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- 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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| 2. |
- 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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