Search

Objective: To evaluate near‐infrared (NIR) spectroscopy in differentiating between benign and malignant bladder pathologies ex vivo immediately after resection, including the grade and stage of malignancy. Patients and Methods: A total of 355 spectra were measured on 71 bladder specimens from patients undergoing transurethral resection of bladder tumour (TURBT) between April and August 2022. Scan time was 5 s, undertaken using a portable NIR spectrometer within 10 min from excision. Specimens were then sent for routine histopathological correlation. Machine learning models were applied to the spectral dataset to construct diagnostic algorithms; these were then tested for their ability to predict the histological diagnosis of each sample using its NIR spectrum. Results: A two‐group algorithm comparing low‐ vs high‐grade urothelial cancer demonstrated 97% sensitivity, 99% specificity, and the area under the receiver operating characteristic curve (AUC) was 0.997. A three‐group algorithm predicting stages Ta vs T1 vs T2 achieved 97% sensitivity, 92% specificity, and the AUC was 0.996. Conclusions: This first study evaluating the diagnostic potential of NIR spectroscopy in urothelial cancer shows that it can be accurately used to assess tissue in an ex vivo setting immediately after TURBT. This offers point‐of‐care assessment of bladder pathology, with potential to influence the extent of resection, reducing both the need for re‐resection where invasive disease may be suspected, and also the potential for complications where extent of diagnostic resection can be limited. Further studies utilising fibre‐optic probes offer the potential for in vivo assessment. [ABSTRACT FROM AUTHOR]

Bladder cancer, the 10th most common cancer globally, primarily manifests as urothelial cell carcinoma. Risk factors involve acquired genetic mutations and congenital predispositions, impacting diagnosis and management. This article discusses the risk factors, clinical presentation, and treatment strategies, with emphasis on providing comprehensive nursing support and patient education to patients with bladder cancer. Bladder cancer, the 10th most common cancer globally, primarily manifests as urothelial cell carcinoma. This article discusses risk factors, treatment strategies, nursing support, and patient education. [ABSTRACT FROM AUTHOR]

Introduction: Radical cystectomy combined with orthotopic urinary diversion is a chosen approach for treating invasive bladder cancer. However, urothelial cell carcinoma is characterized by its potential for recurrence and the development of multiple tumors in the urinary tracts. In the natural progression of transitional cell carcinoma, the remaining ureteral stump is considered a predicted site for possible recurrence after radical cystectomy. Currently, there is no specific recommendation for the diagnosis and management of this condition. Objective: We report a rare case in a 74-year-old male patient who was diagnosed with anterior urethral carcinoma following a history of radical cystectomy and Hautmann ileal neobladder reconstruction. Additionally, we summarize some novel findings regarding risk factors, diagnosis, treatment, and prognosis in patients with recurrent bladder cancer in the urethra after radical cystectomy. Methods: A case report and mini review. Results: The patient was diagnosed with recurrent bladder cancer in the urethral after radical cystectomy using magnetic resonance imaging of the pelvis, cystoscopy, and biopsy. Complete urethrectomy and creation of a permanent percutaneous urinary diversion were performed. No intraoperative or postoperative complications were recorded. The patient was discharged 3 days after the surgery. Conclusion: Urethral cancer following radical cystectomy for bladder cancer treatment is a rare condition. Risk factors for this occurrence include male gender, non-use of orthotopic neobladder reconstruction technique, invasive tumors in the prostatic urethra, and multifocal tumors. The treatment of these tumors can be determined based on the extent of invasion and histological characteristics, leading to the choice between radical urethrectomy or alternative conservative treatments. [ABSTRACT FROM AUTHOR]

The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system’s ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system’s role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response. [ABSTRACT FROM AUTHOR]

The introduction of novel immunotherapies has significantly transformed the treatment landscape of genitourinary (GU) cancers, even becoming the standard of care in some settings. One such type of immunotherapy, immune checkpoint inhibitors (ICIs) like nivolumab, ipilimumab, pembrolizumab, and atezolizumab play a pivotal role by disturbing signaling pathways that limit the immune system's ability to fight tumor cells. Despite the profound impact of these treatments, not all tumors are responsive. Recent research efforts have been focused on understanding how cancer cells manage to evade the immune response and identifying the possible mechanisms behind resistance to immunotherapy. In response, ICIs are being combined with other treatments to reduce resistance and attack cancer cells through multiple cellular pathways. Additionally, novel, targeted strategies are currently being investigated to develop innovative methods of overcoming resistance and treatment failure. This article presents a comprehensive overview of the mechanisms of immunotherapy resistance in GU cancers as currently described in the literature. It explores studies that have identified genetic markers, cytokines, and proteins that may predict resistance or response to immunotherapy. Additionally, we review current efforts to overcome this resistance, which include combination ICIs and sequential therapies, novel insights into the host immune profile, and new targeted therapies. Various approaches that combine immunotherapy with chemotherapy, targeted therapy, vaccines, and radiation have been studied in an effort to more effectively overcome resistance to immunotherapy. While each of these combination therapies has shown some efficacy in clinical trials, a deeper understanding of the immune system's role underscores the potential of novel targeted therapies as a particularly promising area of current research. Currently, several targeted agents are in development, along with the identification of key immune mediators involved in immunotherapy resistance. Further research is necessary to identify predictors of response. ARTICLE HIGHLIGHTS: Immunotherapy has transformed the treatment landscape for many cancer types, including genitourinary malignancies such as renal and bladder cancers.However, not all patients or tumor types, such as prostate cancer, respond to this type of treatment. Understanding the mechanisms of immunotherapy resistance is critical for developing strategies to overcome these challenges. Primary resistance, which is present at the onset of treatment, can bedue to genetic abnormalities or immune system dysregulation. These factors alter the interactions between host cells and cancer cells. Adaptive resistance develops during therapy due to dynamic changes in the levels of growth factors, cytokines, and the tumor microenvironment (TME). Acquired resistance mainly occurs at the genetic and translational levels, involving the downregulation of critical human leukocyte antigen (HLA) molecules and interference with mutational repair. Future therapies may focus on detailed genetic profiling of patients to guide treatment selection and on the use of immune profile monitoring to assist in assessing responsiveness, alongside developing novel targeted therapies and ICIs. Further research is needed to identify predictors of response to ICIs. [ABSTRACT FROM AUTHOR]

Objective We report NHS England data for patients with bladder cancer (BC), upper tract urothelial cancer (UTUC: renal pelvic and ureteric), and urethral cancers from 2013 to 2019. Materials and Methods Hospital episode statistics, waiting times, and cancer registrations were extracted from NHS Digital. Results Registrations included 128 823 individuals with BC, 16 018 with UTUC, and 2533 with urethral cancer. In 2019, 150 816 persons were living with a diagnosis of BC, of whom 113 067 (75.0%) were men, 85 117 (56.5%) were aged >75 years, and 95 553 (91.7%) were Caucasian. Incidence rates were stable (32.7-34.3 for BC, 3.9-4.2 for UTUC and 0.6-0.7 for urethral cancer per 100 000 population). Most patients 52 097 (mean [range] 41.3% [40.7-42.0%]) were referred outside the 2-weekwait pathway and 15 340 (mean [range] 12.2% [11.7-12.6%]) presented as emergencies. Surgery, radiotherapy, chemotherapy, or multimodal treatment use varied with disease stage, patient factors and Cancer Alliance. Between 27% and 29% (n = 6616) of muscle-invasive BCs did not receive radical treatment. Survival rates reflected stage, grade, location, and tumour histology. Overall survival rates did not improve over time (relative change: 0.97, 95% confidence interval 0.97-0.97) at 2 years in contrast to other cancers. Conclusion The diagnostic pathway for BC needs improvement. Increases in survival might be delivered through greater use of radical treatment. NHS Digital data offers a population-wide picture of this disease but does not allow individual outcomes to be matched with disease or patient features and key parameters can be missing or incomplete. [ABSTRACT FROM AUTHOR]

Background: Applying deep learning to digital histopathology is hindered by the scarcity of manually annotated datasets. While data augmentation can ameliorate this obstacle, its methods are far from standardized. Our aim was to systematically explore the effects of skipping data augmentation; applying data augmentation to different subsets of the whole dataset (training set, validation set, test set, two of them, or all of them); and applying data augmentation at different time points (before, during, or after dividing the dataset into three subsets). Different combinations of the above possibilities resulted in 11 ways to apply augmentation. The literature contains no such comprehensive systematic comparison of these augmentation ways. Results: Non-overlapping photographs of all tissues on 90 hematoxylin-and-eosin-stained urinary bladder slides were obtained. Then, they were manually classified as either inflammation (5948 images), urothelial cell carcinoma (5811 images), or invalid (3132 images; excluded). If done, augmentation was eight-fold by flipping and rotation. Four convolutional neural networks (Inception-v3, ResNet-101, GoogLeNet, and SqueezeNet), pre-trained on the ImageNet dataset, were fine-tuned to binary classify images of our dataset. This task was the benchmark for our experiments. Model testing performance was evaluated using accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve. Model validation accuracy was also estimated. The best testing performance was achieved when augmentation was done to the remaining data after test-set separation, but before division into training and validation sets. This leaked information between the training and the validation sets, as evidenced by the optimistic validation accuracy. However, this leakage did not cause the validation set to malfunction. Augmentation before test-set separation led to optimistic results. Test-set augmentation yielded more accurate evaluation metrics with less uncertainty. Inception-v3 had the best overall testing performance. Conclusions: In digital histopathology, augmentation should include both the test set (after its allocation), and the remaining combined training/validation set (before being split into separate training and validation sets). Future research should try to generalize our results. [ABSTRACT FROM AUTHOR]

Background: About 17%–34% of patients with non‐prostatic genitourinary (GU) cancer had stable disease (SD) as their best response to programmed cell death protein 1/programmed death‐ligand 1 (PD‐1/PD‐L1) inhibitors. However, most efficacy studies of PD‐1/PD‐L1 inhibitors are focused on the response and its durability. Little is known about patients' clinical outcomes with SD as their initial response to PD‐1/PD‐L1 inhibitors. Methods: We retrospectively reviewed the clinical outcomes of patients with renal cell carcinoma (RCC) (n = 102) and urothelial carcinoma (UC) (n = 101) treated with PD‐1/PD‐L1 inhibitors. The duration of SD (DoSD) was calculated for patients who had SD as their best response and was defined from the time of SD to radiologically confirmed progressive disease (PD) or death. Results: Fifty‐five patients (27.1%) had SD as the initial response. Among them, 10 patients (18.2%) achieved a response on subsequent assessments. With a median follow‐up duration of 15.2 months, the median DoSD was 8.5 months (range: 3.2–13.8), which was significantly different according to the disease; 9.4 months in RCC and 2.3 months in UC (p = 0.03). If the disease did not progress in 4 months (long SD subgroup), the DoSD (11.0 months) was comparable to the duration of response (12.9 months) in patients who achieved a complete or partial response to PD‐1/PD‐L1 inhibitors. In addition to the cancer type, the clinical factors associated with short DoSD were liver metastases (p = 0.003), neutrophil‐lymphocyte ratio (NLR) > 4.0 (p = 0.001), and platelet‐lymphocyte ratio (PLR) > 194 (p = 0.003). Conclusion: For RCC patients with SD to PD‐1/PD‐L1 inhibitors, if there are no liver metastases and NLR/PLR is below the certain level, they would have similar duration of disease control and survival benefit as those who achieve the response. [ABSTRACT FROM AUTHOR]

Human urothelial cell carcinoma (UCC) and non‐Hodgkin lymphoma are considered environmental cancers in people, but less is known about environment risk for UCC and lymphoma in dogs. The objective of this study was to determine whether dogs with these cancers, compared to unaffected control dogs, live in counties with higher tap water contaminants or higher levels of air pollution as measured by the Environmental Protection Agency (EPA) and by National Air Toxics Assessment chemical exposure risk estimates. Dogs with available home addresses from two previously published case–control populations were included: 66 dogs with UCC and 70 unaffected controls; and 56 boxer dogs with lymphoma and 84 unaffected boxer controls. Tap water total trihalomethanes, which are water disinfection by‐products, were more than threefold higher in UCC case counties of residence compared to controls (p <.0001), and a higher proportion of dogs with UCC lived in counties exceeding EPA ozone limits (41.8%) compared to controls (13.6% p =.0008). More boxers with lymphoma lived in counties exceeding EPA ozone limits (52.1%) compared to controls (29.0%; p =.018), with higher exposure risk estimates for airborne 1,3‐butadiene and formaldehyde (p =.004–.005). These data support the hypothesis that tap water contaminants and airborne environmental pollutants contribute to the risk of both urothelial carcinoma and lymphoma in dogs. If these findings reflect causal relationships, then it is possible that tap water filtration units and more effective air pollution controls could decrease the overall incidence of these cancers in dogs. [ABSTRACT FROM AUTHOR]

Non-muscle-invasive bladder cancer (NMIBC) has one of the highest recurrence rates among all solid cancers and the highest lifetime treatment cost per patient. Therefore, the development of chemoprevention strategies for reducing the occurrence and recurrence of NMIBC as well as its burdens on the healthcare system is valuable. Our aim was to determine whether flavokawain A (FKA), a kava chalcone isolated from the kava plant, can target the in vivo activated Ha-ras pathway for prevention and treatment of NMIBC. UPII-mutant Ha-ras transgenic mice that develop papillary urothelial cell carcinoma were fed orally with vehicle control or FKA-formulated food for 6 months starting at 6 weeks of age. Seventy-nine percent (15/19) of male mice fed with 6 g FKA per kilogram (kg) of food survived beyond the 6 months of treatment, while 31.6% (6/19) of control food-fed male mice survived the 6-month treatment period (p = 0.02). The mean bladder weights in FKA vs. control food-fed mice were 0.216 ± 0.033 vs. 0.342 ± 0.039 g in male mice (p = 0.0413) and 0.043 ± 0.004 vs. 0.073 ± 0.004 g in female mice (p < 0.0001); FKA reduced bladder weight by 37% and 41%, respectively. The tumor burdens, determined by the wet bladder weight, in these mice were inversely related to plasma FKA concentrations. In addition to decreased bladder weight, FKA treatment significantly reduced the incidences of hydronephrosis and hematuria. FKA-treated mice exhibited more well-differentiated tumors in the bladder and ureter. Immunohistochemical analysis of FKA-treated tumors compared to those in the control group revealed fewer Ki-67- and survivin-positive cells and an increased number of p27- and TUNEL-positive cells, indicating that FKA inhibits proliferation and induces apoptosis. Overall, the results suggest that FKA can target the in vivo activated Ha-ras pathway for the prevention and treatment of NMIBC. [ABSTRACT FROM AUTHOR]

The benefit of adding neoadjuvant chemotherapy to bladder-sparing chemoradiation for muscle-invasive bladder cancer remains unclear. This retrospective, large database study of 2566 patients found no survival benefit with the addition of neoadjuvant chemotherapy to definitive chemoradiation. These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, which should be investigated under prospective clinical trials. Background: Bladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown. Patients and Methods: We identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias. Results: We identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation. Conclusion: These results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials. [ABSTRACT FROM AUTHOR]

Chemotherapy and radiotherapy are gold standard treatment for bladder cancer (BC) for over 50 years. The efficacy on early stage BC patients is virtuous. However, patients with aggressive cancer growth benefited less from the therapy. Aberrant p53 was found in more than 50% of high-grade BC patients. Therefore, targeting p53 in a subset of high-grade BC patients expressing aberrant p53 is a promising strategy. In this paper, p53 role in BC carcinogenesis is discussed. Followed by p53-targeting strategies in current BC treatment. Besides, p53-targeting strategies that have been implemented in other types of cancer and their potential to be adapted in BC will be deliberated. Although targeting p53 is promising, none of the strategies studied were successfully implemented in healthcare settings. Restoration of p53 as the guardian of the genome is an exciting area for translational research. It has potential to replace the genotoxic chemotherapy and radiotherapy, thus, eliminating the notorious painful sideeffects on a subset of high-grade BC patients. Searches were performed on PubMed and Google Scholar web using the keywords "bladder cancer" or "urothelial cancer" or "urothelial cell carcinoma" and "p53". Only full papers of research articles and review papers were included for analysis. Papers were categorized as either p53 function, current treatment using p53 and future potential treatment using p53 for details analysis. [ABSTRACT FROM AUTHOR]

Introduction: Prostate specific membrane antigen (PSMA) has become a target for radionuclide imaging and therapy. Previous studies have shown that the expression of PSMA is not specific to prostate tissue. In this study we examine the expression of PSMA in urothelial cell carcinoma (UCC). Methods: Immunhistochemical PSMA-staining was performed in 89 UCC samples. PSMA expression in tumor tissue, adjacent healthy tissue and blood vessels was examined. We furthermore analyzed PSMA-mRNA expression in nine human UCC cell lines. We correlated our findings with clinical data regarding recurrence and progression of UCC. Results: UCC tissue showed a significantly higher PSMA expression compared to healthy urothelial tissue (p < 0.001). Non muscle invasive bladder cancer revealed significantly higher PSMA expression compared to muscle invasive bladder cancer (p < 0.05). PSMA expression significantly differed between various T-stages (p < 0.05) and tumor differentiation (p < 0.001). In four human UCC cell lines PSMA-mRNA was detectable. Those patients who suffered recurrence showed a higher rate of PSMA expression but no correlation to recurrence-free survival was evident. Progression of disease correlated significantly with a higher PSMA expression (p = 0.036). Conclusions: Both UCC tissue and healthy urothelial tissue express PSMA, with significantly higher levels in UCC. We confirmed these findings in human UCC cell lines. In this small first cohort expression of PSMA correlates significant with progression of disease but not with recurrence and recurrence-free survival. These first results make PSMA a promising target for future diagnosis and therapy of UCC. [ABSTRACT FROM AUTHOR]

Arsenic is an environmental toxicant with long-term exposure associated with the development of urothelial carcinomas. Our lab has developed an in-vitro model of urothelial carcinoma by exposing the immortal, but non-tumorigenic bladder cell line, the UROtsa, to arsenite (As3+). These transformed cells form tumors in immune-compromised mice, which resemble urothelial carcinomas with components of the tumor exhibiting squamous differentiation. The goal of the present study was to determine the differences in global gene expression patterns between the As3+-transformed UROtsa cells and the urospheres (spheroids containing putative cancer initiating cells) isolated from these cell lines and to determine if the genes involved in the development of squamous differentiation were enriched in the urospheres. The results obtained in this study show an enrichment of genes such as KRT1, KRT5, KRT6A, KRT6B, KRT6C, KRT14 and KRT16 associated with squamous differentiation, a characteristic feature seen in aggressive basal subtypes of urothelial cell carcinoma (UCC) in the urospheres isolated from As3+-transformed UROtsa cells. In addition, there is increased expression of several of the small proline-rich proteins (SPRR) in the urospheres and overexpression of these genes occur in UCC's displaying squamous differentiation. In conclusion, the cancer initiating cells present in the urospheres are enriched with genes associated with squamous differentiation. • UROtsa cells transformed with arsenite show areas of squamous differentiation. • Urospheres are enriched in squamous differentiation and keratinization genes. • There is lack of stability in the urosphere gene expression pattern. • Epigenetic regulation does not play a role in maintaining urosphere gene expression. [ABSTRACT FROM AUTHOR]

Environmental and occupational exposure to polycyclic aromatic hydrocarbons (PAHs) is associated with adverse health effects in humans. Uncertainty exists regarding the causation of urinary bladder cancer by benzo[ a ]pyrene (B[ a ]P) due to a lack of sufficient data. In this work, we focused on in-vitro DNA damage and the formation of micronuclei and chromosomal aberrations as predictors of cancer risk, applying a wide range of dosages and time periods to quantify the onset, intensity, and duration of the response. We chose two urothelial cell types to compare susceptibility and the ability to increase the malignity of a pre-existing bladder cancer: a cancer cell line (T24) and a pooled sample of primary urinary bladder epithelia cells (PUBEC) from pigs. The highest level of DNA damage assessed by comet assay was observed following 24-h treatment in both cell types, whereas PUBEC cells were clearly more susceptible. Even 4-h treatment induced DNA damage in PUBEC cells with benchmark doses of 0.0027 µM B[ a ]P and 0.00023 µM after 4-h and 24-h exposure, respectively. Nearly no effect was observed for periods of 48 h. The frequency of micronucleus formation increased more markedly in T24 cells, particularly with 24-h treatment. In PUBEC cells, 48-h exposure notably induced the formation of nucleoplasmic bridges and nuclear buds. Even though only one biological replicate was studied due to the sophisticated study design, our results give a strong indication of the potential of B[ a ]P to induce and increase malignity in human-relevant cell types. • Wide range of benzo[ a ]pyrene (B[ a ]P) exposure time and dose. • DNA damage caused by benzo[ a ]pyrene in two urothelial cell types – PUBEC and T24. • Comet assay and Micronucleus assay combined to assess DNA damage in urothelial cells caused by B[ a ]P. • Primary urothelial cells more susceptible to B[ a ]P DNA damage than urinary tumor cells. [ABSTRACT FROM AUTHOR]

Purpose: To compare frequency of new and recurrent urothelial cell carcinoma (UCC) among patients with and without pseudodiverticulosis on imaging.Methods: This retrospective case-control study compared all 113 sequential patients with ureteral pseudodiverticulosis on radiographic urography between 1/1/2002 and 12/31/2012. Six patients were lost to follow-up. 107 patients without pseudodiverticulosis were matched by imaging modality, clinical indication, and tumor grade. Known UCC and primary outcome of new or recurrent UCC were determined through pathology on cystoscopy or clinical follow-up.Results: Nearly half of patients with pseudodiverticulosis had known UCC at the time of imaging (49/107, 46%). Mean cystoscopy follow-up was 7.0 and 4.6 years for pseudodiverticulosis cases with and without known UCC, respectively, and 7.5 and 7.3 years for controls, respectively. Mean clinic follow-up was 7.5 and 6.0 years for pseudodiverticulosis cases with and without known UCC, respectively, and 6.4 and 7.6 years for controls, respectively. Among patients with known UCC at the time of imaging, similar rates of recurrent UCC were demonstrated on follow-up among patients with pseudodiverticulosis (6/49, 12%) and without (7/49, 14%). Among patients with no known history of UCC at the time of imaging, no patients with pseudodiverticulosis developed UCC on follow-up and 5% (3/58) of patients without pseudodiverticulosis developed UCC.Conclusion: Although half of patients with ureteral pseudodiverticulosis have a known diagnosis of UCC, the presence of pseudodiverticulosis did not signify an increased likelihood of developing new or recurrent UCC over the follow-up period. [ABSTRACT FROM AUTHOR]

This article presents methods to improve MR imaging approach of disorders of the renal sinus which are relatively uncommon and can be technically challenging. Multi-planar Single-shot T2-weighted (T2W) Fast Spin-Echo sequences are recommended to optimally assess anatomic relations of disease. Multi-planar 3D-T1W Gradient Recalled Echo imaging before and after Gadolinium administration depicts the presence and type of enhancement and relation to arterial, venous, and collecting system structures. To improve urographic phase MRI, concentrated Gadolinium in the collecting systems should be diluted. Diffusion-Weighted Imaging (DWI) should be performed before Gadolinium administration to minimize T2* effects. Renal sinus cysts are common but can occasionally be confused for dilated collecting system or calyceal diverticula, with the latter communicating with the collecting system and filling on urographic phase imaging. Vascular lesions (e.g., aneurysm, fistulas) may mimic cystic (or solid) lesions on non-enhanced MRI but can be suspected by noting similar signal intensity to the blood pool and diagnosis can be confirmed with MR angiogram/venogram. Multilocular cystic nephroma commonly extends to the renal sinus, however, to date are indistinguishable from cystic renal cell carcinoma (RCC). Solid hilar tumors are most commonly RCC and urothelial cell carcinoma (UCC). Hilar RCC are heterogeneous, hypervascular with epicenter in the renal cortex compared to UCC which are centered in the collecting system, homogeneously hypovascular, and show profound restricted diffusion. Diagnosis of renal sinus invasion in RCC is critically important as it is the most common imaging cause of pre-operative under-staging of disease. Fat is a normal component of the renal sinus; however, amount of sinus fat correlates with cardiovascular disease and is also seen in lipomatosis. Fat-containing hilar lesions include lipomas, angiomyolipomas, and less commonly other tumors which engulf sinus fat. Mesenchymal hilar tumors are rare. MR imaging diagnosis is generally not possible, although anatomic relations should be described to guide diagnosis by percutaneous biopsy or surgery. [ABSTRACT FROM AUTHOR]

Introduction: With the introduction of laparoscopy and now robotics, more patients are able to reap benefit from minimally invasive techniques during urologic surgery. With these advancing technologies, it is important to evaluate whether the outlay of hospital capital actually improves patient care. To date, there has been little literature regarding the impact of these advances on patient outcomes. In this article, we directly compare perioperative outcomes and hospital costs between the older da Vinci Standard/S/Si platform and the newer Xi robotic platform during nephroureterectomy. Methods: A review of our robotic nephroureterectomy database between April 2009 and December 2017 identified 87 patients, 30 in group 1 (Xi) and 57 in group 2 (Standard/S/Si). Preoperative, perioperative, and postoperative parameters as well as hospital costs were evaluated. Independent t-test was performed for continuous variables, while categorical variables were evaluated using chi-square tests or Fisher's exact test. Results: There were no significant differences between groups preoperatively. Operative time using the Xi was shorter, 184.4 vs 232.09 minutes ( p = 0.0035). Other perioperative variables were similar. There was more lymphovascular invasion in group 2 ( p = 0.0108), but there were higher stage tumors in group 1 ( p < 0.0001). More patients underwent lymph node dissection in group 1 ( p = 0.0186). Complications were similar between groups. Costs for anesthesia were less in group 1, which led to decreased total hospitalization costs ( p < 0.001) Conclusion: Operative times were found to be less with the daVinci Xi, without any other significant difference in patient outcomes between the groups. Anesthesia and operating room cost were substantial factors in lowering the overall hospital costs. More multi-institutional studies with larger groups of patients are needed to determine if advancing technology really improves outcomes. [ABSTRACT FROM AUTHOR]

Urothelial Cell Carcinoma (UCC), also called transitional cell carcinoma of the bladder, is the most common malignancy in urinary tract. The prognosis of this disease is highly dependent on the histological grading at diagnosis. Fas/CD95 has a role in apoptotic process, whereas HSP70 has an antiapoptotic role. This study aimed to analyze the expression of Fas/CD95 and HSP70 in low grade and high grade urothelial cell carcinoma in the bladder. This was an analytic observational study with cross sectional approach. Population and sample were paraffin blocks of urothelial cell carcinoma in the Laboratory of Anatomic Pathology, Dr. Soetomo Hospital, Surabaya in the period of January 2011-December 2016. Each grading of urothelial cell carcinoma was randomly sampled. Immunohistochemystry with Fas/CD95 and HSP70 were performed. Expression of Fas/CD95 and HSP70 were assessed semiquantitatively. Expression of Fas/CD95 and HSP70 were analyzed using Mann-Whitney test and Spearman test. The results showed there was significant different in expression of Fas/CD95 and HSP70 in low and high grades in urothelial cell carcinoma. There was no significant correlation between the expression of Fas/CD95 and HSP70 in urothelial cell carcinoma. As a conclusion, the role of CD95 and HSP70 expression can be useful as marker for the diagnosis, especially in the determination of the grade of differentiation. [ABSTRACT FROM AUTHOR]

Background BK polyomavirus ( BKPyV) reactivation is a common clinical occurrence in kidney transplant recipients ( KTR). Several other polyomaviruses have been implicated as pathogens with a direct role in the development of malignancies, raising the question of whether BKPyV might also be oncogenic. Methods This study is the first retrospective, multicenter cohort study evaluating the relative risk for urothelial cell carcinoma ( UCC) associated with BKPyV infection among KTR, and was conducted among veterans who underwent transplantation between 2000 and 2009. BKPyV cases were defined as those veterans with any clinical evidence of BKPyV infection, including positive polymerase chain reaction testing of urine and/or serum for BKPyV or kidney biopsy showing BKPyV-associated nephropathy. Results Among the 646 veterans who met inclusion criteria for the study, 103 had clinical evidence of BKPyV infection (16%). The overall relative risk for developing any malignancy after BKPyV infection was 1.13 (95% confidence interval [ CI] 0.89-1.44). The adjusted relative risk for malignancy after BKPyV infection was greatest with UCC (8.21, 95% CI 0.75-89.7) and with metastatic disease of unknown etiology (8.21, 95% CI 0.75-89.7). The screening prevalence for BKPyV infection increased from 18% for those veterans who underwent transplantation in 2000 to 86% for those veterans who underwent transplantation in 2009, during which time the measured prevalence of BKPyV infection increased from 7% to 24%. Conclusion In this cohort of KTR veterans, no overall increased or decreased relative risk for malignancy was associated with evidence of prior BKPyV infection. A >8-fold increased risk of developing UCC after BKPyV infection was seen, although this risk was not found to be statistically significant. [ABSTRACT FROM AUTHOR]

BACKGROUND: Ring Box Protein-1 (RBX-1), a component of SCF E3 ubiquitin ligases, has a crucial role in bladder urothelial cell carcinoma (UCC) carcinogenesis and progression. OBJECTIVES: In the present study, it is aimed to determine the expression of RBX-1 protein in bladder UCC and the association between tumor grade, stage and RBX-1 expression. METHODS: Ninety UCC samples and 20 samples containing foci of normal bladder urothelium were recruited and analyzed immunohistochemically in terms of RBX-1 expression. Immuno-reactivity scoring system (IRS) was used to determine RBX-1 expression levels. RESULTS: RBX-1 overexpression was associated with high tumor grade (p = 0.001) and advanced stage (p = 0.001). pT1 tumors showed higher RBX-1 expression than pTa tumors. pT2 tumors showed not only higher expression than pTa tumors but also higher expression than the total of pTa and pT1 groups combined. There was no statistically significant relation between RBX-1 expression and patient gender (p = 0.116) or age (p = 0.191). CONCLUSIONS: In bladder UCC, RBX-1 overexpression is associated with high tumor grade and advanced stage and represents biological potential of invasiveness and aggressive disease. Results of the present study have to be supported with further studies to reveal clinical and therapeutic implications of RBX-1 overexpression in bladder UCC. [ABSTRACT FROM AUTHOR]

In this retrospective pilot study, the feasibility of the epithelial cell adhesion molecule (EpCAM) as an imaging target for lymph node (LN) metastatic disease of urothelial cell carcinoma (UCC) of the bladder was investigated. LN metastases and LNs without metastases of patients who underwent pelvic lymph node dissection because of muscle invasive bladder cancer (MIBC) were used. Primary tumors of the same patients were used from cystectomy specimen, transurethral resections, and biopsies. A pathologist, blinded to clinical data, scored EpCAM immunoreactivity. This method determines a total immunostaining score, which is the product of a proportion score and an intensity score. EpCAM expression was observed in 19/20 (95%) LNs with UCC metastases and in 11/12 (92%) of the primary tumors. EpCAM expression was absent in 14/14 (100%) LNs without metastases. Median EpCAM expression (TIS) in LN metastases was 5 (IQR 2.0-8.0) and in the primary tumors 6 (IQR 2.3-11.0). Based on the absence of staining in LNs without metastases, EpCAM show high tumor distinctiveness. EpCAM seems to be a feasible imaging target in LN metastases of UCC of the bladder. Pre- and perioperative visualization of these metastases will improve disease staging and improve the complete resection of LN metastases in MIBC. [ABSTRACT FROM AUTHOR]

Background: Current first-line standard of therapy for metastatic urothelial carcinoma is platinum-based combination chemotherapy. Pembrolizumab in phase III has demonstrated a promising overall response rate of 21.1% in patients with progression or recurrence after platinum-based chemotherapy. Preclinical and clinical evidence suggests that radiotherapy has a systemic anti-cancer immune effect and can increase the level of PD-L1 and tumor infiltrating lymphocytes in the tumor microenvironment. These findings gave rise to the hypothesis that the combination of radiotherapy with anti-PD1 treatment could lead to a synergistic effect, hereby enhancing response rates.Methods: The phase I part will assess the dose limiting toxicity of the combination treatment of stereotactic body radiotherapy (SBRT) with four cycles of pembrolizumab (200 mg intravenously, every 3 weeks) in patients with metastatic urothelial carcinoma. The dose of both pembrolizumab and SBRT will be fixed, yet the patients will be randomized to receive SBRT either before the first cycle of pembrolizumab or before the third cycle of pembrolizumab. SBRT will be delivered (24 Gy in 3 fractions every other day) to the largest metastatic lesion. Secondary objectives include response rate according to RECIST v1.1 and immune related response criteria, progression-free survival and overall survival. The systemic immune effect triggered by the combination therapy will be monitored on various time points during the trial. The PD-L1/TIL status of the tumors will be analyzed via immunohistochemistry and response rates in the subgroups will be analyzed separately. A Simon's two-stage optimum design is used to select the treatment arm associated with the best response rate and with acceptable toxicity to proceed to the phase II trial. In this phase, 13 additional patients will be accrued to receive study treatment.Discussion: The progress made in the field of immunotherapy has lead to promising breakthroughs in various solid malignancies. Unfortunately, the majority of patients do not respond. The current trial will shed light on the toxicity and potential anti-tumor activity of the combination of radiotherapy with anti-PD1 treatment and may identify potential new markers for response and resistance to therapy. Trial registration this trial is registered on clinicaltrials.gov (NCT02826564). [ABSTRACT FROM AUTHOR]

As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single-strand or double-strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or, after a latency period, cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. Although the application of PARP inhibitors (PARPis) initially focused on tumors with BRCA1 or BRCA2 deficiencies, synthetic susceptibilities to PARPis have been expanded due to the identification of tumors with mutations pathways involved in DNA damage repair, in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder cancer and especially prostate cancer, contain subsets of patients with germline and somatic alterations in HR genes that may reflect an increased response to PARPis. In this review, the authors describe the mechanisms and rationale of the use of PARPis in patients with GU cancers, summarize previously reported preclinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can have widespread application in patients with GU cancers. Cancer 2017;123:1912-1924. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Minimally invasive therapy for upper tract urothelial cell cancer has assumed an important role in the management of this relatively uncommon genitourinary malignancy. In this review, current standards for patient selection, surgical approach, as well as overall outcomes will be discussed. Moreover, the use of intraluminal agents in upper tract disease is examined along with its efficacy and associated complications. [ABSTRACT FROM AUTHOR]

Urinary bladder carcinoma (UBC) is the ninth most common malignancy and the second most common urological malignancy after prostate cancer in men. Thoracic metastases occur in more than half of those with muscle-invasive disease, and these generally assume the form of multiple solid parenchymal lesions characteristic of hematogenous seeding of the lung. Unusual patterns of thoracic spread of UBC have also been described albeit sporadically in the form of case reports and series. The aim of our case series is to provide illustrations of several atypical patterns of thoracic involvement by UBC such as isolated mediastinal lymphadenopathy, cavitary lung metastases, malignant pleural effusion, endobronchial disease, and pulmonary tumor embolism. This review is meant to highlight the intersection of the fields of urological oncology and thoracic radiology in the care of patients with UBC. [ABSTRACT FROM AUTHOR]

Utilizing a polymorphism ratio sequencing platform, we performed a complete somatic mutation analysis of the mitochondrial D-loop region in 14 urothelial cell carcinomas. A total of 28 somatic mutations, all heteroplasmic, were detected in 8 of 14 individuals (57.1 %). Insertion/deletion changes in unstable mono- and dinucleotide repeat segments comprise the most pervasive class of mutations (9 of 28), while two recurring single-base substitution loci were identified. Seven variants, mostly insertion/deletions, represent population shifts from a heteroplasmic germline toward dominance in the tumor. In four cases, DNA from matched urine samples was similarly analyzed, with all somatic variants present in associated tumors readily detectable in the bodily fluid. Consistent with previous findings, mutant populations in urine were similar to those detected in tumor and in three of four cases were more prominent in urine. Key messages: [ABSTRACT FROM AUTHOR]

Intravesical Bacillus Calmette-Guérin (BCG) has long been the gold standard treatment of nonmuscle invasive bladder cancer. Recently, there has been an emergence of novel immunotherapeutic agents, which have shown promise in the treatment of urothelial cell carcinoma. These agents aim to augment, modify, or enhance the immune response. Such strategies include recombinant BCG, monoclonal antibodies, vaccines, gene therapy, and adoptive T-cell therapy. Here, we review the emerging immunotherapeutics in the treatment of nonmuscle invasive bladder cancer. [ABSTRACT FROM AUTHOR]

Objectives To describe our robot-assisted nephroureterectomy ( RNU) technique for benign indications and RNU with en bloc excision of bladder cuff ( BCE) and lymphadenectomy ( LND) for malignant indications using the da Vinci Si® and da Vinci Xi robotic platform, with its pros and cons. The port placement described for Si can be used for standard and S robotic systems. This is the first report in the literature on the use of the da Vinci Xi robotic platform for RNU. Patients and Methods After a substantial experience of RNU using different da Vinci robots from the standard to the Si platform in a single-docking fashion for benign and malignant conditions, we started using the newly released da Vinci Xi robot since 2014. The most important differences are in port placement and effective use of the features of da Vinci Xi robot while performing simultaneous upper and lower tract surgery. Patient positioning, port placement, step-by-step technique of single docking RNU- LND- BCE using the da Vinci Si and da Vinci Xi robot are shown in an accompanying video with the goal that centres using either robotic system benefit from the hints and tips. The first segment of video describes RNU- LND- BCE using the da Vinci Si followed by the da Vinci Xi to highlight differences. There was no need for patient repositioning or robot re-docking with the new da Vinci Xi robotic platform. Results We have experience of using different robotic systems for single docking RNU in 70 cases for benign (15) and malignant (55) conditions. The da Vinci Xi robotic platform helps operating room personnel in its easy movement, allows easier patient side-docking with the help of its boom feature, in addition to easy and swift movements of the robotic arms. The patient clearance feature can be used to avoid collision with the robotic arms or the patient's body. In patients with challenging body habitus and in situations where bladder cuff management is difficult, modifications can be made through reassigning the camera to a different port with utilisation of the retargeting feature of the da Vinci Xi when working on the bladder cuff or in the pelvis. The vision of the camera used for da Vinci Xi was initially felt to be inferior to that of the da Vinci Si; however, with a subsequent software upgrade this was much improved. The base of the da Vinci Xi is bigger, which does not slide and occasionally requires a change in table placement/operating room setup, and requires side-docking especially when dealing with very tall and obese patients for pelvic surgery. Conclusions RNU alone or with LND- BCE is a challenging surgical procedure that addresses the upper and lower urinary tract simultaneously. Single docking and single robotic port placement for RNU- LND- BCE has evolved with the development of different generations of the robotic system. These procedures can be performed safely and effectively using the da Vinci S, Si or Xi robotic platform. The new da Vinci Xi robotic platform is more user-friendly, has easy installation, and is intuitive for surgeons using its features. [ABSTRACT FROM AUTHOR]

Malignancies in the renal pelvis are rare and few cases have been described in the literature till date. They present in various morphologies which cause diagnosis dilemma due to their close resemblance to other benign and malignant lesions. Histopathology has a major role in diagnostics since recognition of the morphological variant is important for prognostic and treatment stratification. We report a case of urothelial carcinoma of the renal pelvis with extensive glandular differentiation in a 48‑year‑old male. [ABSTRACT FROM AUTHOR]

Objectives Patients diagnosed with bladder carcinoma in situ ( CIS) and treated with intravesical Bacillus Calmette-Guerin ( BCG) often undergo post-induction random bladder biopsies to assess treatment response. We sought to determine the correlation between post-induction urinary cytology/cystoscopy and histopathological findings obtained by random bladder biopsies. Methods Patients who were treated with BCG between 2006 and 2010 for CIS, had surveillance cystoscopy and cytology, and subsequently underwent random bladder biopsies were selected for analysis. Patients with a history of or concomitant urothelial cell carcinoma ( UCC) stage T1 or higher were excluded. Cystoscopic finings were characterized as follows: negative - no mucosal erythema, raised lesions or papillary tumours; suspicious - mucosal erythema, but no raised lesions or papillary tumours; and positive - sessile or papillary tumours. The accuracy of cytology in predicting the results of subsequent random bladder biopsies was analysed. Results Of 21 patients included, surveillance cystoscopy findings were characterized as negative in nine, suspicious in seven and positive in five. Of 16 patients with negative/suspicious cystoscopy, 13 had agreement between cytology and biopsy, nine of whom were negative and four positive. Three of 16 patients had positive cytology, but negative biopsies; on further investigation of these three, one had CIS and two subsequent UCC. In the positive cystoscopy group, four of five patients had agreement between cytology and biopsy, two of whom were negative and two positive. One of the five patients had negative cytology, but a positive biopsy. Conclusion Our data suggest foregoing random bladder biopsies in patients with negative urine cytology and no evidence of intravesical recurrence on cystoscopy following an induction course of BCG for CIS of the urinary bladder. [ABSTRACT FROM AUTHOR]

BACKGROUND In the Western world, bladder cancer is the fourth most common cancer in men and the eighth most common in women. Recurrences frequently occur, and continued surveillance is necessary to identify and treat recurrent tumors. Efforts to identify risk factors that are potentially modifiable to reduce the rate of recurrence are needed. METHODS Cigarette smoking behavior and body mass index were investigated at diagnosis for associations with bladder cancer recurrence in a population-based study of 726 patients with bladder cancer in New Hampshire, United States. Patients diagnosed with non-muscle invasive urothelial cell carcinoma were followed to ascertain long-term prognosis. Analysis of time to recurrence was performed using multivariate Cox regression models. RESULTS Smokers experienced shorter time to recurrence (continuing smoker hazard ratio [HR] = 1.51, 95% confidence interval [CI] = 1.08-2.13). Although being overweight (body mass index > 24.9 kg/m2) at diagnosis was not a strong independent factor (HR = 1.33, 95% CI = 0.94-1.89), among continuing smokers, being overweight more than doubled the risk of recurrence compared to smokers of normal weight (HR = 2.67, 95% CI = 1.14-6.28). CONCLUSIONS These observational results suggest that adiposity is a risk factor for bladder cancer recurrence, particularly among tobacco users. Future intervention studies are warranted to evaluate whether both smoking cessation and weight reduction strategies reduce bladder tumor recurrences. Cancer 2014;120:408-414. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

A review of the literature was performed to summarize current evidence regarding the efficacy of topical immunotherapy and chemotherapy for upper urinary tract urothelial cell carcinoma (UUT-UCC) in terms of post-treatment recurrence rates. A Medline database literature search was performed in March 2012 using the terms upper urinary tract, urothelial cancer, bacillus Calmette-Guérin (BCG), and mitomycin C. A total of 22 full-text articles were assessed for eligibility, and 19 studies reporting the outcomes of patients who underwent immunotherapy or chemotherapy with curative or adjuvant intent for UUT-UCC were chosen for quantitative analysis. Overall, the role of immunotherapy and chemotherapy for UUT-UCC is not firmly established. The most established practice is the treatment of carcinoma in situ (CIS) with BCG, even if a significant advantage has not yet been proven. The use of BCG as adjuvant therapy after complete resection of papillary UUT-UCC has been studied less extensively, even if recurrence rates are not significantly different than after the treatment of CIS. Only a few reports describe the use of mitomycin C, making it difficult to obtain significant evidence. [ABSTRACT FROM AUTHOR]

Purpose: The utility of the expression of glucose-regulated protein 78 (GRP78) in the evaluation of prognosis depends on the type of tumor. Hence, we aimed to examine the impact of expression of GRP78 and Bcl-2, which are used in the existing prognostic evaluation of ureter tumors, in the evaluation of recurrence and survival rates of ureter tumors. Materials and Methods: In 53 patients who had undergone radical nephroureterectomy for a ureter tumor from March 2002 to March 2012, age, sex, T stage, nuclear grade, bladder recurrence, and survival rate were analyzed at the time of the patient's surgery depending on the extent of immunohistochemical expression of GRP78 and Bcl-2. Results: GRP78 was overexpressed in 25 patients (47.2%). When GRP78 was overexpressed, there was a high T stage (p=0.001) and nuclear grade (p=0.007) and a lot of bladder recurrence (40.0%, p=0.034). Bcl-2 was overexpressed in 16 patients (30.1%), and there were no significant associations with any risk factors (p>0.05, respectively). In the multivariate analysis regarding bladder recurrence, the recurrence rate was higher with higher pT stage (p=0.048) and when GRP78 (p=0.033) was overexpressed. In the Kaplan-Meier survival analysis, although the survival rate was significantly lower in the group in which GRP78 was overexpressed (p=0.03), there was no correlation between Bcl-2 overexpression and survival rate (p=0.07). Conclusions: Patients with ureter tumors who had overexpression of GRP78 had a high T stage and nuclear grade, a lot of bladder recurrence, and a low survival rate. Therefore, if GRP78 is overexpressed in ureter tumor patients, active postoperative follow-up should be carried out. [ABSTRACT FROM AUTHOR]

Background: Extrapulmonary small cell carcinomas have been reported in a variety of organs, and their incidence in the genitourinary tract is second only to that in the gastrointestinal tract. To date, however, only a few cases of small cell carcinoma of the ureter have been reported. Because the extreme rarity of this type of carcinoma, its clinical behaviour, diagnostic methods, and effective treatment modalities have not yet been determined. Case presentation: A 59-year-old man presented with a 1-month history of painless gross haematuria. Urine cytopathology revealed a urothelial carcinoma and computed tomography revealed left hydronephroureterosis with a distal ureteral stone and a mildly enhanced fungating mass just below the stone-impacted site. The preoperative TNM stage was T2N0M0. The patient underwent simultaneous diagnostic ureterorenoscopy and left laparoscopic nephroureterectomy with bladder cuff resection. Gross examination showed a 3.5 × 3.0 × 0.8 cm white, partly yellow mass in the left distal ureter. Light microscopy showed a small cell carcinoma, overlaid on a urothelial carcinoma in situ, invading the ureter and external lateral resection margins. The small cell carcinoma was diffusely positive for neuron-specific enolase, and exhibited focal positivity for CD 56, synaptophysin, chromogranin and cytokeratin 20. The patient was treated with adjuvant chemotherapy, consisting of cisplatin and etoposide, and radiation therapy, and has been well, without evidence of tumour recurrence or metastasis in the 10 months after surgery. Conclusion: Small cell carcinoma of the ureter is rare. Although its clinical behaviour and diagnostic modalities have not been determined and it has yet to be diagnosed immunohistopathologically, multimodality treatment including surgery, chemotherapy and radiotherapy may improve patient survival. [ABSTRACT FROM AUTHOR]

Purpose: Although cisplatin-based chemotherapy is the standard of care for advanced transitional cell carcinoma, tolerability is a challenging issue in unfit patients. This study was conducted to evaluate the efficacy, toxicity, and tolerability of the combination of gemcitabine and carboplatin in unfit patients with advanced transitional cell carcinoma. Methods: Thirty-one patients who had advanced transitional cell carcinoma and one of the following clinical features were evaluated: Eastern Cooperative Oncology Group performance status equal or greater than 2, age older the 75 years or estimated glomerular filtration rate less than 60 ml/min. The patients were treated with carboplatin and gemcitabine delivered every 4 weeks. Results: Of the 31 patients, 71 % had an estimated glomerular filtration rate of less than 60 ml/min, and the remaining patients were treated by this protocol due to poor performance status or age older than 75. The median age of the patients was 74 years old. A total of 162 cycles of treatment were delivered to the patients. The overall response rate was 45.1 %. After the median follow-up of 15 months, the median progression-free survival time was 9.4 months (95 % CI 7.3-11.4) and overall survival time was 20 months (95 % CI 14.9-25.0). Grades 3 and 4 anemia, thrombocytopenia, and neutropenia were observed in 22.6, 6.45, and 6.45 % of patients, respectively. There was no treatment-related mortality in our patient series. Conclusion: The combination of gemcitabine and carboplatin is effective in elderly patients with advanced transitional cell carcinoma or those unfit for cisplatin-based chemotherapy, with manageable toxicity. [ABSTRACT FROM AUTHOR]

Background: We determined the differently expressed protein profiles and their functions in bladder cancer tissues with the aim of identifying possible target proteins and underlying molecular mechanisms for taking part in their progression. Methods: We examined the expression of proteins by proteomic analysis and western blot in normal urothelium, non-muscle-invasive bladder cancers (NMIBCs), and muscle-invasive bladder cancers (MIBCs). The function of cofilin was analyzed using T24 human bladder cancer cells. Results: The expression levels of 12 proteins were altered between bladder cancers and normal bladder tissues. Of these proteins, 14-3-3σ was upregulated in both NMIBCs and MIBCs compared with controls. On the other hand, myosin regulatory light chain 2, galectin-1, lipid-binding AI, annexin V, transthyretin, CARD-inhibitor of NF-κB-activating ligand, and actin prepeptide were downregulated in cancer samples. Cofilin, an actin-depolymerizing factor, was prominent in both NMIBCs and MIBCs compared with normal bladder tissues. Furthermore, we confirmed that cofilin phosphorylation was more prominent in MIBCs than in NMIBCs using immunoblotting and immunohistochemcal analyses. Epidermal growth factor (EGF) increased the phosphorylation of cofilin and elevated the migration in T24 cells. Knockdown of cofilin expression with small interfering RNA attenuated the T24 cell migration in response to EGF. Conclusions: These results demonstrate that the increased expression and phosphorylation of cofilin might play a role in the occurrence and invasiveness of bladder cancer. We suspected that changes in cofilin expression may participate in the progression of the bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To identify the expression profile of early recurring non-muscle-invasive bladder cancer (NMI-BC). Materials and methods: We selected primary NMI-BC according to the following criteria: complete resection, primary occurrence of urothelial cell carcinoma, stage cTa or T1, low grade, no carcinoma in situ. All patients underwent a transurethral resection of the bladder and were followed according to the Guidelines of European Association of Urology. Expression of 110 target genes was studied by using real time quantitative RT-PCR. The correlation between the absolute expression and early recurrence was analyzed by using a Cox regression model. The ability of a gene to distinguish the tumors with early recurrence from those with late recurrence was determined by using a ROC-AUC test. A hierarchical classification was established by using the software of GeneANOVA and tested by a χ2 test. Results: Forty-seven tumors were studied: 25 with early recurrence vs. 22 with late or null recurrence. These 2 groups of tumors have a significantly different expression profile in 3 genes among the 110-gene expression profile: peroxysome proliferator-activated receptor-γ (PPARG) (P = 0.031), stathmin-1 (STMN1) (P = 0.041), Caveolin-2 (CAV2) (P = 0.004). The combination of the expression of these 3 genes was significantly predictive for early recurrence leading to a correct hierarchical classification of the NMI-BC regarding the time-to-recurrence (P < 0.001). Conclusions: This study identifies a concise 3-gene panel that is associated with time to recurrence. This 3-gene signature has to be confirmed in a prospective study and in larger cohort of patients. However, our preliminary results are promising and gene expression profiling seems to be an interesting approach in cTa-T1 tumors for recurrence prediction. [Copyright &y& Elsevier]

Abstract: Objectives: To investigate whether overexpression of p53, MIB-1, and Aurora-A on protein level played a role in the relapse of urothelial carcinomas of the upper urinary tract (UC-UUT). Materials and methods: The following data from the files of 42 patients treated for UC-UUT were collated: age, prior history of cancer, tumor stage and grade, and disease progression. Immunohistochemistry (IHC) for p53, MIB-1, and Aurora-A was performed on tissue microarray sections from tumor tissue. Results: Patients aged 46 to 100 years (mean 70.6 years). Overall, 23 (54%) patients died from progression of UT-UCC. The surgical stage was significantly associated with MIB-1 and Aurora-A overexpression (P = 0.004 for each). Univariate analysis showed that relapse was significantly associated with ureteral localization (P = 0.02), the presence of vascular invasion (VI) (P = 0.003), high grade (P = 0.04), high stage UT-UCCs (P = 0.02), and p53 (P = 0.01), Aurora-A (P = 0.01), and MIB-1 overexpression (P = 0.02). In multivariate analysis, relapse was associated with high grade (P = 0.04), high stage (P = 0.04), VI (P < 0.0001, respectively), and p53 (P = 0.04) and Aurora-A (P = 0.02) overexpression but not with MIB-1 overexpression (P = 0.06). In addition, expressions of p53, MIB-1, and Aurora-A were significantly associated with presence of VI (P = 0.008, P = 0.001, and P = 0.003, respectively). Conclusion: Aurora-A and p53 are important factors in UC-UUT development and might be useful as independent factors for predicting clinical outcome and presence of VI. Aurora-A seems to influence the development of VI and tumor aggressiveness via a mechanism not clearly elucidated yet. [Copyright &y& Elsevier]

Background. Aristolochic acid I (AAI) has been implicated in urothelial cell carcinoma (UCC) in humans. However, whether AAI promotes invasion/migration of UCC has not been established. Methods. A study of human UCC TSGH cells cultured with AAI was conducted. Cell viability, the effects of AAI on the activity of matrix metalloproteinase (MMP)-9, the abilities of invasion/migration and the migration-related proteins (Ras, RhoA, ROCK1, PI-3K, pAkt and nuclear factor-kappaB) of the TSGH cells were assessed. The TSGH cells were subcategorized to 1-day or 30-day AAI exposure. An in vivo study using a nude mice xenograft model was employed to test the antitumor effects of Rho kinase inhibitor or Y27632. Results. A time- and dose-dependent increase in both activity and messenger RNA (mRNA) level of MMP-9 were demonstrated. The mRNA level of urokinase-type plasminogen activator was increased and tissue inhibitor of metalloproteinase-1 was decreased in the cells with 30-day but not 1-day AAI exposure. A dose-dependent enhancement in wound-healing rate and cell migration was demonstrated, especially in the 30-day AAI-exposed cells. Expressions of Ras/RhoA and other migration-related proteins were increased after AAI treatment, which could be inhibited by Y27632. The in vivo results demonstrated that Y27632 was able to attenuate the speed of growth of the inoculated tumors in nude mice. Conclusion. Clinically, the patients with prolonged AAI exposure are highly associated UCC, our results provided in vitro and in vivo evidence that prolonged AAI exposure enhances invasion and migration of human TSGH cells. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: Apaziquone used intravesically showed significant activity in phase I and II marker lesion studies in non-muscle-invasive bladder cancer. The objective of this study was to assess antitumor activity and safety of 3 different formulations of intravesical apaziquone in an orthotopic rat bladder cancer model. Materials and methods: Female Fischer F344 rats were instilled with 1.5 × 106 AY-27 urothelial cell carcinoma cells and divided in 3 treatment groups (n = 10) and 1 placebo group (n = 6). Intravesical treatment was administered for 1 hour on days 2 and 5. Rats were treated with apaziquone in the formulation used in phase I/II clinical trials (group 1); apaziquone with an altered buffering capacity being used in phase III clinical trials (group 2), and apaziquone as in group 2, but without propylene glycol in the diluent (group 3). On days 5 and 14, the bladder wall was inspected by cystoscopy and evaluated for macroscopic tumor growth. After sacrificing the rats (day 14), cystectomy was performed and the bladders were investigated. Results: There were no signs of any toxicity due to the study drug. On histopathologic examination of the bladders 0, 1, and 2 tumors per group were found in group 1, 2, and 3, respectively. In the placebo-treated group, 60% of animals developed tumor, which is comparable to untreated animals. Conclusions: Apaziquone showed an excellent antitumor activity. The effectiveness of apaziquone in this orthotopic rat bladder tumor model corroborates the clinical observations and implies the validity of this model. [Copyright &y& Elsevier]

Background: Parvin-beta (ParvB), a potential tumour suppressor gene, is a focal adhesion protein. We evaluated the role of ParvB in the upper urinary tract urothelial cell carcinoma (UUT-UC).Methods: ParvB mRNA and proteins levels in UUT-UC tissue were investigated by quantitative real-time polymerase chain reaction and western blot analysis, respectively. In addition, the expression of ParvB in tissues from patients with UUT-UC at different stages was evaluated by immunohistochemistry. Furthermore, biological functions of ParvB in urothelial cancer cells were investigated using a doxycycline-inducible overexpression system and siRNA.Results: Western blot and mRNA analysis showed downregulation of ParvB expression in frozen UUT-UC tissue. Immunohistochemistry revealed high staining intensity of ParvB in normal urothelium, which decreased markedly at advanced stages of UUT-UC (P=0.0000). Moreover, ParvB was an independent prognostic indicator for disease-specific survival of patients with UUT-UC. Functional assays indicated that overexpression of ParvB in an urothelial cancer cell line resulted in decreased cell growth rate and ability to migrate. In contrast, knockdown of ParvB expression increased cell migration ability.Conclusions: Downregulation of ParvB expression significantly increased urothelial cancer cell growth and migration. Downexpression of ParvB level in UUT-UC correlated with tumour stage, and was an independent unfavourable prognostic factor for disease-specific survival of patients with UUT-UC. [ABSTRACT FROM AUTHOR]

Abstract: Context: New developments in optical diagnostics have a potential for less invasive and improved detection of bladder cancer. Objective: To provide an overview of the technology and diagnostic yield of recently developed optical diagnostics for bladder cancer and to outline their potential future applications. Evidence acquisition: A PubMed literature search was performed, and papers on Raman spectroscopy (RS), optical coherence tomography (OCT), photodynamic diagnosis (PDD) and narrow-band imaging (NBI) regarding bladder cancer were reviewed. Technology, clinical evidence, and future applications of the techniques are discussed. Evidence synthesis: With RS, the molecular components of tissue can be measured objectively in qualitative and quantitative ways. The first studies demonstrating human in vivo applicability are still awaited. OCT produces high-resolution, cross-sectional images of tissue, comparable with histopathology, and provides information about depth of tumour growth. The first in vivo studies of OCT demonstrated promising diagnostic accuracy. RS and OCT are not suitable for scanning the entire bladder. PDD is a technique using fluorescence to indicate pathologic tissue. Several studies have shown that PDD increases the detection rate of bladder tumours and improves resection, resulting in fewer early recurrences. The relatively low specificity of PDD remains a problem. NBI enhances contrast of mucosal surface and microvascular structures. The NBI technique has clear advantages over PDD, and the two studies published to date have shown promising preliminary results. PDD and NBI do not contribute to histopathologic diagnosis. Conclusions: RS and OCT aim at providing a real-time, minimally invasive, objective prediction of histopathologic diagnosis, while PDD and NBI aim at improving visualisation of bladder tumours. For RS, OCT, and NBI, more research has to be conducted before these techniques can be implemented in the management of bladder cancer. All techniques might be of value in specific clinical scenarios. [Copyright &y& Elsevier]

Abstract: Objectives: The objective of this paper is to examine the contemporary incidence, diagnosis, and treatment of prostatic urothelial carcinoma and make recommendations on the current dilemmas of treating urothelial cancer of the prostate. Methods: A review of English-language literature from 1990 to the present was performed utilizing the U.S. National Library of Medicine''s Pub Med database. Keywords used were urothelial cell carcinoma, prostatic urethral involvement, prostatic duct/acini involvement, carcinoma in situ. Bibliographies of reviewed articles were also searched. Results: Transitional cell carcinoma of the bladder with involvement of the prostate has been reported in multiple studies with an incidence between 12% and 48%. Stromal invasion of the prostate has a reported incidence between 7% and 17%. The incidence of primary transitional cell carcinoma of the prostate has been estimated at 1% to 4% of prostatic malignancies. Degree and depth of prostatic invasion has prognostic significance with 5-year survival rates being 100% for those with urethral mucosal involvement, 50% with ductal/acinar involvement, and 40% with prostatic stromal invasion. The actual anatomic path that urothelial carcinoma invasion occurs also has prognostic significance. Those with contiguous malignant involvement had a 7% 5-year survival rate compared with those with noncontiguous involvement and a 46% 5-year survival rate. Conclusions: Prostatic urothelial carcinoma is often under appreciated and not well understood. Malignant involvement of different anatomic locations of the prostate (i.e., mucosa, ducts, acini, and stroma) influence not only diagnosis but treatment of disease. Although debate exists regarding optimal therapy for mucosal involvement, if the prostatic stroma is involved, radical cystoprostatectomy is the treatment of choice. [Copyright &y& Elsevier]

Bladder cancer is a major public health problem. Currently available therapeutic options seem to be unable to prevent bladder cancer recurrence and progression. To enable preclinical testing of new intravesical therapeutic agents, a suitable bladder tumor model that resembles human disease is highly desirable. The aim of this topic paper was to discuss the problems associated with current in vivo animal bladder tumor models, focusing on the orthotopic syngeneic rat bladder tumor model. In the second part of the paper the development of a potential new orthotopic rat bladder tumor model is described. [ABSTRACT FROM AUTHOR]

Urothelial cell carcinoma in situ (CIS) of the bladder is a superficially diffusive and highly discohesive disease. The authors analyzed the expression of some adhesion molecules (e-cadherin and Ep-CAM) and MUC1 in 32 unifocal and multifocal bladder urothelial cell CIS in an attempt to clarify this discohesion. E-cadherin was strongly expressed, in more than 75% of the cases. The presence of methylation of the CDH1 e-cadherin promoter gene was also investigated, but methylation was found in only one case. Ep-CAM was present in all the cases with a heterogeneous staining pattern. Similarly, MUC1/episialin was variously present in 94% of the cases without a polarized staining pattern and was expressed more strongly in cases with multifocal disease. Because loss of MUC1 polarization leads to interference with cell-cell adhesion mechanisms mediated by cadherins, these findings help explain why bladder urothelial cell CIS often shows a discohesive morphology and multifocality despite a strongly expressed adhesion molecule profile. Finally, Ep-CAM expression might provide some support for future target therapy trials. [ABSTRACT FROM AUTHOR]

Many markers for the detection of bladder cancers have been tested and almost all urinary markers reported are better than cytology with regard to sensitivity, but they score lower in specificity. Currently molecular and genetic changes play an important role in the discovery of new molecular markers for detection, prognostication and surveillance. The purpose of this review is to highlight the most important urinary molecular biomarker developments that have been studied and reported recently. In the current review we have summarized the most recent and relevant published reports on molecular urinary markers. The results of this review show that the first generation of urinary markers did not add much to urinary cytology. The current generation of markers is better, but additional clinical trials are needed. Our knowledge of molecular pathways in bladder cancer is growing and new methods of marker development emerge, but the perfect marker is still to be found. Currently, there are not clinically usable molecular markers that can guide us in diagnosis or surveillance, nor guide us in lowering the frequency of urethrocystoscopy in bladder cancer. [ABSTRACT FROM AUTHOR]

Abstract: Background: Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis. Objective: To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes. Design, setting, and participants: Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1–216 mo) or until death. Measurements: FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the χ2, Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model. Results and limitations: FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract. Conclusions: FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death. [Copyright &y& Elsevier]

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a zinc-binding endopeptidase, which plays a crucial role in tumour growth, invasion and metastasis. We have shown previously that MT1-MMP has higher expression levels in the human urothelial cell carcinoma (UCC) tissue. We show here that siRNA against MT1-MMP blocks invasion in UCC cell lines. Invasion is also blocked by broad-spectrum protease and MMP inhibitors including tissue inhibitor of metalloproteinase-1 and -2. Membrane type-1-MMP can also regulate transcription. We have used expression arrays to identify genes that are differentially transcribed when siRNA is used to suppress MT1-MMP expression. Upon MT1-MMP knockdown, Dickkopf-3 (DKK3) expression was highly upregulated. The stability of DKK3 mRNA was unaffected under these conditions, suggesting transcriptional regulation of DKK3 by MT1-MMP. Dickkopf-3 has been previously shown to inhibit invasion. We confirm that the overexpression of DKK3 leads to decreased invasive potential as well as delayed wound healing. We show for the first time that the effects of MT1-MMP on cell invasion are mediated in part through changes in DKK3 gene transcription. [ABSTRACT FROM AUTHOR]

OBJECTIVE To compare the potential of two diagnostic methods for detecting recurrence of urothelial cell carcinoma (UCC) of the bladder, by (i) detecting alterations in microsatellite DNA markers and loss of heterozygosity (LOH), and (ii) detecting aberrant gene hypermethylation, as UCC has a high recurrence rate in the urinary tract and the disease can invade muscle if new tumours are overlooked. PATIENTS AND METHODS Over 1 year, urine samples were retrieved from 40 patients already diagnosed with bladder UCC (30 pTa, two pTis, eight pT1). Samples were collected 6 months after bladder tumour resection, during the follow-up schedule. We used samples to analyse nine microsatellite markers and the methylation status of 11 gene promoters. Receiver operating characteristic curves were generated and Bayesian statistics used to create an interaction network between recurrence and the biomarkers. RESULTS During the study, 15 of the 40 patients (38%) had a tumour recurrence and 14 were identified by cystoscopy (reference method). Overall, microsatellite markers (area under curve, AUC 0.819, 95% confidence interval, CI, 0.677–0.961) had better performance characteristics than promoter hypermethylation (AUC 0.448, 0.259–0.637) for detecting recurrence. A marker panel of IFNA, MBP, ACTBP2, D9S162 and of RASSF1A, and WIF1 generated a higher diagnostic accuracy of 86% (AUC 0.92, 0.772–0.981). CONCLUSION Microsatellite markers have better performance characteristics than promoter hypermethylation for detecting UCC recurrence. These data support the further development of a combination of only six markers from both methods in urinary DNA. Once validated, it could be used routinely during the follow-up for the early detection and surveillance of UCC from the lower and upper urinary tract. [ABSTRACT FROM AUTHOR]