Clinicopathological risk factors associated with tumor relapse of upper tract urothelial carcinoma after radical nephroureterectomy: A single institution 20-year experience.

Upper tract urothelial carcinoma (UTUC) is a relatively rare yet aggressive malignancy. While radical nephroureterectomy (RNU) remains the cornerstone treatment, UTUC has high local and metastatic relapse rates, leading to a dismal prognosis. To identify the clinicopathological factors associated with an increased risk of local and metastatic relapse in UTUC, we conducted a retrospective analysis of 133 consecutive UTUC patients who underwent RNU from 1998 to 2018.

The transcription factor sex-determining region Y-box 2 (SOX2) in bladder cancer.

Sex-determining region Y-box 2 (SOX2) is a transcription factor with a central role in embryologic development. SOX2 is also an oncogene in several cancer types. Prior work by our group has shown SOX2 activity associates with cell cycle dysregulation in early-stage bladder cancer.

Urothelium-Specific Expression of Mutationally Activated Pik3ca Initiates Early Lesions of Noninvasive Bladder Cancer.

Although approximately 70% of bladder cancers are noninvasive and have high recurrence rates, early-stage disease is understudied. The lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. Although mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable.

Clinical and pathological characteristics of metastatic tumors to the urinary bladder.

Metastatic carcinoma to the urinary bladder is a rare and under-recognized condition in surgical pathology. In this study, we identified 8 cases of true bladder metastasis at our institution in the past 20 years, excluding secondary tumors via direct extension or serosal implantation. The most common tumor type is malignant melanoma (3/8), followed by clear cell renal cell carcinoma (2/8), adenocarcinoma of the gastrointestinal tract (2/8), and breast invasive lobular carcinoma (1/8).

International Society of Urological Pathology Consensus Conference on Current Issues in Bladder Cancer. Working Group 4: Molecular Subtypes of Bladder Cancer-Principles of Classification and Emerging Clinical Utility.

Molecular subtyping has been a major focus of bladder cancer research over the past decade. Despite many promising associations with clinical outcomes and treatment response, its clinical impact has yet to be defined. As part of the 2022 International Society of Urological Pathology Conference on Bladder Cancer, we reviewed the current state of the science for bladder cancer molecular subtyping.

Histologic Analysis of Buccal Graft Quality Stratified by Tobacco Use in Patients Undergoing Substitution Urethroplasty.

Objective: To determine if there are histologic differences relative to tobacco exposure in buccal mucosa. Substitution urethroplasty outcomes may be worse in tobacco users and we investigate if the buccal graft is inherently damaged due to chronic tobacco exposure.

Methods: Subjects undergoing substitution urethroplasty with buccal graft harvest were prospectively consented in this IRB approved study.

FOXA1 repression drives lineage plasticity and immune heterogeneity in bladder cancers with squamous differentiation.

Cancers arising from the bladder urothelium often exhibit lineage plasticity with regions of urothelial carcinoma adjacent to or admixed with regions of divergent histomorphology, most commonly squamous differentiation. To define the biologic basis for and clinical significance of this morphologic heterogeneity, here we perform integrated genomic analyses of mixed histology bladder cancers with separable regions of urothelial and squamous differentiation. We find that squamous differentiation is a marker of intratumoral genomic and immunologic heterogeneity in patients with bladder cancer and a biomarker of intrinsic immunotherapy resistance.

A transcriptional network of cell cycle dysregulation in noninvasive papillary urothelial carcinoma.

Human cancers display a restricted set of expression profiles, despite diverse mutational drivers. This has led to the hypothesis that select sets of transcription factors act on similar target genes as an integrated network, buffering a tumor's transcriptional state. Noninvasive papillary urothelial carcinoma (NIPUC) with higher cell cycle activity has higher risk of recurrence and progression.

Intratumoral Heterogeneity Promotes Collective Cancer Invasion through NOTCH1 Variation.

Cellular and molecular heterogeneity within tumors has long been associated with the progression of cancer to an aggressive phenotype and a poor prognosis. However, how such intratumoral heterogeneity contributes to the invasiveness of cancer is largely unknown. Here, using a tumor bioengineering approach, we investigate the interaction between molecular subtypes within bladder microtumors and the corresponding effects on their invasiveness.

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer.

The molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness.

[Molecular pathology of urogenital tumors : Recommendations from the 2019 International Society of Urological Pathology (ISUP) Consensus Conference].

Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP.

Three-Dimensional Microtumors for Probing Heterogeneity of Invasive Bladder Cancer.

Bladder cancer is an increasingly common malignancy, and muscle invasive bladder cancer is associated with particularly high rates of morbidity and mortality. The morphologic and molecular diversity of bladder cancer poses significant challenges in elucidating the invasion mechanisms responsible for disease progression. Furthermore, conventional invasion assays do not provide a physiological context for studying bladder cancer invasion within 3D microenvironments and have limited ability to capture the contribution of cellular phenotypic heterogeneity to disease progression.

Mutational profile of endometrial hyperplasia and risk of progression to endometrioid adenocarcinoma.

Background: Endometrial hyperplasia is a precursor to endometrioid adenocarcinoma (EMC), the most common uterine cancer. The likelihood of progression to carcinoma may be evaluated by histologic subclassification of endometrial hyperplasia, although these subclasses are subjective and only modestly reproducible among pathologists. Patient care would be improved by a more objective test to predict the risk of cancer progression.

Report From the International Society of Urological Pathology (ISUP) Consultation Conference On Molecular Pathology Of Urogenital Cancers. II. Molecular Pathology of Bladder Cancer: Progress and Challenges.

During the 2019 International Society of Urological Pathology Consultation Conference on Molecular Pathology of Urogenital Cancer, the Working Group on Bladder Cancer presented the current status and made recommendations on the diagnostic use of molecular pathology, incorporating a premeeting survey. Bladder cancers are biologically diverse and can be separated into "molecular subtypes," based on expression profiling. These subtypes associate with clinical behavior, histology, and molecular alterations, though their clinical utility has not been demonstrated at present and use in bladder cancer is not recommended.

Evaluation of PD-L1 and other immune markers in bladder urothelial carcinoma stratified by histologic variants and molecular subtypes.

Although advanced bladder cancer overall has a poor prognosis, a subset of patients demonstrate durable response to immune checkpoint inhibitors. Evidence shows that the response to checkpoint inhibitors may be associated with type and degree of immune infiltration in the tumor microenvironment. Here, we evaluated immune markers stratified by molecular subtypes and histologic variants.

Repression of transcription factor AP-2 alpha by PPARγ reveals a novel transcriptional circuit in basal-squamous bladder cancer.

The discovery of bladder cancer transcriptional subtypes provides an opportunity to identify high risk patients, and tailor disease management. Recent studies suggest tumor heterogeneity contributes to regional differences in molecular subtype within the tumor, as well as during progression and following treatment. Nonetheless, the transcriptional drivers of the aggressive basal-squamous subtype remain unidentified.

Context-dependent activation of SIRT3 is necessary for anchorage-independent survival and metastasis of ovarian cancer cells.

Tumor cells must alter their antioxidant capacity for maximal metastatic potential. Yet the antioxidant adaptations required for ovarian cancer transcoelomic metastasis, which is the passive dissemination of cells in the peritoneal cavity, remain largely unexplored. Somewhat contradicting the need for oxidant scavenging are previous observations that expression of SIRT3, a nutrient stress sensor and regulator of mitochondrial antioxidant defenses, is often suppressed in many primary tumors.

Hypermethylation of FOXA1 and allelic loss of PTEN drive squamous differentiation and promote heterogeneity in bladder cancer.

Intratumoral heterogeneity in bladder cancer is a barrier to accurate molecular sub-classification and treatment efficacy. However, individual cellular and mechanistic contributions to tumor heterogeneity are controversial. We examined potential mechanisms of FOXA1 and PTEN inactivation in bladder cancer and their contribution to tumor heterogeneity.

Genetic Variants Implicate Dual Oxidase-2 in Familial and Sporadic Nonmedullary Thyroid Cancer.

Highly penetrant hereditary thyroid cancer manifests as familial nonmedullary thyroid cancer (FNMTC), whereas low-penetrance hereditary thyroid cancer manifests as sporadic disease and is associated with common polymorphisms, including rs965513[A]. Whole-exome sequencing of an FNMTC kindred identified a novel Y1203H germline dual oxidase-2 (DUOX2) mutation. DUOX2 is enzymatically active, with increased production of reactive oxygen species.

Suppression of p16 Induces mTORC1-Mediated Nucleotide Metabolic Reprogramming.

Reprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis.

Carcinogen-induced bladder cancer in the FVB mouse strain is associated with glandular differentiation and increased Cd274/Pdl-1 expression.

Background: Creation of genetically engineered mouse models of bladder cancer often involves the use of several background strains in conjunction with the carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). However, carcinogen susceptibility in commonly used strains, as well as phenotypic differences is not well characterized.

Objectives: To determine differences in susceptibility and phenotypic outcome following BBN exposure of C57BL/6 and FVB, two strains commonly used for model development.

Characterization of Histone Deacetylase Expression Within In Vitro and In Vivo Bladder Cancer Model Systems.

Epigenetic aberrations are prominent in bladder cancer (BC) and contribute to disease pathogenesis. We characterized histone deacetylase (HDAC) expression, a family of deacetylation enzymes, in both in vitro and in vivo BC model systems and analyzed expression data from The Cancer Genome Atlas (TCGA). Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting analysis was used to determine the expression status of Class I and II HDACs in ten human BC cell lines, while qRT-PCR was used to determine HDAC expression in 24 human tumor specimens.

Maintenance of the bladder cancer precursor urothelial hyperplasia requires FOXA1 and persistent expression of oncogenic HRAS.

Tumorigenesis requires accumulation of genetic and epigenetic alterations, some of which drive tumor initiation. "Oncogene addiction" describes the phenomenon that (1) well-established cancers are dependent on one mutated oncogene or pathway for the maintenance of a malignant phenotype and that (2) withdrawal of the single oncogenic event leads to growth arrest and/or cancer regression. While oncogene addiction has been experimentally validated in advanced tumor models, its role in tumor precursors has not been investigated.