Biology of BCG response in non-muscle invasive bladder cancer - 2021 IBCN Updates Part III.

Bacillus Calmette-Guerin (BCG) remains the only FDA-approved first-line therapy in patients with high-risk non-muscle invasive bladder cancer. Recurrences, even after adequate BCG therapy, are common and the efficacy of second-line therapies remains modest. Therefore, early identification of patients likely to recur and treatment after recurrence remain critical unmet needs in the clinical care of bladder cancer patients. To address these deficits, a better understanding of the mechanisms of resistance to BCG-therapy is needed. The virtual update of the International Bladder Cancer Network (IBCN) on the biology of response to BCG focused on potential mechanisms and markers of resistance to intravesical BCG therapy. The insights from this meeting will be highlighted and put into context of previously reported mechanisms of resistance to BCG in this review.

[Report from the 9th symposium of the German Association for Bladder Cancer Research]. / Bericht vom 9. Symposium des Deutschen Forschungsverbunds Blasenkarzinom.

The annual symposium of the German Research Association for Bladder Carcinoma (DFBK) was organized on February 7th and 8th, 2020, in Düsseldorf. On the first day, eight international guest speakers invited by the DFBK and the Department of Urology of the Heinrich Heine University Düsseldorf presented the current state of research on bladder cancer (BC). Topics were genomic changes and molecular classification in non-muscle-invasive and muscle-invasive BC, prospects and limits of proteome technology in urine diagnostics, function of chromatin regulators in bladder carcinogenesis, cellular reactions to aneuploidy, organoid technology and biobanking, as well as novel aspects of immunotherapy for BC. The second day was dedicated to new results and ideas of the DFBK members on BC pathomechanisms, diagnostics and therapeutic approaches, and most importantly, discussions on the further development of collaborative projects. Additional information is available at http://www.forschungsverbund-blasenkarzinom.de.

[Modern networks : Topics in the working group "Bladder cancer research" of the GeSRU Academics]. / Modernes Netzwerken : Thematische Ausrichtungen in der Arbeitsgruppe "Blasenkarzinom Experimentell" der GeSRU Academics.

In January 2015, the research group "bladder cancer research" was founded as part of the GeSRU Academics research initiative. A general challenge to work successfully in a novel network structure is to identify common scientific topics and technical expertise in the group. Thus, one of the first tasks was to learn about current research projects from members within the group in order to address a project that suits the group's expertise. The following review summarizes three different directions that are key projects in Urologic Departments at German Universities that will be the basis to start fruitful collaborations.

[YB-1-based virotherapy: A new therapeutic intervention for transitional cell carcinoma of the bladder?]. / YB-1-basierte Virotherapie : Ein neues Therapiekonzept beim Urothelkarzinom der Harnblase.

Therapeutic intervention using oncolytic viruses is called virotherapy. This type of virus is defined by the ability to replicate in tumor cells only and to destroy these cells upon replication. In addition, this virus type is able to induce a tumor-directed immune response. Early clinical trials have confirmed the safety profile of oncolytic viruses. Currently, different groups are working on the development of oncolytic viruses with a focus on treatment of nonmuscle invasive bladder cancer (NMIBC). A preliminary active recruiting clinical phase II/III trial ongoing in patients with a NMIBC was recently implemented in the United States. Our research group developed an oncolytic adenovirus that will soon enter a clinical phase I trial in patients diagnosed with glioma. This virus is being further modified for the treatment of NMIBC. In this review article, recent developments in the design and use of virotherapy in bladder cancer are summarized.

The prognostic effect of tumour-infiltrating lymphocytic subpopulations in bladder cancer.

BACKGROUND: Intratumoural lymphocytic infiltration is strongly associated with the outcome of many human epithelial cancers. The current paper investigated whether subpopulations of tumour-infiltrating T lymphocytes are associated with certain clinicopathological parameters and the prognosis of patients with invasive bladder cancer (BCa). PATIENTS AND METHODS: The infiltration densities of the adaptive immune markers CD3 (the whole T cell population), FOXP3 (regulatory T cells; Tregs), CD8 (T effector cells) and CD45R0 (T effector memory cells) were analysed by immunohistochemistry and image analysis with tissue microarrays of tumour tissues from 149 patients with invasive BCa treated with radical cystectomy. The findings were correlated with certain clinicopathological parameters. RESULTS: Higher FOXP3/CD3 [OS: p = 0.016, HR 1.29, 95% confidence intervals (95% CIs 1.05-1.59)] and FOXP3/CD8 (OS: p = 0.013, HR 1.32, 95% CIs 1.06-1.65) ratios were significantly associated with briefer overall survival and time to cancer-specific death; the latter ratio represented an independent prognostic factor according to a multivariate analysis adjusted for pathological T and N stages (HR 1.32, 95% CIs 1.05-1.67, p = 0.018). The infiltration densities of individual markers (CD3, CD8, FOXP3 and CD45R0) were not significantly associated with clinicopathological parameters or survival; however, a trend towards a better outcome was observed for higher log-transformed CD8 (p = 0.070, HR 0.80, 95% CIs 0.63-1.02) and CD3 (p = 0.113, HR 0.84, 95% CIs 0.68-1.04) infiltration values. CONCLUSIONS: A high fraction of Tregs amongst CD3- and CD8-positive lymphocytes indicated a poor prognosis, thereby emphasising the important role that Tregs play in the suppression of the anti-tumour immune response. No single lymphocytic marker was significantly correlated with clinical outcomes, but high CD3 and CD8 infiltration showed trends towards better prognosis.

Circulating tumor cells versus objective response assessment predicting survival in metastatic castration-resistant prostate cancer patients treated with docetaxel chemotherapy.

PURPOSE: Circulating tumor cell (CTC) counts might display a superior prognostic value for overall survival (OS) compared to objective response criteria (OR) in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: CTCs were detected using the CellSearch™ System out of 122 samples during docetaxel chemotherapy (75 mg/m(2)) at baseline (q0) and after 1 (q1), 4 (q4) and 10 (q10) cycles, in mCRPC patients (n = 33). OR was evaluated by morphologic RECIST and clinical criteria after 4 (q4) and 10 (q10) cycles. RESULTS: For OS, analyses revealed a significant prognostic value for categorical (<5 vs. ≥5) CTC counts (q0, p = 0.005; q1, p = 0.001; q4, p < 0.001; q10, p = 0.002), RECIST (q4, p < 0.001; q10, p = 0.02) and clinical criteria (q4, p < 0.001; q10, p = 0.02). Concordance of CTC counts with OR revealed a sensitivity of 83.3-87.5 % and a specificity of 68.0-76.5 % with complementary discriminatory power for OS. Comparing CTC counts with concomitant OR at q4 in multivariate analyses, an independent prognostic value for OS was found for CTC counts (HR 3.3; p = 0.02) similar to clinical (HR 4.9; p = 0.02) and radiologic response (HR 3.4; p = 0.051). Comparing the predictive value for death, early post-treatment CTC counts at q1 demonstrated significant accuracy with an area under the curve of 79.5 % (p = 0.004) similar to CTC counts at q4 (76.7 %; p = 0.009). Radiologic and clinical response at q4 displayed accuracy similar to early CTC counts at q1 (72.2 %; p = 0.03 and 75.0 %; p = 0.02) despite low sensitivities. CONCLUSIONS: CTC counts appear to be an earlier and more sensitive predictor for survival and treatment response than current OR approaches and may provide complementary information toward individualized treatment strategies.

Mutant PIK3CA controls DUSP1-dependent ERK 1/2 activity to confer response to AKT target therapy.

BACKGROUND: Alterations in the phosphoinositide 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway are frequent in urothelial bladder cancer (BLCA) and thus provide a potential target for novel therapeutic strategies. We investigated the efficacy of the AKT inhibitor MK-2206 in BLCA and the molecular determinants that predict therapy response. METHODS: Biochemical and functional effects of the AKT inhibitor MK-2206 were analysed on a panel of 11 BLCA cell lines possessing different genetic alterations. Cell viability (CellTiter-Blue, cell counts), apoptosis (caspase 3/7 activity) and cell cycle progression (EdU incorporation) were analysed to determine effects on cell growth and proliferation. cDNA or siRNA transfections were used to manipulate the expression of specific proteins such as wild-type or mutant PIK3CA, DUSP1 or CREB. For in vivo analysis, the chicken chorioallantoic membrane model was utilised and tumours were characterised by weight and biochemically for the expression of Ki-67 and AKT phosphorylation. RESULTS: Treatment with MK-2206 suppressed AKT and S6K1 but not 4E-BP1 phosphorylation in all cell lines. Functionally, only cell lines bearing mutations in the hotspot helical domain of PIK3CA were sensitive to the drug, independent of other genetic alterations in the PI3K or MAPK signalling pathway. Following MK-2206 treatment, the presence of mutant PIK3CA resulted in an increase in DUSP1 expression that induced a decrease in ERK 1/2 phosphorylation. Manipulating the expression of mutant or wild-type PIK3CA or DUSP1 confirmed that this mechanism is responsible for the induction of apoptosis and the inhibition of tumour proliferation in vitro and in vivo, to sensitise cells to AKT target therapy.Conclusion or interpretation:PIK3CA mutations confer sensitivity to AKT target therapy in BLCA by regulating DUSP1 expression and subsequent ERK1/2 dephosphorylation and can potentially serve as a stratifying biomarker for treatment.

[Molecular lymph node staging in prostate and bladder cancer]. / Molekulares Lymphknotenstaging beim Prostata- und Harnblasenkarzinom.

A positive lymph node status is a major prognostic factor for tumor recurrence and mortality following radical prostatectomy in prostate cancer patients or radical cystectomy in bladder cancer patients. However, despite having histopathologic negative lymph nodes, a substantial proportion of patient suffers from tumor recurrence within a few years after the operation. Tumor recurrence in node-negative patients may result from hematogeneous or lymphatic metastatic spread which remains undetected by standard clinical or histopathologic examinations. Molecular lymph node analysis is a potential method for detection of lymph node metastases with higher sensitivity and for prognostic risk stratification of patients with histopathologic negative lymph nodes.

[Prostate and bladder cancer: detection of disseminated tumor cells in bone marrow]. / Prostata- und Harnblasenkarzinom: Detektion von disseminierten Tumorzellen im Knochenmark.

The prognosis of prostate and bladder cancer patients is predominantly determined by the detection of distant sites of metastasis. In clinical routine, virtually only lymph node staging is of relevance to determine metastasis. Detection and characterization of disseminated tumor cells in peripheral blood or bone marrow is an additional parameter of prognostic significance. In this article, we will summarize recent progress on the prognostic value of disseminated tumor cells in bone marrow and its translation into routine clinical analysis.

[[¹¹C]choline as a pharmacodynamic marker for docetaxel therapy. Response assessment in a LNCaP prostate cancer xenograft mouse model]. / Ansprechen auf eine Docetaxeltherapie im LNCaP-Prostatakarzinom-Xenograft-Mausmodell. Untersuchung mit der [¹¹C]Cholin-Kleintier-PET/CT.

UNLABELLED: The AIM of this study was to determine whether [¹¹C]choline can be used for docetaxel therapy response assessment in a LNCaP-prostate cancer xenograft mouse model using [¹¹C]choline small-animal PET/CT. ANIMALS, METHODS: The androgen-dependent human prostate cancer cell line LNCaP was implanted subcutaneously into the left flanks of 17 SCID-mice, 12.5 mg testosterone platelets were implanted in the neck wrinkle. All mice were injected 4-6 weeks after xenograft implantation with 37 MBq [¹¹C]choline via the tail vein. Dynamic imaging was performed for 60 minutes with a small-animal PET/CT scanner. After the first [¹¹C]choline PET/CT imaging 8 mice were subsequently injected intravenously with docetaxel twice (days 1 and 5) at a dose of 3 mg/kg body weight. 8 mice were treated with PBS as a control. [¹¹C]choline PET/CT imaging was performed on day 7, 14 and 21 after treatment. Image analysis was performed using tumor/muscle (T/M) ratios (ROI(T)/ROI(M) = T/M ratio). RESULTS: All LNCaP tumours could be visualized by [¹¹C]choline PET/CT. Before treatment the mean T/M ratio was 2.0 ± 0.2 in the docetaxel-treated group and 1.9 ± 0.2 in the control group (p = 0.837). There was a reduction in the mean [¹¹C]choline uptake after docetaxel treatment of the tumours of the LNCaP cell line as early as 1 week after initiation of therapy (T/M(mean) ratio 1.5 ± 0.2 after one week, 1.3 ± 0.2 after 2 weeks and 1.4 ± 0.2 after 3 weeks). There was no decrease in [¹¹C]choline uptake in the control group. CONCLUSION: Our results show that [¹¹C]choline has the potential for use in the early monitoring of the therapeutic effect of docetaxel in a LNCaP prostate cancer xenograft animal model.

[Bladder cancer in focus: update 2012 of the German Bladder Cancer Association]. / Das Harnblasenkarzinom im Fokus : Update 2012 des Deutschen Forschungsverbundes Blasenkarzinom e. V.

The German Bladder Cancer Association (DFBK) invited its members to the 3rd annual meeting 2012 in Hannover 4 years after the official founding. The meeting was directed to discuss the progress of ongoing and newly initiated projects and collaborations. In this article we will introduce current research activities and collaborations of the DFBK and would like to invite interested researchers to join this national interdisciplinary research association. The aim of the DFBK is to initiate interdisciplinary collaboration and to support scientific discussions among its members. For further information please visit our website at www.forschungsverbund-blasenkarzinom.de.

[Bladder cancer update: what was new at the 2010 annual congress of the German Association of Urology in Düsseldorf?]. / Blasenkarzinom - Update : Was gab es neues auf dem Jahreskongress 2010 der Deutschen Gesellschaft für Urologie in Düsseldorf?

One of the principal objects of the scientific research network "German Bladder Cancer Network" is to consolidate research activities on bladder cancer. An overview about directions of current projects on this research topic was given at the annual meeting of the German Association of Urology in Düsseldorf from September 22 to 25 September 2010. As representatives of the"German Bladder Cancer Network" we summarize and comment on some of the most interesting projects on bladder cancer presented at this meeting. A special focus will be on current developments in the field of uropathology and on different aspects in preclinical research on bladder cancer.

[EMMPRIN (CD147). A prognostic and potentially therapeutic marker in urothelial cancer]. / EMMPRIN (CD147). Ein prognostischer und potenzieller therapeutischer Marker im Urothelkarzinom.

In 50% of all cases, bladder cancer patients develop tumor progression despite modern surgical methods such as radical cystectomy. A solution to the problem might be the identification and understanding of molecular biomarkers which could result in the development of advanced methods with better preventive, diagnostic, and therapeutic potential. One suitable approach is the identification of a bladder cancer-specific molecular marker in order to enhance patients' outcome. We and others have identified EMMPRIN as a prognostic biomarker in a variety of tumor diseases. EMMPRIN (CD147, extracellular matrix metalloproteinase inducer) is a cell surface protein that is expressed among other cell types, in particular in tumor cells. Since its first description in 1982 it is established that overexpression of EMMPRIN correlates with tumor progression and patient outcome. EMMPRIN expression levels can be used as an independent prognostic factor for survival. Recently, EMMPRIN has been defined as a potential target for tumor therapy in preclinical studies.

EMMPRIN regulates the canonical Wnt/beta-catenin signaling pathway, a potential role in accelerating lung tumorigenesis.

Advances in the field of tumor biology have identified that tumor cells co-opt developmental signaling pathways of embryonic stem cells and thus gain the ability to proliferate, differentiate and alter cell-cell interactions. One such pathway is the Wnt/beta-catenin signaling pathway. High levels of EMMPRIN expression have been shown to correlate with poor prognosis and metastasis in a broad range of tumors. Although a variety of functions are attributed to EMMPRIN in tumorigenesis, the specific mechanism(s) through which it can exert its effects have not been elucidated, until now. In this study, we identify EMMPRIN as a novel regulator of the canonical Wnt/beta-catenin signaling pathway in lung cancer. Increasing EMMPRIN expression levels in lung cancer epithelial cells upregulated the beta-catenin signaling pathway and silencing EMMPRIN inhibited beta-catenin signaling, cell migration, proliferation, anchorage-independent growth and tumor growth in a mouse tumor xenograft model. These results provide a compelling rationale for targeting EMMPRIN for anticancer therapies. Understanding the molecular mechanisms driving EMMPRIN-induced lung tumorigenesis will provide enormous benefits in developing new therapeutic treatments for this and other forms of cancer.

[Educational initiative of the German Society of Urology for innovative research : Workshops 2009]. / Ausbildungsinitiative der Deutschen Gesellschaft für Urologie für innovative Forschung : Workshops 2009.

The tasks of the Working Group on Urological Research (AuF) of the German Society of Urology (DGU) are to support communication and initiation of joint ventures in German urology and to cooperate with associated subjects and neighboring countries. The annual "wet lab workshops" needs a space between annual and "wet lab workshops" on the topics of tumor cell culture, gene silencing, proteomics, and tissue engineering and the use instead of annual topic-related symposium"urological research," organized and carried out by the AuF as of 2009, serve to achieve a close change to closer integration of praxis and theory. This should contribute to a lasting quality improvement of the scientific work in urology. Accomplishing these objectives seems urgently necessary to preserve the interests of urologists, because more than ever research has become indispensable in an increasingly difficult environment of health care policy.

[Symposium of the German Bladder Cancer Association]. / Symposium des Deutschen Forschungsverbundes Blasenkarzinom e.V.

One year after the official founding of the German Bladder Cancer Association the interdisciplinary association organized its first symposium on bladder cancer at the meeting center"Schloss Mickeln" in Düsseldorf in June 2009. The focus of the symposium was on the initiation and implementation of primary objectives of the association. Members from national and international research groups presented and discussed current projects. A period of 12 months has been required to establish a national tissue bank for bladder cancer speciem which will be started in January 2010. The meeting not only stirred new ideas but also promoted new collaborations and served as an innovative platform to discuss novel questions and methodological approaches to study bladder cancer. Additionally, the website www.forschungsverbund-blasenkarzinom.de will provide further information about the German Bladder Cancer Association.

[EMMPRIN (CD147). A new key protein during tumor progression in bladder cancer]. / EMMPRIN (CD147). Ein neues Schlüsselprotein in der Tumorprogression des Harnblasenkarzinoms.

EMMPRIN (CD147) is a cell surface protein that is highly expressed on tumor cells. Elevated EMMPRIN levels have been detected in a variety of malignant tumors and have been associated with tumor progression in experimental and clinical conditions. Recent studies have shown that EMMPRIN is an independent prognostic factor for overall survival in bladder cancer patients. In a multicenter phase II trial, antibodies against EMMPRIN were shown to be successful in hepatocellular cancer therapy. We are characterizing the functional importance of EMMPRIN in bladder cancer in order to evaluate this protein as a new target molecule for therapy.

[Muscle-invasive urothelial carcinoma of the bladder. Detection and topography of micrometastases in lymph nodes]. / Muskelinvasives Urothelkarzinom der Harnblase. Detektion und Topographie von Mikrometastasen in Lymphknoten.

Detection of metastases in lymph nodes is an important prognostic factor for progression-free survival in bladder cancer patients. Patients undergoing radical cystectomy with pelvic lymphadenectomy are randomized in the LEA study (AUO AB 25/02) into two groups receiving standard (obturator and external nodes) or extended lymphadenectomy (complete pelvic nodes up to the inferior mesenteric artery).The aim of this study is the detection of lymph node metastases that are not identified with classic pathological methods using RT-PCR as a highly sensitive and specific method. For detection of occult disseminated tumor cells we analyze the expression of the tumor markers cytokeratin 20 (CK-20), uroplakin II (UP II), mucin 2 (MUC2), and mucin 7 (MUC7).We examined 315 lymph nodes from 19 cystectomy patients for the expression of CK-20. In 93 lymph nodes CK-20 expression was detected whereas only 18 lymph nodes were histopathologically positive. More than one third of CK-20-positive lymph node metastases were located outside the standard lymphadenectomy field. We did not detect any skip lesions. Follow-up data will validate if there is a correlation between detection of occult disseminated tumor cells and progression-free survival.

[German Association for Bladder Cancer Research]. / Deutscher Forschungsverbund Blasenkarzinom e.V.

The "German Association for Bladder Cancer Research" was founded in May 2008 by urologists, scientists, and pathologists. The purpose of this association is to concentrate research activities on a national level, to facilitate collaborations with an interdisciplinary background, and to define standard methodology for a higher quality of scientific results. Additionally, a national database for bladder cancer specimens will be initiated. The website http://www.forschungsverbund-blasenkarzinom.de will provide further information about the German Association for Bladder Cancer Research.