells, which derive from the W12 line, contain HPV DNA as integrated copies. Clonogenic survival was analyzed using 96-well in vitro test. Using flow cytometry cell cycle analyses were performed. Expression of pRb and p53 were analyzed using intracellular staining. RESULTS: W12 cells (intact E2 gene) showed a lower survival fraction than S12 cells. W12 cells developed a G2/M block 24 h after irradiation with 2 Gy whereas S12 showed no G2/M bloc. After irradiation S12 cells developed polyploidy and pRb-positive cells decreased. W12 cells showed no change of pRb-positive cells. CONCLUSIONS: Depending on E2 gene status differences in cell cycle regulation might cause radioresistance. The E2/E7/pRb pathway seems to influence HPV-induced radiosensitivity. Our experiments demonstrated an effect of HPV on radiosensitivity of cervical keratinocytes via viral transcription regulator E2 pathway.
    Type of Publication: Journal article published
    PubMed ID: 23134732
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  • 6
    Keywords: ADHESION ; CHARGED-PARTICLES ; AL2O3
    Abstract: BACKGROUND: The lack of sensitive biocompatible particle track detectors has so far limited parallel detection of physical energy deposition and biological response. Fluorescent nuclear track detectors (FNTDs) based on Al2O3:C,Mg single crystals combined with confocal laser scanning microscopy (CLSM) provide 3D information on ion tracks with a resolution limited by light diffraction. Here we report the development of next generation cell-fluorescent ion track hybrid detectors (Cell-Fit-HD). METHODS: The biocompatibility of FNTDs was tested using six different cell lines, i.e. human non-small cell lung carcinoma (A549), glioblastoma (U87), androgen independent prostate cancer (PC3), epidermoid cancer (A431) and murine (VmDk) glioma SMA-560. To evaluate cell adherence, viability and conformal coverage of the crystals different seeding densities and alternative coating with extracellular matrix (fibronectin) was tested. Carbon irradiation was performed in Bragg peak (initial 270.55 MeV u-1). A series of cell compartment specific fluorescence stains including nuclear (HOECHST), membrane (Glut-1), cytoplasm (Calcein AM, CM-DiI) were tested on Cell-Fit-HDs and a single CLSM was employed to co-detect the physical (crystal) as well as the biological (cell layer) information. RESULTS: The FNTD provides a biocompatible surface. Among the cells tested, A549 cells formed the most uniform, viable, tightly packed epithelial like monolayer. The ion track information was not compromised in Cell-Fit-HD as compared to the FNTD alone. Neither cell coating and culturing, nor additional staining procedures affected the properties of the FNTD surface to detect ion tracks. Standard immunofluorescence and live staining procedures could be employed to co-register cell biology and ion track information. CONCLUSIONS: The Cell-Fit-Hybrid Detector system is a promising platform for a multitude of studies linking biological response to energy deposition at high level of optical microscopy resolution.
    Type of Publication: Journal article published
    PubMed ID: 23758749
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  • 7
    Keywords: LUNG-CANCER ; PROSTATE-CANCER ; POSITRON-EMISSION-TOMOGRAPHY ; COMPUTED-TOMOGRAPHY ; NECK-CANCER ; EXTERNAL-BEAM RADIOTHERAPY ; MODULATED RADIATION-THERAPY ; adaptive radiotherapy ; MAGNETIC-FIELD ; IN-LINE
    Abstract: BACKGROUND: The purpose of this clinical study is to investigate the clinical feasibility and safety of a shuttle-based MR-linac connection to provide MR-guided radiotherapy.Methods/design: A total of 40 patients with an indication for a neoadjuvant, adjuvant or definitive radiation treatment will be recruited including tumors of the head and neck region, thorax, upper gastrointestinal tract and pelvic region. All study patients will receive standard therapy, i.e. highly conformal radiation techniques like CT-guided intensity-modulated radiotherapy (IMRT) with or without concomitant chemotherapy or other antitumor medication, and additionally daily short MR scans in treatment position with the same immobilisation equipment used for irradiation for position verification and imaging of the anatomical and functional changes during the course of radiotherapy. For daily position control, skin marks and a stereotactic frame will be used for both imaging modalities. Patient transfer between the MR device and the linear accelerator will be performed with a shuttle system which uses an air-bearing patient platform for both procedures. The daily acquired MR and CT data sets will be digitally registrated, correlated with the planning CT and compared with each other regarding translational and rotational errors. Aim of this clinical study is to establish a shuttle-based approach for realising MR-guided radiotherapy for certain clinical situations. Second objectives are to compare MR-guided radiotherapy with the gold standard of CT image guidance for quality assurance of radiotherapy, to establish an appropiate MR protocol therefore, and to assess the possibility of using MR-based image guidance not only for position verification but also for adaptive strategies in radiotherapy. DISCUSSION: Compared to CT, MRI might offer the advantage of providing IGRT without delivering an additional radiation dose to the patients and the possibility of optimisation of adaptive therapy strategies due to its superior soft tissue contrast. However, up to now, hybrid MR-linac devices are still under construction and not clinically applicable. For the near future, a shuttle-based approach would be a promising alternative for providing MR-guided radiotherapy, so that the present study was initiated to determine feasibility and safety of such an approach. Besides positioning information, daily MR data under treatment offer the possibility to assess tumor regression and functional parameters, with a potential impact not only on adaptive therapy strategies but also on early assessment of treatment response.
    Type of Publication: Journal article published
    PubMed ID: 24401489
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  • 8
    Keywords: EXPERIENCE ; RADIATION-THERAPY ; OUTCOMES ; CHILDREN ; MANAGEMENT ; ADULTS ; MORBIDITY ; COMBINED SURGERY ; CHILDHOOD CRANIOPHARYNGIOMA ; PEDIATRIC CRANIOPHARYNGIOMAS
    Abstract: PURPOSE: There are already numerous reports about high local control rates in patients with craniopharyngioma but there are only few studies with follow up times of more than 10 years. This study is an analysis of long term control, tumor response and side effects after fractionated stereotactic radiotherapy (FSRT) for patients with craniopharyngioma. PATIENTS AND METHODS: 55 patients who were treated with FSRT for craniopharyngioma were analyzed. Median age was 37 years (range 6-70 years), among them eight children 〈 18 years. Radiotherapy (RT) was indicated for progressive disease after neurosurgical resection or postoperatively after repeated resection or partial resection. A median dose of 52.2 Gy (50 - 57.6 Gy) was applied with typical dose per fraction of 1.8 Gy five times per week. The regular follow up examinations comprised in addition to contrast enhanced MRI scans thorough physical examinations and clinical evaluation. RESULTS: During median follow up of 128 months (2 - 276 months) local control rate was 95.3% after 5 years, 92.1% after 10 years and 88.1% after 20 years. Overall survival after 10 years was 83.3% and after 20 years 67.8% whereby none of the deaths were directly attributed to craniopharyngioma. Overall treatment was tolerated well with almost no severe acute or chronic side effects. One patient developed complete anosmia, another one's initially impaired vision deteriorated further. In 83.6% of the cases with radiological follow up a regression of irradiated tumor residues was monitored, in 7 cases complete response was achieved. 44 patients presented themselves initially with endocrinologic dysfunction none of them showed signs of further deterioration during follow up. No secondary malignancies were observed. CONCLUSION: Long term results for patients with craniopharyngioma after stereotactic radiotherapy are with respect to low treatment related side effects as well as to local control and overall survival excellent.
    Type of Publication: Journal article published
    PubMed ID: 25227427
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  • 9
    Keywords: RADIATION-THERAPY ; PROSTATE-CANCER ; sensitivity ; RANDOMIZED-TRIAL ; BEAM THERAPY ; HEAVY-ION RADIOTHERAPY ; TREATMENT UNCERTAINTIES ; MODULATED PROTON THERAPY ; CLINICAL-PHASE III ; IMPT TREATMENT PLANS
    Abstract: Background: It is expected that physical dose deposition properties render charged particle dose distributions sensitive to targeting uncertainties. Purpose of this work was to investigate the robustness of scanned-beam particle therapy plans against setup errors for different optimization modalities, beam setups and ion species. Material and methods: For 15 patients with skull base tumors, localized in regions of severe tissue density heterogeneity, scanned lateral-opposed-beam treatment plans were prepared with the treatment planning system TRiP98, employing different optimization settings (single-and multiple-field modulation) and ion species (carbon ions and protons). For 10 of the patients, additional plans were prepared with individually selected beam setups, aiming at avoiding severe tissue heterogeneities. Subsequently, multiple rigid positioning errors of magnitude 1-2 mm (i.e. within planning target expansion) were simulated by introducing a shift of the irradiation fields with respect to the computed tomography (CT) data and recomputing the plans. Results: In presence of shifts, in carbon ion plans using a lateral-opposed beam setup and fulfilling clinical healthy tissue dose constraints, the median reduction in CTV V-95% was up to 0.7 percentage points (pp) and 3.5 pp, for shifts of magnitude 1 mm and 2 mm respectively, however, in individual cases, the reduction reached 5.1 pp and 9.7 pp. In the corresponding proton plans similar median CTV V-95% reductions of up to 0.9 pp (1 mm error) and 3.4 pp (2 mm error) were observed, with respective individual-case reductions of at most 3.2 pp and 11.7 pp. Unconstrained plans offered slightly higher coverage values, while no relevant differences were observed between different field modulation methods. Individually selected beam setups had a visible dosimetric advantage over lateral-opposed beams, for both particle species. While carbons provided more conformal plans and generally more advantageous absolute dose values, in presence of setup errors, protons showed greater dosimetric stability, in most of the investigated scenarios. Conclusion: Residual patient setup errors may lead to substantial dose perturbation in scanned-beam particle therapy of skull base tumors, which cannot be dealt with by planning target expansion alone. Choice of irradiation directions avoiding extreme density heterogeneities can improve plan stability against such delivery-time uncertainties.
    Type of Publication: Journal article published
    PubMed ID: 25477197
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  • 10
    Keywords: OPTIMIZATION ; TOXICITY ; CONFORMAL RADIOTHERAPY ; INTENSITY-MODULATED RADIOTHERAPY ; FEASIBILITY ; PHASE-II TRIAL ; RANDOMIZED CONTROLLED-TRIAL ; BEAMS ; SCANNED PROTON ; ABSORBABLE HYDROGEL
    Abstract: BACKGROUND: Ion beam therapy represents a promising approach to treat prostate cancer, mainly due to its high conformity and radiobiological effectiveness. However, the presence of prostate motion, patient positioning and range uncertainties may deteriorate target dose and increase exposure of organs at risk. Spacer gel injected between prostate and rectum may increase the safety of prostate cancer (PC) radiation therapy by separating the rectum from the target dose field. The dosimetric impact of the application of spacer gel for scanned carbon ion therapy of PC has been analyzed at Heidelberg Ion-Beam Therapy Center (HIT). MATERIALS AND METHODS: The robustness of ion therapy treatment plans was investigated by comparison of two data sets of patients treated with and without spacer gel. A research treatment planning system for ion therapy was used for treatment plan optimization and calculation of daily dose distributions on 2 to 9 Computed Tomography (CT) studies available for each of the 19 patients. Planning and daily dose distributions were analyzed with respect to target coverage, maximal dose to the rectum (excluding 1 ml of the greatest dose; Dmax-1 ml) and the rectal volume receiving dose greater than 90% of prescribed target dose (V90Rectum), respectively. RESULTS: The application of spacer gel did substantially diminish rectum dose. Dmax-1 ml on the treatment planning CT was on average reduced from 100.0 +/- 1.0% to 90.2 +/- 4.8%, when spacer gel was applied. The robustness analysis performed with daily CT studies demonstrated for all analyzed patient cases that application of spacer gel results in a decrease of the daily V90Rectum index, which calculated over all patient cases and CT studies was 10.2 +/- 10.4 [ml] and 1.1 +/- 2.1 [ml] for patients without and with spacer gel, respectively. CONCLUSIONS: The dosimetric benefit of increasing the distance between prostate and rectum using spacer gel for PC treatment with carbon ion beams has been quantified. Application of spacer gel substantially reduced rectal exposure to high treatment dose and, therefore, can reduce the hazard of rectal toxicity in ion beam therapy of PC. The results of this study enable modifications of the PC ion therapy protocol such as dose escalation or hypofractionation.
    Type of Publication: Journal article published
    PubMed ID: 25886457
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