1.
Bjerner, Tomas
(författare)
Assessment of Myocardial Perfusion with Magnetic Resonance Imaging and an Intravascular Contrast Agent
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
The intravascular contrast agent NC100150 Injection (Clariscan™) was tested for its ability to induce signal intensity changes in myocardium, both in steady state and during first pass, and thereby demarcating non-perfused myocardium from perfused. Steady state: Ex vivo in pigs and when using 4 mg Fe/kg bodyweight (b.w.) of the contrast agent, a T1-weighted inversion recovery fast spin echo (IR/TSE) sequence could demarcate 95% of the volume of non-perfused myocardium when compared with the volume determined from photographs where non-perfused myocardium was demarcated by fluorescein. A T2*-weighted gradient echo sequence resulted in significantly lower volume estimations of non-perfused myocardium. Under similar conditions and when using 5 mg Fe/kg b.w., a T2-weighted fast spin echo (TSE) demarcated 99% of the volume of non-perfused myocardium. We were not able to implement the IR/TSE sequence in vivo, but the T2-weighted TSE resulted in clear visualization of non-perfused myocardium in vivo in animals. First pass: With a single-shot T2-TSE, one slice was acquired every heartbeat during the first pass of the contrast agent. When using this sequence, non-perfused myocardium was demarcated in animals and the induced signal intensity changes in perfused myocardium (74±18% @ 5 mg Fe/kg b.w.) were comparable to those in patients (59±13 @ 3 mg Fe/kg b.w.), when taking differences in doses into account. Linear dose–response was found in porcine myocardium between R1, R2, and R2* versus dose (0 – 12 mg Fe/kg b.w.) ex vivo and for R1 (in myocardium and blood) versus dose (0 – 5 mg Fe/kg b.w.) in vivo. However, R1 determination in vivo and in the box ex vivo indicated that blood loss (<2/3) from the myocardium occured during the excision of the heart and preparation for the box, meaning that the box situation ex vivo actually corresponds to lower doses in vivo. Finally, the in vivo measurements of R1 in myocardium and blood indicated that at R1 values in blood as high as 13 s-1, the water exchange is in the fast regime through the capillary wall. In conclusion, the feasibility of NC100150 Injection, in steady state and during first pass, for demarcation of non-perfused myocardium when using a T2-weighted TSE sequence has been demonstrated.
2.
Brun, Eva
(författare)
Head and Neck Cancer: Studies on microvessel density, radiation response and FDG PET
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Treatment options of head and neck squamous cell carcinoma (HNSCC) usually include combinations of radiotherapy and surgery, and in some cases addition of chemotherapy. In locally advanced cases cure rates are low. Current prognostic factors cannot foresee the outcome for the individual patient. There is consequently a need for reliable prognostic and predictive factors. Through identification of such factors therapeutic interventions can be made early during therapy to increase tumour control and survival. In the present studies the association between microvessel density (MVD) in tumours and response to radiation has been explored. We have also studied the association between response to radiation and tumour metabolism, both prior to and during therapy (radical radiotherapy and in 10 cases also neoadjuvant chemotherapy). Metabolism was studied with a glucose analogue, FDG, and positron emission tomography, PET.The metabolic rate of FDG was compared to treatment outcome and survival and also to established tumour properties, as cell proliferation, tumourgrade and DNAcontent. Microvessel density showed a complex relation to radiation treatment response and outcome. Among patients with tumours manifesting complete response to radiotherapy MVD was above the lowest quartile of the MVDcounts according to computerised image analysis. In the subsequent study the relationship between higher MVD and response to radiotherapy could not be reproduced, when performed manually. High MVD within the epithelial tumour tissue, not in the tumour stroma, was then found to be an adverse prognostic factor, with a lower probability of local control and a higher rate of distant metastases.Tumour response evaluated histopathologically, after a preoperative radiation dose of 50 Gy was strongly correlated to outcome, regardless of the subsequent radical surgery.This implies that radiosensitivity per se is a strong prognostic marker. Tumour metabolism (FDG PET) was associated to therapy outcome. The pre treatment value was of limited prognostic value whereas the second PET, early during therapy, was associated to therapy outcome, in terms of complete response, local control and survival. When comparing the value of the metabolic rate (MR) to a simpler quantification, the standar-dised uptake value (SUV) of FDG, we found that MR was more strongly correlated to therapy outcome. Furthermore associations were found to be significant only for the primary tumours and not for node metastases. This implies a different pattern of response in node metastases compared to that of the corresponding primary tumour. There was no strong association between tumour metabolism and proliferation, DNA content or histologic grade. MR FDG reflects tumour aggressiveness. Repeated FDG studies during therapy are feasible and might justify therapeutic interventions in non-responders.
3.
Çiray, Ipek
(författare)
Diagnosis and evaluation of therapeutic response of bone metastases.
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
The aim of this study was to investigate different aspects of different imaging modalities in the diagnosis of bone metastases and in the assessment of their response to therapy. The role of CT, with and without clinical information, was investigated as compared to CT-guided bone biopsy in the evaluation of suspected bone metastases. The diagnostic accuracy of CT alone (44%) increased to 82% when clinical information was taken into account, especially for the lesions diagnosed histopathologically as benign. In most cases, CT in combination with clinical information gave enough information about the nature (malignant or benign) of a bone lesion. In uncertain cases the diagnostic accuracy could be improved by means of CT-guided bone biopsy. Possible misinterpretation of new sclerotic lesions when judged according to the WHO criteria during treatment was studied. One hundred and thirty-nine breast cancer patients with bone metastases, who participated a the clinical trial of clodronate therapy, were studied retrospectively. In 8 of the 24 patients considered at conventional radiography to have progressive disease according to WHO criteria, 17 of 52 apparently new sclerotic lesions (33%) were detected on previous bone scintigraphy. WHO criteria may give rice to misinterpretations in patients with new sclerotic lesions. For better assessment more sensitive techniques, e.g. bone scintigraphy, can be used as a complement to conventional radiography. Eighteen breast cancer patients with known bone metastases were studied prospectively regarding evaluation of therapy response. T1-weighted spin echo (SE) and fat-suppressed long echo time inversion recovery turbo spin echo (long TE IR-TSE) MR sequences, conventional radiography, bone scintigraphy and CT-guided bone biopsy were performed before and during systemic chemotherapy. T1-weighted sequences and long TE IR-TSE sequences were compared regarding evaluation of early response of breast cancer bone metastases to chemotherapy, using a combination of clinical, radiographic and scintigraphic examinations as a reference. Therapeutic response evaluation with MR imaging was based on change in tumor size assessed quantitatively by measuring all focal metastases, and on change in pattern and signal intensity (SI) of the metastases, assessed visually. The long TE IR-TSE sequence demonstrated partial response of breast cancer bone metastases to chemotherapy more accurately than the T1-weighted sequence (58% vs. 17%). The effect of granulocyte colony-stimulating factor (G-CSF)-supported chemotherapy on MR images of normal red bone marrow was investigated. A diffuse, homogeneous SI increase was observed visually and quantitatively in initially normal bone marrow during G-CSF therapy, obscuring some focal lesions. No such SI change was visible after G-CSF therapy or in patients not receiving G-CSF. We concluded that G-CSF-supported chemotherapy might induce diffuse SI changes in normal red bone marrow on MRI, and that this might lead to misinterpretations in the evaluation of response of bone metastases. Early response of bone metastases to therapy was assessed in targeted metastatic lesions in breast cancer patients with T1-weighted and long TE IR-TSE MR sequences and CT compared with histopathological findings. The results indicated that the SI increase in the metastatic lesions following therapy on long TE IR-TSE images might be useful in indicating an early response. T1-weighted images are of limited value in assessing alterations in the amount of tumor cells. An increase in electron density on CT can be seen in both responding and progressing lesions.
4.
Edsjö, Anders
(författare)
Neuroblastoma Cell Differentiation: The Role of Neurotrophin Receptor Signaling and N-myc Expression
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Neuroblastoma is a tumor of sympathetic nervous system derivation, mostly afflicting young children. This thesis is focused on a group of receptor proteins for neurotrophic factors, the Trk family, and on N-Myc, a transcription factor, all important in the formation of the sympathetic nervous system as well as in determining neuroblastoma patient outcome. Expression of trkA and trkC is linked to favorable prognosis, while amplification of the N-myc gene is strongly correlated to poor outcome. The role of trkA and trkC in neuroblastoma cell differentiation was studied using neuroblastoma cell lines constitutively expressing trkA or trkC. Stimulation of the trkA- and trkC-transfected cells with their cognate ligands resulted in differentiation of both cell clones, the differentiated trkC-transfected cells lacking important neuronal features present in the differentiated trkA-transfected cells. Signaling elicited by the two receptors was studied and differences described. The possible connection between expression of N-myc and trkB, another trk family member, was tested by examination of expression of these genes in a set of neuroblastomas and neuroblastoma cell lines. Results suggested high expression of N-myc per se to be insufficient to induce trkB expression. In other experiments, retinoic acid, an agent known to induce trkB expression was added to neuroblastoma cells in combination with the ligand of TrkB, brain-derived neurotrophic factor. Data from characterization of the resulting phenotype indicated that a sympathetic neuronal differentiation did not take place in these cells and alternative explanations were suggested. N-myc expression in the developing human sympathetic nervous system was studied using in situ hybridization and the role of N-myc in neuroblastoma cell was examined, utilizing non-N-myc-amplified neuroblastoma cells with constitutive N-myc overexpression as a model system. Overall, the capacity of these cells to differentitate morphologically in response to various differentiation protocols was retained, thus offering an explanation to the lack of correlation between N-myc expression and patient outcome in non-N-myc-amplified tumors.
5.
Frisk, Peter
(författare)
Expressions of mercury-selenium interaction in vitro
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Interaction between mercury and selenium has previously been observed both in man and in animals. The aim of this work was to study expressions of interaction between mercury and selenium in human K-562 cells. Inorganic and organic forms of mercury and selenium were used and cells were either pre-treated with selenium or simultaneously exposed to selenium and mercury. Concentrations of selenium and mercury chosen were indicated by a study of growth inhibition in the individual compounds: a low concentration of selenium and selenomethionine induced slight cell growth inhibition, while a high concentration resulted in a notable growth inhibition. Two mercury concentrations were chosen: one with minimal toxicity and another with high cell toxicity. In addition, uptake and retention patterns of selenomethionine and selenite differed in both selenocompounds.All simultaneous treatments with 3.5 μM methylmercury produced a reduction in cellular mercury with increased selenium concentration. This was particularly obvious in selenite treatments. Growth curves from the simultaneous 3.5 μM methylmercury and selenite treatments indicated protection with increased selenite concentrations. In both exposure protocols, the 5 μM methylmercury treatments were toxic to the cells. In both study protocols, cells exposed to selenite and mercuric chloride manifested increased cellular mercury uptake with increased selenium concentration. In all selenite and 35 μM mercuric chloride treatments, no inhibition of growth was observed, while the 50 μM mercuric chloride treatments were toxic to the cells. Selenite-dependent protection was achieved in both exposure protocols when considering the cellular uptake of mercury. With few exceptions, selenomethionine produced similar effects as selenite on mercuric chloride uptake and growth inhibition.
6.
Gelig Thurfjell, Mercidyl
(författare)
Aspects in mammographic screening : Detection, prediction, recurrence and prognosis
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Screening mammograms comprising of 32 first round, 10 interval and 32 second round detected cancers and 46 normal were examined by an expert screener, a screening radiologist, a clinical radiologist and a computer-assisted diagnosis (CAD) system. The expert screener, screening radiologist, clinical radiologist and the CAD detected 44, 41, 34 and 37 cancers, respectively, while their respective specificities were 80%, 83%, 100% and 22%. Later, with CAD prompting, the screening and the clinical radiologist detected 1 and 3 additional cancers each with unchanged specificities.Screening mammograms comprising 35 first round, 12 interval and 14 second round detected cancers and 89 normal findings were examined without and with previous mammograms by experienced screeners. Without previous mammograms, the screeners detected 40.3 cancers with a specificity of 87%. With previous mammograms, 37.7 cancers were detected with a 96% specificity. The decrease in sensitivity was not significant but the screeners showed significant increase in specificity.Local recurrences in 303 nonpalpable breast cancers with preoperative localizations and breast conservation therapy were evaluated for needle-caused implant metastasis. A total of 214 percutaneous biopsies were performed. There were 33 local recurrences. Needle-caused seeding or implantation as based on the location of the recurrence in comparison to the needle path in the mammograms was suspected in 3/44 (7%) invasive cancers without radiotherapy.The mammographic characteristics of 317 nonpalpable breast cancers were categorized. Logistic regression showed that the risk ratios for a spiculated mass without calcifications and calcifications alone were 12 and 19 for invasive cancer and ductal cancer in situ (DCIS), respectively. Invasive ductal grade 1, ductal grade 2, lobular and ductal grade 3, had a risk ratio (RR) of 28, 17, 11 and 4.6, respectively, for a spiculated mass without calcifications. DCIS nuclear grade 3 and invasive ductal grade 3 had an RR of 17 and 9.7, respectively, for sole casting calcifications.The eight-year survival of 96 1-9 mm invasive breast cancers were investigated in relation to their mammographic appearance, node status and histologic grade. After a median follow-up of 7 years, 6/96 died from breast cancer: 3/14 had calcifications alone, 2/56 had spiculated masses, 1/12 had rounded mass, 5/78 were node-negative and 1/4 was node-positive. The survival rate was 93%: 77% for the calcifications alone, 95% for spiculated masses, 91% for rounded masses, 92% for node-negative and 75% for node-positive. Calcifications alone and node positivity, each, carried a significantly higher risk of death.
7.
Grynfeld, Anna
(författare)
bHLH transcription factors in differentiating neuroblastoma cells
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Neuroblastoma is a tumor of the sympathetic nervous system, and arises during early childhood. The tumor is highly heterogeneous and evidence, such as expression of genes normally only expressed during embryonic and fetal stages, suggests that the tumor is of embryonic origin and that the tumor arises as a consequence of perturbed differentiation during the development of the sympathetic nervous system. Transcription factors implicated in this differentiation program are therefore of potential interest in order to understand the genesis of neuroblastoma. Based on findings in Drosophila, several transcription factors playing vital roles in the development of the vertebrate peripheral nervous system have been identified, some of them belonging to the basic helix-loop-helix (bHLH) family. Amplification of the protooncogene N-Myc is one of the most important genetic aberrations in neuroblastoma. There is a high positive correlation between N-Myc amplification and malignancy, but the molecular consequences of this phenomenon have only been partly investigated. The work presented here describes the roles of the bHLH transcription factors HASH-1, HES-1, and the bHLHZip transcription factors N-Myc, Mad proteins, Mnt/Rox, and Max during neuroblastoma cell differentiation. It suggests that a controlled temporal expression patterns of some of these genes are important in order to allow neuronal differentiation to proceed.
8.
Hong, Jaan
(författare)
Investigation of Incompatibility Reactions Caused by Biomaterials in Contact with Whole Blood Using a New in vitro Model.
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
This thesis describes a new in vitro slide chamber model that makes it possible to conduct studies of molecular and cellular interactions between whole blood and biomaterials. The model proved to be a suitable tool for detection of cell and platelet binding to a biomaterial surface. It was possible to monitor activation of the blood cascade systems and cells in the fluid phase and detect surface-bound molecules.One finding was that thrombin generation is primarily triggered by FXII on a biomaterial surface since corn trypsin inhibitor, inhibited thrombin generation in blood.Another finding was that thrombin generation was dependent on variety types of blood cells, since thrombin generation was almost negligible in platelet-rich plasma. When various preparations of blood cells were used to reconstitute platelet-rich and platelet-poor plasma, erythrocytes were shown to be the most efficient cell type in triggering thrombin generation. Inhibition of platelet aggregation with aspirin and Ro44-9883 was associated with a decrease in thrombin generation, confirming that platelet activation is necessary for normal coagulation activation. These findings suggest that the central events consist of an initial low-grade generation of thrombin that involves erythrocytes and possibly leukocytes which leads to activation of platelets; and a second platelet-dependent amplification loop that produces most of the thrombin.Titanium exposed to whole blood produced high amounts of thrombin. Stainless steel and PVC, generated lower amounts. This indicates that titanium might be less suitable as a biomaterial in devices that are in direct contact with blood for prolonged time. Considering the superior osteointegrating properties of titanium and titanium's response to blood, a correlation between high thrombogenicity and good osteointegration seems to exist.Compstatin, that binds to complement component C3, effectively inhibited the generation of C3a and sC5b-9 and the binding of C3/C3 fragments to the surface. Our results suggest that a biomaterial is able to activate complement through both the classical and alternative pathways and that the classical pathway alone is able to maintain a substantial bioincompatibility reaction. The results show that complement activation is a prerequisite for activation and binding of PMNs to the surface in the in vitro model.
9.
Kadar, Lianna
(författare)
Body Protein and its Change in Patients During Anti-Tumor Treatment
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
The purpose of this study was to investigate how total body protein and its fraction of body weight (body protein fraction) change in cancer patients during different anti-tumor treatments, and to see if these changes have any clinical significance in the form of prognostic value or correlation with disease course and tumor response. In 84 patients, 28 with lung cancer, 24 with gastrointestinal tumors, 30 with breast cancer, 1 with non-Hodgkin lymphoma and 1 with kidney cancer, the total amount of body nitrogen was measured using an in vivo prompt gamma neutron activation technique. Using the relationship 1 g nitrogen to 6.25 g protein, the amount of total body protein was calculated. The measurements of body protein and body weight were made during the period of radiation, cytostatic or hormone treatment. Each patient was his or her own control. The precision of the method for measurement of body protein was ±5% (1 SD). In patients with lung cancer, we noted a significant correlation between changes in total body protein during radiotherapy and the recurrence-free interval and overall survival. Patients, in whom body protein decreased, had a significantly shorter time to tumor recurrence than those in whom body protein increased or remained constant. In patients with gastrointestinal tumors we noted a significant difference between the changes in body protein fraction in the patients with loco-regional disease and the patients with metastasized disease, in whom the changes were greatest. Finally, in patients with metastasized breast cancer there was no significant correlation between change in body protein fraction and tumor response. The conclusions are that the amount of body protein in cancer patients changes during the disease and anti-tumor treatment. The amount of body protein in patients with lung cancer has a prognostic value, as a decrease of body protein is an indicator of tumor invasion and early metastasis as well as a decreased overall survival. In patients with gastrointestinal tumors a correlation between change in body protein fraction and course of the disease was seen.
10.
Koul, Anjila
(författare)
Molecular Genetic Alterations In Endometrial And Ovarian Cancers
2001
Doktorsavhandling (övrigt vetenskapligt/konstnärligt) abstract
Endometrial cancer is the most common gynecological cancer diagnosed in western countries. Complex atypical hyperplasia (CAH) reflects a state of hyperestrinism and its role as a precursor lesion of this cancer is established. Endometrial cancers arising in association with CAH are reported in women of younger age, with early stage disease, favorable histological types, higher progesterone receptor levels and clinically better survival prognosis. However, the molecular events delineated in these two pathogenetic types are less known. Hereditary nonpolyposis colon cancer is caused by germline mutations in DNA mismatch repair (MMR) genes, and associated mainly with cancer in the colon, while endometrial and ovarian cancer are the most common extracolonic malignancies in these patients. Tumors from mutation carriers are characterized by an microsatellite instability (MSI) phenotype, and a subset of sporadic colon cancer demonstrates MSI and somatic mutations in MMR genes. MSI is also reported in a subset of sporadic endometrial cancers, although without identifiable mutation in MMR genes. In this study, endometrial cancers histologically checked for presence/absence of CAH were analyzed for mutations in the TP53, PTEN, KRAS, B-catenin, CDKN2A, BRCA1, and BRCA2 genes, as well as for their DNA ploidy and MSI. Two thirds of the endometrial tumors included in the study contained mutation in either of the seven genes analyzed, but very few cases with coexisting mutations were recorded, suggesting alternate genetic pathways in tumorigenesis. We found that PTEN, KRAS, B-catenin, and TP53 mutations were present in tumors both with and without CAH. PTEN mutations associated with MSI and DNA diploidy, while TP53 mutations related to DNA nondiploidy. Approximately 90% of all endometrial cancers are diagnosed in surgical stage disease I and II, with a five-year survival of 85% to 70%, respectively. A consensus opinion regarding useful prognostic markers to identify a “high-risk” subset among these patients is, however, lacking. In this study, TP53 alterations (mutation or protein overexpression) correlated to several clinicopathological markers of poor prognosis in endometrial cancer, and decreased progression-free survival in both early and advanced stage disease. However, DNA nondiploidy seemed to be an even better marker of poor prognosis in patients with early stage disease (I-II). The strongest risk factor for ovarian cancer is a positive family history of ovarian or breast cancer. While the majority of familial cases are associated with germline BRCA1 or BRCA2 mutation, the frequency of mutations in cases unselected for family history is still unclear. In the present pilot study of ovarian tumors, we detected a surprisingly high frequency of both germline and somatic BRCA-gene mutations, emphasizing the importance of extended analysis of population-based series of patients to determine the true contribution of these predisposing genes to the overall incidence of ovarian cancer in this population. BRCA-gene mutations strongly associated with a serous/seropapillary histological type. Unexpectedly, BRCA1 mutations were seen in two cases of ovarian cancer with brain metastasis.
