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T Mikkelsen

Publications and source records attributed to T Mikkelsen.

At least 19 recordsLinked to original sources
PubMed2004

Can the confidence in long range atmospheric transport models be increased? The pan-european experience of ensemble.

Is atmospheric dispersion forecasting an important asset of the early-phase nuclear emergency response management? Is there a 'perfect atmospheric dispersion model'? Is there a way to make the results of dispersion models more reliable and trustworthy? While seeking to answer these questions the multi-model ensemble dispersion forecast system ENSEMBLE will be presented.

Air Movements↗
PubMed2003

Airborne transmission of foot-and-mouth disease virus from Burnside Farm, Heddon-on-the-Wall, Northumberland, during the 2001 epidemic in the United Kingdom.

The results of a detailed assessment of the atmospheric conditions when foot-and-mouth disease (FMD) virus was released from Burnside Farm, Heddon-on-the-Wall, Northumberland at the start of the 2001 epidemic in the UK are consistent with the hypothesis that the disease was spread to seven of the 12 farms in the immediate vicinity of the source by airborne virus, and airborne infection could not be ruled out for three other premises; the remaining two premises were unlikely to have been infected by airborne virus. The distances involved ranged from less than 1 km up to 9 km. One of the farms which was most probably infected by airborne virus from Burnside Farm was Prestwick Hall Farm, which is believed to have been key to the rapid spread of the disease throughout the country. In contrast, the results of detailed atmospheric modelling, based on a combination of clinical evidence from the field and laboratory experiments have shown that by assuming a relationship between the 24-hour average virus concentrations and subsequent infection, threshold infection levels were seldom reached at the farms close to Burnside Farm. However, significant short-term fluctuations in the concentration of virus can occur, and short-lived high concentrations may have increased the probability of infection and explain this discrepancy.

Animal Husbandry↗
PubMed2002

Photodynamic therapy with photofrin reduces invasiveness of malignant human glioma cells.

In this study we investigated the influence of Photofrin-based photodynamic therapy (PDT) on the migration of two human glioma cell lines in vitro. U87 and U25ln tumour cells were treated with Photofrin at various doses and subjected to a fixed optical (632 nm) dose of 100 mJ/cm(2). Photofrin cytotoxicity was determined using MTT and colony forming assays. Using a matrigel artificial basement membrane migration assay, we demonstrated that low doses of subcytotoxic PDT treatment, such as PDT with 2.5 micro g/ml Photofrin on U87 cells and 1 micro g/ml on U25ln cells, significantly ( p<0.001) inhibited in vitro migration of both cell lines. Furthermore, in a qualitative spheroid confrontation assay, subcytotoxic PDT of co-cultures between tumour spheroids and brain aggregates resulted in an absence of progressive tumour invasion and destruction of the brain aggregate. In conclusion, our data indicate that low-dose subcytotoxic PDT with Photofrin significantly inhibits invasiveness of U87 and U25ln cells.

Animals↗
PubMed2002

Risk of femoral hernia after inguinal herniorrhaphy.

BACKGROUND: Small case series have suggested an increased risk of femoral hernia after previous inguinal herniorrhaphy, but no large-scale data with complete follow-up are available. METHODS: Data were extracted from the Danish Hernia Database covering the interval from 1 January 1998 to 1 July 2001, and included 34 849 groin hernia repairs. RESULTS: Of 1297 femoral hernia repairs, 71 patients had previously had an operation for inguinal hernia within the observation period. These 71 femoral hernias represented 7.9 per cent of all reoperations for groin hernia recorded in the database. The median time to reoperation for a 'recurrent' femoral hernia after previous inguinal herniorrhaphy was 7 months, compared with 10 months for inguinal recurrences. The risk of developing a 'recurrent' femoral hernia after previous inguinal herniorrhaphy was 15 times higher than the rate of femoral hernia repair in the general population. CONCLUSION: This study of 34 849 groin hernia repairs demonstrated a 15-fold greater incidence of femoral hernia after inguinal herniorrhaphy compared with the spontaneous incidence. These femoral recurrences occurred earlier than inguinal recurrences, suggesting that they were possibly femoral hernias overlooked at the primary operation.

Adult↗
PubMed2001

Adults with newly diagnosed high-grade gliomas.

Despite tremendous advances in brain tumor molecular biology and several emerging novel therapies, multimodality therapy that includes surgery, radiation therapy (RT), and chemotherapy is still the cornerstone of high-grade glioma treatment. The first step in high-grade glioma therapy is surgery and a maximal resection should be attempted to reduce the tumor burden before initiation of other adjuvant therapies. External beam radiation therapy (EBRT) generally follows surgery, using conventional dosage, and fractionation, and ideally a three-dimensional conformal technique. Stereotactic radiosurgery (SRS) to maximize cytoreduction may be used in selected cases. Because no curative chemotherapy exists for high-grade glioma, we always consider an investigational agent either before or concurrently with RT. However, the use of a standard cytotoxic agent, such as temozolomide alone or combined with 13-cis-retinoic acid also is a rational choice particularly for patients with relatively good prognostic factors for whom an investigational agent would not be available. The management of anaplastic oligodendroglioma does not differ significantly from other high-grade gliomas in terms of surgery, RT, or investigational or protocol agent; however, these tumors appear to respond to chemotherapy that includes a combination of procarbazine, CCNU, and vincristine (PCV) [1**]. The vincristine provides more toxicity than benefit and it is our practice to only use a combination of procarbazine and CCNU (PC). A single agent, such as temozolomide is an increasingly used and rational choice for anaplastic oligodendroglioma. It is our belief that early, aggressive multimodality treatment still provides the best chance for long-term control of high-grade gliomas, particularly in patients with good prognostic factors. However, despite best therapy and state-of-the-art technology, most patients with high-grade glioma will experience progression or recurrence and will require either a change in the ongoing therapeutic strategy or additional treatment. Better therapies are necessary and progress will only be made through investigation of promising agents in well-designed clinical trials.

Adult↗
PubMed2001

Correlation between magnetic resonance spectroscopy imaging and image-guided biopsies: semiquantitative and qualitative histopathological analyses of patients with untreated glioma.

OBJECTIVE: Since intratumoral heterogeneity of gliomas is not adequately reflected in conventional magnetic resonance imaging (MRI), we sought to determine a correlation between different proton magnetic resonance spectroscopic imaging ((1)H MRSI) metabolic ratios and the degree of tumor infiltration in diffusely infiltrating gliomas. In this report, we describe the microscopic anatomy of gliomas on imaging. METHODS: Image-guided biopsies with semiquantitative and qualitative histopathological analyses from a series of 31 untreated patients with low- and high-grade gliomas were correlated with multivoxel (1)H MRSI referenced to the same spatial coordinates. RESULTS: This series yielded 247 tissue samples and 307 observations. Choline-containing compounds using contralateral creatine and choline for normalization or ipsilateral N-acetylaspartate appear to correlate best with the degree of tumor infiltration. Similar correlations were present within each grade after stratification. Despite the interpatient overlap of metabolic ratios between normal tissue and mild tumor infiltration, preliminary analyses revealed that (1)H MRSI appears more accurate than conventional MRI in defining the tumor boundary and quantifying the degree of tumor infiltration. CONCLUSION: This is the first study showing histopathological validation of tumor boundaries using (1)H MRSI. These results support the conclusion that (1)H MRSI accurately reflects the extent of the disease in patients with gliomas. This has important diagnostic and therapeutic implications for more accurately assessing the burden of disease as well as for planning and assessing response to therapy.

Adolescent↗
PubMed2000

Practice parameters for the management of single brain metastasis.

OBJECT: In January 1998 the Guidelines and Outcomes Committee of the American Association of Neurological Surgeons (AANS) issued a charge for the development of evidence-based practice parameters focusing on the treatment of patients with single metastasis to the brain. The charge was imposed in response to the significant controversy surrounding questions relating to the optimal management strategies for patients with single brain metastasis. METHODS: A team consisting of physicians from the AANS, the American Academy of Neurology, and the American Association of Therapeutic Radiation Oncology convened and the literature was reviewed. Methodically drawing from the best of Class I, II, and III levels of available evidence, authors sought to determine how the literature addressed and disposed of the question of the optimal management for an adult with a known history of cancer and a single metastatic brain lesion. Framing the question in this specific manner allowed researchers to focus directly on treatment issues, without having to consider diagnostic issues. CONCLUSIONS: The results of the evidence-based analysis demonstrated that there was insufficient information to establish standards of care. Data from the literature does, however, support a guideline stating that surgical resection accompanied by whole brain radiation therapy is associated with the best survival rate. Additional lower-quality evidence supports an option for management with radiosurgery.

Brain Neoplasms↗
PubMed2000

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma. NABTT CNS Consortium.

9-Aminocamptothecin (9-AC) was administered as a 72-h i.v. infusion every 2 weeks to a total of 99 adults with high-grade astrocytomas. Fifty-one patients with newly diagnosed glioblastoma multiforme received 9-AC treatment prior to radiation therapy and 48 patients with high-grade astrocytomas were treated at the time of tumor recurrence. Upon entrance into these research protocols, all patients had measurable disease that was evaluated on a monthly basis with volumetric CT or MRI scans. A partial response was defined by > or =50% reduction in the contrast enhancing volume on stable or decreasing doses of glucocorticoids. The study specified that all apparent responders would have central review of their radiologic studies and histopathology. The initial patients treated with 9-AC were also receiving anticonvulsants and were noted to have minimal myelosuppression with this chemotherapy. Thus, 9-AC doses were escalated from the previously reported maximum tolerated dose (MTD) of 850 microg/m2/24 h. We then established new MTDs for patients receiving enzyme-inducing anticonvulsants. We defined these MTDs to be 1,776 microg/m2/24 h for newly diagnosed, previously untreated patients and 1,611 microg/m2/24 h for patients with recurrent disease. Twenty-two patients with newly diagnosed glioblastoma multiforme received 9-AC at doses > or =1,776 microg/m2/24 h. Of these, 18 had evaluable disease on central review, and 0 of 18 (0%) demonstrated a partial or complete response. Twenty-one patients with recurrent high-grade astrocytomas were treated at 1,611 microg/m2/24 h; 20 had evaluable disease and 0 of 20 (0%) had a partial or complete response. Thus, the overall response rate in the 38 evaluable patients treated at the MTD was 0 of 38 (0%). Furthermore, of the 51 evaluable patients who were treated at doses less than the MTD, only one partial response was observed, yielding an overall response rate of 2%. Evidence of drug failure was rapid with tumor progression in one-half of patients after 2 drug cycles. 9-AC lacks evidence of substantial activity in patients with newly diagnosed or recurrent high-grade astrocytomas.

Adult↗
PubMed2000

Carboxyamido-triazole induces apoptosis in bovine aortic endothelial and human glioma cells.

Carboxyamido-triazole (CAI), an inhibitor of non-voltage-gated calcium channels, has been studied in Phase I/II clinical trials following the identification of its inhibitory effects on tumor cell invasion and motility. It has also been reported to inhibit human endothelial cell proliferation, migration, and adhesion to the basement membrane. In glioma, biological assays have shown CAI to be active in inhibiting the phenotypes of invasion and angiogenesis. The exact mechanism of action is not clearly understood, although it appears to work via inhibition of calcium influx in several signal transduction pathways that inhibit cell cycle progression. Recent evidence implicates apoptosis as a contributing mechanism of chemotherapy-induced tumor cytotoxicity. Therefore, we studied the effects of CAI on apoptosis in bovine aortic endothelial cells and a human glioma cell line (U251N) using a variety of methods, including: (a) cell morphology; (b) terminal deoxynucleotidyl transferase-mediated nick end labeling analysis of in situ DNA strand breaks; (c) agarose gel electrophoresis to visualize DNA fragmentation; and (d) flow cytometry. Here we report that the kinetics of CAI-induced apoptosis in bovine aortic endothelial cells and glioma cells was determined to be both dose and time dependent in micromolar concentrations achievable in brain tissue in vivo.

Animals↗
PubMed1998

Feature space analysis of MRI.

This paper presents an MRI feature-space image-analysis method and its application to brain tumor studies. The proposed method generates a transformed feature space in which the normal tissues (white matter, gray matter, and CSF) become orthonormal. As such, the method is expected to have site-to-site and patient-to-patient consistency, and is useful for identification of tissue types, segmentation of tissues, and quantitative measurements on tissues. The steps of the work accomplished are as follows: (1) Four T2-weighted and two T1-weighted images (before and after injection of gadolinium) were acquired for 10 tumor patients. (2) Images were analyzed by an image analyst according to the proposed algorithm. (3) Biopsy samples were extracted from each patient and were subsequently analyzed by the pathology laboratory. (4) Image-analysis results were compared with the biopsy results. Pre- and postsurgery feature spaces were also compared. The proposed method made it possible to visualize the MRI feature space and to segment the image. In all cases, the operators were able to find clusters for normal and abnormal tissues. Also, clusters for different zones of the tumor were found. The method successfully segmented the image into normal tissues (white matter, gray matter, and CSF) and different zones of the lesion (tumor, cyst, edema, radiation necrosis, necrotic core, and infiltrated tumor). The results agreed with those obtained from the biopsy samples. Comparison of pre- with postsurgery and radiation feature spaces illustrated that the original solid tumor was not present in the second study, but a new tissue component appeared in a different location of the feature space. This tissue could be radiation necrosis generated as a result of radiation.

Artifacts↗
PubMed1998

SPARC: a signal of astrocytic neoplastic transformation and reactive response in human primary and xenograft gliomas.

In an attempt to identify genetic alterations occurring early in astrocytoma progression, we performed subtractive hybridization between astrocytoma and glioblastoma cDNA libraries. We identified secreted protein acidic and rich in cysteine (SPARC), a protein implicated in cell-matrix interactions, as a gene overexpressed early in progression. Northern blot and immunohistochemical analyses indicated that transcript and protein were both elevated in all tumor specimens (grades II-IV) examined when compared with levels in normal brain. The level of SPARC expression was found to be tumor-dependent rather than grade-related. Immunohistochemically, SPARC protein was found to be overexpressed in 1) cells in the less cellularly dense regions within the tumor mass, 2) histomorphologically neoplastic-looking cells in adjacent normal brain at the tumor/brain interface, 3) neovessel endothelial cells in both the tumor and adjacent normal brain, and 4) reactive astrocytes in normal brain adjacent to tumor. Using a combination of DNA in situ hybridization and protein immunohistochemical analyses of the human/rat xenograft, SPARC expression was observed in the human glioma cells within the tumor mass, and in cells that invaded along vascular basement membranes and individually into the rat brain parenchyma, suggesting it may be an invasion-related gene. While it remains to be determined whether SPARC functionally contributes to tumor cell invasion, these data suggest that the early onset of increased SPARC expression, though complex, may serve as a signal indicative of neoplastic astrocytic transformation and reactive response to tumor-induced stress.

Animals↗
PubMed1998

Cytostatic Agents in the Management of Malignant Gliomas.

BACKGROUND: Cytotoxic therapy for malignant gliomas is limited by poor delivery and drug resistance, and local therapy is ineffective in managing migratory cells. However, recent developments in malignant glioma therapy involve trials of cytostatic rather than conventional cytotoxic agents. METHODS: The biology of the brain extracellular matrix, tumor invasion, and angiogenesis are reviewed, and the cytostatic agents that inhibit matrix metalloproteinases, angiogenesis, cell proliferation, and signal transduction are discussed, as well as studies of the angiogenic and migratory capacity of malignant brain tumors. RESULTS: Two specific and interrelated areas, anti-invasion (migration) and anti-angiogenesis, are potential areas to develop new treatment strategies. Tumor invasion and angiogenesis are important components of the spread and biologic effects of malignant gliomas. Several proteinase inhibitors are in clinical trial, as well as anti-angiogenic agents and signal transduction cascade inhibitors. CONCLUSIONS: Biologic control of brain tumor cell populations may offer a new management approach to add to currently available management options for malignant brain tumors.

Journal Article↗
PubMed1997

Inhibitory effects of CAI in glioblastoma growth and invasion.

While distant metastases are rare in patients with primary brain malignancies, local growth and invasion are common and life-threatening. Regional infiltration is responsible for the failure of local therapies, resulting in tumor recurrence, progression, and death. The process of invasion requires cellular adhesion, local proteolysis and migration. CAI, carboxyamide-triazole, is an anticancer agent developed as an inhibitor of selected signal transduction pathways. Studies on the effects of CAI on human glioblastoma growth and invasiveness are presented. CAI inhibited proliferation of 6 of 8 cell lines tested in a dose-dependent fashion in vitro (IC50 range 1.5-44 microM), with no effect on the U373 line. Inhibition of adhesion to tissue culture plastic was observed for the H4, T98G, and U373 lines pretreated with CAI; H4 and T98G were inhibited in adhesion to collagen type IV. Incubation with CAI decreased production of the 72 kDa and 92 kDa type IV collagenases in all cell lines, ranging from 16 to 93% inhibition. These observations show that the effects of CAI on cell line behavior can vary between lines that are similar in origin. Despite variability in the inhibitory effects for proliferation and adhesion, CAI is consistently able to inhibit the invasive phenotype of all glioma cell lines in vitro using the Matrigel barrier assay (IC50 range 13-28 microM). These observations suggest that CAI may have benefit in the treatment of gliomas and high grade astrocytomas.

Antineoplastic Agents↗
PubMed1996

Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1.

Glioblastoma multiforme is distinguished from its less malignant astrocytoma precursors by intense angiogenesis and frequent loss of tumor suppressor genes on chromosome 10. Here we link these traits by showing that when a wild-type chromosome 10 was returned to any of three human glioblastoma cell lines U251, U87, or LG11, they lost their ability to form tumors in nude mice and switched to an antiangiogenic phenotype, as measured by the inhibition of capillary endothelial cell migration and of corneal neovascularization. This change in angiogenesis was directly due to the increased secretion of a potent inhibitor of angiogenesis, thrombospondin-1, because: (a) neutralizing thrombospondin completely relieved the inhibition; (b) the inhibitory activity of thrombospondin was not dependent on transforming growth factor beta; and (c) chromosome 10 introduction did not alter secreted inducing activity. The inducing activity was dependent on vascular endothelial cell growth factor and had an ED50 of 10 microg/ml in media conditioned by parental cells and 9-13 microg/ml in media conditioned by chromosome 10 revertants. Normal human astrocytes were also antiangiogenic due to secreted thrombospondin. The effect of chromosome 10 on thrombospondin production in vitro was reflected in patient material. Normal brain and lower grade astrocytomas known to retain chromosome 10 stained strongly for thrombospondin, but 12 of 13 glioblastomas, the majority of which lose chromosome 10, did not. These data indicate that the loss of tumor suppressors on chromosome 10 contributes to the aggressive malignancy of glioblastomas in part by releasing constraints on angiogenesis that are maintained by thrombospondin in lower grade tumors.

Animals↗
PubMed1996

Cerebral tumor volume calculations using planimetric and eigenimage analysis.

Volume determination in cerebral tumors requires accurate and reproducible segmentation. This task has been traditionally accomplished using planimetric methods which define the boundary of the lesion using thresholding and edge detection schemes. These methods lack accuracy and reproducibility when the contrast between the lesion and surrounding tissue is not maximized. Because of this limitation contrast agents are used providing reproducible results for the enhancing portion of the lesion. A novel approach for volume determination has been developed (eigenimage filter) which segments a desired feature (tissue type) from surrounding undesired features in a sequence of images. This method corrects for partial volume effects and has been shown to provide accurate and reproducible volume determinations. In addition, the eigenimage filter does not require the use of contrast and has the capability to segment a lesion into multiple regions. This allows different components of the lesion to be included and monitored in treatment. In this study planimetric methods and the eigenimage filter were compared for segmenting cerebral tumors and determining their volumes. The planimetric methods were reproducible in determining volumes for the enhancing portion of the lesion with interobserver percent differences < 8% and intraobserver percent differences < 4%. The eigenimage filter had interobserver percent differences < 7% and intraobserver percent differences < 3%. In the eigenimage procedure both the enhancing portion of the lesion as well as additional regions within the lesion were identified. Comparing the results obtained from the two methods demonstrated good agreement for presurgical studies (percent differences < 9%). When comparing postsurgical studies large differences were seen. In the postsurgical studies the eigenimage method allowed multiple regions to be followed in subsequent MRI and in two patients showed a volume change that suggested tumor recurrence more clearly. Since the amount of information obtained using the eigenimage filter may allow a more complete assessment of the lesion, it is suggested that it could improve the clinical evaluation of cerebral tumors.

Biophysical Phenomena↗
PubMed1996

Tumor progression and angiogenesis: cathepsin B & Co.

Experimental and clinical evidence reveals that the growth of solid tumors is dependent on angiogenesis. Proteolytic enzymes such as plasminogen activators and matrix metalloproteinases have been implicated in this neovascularization. The role of lysosomal proteases in this process has yet to be explored. Increased expression of the lysosomal cysteine protease cathepsin B has been observed in many etiologically different tumors, including human brain, prostate, breast, and gastrointestinal cancers. Immunohistochemical and in situ histochemical studies have demonstrated expression of cathepsin B in neovessels induced during malignant progression of human glioblastoma and prostate carcinomas. In these two tumor types, neovessels stain strongly for cathepsin B compared with the normal microvasculature. As an initial point to elucidate whether cathepsin B is an important component of the angiogenic response in tumours, we analyzed expression of cathepsin B in endothelial cells during neovessel formation. We present evidence for strong immunostaining of cathepsin B in rat brain microvascular endothelial cells as they form capillary tubes in vitro. This finding is discussed within the general framework of the role of proteolytic enzymes in tumor invasion and angiogenesis.

Animals↗