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- Aljabery, Firas
(författare)
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Staging and tumor biological mechanisms of lymph node metastasis in invasive urinary bladder cancer
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To study the possibility of detecting lymph node metastasis in locally advanced urinary bladder cancer (UBC) treated with radical cystectomy (RC) by using preoperative positron emission tomography/computed tomography (PET/CT) and peroperative sentinel node biopsy (SNB) technique. We also investigate the clinical significance of macrophage traits expression by cancer cells, M2-macrophage infiltration (MI) in tumor stroma and the immunohistochemical expression of biomarkers in cancer cells in relation to clinicopathologic data.Patients and Methods: We studied prospectively 122 patients with UBC, pathological stage pT1–pT4 treated with RC and pelvic lymph node dissection (PLND) during 2005–2011 at the Department of Urology, Linköping University Hospital. In the first study, we compared the results of preoperative PET/CT and conventional CT with the findings of postoperative histopathological evaluation of lymph nodes (LNs). In the second study we investigated the value of SNB technique for detecting pathological LNs during RC in patients with UBC. W also examined the significance of the primary tumor location in the bladder in predicting the site of LN metastases, and the prognostic significance of lympho-vascular invasion (LVI) and lymph node metastasis density (LNMD) on survival. In the third study, we investigate the clinical significance of macrophage infiltration (MI) in tumor stroma and macrophage-traits expression by tumor cells. In the fourth study, we investigate the cell cycle suppression proteins p53, p21, pRb, p16, p14 ARF as well as tumors proliferative protein Ki67 and DNA repair protein ERCC1 expression in cancer cells. The results were compared with clinical and pathological characteristics and outcome.Results: Prior to RC, PET/CT was used to detect LN metastasis in 54 patients. PET/CT had 41% sensitivity, 86% specificity, 58% PPV, and 76% NPV, whereas the corresponding figures for conventional CT were 41%, 89%, 64%, and 77%. SNB was performed during RC in 103 patients. A median number of 29 (range 7–68) nodes per patient were examined. SNs were detected in 83 out of 103 patients (81%). The sensitivity and specificity for detecting metastatic disease by SNB varied among LN stations, with average values of 67% -90%. LNMD or ≥8% and LVI were significantly related to shorter survival. In 103 patients, MI was high in 33% of cases, while moderate and low infiltration occurred in 42% and 25% of tumors respectively. Patients with tumors containing high and moderate compared to low MI had low rate of LN metastases (P=0.06) and improved survival (P=0.06), although not at significant level. The expression of different tumor suppression proteins was altered in 47-91% of the patients. There were no significant association between cancer specific survival (CSS) and any of the studied biomarkers. In case of altered p14ARF, ERCC1 or p21, CSS was low in case of low p53 immunostaining but increased in case of p53 accumulation, although not at a significant level, indicating a possible protective effect of p53 accumulation in these cases.Conclusion: PET/ CT provided no improvement over conventional CT in detection and localization of regional LN metastases in bladder cancer. It is possible to detect the SN but the technique is not a reliable for perioperative localization of LN metastases; however, LVI and LNMD at a cut-off level of 8% had significant prognostic values. MI in the tumor microenvironment but not CD163 expression in tumor cells seems to be synergistic with the immune response against urinary bladder cancer. Our results further indicate that altered p53 might have protective effect on survival in case of altered p14ARF, p21, or ERCC1 indicating an interaction between these biomarkers.
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- Jancke, Georg, 1970-
(författare)
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Aspects of Recurrence and Progression in Ta/T1 Urinary Bladder Cancer
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aims: To evaluate different aspects of recurrence and, when appropriate, progression in primary Ta/T1 urinary bladder cancer.Patients and methods: All evaluable patients diagnosed with primary Ta/T1 urinary bladder cancer in Linköping and Norrköping between 1992 and 2007 were included prospectively in the study cohort. Histopathology results were classified according to the TNM system and were reviewed by a reference pathologist using the WHO 1999 criteria (except in the studies reported in Papers I and IV). Risk factors for local recurrence were evaluated using data from the period 1992–2001 (Paper I). Tumour size (Paper II) and bladder wash cytology (Paper III) at primary diagnosis were assessed regarding the impact on recurrence and progression, and tumour presence in the marginal resection in primary and recurrent Ta/T1 bladder cancer was investigated considering effects on recurrence in patients treated between 2001 and 2010 (Paper IV). Furthermore, surgical experience measured as training status (resident or specialist) and surgical volume (both during the study period and lifetime) were analysed regarding their influence on recurrence and progression (Paper V).Results: Tumour size > 30 mm (p < 0.001) and multiplicity (p = 0.021) were significantly associated with local recurrence (Paper I). Tumour sizes 16–30 mm and > 30 mm were correlated with recurrence (p = 0.003 and p < 0.001, respectively) but not with progression (Paper II). High-grade malignant bladder wash cytology proved to be predictive of both recurrence (p < 0.001) and progression (p = 0.036) as was shown in Paper III. A tumour-positive marginal resection was related to overall (p < 0.001) and local (p < 0.001) recurrence (Paper IV). Transurethral resection of bladder tumours performed by residents was associated with recurrence (p = 0.004) but not with progression. No differences in relation to either recurrence or progression were found for the surgical volume approach at the chosen cut-offs (Paper V).Conclusions: The present studies identified new risk factors for recurrence (tumours > 15 mm, high-grade bladder wash cytology at diagnosis, tumour-positive marginal resection, and surgery performed by residents) and progression (local recurrence and high-grade malignant bladder wash cytology at diagnosis), which in the future may be integrated into follow-up schedules or risk profiles for patients with Ta/T1 urinary bladder cancer.
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- Olsson, Hans
(författare)
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Stage T1 Urinary Bladder Carcinoma : Investigation of A Population-Based Cohort
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Approximately 2 300 new cases of urinary bladder carcinoma (UBC) are diagnosed every year in Sweden. This type of cancer is characterized as a long-standing disease with a high risk of recurrence and progression from an indolent to a more aggressive course. UBC occurs in a non-muscle-invasive form (stages Ta and T1), which is treated mainly with local resection and BCG instillation, and a muscle-invasive form (stage ≥ T2), for which the treatment of choice is irradiation or cystectomy.The aim of the research underlying this thesis was to explore the factors involved in tumor development and progression, and to find prognostic markers for recurrence and progression in patients with primary stage T1 urothelial carcinoma of the bladder (UCB).Tumor tissue in archived paraffin blocks from patients diagnosed with that type of malignancy was used in the four studies that were conducted. This was a population-based project, because all of the patients had been reported to the cancer center in the Southeast Healthcare Region in Sweden from 1992 to 2001. The follow-up time was comparable long in the cases included and was intended to be at least 10 years.The hospital records were reviewed to gather information on clinical characteristics of the tumors, such as size and multiplicity, as well as treatment modalities, recurrence and/or progression, and eventual death from UBC. The original tumor slides were re-evaluated. These two initial activities yielded a study population comprising 211 well-characterized patients with primary T1 UCB. Some of the originally selected patients were excluded due to missing paraffin blocks or poor quality of the tumor material, the latter being particularly important in the genetic analyses conducted in the fourth study.Ordinary light microscopy was performed to evaluate specific tumor characteristics, such as lymphovascular tumor infiltration, and for T1 sub-staging. Immunohistochemistry was carried out to, among other things, analyze cell cycle regulators. Furthermore, pyrosequencing, single-strand conformation analysis (SSCA), and Sanger sequencing were conducted in the fourth study to assess mutations in the p53 gene and murine double minute 2 SNP309 promoter polymorphism. Statistical analyses to estimate the risk of tumor recurrence and progression were carried out in all four investigations.Conclusions: This population-based cohort of patients with well-characterized T1 tumors of the urinary bladder showed high rates of recurrence (80%) and progression (39%), and the aggressiveness is underlined by the fact that 32% died from the disease. Lymphovascular tumor infiltration and abnormal immunohistochemical staining for p16 were found to be associated with tumor progression, and in the future analysis of these parameters might be used in treatment decisions regarding T1 bladder tumors. No other clinical or pathological variable or cell cycle regulator was associated with progression, and none of the genetic analyses conducted in the current studies were helpful in predicting outcome or explaining the mechanisms of tumor development.
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