| 31. |
- Aus, Gunnar, et al.
(författare)
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Prognostic Factors and Survival in Node-Positive (N1) Prostate Cancer : A Prospective Study Based on Data from a Swedish Population-Based Cohort
- 2003
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Ingår i: European Urology. - 0302-2838 .- 1873-7560. ; 43:6, s. 627-631
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Tidskriftsartikel (refereegranskat)abstract
- Objective: At presentation of prostate cancer, patients with proven lymph node metastasis (N1) are comparatively rare. It is difficult to give prognostic information based on the present literature. The aim of this study was to evaluate the impact of known risk factors in patients with pelvic node involvement and without distant metastasis. Methods: From the population-based, prospective prostate cancer tumour registry of the South–East Region in Sweden, we collected data on all 181 patients with N1, M0 prostate cancer diagnosed from January 1987 to October 2000 with a follow-up to December 2001. Mean follow-up was 62 months. Pre-operative risk factors as age, T-category, serum PSA, tumour grade and also primary treatment given was correlated to the outcome. Results: Median age at diagnosis was 65 years. Cancer-specific survival was highly variable with 5-year survival of 72%, a median of 8 years and the projected 13-year figure was 31%. T-category, age, PSA or treatment did not affect the outcome while poorly differentiated tumours had a tendency towards lower cancer-specific survival (p=0.0523) when compared to well and moderately differentiated tumours. Conclusions: This population-based cohort of prostate cancer patients with pelvic node involvement treated principally with non-curative intent had a median cancer-specific survival of 8 years. Preoperatively known risk factors seem to have but a modest impact on the prognosis for patients in this stage of the disease.
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| 32. |
- Amini, Rose-Marie, 1969-
(författare)
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Hodgkin Lymphoma : Studies of Advanced Stages, Relapses and the Relation to Non-Hodgkin Lymphomas
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The relationship between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is not entirely elucidated and a clonal relation may be present more often than previously believed. Mechanisms of tumour progression and resistance to therapy are poorly understood.Between 1974 and 1994 all individuals in Sweden with both HL and NHL were identified. Thirty-two cases were studied using clinical, histopathological and immunohistochemical methods. The second lymphoma often appeared in an aggressive clinical form and a significant correlation between the expression of p53 and LMP-1 in the first and second lymphoma was demonstrated.The treatment outcome for 307 patients with advanced stages of HL, in an unselected population was in accordance with the treatment results of large centres world-wide. Some patients were successfully selected for a shorter chemotherapy-regimen without inferior treatment results.In 124 patients with relapse, the survival of those primarily treated with radiotherapy according to the National guidelines was in accordance with the survival of patients of initially advanced stages. A worse outcome was found for those who received both chemotherapy and radiotherapy initially, probably because of a higher frequency of bulky disease in this group. Immunohistochemical analysis of the tumour suppressor protein p53 and retinoblastoma protein (Rb) of paired samples at diagnosis and at relapse in 81 patients did not reveal any specific staining pattern affecting survival.A novel B-cell line (U-2932) was established from a patient with a diffuse large B-cell lymphoma previously treated for advanced stage and subsequent relapses of HL. An identical rearranged IgH gene was demonstrated in tumour cells from the patient and in U-2932. A p53 point mutation was detected and over-expression of the p53 protein was found. A complex karyotype with high-level amplifications of the chromosomal regions 18q21 and 3q27, i.e. the loci for bcl-2 and bcl-6 were demonstrated.
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| 33. |
- Engellau, Jacob
(författare)
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Prognostic factors in soft tissue sarcoma. Tissue microarray for immunostaining, the importance of whole-tumor sections and time-dependence.
- 2004
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Ingår i: Acta Orthopaedica Scandinavica. - : Medical Journals Sweden AB. - 0001-6470. ; 75:Suppl. 314, s. 5-5
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In adult soft tissue sarcoma (STS) of the extremities and trunk wall, improved prognostic factors are needed to identify patients at high-risk for metastasis. Various factors are included in the many prognostic systems currently in use and the prognostic value of immunohistochemical (IHC) expression of biological markers is unclear. The tissue-preserving, high throughput tissue microarray (TMA) technique for analysis of immunohistochemical expression of biological markers was validated for Ki-67, and was found to yield results comparable to conventional staining methods. TMA was used to study the IHC expression of multiple markers (Ki-67, p53, cyclin A, bcl-2, ß-catenin, CD44, and Pgp) in 218 malignant fi brous histiocytomas (MFH) and in 140 mixed STS. In the MFH series, tumor size and Ki-67, as the only IHC marker, provided independent prognostic information. In the mixed STS series whole-tumor sections were used and TMA was performed in the peripheral tumor growth zone. Whole-tumor sections facilitated assessment of the strong independent prognostic factors for metastasis vascular invasion, hazard ratio (HR) 3.5, tumor necrosis (HR 2.8), and tumor growth pattern (HR 3.2), and the latter also correlated with local recurrence (LR). In comparison, histological malignancy grade, tumor size, and depth were not of independent prognostic value. When TMA was performed from the peripheral tumor growth zone, the IHC expression of Ki-67 (HR 1.9), ß-catenin (HR 2.7), CD44 (HR 2.1) and Pgp (HR 2.4) were independent prognostic factors. Finally, prognostic factors were found to be time-dependent, and most factors lost their prognostic value after 2 years, whereas LR was a strong prognostic factor for metastasis whenever it occurred.
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| 34. |
- Graflund, Marianne, et al.
(författare)
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Immunohistochemical expression of p53, bcl-2, and p21WAF1/CIP1 in early cervical carcinoma : Correlation with clinical outcome
- 2002
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Ingår i: International Journal of Gynecological Cancer. - Malden, USA : BMJ. - 1048-891X .- 1525-1438. ; 12:3, s. 290-298
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to assess the value of p53, bcl-2, and p21WAF1/CIP1 immunoreactivity as predictors of pelvic lymph node metastases (LNM), recurrences, and death due to the disease in early stage (FIGO I-II) cervical carcinomas. FIGO stage, type of histopathology, and tumor grade were also evaluated in this series of patients treated by radical hysterectomy (Wertheim-Meigs) between 1965 and 1990. A total of 172 patients were included. A tumor was regarded as positive when more than 30% of the neoplastic cells exhibited immunoreactivity. Positive immunostaining was found in 8.9% for p53, in 43.5% for bcl-2, and in 25.0% for p21WAF1/CIP1. None of them was able to predict LNM or clinical outcome. Presence of LNM, tumor recurrence, and death from disease were significantly associated with the FIGO stage (P = 0.014, P = 0.009, and P = 0.001, respectively). The 5-year cancer-specific survival rate was 91.6% and the overall survival rate was 90.5%. It was concluded that immunohistochemically detected p53, bcl-2, and p21WAF1/CIP1 appeared to be of no predictive value with regard to LNM, tumor recurrences, or long-term survival in early cervical carcinomas.
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| 35. |
- Höglund, Johanna, 0070-
(författare)
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On the Use of 76Br-labelled Monoclonal Antibodies for PET : Preclinical Evaluation of Halogenated Antibodies for Diagnosis and Treatment of Cancer
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Radioactive substances are used in vivo to localize and characterize malignant tumours, generally by scintigraphic methods. In this context positron emission tomography (PET) in combination with radiolabelled monoclonal antibodies (mAbs) may provide a sensitive and specific method for detection of cancer. Individual dose calculations, based on such PET measurements, may be carried out to predict the possible use of mAbs labelled with therapeutic nuclides. The positron emitter 76Br, with a half-life of 16 h, is a well-suited candidate for radiolabelling and PET imaging. One drawback of radiobromine is that bromide, the ultimate catabolite after degradation of brominated mAb, is only tardily excreted from the body and is evenly distributed throughout the extracellular space, thereby increasing the background radioactivity. The aim of this work was to produce 76Br-mAb preparations with high accumulation and retention in tumour tissue together with a quick clearance of 76Br-labelled catabolites. Furthermore, the possibility to use brominated or iodinated mAbs in combination with PET to predict 211At-mAb dosimetry was evaluated.Monoclonal Abs directed against colorectal cancer were labelled with 76Br using the direct Chloramine-T-method or indirectly by labelling the precursor molecule N-succinimidyl para-(tri-methylstannyl) benzoate with 76Br, which was subsequently conjugated to the mAbs. Monoclonal Ab A33 labelled with 76Br using the two labelling protocols was characterized in vitro and in vivo in a rat tumour xenograft model. The mAb A33 was also labelled with 125I for comparison. In addition, mAb A33 was labelled with 211At, 125I and 76Br using the indirect labelling protocol and the mAb pharmacokinetics was studied in normal rats in order to estimate if data from brominated or iodinated mAb could be used for dosimetry of 211At in healthy organs and tissue.In conclusion, both direct and indirect labelling resulted in high yields and mAbs with preserved immunoreactivity. In vivo characterization of 76Br-brominated mAb A33 showed that the indirect labelling method makes 76Br-brominated mAb A33 a promising candidate for tumour imaging with PET due to the faster excretion of radiolabelled catabolites compared with direct bromination. Finally, mAb A33 labelled with 76Br and 124/125I can be used to predict the 211At dose of astatinated mAb A33 in most organs given that a correction factor is applied for organs with varying uptake.
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| 36. |
- Jerkeman, Mats
(författare)
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Aggressive lymphoma
- 2000
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aggressive lymphoma is a rapidly growing tumour of lymphocyte origin, potentially curable with chemotherapy. In a trial by the Nordic Lymphoma Group, 405 patients with aggressive lymphoma were included, and randomised to receive either the standard chemotherapy regimen, CHOP, or a weekly multidrug regimen, MACOP-B. In this trial, MACOP-B was not superior in terms of response, failure-free or overall survival, but was associated with more non-haematological toxicity and with more pronounced negative effects on health-related quality of life (HRQOL). In this study, we were able to validate the prognostic impact of the International Prognostic Index (IPI). In 92 patients, assessment of HRQOL was performed before, during, and after chemotherapy. In this population, chemotherapy was associated with relatively little negative impact on HRQOL, compared to a reference population. In a multivariate analysis of prognostic factors, pre-treatment global quality was identified as an independent prognostic factor. In 259 patients, immunohistochemical analysis of Ki-67, BCL2, p53 and P-glycoprotein was performed. In a multivariate model, high BCL2 expression, high p53 expression and both very high and low Ki-67 expression were associated with poor prognosis, and were shown to provide additional prognostic information to the IPI. Assessment of BCL2 is proposed to be included as a routine procedure in patients with aggressive lymphoma. In 32 patients with diffuse large B-cell lymphoma (DLBL), frozen lymphoma tissue was available, enabling assessment of BCL6 rearrangement with Southern blot. BCL6 rearrangement was detected in six of 50 patients (12%) and among these, a trend towards superior overall and failure-free survival was noted. In a consecutive series of 81 patients with cytogenetically analysed DLBL, the prognostic impact of cytogenetic aberrations of previously proposed prognostic importance, was analysed. In univariate analysis, der(1q)(21-23), was associated with inferior overall survival. Among patients receiving anthracyclin-based chemotherapy, der(1q)(21-23) remained an adverse prognostic factor in a multivariate analysis, stratified for IPI. The implications of these results in relation to current findings in prognostication and treatment of patients with aggressive lymphoma is discussed.
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| 37. |
- Jögi, Annika
(författare)
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Transcriptional regulation in neuroblastoma cells under normoxic and hypoxic conditions
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The childhood malignancy neuroblastoma develops from early cells of the sympathetic nervous system (SNS), and the tumors often produce catecholamines. Neuroblastoma cells retain several characteristics of immature sympathetic cells including the expression of a number of transcription factors normally expressed during embryogenesis. The genesis of the SNS requires the correct expression pattern of several transcription factors of the basic helix-loop-helix (bHLH) family, such as HASH-1 a pro-neuronal gene. HASH-1 expression is negatively regulated by another bHLH factor, HES-1. In these studies, we show that HASH-1 form transcription activating dimers with the ubiquitously expressed bHLH factor E2-2 in neuroblastoma cells. Furthermore, we establish that the Id proteins, which lack the basic DNA-binding domain and act as dominant negative inhibitors in the bHLH network, bind to HES-1. By dimerization with HES-1 the Id proteins may act to repress the HES-1 mediated transcriptional repression. In addition, HES-1 can alleviate the negative effect of Id proteins on bHLH factor induced transcription, by sequestration of Id. These findings reveal a novel regulatory level of the bHLH network. Solid tumors most often contain regions with impaired circulation and hypoxia. Two transcription factors of the bHLH/PAS subgroup, the hypoxia inducible factors HIF-1a and HIF-2a, are key regulators of the cellular response to oxygen deprivation. Interestingly, HIF-2a is also expressed in the developing SNS and required for catecholamine production, and HIF-2a deficient mice die with bradycardia before birth. The dual implications of HIF-2a in neuroblastoma tumors, involvement in SNS development as well as in adaptation to the tumor microenvironment , prompted us to investigate how neuroblastoma cells respond to growth under hypoxic conditions. Unexpectedly, we found that hypoxia (1% oxygen) drive the neuroblastoma cells toward an immature and neural crest-like phenotype. Several neuronal and neuroendocrine marker genes, such as chromogranin A/B, NPY, and HASH-1, were down-regulated in response to oxygen deprivation, whereas a number of genes expressed during early neural crest development were up-regulated, examplified by c-kit, Notch-1, and Id2. To further delineate the the hypoxic phenotype of human neuroblastoma cells, we have analyzed their gene expression after 72 h exposure to hypoxia employing microarray analysis harboring 35 000 clones. Almost one percent of the represented transcripts were up-regulated more than three-fold and about 0.5 % were down-regulated more than three-fold in response to hypoxia. The microarray results strenghten our view of hypoxic neuroblastoma cells as less mature. To test whether hypoxia-induced dedifferentiation is a neuroblastoma specific event or may occur also in other solid tumors, we have analyzed a panel of ductal breast carcinoma in situ. Also in these tumors, were hypoxia associated with a less mature phenotype of the tumor cells. We propose hypoxia-induced dedifferentiation as one means by which intra-tumor hypoxia drives tumor propagation.
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| 38. |
- Kinhult, Sara
(författare)
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Endothelial and cardiac effects of 5-fluorouracil. An experimental and clinical study.
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The cytostatic drug 5-fluorouracil (5-FU) has been shown to affect both morphology and function of vascular endothelium. These effects could be part of the pathophysiology for 5-FU induced cardiotoxicity. The present thesis explores the mechanisms of this endothelial toxicity. In an animal model, treatment with thromboprophylactic doses of the low-molecular weight heparin (LMWH) dalteparin could not protect the endothelium from damage caused by 5-FU, although the secondary thrombosis was prevented. A subsequent study with three different LMWH (dalteparin, enoxaparin and tinzaparin) showed a moderate endothelial injury after treatment with LMWH alone for up to 60 days. Probucol, a lipid-lowering drug with strong antioxidant properties, was given as prophylaxis for two weeks before 5-FU treatment. With this drug, the endothelium was protected from the negative effects of 5-FU and had a normal morphology. Patients receiving 5-days infusion of 5-FU, combined with cisplatin, were studied for endothelial and cardiac effects. There was a significant increase in markers for endothelial injury (von Willebrand factor and soluble thrombomodulin) and in malondialdehyde, a marker for increased lipoperoxidation and possibly free radical production. Myocardial and echocardiographic parameters were not changed. Human umbilical vein endothelial cells (HUVEC) were incubated with 5-FU. A dose-dependant increase in secretion of endothelin-1 (a potent vasoconstrictor) was shown. No influence of apoptosis was seen. The results indicate increased oxidative stress caused by 5-FU, followed by endothelial damage and secretion of a vasoactive peptide. This could be part of the pathophysiological mechanisms of 5-FU induced cardiotoxicity.
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| 39. |
- Lindqvist, Rikard, et al.
(författare)
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Hospital stay related to TNM-stage and the surgical procedure in primary breast cancer.
- 2004
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Ingår i: Acta Oncologica. - : Informa UK Limited. - 0284-186X .- 1651-226X. ; 43:6, s. 545-50
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Tidskriftsartikel (refereegranskat)abstract
- In Sweden from 1980 to 1995 there was an overall decrease of 56% in mean length of stay (MLOS) for surgical curative breast cancer treatment. The objective of this study was to separate the possible impact of tumour size and lymph node dissemination and changes in surgical procedures. All women diagnosed (n=13 290) with breast cancer between 1982 and 1995 were selected from the Southern Swedish Tumour Register. Data on LOS, diagnoses, and surgical procedures were obtained from the Swedish Hospital Discharge Register. A multi-factorial model was fitted to the data. Discharges where patients were treated with breast conserving surgery had more than two days shorter MLOS (-2.49, 95% CI -1.66) compared with mastectomy. Although TNM data imply a shift from T2 to smaller T1 among operated women the effect on MLOS is negligible when controlled for age, type of operation etc. Changes in clinical practice such as changes in operation technique can explain approximately 13% of the total decrease in MLOS.
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| 40. |
- Massoumi, Ramin
(författare)
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Regulation of the cytoskeleton and the adhesiveness of intestinal epithelial cells by leukotriene D4
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Leukotrienes belong to a family of biologically active conjugated trienes that are formed from arachidonic acid via the 5-lipoxygenase pathway and are important mediators of inflammatory reactions. The CysLT1 receptor that specifically serves as receptor for leukotriene D4 (LTD4) has been identified as a G-protein coupled receptor. Cell-cell and cell-matrix complexes of epithelial cells are interconnected through cytoskeletal filaments and proteins, and they influence the activities and outcome of various cellular processes. This thesis is focused primarily on the effect that LTD4 has on reorganisation of the actin cytoskeleton and on cell-cell and cell-matrix adhesion properties. We found that LTD4 caused dramatic changes in the actin cytoskeleton in intestinal epithelial cells, and an important factor in this context was the impact of this leukotriene on the actin-binding protein vinculin, which included inducing translocation of vinculin from a cell-cell to a cell-matrix complex. In general, cell adhesion favours cell survival signalling, and integrins are the main receptors responsible for mediating the attachment of different types of cells to matrix proteins. We have unequivocally established that direct signalling occurs between the LTD4 receptor and the collagen integrins in two different cell lines respectively derived from human colon carcinoma and intestinal epithelial cells. Increased adhesion of the cancer cells depended on activation of cyclooxygenase-2, an enzyme that is involved in progression of colon cancers, whereas adhesion of the intestinal epithelial cells was augmented by LTD4-induced translocation of protein kinase C to areas where integrins bind to matrix proteins (focal adhesions). In conclusion, inflammatory mediators such as LTD4 can affect cell survival through their impact on specific integrins.
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