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Urinary Bladder Neoplasms: HELP
Articles by Donna Elizabeth Hansel
Based on 59 articles published since 2009
(Why 59 articles?)
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Between 2009 and 2019, Donna Hansel wrote the following 59 articles about Urinary Bladder Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline Update for the practicing pathologist: The International Consultation On Urologic Disease-European association of urology consultation on bladder cancer. 2015

Amin, Mahul B / Smith, Steven C / Reuter, Victor E / Epstein, Jonathan I / Grignon, David J / Hansel, Donna E / Lin, Oscar / McKenney, Jesse K / Montironi, Rodolfo / Paner, Gladell P / Al-Ahmadie, Hikmat A / Algaba, Ferran / Ali, Syed / Alvarado-Cabrero, Isabel / Bubendorf, Lukas / Cheng, Liang / Cheville, John C / Kristiansen, Glen / Cote, Richard J / Delahunt, Brett / Eble, John N / Genega, Elizabeth M / Gulmann, Christian / Hartmann, Arndt / Langner, Cord / Lopez-Beltran, Antonio / Magi-Galluzzi, Cristina / Merce, Jorda / Netto, George J / Oliva, Esther / Rao, Priya / Ro, Jae Y / Srigley, John R / Tickoo, Satish K / Tsuzuki, Toyonori / Umar, Saleem A / Van der Kwast, Theo / Young, Robert H / Soloway, Mark S. ·Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. · Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA. · Department of Pathology, Indiana University School of Medicine, Indianapolis, IN, USA. · Department of Pathology, University of California San Diego, San Diego, CA, USA. · Department of Pathology, Cleveland Clinic Foundation, Cleveland, OH, USA. · Section of Pathological Anatomy, Polytechnic University of Medicine, United Hospitals, Ancona, Italy. · Department of Pathology, University of Chicago, Chicago, IL, USA. · Pathology Section, Fundacio Puigvert, Universitat Autónoma de Barcelona, Barcelona, Spain. · Department of Pathology, Mexican Oncology Hospital, Mexico City, Mexico. · Institute of Pathology, University Hospital Basel, Basel, Switzerland. · Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA. · Institute of Pathology, University Hospital Bonn, Bonn, Germany. · Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, USA. · Department of Pathology, Wellington School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand. · Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, MA, USA. · Department of Pathology, Beaumont Hospital, Dublin, Ireland. · Institute of Pathology, University Erlangen-Nürnberg, Erlangen, Germany. · Institute of Pathology, Medical University Graz, Graz, Austria. · Unit of Anatomical Pathology, Cordoba University Medical School, Faculty of Medicine, Cordoba, Spain. · James Homer Wright Pathology Laboratories, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. · Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. · Department of Pathology and Genomic Medicine, The Methodist Hospital Physician Organization, Weill Cornell Medical College of Cornell University, Houston, TX, USA. · Department Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada. · Department of Pathology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan. · Department of Urology, University of Miami Miller School of Medicine, Miami, FL, USA. ·Mod Pathol · Pubmed #25412849.

ABSTRACT: The International Consultations on Urological Diseases are international consensus meetings, supported by the World Health Organization and the Union Internationale Contre le Cancer, which have occurred since 1981. Each consultation has the goal of convening experts to review data and provide evidence-based recommendations to improve practice. In 2012, the selected subject was bladder cancer, a disease which remains a major public health problem with little improvement in many years. The proceedings of the 2nd International Consultation on Bladder Cancer, which included a 'Pathology of Bladder Cancer Work Group,' have recently been published; herein, we provide a summary of developments and consensus relevant to the practicing pathologist. Although the published proceedings have tackled a comprehensive set of issues regarding the pathology of bladder cancer, this update summarizes the recommendations regarding selected issues for the practicing pathologist. These include guidelines for classification and grading of urothelial neoplasia, with particular emphasis on the approach to inverted lesions, the handling of incipient papillary lesions frequently seen during surveillance of bladder cancer patients, descriptions of newer variants, and terminology for urine cytology reporting.

2 Guideline ICUD-EAU International Consultation on Bladder Cancer 2012: Pathology. 2013

Amin, Mahul B / McKenney, Jesse K / Paner, Gladell P / Hansel, Donna E / Grignon, David J / Montironi, Rodolfo / Lin, Oscar / Jorda, Merce / Jenkins, Lawrence C / Soloway, Mark / Epstein, Jonathan I / Reuter, Victor E / Anonymous960740. ·Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Mahul.Amin@cshs.org ·Eur Urol · Pubmed #23083804.

ABSTRACT: CONTEXT: To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the pathology of bladder cancer using an evidence-based strategy. OBJECTIVE: To standardize descriptions of the diagnosis and reporting of urothelial carcinoma of the bladder and help optimize uniformity between individual pathology practices and institutions. EVIDENCE ACQUISITION: A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to pathology. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS: The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed. CONCLUSIONS: Providing the best management for patients with bladder neoplasia relies on close cooperation and teamwork among urologists, oncologists, radiologists, and pathologists.

3 Review Non-urothelial carcinomas of the bladder. 2019

Park, Sanghui / Reuter, Victor E / Hansel, Donna E. ·Department of Pathology, Ewha Womans University College of Medicine, Seoul, Korea. · Department of Pathology, Memorial Sloan Kettering Cancer Institute, New York, NY. · Department of Pathology, University of California at San Diego, La Jolla, CA, USA. ·Histopathology · Pubmed #30565306.

ABSTRACT: Non-urothelial carcinomas involving the bladder are uncommon and often diagnostically challenging. These carcinomas may show squamous, adenocarcinomatous or neuroendocrine features, with immunohistochemical stains aiding the diagnosis in only a subset of cases. The clinical history in non-urothelial bladder carcinomas is important, given that the differential diagnosis often includes secondary involvement of the bladder by direct extension or metastasis from carcinomas at other sites. This paper will review non-urothelial carcinomas in each of these three morphological categories, emphasising recent changes in diagnostic grouping and challenges in the histopathological diagnosis. Review of bladder cancers with squamous morphology will include discussion of conventional squamous cell carcinoma and verrucous carcinoma and their distinction from urothelial carcinoma with extensive squamous differentiation. Bladder carcinomas with adenocarcinomatous change will include primary bladder adenocarcinoma, urachal adenocarcinoma and tumours of Müllerian type. Finally, neuroendocrine neoplasms of the bladder, including well-differentiated neuroendocrine tumour and neuroendocrine carcinomas, will be discussed. Associated surface findings, risk factors and prognostic features will be described.

4 Review The Emerging Molecular Landscape of Urothelial Carcinoma. 2016

Solomon, James P / Hansel, Donna E. ·Department of Pathology, University of California, San Diego, 200 West Arbor Drive, La Jolla, CA 92103, USA. · Division of Anatomic Pathology, Department of Pathology, University of California, San Diego, 9500 Gilman Drive, MC 0612, La Jolla, CA 92093, USA. Electronic address: dhansel@ucsd.edu. ·Surg Pathol Clin · Pubmed #27523968.

ABSTRACT: Although there have been many recent discoveries in the molecular alterations associated with urothelial carcinoma, current understanding of this disease lags behind many other malignancies. Historically, a two-pathway model had been applied to distinguish low- and high-grade urothelial carcinoma, although significant overlap and increasing complexity of molecular alterations has been recently described. In many cases, mutations in HRAS and FGFR3 that affect the MAPK and PI3K pathways seem to be associated with noninvasive low-grade papillary tumors, whereas mutations in TP53 and RB that affect the G1-S transition of the cell cycle are associated with high-grade in situ and invasive carcinoma. However, recent large-scale analyses have identified overlap in these pathways relative to morphology, and in addition, many other variants in a wide variety of oncogenes and tumor-suppressor genes have been identified. New technologies including next-generation sequencing have enabled more detailed analysis of urothelial carcinoma, and several groups have proposed molecular classification systems based on these data, although consensus is elusive. This article reviews the current understanding of alterations affecting oncogenes and tumor-suppressor genes associated with urothelial carcinoma, and their application in the context of morphology and classification schema.

5 Review Morphologic and Molecular Characteristics of Bladder Cancer. 2015

Solomon, James P / Hansel, Donna E. ·Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA. · Division of Anatomic Pathology, Department of Pathology, University of California, San Diego, 9500 Gilman Drive, MC 0612, La Jolla, CA 92093, USA. Electronic address: dhansel@ucsd.edu. ·Surg Pathol Clin · Pubmed #26612220.

ABSTRACT: Bladder cancer is the fourth most common cancer in men, and is associated with significant morbidity and mortality. Pathologic evaluation of urothelial cancers relies predominantly on histomorphologic features but can be aided in a small subset of cases by immunohistochemical analyses. Distinction of papillary versus flat lesions, low-grade versus high-grade cytology, and histologic variants and the presence or absence of invasive tumor is important for proper clinical management. Advances in the molecular alterations associated with the various subtypes of urothelial carcinoma have been made but such studies are ongoing.

6 Review Prognostic factors in urothelial carcinoma of the bladder: histologic and molecular correlates. 2015

Solomon, James P / Hansel, Donna E. ·Department of Pathology, University of California, San Diego, La Jolla, CA. ·Adv Anat Pathol · Pubmed #25664945.

ABSTRACT: Histologic characterization of urothelial carcinoma remains the most important factor for determining a patient's prognosis and treatment regimen. However, challenges remain in accurately staging and grading many tumors, and substaging remains controversial. Recently, significant insight has been gained into the molecular pathogenesis of bladder cancer that may aid in further characterizing urothelial carcinoma. Many molecular biomarkers have been clinically validated, and some have been shown to provide more prognostic information than histology alone. In addition, a subset of these markers may even represent targets for molecular therapy. Here, we review histologic staging and grading of urothelial carcinoma, as well as discuss many of the clinically relevant molecular markers. As each urothelial carcinoma likely represents a unique biological entity, the need for complete histologic and molecular characterization of these tumors is necessary as we enter the age of personalized medicine.

7 Review Summary of the 8th Annual Bladder Cancer Think Tank: Collaborating to move research forward. 2015

Apolo, Andrea B / Hoffman, Vanessa / Kaag, Matthew G / Latini, David M / Lee, Cheryl T / Rosenberg, Jonathan E / Knowles, Margaret / Theodorescu, Dan / Czerniak, Bogdan A / Efstathiou, Jason A / Albert, Matthew L / Sridhar, Srikala S / Margulis, Vitaly / Matin, Surena F / Galsky, Matthew D / Hansel, Donna / Kamat, Ashish M / Flaig, Thomas W / Smith, Angela B / Messing, Edward / Zipursky Quale, Diane / Lotan, Yair. ·Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, MD. · Bladder Cancer Advocacy Network, Bethesda, MD. · Department of Urology, Penn State Hershey Medical Center, Hershey, PA. · Department of Urology, Baylor College of Medicine, Houston, TX. · Department of Urology, University of Michigan Health System, Ann Arbor, MI. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY. · Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK. · University of Colorado Cancer Center, Denver, CO. · Department of Pathology, MD Anderson Cancer Center, Houston, TX. · Harvard Medical School, Massachusetts General Hospital, Boston, MA. · Department of Immunology, Institut Pasteur, Paris, France. · Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. · Department of Urology, MD Anderson Cancer Center, Houston, TX. · Department of Medical Oncology, Mount Sinai Hospital, New York, NY. · Department of Pathology, University of California, La Jolla, San Diego, CA. · Department of Urology, University of North Carolina, Chapel Hill, NC. · Department of Urology, University of Rochester Medical Center, Rochester, NY. · Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX. Electronic address: yair.lotan@utsouthwestern.edu. ·Urol Oncol · Pubmed #25065704.

ABSTRACT: OBJECTIVES: The 8th Annual Bladder Cancer Think Tank (BCAN-TT) brought together a multidisciplinary group of clinicians, researchers, and patient advocates in an effort to advance bladder cancer research. METHODS AND MATERIALS: With the theme of "Collaborating to Move Research Forward," the meeting included three panel presentations and seven small working groups. RESULTS: The panel presentations and interactive discussions focused on three main areas: gender disparities, sexual dysfunction, and targeting novel pathways in bladder cancer. Small working groups also met to identify projects for the upcoming year, including: (1) improving enrollment and quality of clinical trials; (2) collecting data from multiple institutions for future research; (3) evaluating patterns of care for non-muscle-invasive bladder cancer; (4) improving delivery of care for muscle-invasive disease; (5) improving quality of life for survivors; (6) addressing upper tract disease; and (7) examining the impact of health policy changes on research and treatment of bladder cancer. CONCLUSIONS: The goal of the BCAN-TT is to advance the care of patients with bladder cancer and to promote collaborative research throughout the year. The meeting provided ample opportunities for collaboration among clinicians from multiple disciplines, patients and patient advocates, and industry representatives.

8 Review Novel neoadjuvant therapy paradigms for bladder cancer: results from the National Cancer Center Institute Forum. 2014

Dinney, Colin P N / Hansel, Donna / McConkey, David / Shipley, William / Hagan, Michael / Dreicer, Robert / Lerner, Seth / Czerniak, Bogdan / Waldman, Fred / Groshen, Susan / True, Lawrence D / Petricoin, Emanuel / Theodorescu, Dan / Hruszkewycz, Andrew / Bajorin, Dean. ·Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: cdinney@mdanderson.org. · Department of Pathology, University of California at San Diego, La Jolla, CA. · Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. · Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA. · Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA. · Department of Solid Tumor Oncology, Cleveland Clinic, Cleveland, OH. · Scott Department of Urology, Baylor College of Medicine, Houston, TX. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX. · Quest Diagnostics, San Juan Capistrano, CA. · Department of Preventive Medicine, University of Southern California, Los Angeles, CA. · Department of Pathology, University of Washington Medical Center, Seattle, WA. · Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA. · Department of Surgery-Urology, The University of Colorado, Denver, CO. · National Cancer Institute, Bethesda, MD. · Department of Medicine Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, NY. ·Urol Oncol · Pubmed #25443274.

ABSTRACT: OBJECTIVE: To bridge gaps in translational science and develop the concepts for 2 novel biomarker-driven clinical trials: one in the presurgical setting and the other in the setting of bladder preservation with chemoradiation. METHODS AND MATERIALS: The National Cancer Institute sponsored a forum, "Novel Neoadjuvant Therapy for Bladder Cancer," which brought leading clinical and laboratory-based scientists together with the advocacy community. RESULTS: The group designed a neoadjuvant clinical trial to compare the clinical efficacy of the two frontline chemotherapy regimens (gemcitabine plus cisplatin versus MVAC) and the ability of a gene expression profiling-based algorithm (CoXEN) to predict complete pathological response. The trial was recently opened under the leadership of the Southwest Oncology Group (SWOG, S1314), receiving support for the biomarker studies from the NCI's BISQFP resource. A second clinical trial was planned that will examine the relationship between expression of the DNA repair protein MRE11 and complete response in patients treated with concurrent 5-fluorouracil/mitomycin C plus radiation. CONCLUSION: The meeting provided a unique opportunity to launch a collective effort to establish molecular-based therapies for muscle-invasive urothelial cancer. The goal is to use this framework to develop comparable trials with immunotherapy in non-muscle invasive cancers and to exploit the neoadjuvant platform to develop targeted therapy in muscle-invasive disease.

9 Review Micropapillary bladder cancer: current treatment patterns and review of the literature. 2014

Willis, Daniel L / Flaig, Thomas W / Hansel, Donna E / Milowsky, Matthew I / Grubb, Robert L / Al-Ahmadie, Hikmat A / Plimack, Elizabeth R / Koppie, Theresa M / McConkey, David J / Dinney, Colin P / Hoffman, Vanessa A / Droller, Michael J / Messing, Edward / Kamat, Ashish M. ·Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. · Division of Medical Oncology, University of Colorado Denver, School of Medicine, Denver, CO. · Department of Pathology, UC San Diego, School of Medicine, San Diego, CA. · Division of Hematology/Oncology, University of North Carolina, School of Medicine, Chapel Hill, NC. · Division of Urologic Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO. · Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York City, NY. · Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA. · Department of Urology, Oregon Health and Science University, Portland, OR. · Bladder Cancer Advocacy Network, Bethesda, MD. · Department of Urology, Mount Sinai Hospital, New York City, NY. · Department of Urology, University of Rochester Medical Center, School of Medicine and Dentistry, Rochester, NY. · Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address: akamat@mdanderson.org. ·Urol Oncol · Pubmed #24931270.

ABSTRACT: OBJECTIVES: No guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature. MATERIALS AND METHODS: A survey developed by the Translational Science Working Group of the Bladder Cancer Advocacy Network-sponsored Think Tank meeting was distributed to members of the SUO. The results from 118 respondents were analyzed and presented with a literature review. RESULTS: Most survey respondents were urologists, with 80% considering bladder cancer their primary area of interest. Although 78% of the respondents reported a dedicated genitourinary pathologist at their institution, there were discrepant opinions on how a pathologic diagnosis of MPBC is determined as well as variability on the proportion of MPBC that is clinically significant. Among them, 78% treat MPBC differently than conventional urothelial carcinoma, with 81% reporting that they would treat cT1 MPBC with upfront radical cystectomy. However, the respondents had split opinions regarding the sensitivity of MPBC to cisplatin-based chemotherapy, which affected utilization of neoadjuvant chemotherapy in muscle-invasive disease. CONCLUSIONS: The management of MPBC is diverse among members of the SUO. Although most favors early cystectomy for cT1 MPBC, there is no consensus on the use of neoadjuvant chemotherapy for muscle-invasive MPBC.

10 Review Challenges in the pathology of non-muscle-invasive bladder cancer: a dialogue between the urologic surgeon and the pathologist. 2013

Hansel, Donna E / Miller, Jeremy S / Cookson, Michael S / Chang, Sam S. ·Cleveland Clinic Foundation, Cleveland, OH 44195, USA. hanseld@ccf.org ·Urology · Pubmed #23522296.

ABSTRACT: Approximately 70%-80% of urothelial carcinomas are detected at the stage of non-muscle-invasive bladder cancer (NMIBC). Initial management is often successful, but recurrence is common and leads to a long, burdensome, costly disease course. The quality and efficiency of care depends in part on accurate, clearly communicated descriptions of tumor characteristics. This review identifies current best practices, unmet needs, and key issues in the pathology of NMIBC for the practicing urologist. Reasonable and objective recommendations are provided with the goal of improving urologist-pathologist communication, the efficiency of healthcare utilization, and outcomes for patients with NMIBC.

11 Review A contemporary update on pathology standards for bladder cancer: transurethral resection and radical cystectomy specimens. 2013

Hansel, Donna E / Amin, Mahul B / Comperat, Eva / Cote, Richard J / Knüchel, Ruth / Montironi, Rodolfo / Reuter, Victor E / Soloway, Mark S / Umar, Saleem A / Van der Kwast, Theodorus H. ·Department of Pathology, Cleveland Clinic, Cleveland, OH, USA. hanseld@ccf.org ·Eur Urol · Pubmed #23088996.

ABSTRACT: CONTEXT: Pathology standards for the diagnosis of bladder cancer (BCa) have recently evolved to better reflect patient diagnosis and clinical outcomes. OBJECTIVE: To update pathology reporting standards for BCa. EVIDENCE ACQUISITION: We searched the international medical literature and reviewed all articles that addressed BCa gross dissection, pathologic diagnosis, staging, and reporting as of June 6, 2012. We also reviewed the proceedings from the recent Second International Consultation on Bladder Cancer (Vienna, Austria). The literature selected for review focuses on evidence-based studies that address histopathologic factors in BCa, with emphasis placed on factors that influence patient diagnosis and clinical outcomes. EVIDENCE SYNTHESIS: We separated data into three main components for analysis based on the type of specimen obtained: (1) transurethral resection specimens, with an emphasis on pathologic staging, variants of urothelial carcinoma, angiolymphatic invasion, and relevant ancillary techniques such as immunohistochemistry in assessing these features; (2) cystectomy specimens, with an emphasis on pT0 disease, prostatic involvement by urothelial carcinoma and lymph node dissection and analysis; and (3) cytology correlates, with recommendations for the use of cytology paired with tissue-based sampling. Areas of controversy are described and recommendations based on existing guidelines are provided. The value of a multidisciplinary team is highlighted. CONCLUSIONS: Ongoing international collaborations amongst pathologists have led to emerging standards in the reporting and microscopic diagnosis of BCa specimens. Although some areas remain controversial, we present the most up-to-date data and guidelines relevant to neoplastic pathology of the urinary bladder.

12 Review Summary of the 6th Annual Bladder Cancer Think Tank: new directions in urologic research. 2013

Svatek, Robert S / Rosenberg, Jonathan E / Galsky, Matthew D / Lee, Cheryl T / Latini, David M / Bochner, Bernard H / Weizer, Alon Z / Apolo, Andrea B / Sridhar, Srikala S / Kamat, Ashish M / Hansel, Donna / Flaig, Thomas W / Smith, Norm D / Lotan, Yair. ·Department of Urology, UT Health Science Center San Antonio, San Antonio, TX 78229, USA. ·Urol Oncol · Pubmed #22300756.

ABSTRACT: The 6th Annual Bladder Cancer Think Tank brought together a multidisciplinary group of clinicians, researchers, and representatives from the National Cancer Institute and Industry in an effort to advance bladder cancer research efforts. This year's meeting comprised panel discussions and research involving 5 separate working groups, including the Survivorship, Clinical Trials, Standardization of Care, Data Mining, and Translational Science working groups. In this manuscript, the accomplishments and objectives of the working groups are summarized. Notable efforts include: (1) the development of a survivorship care plan for early and late-stage bladder cancer; (2) the development of consensus criteria for eligibility and endpoints for bladder cancer clinical trials; (3) an improved understanding of current practice patterns regarding the use of perioperative chemotherapy in an effort to standardize care; (4) creation of a comprehensive handbook to assist researchers with developing bladder cancer databases; and (5) identification of response to therapy of high-grade non muscle invasive disease through a collaborative exchange of expertise and resources.

13 Review Small cell bladder cancer: biology and management. 2012

Fahed, Elie / Hansel, Donna E / Raghavan, Derek / Quinn, David I / Dorff, Tanya B. ·University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA. ·Semin Oncol · Pubmed #23040258.

ABSTRACT: Small cell bladder cancer (SCBC) is a rare and aggressive form of bladder cancer. It exhibits similar biological behavior to small cell lung carcinoma. Untreated, it is associated with a very poor prognosis. Appropriate oncologic surgery remains the mainstay of treatment of this disease but is not curative alone in the majority of the cases. Adding systemic therapy to the treatment regimen has been shown to improve survival. The most common chemotherapy regimens used in published series include a platinum complex plus etoposide, although doxorubicin-based regimens and standard urothelial cancer regimens also have been associated with response. Despite robust chemotherapy responses, metastatic disease is associated with relapse and a median overall survival of 18 months or less. Better understanding of the molecular alterations driving SCBC may facilitate the development of new therapeutic strategies and improved outcomes.

14 Review Prognostic value of cell-cycle regulation biomarkers in bladder cancer. 2012

Mitra, Anirban P / Hansel, Donna E / Cote, Richard J. ·Department of Pathology and Center for Personalized Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. ·Semin Oncol · Pubmed #23040249.

ABSTRACT: The determination of prognosis in bladder cancer is currently based on staging methods that rely primarily on the pathological stage of a tumor with limited objective correlates. The development and progression of bladder cancer involve alterations in several cellular pathways. Dysregulation in markers associated with cell-cycle regulation has been the most extensively examined molecular aberration in this cancer. Individual alterations of these markers have been associated with disease outcome, with several observations suggesting that their prognostic potential is independent of pathological stage. While many individual molecules in the cell growth receptor signaling, p53, and retinoblastoma (Rb) pathways have been identified, there is a general lack of consensus on which markers can be adopted in the clinical setting. More recent studies have suggested that the combination of markers as concise panels may be more beneficial in determining the degree of aggressiveness of a given tumor and its impending outcome than individual markers alone. This review will discuss alterations in molecules within pathways controlling cell-cycle regulation in the context of bladder cancer, and their impact on patient outcome when examined individually and in combination.

15 Review Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway. 2010

Ching, Christina Barbara / Hansel, Donna Elizabeth. ·Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA. ·Lab Invest · Pubmed #20661228.

ABSTRACT: A complex equilibrium of biological signals exists within the human body to regulate normal cellular function and growth. Unfortunately, there are various ways in which disruption of these signaling pathways can result in uncontrollable cell growth--an important element in oncogenesis. In particular, the mammalian target of rapamycin (mTOR) pathway appears to play a central role in the development of multiple cancers, including urothelial cell carcinoma (UCC). Although often called 'a master regulator,' mTOR is but one signal in an intricate signaling cascade that controls cell growth and angiogenesis in both normal and cancerous conditions. Other important factors in this pathway include upstream activators such as phosphatidylinositol 3 kinase (PI3K) and Akt, negative regulators such as the tuberous sclerosis complex (TSC) 1/2, and downstream effectors such as p70 S6 kinase and eukaryotic initiation factor eIF4E. On the basis of its important role in tumor growth, efforts have focused on developing means to effectively target the mTOR pathway in hopes of designing new treatments for various tumor types. To address the role of mTOR pathway activity in UCC, we will first review the basic elements of the PI3K/Akt/mTOR pathway and then apply this pathway to bladder cancer oncogenesis. As will be evident, significant progress has been made in defining the role of this pathway in UCC; however, continued research into the nuances of pathway regulation and the usage of targeted inhibition in bladder cancer patients is necessary to define mTOR as a promising target in this disease.

16 Review Emerging concepts in micropapillary urothelial carcinoma. 2010

Watts, Katherine E / Hansel, Donna E. ·Department of Anatomic Pathology, Cleveland Clinic, OH 44195, USA. ·Adv Anat Pathol · Pubmed #20418672.

ABSTRACT: Micropapillary urothelial carcinoma is a relatively uncommon variant of urothelial carcinoma, but its recognition carries important prognostic and treatment implications. Micropapillary morphology occurs in neoplasms arising in many different organ systems and displays aggressive biologic behavior regardless of its site of origin. On account of this association, micropapillary features in urothelial carcinoma should be reported regardless of whether the pattern is focal or dominant. The overall prognosis for micropapillary urothelial carcinoma is poor and recent studies suggest that early treatment with cystectomy could improve outcome, as these tumors are unlikely to respond to chemotherapy when used as a secondary treatment modality. This review discusses the histologic features required for diagnosis and the clinical significance of rendering a diagnosis of micropapillary urothelial carcinoma.

17 Review Utility of diagnostic and prognostic markers in urothelial carcinoma of the bladder. 2009

Coleman, Joshua F / Hansel, Donna E. ·Department of Anatomic Pathology, Glickman Urological and Kidney Institute, Taussig Cancer Institute and Genomic Medicine Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA. ·Adv Anat Pathol · Pubmed #19550368.

ABSTRACT: Urothelial carcinoma (UCC) of the bladder demonstrates diverse morphologic features, often leading to diagnostic challenges in the discrimination between UCC and benign mimickers of neoplasia, and between primary UCC and secondary neoplasms involving the bladder. In situ lesions also provide diagnostic difficulty in some instances, most prominently in the distinction between normal, reactive urothelium and flat urothelial carcinoma in situ. The use of ancillary techniques, including panels of immunohistochemical markers, in distinguishing these entities has aided not only in the diagnosis of UCC, but has also provided insight into the molecular pathogenesis and prognostic value of numerous molecular pathways in UCC. This review focuses on some of the more commonly encountered biomarkers in UCC and their role in addressing key diagnostic and prognostic issues in this disease process.

18 Article SIU-ICUD on bladder cancer: pathology. 2019

Compérat, Eva / Babjuk, Marek / Algaba, Ferran / Amin, Mahul / Brimo, Fadi / Grignon, David / Hansel, Donna / Hes, Ondra / Malavaud, Bernard / Reuter, Victor / van der Kwast, Theo. ·Department of Pathology, Hopital Tenon, HUEP, Sorbonne University, Paris, France. evacomperat@gmail.com. · Department of Urology, Hospital Motol and 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. · Department of Pathology, Fundacio Puigvert, Barcelona, Spain. · Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA. · Department of Urology, University of Tennessee Health Science Center, Memphis, TN, USA. · McGill University Health Center, Glen Site, Office E4-4188, 1001 Decarie Blvd, Montréal, QC, H4A 3J1, Canada. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, IUH Pathology Laboratory, Indianapolis, IN, USA. · Departments of Pathology and Urology, University of California, San Diego, CA, USA. · Charles University and University Hospital Plzen, Pilsen, Czech Republic. · Department of Urology, Institut Universitaire du Cancer de Toulouse, Toulouse, France. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Laboratory Medicine Program, University Health Network, University of Toronto, Toronto, ON, Canada. ·World J Urol · Pubmed #30218308.

ABSTRACT: Many changes have been made during these last years and concepts for understanding bladder cancer have evolved. We make an update with the latest findings of the WHO (World Health Organistaion) 2016, ICCR (International Collaboration on Cancer Reporting) and other official organisms and try to show the latest developments. In this document we provide new consensus guidelines and insights. We kept this document short and concise providing consensus guidelines to clinicians for the best patient care, it should be easy to understand for a non pathologists. We focussed on several burning issues, such as the anatomical and histological understanding of the bladder wall, the prognostic significance of grading and the most challenging problems in staging, we underline our needs from the clinicians such as clinical information, we further discuss the histological subtypes of bladder cancer, which is an extremely important issue in the light of molecular classifications and give prognostic insights. Furthermore, we discuss the ICCR worldwide consensus reporting, urinary cytology with the Paris system and several issues such as frozen section specimen.

19 Article Argininosuccinate Synthetase-1 (ASS1) Loss in High-Grade Neuroendocrine Carcinomas of the Urinary Bladder: Implications for Targeted Therapy with ADI-PEG 20. 2018

Gupta, Sounak / Sahu, Divya / Bomalaski, John S / Frank, Igor / Boorjian, Stephen A / Thapa, Prabin / Cheville, John C / Hansel, Donna E. ·Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. · Department of Pathology, University of California at San Diego, 9500 Gilman Dr., MC 0612, La Jolla, CA, 92093, USA. · Polaris Pharmaceuticals, Inc., San Diego, CA, USA. · Department of Urology, Mayo Clinic, Rochester, MN, USA. · Health Sciences Research, Mayo Clinic, Rochester, MN, USA. · Department of Pathology, University of California at San Diego, 9500 Gilman Dr., MC 0612, La Jolla, CA, 92093, USA. dhansel@ucsd.edu. ·Endocr Pathol · Pubmed #29453600.

ABSTRACT: High-grade neuroendocrine carcinomas (HGNECs) of the urinary bladder encompass small cell (SCNEC) and large cell neuroendocrine carcinomas (LCNEC). Currently, recommended initial management is with systemic chemotherapy, followed by consolidative therapy with either radical cystectomy or radiotherapy in patients with localized disease. Nevertheless, survival in this setting remains poor. We therefore evaluated the potential to modify arginine metabolism as an alternative, targeted therapy approach in these carcinomas. In humans, arginine is a semi-essential amino acid and its synthesis enzyme argininosuccinate synthetase (ASS1) represents the rate-limiting step in arginine biosynthesis. Neoplasms that show low to absent ASS1 expression require extracellular arginine for cancer cell survival, and thus can be targeted using arginine-degrading enzymes such as pegylated arginine deiminase (ADI-PEG 20). An initial study by our group of 19 patients demonstrated that a high percentage of SCNEC lack ASS1 expression. Herein, we evaluated an expanded cohort of 74 radical cystectomy patients with HGNEC, including 63 SCNEC, 5 LCNEC, and 6 mixed morphology HGNEC patients. ASS1 expression was assessed through immunohistochemistry. Fifty-eight (of 74, 78%) patients with HGNEC showed absent ASS1 expression, including all patients with LCNEC and mixed morphology (11 of 11, 100%). Ten-year survival from disease-specific death was not statistically significant between ASS1-expressing and ASS1-deficient cases (p = 0.75). Our results show that HGNEC of the bladder may be candidates for arginine deprivation therapy using drugs such as ADI-PEG 20. Further studies are needed to validate these findings and to determine the therapeutic efficacy of such agents.

20 Article Analysis of T1 Bladder Cancer on Biopsy and Transurethral Resection Specimens: Comparison and Ranking of T1 Quantification Approaches to Predict Progression to Muscularis Propria Invasion. 2018

Leivo, Mariah Z / Sahoo, Debashis / Hamilton, Zachary / Mirsadraei, Leili / Shabaik, Ahmed / Parsons, John K / Kader, Andrew K / Derweesh, Ithaar / Kane, Christopher / Hansel, Donna E. ·Departments of Pathology. · Computer Science and Engineering. · Urology, University of California at San Diego, La Jolla, CA. ·Am J Surg Pathol · Pubmed #29076872.

ABSTRACT: Urothelial carcinoma of the bladder invasive into lamina propria on biopsy or transurethral resection of bladder tumor, termed "T1" disease, progresses to muscularis propria invasion in a subset of patients. Prior studies have proposed histopathologic metrics to predict progression, although methods vary widely and it is unclear which method is most robust. This poses a challenge since recent World Health Organization and American Joint Commission on Cancer editions encourage some attempt to substratify T1 disease. To address this critical problem, we analyzed T1 specimens to test which T1 quantification method is best to predict progression and to then establish the optimal cut-off. Progression was analyzed for all patients or for patients with definitive muscularis propria only. Multivariate analysis and outcomes modeling controlled for additional histopathologic features. Our results suggest that aggregate linear length of invasive carcinoma (ALLICA) measured by optical micrometer is far superior to other methods (P=3.067×10) and could be applied to 100% of specimens. ALLICA retained significance in multivariate analysis and eliminated contribution of other histopathologic features to progression. The best cut-off for ALLICA using a 30% false-positive threshold was 2.3 mm and using a 10% false-positive threshold at 25 mm, although the latter severely limited patients who could achieve this threshold. After comparison of all proposed methods of T1 quantification, we recommend the adoption of the ALLICA measurement and a cut-off of ≥2.3 mm as the best predictor of progression, acknowledging that additional nonhistopathologic methods may be required to increase broad applicability and further reduce the false-positive threshold.

21 Article Serous Carcinoma Mimicking Primary Urothelial Carcinoma on Clinical Evaluation and Pathology: A Potential Diagnostic Pitfall. 2018

Mirsadraei, Leili / Hodkoff, Alexey / Jones, Karra / Shabaik, Ahmed / Kader, A Karim / Saenz, Cheryl C / Montironi, Rodolfo / Tacha, David E / Fadare, Oluwole / Hansel, Donna E. · ·Arch Pathol Lab Med · Pubmed #28795841.

ABSTRACT: CONTEXT: - Serous carcinoma of the gynecologic tract often involves the external bladder wall and can occasionally mimic primary urothelial carcinoma of the bladder. OBJECTIVE: - To define the spectrum of morphologic and immunohistochemical features that characterize serous carcinoma involving the bladder wall and its distinction from urothelial carcinoma. DESIGN: - We reviewed all cases of serous carcinoma secondarily involving the bladder wall from the University of California San Diego and Polytechnic Institute for histopathologic and immunohistochemical features. RESULTS: - We identified 20 cases of Müllerian high-grade serous carcinoma involving the bladder wall. Five cases were clinical mimics of urothelial carcinoma, including 2 cases that presented as a large, transmural, primary bladder mass without precedent gynecologic history in women younger than 60 years, and 3 cases presumed to be new bladder carcinoma occurring distant to a serous carcinoma diagnosis. A subset of cases were morphologic mimics of urothelial carcinoma, which showed nested growth patterns (2 of 20; 10%), squamouslike foci (2 of 20; 10%), spindled/sarcomatoid growth (2 of 20; 10%), basaloid morphology (3 of 20; 15%), and syncytial growth patterns (1 of 20; 5%). Immunohistochemical stains in 17 cases showed immunoreactivity for CK7 (17 of 17; 100%), WT1 (17 of 17; 100%), uroplakin (UP) II (1 of 17; 6%), p63 (2 of 17; 12%), GATA3 (2 of 17; 12%), and PAX8 (17 of 17; 100%). CONCLUSIONS: - A subset of serous carcinomas involving the bladder wall can mimic urothelial carcinoma. Awareness of this mimicker and use of an immunohistochemical panel that includes CK7, WT1, UPII, PAX8, p63, and GATA3 can be helpful in confirming the diagnosis.

22 Article Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. 2017

Robertson, A Gordon / Kim, Jaegil / Al-Ahmadie, Hikmat / Bellmunt, Joaquim / Guo, Guangwu / Cherniack, Andrew D / Hinoue, Toshinori / Laird, Peter W / Hoadley, Katherine A / Akbani, Rehan / Castro, Mauro A A / Gibb, Ewan A / Kanchi, Rupa S / Gordenin, Dmitry A / Shukla, Sachet A / Sanchez-Vega, Francisco / Hansel, Donna E / Czerniak, Bogdan A / Reuter, Victor E / Su, Xiaoping / de Sa Carvalho, Benilton / Chagas, Vinicius S / Mungall, Karen L / Sadeghi, Sara / Pedamallu, Chandra Sekhar / Lu, Yiling / Klimczak, Leszek J / Zhang, Jiexin / Choo, Caleb / Ojesina, Akinyemi I / Bullman, Susan / Leraas, Kristen M / Lichtenberg, Tara M / Wu, Catherine J / Schultz, Nicholaus / Getz, Gad / Meyerson, Matthew / Mills, Gordon B / McConkey, David J / Anonymous7011224 / Weinstein, John N / Kwiatkowski, David J / Lerner, Seth P. ·Canada's Michael Smith Genome Sciences Center, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. · Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · PSMAR-IMIM Lab, Bladder Cancer Center, Department of Medicine, Dana-Farber Cancer Institute and Harvard University, Boston, MA 02215, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard University, Boston, MA 02115, USA. · Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI 49503, USA. · Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Bioinformatics and Systems Biology Laboratory, Federal University of Paraná Polytechnic Center, Curitiba, PR CEP 80.060-000, Brazil. · Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. · Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. · Department of Pathology, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA. · Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Biostatistics and Computational Biology Laboratory, Department of Statistics, University of Campinas, São Paulo, 13.083-859, Brazil. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA. · Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Biospecimen Core Resource, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Pathology and Medical Oncology, Dana-Farber Cancer Institute and Harvard University, Boston, MA 02115, USA. · Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD 21218, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA. Electronic address: jweinste@mdanderson.org. · Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: dk@rics.bwh.harvard.edu. · Scott Department of Urology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: slerner@bcm.edu. ·Cell · Pubmed #28988769.

ABSTRACT: We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.

23 Article Metabolomics analysis reveals distinct profiles of nonmuscle-invasive and muscle-invasive bladder cancer. 2017

Sahu, Divya / Lotan, Yair / Wittmann, Bryan / Neri, Bruce / Hansel, Donna E. ·Department of Pathology, University of California at San Diego, La Jolla, California. · Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. · Metabolon Inc., Durham, North Carolina. ·Cancer Med · Pubmed #28766915.

ABSTRACT: Urothelial carcinoma is the most common form of bladder cancer, but pathway changes that occur with stage-wise progression have not been well defined. We used a metabolomics approach to identify potential metabolic pathways uniquely altered in normal urothelium, nonmuscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC). We performed global metabolomic profiling using GC-mass spectrometry (MS) and LC-MS platforms to identify metabolite signatures between normal urothelium and high-grade urothelial carcinoma of different stages. Pathways globally dysregulated in cancer relative to normal urothelium included glucose, tricarboxylic acid (TCA) cycle, lipid, amino acid, and nucleotide pathways. Urothelial carcinoma showed elevated glucose utilization for glycolysis and increased sorbitol pathway intermediates, consistent with Warburg effect. Anaplerosis to sustain energy production suggested by increased late TCA cycle intermediates, amino acids, and dipeptides occurs in bladder cancer. Urothelial carcinoma also shows altered membrane lipid membrane metabolism and differential derivation of nucleic acid components pyrimidine and purine. In stage comparison, MIBC appears to preferentially enhance cyclooxygenase (COX) and lipoxygenase (LOX) signaling, increase heme catabolism, and alter nicotinamide adenine dinucleotide (NAD+) synthesis with a possible influence from associated inflammatory cells. We identify numerous metabolomic alterations in NMIBC and MIBC that likely reflect underlying pathway changes. Differential pathway activity may have value in designing stage-specific novel therapeutics in urothelial carcinoma.

24 Article Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis. 2017

Duex, Jason E / Owens, Charles / Chauca-Diaz, Ana / Dancik, Garrett M / Vanderlinden, Lauren A / Ghosh, Debashis / Leivo, Mariah Z / Hansel, Donna E / Theodorescu, Dan. ·Departments of Surgery and Pharmacology, University of Colorado, Aurora, Colorado. · Department of Mathematics and Computer Science, Eastern Connecticut State University, Willimantic, Connecticut. · Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado, Aurora, Colorado. · Department of Pathology, University of California San Diego, San Diego, California. · Departments of Surgery and Pharmacology, University of Colorado, Aurora, Colorado. dan.theodorescu@ucdenver.edu. · University of Colorado Comprehensive Cancer Center, Aurora, Colorado. ·Cancer Res · Pubmed #28674079.

ABSTRACT: Elevated tumor expression of the cell surface GPI-linked CD24 protein signals poor patient prognosis in many tumor types. However, some cancer cells selected to be negative for surface CD24 (surCD24

25 Article Differential mTOR pathway profiles in bladder cancer cell line subtypes to predict sensitivity to mTOR inhibition. 2017

Hau, Andrew M / Nakasaki, Manando / Nakashima, Kazufumi / Krish, Goutam / Hansel, Donna E. ·Department of Pathology, University of California, San Diego, La Jolla, CA. · Department of Pathology, University of California, San Diego, La Jolla, CA; Department of Urology, University of California, San Diego, La Jolla, CA. Electronic address: dhansel@ucsd.edu. ·Urol Oncol · Pubmed #28427860.

ABSTRACT: BACKGROUND: Molecular classification of bladder cancer has been increasingly proposed as a potential tool to predict clinical outcomes and responses to chemotherapy. Here we focused on mechanistic target of rapamycin (mTOR) inhibition as a chemotherapeutic strategy and characterized the expression profile of mTOR signaling targets in representative bladder cancer cell lines from basal, luminal, and either basal/luminal ("non-type") molecular subtypes. MATERIALS AND METHODS: Protein and mRNA expression of mTOR signaling components from representative luminal (RT4 and RT112), basal (SCaBER and 5637), and nontype (T24 and J82) bladder cancer cell line subtypes were determined by Western blot and database mining analysis of the Cancer Cell Line Encyclopedia. Cell viability following treatment with either, Torin-2 or KU-0063794, 2 dual mTOR complex 1/2 inhibitors, was determined by MTT assay. Immunoblot analysis of cells treated with Torin-2 or KU-0063794 was performed to determine the effects of mTOR inhibition on expression and phosphorylation status of mTOR signaling components, Akt, 4E-BP1, and ribosomal protein S6. RESULTS: Molecular subtypes of bladder cancer cell lines each exhibited a distinct pattern of expression of mTOR-associated genes and baseline phosphorylation level of Akt and 4E-BP1. Cells with low levels of Akt Ser-473 phosphorylation were more resistant to the cytotoxic effects of mTOR inhibition with Torin-2, but not KU-0063794. Exposure to Torin-2 and KU-0063794 both potently and rapidly inhibited phosphorylation of Akt Ser-473 and Thr-308, and 4E-BP1 T37/46 in cell lines that included basal and nontype subtypes. CONCLUSIONS: Differential gene expression and protein activity associated with mTOR signaling is observed among bladder cancer cell lines stratified into basal, luminal, and nontype subtypes. Urothelial carcinomas characterized by high baseline Akt Ser-473 phosphorylation may be best suited for targeted mTOR therapies.

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