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Objective: To evaluate the impact of adjuvant therapy on oncological outcomes in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC), as due to the poorly-defined and overlapping diagnostic criteria optimal decision-making remains challenging in these patients., Patients and Methods: In this multicentre study, patients treated with transurethral resection of bladder tumour for Ta disease were retrospectively analysed. All patients with low- or high-risk NMIBC were excluded from the analysis. Associations between adjuvant therapy administration with recurrence-free survival (RFS) and progression-free survival (PFS) rates were assessed in Cox regression models., Results: A total of 2206 patients with intermediate-risk NMIBC were included in the analysis. Among them, 1427 patients underwent adjuvant therapy, such as bacille Calmette-Guérin (n = 168), or chemotherapeutic agents, such as mitomycin C or epirubicin (n = 1259), in different regimens up to 1 year. The median (interquartile range) follow-up was 73.3 (38.4-106.9) months. The RFS at 1 and 5 years in patients treated with adjuvant therapy and those without were 72.6% vs 69.5% and 50.8% vs 41.3%, respectively. Adjuvant therapy was associated with better RFS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.89, P < 0.001), but not with PFS (P = 0.09). In the subgroup of patients aged ≤70 years with primary, single Ta Grade 2 <3 cm tumours (n = 328), adjuvant therapy was not associated with RFS (HR 0.71, 95% CI 0.50-1.02, P = 0.06). While in the subgroup of patients with at least one risk factor including patient age >70 years, tumour multiplicity, recurrent tumour and tumour size ≥3 cm (n = 1878), adjuvant intravesical therapy was associated with improved RFS (HR 0.78, 95% CI 0.68-0.88, P < 0.001)., Conclusion: In our study, patients with intermediate-risk NMIBC benefit from adjuvant intravesical therapy in terms of RFS. However, in patients without risk factors, adjuvant intravesical therapy did not result in a clear reduction in the recurrence rate., (© 2024 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Background: Urachal cancer (UrC) is a rare disease with limited availability of representative incidence and clinical data. Although, the prevalence is accounting for less than 1% of bladder tumors, the 5-year survival rate is around only 50% for patients with resectable tumors, and even worse for patients with metastatic disease. Due to the lack of comprehensive prospective studies, our current knowledge of UrC is still limited., Objective: The present study aimed to summarize the available registry-based studies with unselected UrC patients to evaluate its incidence and clinicopathological characteristics., Material and Methods: We conducted a systematic literature search of registry-based UrC publications on the 15th of May 2023 in 5 databases, which identified 4,748 publications. After duplicate removal and selection by 2 independent investigators, 6 publications proved to be appropriate for the final meta-analysis. Estimated incidence and clinicopathological parameters were extracted., Results: Estimated incidence ranged between 0.022 and 0.060/ 100.000 person-years, with the highest occurrence in Japan and the lowest in Canada, while the random effect model calculated an overall incidence rate of 0.04 (95%CI: 0.03-0.05) 100.000 person-years. The median age at first diagnosis was 60 years (range: 58-64). The female to male ratio was 2:3. Lymph node or distant metastases were present in 9% and 14% of patients. The predominant tumour type was adenocarcinoma (86%) followed by urothelial carcinoma (12%) and squamous cell carcinoma (2%). The 5-year survival rate was 51.0% with 95%CI: 45.2-57.4., Conclusions: Our study provides an up-to-date comparison of estimated incidence rates between 6 countries of 3 continents based on rigorously selected registry-based studies. The results suggest low incidence rates for UrC with considerable geographic differences. The present meta-analysis provides unbiased registry-based data on the incidence, clinicopathological parameters and survival of UrC., Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Oligometastatic tumors illustrate a distinct state between localized and systematic disease and might harbor unique biologic features. Moreover, these tumors represent a different clinical entity, with a potential of long-term disease control or even cure, therefore they receive growing attention in the field of urologic oncology., Recent Findings: Currently, there is no consensus on the definition of oligometastatic prostate cancer, most experts limit it to a maximum of three to five lesions and involvement of no more than two organs, excluding visceral metastases. Quality data on oligometastatic bladder cancer is scarce, however, a consensus of experts defined it as a maximum of three metastatic lesions, either resectable or suitable for stereotactic therapy, without restrictions to the number of organs involved. As for kidney cancer, a maximum number of five metastases, without limitations to the location are defined as oligometastatic, with an important implication of timing of developing metastases since diagnosis of the primary tumor., Summary: Defining oligometastatic state among urological tumors reflecting their distinct biological and clinical behavior is crucial to establish a sound framework for future clinical trials, and to facilitate guideline and policy formulation for improved patient care. Advancements in molecular imaging are expected to transform the field of oligometastatic urologic tumors in the future., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Clinical trials revealed significant antitumor activity for immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC). Due to their strict eligibility criteria, clinical trials include selected patient cohorts, and thus do not necessarily represent real-world population outcomes. In this multicentric, retrospective study, we investigated real-world data to assess the effectiveness of pembrolizumab and atezolizumab and to evaluate the prognostic value of routinely available clinicopathological and laboratory parameters. Clinical and follow-up data from mUC patients who received ICIs (01/2017-12/2021) were evaluated. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) were used as endpoints. Patients' (n = 210, n = 76 atezolizumab and 134 pembrolizumab) median OS and PFS were 13.6 and 5.9 months, respectively. Impaired ECOG-PS, the presence of visceral, liver or bone metastases, and hemoglobin levels were independently associated with poor OS and DCR. Furthermore, Bellmunt risk factors and the enhanced Bellmunt-CRP score were shown to be prognostic for OS, PFS and DCR. In conclusion, ICIs are effective treatments for a broad range of mUC patients. Our results confirmed the prognostic value of numerous risk factors and showed that Bellmunt risk scores can further be improved when adding CRP to the model., (© 2023. Springer Nature Limited.)

Lymph node (LN) status is the most significant prognostic factor for invasive urothelial bladder cancer (UBC); however, the optimal extent of LN dissection (LND) is debated. We assessed circulating matrix metalloproteinase-7 (MMP-7) as a prognostic factor and decision-making marker for the extent of LND. Preoperative serum MMP-7 levels were determined in two independent UBC cohorts (n = 188; n = 68) and in one control cohort (n = 97) by using the ELISA method. A systematic review and meta-analysis on the prognostic role of circulating pretreatment MMP-7 levels were performed. Serum MMP-7 levels were higher in patients compared to controls ( p < 0.001) with the highest levels in LN-positive cases. Half of LN-positive UBC patients had low MMP-7 levels, whereas the survival of LN-negative patients with high serum MMP-7 findings was poor. MMP-7 levels were independently associated with poor survival in both cohorts ( p = 0.006, p < 0.001). Accordingly, our systematic review of six eligible publications revealed a 2.5-fold higher mortality risk in patients with high MMP-7 levels. In conclusion, preoperative MMP-7 level is a validated and independent prognostic factor in urothelial cancer. It cannot be used to decide between regional or extended LND but may be useful in identifying LN-negative high-risk patients with potentially undetected metastases.

Urachal carcinoma is a rare malignancy that is uniquely associated with the field of urology. Urachal carcinoma is mostly diagnosed in urological care centers due to its most frequently presenting symptom that is hematuria. Currently available diagnostic and therapeutic knowledge is solely based on case reports and single center series, while no prospective clinical studies are carried out due to the modest number of patients. These circumstances have made creating professional guidelines challenging, hence the treatment of urachal carcinoma is commonly based on individual clinical decisions. In this review, we summarize the epidemiology, diagnostic modalities, prognosis as well as local and systemic therapeutic approaches of urachal carcinoma. Furthermore, we aim to draw conclusions from this knowledge base that may guide clinical decision-making. Finally, we highlight some of the novel therapeutic strategies that hold the potential to improve urachal carcinoma patients' prognosis and quality of life. Orv Hetil. 2023; 164(16): 602-609.

Background: Expression levels of collagens have been implicated in the progression of various cancers and interaction with cytokeratins but are not well studied in bladder cancer (BC). Therefore, we analyzed the gene and protein expression levels of collagen 1A1 (Col1a1/COL1A1), collagen 3A1 (col3a1/COL3A1), collagen 5A2 (col5a2/COL5A2), cytokeratin 14 (krt14/CK14), and cytokeratin 17 (krt17/CK17) in urothelial BC samples of different stages., Methods: In total, 102 fresh frozen and 190 formalin-fixed and paraffin-embedded (FFPE) samples were tested using immunohistochemistry and RT-qPCR. Expression levels were correlated with clinicopathological and follow-up data., Results: Col1a1, col3a1, col5a2 and krt14 mRNA levels were significantly overexpressed in high-grade and muscle-invasive BC (MIBC) compared to low-grade and non-muscle invasive BC (NMIBC) cases. Disease-specific survival (DSS) was shorter in patients with high expression levels of col1a1 (p = 0.004), col3a1 (p = 0.004), and col5a2 (p = 0.028). CK14 (p = 0.020), COL3A1 (p = 0.006), and Col5A2 (p = 0.006) protein expression levels were significantly higher and protein expression levels of CK17 (p = 0.05) were significantly lower in MIBC compared to NMIBC. Furthermore, CK14 (p = 0.002) and COL5A2 (p = 0.006) protein expression level were significantly higher in high-grade compared to low-grade BC. DSS was shorter in patients with high expression levels of COL5A2 (p = 0.033) and CK14 (p = 0.042)., Conclusion: Expression changes of collagens and cytokeratins are univariable prognostic markers in BC., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Urachal adenocarcinomas (UrC) are rare but aggressive. Despite being of profound therapeutic relevance, UrC cannot be differentiated by histomorphology alone from other adenocarcinomas of differential diagnostic importance. As no reliable tissue-based diagnostic biomarkers are available, we aimed to detect such by integrating mass-spectrometry imaging-based metabolomics and digital pathology, thus allowing for a multimodal approach on the basis of spatial information. To achieve this, a cohort of UrC (n = 19) and colorectal adenocarcinomas (CRC, n = 27) as the differential diagnosis of highest therapeutic relevance was created, tissue micro-arrays (TMAs) were constructed, and pathological data was recorded. Hematoxylin and eosin (H&E) stained tissue sections were scanned and annotated, enabling an automized discrimination of tumor and non-tumor areas after training of an adequate algorithm. Spectral information within tumor regions, obtained via matrix-assisted laser desorption/ionization (MALDI)-Orbitrap-mass spectrometry imaging (MSI), were subsequently extracted in an automated workflow. On this basis, metabolic differences between UrC and CRC were revealed using machine learning algorithms. As a result, the study demonstrated the feasibility of MALDI-MSI for the evaluation of FFPE tissue in UrC and CRC with the potential to combine spatial metabolomics data with annotated histopathological data from digitalized H&E slides. The detected Area under the curve (AUC) of 0.94 in general and 0.77 for the analyte taurine alone (diagnostic accuracy for taurine: 74%) makes the technology a promising tool in this differential diagnostic dilemma situation. Although the data has to be considered as a proof-of-concept study, it presents a new adoption of this technology that has not been used in this scenario in which reliable diagnostic biomarkers (such as immunohistochemical markers) are currently not available., (© 2021. The Author(s).)

Urachal carcinoma (UrC) is a rare tumor with remarkable histological and molecular similarities to colorectal cancer (CRC). Adenomatous polyposis coli (APC) is the most frequently affected gene in CRC, but the prevalence and significance of its alterations in UrC is poorly understood. In addition, loss of phosphatase and tensin homologue (PTEN) was shown to be associated with therapy resistance in CRC. Our primary aim was to assess specific genetic alterations including APC and PTEN in a large series of UrC samples in order to identify clinically significant genomic alterations. We analyzed a total of 40 UrC cases. Targeted 5-gene (APC, PTEN, DICER1, PRKAR1A, TSHR, WRN) panel sequencing was performed on the Illumina MiSeq platform (n = 34). In addition, ß-catenin (n = 38) and PTEN (n = 30) expressions were assessed by immunohistochemistry. APC and PTEN genes were affected in 15% (5/34) and 6% (2/34) of cases. Two of five APC alterations (p.Y1075*, p.K1199*) were truncating pathogenic mutations. One of the two PTEN variants was a pathogenic frameshift insertion (p.C211fs). In 29% (11/38) of samples, at least some weak nuclear ß-catenin immunostaining was detected and PTEN loss was observed in 20% (6/30) of samples. The low prevalence of APC mutations in UrC represents a characteristic difference to CRC. Based on APC and ß-catenin results, the Wnt pathway seems to be rarely affected in UrC. Considering the formerly described involvement of PTEN protein loss in anti-EGFR therapy-resistance its immunohistochemical testing may have therapeutic relevance.

Introduction: Urothelial cancer can develop in the renal pelvis, ureters, bladder and the proximal urethra as urothelial tissue can be found in these organs. Upper tract urothelial carcinoma is rare but better understanding of the natural history of the disease is important because bladder recurrence often occurs after radical nephroureterectomy., Aim and Method: Our retrospective study aims to describe the general characteristics of patients treated with radical nephroureterectomy at the Department of Urology, Semmelweis University, between January 1st, 2005 and December 31st, 2016. Additionally, we aimed to identify risk factors of bladder recurrence after radical surgery., Results: 160 patients had radical nephroureterectomy and 135 of them had urothelial upper urinary tract cancer. The mean follow-up period was 32 months (SD: 30.25), bladder recurrence was diagnosed at 31 patients (23%), the average time for the recurrence was 19.6 months (SD: 29.7). Recurrence occurred significantly earlier among older patients (p = 0.007) and it was also associated with hypertonia of the patients (p = 0.035)., Conclusion: Upper tract urothelial cancer recurrence occurs earlier among older and multimorbid patients. Careful watching of these patients (frequent reminder to regular cystoscopy and control examinations) could reduce further complications. Orv Hetil. 2020; 161(21): 881-888.

To optimize treatment decisions in advanced bladder cancer (BC), we aimed to assess the therapy predictive value of STIP1 with regard to cisplatin therapy. Cisplatin-based chemotherapy represents the standard first-line systemic treatment of advanced bladder cancer. Since novel immunooncologic agents are already available for cisplatin-resistant or ineligible patients, biological markers are needed for the prediction of cisplatin resistance. STIP1 expression was analyzed in paraffin-embedded bladder cancer tissue samples of 98 patients who underwent adjuvant or salvage cisplatin-based chemotherapy by using immunohistochemistry. Furthermore, pre-chemotherapy serum STIP1 concentrations were determined in 48 BC patients by ELISA. Results were correlated with the clinicopathological and follow-up data. Stronger STIP1 nuclear staining was associated with worse OS in both the whole patient group (p = 0.034) and the subgroup of patients who received at least 2 cycles of chemotherapy (p = 0.043). These correlations remained significant also in the multivariable analyses (p = 0.035 and p = 0.040). Stronger STIP1 cytoplasmatic immunostaining correlated with shorter PFS both in the whole cohort (p = 0.045) and in the subgroup of patients who received at least 2 cycles of chemotherapy (p = 0.026). Elevated STIP1 serum levels were associated with older patient's age, but we found no correlation between STIP1 serum levels and patients' outcome. Our results suggest that tissue STIP1 analysis might be used for the prediction of cisplatin-resistance in BC. In contrast, pretreatment STIP1 serum levels showed no predictive value for chemotherapy response and survival.

The Slit-Robo pathway has shown to be altered in several malignant diseases. However, its role in bladder cancer is poorly understood. Therefore, we aimed to assess the tissue expression of Robo1 and Robo4 as well as their ligand Slit2 in different stages of bladder cancer to explore possible changes of Slit-Robo signalling during the progression of bladder cancer. Robo1, Robo4 and Slit2 gene expressions were analyzed in 92 frozen bladder cancer tissue samples by using reverse transcription quantitative real-time PCR. Immunohistochemical analyses were performed on 149 formalin-fixed and paraffin-embedded bladder cancer tissue samples. Results were correlated with the clinical and follow-up data by performing both univariable and multivariable analyses. Robo1 and Robo4 nuclear staining intensitiy was significantly higher in low stage and low grade bladder cancer. Elevated Robo1 nuclear staining was associated with better disease-specific survival (DSS) (p = 0.045). Similarly, stronger Robo4 nuclear staining tended to be associated with longer DSS (p = 0.061). We found higher Robo1 and Slit2 gene expression levels in advanced stages of bladder cancer (p = 0.007 and p < 0.001). High Slit2 gene expression was correlated with significantly shorter DSS (p < 0.005), while Robo1 and Robo4 gene expressions were not associated with patients' prognosis. Our results demonstrate that the nuclear expression of Robo1 and Robo4 is associated with a favourable prognosis suggesting that its translocation into the nucleus represent a posttranslational regulation process which may exhibit an antitumor effect in bladder cancer.

Background: Urachal cancer is a rare type of cancer, often following a clinically aggressive course. Due to its rarity, knowledge about its molecular background is still limited. In addition, no sufficiently reliable diagnostic markers are available., Objectives: The aim of the present study is to give an overview of our recent molecular projects on urachal cancer and to connect it with current literature in the field., Materials and Methods: Three projects are introduced. The first project identified and validated diagnostic biomarkers in urachal adenocarcinomas compared to colorectal adenocarcinomas and primary adenocarcinomas of the bladder using various proteomic methods. In the second project, the most relevant differential diagnostic markers between urachal adenocarcinomas and colorectal adenocarcinomas compared to normal tissue (urachal remnants) were determined by analyzing a miRNA panel. Sequence analyses were performed in the third project. The focus was on molecular differences to colorectal adenocarcinomas and urothelial carcinomas., Results and Conclusions: We detected potential biomarker candidates for the immunohistochemical differential-diagnosis and generated a miRNA-based diagnostic scoring system with a potentially high differential-diagnostic significance. The sequence analyses data confirm the molecular autonomy of the urachal adenocarcinomas compared to other entities.

Objectives: Cisplatin-based chemotherapy represents the gold standard in the treatment of advanced bladder cancer (BC) both in the neoadjuvant and adjuvant setting. Since novel immunooncologic agents are available for cisplatin-resistant or ineligible patients, biological markers for the prediction of cisplatin resistance become more important in treatment decisions. Therefore, we aimed to assess the therapy predictive value of 8 promising tissue biomarkers with regard to cisplatin therapy., Methods: Emmprin, survivin, HMGA2, MTA1, RhoGDI, PEG10, TGM2, and TLN1 expressions were analyzed in paraffin-embedded bladder cancer tissue samples of 106 patients who underwent adjuvant or salvage cisplatin-based chemotherapy by using immunohistochemistry. Results were correlated with the clinicopathological and follow-up data by performing both univariable and multivariable survival analyses., Results: Higher HMGA2 nuclear staining intensity and positive survivin nuclear staining were associated with worse overall survival (OS) (P = 0.045 and P = 0.002, respectively). In accordance, survivin nuclear staining also significantly correlated with shorter progression free survival (PFS, P = 0.024), while HMGA2 nuclear positivity tended to correlate with shorter PFS (P = 0.069) after at least 2 cycles of chemotherapy. In the multivariable analyses only survivin remained as an independent predictor of both OS and PFS (P = 0.008 and P = 0.025). None of the other markers proved to be significant predictors of adjuvant or salvage cisplatin-based chemotherapy., Conclusions: Our results demonstrate that survivin represents a promising marker for the prediction of cisplatin resistance in BC. In addition the therapy predictive role of HMGA2 should be further investigated. Immunohistochemical analysis of BC samples provides a feasible way for the prediction of cisplatin-resistance and may therefore provide a valuable tool for optimizing treatment decisions in advanced BC., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Current advances in molecular techniques and bioinformatics allowed the analysis of complex molecular patterns in various cancers including muscle-invasive bladder cancer. As a consequence, in the last few years numerous gene- and protein expression-based molecular classifications have been recommended. Recently a comprehensive consensus classification for muscle-invasive urothelial bladder cancer has been published, distinguishing 6 subgroups with a potential impact on clinical decision-making. At the same time, the therapeutic landscape of muscle-invasive bladder cancer becomes increasingly differentiated as novel checkpoint inhibitors have been available for cisplatin-ineligible and/or resistant patients. Furthermore, promising results have been obtained with FGFR targeting agents. Therefore, molecular subtyping will probably have a crucial role in individualized therapeutic decision-making in bladder cancer. In the present work, we summarize the evolution, recent advances and potential therapeutic relevance of molecular subclassifications in bladder cancer. Orv Hetil. 2019; 160(42): 1647-1654.

Urachal cancer (UrC) is a rare but aggressive malignancy often diagnosed in advanced stages requiring systemic treatment. Although cytotoxic chemotherapy is of limited effectiveness, prospective clinical studies can hardly be conducted. Targeted therapeutic treatment approaches and potentially immunotherapy based on a biological rationale may provide an alternative strategy. We therefore subjected 70 urachal adenocarcinomas to targeted next-generation sequencing, conducted in situ and immunohistochemical analyses (including PD-L1 and DNA mismatch repair proteins [MMR]) and evaluated the microsatellite instability (MSI) status. The analytical findings were correlated with clinicopathological and outcome data and Kaplan-Meier and univariable/multivariable Cox regression analyses were performed. The patients had a mean age of 50 years, 66% were male and a 5-year overall survival (OS) of 58% and recurrence-free survival (RFS) of 45% was detected. Sequence variations were observed in TP53 (66%), KRAS (21%), BRAF (4%), PIK3CA (4%), FGFR1 (1%), MET (1%), NRAS (1%), and PDGFRA (1%). Gene amplifications were found in EGFR (5%), ERBB2 (2%), and MET (2%). We detected no evidence of MMR-deficiency (MMR-d)/MSI-high (MSI-h), whereas 10 of 63 cases (16%) expressed PD-L1. Therefore, anti-PD-1/PD-L1 immunotherapy approaches might be tested in UrC. Importantly, we found aberrations in intracellular signal transduction pathways (RAS/RAF/PI3K) in 31% of UrCs with potential implications for anti-EGFR therapy. Less frequent potentially actionable genetic alterations were additionally detected in ERBB2 (HER2), MET, FGFR1, and PDGFRA. The molecular profile strengthens the notion that UrC is a distinct entity on the genomic level with closer resemblance to colorectal than to bladder cancer., (© 2018 UICC.)

Polymorphic xenobiotic metabolizing enzymes such as N-acetyltransferase 2 (NAT2) or glutathione S-transferase M1 (GSTM1) are known to modulate bladder cancer risk. As no apparent data were available from Hungary, a former member of the eastern European economic organization, a study was performed in Budapest. In total, 182 bladder cancer cases and 78 cancer-free controls were investigated by questionnaire. Genotypes of NAT2, GSTM1, GSTT1, rs1058396 and rs17674580 were determined by standard methods. Current smokers' crude odds ratio (OR) (3.43) and former smokers crude OR (2.36) displayed a significantly increased bladder cancer risk. The risk rose by a factor of 1.56 per 10 pack years. Exposure to fumes was associated with an elevated bladder cancer risk (23% cases, 13% controls). Sixty-four % of the cases and 59% of controls were slow NAT2 acetylators. It was not possible to establish a particular impact of NAT2*6A and *7B genotypes (15 cases, 8%, 5 controls, 7%). GSTT1 exerted no marked influence on bladder cancer (negative 21% cases vs. 22% controls). The portion of GSTM1 negative bladder cancer patients was increased (63% cases vs. 54% controls). The SLC14A1 SNPs rs1058396[AG/GG] and the nearby rs17674580[CT/TT] occurred more frequently in cases (79% and 68%) than controls (77% and 55%). The portion of GSTM1 negative bladder cancer patients is comparable with portions reported from other industrialized areas like Lutherstadt Wittenberg/Germany (58%), Dortmund/Germany (70%), Brescia/Italy (66%) or an occupational case-control series in Germany (56%). Data indicate that GSTM1 is a susceptibility factor for environmentally triggered bladder cancer rather than for smoking-mediated bladder cancer.

Background and Objectives: Urachal carcinoma (UrC) is a rare and poorly investigated disease. Our current knowledge is mainly based on single-institutional studies. Despite growing interest in UrC, the included case numbers in recently published studies are still low. Therefore, we aimed to provide a comprehensive meta-analysis on the clinical, prognostic, and therapeutic aspects of UrC., Methods: A systematic Medline/PubMed search was performed on UrC using the terms "urachal carcinoma," "urachal cancer," and "urachus." Original articles and reviews in English language with case numbers>10 were selected., Results: The vast majority (91%, 489/532) of UrCs are diagnosed at later stages (Sheldon≥III) when the tumor invades the urinary bladder. About 21% (136/646) of UrC patients have distant metastasis at first presentation. Although for patients with non-metastatic UrC surgical treatment provides an acceptable disease control, the systemic treatment of patients with progressed/metastatic UrC-in lack of prospective clinical trials-are less well established. Comparing cisplatin-based and 5-FU-based therapies in 74 published UrC cases, we found the latter to be superior in terms of radiographic response rates (9% vs. 44%, P = 0.043), but the combination of these 2 therapies provided the lowest progression rate (14%) with a similarly high response rate (43%)., Conclusions: Owing to the lack of evidence-based guidelines, the therapy of UrC remains challenging. Given the infrequency of UrC, large prospective studies comparing different systemic therapies can hardly be conducted. Our metadata indicates that 5-FU-containing chemotherapy regimens are more effective than cisplatin-based treatment modalities, whereas their combination seems to provide the strongest antitumor effect. Nevertheless, in the lack of evidences from prospective clinical trials, therapeutic decision-making necessarily remains on an individual basis. In this situation, targeted therapies may provide a reasonable alternative. Therefore, better understanding of the molecular background of UrC is needed to rationalize treatment decisions in UrC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Targeted therapy represents an attractive alternative for rare tumors such as urachal carcinoma (UrC). The aim of this study was to assess the mutations of the most commonly affected 5 genes in the targetable EGFR-pathway in UrC and comapre their frequencies to those of found in urothelial and colorectal cancer., Materials and Methods: Mutational hot-spots of selected genes were tested in 22 UrC samples by pyrosequencing. Mutational patterns were compared to those published for colorectal and urothelial cancers. Furthermore, we sought correlations between mutations and clinicopathological and follow-up data., Results: We found 11 mutations in 10 of 22 (45%) patients. The most frequently mutated gene was KRAS (27%) followed by BRAF (18%) and NRAS (5%), while no mutations were detected in the EGFR and PIK3CA genes. No correlation was found between the mutation status and clinicopathological parameters (Sheldon/Mayo stage, tumor grade, metastases). Furthermore, none of the mutations correlated with progression-free or overall survival., Conclusions: The mutation pattern of UrC is more similar to colorectal than to urothelial cancer. However, the mutation characteristics of UrC seems to be unique suggesting that clinical decision-making for UrC cannot be simply adopted from urothelial or colorectal carcinoma. The high occurence of EGFR-pathway mutations warrants the testing for KRAS and BRAF mutations when considering anti-EGFR therapy in UrC., Competing Interests: CONFLICTS OF INTERESTS None of the authors reported any financial interests or potential conflicts of interest related to this study.

Purpose: Urachal carcinoma of the bladder is a rare malignancy. Its histological phenotype is similar to that of primary bladder and colorectal adenocarcinoma. The aim of this study was to explore the expression and prognostic relevance of 6 select protein markers of urachal carcinoma of the bladder, including p53, Ki67, RHAMM, BGN, IMP3 and MMP-7, which were formerly shown to be prognostic in urothelial carcinoma and colorectal adenocarcinoma., Materials and Methods: Clinical and followup data were obtained on a total of 26 patients with urachal carcinoma of the bladder treated at 2 university hospitals. Immunohistochemical analysis of p53, Ki67, RHAMM, BGN, IMP3 and MMP-7 expression was performed in samples from 15 patients. Clinicopathological parameters and immunohistochemical results were tested for prognostic value on univariable and multivariable analyses., Results: Followup was 50 months. Five-year overall and progression-free survival was 46% and 32%, respectively. On multivariable analysis a positive resection margin was an independent predictor of poor overall survival (p = 0.025). RHAMM (p = 0.0431), IMP3 (p = 0.0052), Ki67 (p = 0.0006) and p53 (p = 0.0024) expression rates were significantly increased in urachal carcinoma of the bladder cells compared to normal urothelium. IMP3 was elevated in Sheldon tumor stage IIIA compared to IIIB or greater (p = 0.0048). None of the analyzed protein markers was associated with survival., Conclusions: The independent prognostic value of a positive resection margin underlines the importance of complete surgical removal of urachal carcinoma of the bladder combined with en bloc resection of the median umbilical ligament and umbilicus. Our results in a limited number of samples show that Ki67, p53, RHAMM and IMP3 expression is enhanced but has no prognostic significance in urachal carcinoma of the bladder., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Updated classification of urothelial cell cancer differentiates low-grade and high-grade cancers, which determines potential clinical outcome. Substantial interobserver variability necessitates new biomarkers to ensure classification. Claudins' specific expression pattern characterizes normal tissues, different tumor types, and defined grades of tumor differentiation. The aim of this study was to examine the expression pattern of claudins and proliferation marker Ki-67 in low-grade and high-grade urothelial cell cancers compared with independent control samples of non-tumorous urothelium, as well as to reveal the predictive usefulness of claudins. The expression of claudins-1, -2, -3, -4, -5, -7, and -10 and Ki-67 was studied with quantitative immunohistochemistry and real-time RT-PCR with relative quantification in 103 samples: 86 urothelial cell cancers (27 low grade, 59 high grade) and 17 non-tumorous urothelia. Results were analyzed regarding overall survival and recurrence-free period as well. High-grade tumors overall showed significantly higher claudin-4 and Ki-67 and significantly lower claudin-7 expression when compared with low-grade ones. High-grade tumors revealed significantly shorter overall survival in Kaplan-Meier analysis. Claudin-4, claudin-7, and Ki-67 might be used as potential markers to differentiate low-grade and high-grade urothelial cell cancers, thereby possibly enhancing accuracy of pathological diagnosis and adding further information to clinical outcome.

The members of the claudin family are major integral transmembrane protein constituents of tight junctions. Normal and neoplastic tissues can be characterized by unique qualitative and quantitative distribution of claudin subtypes, which may be related to clinicopathological features. Differential diagnosis and prognosis of nonmuscle invasive tumor entities of urinary bladder epithelium are often challenging. The aim was to investigate the expression profile of claudins in inverted urothelial papillomas (IUPs), urothelial papillomas (UPs), papillary urothelial neoplasms of low malignant potential (PUNLMPs), and intraepithelial (Ta), low-grade urothelial cell carcinomas (LG-UCCs) in order to reveal potential prognostic and differential diagnostic values of certain claudins. Claudin-1, -2, -4, and -7 protein expressions detected by immunohistochemistry and clinical data were analyzed in 15 IUPs, 20 UPs, 20 PUNLMPs, and 20 LG-UCCs. UPs, PUNLMPs, and LG-UCCs showed significantly decreased claudin-1 expression in comparison to IUPs. LG-UCCs expressing claudin-4 over the median were associated with significantly shorter recurrence-free survival. PUNLMPs expressing claudin-1 over the median revealed significantly longer recurrence-free survival. High claudin-1 protein expression might help to differentiate IUP from UPs, PUNLMPs, and LG-UCCs. High claudin-4 expression may determine an unfavorable clinical course of LG-UCCs, while high claudin-1 expression in PUNLMP was associated with markedly better clinical outcome.

In the past few years, ultrasonography has become the most widespread and easily available diagnostic procedure in gynecological practice. the high-frequency transvaginal probe provides a detailed visualization of the reproductive organs and the urinary bladder. however, in spite of this generally applied examination procedure it's rare when the transvaginal ultrasonography is used to identify bladder tumor. the urologist rather use transabdominal ultrasound for the detection of bladder tumors. the authors report a case in which gynecological sonography contributed to the screening and evaluation of an asymptomatic bladder cancer.