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Biomedical subjects

Dirk Vordermark

Publications and source records attributed to Dirk Vordermark.

At least 19 recordsLinked to original sources

Immunohistochemical detection of osteopontin in advanced head-and-neck cancer: prognostic role and correlation with oxygen electrode measurements, hypoxia-inducible-factor-1alpha-related markers, and hemoglobin levels.

PURPOSE: The tumor-associated glycoprotein osteopontin (OPN) is discussed as a plasma marker of tumor hypoxia. However, the association of immunohistochemical OPN expression in tumor sections with tumor oxygenation parameters (HF5, median pO(2)), the hypoxia-related markers hypoxia-inducible factor-1alpha (HIF-1alpha) and carbonic anhydrase IX (CAIX), or hemoglobin and systemic vascular endothelial growth factor (VEGF) levels has not been investigated. METHODS AND MATERIALS: Tumor tissue sections of 34 patients with advanced head-and-neck cancer treated with radiotherapy were assessed by immunochemistry for the expression of OPN, HIF-1alpha, and CA IX. Relationship of OPN expression with tumor oxygenation parameters (HF5, median pO(2)), HIF-1alpha and CA IX expression, hemoglobin and serum VEGF level, and clinical parameters was studied. RESULTS: Bivariate analysis showed a significant correlation of positive OPN staining with low hemoglobin level (p = 0.02), high HIF-1alpha expression (p = 0.02), and high serum vascular endothelial growth factor level (p = 0.02) for advanced head-and-neck cancer. Furthermore, considering the 31 Stage IV patients, the median pO(2) correlated significantly with the OPN expression (p = 0.02). OPN expression alone had only a small impact on prognosis. However, in a univariate Cox proportional hazard regression model, the expression of either OPN or HIF-1alpha or CA IX was associated with a 4.1-fold increased risk of death (p = 0.02) compared with negativity of all three markers. CONCLUSION: Osteopontin expression detected immunohistochemically is associated with oxygenation parameters in advanced head-and-neck cancer. When the results of OPN, HIF-1alpha, and CA IX immunohistochemistry are combined into a hypoxic profile, a strong and statistically significant impact on overall survival is found.

Adult↗

Glioblastoma multiforme with oligodendroglial component (GBMO): favorable outcome after post-operative radiotherapy and chemotherapy with nimustine (ACNU) and teniposide (VM26).

BACKGROUND: The presence of an oligodendroglial component within a glioblastoma multiforme (GBM) is considered a prognostically favorable factor, but the clinical outcome of patients with glioblastoma multiforme with oligodendroglial component (GBMO) after combined post-operative radiotherapy and chemotherapy has rarely been reported. METHODS: We analyzed overall and progression-free survival in a group of ten consecutive patients initially diagnosed with GBMO between 1996 and 2004 (4.2% of all GBM patients). Median (range) age was 54 (34-73) years, 90% were resected and median radiotherapy dose was 54 (45-60.6) Gy. 80% of patients received post-operative chemotherapy with nimustine (ACNU) and VM26 (teniposide) for a median of 3.5 (1-6) cycles, the remainder were treated with post-operative radiotherapy alone. All specimens were reviewed by an experienced neuropathologist. RESULTS: Neuropathological re-evaluation revealed GBM with an oligodendroglial component of 30% or less in five cases, predominant oligoastrocytic tumors with focal areas of GBM in four patients and WHO grade III oligoastrocytoma with questionable transition to GBM in one patient. Four of ten patients were alive at at 40, 41, 41 and 82 months. The median overall survival (Kaplan-Meier) was 26 months, the 2-year survival rate was 60% (progression-free survival: 9.8 months and 40%, respectively). CONCLUSION: In conclusion, patients with GBMO treated with post-operative radiotherapy and chemotherapy with ACNU/VM26 had a better prognosis than reported for GBM in modern chemoradiation series.

Adult↗

Distinct effects of rectum delineation methods in 3D-conformal vs. IMRT treatment planning of prostate cancer.

BACKGROUND: The dose distribution to the rectum, delineated as solid organ, rectal wall and rectal surface, in 3D conformal (3D-CRT) and intensity-modulated radiotherapy treatment (IMRT) planning for localized prostate cancer was evaluated. MATERIALS AND METHODS: In a retrospective planning study 3-field, 4-field and IMRT treatment plans were analyzed for ten patients with localized prostate cancer. The dose to the rectum was evaluated based on dose-volume histograms of 1) the entire rectal volume (DVH) 2) manually delineated rectal wall (DWH) 3) rectal wall with 3 mm wall thickness (DWH(3)) 4) and the rectal surface (DSH). The influence of the rectal filling and of the seminal vesicles' anatomy on these dose parameters was investigated. A literature review of the dose-volume relationship for late rectal toxicity was conducted. RESULTS: In 3D-CRT (3-field and 4-field) the dose parameters differed most in the mid-dose region: the DWH showed significantly lower doses to the rectum (8.7% +/- 4.2%) compared to the DWH(3) and the DSH. In IMRT the differences between dose parameters were larger in comparison with 3D-CRT. Differences were statistically significant between DVH and all other dose parameters and between DWH and DSH. Mean doses were increased by 23.6% +/- 8.7% in the DSH compared to the DVH in the mid-dose region. Furthermore, both the rectal filling and the anatomy of the seminal vesicles influenced the relationship between the dose parameters: a significant correlation of the difference between DVH and DWH and the rectal volume was seen in IMRT treatment. DISCUSSION: The method of delineating the rectum significantly influenced the dose representation in the dose-volume histogram. This effect was pronounced in IMRT treatment planning compared to 3D-CRT. For integration of dose-volume parameters from the literature into clinical practice these results have to be considered.

Dose-Response Relationship, Radiation↗

Distinct patterns of hypoxic expression of carbonic anhydrase IX (CA IX) in human malignant glioma cell lines.

The hypoxia-inducible enzyme carbonic anhydrase IX (CA IX) has recently been discussed as a surrogate marker of tumor hypoxia, an indicator of prognosis and a potential therapeutic target in malignant glioma. To characterize patterns of expression of CA IX in human malignant glioma cells, we studied CA IX protein, CA9 mRNA and hypoxia-inducible factor-1alpha (HIF-1alpha) protein levels in U87-MG, U251, U373 and GaMG cells exposed to in vitro hypoxia (1, 6 or 24 h at 5%, 1% or 0.1% O(2)). All cell lines displayed a strong hypoxic induction of CA9 mRNA in response to prolonged severe hypoxia with cell-line specific patterns at moderate to mild hypoxia and shorter treatment times. Only U87-MG exhibited a strong constitutive, normoxic expression of CA IX protein without a detectable change under hypoxia. In U251 and GaMG cell lines, a marked induction of CA IX protein in response to severe hypoxia was seen. CA IX changes under severe hypoxia and the inhibitory effect of the glycolysis inhibitor iodoacetate (IAA, 50 microM) on hypoxic CA IX overexpression were paralleled by the results for HIF-1alpha protein. Therefore, immunohistochemical CA IX staining in human malignant glioma specimens can result from low oxygen concentrations or constitutive, oncogene-related, overexpression both of which may be prognostically relevant.

Antigens, Neoplasm↗

Plasma osteopontin levels in patients with head and neck cancer and cervix cancer are critically dependent on the choice of ELISA system.

BACKGROUND: The tumor-associated glycoprotein osteopontin (OPN) is discussed as a plasma surrogate marker of tumor hypoxia and as an indicator of the presence of pleural mesothelioma in asbestos-exposed individuals. The clinical introduction of plasma OPN measurements requires the availability of a reliable enzyme-linked immunosorbence assay (ELISA). METHODS: We compared previously described and currently available ELISA systems on 88 archival plasma samples obtained from patients with head and neck or cervix cancer between 20 days before and 171 after the start of radiotherapy. RESULTS: Median (range) plasma OPN levels were 667 (148.8-2095) ng/ml and 9.8 (3.5-189.5) ng/ml for a previously described and a newly marketed assay, respectively. Although results for different assays were significantly correlated (r = 0.38, p < 0.05, Spearman rank test), between-assay factors ranged from 2.0 to 217.9 (median 74.6) in individual patients. OPN levels in cervix cancer patients were comparable to those of head and neck cancer patients. CONCLUSION: Commercially available OPN ELISA systems produce different absolute plasma OPN levels, compromising a comparison of individual patient data with published results. However, different assays appear to have a similar capacity to rank patients according to plasma OPN level. A review of literature data suggests that plasma OPN levels measured even with identical ELISA systems can only be compared with caution.

Enzyme-Linked Immunosorbent Assay↗

Magnitude and clinical relevance of translational and rotational patient setup errors: a cone-beam CT study.

PURPOSE: To establish volume imaging using an on-board cone-beam CT (CB-CT) scanner for evaluation of three-dimensional patient setup errors. METHODS AND MATERIALS: The data from 24 patients were included in this study, and the setup errors using 209 CB-CT studies and 148 electronic portal images were analyzed and compared. The effect of rotational errors alone, translational errors alone, and combined rotational and translational errors on target coverage and sparing of organs at risk was investigated. RESULTS: Translational setup errors using the CB-CT scanner and an electronic portal imaging device differed <1 mm in 70.7% and <2 mm in 93.2% of the measurements. Rotational errors >2 degrees were recorded in 3.7% of pelvic tumors, 26.4% of thoracic tumors, and 12.4% of head-and-neck tumors; the corresponding maximal rotational errors were 5 degrees , 8 degrees , and 6 degrees . No correlation between the magnitude of translational and rotational setup errors was observed. For patients with elongated target volumes and sharp dose gradients to adjacent organs at risk, both translational and rotational errors resulted in considerably decreased target coverage and highly increased doses to the organs at risk compared with the initial treatment plan. CONCLUSIONS: The CB-CT scanner has been successfully established for the evaluation of patient setup errors, and its feasibility in day-to-day clinical practice has been demonstrated. Our results have indicated that rotational errors are of clinical significance for selected patients receiving high-precision radiotherapy.

Head and Neck Neoplasms↗

3-D reconstruction of anterior mantle-field techniques in Hodgkin's disease survivors: doses to cardiac structures.

BACKGROUND: The long-term dose-effect relationship for specific cardiac structures in mediastinal radiotherapy has rarely been investigated. As part of an interdisciplinary project, the 3-D dose distribution within the heart was reconstructed in all long-term Hodgkin's disease survivors (n = 55) treated with mediastinal radiotherapy between 1978 and 1985. For dose reconstruction, original techniques were transferred to the CT data sets of appropriate test patients, in whom left (LV) and right ventricle (RV), left (LA) and right atrium (RA) as well as right (RCA), left anterior descending (LAD) and left circumflex (LCX) coronary arteries were contoured. Dose-volume histograms (DVHs) were generated for these heart structures and results compared between techniques. RESULTS: Predominant technique was an anterior mantle field (cobalt-60). 26 patients (47%) were treated with anterior mantle field alone (MF), 18 (33%) with anterior mantle field and monoaxial, bisegmental rotation boost (MF+ROT), 7 (13%) with anterior mantle field and dorsal boost (MF+DORS) and 4 (7%) with other techniques. Mean +/- SD total mediastinal doses for MF+ROT (41.7 +/- 3.5 Gy) and for MF+DORS (42.7 +/- 7.4) were significantly higher than for MF (36.7 +/- 5.2 Gy). DVH analysis documented relative overdosage to right heart structures with MF (median maximal dose to RV 129%, to RCA 127%) which was significantly reduced to 117% and 112%, respectively, in MF+ROT. Absolute doses in right heart structures, however, did not differ between techniques. Absolute LA doses were significantly higher in MF+ROT patients than in MF patients where large parts of LA were blocked. Median maximal doses for all techniques ranged between 48 and 52 Gy (RV), 44 and 46 Gy (LV), 47 and 49 Gy (RA), 38 and 45 Gy (LA), 46 and 50 Gy (RCA), 39 and 44 Gy (LAD) and 34 and 42 Gy (LCX). CONCLUSION: In patients irradiated with anterior mantle-field techniques, high doses to anterior heart portions were partly compensated by boost treatment from non-anterior angles. As the threshold doses for coronary artery disease, cardiomyopathy, pericarditis and valvular changes are assumed to be 30 to 40 Gy, cardiac toxicity must be anticipated in these patients. Thus, dose distributions in individual subjects should be correlated to the corresponding cardiovascular findings in these long-term survivors, e. g. by cardiovascular magnetic resonance imaging.

Adolescent↗

Adverse effect of a distended rectum in intensity-modulated radiotherapy (IMRT) treatment planning of prostate cancer.

BACKGROUND AND PURPOSE: The retrospective planning study for intensity-modulated radiotherapy (IMRT) of prostate cancer evaluated whether proximal rectum and supra-anal rectum/anal canal should be delineated as separated organs-at-risk (OARs) to achieve optimal dose distributions to the anorectal region. PATIENTS AND METHODS: For 10 patients with localized prostate cancer IMRT plans were generated with the rectum and anal canal as separated OARs (Rec-sep) and as one single OAR (Rec-tot). Two different treatment planning systems (TPS) were utilized. Influence on dose distributions to target and OARs was analyzed. RESULTS: Results from both TPS showed significantly increased doses to the distal rectum/anal canal for plans Rec-tot compared with Rec-sep in case of a distended rectum in the planning CT study: doses were increased by up to mean 31% (P = 0.02) and 18% (P = 0.03), respectively, in both TPS. For the patient with the largest rectum, the maximum dose increase was 61%. No significant differences in doses to target, bladder, femoral head and proximal rectum were seen. CONCLUSIONS: For patients with a distended rectum in the planning CT, delineation of separated OARs for proximal rectum and distal rectum/anal canal resulted in superior dose distributions to the anorectal region and therefore, we recommend this as standard procedure for IMRT planning of prostate cancer.

Algorithms↗

Influence of rectum delineation (rectal volume vs. rectal wall) on IMRT treatment planning of the prostate.

PURPOSE: To evaluate the delineation of either the rectal volume (RV) or the rectal wall (RW) in intensity-modulated radiotherapy (IMRT) for prostate cancer: influence on dose distribution to the targets and organs at risk (OARs) was investigated. MATERIAL AND METHODS: For ten patients with localized prostate cancer IMRT treatment plans were generated with the RV, wall including the filling, and the RW without the lumen as OAR (plan-RV and plan-RW), respectively. Two different IMRT treatment- planning systems (TPS) were utilized. The influence on target coverage and sparing of OARs was investigated. RESULTS: No influence was seen on target coverage and sparing of the bladder and femoral heads. Doses to the RV were significantly reduced in plan-RV for all evaluated dose levels: maximum 26% and 17%, respectively, in both TPS. The dose distribution to the RW was not significantly different between plan-RV and plan-RW. CONCLUSION: The different delineation of the OAR rectum significantly affected the inverse IMRT treatment-planning process. The use of the RV as OAR resulted in improved dose distributions to the RV. Therefore, it is suggested using the RV as OAR in IMRT treatment planning of the prostate.

Femur Head↗

3-D conformal treatment of prostate cancer to 74 Gy vs. high-dose-rate brachytherapy boost: a cross-sectional quality-of-life survey.

The effects of two modalities of dose-escalated radiotherapy on health-related quality of life (HRQOL) were compared. Forty-one consecutive patients were treated with a 3-D conformal (3-DC) boost to 74 Gy, and 43 with high-dose rate (HDR) brachytherapy boost (2x9 Gy), following 3-D conformal treatment to 46 Gy. Median age was 70 years in both groups, median initial PSA was 7.9 microg/l in 3-DC boost patients and 8.1 microg/l in HDR boost patients. Stage was or=7 in 52% and 47%, respectively. HRQOL was assessed cross-sectionally using EORTC QLQ-C30 and organ-specific PR25 modules 3--32 (median 19) and 4--25 (median 14) months after treatment, respectively. Questionnaires were completed by 93% and 97% of patients, respectively. Diarrhea and insomnia scores were significantly increased in both groups. In the PR25 module, scores of 3-DC boost and HDR boost patients for urinary, bowel and treatment-related symptoms were similar. Among responders, 34% of 3-DC boost patients and 86% of HDR boost patients had severe erectile problems. Dose escalation in prostate cancer by either 3-DC boost to 74 Gy or HDR brachytherapy boost appears to result in similar HRQOL profiles.

Brachytherapy↗

Glucose requirement for hypoxic accumulation of hypoxia-inducible factor-1alpha (HIF-1alpha).

Hypoxia-inducible factor-1alpha (HIF-1alpha) is both a potential endogenous marker of tumor hypoxia and therapeutic target, and elevated HIF-1alpha protein levels have been shown to be associated with increased hypoxic radiation resistance in FaDu human pharyngeal carcinoma cells in vitro. Here, we found that in FaDu xenografts, no significant HIF-1alpha protein accumulation was detectable by either flow cytometry or Western blot, despite the presence of hypoxic (pimonidazole-positive, radiation resistant) cells. To investigate the effect of different tumor microenvironment conditions on hypoxic HIF-1alpha accumulation, we performed in vitro hypoxia experiments (0.1% O2, 24 h) with manipulation of pH (7.4 vs. 6.7), glucose (0-5.5 mM) and serum (0 or 10%) availability in FaDu and HT 1080 human fibrosarcoma cells. Hypoxic induction of HIF-1alpha protein was strongly dependent on glucose availability and largely abolished at 0.55 mM glucose or less in both cell lines. This glucose effect was confirmed in a hypoxia-responsive-element (HRE)/enhanced-green-fluorescent-protein (EGFP) reporter assay in transfected HT 1080 cells and possibly explains a lack of HIF-1alpha protein in hypoxic tumor cells.

Animals↗

Hypofractionated stereotactic re-irradiation: treatment option in recurrent malignant glioma.

BACKGROUND: Hypofractionated stereotactic radiotherapy (HFSRT) is one salvage treatment option in previously irradiated patients with recurrent malignant glioma. We analyzed the results of HFSRT and prognostic factors in a single-institution series. METHODS: Between 1997 and 2003, 19 patients with recurrent malignant glioma (14 glioblastoma on most recent histology, 5 anaplastic astrocytoma) were treated with HFSRT. The median interval from post-operative radiotherapy to HFSRT was 19 (range 3-116) months, the median daily single dose 5 (4-10) Gy, the median total dose 30 (20-30) Gy and the median planning target volume 15 (4-70) ml. RESULTS: The median overall survival (OS) was 9.3 (1.9-77.6+) months from the time of HFSRT, 15.4 months for grade III and 7.9 months for grade IV tumors (p = 0.029, log-rank test). Two patients were alive at 34.6 and 77.6 months. OS was longer after a total dose of 30 Gy (11.1 months) than after total doses of <30 Gy (7.4 months; p = 0.051). Of five (26%) reoperations, none was performed for presumed or histologically predominant radiation necrosis. Median time to tumor progression after HFSRT on imaging was 4.9 months (1.3 to 37.3) months. CONCLUSION: HFSRT with conservative total doses of no more than 30 Gy is safe and leads to similar OS times as more aggressive treatment schemes. In individual patients, HFSRT in combination with other salvage treatment modalities, was associated with long-term survival.

Antineoplastic Agents↗

Characterization of carbonic anhydrase IX (CA IX) as an endogenous marker of chronic hypoxia in live human tumor cells.

PURPOSE: Published clinical studies provide conflicting data regarding the prognostic significance of carbonic anhydrase IX (CA IX) overexpression as an endogenous marker of tumor hypoxia and its comparability with other methods of hypoxia detection. We performed a systematic analysis of CA IX protein levels under various in vitro conditions of tumor hypoxia in HT 1080 human fibrosarcoma and FaDu human pharyngeal carcinoma cells. Because sorting of live CA IX positive cells from tumors provides a tool to study the radiosensitivity of chronically hypoxic cells, we modified and tested a CA IX flow cytometry protocol on mixed hypoxic/aerobic suspensions of HT 1080 and FaDu cells. METHODS AND MATERIALS: HT 1080 and FaDu cells were treated with up to 24 h of in vitro hypoxia and up to 96 h of reoxygenation. To test the effect of nonhypoxic stimuli, glucose and serum availability, pH and cell density were modified. CA IX protein was quantified in Western blots of whole-cell lysates. Mixed suspensions with known percentages of hypoxic cells were prepared for CA IX flow cytometry. The same mixtures were assayed for clonogenic survival after 10 Gy. RESULTS: Hypoxia-induced CA IX protein expression was seen after >6 h at < or =5% O(2), and protein was stable over 96 h of reoxygenation in both cell lines. Glucose deprivation abolished the hypoxic CA IX response, and high cell density caused CA IX induction under aerobic conditions. Measured percentages of CA IX-positive cells in mixtures closely reflected known percentages of hypoxic cells in HT 1080 and were associated with radioresistance of mixtures after 10 Gy. CONCLUSION: CA IX is a stable marker of current or previous chronic hypoxia but influenced by nonhypoxic stimuli. Except the time course of accumulation, all properties of this marker resembled our previous findings for hypoxia-inducible factor-1alpha. A modified flow cytometry protocol provided good separability of CA IX-negative and -positive cells in vitro and can be applied to sort chronically hypoxic cells from tumors.

Antigens, Neoplasm↗

Radiotherapy of prostate cancer with multileaf collimators (MLCs) optimization of the undulating dose distribution at the MLC edge.

BACKGROUND AND PURPOSE: A technical modification for radiotherapy of prostate cancer is presented to smooth the scalloped dose pattern that occurs at treatment field edge, when a multileaf collimator (MLC) has been used. MATERIAL AND METHODS: Ten patients with prostate cancer receiving postoperative, adjuvant irradiation were studied prospectively. By a three-dimensional planning system (TMS, Helax 6.1B) the irradiation was planned for an 18-MV linear accelerator (Primus 1, Siemens). The volumes of interest (VOI) were the planning target volume (PTV; the region of the prostate including the seminal vesicles), the volume of rectum (V(rectum)) and urinary bladder (V(bladder)). Two four-field techniques (0 degrees , 90 degrees , 180 degrees , 270 degrees ) were planned using "beam's eye view" for setting the leaf position of the MLC. For technique A the MLC was adapted to the PTV using a 0 degrees collimator angle for the lateral fields. For technique B the collimator angle of the lateral fields was optimized to compensate the cascade field shape. Dose-volume histograms of PTV, V(rectum) and V(bladder) were analyzed. The dose was prescribed for the reference point according to ICRU 50. Film dosimetry was used to show the dose pattern at the field edge produced by the two techniques. RESULTS: Dose to PTV did not differ between technique A and B. Median dose to V(rectum) was 82.6% for technique A and 77.3% for technique B (p < 0.001). Technique A irradiates a larger V(rectum) than technique B being significant for all isodose levels tested. Median dose to V(bladder) did not differ for technique A and B (p > 0.05). CONCLUSION: The presented technical modification is an effective method to blur the staggered dose distribution that results, when the MLC is conventionally stepped to adapt to the dorsal, irregular PTV border in irradiation of prostate. Especially for irradiation to escalated dose levels, this modification may reduce the dose to the rectum and thus the rectal side effects in comparison to the conventional MLC fields.

Algorithms↗

Response of the plasma hypoxia marker osteopontin to in vitro hypoxia in human tumor cells.

BACKGROUND: Osteopontin (OPN) is recognized as a tumor-associated protein and has recently been shown to be a potential plasma marker of tumor hypoxia in head and neck cancer patients. We sought to detect patterns of OPN accumulation and secretion in human tumor cells during in vitro hypoxia. MATERIALS AND METHODS: The human tumor cell lines A 549 lung carcinoma, U 87 malignant glioma, HT 1080 fibrosarcoma, FaDu pharyngeal carcinoma and HT 29 and HCT 116 colorectal carcinoma were treated with 1, 6 or 24 h of hypoxia (0.1% O2) or 24 h followed by 4 h or 20 of reoxygenation. OPN concentration in the supernatant was measured by ELISA, OPN protein and mRNA levels by Western and Northern blotting. RESULTS: In FaDu, HT 29 and HCT 116, OPN levels in the supernatant remained below 10 ng/ml under all conditions. In A 549, HT 1080 and U 87, mean aerobic OPN concentrations were 2296, 164 and 115 ng/ml, respectively. No increase of OPN in the medium during 24h of hypoxia, but moderate increases during subsequent 24-hour-reoxygenation were observed in these three cell lines. Intracellular OPN protein was present to a similar extent in all six-cell lines under aerobic conditions and also did not accumulate during hypoxia treatment. OPN mRNA response to hypoxia and reoxygenation was very heterogeneous between cell lines. CONCLUSION: Reoxygenation rather than hypoxia appears to induce OPN secretion from human tumor cells in a cell-type specific manner.

Cell Adhesion↗