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Biomedical subjects

O Dahl

Publications and source records attributed to O Dahl.

At least 19 recordsLinked to original sources
PubMed2001

Dosimetric verification of a dedicated 3D treatment planning system for episcleral plaque therapy.

PURPOSE: Episcleral plaque therapy (EPT) is applied in the management of some malignant ocular tumors. A customized configuration of typically 4 to 20 radioactive seeds is fixed in a gold plaque, and the plaque is sutured to the scleral surface corresponding to the basis of the intraocular tumor, allowing for a localized radiation dose delivery to the tumor. Minimum target doses as high as 100 Gy are directed at malignant tumor sites close to critical normal tissues (e.g., optic disc and macula). Precise dosimetry is therefore fundamental for judging both the risk for normal tissue toxicity and tumor dose prescription. This paper describes the dosimetric verification of a commercially available dedicated treatment planning system (TPS) for EPT when realistic multiple-seed configurations are applied. MATERIALS AND METHODS: The TPS Bebig Plaque Simulator is used to plan EPT at our institution. Relative dose distributions in a water phantom, including central axis depth dose and off-axis dose profiles for three different plaques, the University of Southern California (USC) #9 and the Collaborative Ocular Melanoma Study (COMS) 12-mm and 20-mm plaques, were measured with a diode detector. Each plaque was arranged with realistic multiple 125I seed configurations. The measured dose distributions were compared to the corresponding dose profiles calculated with the TPS. All measurements were corrected for the angular sensitivity variation of the diode. RESULTS: Single-seed dose distributions measured with our dosimetry setup agreed with previously published data within 3%. For the three multiple-seed plaque configurations, the measured and calculated dose distributions were in good agreement. For the central axis depth doses, the agreement was within 4%, whereas deviations up to 11% were observed in single points far off-axis. CONCLUSIONS: The Bebig Plaque Simulator is a reliable TPS for calculating relative dose distributions around realistic multiple 125I seed configurations in EPT.

Brachytherapy↗
PubMed2001

Vinblastine and hyperthermia target the neovasculature in BT(4)AN rat gliomas: therapeutic implications of the vascular phenotype.

PURPOSE: The antivascular and antitumor activity of vinblastine and hyperthermia at different tumor volumes were examined in the subcutaneous (s.c.) BT(4)An rat glioma model. METHODS AND MATERIALS: The influence of vinblastine (3 mg/kg) and hyperthermia (44 degrees C/60 min) on tumor growth was assessed in small (100 mm(3)) and large (200 mm(3)) BT(4)An tumors. To disclose how vinblastine and hyperthermia interacted in the neoplasms, tumor blood flow and the extent of vascular damage, hypoxia, cell proliferation, and apoptosis were assessed after treatment. The content of smooth muscle cells/pericytes in the tumor vasculature was examined in small and large tumors to assess how the vascular phenotype changed during tumor growth. RESULTS: In the large tumors, vinblastine reduced the blood flow, but the tumor growth was not affected. The combination of drug and local heating yielded massive vascular damage and a significant tumor response. The small neoplasms had a higher content of smooth muscle cells/pericytes in the vessel walls (host vasculature), and the tumor vasculature displayed a higher resistance to vascular damage than the large neoplasms. Yet, vinblastine alone exhibited a potent antiproliferative activity and induced massive apoptosis in the small tumors, and the drug significantly inhibited tumor growth. The addition of hyperthermia yielded no additional growth delay in the small tumors. CONCLUSION: The antivascular properties of vinblastine and hyperthermia can be exploited to facilitate vascular damage in BT(4)An solid tumors with a low content of host vasculature.

Animals↗
PubMed2001

Can dose-response models predict reliable normal tissue complication probabilities in radical radiotherapy of urinary bladder cancer? The impact of alternative radiation tolerance models and parameters.

PURPOSE: To analyze the consequences of selecting alternative normal tissue complication probability (NTCP) models and parameters for evaluation of radiotherapy of urinary bladder cancer. METHODS AND MATERIALS: Treatment plans of 24 bladder cancer patients referred to radical 4-field conformal radiotherapy were analyzed. Small intestinal and rectal NTCPs were determined using both the probit and relative seriality models with several sets of published radiation tolerance parameters. Various combinations of NTCP models and parameters were applied to find the prescription dose in individual patients as well as to estimate the benefit of the conformal radiotherapy setup. RESULTS: Different risk estimates were predicted from the two NTCP models, even when the same clinical radiation tolerance doses were fitted into the two models. The demonstrated variability translated into significant deviations (7-10 Gy) in the recommended prescription doses. Even if it was possible to discriminate between a 2-field plan and the 4-field conformal setup using a given complication model and set of tolerance parameters, the estimated benefit of the conformal treatment in terms of permitted dose escalation varied with as much as 10-12 Gy between the different NTCP models/parameters used. CONCLUSION: Different NTCP models and tolerance parameters might propose different answers to important clinical questions in radiotherapy treatment of bladder cancer, such as dose prescription and scoring of rival treatment plans. We therefore recommend that the variability caused by tolerance parameter uncertainty and model selection should be taken into account in dose-response modeling of radiotherapy treatment.

Aged↗
PubMed2001

Synthesis of pyrrolidinone PNA: a novel conformationally restricted PNA analogue.

To preorganize PNA for duplex formation, a new cyclic pyrrolidinone PNA analogue has been designed. In this analogue the aminoethylglycine backbone and the methylenecarbonyl linker are connected, introducing two chiral centers compared to PNA. The four stereoisomers of the adenine analogue were synthesized, and the hybridization properties of PNA decamers containing one analogue were measured against complementary DNA, RNA, and PNA strands. The (3S,5R) isomer was shown to have the highest affinity toward RNA, and to recognize RNA and PNA better than DNA. The (3S,5R) isomer was used to prepare a fully modified decamer which bound to rU10 with only a small decrease in Tm (delta Tm/mod = 1 degree C) relative to aminoethylglycine PNA.

Magnetic Resonance Spectroscopy↗
PubMed2001

Combretastatin A-4 and hyperthermia;a potent combination for the treatment of solid tumors.

BACKGROUND AND PURPOSE: Attacking tumor vasculature is a promising approach for the treatment of solid tumors. The tubulin inhibitor combretastatin A-4 disodium phosphate (CA-4) is a new vascular targeting drug which displays a low toxicity profile. We wanted to investigate how CA-4 influences tumor perfusion in the BT4An rat glioma and how the vascular targeting properties of CA-4 could be exploited to augment hyperthermic damage towards tumor vasculature. MATERIAL AND METHODS: We used the (86)RbCl extraction technique to assess how CA-4 influences tumor perfusion, and the tumor endothelium was examined for morphological changes induced by the drug. We combined CA-4 (50 mg/kg i.p.) with hyperthermia (44 degrees C, 60 min) at different time intervals to evaluate how therapy should be designed to affect tumor growth, and we studied the tumors histologically to assess tissue viability. RESULTS: We found that CA-4 induced a profound, but transient reduction in tumor perfusion 3-6 h postinjection. If hyperthermia was administered 3-6 h after injecting CA-4, massive hemorrhagic necrosis developed, and tumor response was significantly enhanced compared to simultaneous administration of the two treatment modalities (P<0.005). CA-4 alone had no influence on tumor growth and failed to disrupt the vasculature of the BT4An solid tumors. Interestingly though, a mild endothelial edema was observed in some tumor areas 3 h after injecting CA-4. CONCLUSIONS: We conclude that the combination of CA-4 and hyperthermia is a potent therapeutic option for BT4An tumors, but the selection of adequate time intervals between CA-4 and hyperthermia are imperative to obtain tumor response.

Animals↗
PubMed2001

Partially wedged beams improve radiotherapy treatment of urinary bladder cancer.

BACKGROUND AND PURPOSE: Partially wedged beams (PWBs) having wedge in one part of the field only, can be shaped using dynamic jaw intensity modulation. The possible clinical benefit of PWBs was tested in treatment plans for muscle-infiltrating bladder cancer. MATERIAL AND METHODS: Three-dimensional treatment plans for 25 bladder cancer patients were analyzed. The originally prescribed standard conformal four-field box technique, which includes the use of lateral ordinary wedge beams, was compared to a modified conformal treatment using customized lateral PWBs. In these modified treatment plans, only the anterior parts of the two lateral beams had a wedge. To analyze the potential clinical benefit of treatment with PWBs, treatment plans were scored and compared using both physical parameters and biological dose response models. One tumour control probability model and two normal tissue complication probability (NTCP) models were applied. Different parameters for normal tissue radiation tolerance presented in the literature were used. RESULTS: By PWBs the dose homogeneity throughout the target volume was improved for all patients, reducing the average relative standard deviation of the target dose distribution from 2.3 to 1.8%. A consistent reduction in the maximum doses to surrounding normal tissue volumes was also found. The most notable improvement was demonstrated in the rectum where the volume receiving more than the prescribed tumour dose was halved. Treatment with PWBs would permit a target dose escalation of 2-6 Gy in several of the patients analyzed, without increasing the overall risk for complications. The number of patients suitable for dose escalation ranged from 3 to 15, depending on whether support from all or only one of the five applied NTCP model/parameter combinations were required in each case to recommend dose escalation. CONCLUSION: PWBs represent a simple dose conformation tool that may allow radiation dose escalation in the treatment of muscle-infiltrating urinary bladder tumours.

Adult↗
PubMed2001

Tumor vasculature is targeted by the combination of combretastatin A-4 and hyperthermia.

BACKGROUND AND PURPOSE: Combretastatin A-4 disodium phosphate (CA-4) enhances thermal damage in s.c. BT(4)An rat gliomas. We currently investigated how CA-4 and hyperthermia affect the tumor microenvironment and neovasculature to disclose how the two treatment modalities interact to produce tumor response. METHODS: By confocal microscopy and immunostaining for von Willebrand factor, we examined the extent of vascular damage subsequent to CA-4 (50 mg/kg) and hyperthermia (waterbath 44 degrees C, 60 min). The influence on tumor oxygenation was assessed using interstitial pO(2)-probes (Licox system) and by immunostaining for pimonidazole. We examined the direct effect of CA-4 on the tumor cell population by flow cytometry (cell cycle distribution) and immunostaining for beta-tubulin (cytoskeletal damage). RESULTS: Whereas slight vascular damage was produced by CA-4 in the BT(4)An tumors, local hyperthermia exhibited moderate anti-vascular activity. In tumors exposed to CA-4 3 h before hyperthermia, massive vascular damage ensued. CA-4 reduced the pO(2) from 36.1 to 17.6 mmHg (P=0.01) in the tumor base, and tumor hypoxia increased slightly in the tumor center (pimonidazole staining). Extensive tumor hypoxia developed subsequent to hyperthermia or combination therapy. Despite a profound influence on beta-tubulin organization in vitro, CA-4 had no significant effect on the cell cycle distribution in vivo. CONCLUSION: Our results indicate that the anti-vascular activity exhibited by local hyperthermia can be augmented by previous exposure to CA-4.

Animals↗
PubMed2000

[Treatment of renal carcinoma with distant metastases].

BACKGROUND: There is no effective standard therapy for patients with distant metastases from renal cell carcinoma. Physicians should, however, know about the different treatment options and their efficacy in order to adequately inform and treat their patients. MATERIAL AND METHODS: Current relevant literature and experience at the Norwegian Radium Hospital are reviewed with emphasis on systemic therapy. RESULTS: Nephrectomy is indicated if the aim is to palliate or prevent local symptoms due to a large primary tumour, or if the operation renders a patient eligible for a clinical trial. Local symptoms due to metastatic lesions should be managed surgically or by radiotherapy. Hormone treatment and current chemotherapy are ineffective. In selected patients interferon-alpha (IFN-alpha) results in an approximately 15% response rate and 4-6 months' prolongation of life. Combination therapy with interleukins or with other drugs is experimental. INTERPRETATION: Patients with metastatic renal cell carcinoma should primarily be included in clinical trials. If this is not possible, interferon-alpha monotherapy represents today's standard systemic treatment, to be offered to selected and informed patients.

Antineoplastic Agents, Hormonal↗
PubMed2000

The new tubulin-inhibitor combretastatin A-4 enhances thermal damage in the BT4An rat glioma.

PURPOSE: To investigate the toxicity of combretastatin A-4 disodium phosphate (CA-4) and its vascular effects in the subcutaneous (s.c.) BT4An rat glioma, and additionally, to determine the tumor response of CA-4 combined with hyperthermia. METHODS AND MATERIALS: For assessment of drug toxicity, rats were given 50, 75, or 100 mg/kg CA-4 and followed by daily registration of weight and side effects. Interstitial tumor blood flow was determined by laser Doppler flowmetry in rats injected with 50 mg/kg CA-4. In the tumor response study we administered CA-4 50 mg/kg alone or combined with hyperthermia (waterbath 44 degrees C for 60 min) 0 or 3 h later. RESULTS: We found that CA-4, at a well-tolerated dose of 50 mg/kg, induced a considerable time-dependent decrease in the tumor blood flow. Tumor blood flow was reduced by 47-55% during the first 110 min after injecting CA-4, and thereafter remained decreased until the measurements were terminated. Administering CA-4 3 h before hyperthermia yielded the best tumor response and increased tumor growth time significantly compared with simultaneous administration of CA-4 and hyperthermia (p = 0.03). Interestingly, CA-4 alone did not influence tumor growth. CONCLUSION: CA-4 induces a gradual reduction in tumor blood flow which can be exploited to sensitize the BT4An tumor for hyperthermia.

Animals↗
PubMed2000

ARCON: accelerated radiotherapy with carbogen and nicotinamide in head and neck squamous cell carcinomas. The experience of the Co-operative group of radiotherapy of the european organization for research and treatment of cancer (EORTC).

BACKGROUND: Since there is increasing evidence that both acute (perfusion-limited) and chronic (diffusion-limited) hypoxia, and tumor repopulation may prejudice the outcome of radiotherapy, the combination of carbogen (95% oxygen-5% carbon dioxide) and nicotinamide with accelerated radiotherapy (ARCON) should reduce the impact of these factors of radioresistance. AIM: This clinical study was aimed at determining the feasibility, as well as the qualitative and quantitative toxic effects of a therapeutic approach based on ARCON, and assessing the tumor response rates that can be achieved with this regime in patients with locally advanced tumors of the head and neck. METHODS: A phase I/II study conducted between 1993 and 1996 by the Co-operative Group of Radiotherapy of the EORTC included three consecutive steps: accelerated fractionation (AF) combined with carbogen (11 analyzable patients), AF combined with the daily administration of nicotinamide (n=10), and AF with both carbogen and nicotinamide (n=17). Radiotherapy was based on an accelerated regime (72 Gy in 5.5 weeks). Nicotinamide was delivered 90 min before the first irradiation session, at a daily dose of 6 g. Carbogen breathing started 5 min before irradiation and lasted throughout the entire radiotherapy sessions. RESULTS: No significant difference in loco-regional toxicity was found among the three study steps, when carbogen and nicotinamide, either alone or in combination, were combined with AF. The feasibility of the ARCON protocol, as proposed in the present EORTC study, appears to be significantly impaired when nicotinamide is added, at a daily dose of 6 g, to AF and carbogen, in an unselected group of patients. More than 20% of patients experienced grade 2 or 3 emesis. It also demonstrates, in unselected groups of patients, no significant difference in tumor response and local control when carbogen and nicotinamide, either alone or in combination, are added to accelerated radiotherapy. The percentages of objective response at 2 months were 81, 70 and 87%, respectively. CONCLUSION: Future ARCON trials should target selected head and neck tumor localizations and stages, and a lower nicotinamide dose is needed to reduce severe upper gastro-intestinal toxicity.

Adult↗
PubMed2000

Adapting the waterproof BMS-96 diode array for isodose determination of dynamic beams.

We report the application of the Schuster BMS-96 waterproof linear diode array for isodose determination of dynamic beams. The array recorded beam profiles correctly, while depth dose distributions of dynamic beams with large variations in dose rate were registered erroneously. The deviations could be eliminated by appropriate software modifications. Until the software is revised, true isodoses can be obtained by rescaling each individual profile to the depth dose curve as measured with a single ionization chamber. After the corrections presented in the paper, isodoses interpolated from these corrected data sets agreed with ionization chamber measurements within 1-2%.

Radiation Dosage↗
PubMed2000

Dose-volume analysis of different stereotactic radiotherapy mono-isocentric techniques.

Several stereotactic irradiation techniques, using Linacs with the patient in lying and sitting position and a Gamma Knife Unit, were compared with regard to mono-isocentric three-dimensional dose distributions. Three types of target volumes, a sphere and two ellipsoids, were used for the comparisons. All three targets were centered on a real head, reconstructed from transversal CT scans. The ARTEMIS 3D Treatment Planning System, developed by the Tenon Hospital, Paris, was used for the dosimetry and the dose-volume histogram (DVH) calculation. For the comparative study, several quantitative parameters were used, derived from the dose-volume histogram calculation. Differential DVHs were plotted for each target volume and beam arrangement. Irradiation techniques were compared by deriving quantitative parameters from the DVHs such as mean and integral dose delivered to the target and normal tissue irradiated, as well as by the relative volume of the examined areas. All techniques used in this study produced very similar dose distributions. The small differences confirm the capability of the studied techniques to produce the same irradiation effects. By changing from the spherical target shape to a more elliptical shape, more of the normal tissue was irradiated with higher doses. For elliptical cases we therefore identified a need for more conformal stereotactic planning.

Brain Neoplasms↗
PubMed2000

Partially wedged radiation beams.

To increase dose homogeneity within certain radiotherapy targets, we defined a partially wedged radiation beam as a beam with wedge modification in one part of the field only. Partially wedged beams may be beneficial in cases with curved surfaces inside parts of the beam only, where they may compensate for missing tissue and/or for variations in depth to the target region. Possible sites suitable for partially wedged beams include urinary bladder and tangential breast irradiation. Customized partially wedged beams were delivered applying dynamic collimation techniques. Two different linear detector arrays, a semiconductor diode array and an ionization chamber array, were used independently in the same standard water tank to verify that the partially wedged beams were delivered according to the definition. Dose calculations of partial wedge fields were implemented in our treatment planning system and compared with the measured dose distributions. We re-planned a representative treatment plan for both advanced urinary bladder cancer and tangential breast irradiation using partially wedged beams. For both patients the target dose homogeneity was improved, and the doses to surrounding critical normal tissues were reduced.

Algorithms↗
PubMed1999

Double duplex invasion by peptide nucleic acid: a general principle for sequence-specific targeting of double-stranded DNA.

Pseudocomplementary PNAs containing diaminopurine.thiouracil base pairs have been prepared and are shown to bind with high specificity and efficiency to complementary targets in double-stranded DNA by a mechanism termed "double duplex invasion" in which the duplex is unwound and both DNA strands are targeted simultaneously, each by one of the two pseudocomplementary peptide nucleic acids (PNAs). On the basis of our results we predict that (for decameric targets) more than 80% of all sequences can be targeted by straightforward Watson-Crick base pairing by using this approach in its present form. Targeting of pseudocomplementary PNAs to the promoter of the T7 phage RNA polymerase effectively inhibits transcription initiation. These results have important implications in the development of gene therapeutic agents as well as for genetic diagnostic and molecular biology applications.

Adenine↗
PubMed1999

ARCON: accelerated radiotherapy with carbogen and nicotinamide in non small cell lung cancer: a phase I/II study by the EORTC.

BACKGROUND: Non small cell lung cancers (NSCLC) are rapidly proliferating tumours, which are characterized by the presence of extensive hypoxic components, especially in patients with advanced loco-regional disease. Previous studies suggest a deleterious impact of acute (perfusion-limited) hypoxia on the outcome of radiotherapy for these tumours. AIM: This pilot study was aimed at determining the feasibility and tumour response rates that can be achieved with an ARCON regime in patients with locally advanced, staged IIIA or B, NSCLC tumours. METHODS: The phase I/II study included three steps: accelerated fractionation (AF) combined with carbogen (ten analysable patients), AF together with the daily administration of nicotinamide (n = 11 ) and AF with both carbon and nicotinamide (n = 14). Radiotherapy was based on a large daily dose per fraction (2.75 Gy up to 55 Gy in 4 weeks). Nicotinamide was administered at a dose of 6 g per patient per treatment day and carbogen was inhaled for 5 min before and during radiotherapy. RESULTS: The incidence of grade 3 + acute toxicity during the irradiation did not exceed 10%, neither in the lung parenchyma nor in the mediastinum. No significant difference was found in loco-regional, radio-induced toxicity among the three study steps. Although a similar fraction of patients showed grade 2 or 3 emesis in all the steps, of the 25 patients entered in the two Nicotinamide containing steps 10 (40%) developed grade 2 or greater reactions which significantly detracted from their quality of life. There was no significant difference in tumour clearance rate among the three steps. The percentage of objective responses at 2 months was 60, 54 and 57% in steps 1, 2 and 3, respectively. CONCLUSION: The feasibility of this ARCON protocol, using 2.75 Gy doses per fraction over 4 weeks, is good as regards radiotherapy-related side effects but it appears necessary in future to reduce the dose of Nicotinamide to reduce the incidence of nausea and vomiting. There was no significant difference in time to progression among the three study steps.

Administration, Inhalation↗