Bladder Cancer Recurrence In Patients Research Articles

The Effect of the HALP Score on the Development of Bladder Cancer Recurrence in Patients Undergoing Radical Nephroureterectomy for Upper Urinary Tract Tumours.

We aimed to investigate the effect of the haemoglobin, albumin, lymphocyte and platelet (HALP) score on pathologic results and bladder cancer recurrence (BCR) in patients operated for upper urinary tract tumours (UTUCs). HALP scores of all patients were calculated. Demographic data, preoperative blood parameters, pathologic data and the BCR development status of patients with low and high HALP scores were compared. Haemoglobin (11.2±2.3 g/dL vs. 12.9±2.4 g/dL), albumin (4.0±0.8 g/dL vs. 4.4±0.9 g/dL) and HALP score (38.2±2.9 vs. 43.4±3.1) were statistically lower in the BCR (+) group compared with the BCR (-) group (p<0.001). The ROC curve showed that the optimal cut-off point for the HALP score was 40.8. Multivariate analyses showed that the HALP score was effective on Tumour Grade, Tumour Stage, BCR. We have shown that patients with lower HALP scores have a more advanced stage and higher-grade pathologic outcomes and have a higher risk of developing BCR.

Abstract A011: Bladder cancerization is linked to epithelial basalization and is reversed by EGF inhibition

Abstract Introduction: Epithelial changes can extend beyond the boundaries of an incipient tumor, leading to cancer recurrence even after effective excision of the primary tumor. This ‘field cancerization’ and consequent high recurrence rate is especially pronounced in bladder cancer. The purpose of this study is to characterize the urothelium in the context of ‘field cancerization’ in a mouse model of bladder cancer as well as in patients with bladder cancer and to determine if reversal of the field effect will prevent tumor formation. Results: We investigated field cancerization by single cell transcriptomics (scRNA-Seq) in a murine (male FVB mice) bladder carcinogenesis model using N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) and found that prior to overt tumor formation urothelial cells throughout the entire bladder take on a strongly basal phenotype, characterized by reduced expression of differentiation markers (i.e. Upk1a, Upk2, and Upk3a) and increased expression of basal markers (i.e. Krt14, Krt6a, Krt5). Using monocle, we applied single cells from a BBN treated mouse bladder library to a pseudotime trajectory generated from a control mouse bladder library in order to unbiasedly characterize urothelial differentiation in the non-tumor urothelium of BBN treated mouse bladders. scRNA-Seq analysis of non-tumor urothelium from bladder cancer patients revealed a similar ‘basalization’ among non-tumor urothelial cells. In order to apply our single cell findings to bulk RNA-seq data, we developed a basal index from differentially expressed genes in basal clusters versus non-basal clusters from healthy control human urothelium single cell libraries, and we applied this basal index to non-tumor bladder samples from the The Cancer Genome Atlas (TCGA). We found that among a small subset of patients with paired tumor and non-tumor urothelium in the bladder TCGA dataset, the basal index, when applied to the non-tumor urothelium, was prognostic of survival. Finally, we found that basalization in BBN treated mice could be reversed pharmacologically by epidermal growth factor (EGF) pathway antagonism using erlotinib and trametinib and that over a 4-month time course this reversal dramatically decreased tumor incidence and improved survival, suggesting a new, more effective approach using mechanism-based cancer drugs for the prevention of bladder cancer recurrence in patients. Conclusions: The non-tumor urothelium in BBN treated mouse bladders, prior to overt tumor formation, demonstrates a basal phenotype which we characterize with scRNA-Seq and pseudotime analysis. Similarly, in patients with bladder cancer we observe that the non-tumor urothelium also takes on a basal phenotype. This ‘basalization’ of the non-tumor urothelium may potentially be prognostic, and pharmacologic reversal of the basal phenotype in the non-tumor urothelium using EGF pathway inhibitors prevents tumors in BBN treated mice. Citation Format: Aaron M. Kershner, Kris B. Prado, Bernhard M. Kiss, Karim Mrouj, Lolita Penland, Wan-Jin Lu, Jiyun Choi, Edward Diaz, Rovin Lachmansingh, Bertha Chen, Chia-Sui Kao, Joseph C. Liao, Philip A. Beachy. Bladder cancerization is linked to epithelial basalization and is reversed by EGF inhibition [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A011.

Protein Biomarker Discovery Studies on Urinary sEV Fractions Separated with UF-SEC for the First Diagnosis and Detection of Recurrence in Bladder Cancer Patients

Urinary extracellular vesicles (EVs) are an attractive source of bladder cancer biomarkers. Here, a protein biomarker discovery study was performed on the protein content of small urinary EVs (sEVs) to identify possible biomarkers for the primary diagnosis and recurrence of non-muscle-invasive bladder cancer (NMIBC). The sEVs were isolated by ultrafiltration (UF) in combination with size-exclusion chromatography (SEC). The first part of the study compared healthy individuals with NMIBC patients with a primary diagnosis. The second part compared tumor-free patients with patients with a recurrent NMIBC diagnosis. The separated sEVs were in the size range of 40 to 200 nm. Based on manually curated high quality mass spectrometry (MS) data, the statistical analysis revealed 69 proteins that were differentially expressed in these sEV fractions of patients with a first bladder cancer tumor vs. an age- and gender-matched healthy control group. When the discriminating power between healthy individuals and first diagnosis patients is taken into account, the biomarkers with the most potential are MASP2, C3, A2M, CHMP2A and NHE-RF1. Additionally, two proteins (HBB and HBA1) were differentially expressed between bladder cancer patients with a recurrent diagnosis vs. tumor-free samples of bladder cancer patients, but their biological relevance is very limited.

μ-opioid receptor agonist facilitates circulating tumor cell formation in bladder cancer via the MOR/AKT/Slug pathway: a comprehensive study including randomized controlled trial.

μ-opioid receptor agonists (MORAs) are indispensable for analgesia in bladder cancer (BC) patients, both during surgery and for chronic pain treatment. Whether MORAs affect BC progression and metastasis remains largely unknown. This study focused on the effects of MORAs on the formation of circulating tumor cells (CTCs) in BC and aimed to provide potential therapeutic targets, which would retain the pain-relieving effects of MORAs in BC patients without sacrificing their long-term prognosis. Different preclinical models were used to identify the effects of MORAs on the progression of BC. A novel immunocapture microfluidic chip was utilized to analyze whether MORAs affected the number of CTCs in mouse models and clinical BC patients. Bioinformatic analyses, total transcriptome sequencing, and molecular biology methods were then used to investigate the underlying mechanisms in these models and in BC cell lines. Mouse models of hematogenous metastasis and in situ BC demonstrated that tumor metastasis was significantly increased after MORA treatment. A significant increase in the number of mesenchymal and/or epithelial CTCs was detected after MORA treatment in both the mouse models and clinical trial patients. Mechanistically, MORAs facilitated the formation of CTCs by activating the MOR/PI3K/AKT/Slug signaling pathway, hereby promoting the epithelial-mesenchymal transition (EMT) of BC cells, as knockdown of MOR, Slug or blockade of PI3K inhibited the EMT process and CTC formation. MORAs promoted BC metastasis by facilitating CTC formation. The EMT-CTC axis could be targeted for preventive measures during MORA treatment to inhibit the associated tumor metastasis or recurrence in BC patients.

Üst üriner trakt ürotelyal tümörlerinde radikal nefroüretrektomi sonrası intravezikal nüks için risk faktörleri: retrospektif tek merkezli çalışma

Objective: We examined factors predicting metachronous recurrence of bladder cancer in our series of patients who underwent radical nephroureterectomy (RNU) for upper system urothelial carcinoma (UTUC). Material and Methods: Patients with UTUC-induced RNU in our center from September 2009 to March 2020 were included in the study. Patients were classified as having and not having an intravesical recurrence (IVR), and the factors predicting recurrence were evaluated. Results: A total of 50 patients were included in the study. IVR was developed in 19 (38%) of 50 patients, with a mean follow-up of 39.5 ± 25.3 months. There was no significant difference between the two groups in demographic characteristics, admission hemoglobin, glomerular filtration rate, and degree of hydronephrosis in preoperative ureterorenoscopy and cytology positivity history (p&gt;0.05). The IVR (+) group had significantly more previous history of bladder cancer (35.5% vs. 52.6%, p=0.019, respectively). While the number of patients with ureteral tumors was 10 (32.3%) in the IVR (-) group, it was 9 (47.4%) in the IVR (+) group, and it was significantly higher. There are 28 (56%) patients with T2-T4 pathology in the entire patient group, and the rate is significantly greater in the IVR (+) group (63.2% vs. 51.6%, p=0.038, respectively). Conclusion: Caution should be exercised for metachronous bladder cancer recurrence in patients with a previous history of bladder cancer, especially in ureteral and high pathological T-stage UTUCs.

How Cancer Cells Invade Bladder Epithelium and Form Tumors: The Mouse Bladder Tumor Model as a Model of Tumor Recurrence in Patients.

Non-muscle-invasive bladder cancer is the most common form of bladder cancer. The main problem in managing bladder tumors is the high recurrence after the transurethral resection of bladder tumors (TURBT). Our study aimed to examine the fate of intravesically applied cancer cells as the implantation of cancer cells after TURBT is thought to be a cause of tumor recurrence. We established an orthotopic mouse bladder tumor model with MB49-GFP cancer cells and traced them during the first three days to define their location and contacts with normal urothelial cells. Data were obtained by Western blot, immunolabeling, and light and electron microscopy. We showed that within the first two hours, applied cancer cells adhered to the traumatized epithelium by cell projections containing α3β1 integrin on their tips. Cancer cells then migrated through the epithelium and on day 3, they reached the basal lamina or even penetrated it. In established bladder tumors, E-cadherin and desmoplakin 1/2 were shown as feasible immunohistochemical markers of tumor margins based on the immunolabeling of various junctional proteins. Altogether, these results for the first time illustrate cancer cell implantation in vivo mimicking cellular events of tumor recurrence in bladder cancer patients.

P0825 - Fear of cancer recurrence in bladder cancer patients undergoing radical cystectomy with urinary diversion - Preliminary results from a prospective study (NCT04535921)

P0825 - Fear of cancer recurrence in bladder cancer patients undergoing radical cystectomy with urinary diversion - Preliminary results from a prospective study (NCT04535921)

Prognostic value of Balkan endemic nephropathy and gender on upper tract urothelial carcinoma outcomes after radical nephroureterectomy: A cohort study

BackgroundTo identify the prognostic impact of residence in a BEN-endemic area and gender on upper tract urothelial carcinoma (UTUC) outcomes in Serbian patients treated with radical nephroureterectomy (RNU). MethodsThe study included 334 consecutive patients with UTUC. Patients with permanent residence in Balkan endemic nephropathy (BEN) or non-endemic areas from their birth to the end of follow-up were included in the analysis. Cox regression analyses were used to address recurrence-free (RFS) and cancer-specific survival (CSS) estimates. ResultsFemale patients were more likely to have preoperative pyuria (P = 0.01), tumor multifocality was significantly associated with the female gender (P = 0.003). Gender was not associated with pathologic stage and grade, lymph node metastasis, lymphovascular invasion, adjuvant chemotherapy, bladder cancer history, tumor size, distribution of tumor location, preoperative anemia and demographic characteristics. A total of 107 cases recurred, with a median time to bladder recurrence of 24.5 months. History of bladder tumor (HR, 1.98; P = 0.005), tumor multifocality (HR, 3.80; P < 0.001) and residence in a BEN-endemic area (HR, 1.81; P = 0.01) were independently associated with bladder cancer recurrence. The 5-year bladder cancer RFS for the patients from areas of BEN was 77.8 % and for the patients from non-BEN areas was 64.7 %. The 5-year CSS for the men was 66.2% when compared to 66.6% for the women (P = 0.55). ConclusionsResidence in a BEN-endemic area represents an independent predictor of bladder cancer recurrence in patients who underwent RNU. Gender cannot be used to predict outcomes in a single-centre series of consecutive patients who were treated with RNU for UTUC.

Clinical and pathological factors predictıve of bladder cancer recurrence in patients with upper tract prımary TCC.

To evaluate predictive clinical and histopathological risk factors for bladder cancer recurrence in patients who underwent nephroureterectomy for primary upper urinary tract transitional cell carcinoma (TCC). Data of 111 patients, who were diagnosed with upper urinary tract TCC and underwent nephroureterectomy were reviewed A total of 65 patients were included in the study, after excluding 34 patients. Results: Bladder cancer recurrence developed in 20 (30.7%) of the 65 patients under evaluation. The recurrence-free survival rates in the 1st, 3rd, and 5th years were 78.4%, 70.7% and 69.2%, respectively. Lymphovascular invasion and a positive surgical margin were defined as risk factors for bladder cancer recurrence. In addition, patients with multiple tumors and low stage and grade pathology had a high rate of bladder cancer recurrence, although this was not statistically significant. After nephroureterectomy, a careful follow-up is required in terms of bladder tumor recurrence especially in patients with a positive surgical margin, lymphovascular invasion, low-grade tumors, or multifocal tumors.

Detection of Urothelial Bladder Cancer Based on Urine and Tissue Telomerase Activity Measured by Novel RT-TRAP-2PCR Method.

Purpose: To assess the diagnostic performance of urine telomerase activity (TA) in detecting bladder cancer (BCa) using the modified Telomeric Repeat Amplification Protocol (TRAP) and the Real Time Telomeric Repeat Amplification Protocol with double Polymerase Chain Reaction (RT-TRAP-2PCR). Methods: In this case-control study, matching urine (in the pre- and post-surgical period) and tissue samples from 68 patients with BCa were assessed for TA. As a control, 45 urine samples were examined from non-BCa patients. TA levels were measured using TRAP and RT-TRAP-2 PCR methods. Results: Preoperative urinary TA was elevated in 64 (94.1%) of the 68 BCa patients. Urine TA was undetectable in 44 control patients, while TA was detected in one patient with histologically verified cystitis. Sensitivity for BCa detection of 94.1% and specificity of 97.8% were observed for urinary TA, while tissue TA had 100% sensitivity and 97.8% specificity. Both urine and tissue TA levels were not significantly higher in patients with muscle-invasive disease compared to those with non-muscle invasive BCa (p > 0.05). Urine and tissue TA levels were not associated with higher tumor grade, stage, and number of tumors (p > 0.05). However, the association was found between higher urinary and tissue TA levels with tumor size ≥ 3 cm (p = 0.02 and p = 0.01, respectively). During the first postoperative year, 17 BCa patients experienced disease recurrence, and urinary TA was present in 14 (82.4%) of these patients. The sensitivity and specificity of urinary TA levels for BCa recurrence in patients with non-muscle invasive bladder cancer (NMIBC) during follow-up were 82% and 94.4%, respectively. Conclusions: This pilot study demonstrates a high diagnostic performance of urinary and tissue TA levels measured by a new RT-TRAP-2PCR method for detecting and monitoring BCa. Additionally, the association was found between higher urinary and tissue TA levels with tumor size ≥ 3 cm; however, higher TA levels failed for significant correlation with advanced tumor stage and grade. Our study could serve as a benchmark for the evaluation of novel biomarkers using the RT-TRAP-2PCR method.

Predictive Value of Duration and Frequency of Macroscopic Haematuria for Stage, Prognosis and Recurrence in Bladder Cancer Patients

Predictive Value of Duration and Frequency of Macroscopic Haematuria for Stage, Prognosis and Recurrence in Bladder Cancer Patients

Reduction of Bladder Cancer Chemosensitivity Induced by the Effect of HOXA-AS3 as a ceRNA for miR-455-5p That Upregulates Notch1.

Chemoresistance is one of the main causes of recurrence in bladder cancer patients and leads to poor prognosis. Recently, long non-coding RNAs, like HOXA-AS3, have been reported to regulate chemoresistance in several types of cancer. In this study, we aimed to determine whether HOXA-AS3 can mediate cisplatin resistance in bladder cancer, and its potential mechanism of action. We determined the viability, proliferation, and apoptosis of bladder cancer cells using a CCK-8 assay, EdU staining, and flow cytometry, respectively. We used western blot analysis to assess the expression of markers of epithelial-mesenchymal transition (EMT) and Notch1. We then confirmed expression of these EMT-related markers by immunofluorescence analysis. We found that hypoxia promoted resistance to cisplatin and upregulated the level of HOXA-AS3 in BC cells. Inhibition of HOXA-AS3 enhanced hypoxia-induced cisplatin sensitivity by regulating EMT and Notch1 in BC cells. A dual-luciferase reporter assay confirmed that HOXA-AS3 directly targets miR-455-5p and that Notch1 was a potential target of miRNA-455-5p. We also found that the positive effect of HOXA-AS3 inhibition on cisplatin resistance and tumorigenesis was alleviated when BC cells were transfected with miR-455-5p. Finally, we showed combining HOXA-AS3 small interfering RNA (siRNA) with cisplatin treatment inhibited tumorigenesis in a BALB/c nu/nu mouse model. Our findings indicate that HOXA-AS3 may function as a competing endogenous RNA (ceRNA) of miR-455-5p to regulate Notch1 and play an important role in regulating chemotherapeutic drug sensitivity in BC cells. Therefore, HOXA-AS3 may be a novel therapeutic target for treating bladder cancer.

Deep Learning–based Recurrence Prediction in Patients with Non–muscle-invasive Bladder Cancer

BackgroundNon–muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrence of the disease, which is difficult to predict. ObjectiveTo combine digital histopathology slides with clinical data to predict 1- and 5-yr recurrence-free survival of NMIBC patients using deep learning. Design, setting, and participantsData of patients undergoing a transurethral resection of a bladder tumor between 2000 and 2018 at a Dutch academic medical center were selected. Corresponding histological slides were digitized. A three-step approach was used to predict 1- and 5-yr recurrence-free survival. First, a segmentation network was used to detect the urothelium on the digital histopathology slides. Second, a selection network was trained for the selection of patches associated with recurrence. Third, a classification network, combining the information of the selection network with clinical data, was trained to give the probability of 1- and 5-yr recurrence-free survival. Outcome measurements and statistical analysisThe accuracy of the deep learning–based model was compared with a multivariable logistic regression model using clinical data only. Results and limitationsIn the 1- and 5-yr follow-up cohorts, 359 and 281 patients were included with recurrence rates of 27% and 63%, respectively. The areas under the curve (AUCs) of the model combining digital histopathology slide data with clinical data were 0.62 and 0.76 for 1- and 5-yr recurrence predictions, respectively, which were higher than those of the model using digital histopathology slide data only (AUCs of 0.56 and 0.72, respectively) and the multivariable logistic regression (AUCs of 0.58 and 0.57, respectively). ConclusionsIn our population, the deep learning–based model combining digital histopathology slides and clinical data enhances the prediction of recurrence (within 5 yr) compared with models using clinical data or image data only. Patient summaryBy combining histopathology images and patient record data using deep learning, the prediction of recurrence in bladder cancer patients is enhanced.

STAT3 enhances radiation-induced tumor migration, invasion and stem-like properties of bladder cancer.

Bladder cancer (BCa) is the most common cancer of the human urinary system, and is associated with poor patient prognosis and a high recurrence rate. Cancer stem cells (CSCs) are the primary cause of tumor recurrence and metastasis, possessing self-renewal properties and resistance to radiation therapy. Our previous studies indicated that phosphorylated signal transduction and transcription activator 3 (STAT3) may be a potential biomarker to predict radiation tolerance and tumor recurrence in patients with BCa, following conventional radiotherapy. The aim of the present study was to investigate the underlying mechanism of STAT3 in the radio-resistance of BCa cells. It was found that fractionated irradiation promoted the activation of two STAT3-associated CSCs signaling pathways in BCa cells, namely suppressor of variegation 3–9 homolog 1/GATA binding protein 3/STAT3 and Janus kinase 2/STAT3. Surviving cells exhibited elevated migratory and invasive abilities, enhanced CSC-like characteristics and radio-resistance. Furthermore, knockdown of STAT3 expression or inhibition of STAT3 activation markedly decreased the self-renewal ability and tumorigenicity of radiation-resistant BCa cells. Kaplan-Meier analysis revealed that decreased STAT3 mRNA levels were associated with increased overall survival times in patients with BCa. Taken together, these data indicated that STAT3 may be an effective therapeutic target for inhibiting the progression, metastasis and recurrence of BCa in patients receiving radiotherapy.

Diagnostic and Predictive Values of Inflammatory Factors in Pathology and Survival of Patients Undergoing Total Cystectomy.

Background Inflammation and tumorigenesis are related. We conducted this study to evaluate whether inflammatory factors (IFs) have a diagnostic value for pathology and a predictive value for survival and recurrence in bladder cancer patients undergoing total cystectomy. Methods The patients who were diagnosed with bladder cancer and underwent total cystectomy in our center from 2014 to 2020 were enrolled. The values of neutrophil to lymphocyte ratio (NLR), derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and systemic immune-inflammation index (SII) were calculated by blood routine test results before operation. The AUC of ROC was calculated to judge the diagnostic value of the IFs in pathology and their corresponding cut-off values. For overall survival (OS) and recurrence-free survival (RFS), the above IFs were grouped according to the cut-off value. The differences between different groups were analyzed by the Kaplan-Meier curves, and the predictive value of these IFs was determined by the Cox proportional hazards regression model. Results A total of 79 patients were enrolled. All IFs had no diagnostic value for the pathological grade, tumor T stage, and systemic metastasis. Only NLR (AUC = 0.706, cut‐off value = 3.12, sensitivity = 75.00%, specificity = 70.00%, P = 0.014), dNLR (AUC = 0.700, cut‐off value = 2.49, sensitivity = 66.67%, specificity = 76.67%, P = 0.015), and SII (AUC = 0.704, cut‐off value = 463.56, sensitivity = 100.00%, specificity = 40.00%, P = 0.004) had a diagnostic value for lymph node metastasis. The median follow-up time was 31 months, and there was no significant difference in OS between the two groups for all IFs. For RFS, Kaplan-Meier suggested PLR might be predictive when the cut-off value was 266.70 (P = 0.044), but the subsequent Cox proportional hazards regression analysis showed that all IFs had no predictive value for OS and RFS. Conclusions We found that in patients undergoing total cystectomy preoperative NLR, dNLR and SII had a diagnostic value for lymph node metastasis, while all these five IFs had no predictive value for OS and RFS. However, this conclusion needs to be further verified by large-scale studies in the future.

Identification of a six-lncRNA signature based on a competing endogenous RNA network for predicting the risk of tumour recurrence in bladder cancer patients.

Bladder cancer (BC) is the most common malignancy involving the urinary system, and is characterized by a high recurrence rate. It is important to identify potential lncRNA signatures capable of predicting tumour recurrence risk and assessing recurrence prognosis in BC patients. We extracted data from The Cancer Genome Atlas and identified 381 differentially expressed lncRNAs, 855 mRNAs and 70 miRNAs between non-recurrent and recurrent BC tissues. Subsequently, a competing endogenous RNA (ceRNA) network composed of 29 lncRNAs, 13 miRNAs and 4 mRNAs was established. We used univariate and multivariate Cox regression to analyse the relationship between the 29 lncRNAs and recurrence-free survival (RFS) in BC patients. Six lncRNAs had significant prognostic values, and their cumulative risk score indicated that this 6-lncRNA signature independently predicted RFS in BC patients. We applied a receiver operating characteristic (ROC) analysis to assess the efficiency of our prognostic models. High-risk patients exhibited a poorer prognosis than low-risk patients did. Additionally, the 6-lncRNA signature showed a significant correlation with BC clinicopathological characteristics, which indicates that it could be used for effective risk stratification. The current study provides novel insights into the lncRNA-related ceRNA network and this 6-lncRNA signature may be an independent prognostic factor in predicting the recurrence of BC patients.

Validation of a Novel, Sensitive, and Specific Urine-Based Test for Recurrence Surveillance of Patients With Non-Muscle-Invasive Bladder Cancer in a Comprehensive Multicenter Study.

Bladder cancer (BC), the most frequent malignancy of the urinary system, is ranked the sixth most prevalent cancer worldwide. Of all newly diagnosed patients with BC, 70–75% will present disease confined to the mucosa or submucosa, the non-muscle-invasive BC (NMIBC) subtype. Of those, approximately 70% will recur after transurethral resection (TUR). Due to high rate of recurrence, patients are submitted to an intensive follow-up program maintained throughout many years, or even throughout life, resulting in an expensive follow-up, with cystoscopy being the most cost-effective procedure for NMIBC screening. Currently, the gold standard procedure for detection and follow-up of NMIBC is based on the association of cystoscopy and urine cytology. As cystoscopy is a very invasive approach, over the years, many different noninvasive assays (both based in serum and urine samples) have been developed in order to search genetic and protein alterations related to the development, progression, and recurrence of BC. TERT promoter mutations and FGFR3 hotspot mutations are the most frequent somatic alterations in BC and constitute the most reliable biomarkers for BC. Based on these, we developed an ultra-sensitive, urine-based assay called Uromonitor®, capable of detecting trace amounts of TERT promoter (c.1-124C > T and c.1-146C > T) and FGFR3 (p.R248C and p.S249C) hotspot mutations, in tumor cells exfoliated to urine samples. Cells present in urine were concentrated by the filtration of urine through filters where tumor cells are trapped and stored until analysis, presenting long-term stability. Detection of the alterations was achieved through a custom-made, robust, and highly sensitive multiplex competitive allele-specific discrimination PCR allowing clear interpretation of results. In this study, we validate a test for NMIBC recurrence detection, using for technical validation a total of 331 urine samples and 41 formalin-fixed paraffin-embedded tissues of the primary tumor and recurrence lesions from a large cluster of urology centers. In the clinical validation, we used 185 samples to assess sensitivity/specificity in the detection of NMIBC recurrence vs. cystoscopy/cytology and in a smaller cohort its potential as a primary diagnostic tool for NMIBC. Our results show this test to be highly sensitive (73.5%) and specific (93.2%) in detecting recurrence of BC in patients under surveillance of NMIBC.

Definitive BCG immunotherapy versus radical cystectomy in intermediate or high-risk nonmuscle invasive bladder cancer patients: A retrospective study.

At present, intravesical Bacillus Calmette-Guerin (BCG) immunotherapy is recommended for prophylaxis purposes after transurethral resection of bladder tumor, but has chances of recurrence. Radical cystectomy reduces the risk of recurrence in bladder cancer patients, but may have chances of postoperative complications. The objective of the study was to test the hypothesis that radical cystectomy has overtreatment and definitive BCG immunotherapy has undertreatment in intermediate or high-risk nonmuscle invasive bladder cancer patients. Data regarding biopsies, ultrasound, the computed tomography scan, adopted treatment strategy, treatment-emergent adverse effect, and a follow-up period of 312 patients with confirmed nonmuscle invasive bladder cancer (pTa, pTis, or pT1 stage; intermediate or high-risk cancer) were reviewed. Patients who had received definitive intravesical BCG immunotherapy were included in BCG group (n = 210) and those who underwent radical cystectomy were included in RXC group (n = 87). Clinical decision-making for treatment strategies was evaluated for both groups. Cystitis was frequently observed in all patients who received BCG immunotherapy. In RXC group, ileus was frequently observed in all patients in early days after the operation. During 2 years of the follow-up period, biopsies, ultrasound, and the computed tomography scan reported that BCG group had fewer numbers of negative cancer patients after treatment than the RXC group after surgery (P < .0001). Total expenditure for BCG immunotherapy was higher than radical cystectomy (22,945 ± 945 ¥/patient vs 17,985 ± 545 ¥/patient; P < .0001). Definitive BCG immunotherapy had undertreatment and radical cystectomy had overtreatment for intermediate or high-risk invasive bladder cancer patients (level of evidence III).

Reduce bladder cancer recurrence in patients treated for upper urinary tract urothelial carcinoma: The REBACARE-trial.

BackgroundFollowing radical nephro-ureterectomy for urothelial carcinoma of the upper urinary tract (UUT), the reported bladder recurrence rate of urothelial carcinoma is 22–47%. A single intravesical instillation of chemotherapy within 10 days following nephro-ureterectomy has the potential to decrease the risk of a bladder recurrence significantly. Despite recommendation by the European Association of Urology guideline to administer a single instillation postoperatively, the compliance rate is low because the risk of extravasation of chemotherapy.AimTo reduce the risk of bladder cancer recurrence by a single intravesical instillation of Mitomycin immediately (within 3 h) before radical nephro-ureterectomy or partial ureterectomy.MethodsAdult patients (age ≥ 18 years) with a (suspicion of a) urothelial carcinoma of the UUT undergoing radical nephro-ureterectomy or partial ureterectomy will be eligible and will receive a single intravesical instillation of Mitomycin within 3 h before surgery. In total, 170 patients will be included in this prospective, observational study. Follow-up will be according to current guidelines.ResultsThe primary endpoint is the bladder cancer recurrence rate up to two years after surgery. Secondary endpoints are: a) the compliance rate; b) oncological outcome; c) possible side-effects; d) the quality of life; e) the calculation of costs of a single neoadjuvant instillation with Mitomycin and f) molecular characterization of UUT tumors and intravesical recurrences.ConclusionsA single intravesical instillation of Mitomycin before radical nephro-ureterectomy or partial ureterectomy may reduce the risk of a bladder recurrence in patients treated for UUT urothelial carcinoma and will circumvent the disadvantages of current therapy.

MP48-10 VALIDATION OF NRF2 PATHWAY DYSREGULATION IN UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2017MP48-10 VALIDATION OF NRF2 PATHWAY DYSREGULATION IN UROTHELIAL CARCINOMA Natalia Leva, Thomas Sanford, Maxwell Meng, and Sima Porten Natalia LevaNatalia Leva More articles by this author , Thomas SanfordThomas Sanford More articles by this author , Maxwell MengMaxwell Meng More articles by this author , and Sima PortenSima Porten More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1491AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES There is a well-established relationship between oxidative stress and the development and progression of bladder cancer. Prior clinical trials have shown a decrease in bladder cancer recurrence in patients on a high dose anti-oxidant vitamin regimen. In a previous integrative analysis of TCGA methylation data, we found genes in the Nrf2 pathway, an important regulatory pathway in response to oxidative stress, to be hyper-methylated and thus down regulated in bladder cancer. We sought to further characterize the activity of Nrf2 pathway gene expression in normal urothelium, and urothelium with non-muscle invasive and muscle invasive cancer. METHODS We identified a publically available gene expression microarray dataset using the gene expression omnibus (GSE 3167) that included 10 patients with normal urothelium, 15 patients with stage Ta urothelial carcinoma, 8 patients with carcinoma in situ, and 13 patients with muscle invasive disease. We used the Nrf2 pathway signature discovered in our initial analysis. We evaluated the clustering of samples according to the Nrf2 pathway in an unsupervised pathway using the heatmap.2 function in R. RESULTS Our clustering analysis on an independent dataset showed that the Nrf2 signature separates urothelial carcinoma from normal samples. The genes driving this clustering included KEAP1, GPX3, PGO, and TXN, all of which had higher levels of expression in normal tissue compared with tumor tissue, consistent with downregulation of Nrf2 dependent genes in tumor tissue. There did appear to be some independent clustering of low grade and muscle invasive disease, but this was less pronounced than the clustering of normal urothelium versus urothelial carcinoma. CONCLUSIONS This study corroborates prior findings and shows that genes in the Nrf2 pathway are inactivated in urothelial carcinoma. The expression of Nrf2 genes was decreased in patients with urothelial carcinoma. The lack of clear clustering among different stages of disease suggests that decreased expression of genes in the Nrf2 pathway is an early event in the pathogenesis of urothelial carcinoma. Our data demonstrate a biochemical description of the pathway by which antioxidant mechanisms may affect progression of urothelial carcinoma. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e640 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Natalia Leva More articles by this author Thomas Sanford More articles by this author Maxwell Meng More articles by this author Sima Porten More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...