7,629 research outputs found

    Treatment of non-muscle invasive bladder cancer with Bacillus Calmette–Guerin (BCG): Biological markers and simulation studies

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    AbstractIntravesical Bacillus Calmette–Guerin (BCG) vaccine is the preferred first line treatment for non-muscle invasive bladder carcinoma (NMIBC) in order to prevent recurrence and progression of cancer. There is ongoing need for the rational selection of i) BCG dose, ii) frequency of BCG administration along with iii) synergistic adjuvant therapy and iv) a reliable set of biochemical markers relevant to tumor response. In this review we evaluate cellular and molecular markers pertinent to the immunological response triggered by the BCG instillation and respective mathematical models of the treatment. Specific examples of markers include diverse immune cells, genetic polymorphisms, miRNAs, epigenetics, immunohistochemistry and molecular biology ‘beacons’ as exemplified by cell surface proteins, cytokines, signaling proteins and enzymes. We identified tumor associated macrophages (TAMs), human leukocyte antigen (HLA) class I, a combination of Ki-67/CK20, IL-2, IL-8 and IL-6/IL-10 ratio as the most promising markers for both pre-BCG and post-BCG treatment suitable for the simulation studies.The intricate and patient-specific nature of these data warrants the use of powerful multi-parametral mathematical methods in combination with molecular/cellular biology insight and clinical input

    Better prognostic markers for nonmuscle invasive papillary urothelial carcinomas

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    Bladder cancer is a common type of cancer, especially among men in developed countries. Most cancers in the urinary bladder are papillary urothelial carcinomas. They are characterized by a high recurrence frequency (up to 70 %) after local resection. It is crucial for prognosis to discover these recurrent tumours at an early stage, especially before they become muscle-invasive. Reliable prognostic biomarkers for tumour recurrence and stage progression are lacking. This is why patients diagnosed with a non-muscle invasive bladder cancer follow extensive follow-up regimens with possible serious side effects and with high costs for the healthcare systems. WHO grade and tumour stage are two central biomarkers currently having great impact on both treatment decisions and follow-up regimens. However, there are concerns regarding the reproducibility of WHO grading, and stage classification is challenging in small and fragmented tumour material. In Paper I, we examined the reproducibility and the prognostic value of all the individual microscopic features making up the WHO grading system. Among thirteen extracted features there was considerable variation in both reproducibility and prognostic value. The only feature being both reasonably reproducible and statistically significant prognostic was cell polarity. We concluded that further validation studies are needed on these features, and that future grading systems should be based on well-defined features with true prognostic value. With the implementation of immunotherapy, there is increasing interest in tumour immune response and the tumour microenvironment. In a search for better prognostic biomarkers for tumour recurrence and stage progression, in Paper II, we investigated the prognostic value of tumour infiltrating immune cells (CD4, CD8, CD25 and CD138) and previously investigated cell proliferation markers (Ki-67, PPH3 and MAI). Low Ki 67 and tumour multifocality were associated with increased recurrence risk. Recurrence risk was not affected by the composition of immune cells. For stage progression, the only prognostic immune cell marker was CD25. High values for MAI was also strongly associated with stage progression. However, in a multivariate analysis, the most prognostic feature was a combination of MAI and CD25. BCG-instillations in the bladder are indicated in intermediate and high-risk non-muscle invasive bladder cancer patients. This old-fashion immunotherapy has proved to reduce both recurrence- and progression-risk, although it is frequently followed by unpleasant side-effects. As many as 30-50% of high-risk patients receiving BCG instillations, fail by develop high-grade recurrences. They do not only suffer from unnecessary side-effects, but will also have a delay in further treatment. Together with colleagues at three different Dutch hospitals, in Paper III, we looked at the prognostic and predictive value of T1-substaging. A T1-tumour invades the lamina propria, and we wanted to separate those with micro- from those with extensive invasion. We found that BCG-failure was more common among patients with extensive invasion. Furthermore, T1-substaging was associated with both high-grade recurrence-free and progression-free survival. Finally, in Paper IV, we wanted to investigate the prognostic value of two classical immunohistochemical markers, p53 and CK20, and compare them with previously investigated proliferation markers. p53 is a surrogate marker for mutations in the gene TP53, considered to be a main characteristic for muscle-invasive tumours. CK20 is a surrogate marker for luminal tumours in the molecular classification of bladder cancer, and is frequently used to distinguish reactive urothelial changes from urothelial carcinoma in situ. We found both positivity for p53 and CK20 to be significantly associated with stage progression, although not performing better than WHO grade and stage. The proliferation marker MAI, had the highest prognostic value in our study. Any combination of variables did not perform better in a multivariate analysis than MAI alone

    Urological Cancer 2021

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    Cancer of the urological sphere is a disease continuously increasing in numbers in the statistics of tumor malignancies in Western countries. Although this fact is mainly due to the contemporary increase of life expectancy of the people in these geographic areas, many other factors do contribute as well to this growth. Urological cancer is a complex and varied disease of different organs and mainly affects the male population. In fact, kidney, prostate, and bladder cancer are regularly included in the top-ten list of the most frequent neoplasms in males in most statistics. The female population, however, has also increasingly found itself affected by renal and bladder cancer in the last decade. Considering these altogether, urological cancer is a problem of major concern in developed societies. This Topic Issue of Cancers intends to shed some light into the complexity of this field and will consider all useful and appropriate contributions that scientists and clinicians may provide to improve urological cancer knowledge for patients’ benefit. The precise identification of the molecular routes involved, the diagnostic pathological criteria in the grey zones, the dilemma of T1G3 management, and the possible treatment options between superficial, nonmuscle-invasive and muscle-invasive diseases will be particularly welcomed in this Issue

    DIAGNOSIS AND TREATMENT OF UROTHELIAL CARCINOMA OF THE BLADDER

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    Chapter 1 is a general introduction. Chapter 2 describes currently known methylation markers in urine for diagnosis of bladder cancer and their diagnostic accuracy. In Chapter 3 several methylation markers in urine are evaluated to use for diagnosis of bladder cancer and an optimal two gene panel is proposed. In chapter 4 several additives are tested to preserve urinary DNA prior to the analysis of methylation markers in urine. A protocol for preservation is proposed. In chapter 5 the two systems used for grading bladder cancer are tested to determine their reproducibility, both are poorly reproducible. In chapter 6, several measurents are used to determine whether a more objective method to determine bladder cancer grade is possible. In chapter 7 the value of an immediate instillation of mitomycin C after transurethral resection of a bladder tumor is evaluated in a randomised controlled trial. The study shows that an immediate instillation reduces the risk of recurrent bladder cancer. In chapter 8, we evaluate whether the value of an immediate instillation is different in several subgroups of patients. We found that an immediate instillation is effective in all risk groups. In Chapter 9, the timing of an immediate instillation of mitomycin C is investigated. We found that, altough it is recommended to administer an immediate instillation as soon a possible after transurethral resection of a bladder tumour, patients may still benefit from an instillation 1 day after transurethral resection. In chapter 10, interleukin-2 instillations are tested in patients with bladder cancer with and without a marker lesion. The study was closed prematurely so no soli conclusions can be made. However no clear benefit of a marker lesion was detected. In part 3 bladder preservation using brachytherapiy in high risk non muscle invasive bladder cancer, and muscle invasive bladder cancer is evaluatied. We found that brachytherapy is a good alternative to cystectomy in selected patients, without compromising survival. Additionally, the implantaion of the brachytherapey cathethers can safely be conducted using a robot-assisted laparoscopic approach

    Prognostic value of biological markers in superficial bladder tumors

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    The early identification of urinary bladder cancer patients, who are at a high risk of developing recurrences and tumor progression, is of utmost importance, because they require a more aggressive therapeutic approach and close follow-up. The routine use of new prognosticators, more specific and reliable than the established clinicopathologic factors, is therefore mandatory. The present work reviews some of the most significant biological tumor markers (cell cycle proteins, blood group antigens, tumor suppressor genes, oncogenes, CD44 gene transcripts, etc.) defined immunohistochemically in bladder cancer patients. It summarizes most of the recently published results of the clinical trials, using these markers as predictors of the tumor growth, invasion and metastasis. It is also an attempt to highlight the present state of the problem, the still existing controversy and some of the hypotheses concerning the predictive potential of the recently detected tumor markers.Biomedical Reviews 1995; 4: 85-94

    Progress in Personalizing Chemotherapy for Bladder Cancer

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    Platinum-based chemotherapy is commonly used for the treatment of locally advanced and metastatic bladder cancer. However, there are currently no methods to predict chemotherapy response in this disease setting. A better understanding of the biology of bladder cancer has led to developments of molecular biomarkers that may help guide clinical decision making. These biomarkers, while promising, have not yet been validated in prospective trials and are not ready for clinical applications. As alkylating agents, platinum drugs kill cancer cells mainly through induction of DNA damage. A microdosing approach is currently being tested to determine if chemoresistance can be identified by measuring platinum-induced DNA damage using highly sensitive accelerator mass spectrometry technology. The hope is that these emerging strategies will help pave the road towards personalized therapy in advanced bladder cancer

    Chemoprevention of BBN-Induced Bladder Carcinogenesis by the Selective Estrogen Receptor Modulator Tamoxifen

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    AbstractBladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8–20 weeks) or concurrent and subsequent (8–32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non-muscle-invasive disease was present in animals treated with tamoxifen before (5–8 weeks) or after (20–32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence
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