Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes.

Background: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy.

Objective: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy.

Design, Setting, And Participants: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining.

Molecular changes during progression from nonmuscle invasive to advanced urothelial carcinoma.

Molecular changes occurring during invasion and clinical progression of cancer are difficult to study longitudinally in patient-derived material. A unique feature of urothelial bladder cancer (UBC) is that patients frequently develop multiple nonmuscle invasive tumors, some of which may eventually progress to invade the muscle of the bladder wall. Here, we use a cohort of 73 patients that experienced a total of 357 UBC diagnoses to study the stability or change in detected molecular alterations during cancer progression.

Molecular subtypes applied to a population-based modern cystectomy series do not predict cancer-specific survival.

Objectives: To investigate the preoperative prognostic value of molecular subtypes in relation to clinical information, histopathological findings, and molecular markers for patients with bladder cancer treated with radical cystectomy.

Patients And Methods: After standard preoperative staging, a population-based cohort of 519 patients underwent radical cystectomy between 2006 and 2011. Following pathological review of all transurethral resection of bladder tumor specimens, tissue microarrays were constructed, and RNA was extracted from formalin-fixed tissue blocks.

Low Frequency of Intratumor Heterogeneity in Bladder Cancer Tissue Microarrays.

Background: Intratumoral heterogeneity (ITH) is associated with clinical challenges such as possible differences in response to treatment and difficulties in classifying the tumor. Previously, ITH has been described in bladder cancer using detailed genetic analyses. However, in this disease, it is not known to what extent ITH actually occurs, or if it involves molecular subtyping, when assessment is achieved by immunohistochemistry (IHC) on the protein level using tissue microarrays (TMAs), the method most widely applied when analyzing large sample numbers.

HER2 and EGFR amplification and expression in urothelial carcinoma occurs in distinct biological and molecular contexts.

We analyzed a cohort of 599 cases of urothelial carcinoma for EGFR, ERBB2, and ERBB3 gene expression and genomic alterations. The cohort consisted of a reference set (n = 292) comprising all stages and grades and one set (n = 307) of advanced tumors. All cases were previously classified into urothelial carcinoma molecular subtypes.

St Gallen molecular subtypes in screening-detected and symptomatic breast cancer in a prospective cohort with long-term follow-up.

Background: Diagnosis by screening mammography is considered an independent positive prognostic factor, although the data are not fully in agreement. The aim of the study was to explore whether the mode of detection (screening-detected versus symptomatic) adds prognostic information to the St Gallen molecular subtypes of primary breast cancer, in terms of 10-year cumulative breast cancer mortality (BCM).

Methods: A prospective cohort of patients with primary breast cancer, who had regularly been invited to screening mammography, were included.

A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma.

Background: One third of patients with stage T1 urothelial carcinoma (UC) progress to muscle-invasive disease requiring radical surgery. Thus, reliable tools are needed for risk stratification of stage T1 UC.

Objective: To investigate the extent to which stratification of stage T1 tumours into previously described molecular pathologic UC subtypes can provide improved information on tumour progression.

Infiltration of CD3⁺ and CD68⁺ cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors.

Objectives: Urothelial carcinoma (UC) aggressiveness is determined by tumor inherent molecular characteristics, such as molecular subtypes, as well as by host reactions directed toward the tumor. Cell types responsible for the host's response include tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). The aim of the present investigation was to explore the immunological response in relation to UC molecular subtypes and to evaluate the prognostic effect of TIL and TAM counts in tissue sections from muscle-invasive (MI) tumors.

Toward a molecular pathologic classification of urothelial carcinoma.

We recently defined molecular subtypes of urothelial carcinomas according to whole genome gene expression. Herein we describe molecular pathologic characterization of the subtypes using 20 genes and IHC of 237 tumors. In addition to differences in expression levels, the subtypes show important differences in stratification of protein expression.

Biomarker expression and St Gallen molecular subtype classification in primary tumours, synchronous lymph node metastases and asynchronous relapses in primary breast cancer patients with 10 years' follow-up.

Molecular profiles of asynchronous breast cancer metastases are of clinical relevance to individual patients' treatment, whereas the role of profiles in synchronous lymph node metastases is not defined. The present study aimed to assess individual biomarkers and molecular subtypes according to the St Gallen classification in primary breast tumours, synchronous lymph node metastases and asynchronous relapses and relate the results to 10-year breast cancer mortality (BCM). Tissue microarrays were constructed from archived tissue blocks of primary tumours (N = 524), synchronous lymph node metastases (N = 147) and asynchronous relapses (N = 36).

The combination of Ki67, histological grade and estrogen receptor status identifies a low-risk group among 1,854 chemo-naïve women with N0/N1 primary breast cancer.

Background: The aim was to confirm a previously defined prognostic index, combining a proliferation marker, histological grade, and estrogen receptor (ER) in different subsets of primary N0/N1 chemo-naïve breast cancer patients.

Methodsdesign: In the present study, including 1,854 patients, Ki67 was used in the index (KiGE), since it is the generally accepted proliferation marker in clinical routine. The low KiGE-group was defined as histological grade 1 patients and grade 2 patients which were ER-positive and had low Ki67 expression.

Bladder wash cytology at diagnosis of Ta-T1 bladder cancer is predictive for recurrence and progression.

Objective: To evaluate the effect of the bladder wash cytology finding at the primary diagnosis of Stage Ta-T1 urinary bladder cancer on recurrence and progression.

Methods: The clinical and pathologic characteristics of all patients with primary Stage Ta-T1 urinary bladder cancer were prospectively registered. The data were divided according to the bladder wash cytology results at diagnosis.

Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma.

Similar to other malignancies, urothelial carcinoma (UC) is characterized by specific recurrent chromosomal aberrations and gene mutations. However, the interconnection between specific genomic alterations, and how patterns of chromosomal alterations adhere to different molecular subgroups of UC, is less clear. We applied tiling resolution array CGH to 146 cases of UC and identified a number of regions harboring recurrent focal genomic amplifications and deletions.

A molecular taxonomy for urothelial carcinoma.

Purpose: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features.

The value of bladder mapping and prostatic urethra biopsies for detection of carcinoma in situ (CIS).

Unlabelled: It is well known that CIS is a major risk factor for muscle-invasive bladder cancer and that this entity can be difficult to diagnose. Taking cold-cup mapping biopsies from different areas of the bladder (BMAP) is commonly used in patients at risk of harbouring CIS. The diagnostic accuracy of this approach has not been assessed until now.

A systematic study of gene mutations in urothelial carcinoma; inactivating mutations in TSC2 and PIK3R1.

Background: Urothelial carcinoma (UC) is characterized by frequent gene mutations of which activating mutations in FGFR3 are the most frequent. Several downstream targets of FGFR3 are also mutated in UC, e.g.

Can tissue microarray-based analysis of protein expression predict recurrence of stage Ta bladder cancer?

Objective: Being able to predict the recurrence or progression of non-muscle-invasive bladder cancer would facilitate effective planning of treatments and follow-up. Biomarkers are needed that can supply prognostic information beyond that provided by clinical and pathological parameters. Tissue microarray (TMA)-based analysis of Ta bladder tumours was used to investigate the prognostic value of expression of several proteins involved in bladder carcinogenesis.

Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome.

In the present investigation, we sought to refine the classification of urothelial carcinoma by combining information on gene expression, genomic, and gene mutation levels. For these purposes, we performed gene expression analysis of 144 carcinomas, and whole genome array-CGH analysis and mutation analyses of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 in 103 of these cases. Hierarchical cluster analysis identified two intrinsic molecular subtypes, MS1 and MS2, which were validated and defined by the same set of genes in three independent bladder cancer data sets.

MiRNA expression in urothelial carcinomas: important roles of miR-10a, miR-222, miR-125b, miR-7 and miR-452 for tumor stage and metastasis, and frequent homozygous losses of miR-31.

We analyzed 34 cases of urothelial carcinomas by miRNA, mRNA and genomic profiling. Unsupervised hierarchical clustering using expression information for 300 miRNAs produced 3 major clusters of tumors corresponding to Ta, T1 and T2-T3 tumors, respectively. A subsequent SAM analysis identified 51 miRNAs that discriminated the 3 pathological subtypes.

Recurrent and multiple bladder tumors show conserved expression profiles.

Background: Urothelial carcinomas originate from the epithelial cells of the inner lining of the bladder and may appear as single or as multiple synchronous tumors. Patients with urothelial carcinomas frequently show recurrences after treatment making follow-up necessary. The leading hypothesis explaining the origin of meta- and synchronous tumors assumes a monoclonal origin.

Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors.

Background: Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications.

Tissue microarray based analysis of prognostic markers in invasive bladder cancer: much effort to no avail?

Purpose: To evaluate altered protein expression with tissue microarray methodology for 15 different markers with potential prognostic significance in invasive bladder cancer.

Materials And Methods: Invasive tumor was sampled with the tissue-arraying instrument in 133 consecutive patients who underwent radical cystectomy, and at least 3, 0.6-mm tissue cores were obtained.

Prospective study of transitional cell carcinoma in the prostatic urethra and prostate in the cystoprostatectomy specimen. Incidence, characteristics and preoperative detection.

Objectives: To prospectively evaluate the incidence of transitional cell carcinoma (TCC) in the prostatic urethra and prostate in the cystoprostatectomy specimen, investigate characteristics of bladder tumours in relation to the risk of involvement of the prostatic urethra and prostate and examine the sensitivity of preoperative loop biopsies from the prostatic urethra.

Material And Methods: Preoperatively, patients were investigated with cold cup biopsies from the bladder and transurethral loop biopsies from the bladder neck to the verumontanum. The prostate and bladder neck were submitted to sagittal whole-mount pathological analysis.