| 1. |
- Lidgren, Anders, 1975-
(författare)
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Hypoxia inducible factor-1α in renal cell carcinoma
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Hypoxia Inducible Factor-1α in Renal Cell Carcinoma Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability. Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters. Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis. TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis. GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen. HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed. Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.
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| 2. |
- Crnalic, Sead, 1960-
(författare)
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Metastatic spinal cord compression in prostate cancer : clinical and morphological studies
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Bone metastases occur in most patients with advanced hormone-refractory prostate cancer causing pain, pathologic fractures, and spinal cord compression. Few studies specifically address surgical treatment of metastatic spinal cord compression (MSCC) in prostate cancer. Criteria for identifying patients who may benefit from surgery are poorly defined. Most of the current knowledge regarding tumor biology in prostate cancer is based on studies of primary tumors or soft tissue metastases. The mechanisms regulating growth of bone metastases are not fully established. Aims: a) to evaluate outcome after surgery for MSCC in prostate cancer and to identify prognostic factors for survival and functional recovery; b) to evaluate current practice for referral of prostate cancer patients with MSCC; c) to analyze expression of androgen receptor (AR), cell proliferation, apoptosis, and prostate-specific antigen (PSA) in bone metastases with regard to survival after surgery for complications of bone metastases. Patients and Methods: We retrospectively evaluated the hospital records of 68 consecutive patients operated for metastatic spinal cord compression. Tumor tissue from bone metastases was obtained on spinal surgery (54 patients), fracture surgery (4 patients) and biopsy (2 patients), and analyzed by immunohistochemistry. Results: Study I: Mortality and complication rate after surgery was high. Patients with hormone-naïve disease and those with hormone-refractory disease with good performance status and without visceral metastases had more favorable survival. The ability to walk after surgery was related to better survival. Study II: A new score for prognosis of survival after surgery for spinal cord compression includes: hormone status of prostate cancer, Karnofsky performance status, evidence of visceral metastasis, and preoperative serum PSA. The score is simple, tumor specific, and easy to apply in clinical practice. Study III: Our results suggest that delays in diagnosis and treatment may have negative impact on functional outcome. Pretreatment ability to walk, hormone status of prostate cancer, and time from loss of ambulation influenced neurological recovery after surgery for spinal cord compression. Study IV: High nuclear AR immunostaining in bone metastases and high preoperative serum PSA were associated with a poor outcome after metastasis surgery in patients with hormone-refractory prostate cancer. Short-term effect of castration therapy disclosed that nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected. Conclusion: Prostate cancer patients with metastatic spinal cord compression represent a heterogeneous group. We identified prognostic factors for survival and functional outcome, which may help clinicians in making decisions about treatment. Our results also implicate the need for development of local and regional guidelines for treatment of patients with spinal cord compression, as well as the importance of information to patients at risk.
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| 3. |
- Jacobsen, Jan, 1957-
(författare)
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Vascular endothelial growth factor in renal cell carcinoma
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Angiogenesis is essential for tumour growth. Vascular endothelial growth factor (VEGF) and its isoforms were investigated in relation to the clinical course in a large number of patients with renal cell carcinoma (RCC). Methods. RCC subtypes and behaviour were established by clinicopathological criteria and surveillance. VEGF expression was analysed in serum by enzyme-linked immuno-sorbent assay (ELISA) and in tumour tissue by reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry (IHC), and Western blot (WB). Results. Serum VEGF (S-VEGF) was increased in RCC compared to control group. S-VEGF correlated with tumour stage and grade and was associated with survival in men but not in women. S-VEGF correlated with blood platelet counts, which were inversely correlated to increasing age in women, and they were decreased in chronically medicated patients, particularly in men. In contrast to S-VEGF, platelet counts associated with survival only in patients free of medication and chronic diseases. RT-PCR showed a correlation between VEGF121/VEGF165 mRNA and between VEGF165/VEGF-R1 mRNA. There was no association between different VEGF mRNA isoforms and S-VEGF. Conventional renal cell carcinoma (CRCC) had higher VEGF165, VEGF121, and VEGF-R1 mRNA levels compared with papillary renal cell carcinoma (PRCC). IHC VEGF staining was strong in kidney cortex. Kidney tumour showed a considerable variation in cytoplasmatic VEGF expression, which correlated with tumour size. Although, there was no difference in VEGF expression between the RCC types, VEGF expression was associated with survival only in CRCC. WB showed a strong protein expression of both VEGF189 and VEGF165 in kidney cortex. In kidney tumour, expression of VEGF189 varied the most, VEGF165 less so, and VEGF121 was rarely detected. Both CRCC and PRCC expressed low levels of VEGF189 and VEGF165 compared with kidney cortex. Chromophobe renal cell carcinoma (ChRCC) expressed VEGF189 levels comparable to those from kidney cortex, while VEGF165 was lower. In PRCC and ChRCC, VEGF189 levels correlated inversely with advancing tumour stage, and in PRCC, VEGF165 levels correlated inversely with increasing tumour size. VEGF189 was an independent prognostic factor for survival in patients with PRCC. Conclusions. S-VEGF has a stronger association to progression in RCC than platelet count. CRCC showed high levels of VEGF mRNA isoforms and VEGF-R1 mRNA compared to PRCC. VEGF mRNA isoforms expression decreased with advancing stage. IHC demonstrated VEGF expression in cell cytoplasm related to tumour growth, particular in CRCC. Different VEGF isoform patterns were found in different RCC types. Protein VEGF189 expression was associated with tumour stage and was an independent prognostic factor in PRCC. Protein VEGF165 expression was generally low and had no prognostic value. The trend for decreasing levels of VEGF isoforms in advanced tumour stages may indicate that angiogenic activity is an early event in tumour growth induced by VEGF, but that during later tumour progression the role of VEGF is less clear.
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| 4. |
- Järemo, Helena, 1988-
(författare)
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MicroRNA expression profiles in prostate cancer bone metastases : functional effects of microRNA-23c, -375, and -4328
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Non-coding microRNAs (miRNAs) function as post-transcriptional regulators of gene expression by interacting with messenger RNA. Dysregulation of miRNAs has many possible consequences, including tumor-suppressive or -promoting ones, and restoring or preventing the effects of miRNA alteration has therapeutic potential.Metastatic prostate cancer (PC) spreads to the bone and is treated with castration therapy. Eventually, metastases relapse into castration-resistant PC (CRPC) growth. Recently, our laboratory described metastatic PC subtypes, termed MetA-C, defined based on transcriptomic differences and linked to different morphology and prognosis. Patients with MetB metastases have particularly poor prognosis.The overall aim of the thesis was to identify novel biomarkers and therapeutic targets for metastatic PC, with a focus on miRNAs. The specific aims were to: (1) identify miRNAs associated with PC progression into bone metastasis, and their functional roles; (2) verify the MetA-C subtypes, their prognostic importance, and their relation to genetic profiles in independent validation cohorts; (3) explore miRNA expression profiles of PC bone metastases, specifically in relation to the MetA-C subtypes, and whether specific miRNAs show potential to inhibit the aggressive MetB subtype.Study 1: Differentially expressed miRNAs (n=79) were identified by microarray analysis by comparing miRNA levels in bone metastatic (n=14) or localized PC (n=7) samples to benign samples (n=7). Downregulation of miRNA-23c and -4328 was verified by qRT-PCR analysis, including a larger cohort of bone metastases (n=67). Overexpression of miRNA-23c or -4328 in PC cells resulted in attenuated cell growth in vitro. High levels of miRNA-23c were detected in extracellular vesicles shed from overexpressing cells. Overexpression of miRNA-23c did not obviously affect tumor growth or angiogenesis in vivo. Study 2: The existence and prognostic value of the MetA-C subtypes was verified by transcriptomic analysis of bone metastasis samples (n=103), and by subtyping publicly available data from metastatic samples (n=573) from external patient cohorts. The MetB subtype was associated with high tumor-cell proliferation, low androgen receptor activity, and poor prognosis in all cohorts, and provided independent prognostic information in addition to genetic aberrations.Study 3: The miRNA profiles of 96 bone metastasis samples from Study 2 were examined using microarray analysis. Four sample clusters not obviously related to the MetA-C subtypes were observed. Expression levels of miRNA-375, however, were inversely related to MetB. MiRNA-375 overexpression in C4-2B resulted in a cellular switch of subtype, from being dominant MetB to dominant MetA. In parallel, reduced cell growth and signs of increased cell adhesion were observed.In conclusion, altered miRNA profiles may contribute to progression of PC into bone metastasis, and to the development of different metastasis subtypes. The MetB subtype is associated with poor prognosis and low expression of miRNA-375. Therapy stratification based on the MetA-C subtypes should be considered in the future. Restoration of miRNA-375 in MetB tumors may offer a novel treatment option.
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| 5. |
- Josefsson, Andreas, 1979-
(författare)
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Prognostic markers in prostate cancer : studies of a watchful waiting cohort with long follow up
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Prostate Cancer (PC) is a common and highly variable disease. Using current diagnostic methods, the prostate specific antigen (PSA) blood test and histological grading of prostate tissue needle biopsies, it is often difficult to evaluate whether the patient has a PC that requires active treatment or not. The absolute majority of all 10,000 cases of PCs diagnosed annually in Sweden have tumours graded as Gleason score (GS) 6-7 and a PSA value in blood below 10. Many of these are harmless and can be left without active treatment and hence spared problematic post-therapy side-effects, others are highly malignant and require early diagnosis and treatment. Better prognostic markers are needed and the aim of this study was to evaluate prognostic markers and to test if these markers could identify patients with indolent tumours. Methods: We have studied tumour material from 419 men consecutively diagnosed with PC at transurethral resection (1975-1990). The majority of these patients (295) had no metastasis at diagnosis and was not given any curative treatment and only hormonal treatment upon symptoms from metastatic progression. Standard histological sections and tissue microarrays (TMA) from these tumours and surrounding normal prostate tissue were stained and evaluated for cell proliferation (Ki67), blood vessels (endoglin and von Willebrand factor, vWf) and the extracellular matrix component hyaluronan (HA). An orthotopic rat PC model was used to explore hyaluronan staining, hyaluronic acid synthase (HAS)-1 mRNA levels and the effect of local HA treatment on tumour growth. Results: Tumour cell proliferation (Ki67) and the density of intra-tumoural endoglin stained blood vessels were independent prognostic markers (i.e. they added prognostic information to the conventional prognostic markers; clinical stage and GS). None of the GS 6 patients with low staining for both Ki67 and endoglin died of PC within 15 years of follow-up. High HA staining in the tumour epithelium and stroma was a negative prognostic marker of cancer specific survival but they were not independent of GS. High HA staining and high vascular density in the stroma of the surrounding morphologically normal prostate were prognostic for short cancer specific survival. Implantation of tumour cells in the normal rat prostate resulted in an increase in HA and HAS-1 mRNA levels in the prostate tissue surrounding prostate tumours. Concurrently intra-prostatic injection of HA also stimulated tumour growth. Conclusions: By evaluating both tumour cell proliferation (Ki67) and vascular density, it is possible to identify patients with very low risk of cancer specific death in the absence of active treatment. Prostate tumours influence the surrounding non-malignant prostate tissue, for example they cause an increased angiogenesis and synthesis of hyaluronan. Such responses can possibly be used to diagnose PC and to evaluate PC aggressiveness.
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| 6. |
- Sandlund, Johanna, 1979-
(författare)
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Angiogenesis in human renal cell carcinoma : hypoxia, vascularity and prognosis
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Angiogenesis is recognised as a critical step in tumour progression. The angiogenic switch is activated by various trigger signals, such as hypoxia, low pH, and genetic mutations. Renal cell carcinoma (RCC) is often an aggressive tumour, and advanced disease has limited treatment options and bad prognosis. This study was focused on markers of angiogenesis in RCC: endoglin (CD105) and CD31 assessing microvessel density (MVD), and carbonic anhydrase (CA) IX and hypoxia-inducible factor (HIF)-2α expressed at hypoxia. Upregulation of HIF is also associated with inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene, which is common in conventional/clear cell (c)RCC. Method: A tumour bank containing 308 tumours from patients operated 1982-2003 was used. The tumours were well characterised regarding tumour type, TNM stage, nuclear grade, tumour size, and patient survival. The tumours were prepared in tissue microarrays and fresh frozen in whole sections. To analyse the expression of endoglin, CD31, CA IX, and HIF-2α mRNA, immunohistochemistry and real-time PCR were used. Results: There was a higher endoglin expression in cRCC than in papillary (p)RCC and chromophobe (ch)RCC, and a higher CD31 expression in cRCC than in pRCC. MVD correlated inversely to TNM stage and nuclear grade in cRCC. There was also an inverse correlation between tumour diameter and CD31 expression in cRCCs. Patients with cRCC with high MVD had a more favourable prognosis than patients with lower MVD. Endoglin and CD31 were not independent prognostic factors. The CA IX expression was higher in cRCC than in pRCC and chRCC. Patients with cRCC expressing low CA IX had a significantly less favourable prognosis compared with those with higher expression. CA IX is an independent prognostic factor. There was a higher HIF-2α mRNA expression in cRCC than in pRCC and chRCC. In cRCC, there was a significant inverse correlation between HIF-2α mRNA expression, and TNM stage and nuclear grade. There was also an inverse correlation between HIF-2α mRNA expression and tumour size among patients with cRCC. HIF-2α was not an independent prognostic factor. Conclusion: In these studies, the factors related to hypoxia and vascularity were all inversely correlated to tumour aggressiveness in cRCC. MVD, CA IX, and HIF-2α expression were also higher in cRCC than in pRCC and chRCC. The relationship between angiogenesis, vascularity, and hypoxia is ambiguous. A line of reasoning including mutations increasing angiogenesis in advanced disease may also be applied to RCC. Measurements of individual angiogenic factors seem to provide prognostic information, and can potentially be combined in patient monitoring and treatment.
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| 7. |
- Stenman, Katarina, 1963-
(författare)
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Prostate Cancer Diagnosis : experimental and Clinical Studies With HRMAS NMR Spectroscopy
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- A few abnormal cells found in a small piece of prostate tissue are most consequential for a man’s future. The prevalence of prostate cancer (PCa) is increasing globally. The main instigating factor for this cancer is not yet known, but it appears to be the consequence of many variables such as an increasingly older population, more frequent PSA-testing, and factors involving lifestyle. Prostate cancer screening, as an equivalent for breast cancer screening, has been suggested but unfortunately there are no accurate diagnostic tools available for this type of screening. The reason for this is simply that the prostate is one of the most difficult organs to diagnose and, consequently, PCa screening would generate far too many false-positive and false-negative results. The prostate is not easily accessible as it is deeply-seated in the male pelvic area, wrapped around the urethra and surrounded by sensitive vital organs. Furthermore, PCa is frequently multi-focal, and the cancer cells have a tendency of assimilating among normal cells and, thus, do not always form solid lumps. Therefore, prostate tumors are often not felt by digital rectal examination (DRE) or identified by imaging. The PSA-test is not reliable as it is more prostate-specific than cancer-specific. Due to increasing prostate awareness, more early-stage and locally confined PCa are being detected. This is saving lives, although there is a high risk of over treatment and unnecessary side-effects. The increased detection of PCa requires sophisticated diagnostic methods and highly skilled clinicians who can discern between indolent and aggressive cancers. The current “gold-standard” for PCa diagnosis is biopsy grading by pathologists using the Gleason score system, which is a difficult task. Therefore, innovative methods to improve the precision of prostate diagnosis, by increased biopsy sensitivity and tumor localization, are of essence. In light of these difficulties, the metabolomic approach using 1D and 2D high-resolution magic angle spinning (HRMAS) NMR spectroscopy combined with histopathology on intact prostatectomy specimens was evaluated in this research project. The non-destructive nature of HRMAS NMR enables spectroscopic analysis of intact tissue samples with consecutive histological examinations under light microscope. Metabolomics aids in the unraveling and the discovery of organ-specific endogenous metabolites that have the potential to be reliable indicators of organ function and viability, extrinsic and intrinsic perturbations, as well as valuable markers for treatment response. The results may, therefore, be applied clinically to characterize an organ by utilizing biomarkers that have the capacity to distinguish between disease and health. The aim was to characterize the human and the rat prostate in terms of its intermediary metabolism, which I show here to differ between species and anatomical regions. Furthermore, the aim is to seek the verification of HRMAS NMR derived metabolites which are known to be a part of the prostate metabolome such as, citrate, choline, and the polyamines which were performed, but also the identification of metabolites not previously identified as part of the local prostate metabolism, such as Omega-6, which was detected in tumors. The extended aim was to elucidate novel bio-markers with clinical potential. In this study, the common phyto-nutrient, inositol, which appears to possess protective properties, was identified as being a potentially important PCa bio-marker for the distinction between the more indolent Gleason score 6 and the more aggressive Gleason score 7 in non-malignant prostate tissues with tumors elsewhere in the organ. Further studies in this area of PCa research are therefore warranted.
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| 8. |
- Wänman, Johan, 1983-
(författare)
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Clinical and morphological aspects of metastatic spinal cord compression
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Metastatic spinal cord compression (MSCC) is a serious complication of cancer leading to demyelination and axonal damage of the spinal cord with a risk of para/tetraplegia. It is most common in patients with known cancer but may also be the initial manifestation of malignancy (IMM). Patients with MSCC as the IMM have rarely been studied as a separate group. The interaction between the tumour and bone in spinal bone metastasis interferes with regulatory mechanisms, causing the formation of less mechanically competent bone and increasing the risk of spinal instability and fracture. The Spinal Instability Neoplastic Score (SINS) has been proposed as a tool in order to help clinicians evaluate tumour-related spinal instability. The SINS has shown excellent inter- and intraobserver reliability, but its prognostic value is still controversial. Bone metastases from prostate cancer are generally classified as osteoblastic due to increased bone formation. However, this categorization is probably oversimplified since there are overlapping bone cell activities between osteoblastic and osteolytic metastases. Prostate cancer bone metastases can also have a myeloma-like radiological appearance, but little is known about this subgroup of lesions. Aims: The aims of this work were as follows: a) to evaluate outcomes after surgery in patients with MSCC as the IMM; b) to analyse the prognostic value of the SINS regarding survival and neurological function after surgery for MSCC in patients with prostate cancer and haematological malignancies; and c) to analyse the clinical and morphological features of prostate cancer spinal bone metastases with a myeloma-like radiological appearance. Patients and methods: In studies I-III, we retrospectively evaluated the outcomes after surgery for MSCC in patients with MSCC as the IMM (study I, n=69), prostate cancer (study II, n=110) and haematological malignancies (study III, n=48). In study IV, tumour tissue samples from bone metastases obtained during surgery for MSCC in 110 patients with prostate cancer were analysed by immunohistochemistry and molecular transcriptomic analyses, and the results were related to the radiological appearance and clinical outcomes. Results: Study I: The primary tumour was identified in 59 of 69 patients. The median postoperative survival after surgery for MSCC was 20 months. Patients with prostate cancer had the longest median survival (6 years), and patients who were defined as having cancer of unknown primary tumour had the shortest median survival (3.5 months). Surgery maintained and improved the ability to walk in these patients. Study II: A total of 106 of 110 patients met the SINS criteria for potential instability or instability. There was no statistically significant difference in the overall risk of death between the SINS potentially unstable and unstable SINS categories, or in the risk of loss of ambulation one month after surgery. Study III: The median postoperative survival was 71.5 months in patients with myeloma and 58.7 months in patients with lymphoma. The SINS was not related to postoperative survival or neurological outcomes. The ability to walk before surgery was strongly associated with the postoperative ambulatory status. On multivariate Cox regression analysis, the ability to walk and a higher blood haemoglobin level prior to surgery were associated with superior survival. Study IV: A myeloma-like radiological appearance of prostate cancer spinal bone metastases was associated with poor survival and neurological outcomes after surgery for MSCC. Conclusions: Patients with MSCC as the IMM resemble a heterogeneous group in which survival is highly dependent on the type of primary tumour. A diagnostic workup is essential before a prognosis can be estimated in order to select candidates for surgery. The SINS may be helpful in selecting patients for surgery for MSCC, but it cannot be used to predict postoperative survival or neurological outcomes in patients with prostate cancer or in patients with haematological malignancies. A myeloma-like radiological appearance of prostate cancer spinal bone metastases is a strong negative predictor for survival and neurological outcomes after surgery for MSCC.
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| 9. |
- Bergh, Ann-Charlotte, 1980-
(författare)
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Importance of microenvironment and antigen in the regulation of growth and survival of CLL cells
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Chronic lymphocytic leukemia (CLL) cells rapidly die when put in culture implying that microenvironmental signals delivered by accessory cells confer CLL cells with a growth advantage. Recent findings show that CLL cells are antigen experienced and antigen binding play a critical role in the pathogenesis of the disease. The overall aim of this thesis was to study the influence of the microenvironment and antigen binding in CLL.In paper I, we studied the influence of the small redox-regulatory molecule thioredoxin (Trx) on CLL cell survival and proliferation. We found Trx to be highly expressed in CLL lymph nodes (LNs), secreted from stromal cells surrounding proliferating CLL cells in proliferation centers, indicating growth promoting properties. Secreted Trx was also shown to protect CLL cells from apoptosis.In paper II, oxidized LDL was added to subset #1 CLL cells. However, in contrast to our hypothesis, we could not observe activation and proliferation of CLL cells. Instead subset #1 CLL cells were unresponsive/anergic through the B cell receptor (BcR). This anergic state could however be overcome by “wash out” of bound antigen or addition of toll-like receptor 9 stimulation in some patients.Gene expression profiles differ between groups of CLL patients and in peripheral blood (PB) and LN compartment, due to different microenvironments. However, it is not known whether these differences also apply for DNA methylation. In paper III, we identified various genes that were alternatively methylated between IGHV mutated (M) and unmutated (UM) groups. For example prognostic genes, CLLU1 and LPL, genes involved in B cell signaling, IBTK, as well as numerous TGF-β and NF-κB/TNF pathway genes.The intensity and duration of BcR signals are fine-tuned by enhancing or inhibitory coreceptors. SHP-1 inhibits BcR-signals by dephosphorylation. In paper IV, we compared the expression and activity of SHP-1 in CLL cells from LN with matched PB samples. However, in contrast to our hypothesis, SHP-1 activity/phosphorylation status in PB and LN, did not differ significantly.This thesis, add another piece to the puzzle, on how the microenvironment and antigens influence CLL pathogenesis. Since great variations among individuals are seen, further studies in different groups of patients are necessary to elucidate the importance of antigen for the development of CLL.
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| 10. |
- Bovinder Ylitalo, Erik, 1985-
(författare)
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Molecular heterogeneity of prostate cancer bone metastasis
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Castration-resistant prostate cancer (CRPC) develops after androgen deprivation therapy of advanced PC, often with metastatic growth in bone. Patients with metastatic CRPC have very poor prognosis. Growth of CRPC, in most but not all patients, seems to involve androgen receptor (AR) activity, despite castrate levels of serum testosterone. Multiple mechanisms behind AR activation in castrated patients have been described, such as AR amplification, AR mutations, expression of constitutively active AR variants, and intra-tumoral steroid synthesis. However, other mechanisms beside AR activation are also involved and CRPC patients with tumors circumventing the need for AR stimulation will probably not benefit from AR targeting therapies but will need alternative treatments.Available treatments for CRPC are chemotherapy, AR antagonists or inhibition of androgen-synthesis. Novel drugs are constantly under development and several new therapies has recently been approved for clinical use. These include, in addition to new AR targeting therapies also immunotherapy, osteoclast inhibitors and bone-targeting radiopharmaceuticals. Due to heterogeneous mechanisms behind CRPC and that newly developed therapies are based on different mechanisms of action, there are reasons to believe that CRPC patients show different therapy responses due to diverse molecular properties of individual tumors. Although there are promising prospects, no biomarkers are used today for patient stratification into different treatments. Another important aspect is that, when effective, any therapy will probably induce tumor responses that subsequently cause further molecular diversities and alternative paths for development of tumor relapse and castration-resistance. Such mechanisms are important to understand in order to develop new treatment strategies.In this thesis, global gene expression and methylation patterns were studied in bone metastases obtained from PC patients going through metastasis surgery for spinal cord compression. Gene expression patterns were analyzed by multivariate statistics and ontology analysis with the aim to identify subgroups of biological/pathological relevance. Interesting findings from array analysis were verified using qRT-PCR and immunohistochemical analysis. In addition, a xenograft mouse model was used to study the effects of abiraterone (steroidogenesis inhibitor) and cabazitaxel (taxane), and subsequently developed resistance mechanisms in the 22Rv1 PC cell line expressing high levels of AR-V7; a constitutively active AR splice variant associated with a poor prognosis and resistance to AR targeting therapies.In summary, results showed that the majority of CRPC bone metastases were AR-driven, defined from high levels of AR-regulated gene transcripts, while a smaller sub-group was non-AR-driven (paper I). AR-driven bone metastases had high metabolic activity in combination with downregulated immune responses while non-AR-driven cases had a more pronounced immune response (paper I) and higher bone cell activity (paper II). Paper III identified pronounced hypermethylation in primary prostate tumors probably causing a suppressed anti-tumor immune-response whereas metastases showed a different methylation pattern related to increased AR activity and patient outcome. In paper IV, 22Rv1 xenografts showed poor response to abiraterone and initially excellent response to cabazitaxel, but eventually resistance occurred probably due to an upregulation of the ABCB1 transporter protein. Anti-androgens partly reversed the resistance.In conclusion, we have identified molecular heterogeneities in clinical bone metastases associated with biological characteristics, which could perhaps be used both for stratifying patients into treatment modalities, and to aid in further development of effective therapies for CRPC.
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| 11. |
- Halin, Sofia, 1977-
(författare)
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Targeting the prostate tumor microenvironment and vasculature : the role of castration, tumor-associated macrophages and pigment epithelium-derived factor
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Prostate cancer is the most common cancer among Swedish men. For patients with metastatic prostate cancer the standard therapy is castration, a treatment that initially provides symptomatic relief but unfortunately is not curative. New therapeutic targets for advanced prostate cancer are therefore needed. Prostate cancers are composed of tumor epithelial cells as well as many non-epithelial cells such as cancer associated fibroblasts, blood vessels and inflammatory cells. Many components of the tumor microenvironment such as tumor associated macrophages and angiogenesis have been shown to stimulate tumor progression. This thesis aims to explore mechanisms by which the local environment influences prostate tumor growth and how such mechanisms could be targeted for treatment. MATERIALS AND METHODS: We have used animal models of prostate cancer, in vitro cell culture systems and clinical materials from untreated prostate cancer patients with long follow up. Experiments were evaluated with stereological techniques, immunohistochemistry, western blotting, quantitative real-time PCR, PCR arrays and laser micro dissection. RESULTS: We found that the presence of a tumor induces adaptive changes in the surrounding non-malignant prostate tissue, and that androgen receptor negative prostate tumor cells respond to castration treatment with temporarily reduced growth when surrounded by normal castration-responsive prostate tissue. Further, we show that macrophages are important for prostate tumor growth and angiogenesis in the tumor and in the surrounding non-malignant tissue. In addition, the angiogenesis inhibitor Pigment epithelium-derived factor (PEDF) was found to be down-regulated in metastatic rat and human prostate tumors. Over-expression of PEDF inhibited experimental prostate tumor growth, angiogenesis and metastatic growth and stimulated macrophage tumor infiltration and lymphangiogenesis. PEDF was found to be down-regulated by the prostate microenvironment and tumor necrosis factor (TNF) α. CONCLUSIONS: Our studies indicate that not only the nearby tumor microenvironment but also the surrounding non-malignant prostate tissue are important for prostate tumor growth. Both the tumor and the surrounding non-malignant prostate were characterized by increased angiogenesis and inflammatory cell infiltration. Targeting the surrounding prostate tissue with castration, targeting tumor associated macrophages, or targeting the vasculature directly using inhibitors like PEDF were all shown to repress prostate tumor growth and could prove beneficial for patients with advanced prostate cancer.
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| 12. |
- Hammarsten, Peter, 1977-
(författare)
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Androgen controlled regulatory systems in prostate cancer : potential new therapeutic targets and prognostic markers
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BACKGROUND: Prostate cancer is by far the most common cancer among Swedish men. Some patients have an aggressive lethal disease, but the majority of affected men have long expected survival. Unfortunately, the diagnostic tools available are insufficient in predicting disease aggressiveness. Novel prognostic markers are therefore urgently needed. Furthermore, metastatic prostate cancer is generally treated with castration, but the long-term effects are insufficient. Additional studies are therefore needed to explore how the effects of this therapy can be enhanced. Prostate growth and regression is beside testosterone controlled by locally produced regulators. Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) are two of the major regulators in the normal prostate and in prostate tumours. MATERIALS AND METHODS: VEGF and EGFR were explored in the prostate, by treating rats with either anti-VEGF or anti-EGFR treatment during castration and testosterone-stimulated prostate growth. Rats with implanted androgen-independent prostate tumours were treated with an inhibitor of both VEGF receptor-2 (VEGFR-2) and EGFR. Stereological techniques, immunohistochemistry, western blotting and quantitative real-time PCR were used to evaluate these experiments. Furthermore, prostate tissue from untreated prostate cancer patients was used to retrospectively explore the expression of phosphorylated-EGFR (pEGFR) in relation to outcome. RESULTS: Anti-VEGF treatment during testosterone-stimulated prostate growth, inhibited vascular and prostate growth. Anti-EGFR treatment during castration and testosterone-stimulated prostate growth resulted in enhanced castration effects and inhibited prostate growth. Anti-vascular treatment of androgen-independent prostate cancer with an inhibitor of VEGFR-2 and EGFR, that targets the normal and tumour vasculature, enhanced the effects of castration. Low immunoreactivity for pEGFR in prostate epithelial cells, both in the tumour and also in the surrounding non-malignant tissue, was associated with good prognosis. CONCLUSIONS: Anti-vascular treatment, with an inhibitor of VEGFR-2 and EGFR, in combination with castration could be an effective way to treat androgen-insensitive prostate tumours. VEGF and EGFR signalling are necessary components in testosterone-stimulated prostate growth. Phosphorylation of EGFR could be a useful prognostic marker for prostate cancer patients. Tumours may affect the surrounding non-malignant tissue and pEGFR immunoreactivity in the morphologically normal prostate tissue can be used to retrieve prognostic information.
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| 13. |
- Nilsson, Erik, et al.
(författare)
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The grade of individual prostate cancer lesions predicted by magnetic resonance imaging and positron emission tomography
- 2023
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Ingår i: Communications Medicine. - : Springer Nature. - 2730-664X. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Multiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) are widely used for the management of prostate cancer (PCa). However, how these modalities complement each other in PCa risk stratification is still largely unknown. We aim to provide insights into the potential of mpMRI and PET for PCa risk stratification.Methods: We analyzed data from 55 consecutive patients with elevated prostate-specific antigen and biopsy-proven PCa enrolled in a prospective study between December 2016 and December 2019. [68Ga]PSMA-11 PET (PSMA-PET), [11C]Acetate PET (Acetate-PET) and mpMRI were co-registered with whole-mount histopathology. Lower- and higher-grade lesions were defined by International Society of Urological Pathology (ISUP) grade groups (IGG). We used PET and mpMRI data to differentiate between grades in two cases: IGG 3 vs. IGG 2 (case 1) and IGG ≥ 3 vs. IGG ≤ 2 (case 2). The performance was evaluated by receiver operating characteristic (ROC) analysis.Results: We find that the maximum standardized uptake value (SUVmax) for PSMA-PET achieves the highest area under the ROC curve (AUC), with AUCs of 0.72 (case 1) and 0.79 (case 2). Combining the volume transfer constant, apparent diffusion coefficient and T2-weighted images (each normalized to non-malignant prostatic tissue) results in AUCs of 0.70 (case 1) and 0.70 (case 2). Adding PSMA-SUVmax increases the AUCs by 0.09 (p < 0.01) and 0.12 (p < 0.01), respectively.Conclusions: By co-registering whole-mount histopathology and in-vivo imaging we show that mpMRI and PET can distinguish between lower- and higher-grade prostate cancer, using partially discriminative cut-off values.
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| 14. |
- Nilsson, Maria, 1984-
(författare)
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Tumor instructed normal tissue : studies of potential extratumoral biomarkers and therapeutic targets in prostate cancer
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer is the most common cancer in men in Sweden and but luckily the majority of the patients will carry on their life without any consequences from the disease. Unfortunately, some will develop aggressive tumors and eventually die. However, current prognostic and diagnostic techniques used to distinguish lethal prostate cancer from harmless prostate cancer are insufficient. It is therefore necessary to find novel diagnostic and prognostic markers, so aggressive prostate cancer can be detected and treated as early as possible whilst allowing non-aggressive variants to be safely left without extensive treatment. Interestingly, aggressive tumors have been shown to induce certain adaptive changes in the non-malignant parts of the tumor-bearing prostate – changes probably necessary for subsequent tumor growth and spread. Our research group have termed this response “Tumor Instructed (and thus Indicating) Normal Tissue (TINT)” and proposed this tissue as an alternative source of diagnostic/ prognostic markers. The aim of this thesis is to analyze factors related to tumor aggressiveness in prostate TINT. Experimental studies and studies on patient material were executed to investigate potential TINT markers at the mRNA and protein level.In patients we saw that high expression of lysyl oxidase (LOX) in TINT epithelial cells was associated with poor prognosis and served as a prognostic factor. In an animal model, created by injecting tumor cells into rat prostates, expression of LOX was increased in the surrounding non-malignant tissue. If LOX was inhibited while tumors were establishing in the prostate, tumor growth was decreased. In contrast, if LOX was inhibited after tumors were established, tumor growth was increased. Taken together, this suggests that tumors can induce LOX expression in TINT and that the function of LOX is context dependent.Another gene that was significantly increased in TINT was heme oxygenase-1 (HO-1). TINT in rat prostates injected with aggressive tumor cells was infiltrated by HO-1 expressing macrophages. In patients, HO-1 expressing macrophages was mainly seen in the invasive front of high-grade primary tumors, which also correlated with the presence of bone metastases. HO-1 expressing macrophages was more common in bone metastases than in primary tumors, and had an inverse correlation to AR expression in castration resistant prostate cancer.Microseminoprotein-β (MSMB) is normally expressed by prostate epithelial cells but is reduced in prostate tumors. Decreased levels of MSMB in serum are currently used as a biomarker for prostate cancer. Both in experimental studies and in patients, we saw that levels of MSMB were also decreased in TINT and related to tumor aggressiveness. This suggests that decreased levels of MSMB in serum could be caused by decreased levels of MSMB in the non-malignant prostate tissue and that TINT-markers possibly could be measured in blood.In conclusion, findings presented in this thesis show several alterations in TINT associated with tumor aggressiveness which have good potential of being useful as clinical prognostic markers for prostate cancer after further research.
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| 15. |
- Norén Nyström, Ulrika, 1965-
(författare)
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Vascular density and bone marrow fibrosis in childhood acute lymphoblastic leukemia
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: In childhood acute lymphoblastic leukemia (ALL), the cure rate has now reached 80% in the western world. Even so, 15¬–20% will die from the disease or treatment-related causes, among them children who did not present any known unfavorable features at diagnosis. Treatment of childhood ALL is risk-adapted, meaning that certain factors that are related to the child or the leukemic blasts stratifies to more or less intensive treatment. In this thesis, characteristics of the bone marrow (BM) stroma, reflecting the interaction between the leukemic cells and their microenvironment, were evaluated. The aims were to investigate these factors in relation to other known data in order to further understand the biology of leukemia, and to suggest additional risk factors that would further improve decision making for the treatment of individual children diagnosed with ALL. Methods: We retrospectively investigated microvessel density (MVD), blast-congested vessel fraction (BCVF), and degree of fibrosis – reticulin fiber density (RFD) – in sections from diagnostic BM biopsies from children diagnosed in Umeå, Uppsala, and Stockholm. RFD was also studied in BM sections from treatment day 29. Results: RFD had prognostic impact in patients with high-hyperdiploid (HeH) leukemia. Moreover, rapid reduction of RFD during induction treatment was associated with a favorable prognosis compared to slow reduction, in B-cell precursor (BCP) ALL patients. There was also a correlation between RFD at diagnosis and minimal residual disease (MRD) measured by flow cytometry on treatment day 29 in BCP patients. BCP patients with high RFD and high MVD had an unfavorable outcome compared to all other BCP patients. In addition, MVD and RFD were both associated with immunophenotype, and MVD with cytogenetic aberrations. There was a correlation between MVD and WBC count in BCP high-risk patients. There was also a strong correlation between BCVF and WBC count in all BCP patients, but not between BCVF and MVD or RFD. There was a negative correlation between MVD and in vitro cellular resistance to several drugs in BCP patients. A drug-resistance score combining the drugs most strongly correlated to MVD – cytarabine, doxorubicin, and dexametasone (ADD score) – identified the prognostic potential of ADD score in HeH patients with no unfavorable features. Conclusions: Taken together, these studies indicate that stroma factors in leukemia are related to both phenotypic and genotypic features of acute leukemia. Stroma factors also seem to influence the response to induction treatment, in vitro drug resistance, and outcome in certain subgroups of childhood ALL patients. The results emphasize the importance of BM stroma in leukemia and the need for greater use of BM biopsy at diagnosis.
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| 16. |
- Rönnqvist, Hans, 1977-
(författare)
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Predicting surfacing internal erosion in moraine core dams
- 2010
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dams that comprise broadly and widely graded glacial materials, such as moraines, have been found to be susceptible to internal erosion, perhaps more than dams of other soil types. Internal erosion washes out fine-grained particles from the filling material; the erosion occurs within the material itself or at an interface to another dam zone, depending on the mode of initiation. Whether or not internal erosion proceeds depend on the adequacy of the filter material. If internal erosion is allowed, it may manifest itself as sinkholes on the crest, increased leakage and muddy seepage once it surfaces, which here is called surfacing internal erosion (i.e. internal erosion in the excessive erosion or continuation phase). In spite of significant developments since the 1980s in the field of internal erosion assessment, the validity of methods developed by others on broadly graded materials are still less clear because most available criteria are based on tests of narrowly graded granular soils. This thesis specifically addresses dams that are composed of broadly graded glacial soils and investigates typical indicators, signs and behaviors of internal erosion prone dams. Based on a review of 90+ existing moraine core dams, which are located mainly in Scandinavia as well as North America and Australia/New Zealand, this thesis will show that not only the filter’s coarseness needs to be reviewed when assessing the potential for internal erosion to surface (i.e., erosion in the excessive or continuing phase); in addition, the grading stability of the filter and the core material as well as non-homogeneities that are caused by filter segregation need to be studied. Cross-referencing between these aspects improves the assessment of potential for internal erosion in dams of broadly graded soils and furthermore it provides aid-to-judgment.
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| 17. |
- Sandgren, Kristina, et al.
(författare)
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Histopathology-validated lesion detection rates of clinically significant prostate cancer with mpMRI, [68Ga]PSMA-11-PET and [11C]Acetate-PET
- 2023
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Ingår i: Nuclear medicine communications. - : Lippincott Williams & Wilkins. - 0143-3636 .- 1473-5628. ; 44:11, s. 997-1004
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Tidskriftsartikel (refereegranskat)abstract
- Objective: PET/CT and multiparametric MRI (mpMRI) are important diagnostic tools in clinically significant prostate cancer (csPC). The aim of this study was to compare csPC detection rates with [68Ga]PSMA-11-PET (PSMA)-PET, [11C] Acetate (ACE)-PET, and mpMRI with histopathology as reference, to identify the most suitable imaging modalities for subsequent hybrid imaging. An additional aim was to compare inter-reader variability to assess reproducibility.Methods: During 2016–2019, all study participants were examined with PSMA-PET/mpMRI and ACE-PET/CT prior to radical prostatectomy. PSMA-PET, ACE-PET and mpMRI were evaluated separately by two observers, and were compared with histopathology-defined csPC. Statistical analyses included two-sided McNemar test and index of specific agreement.Results: Fifty-five study participants were included, with 130 histopathological intraprostatic lesions >0.05 cc. Of these, 32% (42/130) were classified as csPC with ISUP grade ≥2 and volume >0.5 cc. PSMA-PET and mpMRI showed no difference in performance (P = 0.48), with mean csPC detection rate of 70% (29.5/42) and 74% (31/42), respectively, while with ACE-PET the mean csPC detection rate was 37% (15.5/42). Interobserver agreement was higher with PSMA-PET compared to mpMRI [79% (26/33) vs 67% (24/38)]. Including all detected lesions from each pair of observers, the detection rate increased to 90% (38/42) with mpMRI, and 79% (33/42) with PSMA-PET.Conclusion: PSMA-PET and mpMRI showed high csPC detection rates and superior performance compared to ACE-PET. The interobserver agreement indicates higher reproducibility with PSMA-PET. The combined result of all observers in both PSMA-PET and mpMRI showed the highest detection rate, suggesting an added value of a hybrid imaging approach.
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| 18. |
- Sandgren, Kristina, et al.
(författare)
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Registration of histopathology to magnetic resonance imaging of prostate cancer
- 2021
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Ingår i: Physics and Imaging in Radiation Oncology. - : Elsevier. - 2405-6316. ; 18, s. 19-25
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose: The diagnostic accuracy of new imaging techniques requires validation, preferably by histopathological verification. The aim of this study was to develop and present a registration procedure between histopathology and in-vivo magnetic resonance imaging (MRI) of the prostate, to estimate its uncertainty and to evaluate the benefit of adding a contour-correcting registration.Materials and methods: For twenty-five prostate cancer patients, planned for radical prostatectomy, a 3D-printed prostate mold based on in-vivo MRI was created and an ex-vivo MRI of the specimen, placed inside the mold, was performed. Each histopathology slice was registered to its corresponding ex-vivo MRI slice using a 2D-affine registration. The ex-vivo MRI was rigidly registered to the in-vivo MRI and the resulting transform was applied to the histopathology stack. A 2D deformable registration was used to correct for specimen distortion concerning the specimen's fit inside the mold. We estimated the spatial uncertainty by comparing positions of landmarks in the in-vivo MRI and the corresponding registered histopathology stack.Results: Eighty-four landmarks were identified, located in the urethra (62%), prostatic cysts (33%), and the ejaculatory ducts (5%). The median number of landmarks was 3 per patient. We showed a median in-plane error of 1.8 mm before and 1.7 mm after the contour-correcting deformable registration. In patients with extraprostatic margins, the median in-plane error improved from 2.1 mm to 1.8 mm after the contour-correcting deformable registration.Conclusions: Our registration procedure accurately registers histopathology to in-vivo MRI, with low uncertainty. The contour-correcting registration was beneficial in patients with extraprostatic surgical margins.
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| 19. |
- Strömvall, Kerstin, 1980-
(författare)
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Extratumoral effects of highly aggressive prostate cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Prostate cancer (PC) is the most common cancer in Sweden. Most patients have slow growing tumors that will not cause them any harm within their lifetime, but some have aggressive tumors and will die from their disease. The ability of current clinical practice to predict tumor behavior and disease outcome is limited leading to both over- and undertreatment of PC patients. The men who die from their disease are those that develop metastases. It is therefore of great value to find better and more sensitive prognostic techniques, so that metastatic spread can be detected (or predicted) at an early time point, and so that appropriate treatment can be offered to each subgroup of patients. The aim of this thesis was to investigate if, and by what means, highly aggressive prostate tumors influence extratumoral tissues such as the non-malignant parts of the prostate and regional lymph nodes (LN), and also if any of our findings could be of prognostic importance. Gene- and protein expression analysis were the main methods used to address these questions. Our research group has previously introduced the expression Tumor Instructed (Indicating) Normal Tissue (TINT), and we use the term TINT-changes when referring to alterations in non-malignant tissue due to the growth of a tumor nearby or elsewhere in the body. In the Dunning rat PC-model we found that MatLyLu (MLL)-tumors, having a high metastatic ability, caused pre-metastatic TINT-changes that differ from those caused by AT1-tumors who have low metastatic ability. Prostate-TINT surrounding MLL-tumors had elevated immune cell infiltration, and gene ontology enrichment analysis suggested that biological functions promoting tumor growth and metastasis were activated in MLL- while inhibited in AT1-prostate-TINT. In the regional LNs we found signs of impaired antigen presentation, and decreased quantity of T cells in the MLL-model. One of the downregulated genes in the MLL-LNs was Siglec1 (also known as Cd169), expressed by LN resident macrophages that are important for antigen presentation. When examining metastasis-free LN tissue from PC patients we found CD169 expression to be a prognostic factor for PC-specific survival, and reduced expression was linked to an increased risk of PC-specific death. Some of our findings in prostate- and LN-TINT could be seen already when the tumors were very small suggesting that differences in TINT-changes between tumors with different metastatic capability can be detected early in tumor progression. However, before coming of use in the clinic more research is needed to better define a suitable panel of prognostic TINT-factors as well as the right time window of when to use them.
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| 20. |
- Thellenberg Karlsson, Camilla, 1972-
(författare)
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Prostate cancer : epidemiological studies of risk factors
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In spite of the fact that prostate cancer is the most common male cancer in both Sweden and many other countries in the developed world, little is known of risk factors and predisposing conditions. The only well recognized risk factors are age, race and familial aggregation. More knowledge about risk factors could lead to better preventive measures together with better treatments. One way to evaluate this is to study second primary cancers; the connection between two different cancers can give valuable insight in etiology or clues to shared risk factors. This thesis aims at evaluating risk factors for prostate cancer. We constructed a cohort of 135,713 men diagnosed with prostate cancer and reported to the Swedish Cancer Registry 1958-1996. The cohort was followed for second primary cancers and a doubled risk of male breast cancer was found. We also noted increased risks for small intestine cancers and melanoma. As a follow-up on the increased risk of male breast cancer, we performed a nested case – control study. Included cases were men with first prostate and then breast cancer (n = 41) matched to men with only prostate cancer (n =81). For these men, we collected medical records and extracted data regarding treatment. Furthermore, all men diagnosed with both prostate and breast cancer irrespective which came first (n = 83) were used as probands. To both these sets of cases with breast and prostate cancer, we identified first degree relatives and grandchildren from parish offices throughout Sweden. Linking to the Cancer Registry retrieved all cancer diagnoses amongst relatives. Results from this study show a relation between estrogen treatment of prostate cancer and the risk of developing breast cancer. We also found that a small part of the cases with both cancers appeared in families with inheritance patterns possibly attributed to BRCA2. As estrogen treatment seemed involved in increased risk of breast cancer after prostate cancer, we wanted to investigate the newly discovered Estrogen receptor β and the relation to prostate cancer risk. Previous reports have shown that ERβ acts as a negative regulator of proliferation. ERβ expression occurs mainly in prostatic epithelial cells and the expression gradually diminishes when cancer develops and aggravates. We used a single nucleotide polymorphism (SNP) association study approach to evaluate genetic variation in ERβ as a risk factor for prostate cancer. One SNP, located in the promoter region associated with a small increased risk of prostate cancer whereas variation in the rest of the gene did not. In the last paper, we investigated trans-urethral resection (TURP) of the prostate due to benign prostate hyperplasia (BPH) as a risk factor for later development of prostate cancer. Evidence has gathered that both BPH and prostate cancer are associated to inflammation. By comparing incidence and mortality in a cohort of 7,901 men with the general population there appeared to be an increased risk of prostate cancer but decreased mortality. Analyzing this increased risk further, we conducted a nested case - control study with men extracted from the cohort. Cases had a TURP and later developed prostate cancer and controls just had a TURP. We then evaluated the specimens from TURP regarding extent of inflammation, degree of androgen receptor down regulation and expression of p53, all factors previous associated with prostate cancer. None of these parameters differed between cases and controls and they can therefore not explain the increased risk. Decreased mortality but increased risk might be explained by surveillance bias, which means more medical attention to these patients, resulting in diagnosing clinically non-significant cancers. In summary, our results show a doubled risk of male breast cancer following prostate cancer. A risk that can be attributed to the use of estrogen to treat prostate cancer or to some extent a possible mutation in BRCA2. We also propose that a SNP change in the ERβ promoter confer a small increased risk of prostate cancer. A small risk elevation of prostate cancer following TURP most probable could depend on surveillance bias.
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| 21. |
- Zarei, Maryam, et al.
(författare)
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Accuracy of gross tumour volume delineation with [68Ga]-PSMA-PET compared to histopathology for high-risk prostate cancer
- 2024
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Ingår i: Acta Oncologica. - : MJS Publishing, Medical Journals Sweden. - 0284-186X .- 1651-226X. ; 63, s. 503-510
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The delineation of intraprostatic lesions is vital for correct delivery of focal radiotherapy boost in patients with prostate cancer (PC). Errors in the delineation could translate into reduced tumour control and potentially increase the side effects. The purpose of this study is to compare PET-based delineation methods with histopathology.MATERIALS AND METHODS: The study population consisted of 15 patients with confirmed high-risk PC intended for prostatectomy. [68Ga]-PSMA-PET/MR was performed prior to surgery. Prostate lesions identified in histopathology were transferred to the in vivo [68Ga]-PSMA-PET/MR coordinate system. Four radiation oncologists manually delineated intraprostatic lesions based on PET data. Various semi-automatic segmentation methods were employed, including absolute and relative thresholds, adaptive threshold, and multi-level Otsu threshold.RESULTS: The gross tumour volumes (GTVs) delineated by the oncologists showed a moderate level of interobserver agreement with Dice similarity coefficient (DSC) of 0.68. In comparison with histopathology, manual delineations exhibited the highest median DSC and the lowest false discovery rate (FDR) among all approaches. Among semi-automatic approaches, GTVs generated using standardized uptake value (SUV) thresholds above 4 (SUV > 4) demonstrated the highest median DSC (0.41), with 0.51 median lesion coverage ratio, FDR of 0.66 and the 95th percentile of the Hausdorff distance (HD95%) of 8.22 mm.INTERPRETATION: Manual delineations showed a moderate level of interobserver agreement. Compared to histopathology, manual delineations and SUV > 4 exhibited the highest DSC and the lowest HD95% values. The methods that resulted in a high lesion coverage were associated with a large overestimation of the size of the lesions.
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| 22. |
- Adamo, Hanibal Hani, 1984-
(författare)
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TINT Tumor Indicating Normal Tissue : new field of diagnostic biomarkers for prostate cancer
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Prostate cancer is the most common cancer in Sweden. Due its highly variable behavior, multifocal nature, and insufficient diagnostic methods, prostate cancer is difficult to diagnose and prognosticate. Some patients have an aggressive lethal disease, but the majority of prostate cancer patients have slow-growing, non-lethal disease with long expected survival without treatment. Current diagnostic methods―serum levels of prostate-specific antigen (PSA) and histological grading of biopsied prostate tissue―often do not give the information required to be able to safely differentiate indolent tumors from potentially lethal ones. Many prostate cancers are difficult to detect by imaging, so tissue biopsy cannot be safely guided towards the tumor, and particularly not towards the most aggressive forms. To overcome this problem, multiple needle biopsies are taken from the organ, but biopsies are small and they sample less than 1% of the whole prostate. In this thesis, we explore the non-malignant prostate tissue adjacent to tumors, which is always sampled in biopsies, and we study adaptive changes in this tissue, which may provide new diagnostic and prognostic markers for prostate cancer. We have therefore proposed that this type of tissue should be termed TINT (Tumor Instructed/indicating Normal Tissue). Methods: In our studies, we used orthotopic rat prostate cancer models with tumors of different aggressiveness. We also used clinical materials from patients diagnosed with prostate cancer at transurethral resection (1975‒1990); the majority of these men were followed with watchful waiting. Analyses were performed with whole-genome expression array, quantitative real-time PCR, immunohistochemistry, and western blotting. Results: Using the animal model, we found that the presence of a tumor induces changes in gene expression in the surrounding tumor-bearing organ (TINT). The gene signature of TINT was linked to processes such as extracellular matrix organization, immune responses, and inflammation. We also showed that some of these adaptive TINT changes appear to be related to the aggressiveness and metastatic potential of the growing tumor, such as increases in macrophages, in mast cells, in vascular densities, and in vascular cell-proliferation. Some of these findings were confirmed by our observations in patient samples. We found that high staining of the extracellular matrix component hyaluronan in the stroma of the non-malignant prostate tissue was prognostic for short cancer-specific survival. We also found that an elevated proportion of C/EBP-beta positive epithelial cells in non-malignant (TINT) prostate tissue was associated with a good prognosis. Conclusions: Using animal experiments and patient samples, we showed that the presence of prostate cancer induces changes in the tumor-bearing organ, alterations associated with tumor aggressiveness, and that grading of these changes in TINT can be used to predict outcome in prostate cancer patients.
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| 23. |
- Adolfsson, Annsofie, 1960-, et al.
(författare)
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Miscarriage : women’s experience and its cumulative incidence
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Many women experience miscarriage every year. Every fourth woman who has given birth reports that she has previous experience of miscarriage. In a study of all women in the Swedish Medical Birth Register 1983-2003, we found that the number of cases of self reported miscarriage had increased in Sweden during this 21 year period. This increase can be explained by the introduction of sensitive pregnancy tests around 1990, as well as an increase in the mean age of the mothers, by approximately 3 years, during the observation period. The risk of miscarriage is 13% with the first child. With subsequent pregnancies, the risk of miscarriage is 8%, 6% and 4% with the second, third and fourth child, respectively.Thirteen of these women who had suffered a recent miscarriage were interviewed four months later, and their feelings of guilt and emptiness were explored. Their experience was that they wanted their questions to be answered, and that they wanted others to treat them as the mothers to be that they felt themselves to be. They also experienced the need for time to grieve their loss.Measurement of grief by means of the Perinatal Grief Scale (PGS) is used in research but has also been proposed for clinical use. We have translated this psychological instrument to Swedish, back-translated and tested it in a small pilot study. In a randomized controlled study, women with early miscarriage were allocated, either to a structured visit (study group) or a regular visit (control group) to a midwife. The structured visit was conducted according to the Swanson caring theory. We could conclude that the structured visit had no significant effect on grief compared to the regular visit, as measured using the PGS. However, women with the sub-diagnosis missed abortion have significantly more grief four months after early miscarriage, regardless of visit type.We also performed a content analysis of the tape-recorded structured follow-up visit. The code-key used was Bonanno and Kaltman’s general grief categorization. Women’s expression of grief after miscarriage was found to be very similar to the grief experienced following the death of a relative. Furthermore, the grief was found to be independent of number of children, women’s age, or earlier experience of miscarriage.Conclusions: Every fourth woman who gives birth reports that she has also experienced early miscarriage. The experience of these women is that they have suffered a substantial loss and their reaction is grief similar to that experienced following the death of a relative.
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| 24. |
- Candefjord, Stefan, et al.
(författare)
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Combining scanning haptic microscopy and fibre optic Raman spectroscopy for tissue characterization
- 2012
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Ingår i: Journal of Medical Engineering & Technology. - : Taylor & Francis. - 0309-1902 .- 1464-522X. ; 36:6, s. 319-327
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Tidskriftsartikel (refereegranskat)abstract
- The tactile resonance method (TRM) and Raman spectroscopy (RS) are promising for tissue characterization in vivo. Our goal is to combine these techniques into one instrument, to use TRM for swift scanning, and RS for increasing the diagnostic power. The aim of this study was to determine the classification accuracy, using support vector machines, for measurements on porcine tissue and also produce preliminary data on human prostate tissue. This was done by developing a new experimental set-up combining micro-scale TRMscanning haptic microscopy (SHM)for assessing stiffness on a micro-scale, with fibre optic RS measurements for assessing biochemical content. We compared the accuracy using SHM alone versus SHM combined with RS, for different degrees of tissue homogeneity. The cross-validation classification accuracy for healthy porcine tissue types using SHM alone was 6581%, and when RS was added it increased to 8187%. The accuracy for healthy and cancerous human tissue was 6770% when only SHM was used, and increased to 7277% for the combined measurements. This shows that the potential for swift and accurate classification of healthy and cancerous prostate tissue is high. This is promising for developing a tool for probing the surgical margins during prostate cancer surgery.
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| 25. |
- Lindahl, Olof A, et al.
(författare)
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A tactile resonance sensor for prostate cancer detection – evaluation on human prostate tissue
- 2021
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Ingår i: Biomedical Engineering & Physics Express. - : Institute of Physics (IOP). - 2057-1976. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer surgery risks erectile problems and incontinence for the patient. An instrument for guiding surgeons to avoid nerve bundle damage and ensure complete cancer removal is desirable. We present a tactile resonance sensor made of PZT ceramics, mounted in a 3D motorized translation stage for scanning and measuring tissue stiffness for detecting cancer in human prostate. The sensor may be used during surgery for guidance, scanning the prostate surface for the presence of cancer, indicating migration of cancer cells into surrounding tissue. Ten fresh prostates, obtained from patients undergoing prostate cancer surgery, were cut into 0.5 cm thick slices. Each slice was measured for tissue stiffness at about 25 different sites and compared to histology for validation cancer prediction by stiffness. The statistical analysis was based on a total of 148 sites with non-cancer and 40 sites with cancer. Using a generalized linear mixed model (GLMM), the stiffness data predicted cancer with an area under the curve of 0.74, after correcting for overfitting using bootstrap validation. Mean prostate stiffness on the logarithmic scale (p = 0.015) and standardized Z-scores (p = 0.025) were both significant predictors of cancer. This study concludes that stiffness measured by the tactile resonance sensor is a significant predictor of prostate cancer with potential for future development towards a clinical instrument for surgical guidance.
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| 26. |
- Tran, Phong, et al.
(författare)
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Imbalanced dNTP pools induce mutator and cancer phenotypes in mice
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The high accuracy of DNA replication is achieved through the nucleotide selectivity of DNA polymerases, polymerase proofreading, and the mismatch repair (MMR) system that act in series. While defects in proofreading and MMR are strongly associated with the development of cancers, decreased nucleotide selectivity due to mutations in replicative DNA polymerases is an uncommon driver of cancer development. Because nucleotide selectivity can also be decreased by imbalanced dNTP pools, we investigated to what extent imbalanced dNTP pools can induce cancers. To this end we developed a mouse model with a mutation in the allosteric specificity site of ribonucleotide reductase, which is responsible for the balanced production of dNTPs. These mice had ~2-fold increased dCTP and dTTP levels and normal dATP and dGTP levels. Despite this mild dNTP pool imbalance, mutant mice had a higher incidence and an earlier onset of cancers, and these were different from the cancers that developed in wild-type controls. Because dNTP pool imbalances can be caused by defects in a plethora of genes, we propose that decreased nucleotide selectivity might be a major factor contributing to the development of spontaneous cancers.
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