scholarly journals Metabolomic credentialing of murine carcinogen-induced urothelial cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hesham Afify ◽  
Alia Ghoneum ◽  
Sameh Almousa ◽  
Ammar Yasser Abdulfattah ◽  
Bailey Warren ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Human Disease ◽  
Urothelial Cancer ◽  
Treatment Options ◽  
Chemical Carcinogenesis ◽  
Metabolomic Profiling ◽  
Species Analysis ◽  
Metabolic Heterogeneity ◽  
Muscle Invasive ◽  
Common Malignancy

AbstractBladder cancer (BCa) is the most common malignancy of the urinary system with increasing incidence, mortality, and limited treatment options. Therefore, it is imperative to validate preclinical models that faithfully represent BCa cellular, molecular, and metabolic heterogeneity to develop new therapeutics. We performed metabolomic profiling of premalignant and non-muscle invasive bladder cancer (NMIBC) that ensued in the chemical carcinogenesis N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model. We identified the enriched metabolic signatures that associate with premalignant and NMIBC. We found that enrichment of lipid metabolism is the forerunner of carcinogen-induced premalignant and NMIBC lesions. Cross-species analysis revealed the prognostic value of the enzymes associated with carcinogen-induced enriched metabolic in human disease. To date, this is the first study describing the global metabolomic profiles associated with early premalignant and NMIBC and provide evidence that these metabolomic signatures can be used for prognostication of human disease.

scholarly journals Treatment options for muscle-invasive urothelial cancer for patients who were not eligible for cystectomy or neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin

Cancer ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 2181-2187 ◽  
Author(s):  
Celestia S. Higano ◽  
Catherine M. Tangen ◽  
Wael A. Sakr ◽  
James Faulkner ◽  
Saul E. Rivkin ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Urothelial Cancer ◽  
Treatment Options ◽  
Muscle Invasive

Neoadjuvant or adjuvant immunotherapy in bladder cancer: biological opportunity or clinical utility?

2021 ◽  
pp. 030089162110616
Author(s):  
Fausto Petrelli ◽  
Gianluca Perego ◽  
Ivano Vavassori ◽  
Andrea Luciani
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Phase Iii ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Cancer Of The Bladder ◽  
Muscle Invasive

In urothelial cancer of the bladder, the introduction of immunotherapy with immune checkpoint inhibitors represents progress in the management of the disease’s early and advanced stages. In particular, recent studies have implemented these drugs in the neoadjuvant and adjuvant phases to treat muscle-invasive bladder cancer. In some studies, patients received neoadjuvant immune checkpoint inhibitors alone (PURE and ABACUS) to treat muscle invasive bladder cancer, whereas other studies provided this therapy to cisplatin-ineligible patients. Furthermore, a large Phase III study (CheckMate 247) compared placebo with adjuvant nivolumab therapy in patients with high-risk urothelial cancer after neoadjuvant chemotherapy and surgery or surgery alone. Despite some uncertain niches (nonbladder, PD-L1-negative tumors, and node-negative resected cancers), certain biological opportunities (exploring new targets, evaluating in vivo pathologic response, focusing on biomarkers for response) and clinical uses (avoiding chemotherapy at all or in frail patients, attaining similar pathologic complete response rates as in cisplatin-based chemotherapy) are valid reasons for incorporating these agents into the therapeutic armamentarium of medical uro-oncologists.

scholarly journals The dynamics of the inflammatory response during BBN-induced bladder carcinogenesis in mice

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Marina Degoricija ◽  
Jelena Korac-Prlic ◽  
Katarina Vilovic ◽  
Tonci Ivanisevic ◽  
Benedikt Haupt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Inflammatory Response ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Locally Advanced ◽  
Histopathological Analysis ◽  
Tumor Escape ◽  
Induced Tumors ◽  
Frequent Mutations ◽  
Muscle Invasive

Abstract Background Bladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC. Methods Bladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment. Results We characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape. Conclusions Despite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO): A single-arm, open-label window-of-opportunity trial of neoadjuvant abemaciclib in platinum-ineligible muscle invasive bladder cancer patients.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS606-TPS606
Author(s):  
Jones Nauseef ◽  
Panagiotis J. Vlachostergios ◽  
Ana M. Molina ◽  
David M. Nanus ◽  
Cora N. Sternberg ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Clinical Trial ◽  
Bladder Cancer ◽  
Neoadjuvant Therapy ◽  
Urothelial Cancer ◽  
Window Of Opportunity ◽  
Muscle Invasive Bladder Cancer ◽  
Cell Cycle Genes ◽  
Cell Cycle Inhibition ◽  
Muscle Invasive

TPS606 Background: The standard of care for clinically localized muscle-invasive bladder cancer (MIBC) is neoadjuvant platinum-based combination chemotherapy followed by radical cystectomy (RC). Up to 40% of patients (pts) are ineligible to receive cisplatin and proceed to RC without any neoadjuvant therapy. We and others have demonstrated enrichment of molecular alterations in cell cycle genes in MIBC, including copy number losses of CDKN2A in 41% of pts. Abemaciclib is a unique CDK4/6 inhibitor with single agent activity and a target kinome distinct from other CDK4/6 inhibitors. We have demonstrated that CRISPR knockout of CDKN2A increases susceptibility to abemaciclib in bladder cancer cell lines. Beyond tumor-intrinsic effects, abemaciclib also modulates the tumor microenvironment (TME) via upregulating human endogenous retroviral elements and increasing T cell infiltration. Methods: Cell cycLe inhibitiON to target the EVolution of urOthelial cancer (CLONEVO) is a single arm, window-of-opportunity trial of neoadjuvant abemaciclib which will evaluate tumor cell and TME changes in response to abemaciclib. Enrolled pts must be ineligible for platinum-based neoadjuvant therapy for resectable MIBC. Pts receive abemaciclib (200 mg BID PO) for 4 weeks prior to RC. Tumor tissue collected via transurethral resection of bladder tumor (TURBT) and residual tumor at RC undergo single cell RNA sequencing and whole-exome sequencing. Patient-derived organoids and xenografts are generated for a co-clinical trial of abemaciclib alone or in combination. The primary endpoint is the measurement of changes in cell cycle dynamics. Secondary objectives are assessment of toxicity via NCI CTCAE v 5.0 and pathologic downstaging of MIBC. We will perform targeted sequencing of a panel of cell cycle genes in serial plasma and urine cell free DNA to evaluate changes in the variant allele fractions of somatic alterations. The novel design of this trial allows dynamic in vivo assessment of tumor changes and creates a new paradigm for studying tumor evolution in real time. Clinical trial information: NCT03837821.

scholarly journals Recognition and Treatment of BCG Failure in Bladder Cancer

2011 ◽  
Vol 11 ◽  
pp. 602-613 ◽  
Author(s):  
Andrew J. Lightfoot ◽  
Henry M. Rosevear ◽  
Michael A. O'Donnell
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Treatment Options ◽  
Standard Of Care ◽  
Complete Response ◽  
Bcg Therapy ◽  
Risk Patients ◽  
Bcg Failure ◽  
Muscle Invasive ◽  
American Urological Association

Patients with high-grade Ta, T1, or carcinomain situnon–muscle-invasive bladder cancer (NMIBC) are at high risk for recurrence and, more importantly, progression. Thus, both the American Urological Association and European Association of Urology recommend initial intravesical treatment with bacillus Calmette-Guerin(BCG) followed by maintenance therapy for a minimum of 1 year. The complete response rate to BCG therapy in patients with high-risk NMIBC can be as high as ∼80%; however, most patients with high-risk disease suffer from recurrence. BCG failure can be further characterized into BCG refractory, BCG resistant, BCG relapsing, and BCG intolerant. Current recommendations include one further course of BCG or cystectomy. In patients who continue to fail conservative treatment and who refuse surgical therapy or are not surgical candidates, treatment options become even more complicated. In this setting, treatment options are limited and include repeat BCG treatment, an alternate immunotherapy regimen, chemotherapy, or device-assisted therapy. To date, however, further research is necessary for all secondary treatment options in order to determine which might be the most efficacious. All conservative treatments should be considered investigational. Currently, cystectomy remains the standard of care for high-risk patients who have failed BCG therapy.

scholarly journals Incidence and Predictors of Secondary Upper Tract Urothelial Cancer in Patients with High-Risk Non-Muscle Invasive Urinary Bladder Cancer and its Impact on Imaging Surveillance: A Retrospective Analysis with 1501 Patients

2021 ◽  
Vol 2 (3) ◽  
pp. 151-157
Author(s):  
Ebrahim Elsaeed Abouelenein ◽  
Mohamed Elawdy ◽  
Diaa-Eldin Taha ◽  
Yasser Osman ◽  
Bedeir Ali-El Dein ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Urothelial Cancer ◽  
Multivariable Analysis ◽  
Bladder Tumors ◽  
Upper Tract ◽  
Upper Tract Urothelial Cancer ◽  
Imaging Surveillance ◽  
Muscle Invasive

Objectives: We aimed to study the incidence and predictors of upper tract urothelial cancer (UTUC) in patients with high-risk non-muscle invasive bladder cancer (HR-NMIBC). Methods: Patients who had HR-NMIBC were reviewed to identify those who subsequently developed UTUC. Complete transurethral resection was performed, and biopsies were collected for histopathology followed by intravesical chemoimmunotherapy. Patients were screened annually by computed tomography (CT) for UTUC. Results: Data for 1501 patients were reviewed. UTUC developed in 59 (4%) after a median of 20 months after HR-NMIBC. Most patients were symptomatic, but UTUC was discovered on routine follow-up imaging in 28%. On bivariate analysis, only multiple bladder tumors and the number of bladder recurrences were predictors for UTUC (P = 0.01 and P = 0.008, respectively). Multiple bladder tumors and ≥ 3 bladder recurrences remained significant on multivariable analysis. Conclusion: UTUC after HR-NMIBC is uncommon (4%). Despite routine follow-up CT imaging, recurrence was detected due to symptoms in most patients, and based on imaging only in 28%. Imaging surveillance can be prioritized in patients with multiple bladder tumors and those with ≥ 3 bladder recurrences. For the other patients, the benefit of imaging surveillance has to be weighed against the risks.

scholarly journals ATF2 promotes urothelial cancer outgrowth via cooperation with androgen receptor signaling

2018 ◽  
Vol 7 (12) ◽  
pp. 1397-1408 ◽  
Author(s):  
Satoshi Inoue ◽  
Taichi Mizushima ◽  
Hiroki Ide ◽  
Guiyang Jiang ◽  
Takuro Goto ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Androgen Receptor ◽  
Urothelial Cancer ◽  
Nuclear Translocation ◽  
Significant Inhibition ◽  
Migration And Invasion ◽  
Cycle Phase ◽  
Low Grade ◽  
Urothelial Cells ◽  
Muscle Invasive

We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

scholarly journals Unusual Tibial Site Metastases from a Muscle Invasive Urothelial Carcinoma: A Rare Case Report

2020 ◽  
Vol 5 (09) ◽  
pp. 382-384
Author(s):  
Kastanis G. ◽  
Bachlitzanaki M. ◽  
Pantouvaki A. ◽  
Magarakis G. ◽  
Spyrantis M.
Keyword(s):  
Bladder Cancer ◽  
Urothelial Carcinoma ◽  
Rare Case ◽  
Common Type ◽  
Diaphyseal Bone ◽  
Rare Manifestation ◽  
Rare Case Report ◽  
Muscle Invasive ◽  
Considerable Morbidity ◽  
Common Malignancy

Bladder cancer is a common malignancy of genitourinary tract with a considerable morbidity and mortality. Muscle invasive urothelial carcinoma is the most common type of cancer especially in ages over 65 years old. Though various metastases have been observed, bone localization is the second site metastases and is appeared in pelvis and spine. We present a case with tibial diaphyseal bone metastases from urothelial carcinoma as a rare manifestation and we review the literature among diagnoses and therapeutic management.

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