Martina Schiebe

Analysis of mdm2 and p53 gene alterations in glioblastomas and its correlation with clinical factors.

Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with probably prognostic implications. To elucidate the involvement of murine-double-minute (mdm)2 gene amplifications and mutations of the tumor suppressor gene p53 in the tumorigenesis of malignant gliomas we analyzed a series of 75 glioblastomas. The p53 mutations occur in one-third of glioblastomas, mdm2 amplifications were found in 13% of cases. Our analysis revealed a hot spot in the p53 gene locus in codon 156, the same point mutation was detected in 4 tumor samples. None of the mdm2 amplified tumors had p53 mutations, supporting the hypothesis, that mdm2 amplifications are alternative mechanisms for p53 inactivation. Patients with p53 mutated tumors were significantly younger characterized by a mean age of 44 years. Additionally association with longer overall survival could be detected for this subgroup of patients. In our study, survival estimation revealed a significant correlation of mdm2 gene amplification with shorter survival time, and support the hypothesis, that mdm2 oncogene activation appears to occur late in tumor progression and may be characteristic as negative prognostic marker.

Loss of heterozygosity at 11p15 and p53 alterations in malignant gliomas

Purpose: Malignant gliomas are the most frequent primary brain tumors. Recent studies defined several genetic markers, which might characterize molecular-biological subsets of glioblastomas with prognostic implications. In the later steps of tumor-progression, deletions on chromosome 11p15 and mutations of the tumor suppressor gene p53 were determined for different malignancies. To elucidate the involvement of 11p15 deletions in the tumorigenesis of malignant gliomas, we analyzed a series of 50 glioblastomas for loss of heterozygosity (LOH). Methods: Paired tissue and blood samples from 50 patients with glioblastoma multiforme were included. Microsatellite markers located on 11p15.1–11p15.5 were used for LOH analysis. Additionally, mutation analysis of the tumor suppressor gene p53 was performed, which might correlate with favorable survival in glioblastomas. Results: The region 11p15.4–5 was deleted heterozygously in 28% of cases representing 15 cM. Twenty-six glioblastomas did not show allelic loss for any locus. Our data revealed close association of LOH 11p15 with p53 mutations, and survival analysis showed a trend indicating better prognosis in glioblastomas characterized by LOH 11p15. Conclusion: In the tumorigenesis of malignant gliomas, p53 mutations and 11p15 deletions seem to indicate a genetic subset of tumors with favorable prognostic value.

Irradiation of Histiocytosis X confined to the oral mucosa

Background: Histiocytosis X is a rare granulomatous disease and it is still under debate as to whether this disease has to be counted among malignant tumors or benign immunologic lesions. The typical localization is confined to the bone. In rare cases histiocytosis X may be localized in the oropharyngeal mucosa. Patients and Methods: We report about a case of a 75-year-old woman presenting with histiocytosis X lesions solely located in the oral cavity. A total dose of 19.5 Gy was administered without any side effects. Results: Two weeks after completion of irradiation a rapid regression of mucosal ulcerations and improvement of symptoms occurred. In a follow-up of 24 months the patient is still in complete remission observed. Conclusion: Review of the literature revealed only casuistic reports about solitary lesions of histiocytosis X without bone involvement in the adulthood. External beam radiotherapy with total doses between 10 and 20 Gy seems to be effective for local control of this disease.Hintergrund: Die Histiozytosis X ist eine seltene granulomatöse Erkrankung. Typische Lokalisationen sind Schädel, Becken, Wirbelsäule und die langen Röhrenknochen. In seltenen Fällen sind lokalisierte Manifestationen im Bereich der Schleimhäute nachweisbar. Patient und Methode: Wir berichten über eine 75-jährige Patientin mit isolierter Manifestation einer Histiozytosis X im Bereich der Mundschleimhäute. Die Radiotherapie der Oropharynxregion wurde in konventioneller Fraktionierung bis zu einer Gesamtdosis von 19,5 Gy ohne Nebenwirkungen appliziert. Ergebnis: Zwei Wochen nach Strahlentherapie hatten sich die histiozytären Ulzerationen im Bereich der Gingiva und des Gaumens fast komplett zurückgebildet. Nach 24 Monaten befindet sich die Patientin weiterhin in kompletter Remission. Schlussfolgerung: Solitäre Manifestationen einer Histiozytosis X ohne Knochenbeteiligung im Erwachsenenalter sind in der Literatur kasuistisch beschrieben. Zur Lokaltherapie scheinen Gesamtdosen zwischen 10 und 20 Gy ausreichend zu sein.

Phase I study of oral uracil and Tegafur plus leucovorin and pelvic radiation in patients with recurrent rectal cancer.

Continuous 5-fluorouracil (5-FU) infusion during radiation therapy is superior to the application of bolus 5-FU schedules. As an oral therapy, that provides prolonged fluoropyrimidine exposure, uracil and Tegafur (UFT) plus leucovorin (LV) has shown favorable activity with only moderate toxicity in colorectal cancer. The present study was designed to evaluate the safety of UFT+LV combined with pelvic radiation to determine the maximum-tolerated dose (MTD) in recurrent rectal cancer. Patients with recurrent rectal cancer received escalating doses of UFT (starting at 250 mg/m2/day with 50 mg/m2/day increments between consecutive cohorts) and fixed doses of LV (90 mg). The UFT+LV combination was given 5 days per week simultaneously to a 5-week course of irradiation up to a total dose of 50.4 Gy, 1.8 Gy daily fractions followed by a boost of 5.4 or 9.0 Gy to the gross tumor volume. Nineteen patients were treated and 14 received the full chemotherapy with delivery of all planned radiotherapy. The MTD of UFT was 400 mg/m2/day due to the occurrence of dose-limiting diarrhea and emesis. Toxicities were mild and manageable on the lower dose levels. Treatment was feasible mainly on an outpatient base. We conclude that combined chemoradiation with oral UFT+LV is feasible and well tolerated for recurrent rectal cancer patients undergoing pelvic radiation. The safety profile appears comparable to that of i.v. dosing without requiring any i.v. port systems. The recommended doses for further phase II chemoradiation trials are 350 mg/m2/day UFT+90 mg LV.

CT-Based Virtual Simulation Using the AdvantageSim 4.1.® System Description of Reliability and Accuracy

Background: CT simulation systems provide integration of CT-based planning target volumes, which allows to operate without the conventional simulator. The aim of our study was the quantitative assessment of the accuracy of field alignment and isocenter position using the new virtual simulation system AdvantageSim 4.1.® for different treatment regions. Patients and Methods: Twenty-seven patients with prostate cancer, 23 patients with head and neck cancer and 30 lung cancer patients were included in this prospective trial. CT-based virtual simulation was performed to define treatment isocenter position. The linear discrepancies of the digitally reconstructed beams eye views were compared with the conventional simulation and first treatment verification images. Results: Among all patients the mean difference of isocenter position between conventional and virtual simulation was 3.5 mm. The isocenter displacements ranged from 0 to 6 mm. There was no significant difference in isocenter accuracy between the different treatment regions. Conclusions: Virtual simulation with AdvantageSim 4.1.® is feasible in daily routine and allows to replace conventional simulation for different target volumes with a reliable accuracy of isocenter and field alignment. The beams eye views allow the precise evaluation of the coverage of the planning target volume and the shielding of organs at risk.Hintergrund: CT-gestützte Simulationssysteme ermöglichen die Bestrahlungsplanung ohne konventionelle Simulationsaufnahmen. Verglichen werden sollte die Präzision des neuen virtuellen CT-Simulators AdvantageSim 4.1.® mit der konventionellen Röntgensimulation für unterschiedliche Bestrahlungsregionen. Patientengut und Methode: Bei 27 Prostatakarzinompatienten, 23 Patienten mit Kopf-Hals-Tumoren und 30 Bronchialkarzinompatienten erfolgte eine virtuelle Simulation mit AdvantageSim 4.1.®. Nach Festlegung des Bestrahlungsplans und der virtuell definierten Isozentrumslage wurde zusätzlich eine konventionelle Simulation durchgeführt. Die Genauigkeit der digital rekonstruierten beams eye views wurde im Vergleich zu den konventionellen Simulations- und Verifikationsaufnahmen ermittelt. Ergebnisse: Die mittlere Abweichung der virtuell am Patienten ermittelten Isozentrumsposition im Vergleich zur konventionellen Simulation war 3,5 mm. Die Verschiebung der Isozentrums- und Lasermarkierungen betrug 0 bis 6 mm ohne signifikanten Unterschied bezüglich der verschiedenen Bestrahlungsregionen. Schlussfolgerung: Das neue virtuelle Simulationssystem AdvantageSim 4.1.® erreicht eine ausreichende Präzision und ersetzt bei 3D-geplanten Bestrahlungsfeldern für ausgewählte Lokalisationen die konventionelle Simulation. Durch relative Wichtung der Dichtewerte im Patientenmodell lassen sich die Zielvolumina und Risikoorgane exakter beurteilen.