Biomedical subjects

Gerhard Grabenbauer

Publications and source records attributed to Gerhard Grabenbauer.

18 recordsLinked to original sources

PubMed2006

Survival and quality of life after hypofractionated stereotactic radiotherapy for recurrent malignant glioma.

PURPOSE: To prospectively evaluate efficacy, side effects and quality of life in patients with recurrent malignant glioma after hypofractionated stereotactic radiotherapy. METHODS AND MATERIALS: From 1/2003 to 8/2005, 15 patients with recurrent malignant glioma were prospectively scheduled for hfSRT with 5 x 7 Gy (90%-isodose). Median gross tumor volume and planning target volume were 5.75 (range, 0.77-21.94) and 22.4 (range, 4.22-86.79) cc, respectively. Irradiation was performed with the dedicated stereotactic radiosurgery system Novalistrade mark (BrainLAB, Heimstetten, Germany). RESULTS: Rates of remission, no change and progressive disease were 27%, 33%, and 40%, respectively, after a median follow-up of 9 months. Progression-free survival rates at 6 and 12 months were 75% and 53% respectively. Quality of life, measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire scores could be kept stable in two thirds of the patients for a median time of 9 months, respectively. CONCLUSION: Hypofractionated stereotactic radiotherapy with 5 x 7 Gy of recurrent high grade glioma is an effective treatment that helps to maintain quality of life for an acceptable period, comparable to the results obtained with current chemotherapy schedules. Combined approaches of radiotherapy, chemotherapy and other targeted therapies deserve further inverstigation.

Adult↗

PubMed2006

Phase II trial of hypofractionated stereotactic radiotherapy for brain metastases: results and toxicity.

PURPOSE: To prospectively evaluate efficacy and side effects of hypofractionated stereotactic radiotherapy (hfSRT) for irresectable brain metastases not amenable to radiosurgery (SRS). METHODS AND MATERIALS: From 1/2003 to 2/2005, 51 patients with 72 brain metastases were included in a prospective phase II-trial and accepted for treatment at the dedicated stereotactic radiosurgery system Novalis (BrainLAB, Heimstetten, Germany). In case of planned or prior whole brain radiotherapy (WBRT), hfSRT was to be performed with 5 x 6 Gy, otherwise with 5 x 7 Gy. This dose was prescribed to the 90% isodose line which should cover 100% of the planning target volume (PTV). RESULTS: Rates of complete remission (CR), partial remission (PR), no change (NC) and progressive disease (PD) were 66.7%, 18.1%, 12.5% and 2.8%, respectively, after a median follow-up of 7 months. Median survival was 11 months. Disease-specific survival and survival related to brain metastases were strongly associated with the size of gross tumor volume (GTV), the planning target volume (PTV), Karnofsky Performance Score (KPS) and number of metastases. Side effects, i.e., increase in T2w-signal area, duration of steroid intake and size of new or progressive necrotic centre of metastasis, were dependent on the volume of normal brain irradiated with more than 4 Gy per fraction (V(4Gy)). Significantly more patients with a V(4Gy)> or =23 cc developed radiological signs of side effects from hfSRT. CONCLUSION: Hypofractionated stereotactic radiotherapy with 5 x 6-7 Gy is an effective and safe treatment for brain metastases not amenable to single high-dose radiosurgery. The normal brain volume receiving >4 Gy per fraction may not exceed 20 cc.

Adult↗

PubMed2006

Dose escalation in large anterior skull-base tumors by means of IMRT. First experience with the Novalis system.

PURPOSE: To evaluate the feasibility and tolerance of dose escalation with stereotactic intensity-modulated radiotherapy (sIMRT) for skull-base tumors. PATIENTS AND METHODS: Between 01/2003 and 12/2004, twelve patients were treated. Nine were exclusively treated at the Novalis site with one planning target volume (PTV) field boost, three were administered boost IMRT treatment (two with each one PTV-shrinking field, one with single PTV) after conventional three-dimensional conformal radiotherapy. This resulted in 23 PTVs with a median volume of 93.63 cm3 (range, 88.58-125.88 cm3). Dose calculation was done by the pencil-beam algorithm. Median total doses of 66.6, 77.4, and 63.9 Gy were prescribed for sIMRT alone, sIMRT after 3-D conformal irradiation of the nasopharynx and cervical lymph nodes with 59.4 Gy, and for reirradiation, respectively. RESULTS: 95% isodose PTV coverage was reached in 86.5% (range, 80-93%). Homogeneity (Dmax/Dref) was 1.11, 1.09, and 1.08. Median total doses to 50% of chiasm, right and left optic nerve were 16.21, 16.82 and 10.23 Gy. 11/12 patients are locally controlled with a median follow-up of 11 months (range, 3-23 months), one has died of pulmonary embolism after cerebrospinal dissemination of retinal adenocarcinoma. CONCLUSION: SIMRT enables dose escalation to tumors located close to critical organs. Inverse planning for micro-multileaf collimator stereotactic irradiation is practicable in the daily routine irradiation program. SIMRT needs special verification and still, the following parameters have to be standardized: IMRT dose specification, dose maxima, length of radiation delivery time.

Adult↗

PubMed2006

Hypofractionated stereotactic radiotherapy for primary and secondary intrapulmonary tumors: first results of a phase I/II study.

PURPOSE: To evaluate the feasibility, efficacy, and side effects of dose escalation in hypofractionated stereotactic radiotherapy (hfSRT) for intrapulmonary tumors with the Novalis system (BrainLAB AG, Heimstetten, Germany). PATIENTS AND METHODS: From 07/2003 to 01/2005, 21 patients/39 tumors were treated with 5 x 7 Gy (n = 21; total dose 35 Gy) or 5 x 8 Gy (n = 18; total dose 40 Gy). There were three cases of primary lung cancer, the remainder were metastases. Median gross tumor volume (GTV) and planning target volume (PTV) were 2.89 cm(3) (range, 0.15-67.94 cm(3)) and 25.75 cm(3) (range, 7.18-124.04 cm(3)), respectively. RESULTS: Rates of complete remission, partial remission, no change, and progressive disease were 51%, 33%, 3%, and 13%, respectively. No grade 4 toxicity occurred, nearly all patients had grade 1 initially. One grade 3 toxicity, i.e., dyspnea, was documented for a period of 6 months after therapy. Radiosurgery quality assurance guidelines could be met. CONCLUSION: hfSRT of primary and secondary lung tumors using a schedule of five fractions at 7-8 Gy each was well tolerated. Further dose escalation is planned.

Adenocarcinoma↗

PubMed2005

Expression of bone morphogenic protein 2/4, transforming growth factor-beta1, and bone matrix protein expression in healing area between vascular tibia grafts and irradiated bone-experimental model of osteonecrosis.

PURPOSE: For the surgical treatment of osteoradionecrosis after multimodal therapy of head-and-neck cancers, free vascular bone grafts are used to reconstruct osseous structures in the previously irradiated graft bed. Reduced, or even absent osseous healing in the transition area between the vascular graft and the irradiated graft bed represents a clinical problem. Inflammatory changes and fibrosis lead to delayed healing, triggered by bone morphogentic protein 2/4 (BMP2/4) and transforming growth factor (TGF)-beta(1). Given the well-known fibrosis-inducing activity of TGF-beta(1), an osteoinductive effect has been reported for BMP2/4. However, the influence of irradiation (RT) on this cytokine expression remains elusive. Therefore, the aim of the present in vivo study was to analyze the expression of BMP2/4, TGF-beta(1), collagen I, and osteocalcin in the transition area between the bone graft and the graft bed after RT. METHODS AND MATERIALS: Twenty Wistar rats (male, weight 300-500 g) were used in this study. A free vascular tibia graft was removed in all rats and maintained pedicled in the groin region. Ten rats underwent RT with 5 x 10 Gy to the right tibia, the remainder served as controls. After 4 weeks, the previously removed tibia grafts were regrafted into the irradiated (Group 1) and nonirradiated (Group 2) graft beds. The interval between RT and grafting was 4 weeks. After a 4-week osseous healing period, the bone grafts were removed, and the transition area between the nonirradiated graft and the irradiated osseous graft bed was examined histomorphometrically (National Institutes of Health imaging program) and immunohistochemically (avidin-biotin-peroxidase complex) for the expression of BMP2/4, TGF-beta(1), collagen I, and osteocalcin. RESULTS: Absent or incomplete osseous healing of the graft was found in 9 of 10 rats after RT with 50 Gy and in 1 of 10 of the rats with nonirradiated osseous grafts. Histomorphometrically, the proportion of osseous healing in the transition area was 17% in Group 1 and 48% in Group 2 (p = 0.001). Compared with the nonirradiated rats, reduced enchondral and perichondral ossification was found in the healing area after RT, with a reduction of BMP2/4 and osteocalcin expression. TGF-beta(1) and collagen I expression in the transition area to the irradiated osseous graft bed was significantly increased compared with that in the nonirradiated osseous graft bed. CONCLUSION: After RT, osseous healing of vascular bone grafts is significantly reduced and may be a result of radiation-induced inhibition of BMP2/4 and osteocalcin expression. In addition, induction of TGF-beta(1) and collagen I expression occurs. Because the effects of the TGF-beta superfamily are manifold and partially unknown, additional research directions could be in the exogenous application of BMP2/4 and inhibition of TGF-beta(1) by antibody treatment to search for appropriate therapeutic approaches for improving osseous healing in the irradiated graft bed.

Animals↗

PubMed2005

Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 Prospective Randomized Trial.

PURPOSE: To report the results and corresponding acute and late reactions of a prospective, randomized, clinical study in locally advanced head and neck cancer comparing concurrent fluorouracil (FU) and mitomycin (MMC) chemotherapy and hyperfractionated accelerated radiation therapy (C-HART; 70.6 Gy) to hyperfractionated accelerated radiation therapy alone (HART; 77.6 Gy). PATIENTS AND METHODS: Three hundred eighty-four stage III (6%) and IV (94%) oropharyngeal (59.4%), hypopharyngeal (32.3%), and oral cavity (8.3%) cancer patients were randomly assigned to receive either 30 Gy (2 Gy every day) followed by 1.4 Gy bid to a total of 70.6 Gy concurrently with FU (600 mg/m(2), 120 hours continuous infusion) days 1 through 5 and MMC (10 mg/m(2)) on days 5 and 36 (C-HART) or 14 Gy (2 Gy every day) followed by 1.4 Gy bid to a total dose of 77.6 Gy (HART). The data were analyzed on an intent-to-treat basis. RESULTS: At 5 years, the locoregional control and overall survival rates were 49.9% and 28.6% for C-HART versus 37.4% and 23.7% for HART, respectively (P = .001 and P = .023, respectively). Progression-free and freedom from metastases rates were 29.3% and 51.9% for C-HART versus 26.6% and 54.7% for HART, respectively (P = .009 and P = .575, respectively). For C-HART, maximum acute reactions of mucositis, moist desquamation, and erythema were lower than with HART, whereas no differences in late reactions and overall rates of secondary neoplasms were observed. CONCLUSION: C-HART (70.6 Gy) is superior to dose-escalated HART (77.6 Gy) with comparable or less acute reactions and equivalent late reactions, indicating an improvement of the therapeutic ratio.

Actuarial Analysis↗

PubMed2005

Radiosurgery of small skull-base lesions. No advantage for intensity-modulated stereotactic radiosurgery versus conformal arc technique.

BACKGROUND AND PURPOSE: Intensity-modulated stereotactic radiotherapy (IMSRT) has shown the ability to conform the dose to concavities and to better avoid critical organs for large tumors. Given the availability of an electronically driven micro-multileaf collimator, both intensity-modulated stereotactic radiosurgery (IMSRS) and dynamic conformal arc (DCA) technique (DCA) can be performed at the Novalis Shaped Beam Surgery Center, University of Erlangen-Nuremberg, Germany, since 12/2002. This study evaluates both techniques in small skull-base tumors treated with radiosurgery. MATERIAL AND METHODS: Between 12/2002 and 04/2004, a total of 109 radiosurgical procedures were performed in 77 patients, equally distributed between patients with acoustic neuroma (AN), pituitary adenoma (PA) and meningeoma (M). Six index patients (n = 2 AN, n = 1 PA, n = 3 M) routinely planned for dynamic arc stereotactic radiosurgery were replanned using the IMSRS approach (BrainScan, BrainLAB, Heimstetten, Germany). The RTOG radiosurgery quality assurance guidelines, isodose volumes, doses to organs at risk (OAR), and dose delivery criteria were compared. RESULTS: DCA was superior to IMSRS for homogeneity and coverage. IMSRS could keep the high-dose-irradiated volumes (90% isodose volume) lower than DCA in the PA and AN with very small volumes, but all other lower dose volumes were larger for IMSRS. Dose maxima to OAR were higher for IMSRS. Treatment delivery time for IMSRS would clearly exceed treatment time for DCA by a factor of 2-3. The integral absorbed dose to the brain was much higher in the IMSRS than in the DCA approach (factor 2-3). CONCLUSION: RTOG radiosurgery guidelines were best met by the DCA rather than IMSRS approach for the treatment of small skull-base lesions. The IMSRS approach will increase the time for planning, dose delivery and integral dose to the brain. Thus, IMSRT techniques are recommended for fractionated stereotactic radiotherapy to larger volumes rather than for radiosurgery in small skull-base lesions.

Adenoma↗

PubMed2005

Restricted-expressed proliferation-associated protein (Repp86) expression in squamous cell carcinoma of the oral cavity.

PURPOSE: To determine the expression of repp86 (restricted-expressed protein of 86 kDa theoretical molecular mass), a proliferation- associated protein expressed in S-, G(2)- and M-phases of the cell cycle, in samples of normal mucosa as well as squamous cell carcinoma of the oral cavity (OSCC). PATIENTS AND METHODS: The repp86 labeling index (LI) was determined imunohistochemically in ten samples of normal oral mucosa and 59 samples of OSCC. Repp86 LI was correlated with tumor stage, histopathologic grading, and the expression of Ki-67 and topoisomerase IIalpha. RESULTS: Repp86 was detectable in all tissues analyzed. The mean LI was 4.7% for normal mucosa and 18.4% for squamous cell carcinoma (p < 0.0001). Repp86 expression was not related to tumor size, lymph node invasion, or histopathologic grading but was positively correlated with Ki-67 index (r = 0.48; p < 0.01) as well as with topoisomerase IIalpha (r = 0.39; p < 0.01). Ki-67 and topoisomerase IIalpha levels were also significantly correlated with each other (r = 0.34; p < 0.05). CONCLUSION: These results indicate that repp86 expression can be an additional proliferation marker among Ki-67 and topoisomerase IIalpha in OSCC. Further research will be directed at the evaluation of the prognostic value of repp86 expression in OSCC as well as in leukoplakia and early-stage OSCC.

Adult↗

PubMed2005

Cytogenetic instability in young patients with multiple primary cancers.

Patients younger than 45 years with multiple cancers and a family history of cancer were identified and examined for cytogenetic instability. The cohort included 50 individuals: 19 patients suffering from at least 2 independent cancers, 11 healthy control individuals, a positive control group of 5 highly radiosensitive patients (>grade 3, RTOG), and a tumor control group of 15 patients with a single tumor. Peripheral blood lymphocytes were irradiated in vitro (0.7 Gy, 2.0 Gy). Metaphase chromosomes 1, 2, and 4 were labeled by means of 3-color fluorescence in situ hybridization. Chromosomal aberrations (breaks per metaphase [B/M], complex chromosomal rearrangements [CCR/M]) were analyzed. Very high levels of chromosomal aberrations were detected in a "core group" of 5 patients. These patients displayed much higher rates of B/M and CCR/M than controls. Ten patients had moderately elevated chromosomal aberrations and 4 patients were indistinguishable from controls. We conclude that a significant proportion of young patients with multiple tumors and a family background of cancer display cytogenetic instability.

Adult↗

PubMed2005

Ewing sarcoma of the mandible in a child: interdisciplinary treatment concepts and surgical reconstruction.

Ewing's sarcoma is the second most common primary bone malignancy in childhood and adolescence. We present a standardized interdisciplinary treatment protocol according to the EURO-E.W.I.N.G. 99 study, applied in the treatment of a 7-year-old patient with localized Ewing's sarcoma of the left mandible. After six blocks of VIDE (vincristine/ifosfamide/doxorubicin/etoposide) chemotherapy and stem cells rescue, intensity modulated external radiation with 48.6 Gy and subsequent high dose therapy with busulphan-melphalan were administered. Tumor resection and immediate bony reconstruction was performed using a microvascular fibula graft 10 weeks after radiation. Because of the effective neoadjuvant treatment, no extensive soft tissue resection was necessary. Healing of the osteosynthesis was uneventful. No local or systemic recurrence and no signs of significant facial deformity were found after 12 month follow-up. The presented case underlines the requirement for multidisciplinary protocols involving radiologists, pathologists, oncologists, radiation oncologists, and surgeons for accurate diagnosis and appropriate therapy. To preserve cosmetics and function within the craniofacial area after tumor resection in children, microvascular reconstructive procedures can be successfully performed with a vascularized fibular graft.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Impact of various parameters in detecting chromosomal aberrations by FISH to describe radiosensitivity.

BACKGROUND AND PURPOSE: Analysis of radiation-induced chromosomal aberrations is regarded as the "gold standard" for classifying individual radiosensitivity. A variety of different parameters can be used. The crucial question, however, is to explore which parameter is suited best to describe the differences between patients with increased radiosensitivity and healthy individuals. PATIENTS AND METHODS: In this study, five patients with severe radiation-induced late effects of at least grade 3, classified according to the Radiation Therapy Oncology Group (RTOG), and eleven healthy individuals were examined retrospectively. Peripheral blood lymphocytes were irradiated in vitro with 0.7 Gy and 2.0 Gy prior to cultivation and stained by means of three-color fluorescence in situ hybridization (FISH). The detailed analysis was focused on the number of breaks per metaphase, on breaks from complex chromosomal rearrangements per metaphase, as well as on the percentage of translocations, dicentric chromosomes, breaks, and excess acentric fragments-each in comparison with the total number of mitoses analyzed. RESULTS: Using the number of breaks from complex chromosomal rearrangements after 2.0 Gy, radiosensitive patients as endpoint were clearly to be distinguished (p = 0.001) from healthy individuals. Translocations (p = 0.001) as well as breaks per metaphase (p = 0.002) were also suitable indicators for detecting differences between patients and healthy individuals. The parameters "percentage of dicentric chromosomes", "breaks", and "excess acentric fragments" in comparison to the total number of mitoses analyzed could neither serve as meaningful nor as significant criteria, since they showed a strong interindividual variability. CONCLUSION: To detect a difference in chromosomal aberrations between healthy and radiosensitive individuals, the parameters "frequency of breaks per metaphase", "complex chromosomal rearrangements", and "translocations" are most suitable.

Adult↗

PubMed2004

Phase II trial of hyperfractionated accelerated split-course radiochemotherapy with 5-FU and Cis-DDP in advanced head and neck cancer: results and toxicity.

BACKGROUND: . Simultaneous radiochemotherapy resulted in a significant benefit improving both local control and overall survival in advanced head and neck cancer. In this phase II study the efficacy and toxicity of a hyperfractionated accelerated split course radiotherapy with simultaneous application of 5-FU and cisplatin were evaluated in patients with locally advanced tumors of the oral cavity, oro- and hypopharynx. PATIENTS AND METHODS: . Between 1991 and 2002 the study recruited 45 patients. 41 (92%) presented with stage IV, 2 (4%) with stage II and III tumors, respectively. Radiation was delivered twice daily by a single dose of 1.5 Gy to a median total dose of 72 Gy with a 1 week break scheduled at 30 Gy. Chemotherapy consisting of 5-FU (800 mg/m(2)/d i.v.) and cisplatin (20 mg/m(2)/d i.v. bolus) was administered during the 1st and 5th treatment week. RESULTS: . Overall survival, cause-specific survival, locoregional tumor-free survival and distant metastasis-free survival were 53%, 65%, 77% and 73%, respectively, at 3 years. Mean follow-up was 21 months. Neutropenia was the only grade-4 toxicity that occurred in 2 patients. CONCLUSION: . This regimen is effective and safe, however, distant relapses clearly exceed local failure rates. Future studies have to contemplate the implementation of new chemotherapeutic agents and the feasibility and efficacy of maintenance chemotherapy.

Adult↗

PubMed2004

Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1)-treatment in irradiated rat tissue.

BACKGROUND AND PURPOSE: Wound healing disorders and the development of fibrosis following surgery in preirradiated tissue are clinically well characterised and may even become more pronounced with increasing use of neoadjuvant radiochemotherapy. The cytokine transforming growth factor beta 1 TGFbeta1 has a key role either in the wound healing process or induction of fibrosis. Following activation of the TGFbeta receptors, intracellular signal transduction is mediated by a variety of Smad proteins. Smad-3 acts as an activator of signal transduction, whereas Smad-7 has an inhibitory effect. This study evaluated the biological effect of neutralizing TGFbeta1 antibodies, the relationship between TGFbeta1 and Smad-3/7 expression and changes of collagen synthesis, following inhibition of TGFbeta1 activity in irradiated rat tissue. PATIENTS AND METHODS: A total of 45 Wistar rats (male, weight 300-450 g) were used. A free myocutaneous gracilis flap was transplanted in all rats and animals were allocated into 3 groups as follows: Group 1 (n = 15 rats) treated with surgery alone (TX); Group 2 (n = 15 rats) preoperative radiotherapy (RT) followed by TX; Group 3 (n = 15 rats) RT+TX+anti-TGFbeta1-treatment. The interval between end of radiotherapy and grafting was 10 days. For anti-TGFbeta1 treatment, 1 microg anti-TGFbeta1/500 microl PBS were locally applied s.c. intraoperatively and on day 1 to 7 after surgery. Tissue samples were collected perioperatively and on days 3, 7, 14, 28 following surgery from the transition area between the graft and the graft bed. ECM synthesis and expression of TGFbeta1, Smad-3, Smad-7, prolyl-hydroxyprolinase-beta were quantitated by immunohistochemistry (labelling indices). Changes in collagen synthesis were assessed qualitatively by polarisation microscopy of sirius red staining and collagen I immunohistochemistry. The different regulation of inhibitory Smad-7 was detected in irradiated and irradiated plus anti-TGFbeta1 treated animals by semiquantitative RT-PCR and the nucleocytoplasmic shuttling of phosphorylated Smad-3 was shown by isolation of nuclear proteins and Western blot analysis. RESULTS: Following anti-TGFbeta1 treatment, an attenuated expression of TGFbeta1, a reduction in EMC synthesis and fibrosis could be observed in irradiated tissue compared to the irradiated tissue without anti-TGFbeta1-treatment. While preoperative RT increases the expression of Smad-3/7 proteins, an upregulation of Smad-7 from day 3 until day 14 following surgery and a downregulation of Smad-3 on day 14 after surgery could be observed following anti-TGFbeta1-treatment. The samples which were irradiated alone displayed a reduced signal for Smad-7 mRNA and an induction of Smad-3 protein phosphorylation shown by nucleocytoplasmic shuttling. In contrast, the anti-TGFbeta1-treated samples showed an increase in Smad-7 mRNA and a downregulation of Smad-3 phosphorylation. Prolyl-hydroxyprolinase-beta expression and collagen I synthesis were reduced following anti-TGFbeta1-treatment. CONCLUSIONS: A reduction of Smad-3 proteins in parallel with an increase of Smad-7 may contribute to the inhibitory effect and the reduction of ECM synthesis after blocking of TGFbeta1 activity by treatment with neutralizing antibodies. This may indicate a molecular mechanism in the therapeutic intervention to reduce fibrosis, hypertrophic scar formation and chronic wound healing disorders.

Animals↗

PubMed2004

Effects of low energy protons on clonogenic survival, DSB repair and cell cycle in human glioblastoma cells and B14 fibroblasts.

BACKGROUND AND PURPOSE: The reaction of human tumor cells and mammalian normal tissue to irradiation with low energy protons and X-rays was examined. MATERIAL AND METHODS: An irradiation facility with a vertical proton beam was set up at the Tandem accelerator at the University of Erlangen. U-138MG human glioblastoma cells and B14 hamster fibroblasts were irradiated with 5.7 and 7.0 MeV protons (LET 7.27 and 6.23 keV/microm) and with 120 kV X-rays. The inactivation was measured by the colony forming assay, induction and repair of DNA double strand breaks (DSB) by constant field gel electrophoresis and cell cycle control by image cytometry. RESULTS: An obvious reduction of the shoulder of the dose effect curve was determined. This effect was more pronounced for the glioblastoma cell line. The RBE at 10% survival was measured as 1.78 +/- 0.09 for glioblastoma cells and 1.18 +/- 0.06 for B14 fibroblasts. The induction of DNA DSB in glioblastoma cells showed an RBE of 0.96 +/- 0.06, after 24h repair time an RBE of 2.63 +/- 0.07 was calculated. Protons had a larger and enduring effect on G2 arrest of cell cycle than X-rays, 72 hours after irradiation with 10 Gy an RBE of 1.57 +/- 0.05 was calculated. CONCLUSIONS: The effect of higher LET irradiation was more distinct for tumor cells than for normal tissue. Both cell lines showed a higher RBE for cell survival than the value of 1.1 normally used for proton therapy. Repair capacity of DNA DSB was reduced following low energy proton irradiation and G2 arrest was induced to a larger degree. Further experiments are needed to elucidate if this could be a reason for lower cell survival.

Cell Cycle↗

PubMed2004

Anti-TGFbeta1 antibody for modulation of expression of endogenous transforming growth factor beta 1 to prevent fibrosis after plastic surgery in rats.

The cytokine transforming growth factor beta 1 (TGFbeta1) substantially influences synthesis of extracellular matrix, fibrosis, and neoangiogenesis during wound healing in a dose dependent manner. We carried out experiments in rats to measure the degree of reduction of disorders of wound healing and fibrosis produced by inhibition of endogenous TGFbeta1 by polyclonal antibodies (poAB). A free myocutaneous gracilis flap was transplanted from the groin to the neck region in 30 Wistar rats (300-450 g body weight). In 15 animals intraoperatively and daily from days 3 to 7 postoperatively, 1 microg anti-TGFbeta1 poAB in 500 microl of phosphate buffered saline (PBS) were injected into the neck region. Fifteen animals served as controls. On postoperative days 3, 4, 5, 7, 14, and 28 the expression of endogenous TGFbeta1 in cytoplasm was analysed by immunohistochemistry (ABC-POX; AEC), in situ hybridisation of TGFbeta1-mRNA, and Sirus Red staining of collagen matrix; it was quantified using labelling indices. Neutralisation of the TGFbeta1 activity by specific poAB resulted in inhibition of the cytoplasmatic expression compared with untreated animals. In the transition area between grafted tissue and graft bed, a significant reduction of TGFbeta1 expression (mean (S.D.) 34.7 (6.5)) was found from day 5 in the group treated with anti-TGFbeta1 poAB compared with the control group (mean (S.D.) 48.1 (6.6)) (P <0.03). Up to day 14 the endogenous expression of TGFbeta1 (mean (S.D.) 30.0 (2.8)) was reduced after the application of TGFbeta1 poAB compared with the control group (mean (S.D.) 44.0 (12.3)). Sirus Red staining indicated a more complex packed structure and generally more prominent collagen types I-IV fibres in untreated animals than in animals that were given anti-TGFbeta1 poAB. Expression of TGFbeta-mRNA by in situ hybridisation was reduced in fibroblasts in animals that were given anti-TGFbeta1 poAB. The results indicate that anti-TGFbeta1 might improve the healing of free flaps in the graft beds of patients who are prone to excessive fibrosis.

Anastomosis, Surgical↗

PubMed2003

Fatal toxicity following radio- and chemotherapy of medulloblastoma in a child with unrecognized Nijmegen breakage syndrome.

BACKGROUND: In large-scale pediatric chemo- and radiotherapy trials a proportion of patients as high as 10-15% is usually reported as having severe treatment related toxicity occasionally resulting in toxic death. Little is known on the underlying predisposition of the individual child. Several hereditary disorders including immunodeficiency (ID) syndromes or repair disorders, Ataxia Telangiectasia (AT), and Nijmegen breakage syndrome (NBS) were associated with an elevated risk for severe treatment related toxicity. PROCEDURE: This report involves the case of a 7-year-old boy with medulloblastoma who suffered from remarkably severe side effects during and after postoperative radio- and chemotherapy. Several months following craniospinal radiation with a total dose of 36 Gy, late normal tissue side effects were observed within the treated volume. Eighteen months after initiation of treatment the patient died due to protracted cardiopulmonary failure. RESULTS: To quantify the intrinsic radiation sensitivity, lymphoblastoid cells were used to examine chromosomal aberrations by fluorescence in situ hybridization detecting between two to ninefold higher chromosomal breakage rates in comparison to cells of average cancer patients. Skin fibroblasts showed in the clonogenic survival assays a twofold increased sensitivity. Western blotting demonstrated a typical lack of Nbs1. PCR-SSCP analysis followed by direct sequencing of positive samples revealed a homozygous truncating mutation of the NBS1 gene (657del5). CONCLUSIONS: This case highlights that severe treatment related complications in pediatric cancer patients may be the result of increased intrinsic radio- and chemosensitivity due to NBS, AT, and other ID syndromes. It is suggested to exclude such conditions in all patients with anthropometric parameters below the 3rd centile and other signs suggestive for repair disorders or ID syndromes.

Abnormalities, Multiple↗

PubMed2003

[Evaluation of quality of life of patients with oral squamous cell carcinoma. Comparison of two treatment protocols in a prospective study-first results].

BACKGROUND: The treatment of oral cancer has a strong impact on the quality of life. In recent years different therapeutic concepts have been developed, these include preoperative simultaneous "neoadjuvant" radiochemotherapy (RCT) and one-stage surgery with tumor ablation and reconstruction. When considering long-term survival, there is substantial evidence that evidenced modality treatment including neoadjuvant RCT is superior to the primary surgical approach with postoperative radiation. PATIENTS AND METHODS: This longitudinal study prospectively evaluates quality of life in two groups consisting of 53 neoadjuvant and primarily surgically treated patients with oral cancer, using the quality-of-life core questionnaire (QLQ-C30) and the head and neck cancer module (H and N 35) of the European Organization for Research and Treatment of Cancer (EORTC). RESULTS: Postoperatively both groups showed a marked reduction in quality of life. 1 year later quality of life had equalized between the two groups to such an extent that the quality of life scores had almost reached the preoperative level. Both groups showed specific impairments in the symptom scales. In the neoadjuvant therapy group however, global health and the emotional status were reduced to a greater degree than in the other group. CONCLUSION: Temporary limitations in quality of life can be expected after tumor treatment of oral cancer as presented here. Neoadjuvant therapy concept is more aggressive and might result in a longer disease-free survival, but the restriction in quality of life is more severe. Primary goal is the eradication of the tumor. Nevertheless preservation or reconstruction of a maximum of function is essential for a high level of quality of life.

Adult↗

PubMed2002

Transforming growth factor beta1 and beta2 (TGFbeta2 / TGFbeta2) profile changes in previously irradiated free flap beds.

BACKGROUND: Following preoperative radiotherapy prior to ablative surgery of squamous epithelial carcinomas of the head and neck region, inflammatory changes and the expression of cytokines involved in wound healing could be observed. These processes lead to a delayed healing of free flaps in the graft bed. The aim of the present experimental study was to analyze the expression profiles of transforming growth factor (activated TGFbeta(1), TGFbeta(2)) and latency-associated peptide (LAP) in the irradiated graft beds and the transition area between grafts and irradiated graft beds. METHODS: In Wistar rats (male, weight 300-500 g) undergoing preoperative irradiation of the neck region with 30 Gy (30 animals) and non-irradiated rats (42 animals), a free myocutaneous gracilis flap taken from the groin was transplanted to the irradiated region of the neck. The interval between irradiation and transplantation was 4 weeks. In each group on postoperative days 3, 7, 14, and 28, cytoplasmatic expression of activated TGFbeta(1), LAP, and TGFbeta(2) was analyzed by immunohistochemistry to determine labeling indices (positive stained cells/total cells). RESULTS: The success rate in graft beds irradiated with 30 Gy was 76% and in non-irradiated graft beds was 86% (p =.02). In the graft beds irradiated with 30 Gy, there was an increased expression of activated TGFbeta(1) (range, 19.0-33.0), LAP (14.0-21.0), and TGFbeta(2) (3.0-19.5) together with obvious fibrosis. The expression was located in perivascular fibroblasts and endothelial cells. In contrast, a lower expression of activated TGFbeta(1) (11.0-21.0), LAP (1.0-8.0), and TGFbeta(2) (0.0-0.9) (p =.006) was observed in non-irradiated graft beds. In the transition area between graft and irradiated graft bed, high expression of activated TGFbeta(1) (37.0), LAP (19.0), and TGFbeta(2) (16.7-33.4) was observed on the 3rd postoperative day in contrast to the transition area in non-irradiated graft beds (activated TGFbeta(1) 26.0, LAP 7.0, and TGFbeta(2) 0.l). CONCLUSION: The radiation induced, increased de novo synthesis of LAP, activation of TGFbeta(1), and increased expression of TGFbeta(2) may represent at least one mechanism for the increased fibrosis and wound healing disorders seen in irradiated tissues and in the transition area to graft tissue. The expression of TGFbeta(1,) LAP, and TGFbeta(2) might possess prognostic value with regard to wound healing and fibrosis in previously irradiated graft beds.

Animals↗