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Peter Sminia

Publications and source records attributed to Peter Sminia.

18 recordsLinked to original sources
PubMed2006

Angiogenesis-independent tumor growth mediated by stem-like cancer cells.

In this work, highly infiltrative brain tumors with a stem-like phenotype were established by xenotransplantation of human brain tumors in immunodeficient nude rats. These tumors coopted the host vasculature and presented as an aggressive disease without signs of angiogenesis. The malignant cells expressed neural stem cell markers, showed a migratory behavior similar to normal human neural stem cells, and gave rise to tumors in vivo after regrafting. Serial passages in animals gradually transformed the tumors into an angiogenesis-dependent phenotype. This process was characterized by a reduction in stem cells markers. Gene expression profiling combined with high throughput immunoblotting analyses of the angiogenic and nonangiogenic tumors identified distinct signaling networks in the two phenotypes. Furthermore, proinvasive genes were up-regulated and angiogenesis signaling genes were down-regulated in the stem-like tumors. In contrast, proinvasive genes were down-regulated in the angiogenesis-dependent tumors derived from the stem-like tumors. The described angiogenesis-independent tumor growth and the uncoupling of invasion and angiogenesis, represented by the stem-like cancer cells and the cells derived from them, respectively, point at two completely independent mechanisms that drive tumor progression. This article underlines the need for developing therapies that specifically target the stem-like cell pools in tumors.

Animals↗
PubMed2006

Radical radiotherapy for invasive bladder cancer: What dose and fractionation schedule to choose?

PURPOSE: To establish the alpha/beta ratio of bladder cancer from different radiotherapy schedules reported in the literature and provide guidelines for the design of new treatment schemes. METHODS AND MATERIALS: Ten external beam radiotherapy (EBRT) and five brachytherapy schedules were selected. The biologically effective dose (BED) of each schedule was calculated. Logistic modeling was used to describe the relationship between 3-year local control (LC3y) and BED. RESULTS: The estimated alpha/beta ratio was 13 Gy (95% confidence interval [CI], 2.5-69 Gy) for EBRT and 24 Gy (95% CI, 1.3-460 Gy) for EBRT and brachytherapy combined. There is evidence for an overall dose-response relationship. After an increase in total dose of 10 Gy, the odds of LC3y increase by a factor of 1.44 (95% CI, 1.23-1.70) for EBRT and 1.47 (95% CI, 1.25-1.72) for the data sets of EBRT and brachytherapy combined. CONCLUSION: With the clinical data currently available, a reliable estimation of the alpha/beta ratio for bladder cancer is not feasible. It seems reasonable to use a conventional alpha/beta ratio of 10-15 Gy. Dose escalation could significantly increase local control. There is no evidence to support short overall treatment times or large fraction sizes in radiotherapy for bladder cancer.

Brachytherapy↗
PubMed2006

Genetic profiling of a distant second glioblastoma multiforme after radiotherapy: Recurrence or second primary tumor?

OBJECT: In nearly all patients with glioblastoma multiforme (GBM) a local recurrence develops within a short period of time. In this paper the authors describe two patients in whom a second GBM developed after a relatively long time interval at a site remote from the primary tumor. The genetic profiles of the tumors were compared to discriminate between distant recurrence and a second primary tumor. METHODS: Both patients harboring a supratentorial GBM were treated with surgery and local high-dose radiotherapy. Local control of the disease at the primary tumor site was achieved. Within 2 years, a second GBM developed in both patients, not only outside the previously irradiated target areas but infratentorially in one patient and in the opposite hemisphere in the other. The tumors were examined for the presence of several genetic alterations that are frequently found in GBMs--a loss of heterozygosity at chromosome regions 1p36, 10pl5, 19q13, and 22q13, and at the CDKN2A, PTEN, DMBT1, and TP53 gene regions; a TP53 mutation; and EGFR amplification. In the first patient, genetic profiling revealed that the primary tumor had an allelic imbalance for markers in several chromosome regions for which the second tumor displayed a complete loss. In the second patient, genetic profiling demonstrated the presence of genetic changes in the second tumor that were identical with and additional to those found in the primary tumor. CONCLUSIONS: Based on the similarities between the genetic profiles of the primary and the second tumors in these patients, the authors decided that in each case the second distant GBM was a distant recurrence rather than a second independent primary tumor.

Adult↗
PubMed2006

Combined modality therapy of gemcitabine and irradiation on human glioma spheroids derived from cell lines and biopsy tissue.

Multicellular tumor spheroids have been used to examine aspects of combined modality treatment since they often recreate the in vivo tumor environment much more closely than other models. The radioenhancement by gemcitabine (dFdC) on human glioma spheroids derived from cell lines (CLS) and biopsy tissue, grown as organotypic multicellular spheroids (OMS), was studied. CLS of GaMg and U87 and OMS of four glioblastoma patients were used. Radiochemosensitvity was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. Cell death (ethidium homodimer) was studied using a fluorescence cell viability assay. In CLS, combination treatment led to migration inhibition in GaMg and U87 of 85% and 62% (dFdC 46% and 52%, RT 21% and 43%) and proliferation inhibition of 83% and 85%, respectively. Following dFdC + RT in OMS (% of cases), apoptosis and p21 expression increased (50%), p53 expression increased (75%) and cell proliferation decreased (75%). Only minor morphological damage was observed. Confocal laser scanning microscopy identified an increased dead cell core after dFdC + RT (50%). In conclusion, dFdC can lead to an additively radioenhancement in CLS and individual OMS.

Antimetabolites, Antineoplastic↗
PubMed2005

Effects of irradiation and cisplatin on human glioma spheroids: inhibition of cell proliferation and cell migration.

PURPOSE: Investigation of cell migration and proliferation of human glioma cell line spheroids (CLS) and evaluation of morphology, apoptosis, and immunohistochemical expression of MIB-1, p53, and p21 of organotypic muticellular spheroids (OMS) following cisplatin (CDDP) and irradiation (RT). MATERIAL AND METHODS: Spheroids of the GaMg glioma cell line and OMS prepared from biopsy tissue of six glioblastoma patients were used. Radiochemosensitvity (5 microg/ml CDDP followed by RT) was determined using migration and proliferation assays on CLS. In OMS, histology and immunohistochemical studies of MIB-1, p53, and p21 expression were examined 24 and 48 h following treatment. RESULTS: Combination treatment led to a migration inhibition of 38% (CDDP 13%; RT 27%) and specific growth delay of 2.6 (CDDP 1.3; RT 2.1) in CLS. Cell cycle analysis after combination treatment showed an accumulation of cells in the G2/M phase. In OMS, apoptosis increased, cell proliferation decreased, and p53/p21 expression increased more pronounced following CDDP+RT. No morphological damage was observed. CONCLUSION: CDDP can lead to enhancement of the RT effect in spheroids of both human glioma cell line spheroids and biopsy spheroids from glioblastoma specimens. The exerted effect is additive rather than synergistic.

Antineoplastic Agents↗
PubMed2005

Expression of cyclooxygenase-2 and epidermal growth factor receptor in primary and recurrent glioblastoma multiforme.

PURPOSE: To investigate the pattern and level of cyclooxygenase-2 (COX-2) expression in a series of high grade primary and recurrent glioblastoma multiforme (GBM) and correlation with time to recurrence and patients' survival following therapy. The relationship between COX-2 and epidermal growth factor receptor (EGFR) immunoreactivities was evaluated. MATERIALS AND METHODS: Specimens of 14 primary and 14 recurrent GBMs (eight pairs) following surgery and full course radiation therapy were processed for immunostaining on COX-2 and EGFR. Tumor cell positivity was semi-quantitatively scored. COX-2 scores of the primary tumor and recurrence were correlated with the time to radiological tumor progression and patients' survival. RESULTS: COX-2 positive tumor cells were disseminated throughout the tumor parenchyma. The intensity and pattern of COX-2 expression were heterogeneous, with predominant expression in areas surrounding tumor necrosis. Scoring of COX-2 positivity revealed values between 1 and 80% of the cells. Primary GBMs with COX-2 expression levels between 25% and 70% of the tumor cells showed a shorter time to radiological recurrence than GBMs with <10% COX-2 positive tumor cells (respectively, 219 +/- 50 and 382 +/- 77 days). No correlation was found between the COX-2 expression in the primary tumor and patients' survival (r (s) = -0.073) following therapy. No correlation was found either between COX-2 and EGFR immunoreactivity. CONCLUSIONS: Immunohistochemical expression of COX-2 in GBM showed large variation. Hence, determination of COX-2 expression in tumor specimen for each individual might be relevant for selection of those patients, who could benefit from adjuvant therapy with selective COX-2 inhibitors.

Adult↗
PubMed2005

Hyperbaric oxygen and radiotherapy.

BACKGROUND: Hyperbaric oxygen (HBO) therapy is the inhalation of 100% oxygen at a pressure of at least 1.5 atmospheres absolute (150 kPa). It uses oxygen as a drug by dissolving it in the plasma and delivering it to the tissues independent of hemoglobin. For a variety of organ systems, HBO is known to promote new vessel growth into areas with reduced oxygen tension due to poor vascularity, and therewith promotes wound healing and recovery of radiation-injured tissue. Furthermore, tumors may be sensitized to irradiation by raising intratumoral oxygen tensions. METHOD: A network of hyperbaric facilities exists in Europe, and a number of clinical studies are ongoing. The intergovernmental framework COST B14 action "Hyperbaric Oxygen Therapy" started in 1999. The main goal of the Working Group Oncology is preparation and actual implementation of prospective study protocols in the field of HBO and radiation oncology in Europe. RESULTS: In this paper a short overview on HBO is given and the following randomized clinical studies are presented: a) reirradiation of recurrent squamous cell carcinoma of the head and neck after HBO sensitization; b) role of HBO in enhancing radiosensitivity on glioblastoma multiforme; c) osseointegration in irradiated patients; adjunctive HBO to prevent implant failures; d) the role of HBO in the treatment of late irradiation sequelae in the pelvic region. The two radiosensitization protocols (a, b) allow a time interval between HBO and subsequent irradiation of 10-20 min. CONCLUSION: Recruitment of centers and patients is being strongly encouraged, detailed information is given on www.oxynet.org.

Combined Modality Therapy↗
PubMed2005

Lymphatic fistulas: obliteration by low-dose radiotherapy.

BACKGROUND: Lymphatic drainage from the surgical wound is an uncommon but challenging complication of surgical intervention. Protracted lymphorrhea contributes to morbidity, favors infections and results in a prolonged hospital stay. Treatment options include surgical ligation and, more conservatively, leg elevation, continuous local pressure, subatmospheric pressure dressings, and low-dose radiotherapy. This study examines the efficacy of low-dose radiotherapy. PATIENTS AND METHODS: 17 patients (19 fistulas) with lymphorrhea following vena saphena harvesting (n = 7), femoropopliteal bypass (n = 3), varicose vein surgery (n = 2), hip arthroplasty (n = 3; five fistulas), shunt surgery (n = 1), and piercing (n = 1) were referred for external radiotherapy. Depending on the depth of the fistula, orthovoltage (n = 12), electrons (4-11 MeV; n = 2) or photons (8 MV; n = 3) were used. Fractions between 0.3 Gy and 2 Gy were applied; the individual total dose depended on the success of the radiotherapy, i. e., the obliteration of the lymph fistula, and varied from 1 to 12 Gy. RESULTS: In 13 out of 17 patients complete obliteration of the fistula was achieved. Interestingly, this was achieved in nine of the ten patients irradiated with total doses of </=3 Gy and with fraction sizes ranging from 0.3 to 0.5 Gy. In one patient with hip arthroplasty, only two out of three fistulas disappeared after 12 Gy and in a further three cases no distinct benefit was observed after 2.4 Gy, 8 Gy, and 10.5 Gy, respectively. No treatment-related side effects occurred. CONCLUSION: Radiotherapy represents an efficacious and economical treatment option in cases of persistent lymphorrhea and is able to reduce the risk of secondary infection, to decrease the duration of hospitalization, and to reduce overall costs for the individual patient. Daily scoring of treatment efficacy is recommended, because radiotherapy can be terminated as soon as lymphorrhea has stopped. Very low total doses with 0.3-0.5 Gy fraction size are recommended up to a maximum of 10-12 Gy in nonresponders.

Aged↗
PubMed2005

Oncolytic virotherapy of meningiomas in vitro with replication-competent adenovirus.

OBJECTIVE: To evaluate the efficacy of the conditionally replicating adenovirus (Ad) Ad.d24 for oncolysis of benign and malignant meningiomas. METHODS: Primary meningioma cells and organotypic spheroids were cultured from tumor biopsies of 12 consecutive unselected patients. Four different Ads were constructed and tested on meningioma cells and spheroids: a replication-deficient Ad encoding the luciferase marker gene (Ad.Luc), a replication-competent Ad with complete E1 region (Ad.E1+), a replication-competent Ad encoding the luciferase gene in the E3 region (Ad.E1Luc), and a conditionally replicating Ad with an E1ACR2 deletion (Ad.d24). Replication of the latter is restricted to cells with a defective retinoblastoma pathway, whereas Ad.E1+ and Ad.E1Luc can replicate in all human cells like a wild-type Ad. Their oncolytic activity was compared in primary meningioma cells and spheroids by use of viability and outgrowth assays. RESULTS: Adenoviral penetration into organotypic meningioma spheroids was detected with the replication-competent Ad.E1Luc, whereas infection with the replication-deficient Ad.Luc was limited to the outer layer of the spheroid. Replication of the Ads and oncolysis was demonstrated in primary cell cultures of meningioma cells at high dose, i.e., greater than 50 plaque-forming units per cell. At a lower dose of 5 plaque-forming units per cell, Ad.d24 kills meningioma cells more efficiently than Ad.E1+. Infection of organotypic meningioma spheroids with Ad.d24 resulted in decreased viability and suppression of outgrowth as compared with untreated control spheroids. CONCLUSION: Infection of meningioma cells and spheroids with replication-competent Ads results in efficient oncolysis. The Ad modified to replicate selectively in retinoblast-mutant cells, Ad.d24, seemed to be an efficient oncolytic agent in benign, atypical, and malignant meningiomas.

Adenoviridae↗
PubMed2004

Low-dose-rate brachytherapy is superior to high-dose-rate brachytherapy for bladder cancer.

PURPOSE: To determine the efficacy and safety of a high-dose-rate (HDR) brachytherapy schedule in the treatment of bladder cancer and to investigate the impact of different values of repair half-times and alpha/beta ratios on the design of the HDR schedule. METHODS AND MATERIALS: Between 2000 and 2002, 40 patients with T1G3 and T2 bladder carcinoma were treated with 30 Gy external beam radiotherapy followed by interstitial HDR brachytherapy to a total dose of 32 Gy in 10 sessions of 3.2-Gy fractions in two fractions daily with a 6-h interfraction interval. The local control rate and toxicity were compared with a historical group of 108 patients treated with 30 Gy external beam radiotherapy followed by 40-Gy interstitial low-dose-rate (LDR) brachytherapy. The HDR schedule was designed to be biologically equivalent to the previously used LDR schedule with the linear-quadratic model, including incomplete mono-exponential repair. RESULTS: The local control rate at 2 years was 72% for HDR vs. 88% for LDR brachytherapy (p = 0.04). In the HDR group, 5 of 30 evaluable patients encountered serious late toxicity: 4 patients developed a contracted bladder with inadequate capacity (<100 mL), and 1 patient required cystectomy because of a painful ulcer at the implant site. In the LDR group, only 2 of 84 assessable patients developed serious late toxicity. One patient developed a persisting vesicocutaneous fistula and the other a urethral stricture due to fibrosis. The difference in observed late toxicity for HDR vs. LDR was statistically significant (p = 0.005). The increased late toxicity with the HDR schedule compared with the LDR schedule suggests a short repair half-time of 0.5-1 h for late-responding normal bladder tissue. CONCLUSION: Local control of HDR brachytherapy for bladder cancer was disappointing and late toxicity unexpectedly high. The increase in late toxicity suggested a short repair half-time of 0.5-1 h for late-responding normal bladder tissue, which would not support HDR brachytherapy in the treatment of bladder cancer. The analysis demonstrated that the calculation of equivalent HDR schedules on the basis of the LDR schedules used in clinical practice might be hazardous.

Aged↗
PubMed2004

Effect of single dose irradiation on human glioblastoma spheroids in vitro.

Investigation of the predictive value of a radiosurgery-relevant treatment of glioblastoma spheroids. Organotypic multicellular spheroids were cultured and irradiated (20 Gy). Morphology, apoptosis and immunohistochemical expression of p53, p21, MIB-1, TGF-beta and VEGF were examined 4 h, 24 h, 7 days, and 14 days following treatment. Cell proliferation decreased, while apoptosis was increased. No morphological damage was observed. p53 expression was significantly increased after 4 h. TGF-beta and VEGF expression were only slightly altered. Particularly early changes in proliferation and apoptosis can be observed in spheroids. Individual response differences suggest spheroids of human gliomas to be useful for monitoring radiosurgery effects.

Biomarkers, Tumor↗
PubMed2003

Prophylactic hyperbaric oxygen treatment and rat spinal cord re-irradiation.

Normal tissue injury may lead to severe, life threatening, late side effects after therapeutic use of irradiation. Neurological complications caused by radiation of the spinal cord are ascribed to progressive, irreversible damage to the vasculature. Hyperbaric oxygen (HBO) is known to induce angiogenesis in irradiated tissue and has been proven to reduce late radiation injury in several normal tissues when applied during the latent period before complications become manifest. In the present study: (1). the prophylactic potential of HBO; (2). optimal timing of HBO therapy after spinal cord irradiation, i.e. during the latent period; and (3). effect of HBO on the re-irradiation tolerance of the spinal cord were investigated. The rat cervical spinal cord was locally X-ray irradiated with ten fractions of 6.5 Gy in 11 days. Five treatment groups (n=10) included: irradiation alone and irradiation followed by 30 HBO treatments (100% oxygen at 240 kPa for 90 min) during latency, with HBO starting either immediately, 5, 10 or 15 weeks after the primary irradiation course. One year after the primary treatment, the same spinal cord volume was re-irradiated with 20 Gy single dose. During life span, the animals were observed on the incidence of myelitis and the duration of the latent period. The actuarial analysis revealed no significant difference in neurological complications free survival between the irradiation alone and the irradiation+HBO treatment groups. A tendency towards radiosensitization was found in the group in which the primary irradiation course was immediately followed by the HBO treatment course. The data show that HBO applied during the latent period of progressively developing irradiation damage to the spinal cord does not increase the re-irradiation tolerance of this tissue.

Animals↗
PubMed2002

The optimal fraction size in high-dose-rate brachytherapy: dependency on tissue repair kinetics and low-dose rate.

BACKGROUND AND PURPOSE: Indications of the existence of long repair half-times on the order of 2-4 h for late-responding human normal tissues have been obtained from continuous hyperfractionated accelerated radiotherapy (CHART). Recently, these data were used to explain, on the basis of the biologically effective dose (BED), the potential superiority of fractionated high-dose rate (HDR) with large fraction sizes of 5-7 Gy over continuous low-dose rate (LDR) irradiation at 0.5 Gy/h in cervical carcinoma. We investigated the optimal fraction size in HDR brachytherapy and its dependency on treatment choices (overall treatment time, number of HDR fractions, and time interval between fractions) and treatment conditions (reference low-dose rate, tissue repair characteristics). METHODS AND MATERIALS: Radiobiologic model calculations were performed using the linear-quadratic model for incomplete mono-exponential repair. An irradiation dose of 20 Gy was assumed to be applied either with HDR in 2-12 fractions or continuously with LDR for a range of dose rates. HDR and LDR treatment regimens were compared on the basis of the BED and BED ratio of normal tissue and tumor, assuming repair half-times between 1 h and 4 h. RESULTS: With the assumption that the repair half-time of normal tissue was three times longer than that of the tumor, hypofractionation in HDR relative to LDR could result in relative normal tissue sparing if the optimum fraction size is selected. By dose reduction while keeping the tumor BED constant, absolute normal tissue sparing might therefore be achieved. This optimum HDR fraction size was found to be largely dependent on the LDR dose rate. On the basis of the BED(NT/TUM) ratio of HDR over LDR, 3 x 6.7 Gy would be the optimal HDR fractionation scheme for replacement of an LDR scheme of 20 Gy in 10-30 h (dose rate 2-0.67 Gy/h), while at a lower dose rate of 0.5 Gy/h, four fractions of 5 Gy would be preferential, still assuming large differences between tumor and normal tissue repair half-times and equal overall treatment time. For the same fraction size, an even larger normal tissue sparing can be obtained by prolongation of the HDR overall treatment time. CONCLUSION: Radiobiologic model calculations presented here aim to demonstrate that hypofractionation in HDR might have its opportunities for widening the therapeutic window, but definitely has its limits. For each specific combination of the parameters, a theoretical optimal HDR fraction size with regard to relative or absolute normal tissue sparing can be estimated, but because of uncertainty in the biologic parameters, these hypofractionation schemes cannot be generalized for all HDR brachytherapy indications.

Brachytherapy↗
PubMed2002

Hyperbaric oxygen therapy for cognitive disorders after irradiation of the brain.

PURPOSE: Analysis of the feasibility and effect of hyperbaric oxygen treatment (HBO) on cognitive functioning in patients with cognitive disorders after irradiation of the brain. PATIENTS AND METHOD: Seven patients with cognitive impairment after brain irradiation, with an interval of at least 1.5 years after treatment, were treated with 30 sessions of HBO in a phase I-II study. A comprehensive neuropsychological test battery was performed before treatment, at 3 and 6 months thereafter. Patients were randomized into an immediate treatment group and a delayed treatment group. The delayed group had a second neuropsychological test at 3 months without treatment in that period and started HBO thereafter. RESULTS: All eligible patients completed the HBO treatment and the extensive neuropsychological testing. One out of seven patients had a meaningful improvement in neuropsychological functioning. At 3 months there was a small, but not significant benefit in neuropsychological performance for the group with HBO compared to the group without HBO treatment. Six out of seven patients eventually showed improvement after HBO in one to nine (median 2.5) of the 31 tests, although without statistical significance. CONCLUSION: HBO treatment was feasible and resulted in a meaningful improvement of cognitive functioning in one out of seven patients. Overall there was a small but not significant improvement.

Adolescent↗
PubMed2002

Re-irradiation of the human spinal cord.

PURPOSE: Experimental animal data give evidence of long-term recovery of the spinal cord after irradiation. By extrapolation of these data, re-irradiation regimens were designed for eight patients who required palliative radiotherapy. As a consequence of re-irradiation, their spinal cords were exposed to cumulative doses exceeding the tolerance dose. Radiobiological and clinical data are presented. PATIENTS AND METHOD: Eight patients were re-irradiated on the cervical (n = 1), thoracic (n = 5) and lumbar (n = 2) spinal cord. The time interval between the initial and re-treatment ranged from 4 months to 12.7 years (median: 2.5 years). (Re-)treatment schemes were designed and analyzed on basis of the biologically effective dose (BED) according to the linear-quadratic model. The repair capacity (alpha/beta ratio) for the cervico-thoracic and lumbar spinal cord was assumed to be 2 Gy and 4 Gy, with a BEDtolerance of 100 Gy and 84 Gy, respectively. RESULTS: The cumulative irradiation dose applied to the spinal cord varied between 125 and 172% of the BEDtolerance. During follow-up, ranging from 33 days to > 4.5 years (median: 370 days) none of the patients developed neurological complications. Seven patients died from tumor progression, and one patient is still alive. CONCLUSION: Long-term recovery of the spinal cord from radiation injury, which has been demonstrated in rodents and primates, may also occur in humans.

Bone Neoplasms↗
PubMed2002

Radiosensitivity and TP 53, EGFR amplification and LOH10 analysis of primary glioma cell cultures.

AIM: Determination of in-vitro radiosensitivity and genetic alterations of cell cultures derived from human glioma biopsy tissue and established glioma cell lines. MATERIAL AND METHODS: Fresh brain tumor specimens of six patients were processed to early passage cell cultures. In addition the cell lines D 384 and Gli 6 were used. Cell cultures were irradiated with doses from 2 to 10 Gy. Following irradiation, cell survival was determined by clonogenic assay and survival curves were generated. The surviving fractions after 2 Gy (SF2) and 4 Gy (SF4) were used as radiosensitivity parameters. Genetic analysis included determination of the mutational and loss of heterozygosity (LOH) status of TP 53 (exons 5-8), the LOH 10- and epidermal growth factor receptor gene (EGFR) amplification status. RESULTS: The SF2 and SF4 values ranged from 0.54 to 0.88 (mean: 0.70) and from 0.13 to 0.52 (mean: 0.32), respectively. Genetic alterations were found in the Gli 6 cell line and in two primary cell cultures. The genetic profile of Gli 6 showed LOH but no TP 53 mutation, complete LOH 10 and no EGFR amplification. The VU 15 cell culture showed TP 53 mutation but no LOH 10 or EGFR amplification, while VU 24 showed incomplete LOH 10, EGFR amplification and no TP 53 mutation. In the other four cell cultures and D 384 cell line no genetic alterations were diagnosed. Histopathological classification of glioblastoma multiforme and/or genetic alterations resulted in lower radiosensitivity. CONCLUSION: In this small series of early passage glioma cell cultures low radiosensitivity and alterations in cell regulatory genes were seen. Further testing of biological behavior in larger series of patient-derived material is ongoing.

Adult↗
PubMedDate not supplied

Oxygenation and response to irradiation of organotypic multicellular spheroids of human glioma.

PURPOSE: Investigation of the oxygenation status of organotypic multicellular spheroids (OMS) and their response to irradiation. MATERIALS AND METHODS: Tumour specimens of glioblastoma multiforme patients (n = 16) were initiated as OMS. Following 20 Gy gamma-irradiation, the cell migratory capacity was evaluated. Spheroid oxygenation was determined by micro-electrode pO2 measurements and pimonidazole immunostaining. Spheroids prepared from established human glioma cell lines were used as a reference. RESULTS: Irradiation inhibited spheroid outgrowth by 12 to 88% relative to the non-irradiated controls. A large interpatient variation was noticed. Oxygen measurements revealed a gradual decrease in pO2 level from the periphery to the core of the spheroids, but the pO2 values remained within an oxygenated range. However, in the cell line spheroids an intermediate layer of hypoxia surrounding the central core was observed. CONCLUSION: Cell line spheroids with a hypoxic cell fraction and well-oxygenated OMS both show high resistance to irradiation, indicating that hypoxia may not be the biological factor determining the radioresistance of glioma spheroids in vitro.

Brain Neoplasms↗