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Purpose:Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth.Experimental Design:Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni- and multivariable survival analyses were used to characterize clinical outcomes.Results:In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65% NE-like vs. 82% overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors.Conclusions:A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

The morbidity associated with radical cystectomy (RC) for muscle-invasive bladder cancer (MIBC) has fueled investigations into the feasibility of bladder preservation strategies after a favorable clinical response to neoadjuvant therapy (NAT). Identifying optimal candidates for bladder preservation is predicated on our ability to identify tumors with inherent cisplatin sensitivity and accurately stage patients before and after NAT. In the present review, we evaluate the accuracy and limitations of contemporary staging modalities and investigate clinical outcomes in patients with MIBC who were managed with bladder preservation after NAT. Lastly, we discuss the predictive role of cisplatin-sensitizing DNA damage response (DDR) gene alterations as a foundational component to current prospective clinical trials evaluating bladder preservation in the setting of MIBC.

Bladder cancer is a biologically heterogeneous disease with variable clinical presentations, outcomes and responses to therapy. Thus, the clinical utility of single biomarkers for the detection and prediction of biological behavior of bladder cancer is limited. We have previously identified and validated a bladder cancer diagnostic signature composed of 10 biomarkers, which has been incorporated into a multiplex immunoassay bladder cancer test, Oncuria™. In this study, we evaluate whether these 10 biomarkers can assist in the prediction of bladder cancer clinical outcomes. Tumor gene expression and patient survival data from bladder cancer cases from The Cancer Genome Atlas (TCGA) were analyzed. Alignment between the mRNA expression of 10 biomarkers and the TCGA 2017 subtype classification was assessed. Kaplan–Meier analysis of multiple gene expression datasets indicated that high expression of the combined 10 biomarkers correlated with a significant reduction in overall survival. The analysis of three independent, publicly available gene expression datasets confirmed that multiplex prognostic models outperformed single biomarkers. In total, 8 of the 10 biomarkers from the Oncuria™ test were significantly associated with either luminal or basal molecular subtypes, and thus, the test has the potential to assist in the prediction of clinical outcome.

Context Grading is the mainstay for treatment decisions for patients with non–muscle-invasive bladder cancer (NMIBC). Objective To determine the requirements for an optimal grading system for NMIBC via expert opinion. Evidence acquisition A multidisciplinary working group established by the International Society of Urological Pathology reviewed available clinical, histopathological, and molecular evidence for an optimal grading system for bladder cancer. Evidence synthesis Bladder cancer grading is a continuum and five different grading systems based on historical grounds could be envisaged. Splitting of the World Health Organization (WHO) 2004 low-grade class for NMIBC lacks diagnostic reproducibility and molecular-genetic support, while showing little difference in progression rate. Subdividing the clinically heterogeneous WHO 2004 high-grade class for NMIBC into intermediate and high risk categories using the WHO 1973 grading is supported by both clinical and molecular-genetic findings. Grading criteria for the WHO 1973 scheme were detailed on the basis of literature findings and expert opinion. Conclusions Splitting of the WHO 2004 high-grade category into WHO 1973 grade 2 and 3 subsets is recommended. Provision of more detailed histological criteria for the WHO 1973 grading might facilitate the general acceptance of a hybrid four-tiered grading system or—as a preferred option—a more reproducible three-tiered system distinguishing low-, intermediate (high)-, and high-grade NMIBC. Patient summary Improvement of the current systems for grading bladder cancer may result in better informed treatment decisions for patients with bladder cancer.

There are conflicting reports regarding radical cystectomy complication risk from obesity subcategories, and a BMI threshold below which complication risk is notably reduced is undefined. A BMI threshold may be helpful in prehabilitation to aid patient counseling and inform weight loss strategies to potentially mitigate obesity-associated complication risk. This study aims to identify such a threshold and further investigate the association between BMI subcategories and perioperative complications from radical cystectomy.Data were extracted from the Canadian Bladder Cancer Information System, a prospective registry across 14 academic centers. Five hundred and eighty-nine patients were analyzed. Perioperative (≤90 days) complications were compared between BMI subcategories. Unconditional multivariable logistic regression and cubic spline analysis were performed to determine the association between BMI and complication risk and identify a BMI threshold.Perioperative complications were reported in 51 (30%), 97 (43%), and 85 (43%) normal, overweight, and obese patients (Complication risk from radical cystectomy is independently associated with BMI. Both overweight and obese patients are at increased risk compared to normal BMI patients. A BMI threshold of 34 kg/m

The Urologic Oncology Journal was founded 25 years ago and we reviewed the literature since that time in the area of urothelial cancer to see the progress and pitfalls we have made over this time period. A comprehensive literature search was conducted by the authors involved who are all actively involved in research, clinical trials, and treatment for urothelial cancer and the results were summarized over the past 25 years. The field of urothelial cancer has evolved tremendously in the last 25 years with the incorporation of molecular subtyping, novel imaging, immunotherapy, and robotic surgery. However, treatments such as BCG and radical cystectomy have remained steadfast over the last 25 years. Although we have a better understanding of the biology of bladder cancer, we still have a long way from being able to cure patients with bladder cancer and eliminate morbidity from treatments. Nevertheless, considerable progress has been made since the founding of the Urologic Oncology Journal 25 years ago.

The Urologic Oncology Journal was founded 25 years ago and we reviewed the literature since that time in the area of urothelial cancer to see the progress and pitfalls we have made over this time period. A comprehensive literature search was conducted by the authors involved who are all actively involved in research, clinical trials, and treatment for urothelial cancer and the results were summarized over the past 25 years. The field of urothelial cancer has evolved tremendously in the last 25 years with the incorporation of molecular subtyping, novel imaging, immunotherapy, and robotic surgery. However, treatments such as BCG and radical cystectomy have remained steadfast over the last 25 years. Although we have a better understanding of the biology of bladder cancer, we still have a long way from being able to cure patients with bladder cancer and eliminate morbidity from treatments. Nevertheless, considerable progress has been made since the founding of the Urologic Oncology Journal 25 years ago.

Purpose To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC). Materials and methods We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age. Results pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6–37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p p = 0.002) compared to those with luminal papillary subtype. Conclusions While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.

Background Controversy still exists regarding efficacy of multimodality treatment (MMT) vs. radical cystectomy (RC) for urothelial carcinoma of the urinary bladder (UCUB). Methods Within the SEER database (2004-2016), we retrospectively identified patients with stage T2N0M0 UCUB. Competing risks regression (CRR) tested cancer-specific mortality (CSM) and adjusted for other-cause mortality after MMT vs. RC. Exact matching for age was applied. Subgroup analyses focused on differences in chemotherapy or lymph node dissection rates. In sensitivity analyses, we accounted for 40% understaging rate in patients who underwent MMT. Results Of 9862 patients with T2N0M0 UCUB, 2675 (27.1%) underwent MMT vs. 5751 (58.3%) RC vs. 1436 (14.6%) radiotherapy (RT) without chemotherapy. MMT rate increased (annually +3.0%, P Conclusion In patents with T2N0M0, MMT or even more so RT alone may be associated with higher CSM than RC, even in exact age-matched multivariate CRR analyses, which adjust for other-cause mortality. In consequence, patients with T2 UCUB should be informed of this possible CSM disadvantage outside of highly specialized centers.

Bladder-preserving therapy using radical transurethral resection of bladder tumor is currently not a reasonable curative treatment option given the inaccuracy of diagnostic modalities. However, owing to the disadvantages of radical cystectomy, research on bladder-preserving treatment options remains important.

Purpose: To systematically review the literature to investigate racial disparities among bladder cancer clinical trial enrollees. Methods: A systematic review was conducted using Ovid, MEDLINE® to identify clinical trials between 1970 and 2020. Articles were reviewed and were included if they assessed race in their outcomes reporting among bladder cancer patients enrolled in clinical trials. The review was conducted in accordance with the PRISMA statement. Results: We identified 544 clinical trials meeting our initial search criteria, with only 24 (4.4%) studies reporting racial demographic data. Enrollees were largely Caucasian (81–98%), with a strikingly small proportion of enrolled patients consisting of African-Americans (2–8%) and Hispanics (2–5%). Only one of the studies reported results on the efficacy and safety/tolerability of the tested treatment separately for racial groups and performed analyses stratified by race. Conclusion: Race is poorly studied in bladder cancer clinical trials. Trial cohorts may not reflect multicultural populations. The potential association between race and efficacy, safety or tolerability of the tested interventions is unknown. Given the up to twofold increase in bladder cancer-specific death among African-Americans, further research is needed to address the impact of race in clinical trials, while encompassing socioeconomic factors and disease risk factor exposures.

The path to approval of novel therapeutics for patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) requires demonstration of efficacy in eradicating carcinoma in situ (CIS), as determined by cytology, white light cystoscopy and only sometimes mandatory re-biopsy. This paradigm is based on the premise that CIS, in contrast to papillary tumors, cannot be completely resected. We aimed to determine the accuracy of CIS by standard means and the rate at which CIS may be eradicated by transurethral bladder tumor resection (TURBT).We performed a retrospective analysis of consecutive patients who underwent radical cystectomy (RC) for high risk NMIBC or muscle invasive bladder cancer (MIBC) between 2005 and 2019 in a tertiary academic center. The concordance in the presence of CIS in matched TURBT and RC samples was calculated.Complete pathologic information was available for 816 patients with urothelial carcinoma. CIS was detected at TURBT in 354 (43.4%) patients (64.0% NMIBC, 32.3% MIBC) and at RC in 436 (53.4%) patients (64.7% NMIBC, 47.4% MIBC). CIS was missed by TURBT in 199 (45.6%) of those cases (NMIBC 25.4%, MIBC 60.6%). CIS detected on TURBT was not found in the RC specimen in 33.1% (117/354) of cases. Lack of prospective bladder mapping and central pathology review are limitations.Our results suggest that TURBT is inaccurate in detecting CIS. The absence of CIS in the RC specimen after detection in the matched TURBT specimen suggests that CIS may be completely resected by TURBT in a proportion of patients. These factors need to be considered in the design of clinical trials in patients with NMIBC. The use of random biopsies or enhanced cystoscopy could improve the accuracy of CIS detection, but the former is associated with patient morbidity and randomization would alleviate concern about these variables impacting clinical trial outcomes.

Supplemental Digital Content is available in the text., Large cell neuroendocrine carcinoma (LCNEC) of the urinary tract is a rare disease. We present a relatively large retrospective cohort of urinary LCNEC, 20 from the urinary bladder, and 2 from the ureter, from a single institution. The patients included 16 men and 6 women with a median age of 74.5 years. Most LCNEC presented at an advanced stage with tumors invading the muscularis propria and beyond (21/22). Eight cases were pure LCNEC, while 14 cases were mixed with other histologic types, including conventional urothelial carcinoma (n=9), carcinoma in situ (n=7), small cell carcinoma (n=6), and urothelial carcinoma with glandular (n=3) features. Most LCNEC expressed neuroendocrine markers synaptophysin (22/22), chromogranin (13/16), CD56 (7/7), TTF1 (8/8), and INSM1 (2/3). They were negative for common urothelial markers including HMWCK (0/3), p40/p63 (0/6), CK20 (0/10), and had variable GATA3 staining (4/8). Ki-67 stained 25% to nearly 100% tumor cell nuclei. Patient survival was associated with cancer stage, and pure LCNEC showed worse survival than mixed LCNEC. Compared with small cell carcinoma at similar stages from a prior study, LCNEC had a worse prognosis only when patients developed metastatic disease. For organ-confined LCNEC, neoadjuvant chemotherapy followed by radical resection is the treatment option to achieve long-term survival.

Radical cystectomy is curative in only approximately 50% of patients with muscle-invasive bladder cancer. Although perioperative radiotherapy has been tested with the intent of improving locoregional disease control, there currently is no role for this modality in routine care. Perioperative systemic therapy is used with the intent of reducing the risk of systemic recurrence. Robust trial evidence supports the use of neoadjuvant cisplatin-based chemotherapy, with adjuvant chemotherapy offered as an alternative if neoadjuvant therapy is not administered. Perioperative immunotherapy represents the next frontier in perioperative therapy. Further biomarker development is required to guide treatment in individual patients.

There is an underutilization of potentially curative treatments for patients with muscle-invasive bladder cancer. Contemporary trimodality bladder-preservation therapy - which includes a maximally safe transurethral resection of the bladder tumor followed by concurrent chemoradiation and close cystoscopic surveillance with salvage cystectomy reserved for invasive tumor recurrence - can help fulfill this unmet need. Over the past few decades, cumulative published data from prospective clinical trials and large institutional series have established trimodality therapy (TMT) for select patients as a safe and effective alternative to upfront cystectomy. Indeed, TMT is now supported as an accepted option for muscle-invasive bladder cancer patients by numerous clinical guidelines. Following TMT, the vast majority of long-term survivors maintain their native bladders, which tend to function well with relatively low rates of long-term toxicity and good long-term quality of life. There is the potential to further improve outcomes by optimizing systemic therapy integration and by validating predictive biomarkers for improved patient and treatment selection. TMT offers a unique opportunity for urologic surgeons, radiation oncologists and medical oncologists to work hand-in-hand in a multidisciplinary effort to deliver such therapy optimally, to support its research, to promote informed decision-making and ultimately to preserve the autonomy of patients with bladder cancer. The third annual meeting of the Johns Hopkins Greenberg Bladder Cancer Institute/American Urological Association Translational Research Collaboration allowed bladder cancer experts to meet and advance this mission.

In 1997 an international group of scientists organized a meeting in Barcelona, Spain, to discuss the use of biomarkers in the management of patients with bladder cancer. This meeting was the offspring of an - initially informal - group that finally resulted in the foundation and incorporation of the International Bladder Cancer Network (IBCN) e.V. in 2005. Over the years the group has supported several research initiatives and generated several recommendations on the use of biomarkers in the diagnosis and treatment of bladder cancer. Meeting quality was generated by inviting experts presenting state-of-the-art lectures or work in progress reports, interdisciplinarity and the limited number of participants supporting an open and personal exchange resulted in a format increasingly attracting participants from all over the world. The recent limitations caused by the Covid-19 pandemic were partially met by organizing several well attended webinars. The future challenge is to maintain the IBCN meeting spirit despite an increasing interest of the scientific community and industrial partners to participate. However, the integration of and interaction between increasingly more specialized disciplines is a challenge that can be better catalyzed by an international multidisciplinary network than mostly national professional associations.

The benefit of neoadjuvant systemic therapy (NAST) is not yet supported by randomized controlled trials in upper tract urothelial carcinoma (UTUC), but the evidence is increasing. This narrative systematic review was conducted to evaluate the available evidence on the role of NAST in patients undergoing radical nephroureterectomy (RNU) for UTUC.We searched for all relevant articles or conference abstracts published and indexed in PubMed, Embase, and Scopus on July 19, 2021. The study was reported according to the PRISMA criteria and designed within the PICOS framework. We included studies comparing patients with non-metastatic UTUC who received neoadjuvant chemotherapy (NAC) or immunotherapy (NAI) with patients who underwent definitive surgery alone or surgery plus adjuvant systemic therapy. Prospective uncontrolled studies were also included.We identified 27 reports (NAC, N.=24 and NAI, N.=3) published between 2010 and 2021. Twenty of the 24 studies on NAC were retrospective comparative analyses, whereas the remaining four were prospective single-arm studies. One of the three NAI studies exclusively enrolled patients with UTUC. NAC was associated with improved survival and better pathological response relative to surgery alone, but there was no clear advantage when compared to surgery plus adjuvant chemotherapy. Overall, the drug-induced toxicity and risk of disease progression were acceptable but the inherent bias across study designs, inadequate reporting and heterogeneous definition of primary outcomes render it difficult to synthesize results, compare centers, and inform practice.The current level of evidence supporting NAST for UTUC is relatively low and the inability to predict responsiveness and thereby pinpoint the optimal candidates remains a major challenge. There is a need to compare NAST to adjuvant therapies using clearly defined primary endpoints as minimum reporting standards developed by a multidisciplinary team.

BACKGROUND: Bladder cancers have high total mutation burdens resulting in genomic diversity and intra- and inter-tumor heterogeneity that may impact the diversity of gene expression, biologic aggressiveness, and potentially response to therapy. To compare bladder cancers among patients, an organizational structure is necessary that describes the tumor at the histologic and molecular level. These “molecular subtypes”, or “expression subtypes” of bladder cancer were originally described in 2010 and continue to evolve secondary to next generation sequencing (NGS) and an increasing public repository of well-annotated cohorts. OBJECTIVE: To review the history and methodology of expression-based subtyping of non-muscle invasive (NMIBC) and muscle invasive bladder cancer (MIBC). METHODS: A literature review was performed of primary papers from PubMed that described subtyping methods and their descriptive feature including search terms of “subtype”, and “bladder cancer”. RESULTS: 21 papers were identified for review. Tumor subtyping developed from N = 2 to N = 6 subtyping schemes with most subtypes comprised of at least luminal and basal tumors. Most NMIBCs are luminal cancers and luminal MIBCs may be associated with less aggressive features, while one study of basal tumors identified a better clinical outcome with systemic chemotherapy. Tumors with a P53-like may have intrinsic resistance to chemotherapy. The heterogeneity of tumors, which is likely derived from stromal components and immune cell infiltration, affect subtype calls. CONCLUSION: Subtyping, while still evolving, is ready for testing in clinical trials. Improved patient selection with tumor subtyping may help with tumor classification and potentially match patient or tumor to therapy.

Background Radical cystectomy (RC) is often performed for T1 variant histology bladder cancer (VHBC), based on weak clinical evidence. We tested for cancer specific survival (CSS) differences after RC between T1 VHBC vs. urothelial carcinoma of the urinary bladder (UBC). Methods Within the Surveillance, Epidemiology and End Results registry (SEER, 2001–2016), we retrospectively identified T1N0M0 VHBC (adenocarcinoma, squamous cell carcinoma [SqCC], neuroendocrine carcinoma and other VHBC) and UBC patients. Kaplan-Meier plots, multivariate Cox regression models (CRM) with inverse probability treatment weighting (IPTW) and competing risks regression (CRR) tested CSS rates after RC in stage T1 vs. no-RC according to VHBC type and UBC. Results Of all 37,528 T1N0M0 bladder cancer patients, 1726 (4.6%) harboured VHBC. Of those, 598 (1.6%) had SqCC, 409 (1.1%) adenocarcinoma, 249 (0.7%) neuroendocrine carcinoma and 470 (1.3%) other VHBC. RC was performed in 7.4–11.0% of VHBC vs. 5.1% of high grade UBC patients. In patients with neuroendocrine and SqCC, RC was associated with higher CSS rates than any other surgical treatment modality (both p ≤ 0.01). Sixty-month CSS was 100% vs. 67% in neuroendocrine and 86% vs. 66% in SqCC in unadjusted analyses and remained statistically significantly higher in multivariate, IPTW adjusted analyses and in multivariate CRR. No difference was recorded for adenocarcinoma or other VHBC types. Conclusions RC for stage T1N0M0 VHBC appears to provide a protective effect with respect to CSS in patients with SqCC and neuroendocrine carcinoma, but not in adenocarcinoma or other VHBC.

Active germ cell malignancies express high levels of specific circulating micro-RNAs (miRNAs), including miR-371a-3p (miR371), which is undetectable in teratoma. Teratoma markers are urgently needed for theselection of patients and treatments because of the risk of malignant transformation and growing teratoma syndrome. To assess the accuracy of plasma miR375 alone or in combination with miR371 in detecting teratoma, 100 germ cell tumor patients, divided into two cohorts, were enrolled in a prospective multi-institutional study. In the discovery cohort, patients with pure teratoma and with no/low risk of harboring teratoma were compared; the validation cohort included patients with confirmed teratoma, active germ cell malignancy, or complete response after chemotherapy. The area under the receiver operating characteristic curve values for miR375, miR371, and miR371-miR375 were, respectively, 0.93 (95% confidence interval [CI]: 0.87-0.99), 0.59 (95% CI: 0.44-0.73), and 0.95 (95% CI: 0.90-0.99) in the discovery cohort and 0.55 (95% CI: 0.36-0.74), 0.74 (95% CI: 0.58-0.91), and 0.77 (95% CI: 0.62-0.93) in the validation cohort. Our study demonstrated that the plasma miR371-miR375 integrated evaluation is highly accurate to detect teratoma. PATIENT SUMMARY: The evaluation of two micro-RNAs (miR375-miR371) in the blood of patients with germ cell tumors is promising to predict teratoma. This test could be particularly relevant to the identification of teratoma in patients with postchemotherapy residual disease. info:eu-repo/semantics/publishedVersion

Bacillus Calmette–Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic., Bacillus Calmette–Guérin (BCG) has been used to prevent tuberculosis for a century and is also a standard approach for the treatment of non-muscle-invasive bladder cancer. However, BCG also has a plethora of non-specific effects that occur via the induction of trained immunity and have raised the hypothesis that BCG vaccination could be used to protect against coronavirus disease 2019 (COVID-19). In this Perspective, the authors describe the history of BCG, discuss the mechanisms of its effects, and consider its potential role during the COVID-19 pandemic.

407 Background: Active surveillance is routinely recommended to manage patients (pts) with clinical stage I (CSI) germ cell testicular tumors (GCT), the most common presentation of newly diagnosed GCT. Circulating plasma miR371a-3p (miR371) has shown high sensitivity and specificity in pts with metastatic non teratoma GCT or in pts with clinically detectable testicular GCT prior to orchiectomy. However, limited data are available about this biomarker accuracy to detect minimal residual disease post-orchiectomy in pts on active surveillance for early stage disease. Methods: CSI GCT pts with available plasma samples after radical orchiectomy enrolled in the British Columbia provincial biobank research program were selected for this study. RT-PCR was used for qualitative miR371 analysis. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated for miR371 and compared to the same operating characteristics of current gold standard diagnostic tests. Relapse free survival (RFS) was correlated to post-orchiectomy miR371 (positive or negative) status. Fisher’s exact test was used to evaluate the sensitivity and specificity, unpaired t-test for comparison of miR371 expression. RFS was calculated using the Kaplan-Meier method, and differences between groups were estimated using the log rank test, 2-sided and with 5% significance threshold. Results: With a median follow-up of 41 months, 101 pts with CSI GTCwere included, of whom 35 (34.6%) experienced a disease relapse during the follow-up. miR371 was positive in 22/35 (62.8%) of the relapsed pts. miR371 positivity preceded clinical evident disease by a median of 3 months (range: 1-12 months).The specificity and PPV were 100% (95% CI: 94.5 - 100 for both), sensitivity 62.8% (95% CI: 44.9 - 78.5), NPV 83.5% (95% CI: 76.7 - 88.6) and AUC 0.81 (95% CI: 0.71 - 0.91). No false positive results were observed. The RFS of the pts with positive post-orchiectomy miR371 was significantly shorter (median: 3.5 months vs. not reached; p seminoma). Conclusions: miR371 has high specificity and PPV in detecting GCT at an early stage and could be used to guide treatment selection after orchiectomy. Further studies, including the SWOG S1823 clinical trial, are ongoing or have been planned in this setting for validation of clinical utility.

449 Background: Pelvic lymph node irradiation is still under debate for patients with muscle-invasive bladder cancer (MIBC) planned for curative-intent radiation-based therapy (RT). A previous randomized trial suggested bladder-only (BO)-RT was effective in reducing RT-related toxicity, while associated with non-inferior oncological outcomes – bladder preservation rates, disease-free survival, and overall survival (OS) – compared to whole-pelvis (WP)-RT. In this study, we sought to evaluate the impact of the radiation volume (BO-RT vs. WP-RT) on main oncological outcomes in patients with MIBC. Methods: This nationwide study included patients with urothelial MIBC (cT2-4aN0-2M0) who underwent curative RT at 10 academic centers across Canada. Patients clinically staged with pelvic or abdominal wall invasion (cT4b) or enlarged lymph nodes beyond the common iliac bifurcation (cN3) before RT were excluded. Patients were divided into two groups based on the RT volume: WP-RT vs. BO-RT. Inverse probability of treatment weighting (IPTW) and absolute standardized differences (ASDs) were used to balance baseline covariates across treatment groups. Regression models were used to assess the impact of the RT volume on the rates of complete response (CR) to treatment, cancer-specific survival (CSS), and OS while adjusting for potential confounding variables in the weighted cohorts. Results: A total of 599 patients were analyzed, out of whom 369 (61.6%) underwent WP-RT. Patients in the WP-RT group were younger (mean age 73.2 vs. 77.4; ASD 0.41), and more likely to have an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 (82.1% vs. 73.5%; ASD 0.21), clinical node-positive disease (12.5% vs. 2.2%; ASD 0.40), and lymphovascular invasion (26.3% vs. 16.1%; ASD 0.25), compared to BO-RT. In addition, WP-RT patients were more commonly treated with neoadjuvant chemotherapy (20.9% vs. 10.4%; ASD 0.29) and concurrent chemotherapy (76.7% vs. 56.5%; ASD 0.44), compared to BO-RT. In the IPTW cohort, age, gender, ECOG PS, clinical staging, the proportion of patients with carcinoma in situ, lymphovascular invasion, variant urothelial histologies, hydronephrosis, and whose tumours were completely resected before RT, treated with NAC, and treated with concurrent chemotherapy were well balanced across groups (all ASDs < 0.10). In multivariable analysis, WP-RT did not impact CR rates post-RT (OR 1.14; p=0.526) but was associated with both CSS (HR 0.66; p=0.016) and OS (HR 0.68; p=0.002), independently of other prognostic factors (Table). Conclusions: Our study demonstrated a significant survival benefit with the use of WP-RT compared to BO-RT in patients with MIBC treated with curative intent. Additional randomized controlled trials are needed to confirm our findings.

528 Background: Novel therapies are required for BCG-unresponsive, high risk non-muscle invasive bladder cancer. We report the interim results of a Phase II Clinical Study of Intravesical Photo Dynamic Therapy (PDT) in patients with BCG-Unresponsive Carcinoma In-Situ (CIS) with or without papillary disease. Methods: Out of a planned 125 patients, 42 patients have been enrolled and treated with two Study Treatments (Day 0 and Day 180) consisting of an intravesical instillation of the photosensitizer TLD-1433 (0.70 mg/cm2) followed by activation with a 520 nm intravesical laser under general anesthesia (Study Device TLC-3200) to a total of 90 J/cm2 of laser light. The primary outcome assessed was efficacy, evaluated by Complete Response (CR), at any point in time. The secondary outcome was duration of CR at 12 months, post initial CR. A tertiary objective is safety, evaluated by the incidence and severity of Adverse Events, Grade 4 or higher that do not resolve within 450 days post treatment. Patients with a negative cystoscopy and positive cytology have been defined as indeterminate response (IR), as these patients remain under investigation for lower and upper tract urothelial carcinoma. Results: Interim analyses included the first 42 patients, along with 3 patients treated in a preceding Phase Ib NMIBC clinical study assessing the safety of TLD-1433 PDT who weretreated at the same parameters, for a total of 45 patients. Data for the primary and secondary outcomes are listed in the table.The interim clinical data demonstrates a 90 day CR of 50% and a duration of response at 360 and 450 days of 35% and 21%, respectively.There have been eight Serious Adverse Events (SAE) identified (2 Grade II (tachycardia, hematuria), 3 Grade III (acute kidney injury, cellulitis), 2 Grade IV (urosepsis, depression/anxiety) and 1 Grade V). None of the SAEs were deemed to be directly related to the PDT. Conclusions: The interim data support that treatment with Photo Dynamic Therapy provides a viable treatment option for patients with BCG unresponsive CIS (+/- papillary disease) with an acceptable ongoing safety profile. Clinical trial information: NCT03945162 . [Table: see text]

549 Background: The PURE-01 clinical trial reported the use of neoadjuvant treatment with pembrolizumab prior to radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC; cT2–3N0M0; PMID 30343614). We have previously reported that specific molecular subtypes (i.e. basal or claudin-low) and immune signatures are associated with more favorable survival. However, reports on the detailed tumor biology of patients (pts) who relapsed after neoadjuvant pembrolizumab are lacking. Herein, we provide a detailed characterization of relapsing pts and identify distinct gene expression patterns with potential utility as novel biomarkers. Methods: Microarray data from transurethral resection of the bladder tumor (TURBT; N=102) and matched RC (N=25) tissue from the PURE-01 trial were analyzed. Gene expression signatures and molecular subtypes were assigned as previously described (PMID 32165065). The Kaplan-Meier method was used to estimate differences in patient outcomes. Immune-signatures were split by median for survival analysis. All significance testing used a two-sided t-test at a threshold of 0.05. Results: Differential gene expression analysis identified KRT20 and H19 to be enriched in relapsing patients (both p

Over the past decade, genomic and transcriptomic analyses have uncovered promising tumor antigens including immunotherapeutic targets in bladder cancer (BCa). Conventional tumor antigens are proteins expressed on the plasma membrane of tumor cells such as EGFR, FGFR3, and ERBB2 in BCa, which can be targeted by antibodies or similar epitope-specific binding reagents. The cellular proteome consists of ∼100,000 proteins but the expression of these proteins is rarely unique to tumor cells. Many tumor-associated proteins are post-translationally modified with phosphorylation, glycosylation, ubiquitination, or SUMOylation moieties. Although these modifications expand the complexity, they potentially offer novel targeting opportunities across tumor sub-populations. Experimental targeting of cancer-specific post-translational modifications (PTMs) has shown encouraging results in pre-clinical models of BCa, which could potentially overcome issues with inherent intra-tumor heterogeneity due to simultaneous expression on different proteins. Here, we review current knowledge on post-translational modifications in BCa and highlight recent efforts in experimental targeting strategies.

Enhanced Recovery After Surgery (ERAS) is a perioperative approach to managing surgical patients. The impact of ERAS on radical cystectomy (RC) outcomes remains understudied.To review the literature regarding ERAS protocols and RC outcomes. The primary outcome was hospital length of stay (LOS).A systematic review of the articles published from 1970 through 2018 was conducted. Individual patient data (IPD) were requested and a meta-analysis was performed.A total of 4197 articles were retrieved and 22 (reporting 4048 patients) were selected for the review. LOS followed by 30-d and that followed by 90-d complications were the most common endpoints. ERAS use was associated with reduced morbidity, quicker bowel recovery, and shorter LOS, without affecting mortality. IPD were obtained for 2077 patients from 11 studies. In multivariable models, LOS was associated with ERAS use (regression coefficient: -4.54 [95% confidence interval {CI}: -5.79 to -3.28] d with ERAS p 0.001) and Charlson Comorbidity Index (+1.64 [1.38-1.90] d for each point increase, p 0.001), and varied between hospitals (from -1.59 [-3.03 to -0.14] to +4.55 [1.89-7.21] d, p 0.03). Individual ERAS components associated with shorter LOS included no nasogastric (NG) tube (-8.70 [-11.9 to -5.53] d, p 0.001) and local anesthesia blocks compared with regional anesthesia (-3.29 [-6.31 to -0.27] d, p = 0.03).ERAS protocols were associated with reduced LOS and postoperative complication rate. Avoidance of NG tubes and use of local anesthesia blocks were significantly associated with reduced LOS. These findings reflect different components of recovery, which ERAS can optimize and further support documentation of the use of ERAS components when reporting RC outcomes.Use of enhanced recovery in patients undergoing surgery to remove the bladder is associated with fewer surgical complications and a shorter hospital stay. Avoidance of nasogastric tubes and use of local anesthesia after the operation were associated with a shorter length of stay.

Urothelial carcinoma differentiates into variant histological subtypes in approximately 25% of cases. Since every histological variant has unique characteristics, including metastatic potential, expression of immunotherapy targets, and susceptibility to radiation or chemotherapy, every variant offers a unique diagnostic and therapeutic challenge. However, since any single variant is relatively rare, there is a risk of missed pathological diagnosis and sub-optimal clinical management. Ensuring awareness among pathologists and wide-spread familiarity with the nuances of variants among urologists is therefore essential. Additionally, variant histologies may act as an intermediate between classical clinicopathological staging of bladder cancer and evolving molecular classification. Therefore, this review aims to provide a brief overview of the diagnostic, prognostic, and therapeutic implications of each variant histologic subtype. Despite the development of standardized diagnostic criteria, the diagnosis of variant histologies continues to pose a challenge and results in significant interobserver variability. The prognosis of any single variant is poorly studied. However, squamous and glandular differentiation are thought to have little effect on prognosis while micropapillary, sarcomatoid, plasmacytoid, and small cell carcinomas are associated with a poor prognosis. Although evidence surrounding therapeutic strategies is sparse, management guidelines have been developed for variant histologies, which are often treated more aggressively than pure urothelial carcinoma. For example, the presence of variant histology warrants radical cystectomy in patients with T1 disease. Recommendations surrounding neo-adjuvant chemotherapy and radiation therapy also differ with each variant. As new treatments emerge for advanced bladder cancer, studying outcomes in each variant will become critical. Since prognosis and management hinge on the presence of variant histologies, accurate diagnosis and a thorough understanding of these variants are imperative for optimal management of urothelial carcinoma.

OBJECTIVE To assess the differential response to neoadjuvant chemotherapy (NAC) in patients with urothelial carcinoma of the bladder (UCB) compared to upper tract urothelial carcioma (UTUC) treated with radical surgery. PATIENTS AND METHODS Data from 1299 patients with UCB and 276 with UTUC were obtained from multicentric collaborations. The association of disease location (UCB vs UTUC) with pathological complete response (pCR, defined as a post-treatment pathological stage ypT0N0) and pathological objective response (pOR, defined as ypT0-Ta-Tis-T1N0) after NAC was evaluated using logistic regression analyses. The association with overall (OS) and cancer-specific survival (CSS) was evaluated using Cox regression analyses. RESULTS A pCR was found in 250 (19.2%) patients with UCB and in 23 (8.3%) with UTUC (P

Paternally expressed gene 10 (PEG10) has been associated with neuroendocrine muscle-invasive bladder cancer (MIBC), a subtype of the disease with the poorest survival. In this work, we further characterized the expression pattern of PEG10 in The Cancer Genome Atlas database of 412 patients with MIBC, and found that, compared with other subtypes, PEG10 mRNA level was enhanced in neuroendocrine-like MIBC and highly correlated with other neuroendocrine markers. PEG10 protein level also associated with neuroendocrine markers in a tissue microarray of 82 cases. In bladder cancer cell lines, PEG10 expression was induced in drug-resistant compared with parental cells, and knocking down of PEG10 resensitized cells to chemotherapy. Loss of PEG10 increased protein levels of cell-cycle regulators p21 and p27 and delayed G1–S-phase transition, while overexpression of PEG10 enhanced cancer cell proliferation. PEG10 silencing also lowered levels of SLUG and SNAIL, leading to reduced invasion and migration. In an orthotopic bladder cancer model, systemic treatment with PEG10 antisense oligonucleotide delayed progression of T24 xenografts. In summary, elevated expression of PEG10 in MIBC may contribute to the disease progression by promoting survival, proliferation, and metastasis. Targeting PEG10 is a novel potential therapeutic approach for a subset of bladder cancers.

Bladder cancer is a heterogeneous disease classified into two broad molecular subtype categories, basal and luminal, with critical treatment and prognostic implications. Recent studies have shown the utility of immunohistochemistry in predicting bladder cancer molecular subtypes, with a two-marker approach using GATA3 and CK5/6 showing over 80% reliability. In the current study, we calculated the accuracy of uroplakin II (UPII), a marker of urothelial differentiation, with different scores (0:1%, 1+: 1-10%, 2+: 10-50%, 3+:50%) to predict RNA-based luminal versus basal subtypes in a cohort of muscle-invasive bladder cancer-received neoadjuvant chemotherapy followed by radical cystectomy. The 1% cutoff of the UPII stain predicts the luminal subtype with the sensitivity and specificity of 95% and 56%, respectively. With a UPII cutoff of 10%, the sensitivity and specificity were 93% and 81%, respectively, and with a UPII cutoff of 50%, the sensitivity and specificity were 91% and 96%, respectively. The prediction performance of UPII was better than either GATA3 or CK5/6. There was no significant difference in prognoses between UPII 0-2+ and UPII 3+ patients in this cohort. The current study shows that evaluating the staining proportion score of UPII can accurately predict basal and luminal subtypes of muscle-invasive bladder cancer.

Chemotherapy is a standard therapy for muscle-invasive bladder cancer (MIBC). However, genomic alterations associated with chemotherapy sensitivity in MIBC have not been fully explored. This study aimed to investigate the genomic landscape of MIBC in association with the response to chemotherapy and to explore the biological role of genomic alterations. Genomic alterations in MIBC were sequenced by targeted exome sequencing of 409 genes. Gene expression in MIBC tissues was analyzed by western blotting, immunohistochemistry, and RNA microarray. Cellular sensitivity to gemcitabine and gemcitabine metabolite was examined in bladder cancer cells after modulation of candidate gene. Targeted exome sequencing in 20 cases with MIBC revealed various genomic alterations, and we focus on DPYD. Conversely, high DPYD and dihydropyrimidine dehydrogenase (DPD) expression was associated with poor response to gemcitabine-containing chemotherapy among patients with MIBC, as well as gemcitabine resistance in bladder cancer cells. DPD suppression rendered cells vulnerable to gemcitabine, while DPD overexpression made cells gemcitabine-resistant through reduced activity of the cytotoxic gemcitabine metabolite difluorodeoxycytidine diphosphate. This study revealed the novel role of DPD in gemcitabine metabolism. It has been suggested that DPYD genomic alterations and DPD expression are potential predictive biomarkers in gemcitabine treatment.