Treatment Of Urothelial Carcinoma Research Articles

Research progress on PD-1 and PD-L1 inhibitors in the treatment of metastatic urothelial carcinoma.

Urothelial carcinoma (UC) is a very common malignant tumor. In the past few decades, platinum-based chemotherapy has been regarded as the standard recommended regimen for patients with metastatic urothelial carcinoma (mUC) who can receive either cisplatin or carboplatin. The emergence of immune checkpoint inhibitors (ICIs) brought some hope for possible treatments for mUC patients who were unfit for platinum therapy. ICIs drugs have emerged as new potential weapons to overcome UC in our lifetime. ICIs block the binding of programmed death-1 (PD-1) to programmed death-ligand 1 (PD-L1), leading to enhancement of the immune function of antitumor T cells. In the treatment of UC, ICIs show an apparent ascendancy and effectively enhance survival rates. With good tolerability and remarkable effects, ICIs have given thousands of patients hope. This article mainly shows the application of PD-1 and PD-L1 inhibitors in mUC.

Precision Medicine to Treat Urothelial Carcinoma-The Way Forward.

The treatment of urothelial carcinoma (UC) is challenging given its molecular heterogeneity and variable response to current therapies. To address this, many tools, including tumor biomarker assessment and liquid biopsies, have been developed to predict prognosis and treatment response. Approved therapeutic modalities for UC currently include chemotherapy, immune checkpoint inhibitors, receptor tyrosine kinase inhibitors, and antibody drug conjugates. Ongoing investigations to improve the treatment of UC include the search for actionable alterations and the testing of novel therapies. An important objective in recent studies has been to increase efficacy while decreasing toxicity by taking into account unique patient and tumor-related factors-an endeavor called precision medicine. The aim of this review is to highlight advancements in the treatment of UC, describe ongoing clinical trials, and identify areas for future study in the context of precision medicine.

EE41 Cost-Utility of Nivolumab Versus Observation for the Adjuvant Treatment of Urothelial Carcinoma (UC) for Patients Who Are at High-Risk of Recurrence: A Canada Public Payer Perspective

To estimate the cost-utility of adjuvant UC treatment with nivolumab versus observation after radical resection from a Canadian public-payer perspective.

Antibody-Drug Conjugates in the Treatment of Urothelial Cancer.

Antibody-drug conjugates (ADCs) have transformed the treatment landscape in oncology and become an essential therapeutic modality. In urothelial carcinoma (UC), the two ADCs that have been especially successful in clinical practice are enfortumab vedotin and sacituzumab govitecan. These drugs are currently approved as monotherapy for later lines of treatment in locally advanced or metastatic UC and have had a significant impact for patients with limited treatment options. Combinational trials, as well as additional ADCs, are currently being investigated in the treatment of UC for subsequent lines of therapy as overall survival rates remain dismal.

Real-world effectiveness of pembrolizumab as first-line therapy for cisplatin-ineligible patients with advanced urothelial carcinoma: the ARON-2 study.

The advent of immune-checkpoint inhibitors has challenged previous treatment paradigms for advanced urothelial carcinoma (UC) in the post-platinum setting as well as in the first-line setting for cisplatin-ineligible patients. In this study, we investigated the effectiveness of pembrolizumab as first-line treatment for cisplatin-ineligible UC. Data from patients aged ≥ 18years with cisplatin-ineligible UC and receiving first-line pembrolizumab from January 1st 2017 to September 1st 2022 were collected. Cisplatin ineligibility was defined according to the Galsky criteria. Thirty-three Institutions from 18 countries were involved in the ARON-2 study. Our analysis included 162 patients. The median follow-up time was 18.9months (95%CI 15.3-76.9). In the overall study population, the median OS was 15.8months (95%CI 11.3-32.4). The median OS was significantly longer in males versus females while no statistically significant differences were observed between patients aged < 65y versus ≥ 65y and between smokers and non-smokers. According to Recist 1.1 criteria, 26 patients (16%) experienced CR, 32 (20%) PR, 39 (24%) SD and 55 (34%) PD. Our data confirm the role of pembrolizumab as first-line therapy for cisplatin-unfit patients. Further studies investigating the biological and immunological characteristics of UC patients are warranted in order to optimize the outcome of patients receiving immunotherapy in this setting.

Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis

PurposeTo analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex.MethodsThree databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting.ResultsOverall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55–0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68–0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females.ConclusionsOS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.

Whole exome sequencing analysis of canine urothelial carcinomas without BRAF V595E mutation: Short in-frame deletions in BRAF and MAP2K1 suggest alternative mechanisms for MAPK pathway disruption.

Molecular profiling studies have shown that 85% of canine urothelial carcinomas (UC) harbor an activating BRAF V595E mutation, which is orthologous to the V600E variant found in several human cancer subtypes. In dogs, this mutation provides both a powerful diagnostic marker and a potential therapeutic target; however, due to their relative infrequency, the remaining 15% of cases remain understudied at the molecular level. We performed whole exome sequencing analysis of 28 canine urine sediments exhibiting the characteristic DNA copy number signatures of canine UC, in which the BRAF V595E mutation was undetected (UDV595E specimens). Among these we identified 13 specimens (46%) harboring short in-frame deletions within either BRAF exon 12 (7/28 cases) or MAP2K1 exons 2 or 3 (6/28 cases). Orthologous variants occur in several human cancer subtypes and confer structural changes to the protein product that are predictive of response to different classes of small molecule MAPK pathway inhibitors. DNA damage response and repair genes, and chromatin modifiers were also recurrently mutated in UDV595E specimens, as were genes that are positive predictors of immunotherapy response in human cancers. Our findings suggest that short in-frame deletions within BRAF exon 12 and MAP2K1 exons 2 and 3 in UDV595E cases are alternative MAPK-pathway activating events that may have significant therapeutic implications for selecting first-line treatment for canine UC. We developed a simple, cost-effective capillary electrophoresis genotyping assay for detection of these deletions in parallel with the BRAF V595E mutation. The identification of these deletion events in dogs offers a compelling cross-species platform in which to study the relationship between somatic alteration, protein conformation, and therapeutic sensitivity.

Diversity, equity, and inclusion in genitourinary clinical trials leading to FDA novel drug approval: An assessment of the FDA center for drug evaluation and research drug trials snapshot

To determine the distribution of race and ethnicity among genitourinary oncology trial participants leading to FDA approval of novel molecular entities/biologics. Secondarily, we evaluated whether the proportion of Black participants in clinical trials increased over time. We quired the FDA Center for Drug Evaluation and Research Drug Trials Snapshot (DTS) between 2015 and 2020 for urologic oncology clinical trials leading to FDA approval of novel drugs. Enrollment data was stratified by race and ethnicity. Cochran-Armitage Trend tests were used to examine changes in Black patient participation over years. Nine clinical trials were identified that led to FDA approval of 5 novel molecular entities for prostate and 4 molecular entities for urothelial carcinoma treatment. Trials for prostate cancer included 5202 participants of which 69.8% were White, 4.0% Black, 11.0% Asian, 3.6% Hispanic, <1% American Indian/Alaska Native or Native Hawaiian/Pacific Islander, 3% other. Trials in urothelial carcinoma had 704 participants of which 75.1% were male, 80.8% White, 2.3% Black, 2.4% Hispanic, <1% American Indian/Alaska Native or Native Hawaiian/Pacific Islander, 5% other. Black participation rates over time did not change for urothelial (P=0.59) or the combined cancer cohort (P=0.29). Prostate cancer enrollment trends among Black participant declined over time (P=0.03). Participants in genitourinary clinical trials leading to FDA approval of novel drugs are overwhelmingly white. Involving stakeholders who represent the needs and interests of underrepresented populations in the design and implementation of clinical trials of novel agents may be a strategy to increase diversity, equity, and inclusion among genitourinary clinical trials.

Sarcomatoid urothelial carcinoma of the renal pelvis treated with immunotherapy

BackgroundSarcomatoid carcinoma is a rare, high-grade malignancy with epithelial and mesenchymal components. It may be a good candidate for immunotherapy because it is associated with overexpression of programmed cell death ligand 1. Sarcomatoid urothelial carcinoma (UC) of the upper urinary tract is extremely rare. Here we report the first case of sarcomatoid UC of the renal pelvis that responded to immunotherapy.Case presentationA 79-year-old man was referred to our hospital complaining of various symptoms, including anorexia and abdominal pain. A computed tomography scan revealed a right atrial tumor, a 9 cm left renal mass with a renal vein tumor thrombus, para-aortic lymphadenopathy, and multiple small lung nodules. The patient underwent resection of the right atrial tumor. Pathological analysis of the tumor did not lead to an accurate diagnosis even after several rounds of immunohistochemistry. He underwent a needle biopsy of the left kidney and was initially diagnosed with collecting duct carcinoma, a rare subtype of renal cell carcinoma (RCC). Following the initial diagnosis, immunotherapy with nivolumab and ipilimumab commenced. Thereafter, almost all lesions, including the left renal tumor, were reduced in size. However, he underwent a left nephrectomy approximately a year after beginning immunotherapy due to repeated left renal bleeding. Histological examination of the nephrectomy specimen revealed two forms of cancer—sarcomatoid UC and conventional high-grade UC. Two months after surgery, the patient was found to have new lung metastases. He underwent chemotherapy with gemcitabine and cisplatin, followed by immunotherapy with pembrolizumab. However, both treatments were ineffective. The patient died of cancer 19 months after his first admission.ConclusionsThe presented case of sarcomatoid UC of the renal pelvis that partially responded to immunotherapy suggests that immunotherapy can be a promising treatment for sarcomatoid UC.

Evolving systemic management of urothelial cancers.

Bladder cancer is the 12th most common cancer worldwide. Historically, the systemic management of urothelial carcinoma has been confined to platinum-based chemotherapy. In this review, we discuss the evolving landscape of systemic treatment for urothelial carcinoma. Since 2016, when the Food and Drug Administration approved the first immune checkpoint inhibitor (CPI), programmed cell death 1 and programmed cell death ligand 1 inhibitors have been evaluated in the nonmuscle invasive bladder cancer, localized muscle invasive bladder cancer as well as advanced/metastatic bladder cancer settings. Newer approved treatments such as fibroblast growth factor receptor (FGFR) inhibitors and antibody-drug conjugates (ADCs) represent second-line and third-line options. These novel treatments are now being assessed in combination as well as with older traditional platinum-based chemotherapy. Novel therapies continue to improve bladder cancer outcomes. Personalized approach with well validated biomarkers are important to predict response to therapy.

Pretreatment Hemoglobin Levels and Platelet-to-Lymphocyte Ratio Predict Survival Benefit from Pembrolizumab in Advanced Urothelial Carcinoma.

Several prognostic risk factors have been recognized when using cisplatin-based conventional chemotherapy for the treatment of advanced urothelial carcinoma (UC); these include performance status (PS), liver metastasis, hemoglobin (Hb) levels, time from prior chemotherapy (TFPC), and other systemic inflammation scores including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). However, the benefit of these indicators for predicting outcome of immune checkpoint inhibitors is not fully understood. Here, we investigated the predictive value of the indicators in patients who received pembrolizumab for the treatment of advanced UC. Seventy-five patients who received pembrolizumab treatment for advanced UC were included. The Karnofsky PS, liver metastasis, hemoglobin levels, TFPC, NLR, and PLR were analyzed, and their relationship with overall survival (OS) was determined. All factors were highlighted as significant prognostic indicators for OS in the univariate proportional regression analysis (p<0.05 for each). Multivariate analysis revealed that Karnofsky PS and liver metastasis were independent prognostic indicators for OS (p<0.01) but were applicable only for a small number of patients. Notably, the combined analysis with low Hb levels and high PLR was significantly associated with OS in patients who could gain less benefit from pembrolizumab at a median of 6.6 [95% confidence interval (CI)=4.2-9.0] versus 15.1 (95% CI=12.4-17.8) months (p=0.002). The combination of Hb levels and PLR may be a broadly applicable indicator for the outcome of pembrolizumab as second-line chemotherapy in patients with advanced UC.

Artesunate Exhibits Synergy With Cisplatin and Cytotoxicity for Upper Tract and Bladder Urothelial Carcinoma Cells.

Urothelial carcinoma (UC) may arise from the urothelium of the upper tract and the bladder. Cisplatin-based therapy remains the gold standard for UC treatment. The poor 5-year survival rate of UC patients creates an urgent need to develop new drugs for advanced UC therapy. Artesunate (ART), a traditional Chinese medicine for treating malaria, is a potential anticancer agent, but its antigrowth effects on upper tract and bladder UC have not been investigated. The antigrowth effect of ART in HT 1376 (bladder UC cells) and BFTC 909 [upper tract urothelial carcinoma (UTUC) cells] was determined by the CCK-8 assay. Flow cytometric analysis was used to evaluate the cell cycle distribution and apoptosis. The cell cycle, apoptosis, and autophagy-related protein expression were analyzed by western blotting. The efficacy of combination treatment with cisplatin was determined by the Calcusyn software. ART induced HT 1376 and BFTC 909 cell death in a concentration- and time-dependent manner, inducing G2/M cell-cycle arrest. ART induced apoptosis and redox imbalance in HT 1376 and BFTC 909 cells. Application of the reactive oxygen species (ROS) scavenger, N-acetyl-L-cysteine (NAC), attenuated cell death in ART-treated UC cells. BFTC 909 cells show a better response after ART treatment. ART may be a candidate drug for treating UTUC and bladder UC while increasing the therapeutic effect of cisplatin.

A Short Overview on Therapeutic Biomarkers for Muscle Invasive Bladder Carcinoma

Urothelial carcinoma (UC) is the second most common urologic malignancy after prostatic adenocarcinoma. UC comprises more than 90% of urinary bladder tumours. The intense research involving the different molecular aspects of bladder malignancies offers potential opportunities to improve understanding of bladder cancer biology; helps to identify disease earlier; and improves prediction of outcomes or helps targeted therapy. This review highlights the general concepts of the molecular features: molecular pathways for bladder carcinomas and molecular biomarkers for potential target for treatment of UC of the bladder. This discussion could improve the understating of pathogenesis as well as will provide new therapeutic modules, e.g., targeted therapy. This article is a review of bladder cancer genetics, focusing on molecular changes and their significance in the pathogenesis and progression of muscle invasive UC. Also, the relevant genetic biomarkers and their products, and new therapeutic targets and agents that are being developed are presented here.

Variation of renal function in patients with urothelial carcinoma treated by tislelizumab-based immunochemotherapy.

494 Background: Treatment based on PD-1 ICIs brings advances to the treatment of urothelial carcinoma (UC). Although acute renal insufficiency is not common in iRAEs, the safety of immunotherapy in patients with renal impairment is still unknown. Consequently, we intend to investigate the effect of immunochemotherapy on nephritic function in the short term. Methods: Between July 2019 and September 2022, data of patients (pts) with UC that underwent tislelizumab based immunochemotherapy, including demographic information (age, gender), and creatinine level in baseline, after the first, second and third cycle (C1, C2 and C3) of immunotherapy in the Second Hospital of Tianjin medical University was collected and analyzed retrospectively. Estimated glomerular filtration rate (eGFR) is calculated according to CKD-EPI formula 2009, while pts were subdivided into different groups according to baseline eGFR, referencing to CKD categories in the K-DIGO 2012 guidelines for CKD classes. Data analyses were conducted using paired samples Wilcoxon Signed Rank Test and Kruskal-Wallis H test. Results: 163 pts have been included in our analyse totally. The median age was 67 years (IQR 61-74) and 128 (78.5%) were male. 135 (82%) pts received ICIs as perioperative treatment, while 19 (12%) pts were treated after radical operation. Metastasis is found in 9 (6%) pts before firstly received immunotherapy. Median creatinine (Cr) in baseline was 80.2umol/L (IQR 68.3-95.8), while median EGFR was 82.6 (IQR 64.3-93.8) mL/min/1. 73m2 in all pts. According to CKD categories in the K-DIGO 2012 guidelines, at baseline, 57 pts are classified as G1 (eGFR≥90 mL/min/1.73m2), 74 pts as G2(eGFR &lt;90 mL/min/1.73 m2 and≥60 mL/min/1.73 m2), 30 as G3 (eGFR &lt;60 mL/min/1.73 m2 and≥30 mL/min/1.73 m2), and 2 as G4 (eGFR &lt;30 mL/min/1.73 m2 and≥15 mL/min/1.73 m2). No significant difference in eGFR between pts with CKD G1-2 in comparison to baseline and after the first (C1), second (C2) or third cycle(C3) of tislelizumab based immunotherapy (All p &gt;0.05). Notably, we found that eGFR improved in pts with CKD G3-4 when the first, second and third cycle completed, in comparison to the baseline.(p&lt;0.001, &lt;0.001, =0.002). Conclusions: Despite renal impairment is common in pts with UC, no evidence suggests that it is contraindicated for tislelizumab based treatment. More importantly, PD-1 immunotherapy may provide better nephritic benefits in patients with renal insufficiency. [Table: see text]

Site-Specific Differences in PD-1 Blockade Success and Biomarkers in Urothelial Carcinoma Treated with Pembrolizumab.

Since tumors in different human organs may have different tumor microenvironments, we evaluate time-course changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC. A total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 criteria. The serum CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration. Site-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P=.005) and CRP kinetics (P=.035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis. We revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts.

Hypoxia inducible factor‐1 activator munc‐18‐interacting protein 3 promotes tumour progression in urothelial carcinoma

AbstractBackgroundAlthough the introduction of multiple agents targeting immune and oncogenic signaling pathways has substantially changed the treatment strategies for urothelial carcinoma (UC), these drugs still have some limitations, such as adverse effects and limited responses depending on the molecular subtype of UC. Therefore, the development of novel molecular‐targeted therapies is required. Munc18‐1‐interacting protein 3 (Mint3), which specifically activates hypoxia inducible factor‐1 (HIF‐1) during normoxia in cancer and some stromal cells, might be a good target for UC treatment without severe adverse effects. However, the expression and function of Mint3 in UC remain unclear.MethodsWe prepared bladder cancer (n = 117) and upper tract UC (n = 207) cohorts and analyzed the correlation between Mint3 expression in the tissue microarray and the clinicopathological factors/prognosis. To clarify the function of Mint3 in UC cells, control and Mint3‐depleted UC cells were analyzed for HIF‐1 activity, HIF‐1 target gene expression, cell proliferation, glycolysis, motility and invasion in vitro. Tumorigenicity and angiogenesis in control and Mint3‐depleted UC cells were analyzed in mouse xenograft models. A Mint3 inhibitor, naphthofluorescein and gemcitabine were administrated into UC xenograft‐bearing mice.ResultsMint3 was expressed at various levels in UC cells; high expression was correlated with a poor prognosis but not with the molecular subtype of UC in two independent UC cohorts. Mint3 depletion did not affect cell proliferation but attenuated HIF‐1 activity, HIF‐1 target gene expression, glycolysis and motility/invasion in both luminal‐ and basal‐molecular‐subtype UC cells in vitro. Mint3 depletion in UC cells also attenuated tumour growth and angiogenesis in xenograft models. In addition, pharmacological inhibition of Mint3 sensitized chemo‐resistant UC xenografts to gemcitabine.ConclusionsOur findings indicate that Mint3 is a potential target for UC therapy with or without chemotherapy, independent of the molecular subtype of UC.

Increasing Biomarker Guidance in the Treatment of Urothelial Carcinoma: Systematic Review of International Clinical Trials

Purpose: Precision oncology requires biomarker testing from tumor tissue for clinical decision-making and selection of targeted therapies. We systematically evaluated the role of tissue biomarker testing within interventional clinical trials for locally advanced and metastatic urothelial carcinoma (UC). Methods: A systematic search within the publicly available ClinicalTrials.gov database was performed for the period 1995 to January 2020. We searched for all interventional studies on systemic treatments for advanced UC. Two investigators independently screened the records and extracted the data for statistical analyses. Results: We included 356 studies out of 827 initial records in the final analysis. The overall number of interventional trials in UC patients significantly increased during the past 25 years. Forty-three studies (12.1%) required specific biomarker testing as a prerequisite for inclusion. Of the remaining 313 trials, explorative biomarkers of interest were studied in 83 studies (23.3%). In trials with obligate biomarker testing as a precondition for study inclusion, only 3 studies (7%) required an actual fresh pretreatment biopsy, while the majority of studies did not state any tissue requirements (55.8%) or accepted archival tissue samples (37.3%). Among studies without biomarker prerequisites, freshly obtained tissue samples were required in 16.3% of studies evaluating immune checkpoint inhibition and 5.7% evaluating targeted therapy. The collection of archival tissue was allowed in 67.4% and 20% of studies evaluating immune checkpoint inhibitors and targeted therapies, respectively. Conclusion: There has been an increase in the number of studies using biomarker-guided interventions for the treatment of advanced UC over the past 25 years. Studies investigating druggable targets in actual UC biopsies immediately before treatment are still rare. Standardized criteria for tissue-based biomarker testing may further accelerate personalized treatment of patients with advanced UC.

CDCP1 expression is frequently increased in aggressive urothelial carcinoma and promotes urothelial tumor progression

The prognosis of patients with advanced urothelial carcinoma (UC) remains poor and improving treatment continues to be a major medical need. CUB domain containing protein 1 (CDCP1) is a known oncogene in various types of solid cancers and its overexpression is associated with impaired prognosis. However, its role in UC remains undetermined. Here we assessed the clinical relevance of CDCP1 in two cohorts of UC at different stages of the disease. Immunohistochemistry showed that CDCP1 is highly expressed in advanced UC, which significantly correlates with shorter overall survival. Importantly, the basal/squamous UC subtype showed significantly enriched CDCP1 at the mRNA and protein levels. The functional role of CDCP1 overexpression was assessed taking advantage of ex vivo organoids derived from the CDCP1pcLSL/+ transgenic mouse model. Furthermore, CDCP1 knockout UC cell lines were generated using CRISPR/Cas9 technology. Interestingly, CDCP1 overexpression significantly induced the activation of MAPK/ERK pathways in ex vivo organoids and increased their proliferation. Similarly, CDCP1 knockout in UC cell lines reduced their proliferation and migration, concomitant with MAPK/ERK pathway activity reduction. Our results highlight the relevance of CDCP1 in advanced UC and demonstrate its oncogenic role, suggesting that targeting CDCP1 could be a rational therapeutic strategy for the treatment of advanced UC.

Oncologic and Renal Function Outcomes of Segmental Ureterectomy Versus Radical Nephroureterectomy for Urothelial Carcinoma of the Ureter

Purpose: The gold standard for treatment of urothelial carcinoma (UC) of the ureter is radical nephroureterectomy (RNU) with bladder cuff excision. However, segmental ureterectomy (SU) can be considered in specific cases, such as serious renal insufficiency or solitary kidney. This study evaluated oncologic and renal function outcomes of SU compared with RNU for treatment of UC of the ureter. Materials and Methods: This single-center retrospective study assessed 99 patients who underwent SU or RNU for UC of the ureter from October 2005 to May 2021. Exclusion criteria were end-stage renal disease managed with regular hemodialysis (10 patients) and previous or concurrent radical cystectomy due to muscle-invasive bladder cancer (20 patients). The study enrolled 69 patients, with 39 in the RNU group and 30 in the SU group, to compare perioperative outcomes and renal function outcomes between the groups. Kaplan–Meier analysis and the log-rank test were performed to compare overall survival (OS), cancer-specific survival (CSS), intravesical recurrence-free survival (IVRFS), and disease-free survival (DFS) between the groups. Results: The mean age was 67.5 years in the RNU group and 68.3 years in the SU group. The median tumor length was 3.2 cm in the RNU group and 2.4 cm in the SU group. Patients who underwent RNU had a significantly decreased estimated glomerular filtration rate at 3 months postoperatively (−6.4 vs. 3.5 mL/min/1.73 m2; P = 0.001). No significant differences were found for OS, CSS, and IVRFS between the groups. However, the SU group had shorter DFS (P = 0.029). Conclusion: Results showed that SU may preserve better renal function. The OS and CSS were comparable between the groups; however, the SU group had shorter DFS. When preservation of renal function is warranted, SU may be considered for patients with UC of the ureter.

Urine and fecal microbiota in a canine model of bladder cancer and comparison of canine and human urine microbiota

Urothelial carcinoma (UC) is the tenth most diagnosed cancer in humans worldwide. Dogs are a robust model for invasive UC as tumor development and progression is similar in humans and dogs. Recent studies in humans have revealed alterations in urine microbiota in individuals with UC; however, microbial alterations in dogs with UC have not been evaluated. The objective of this pilot study was to compare the urine and fecal microbiota of dogs with UC and matched healthy controls. DNA was extracted from urine and fecal samples followed by 16S rRNA sequencing and analyses using QIIME2 and R. Dogs with UC had significantly decreased microbial diversity (Kruskal–Wallis; Shannon, p = 0.048) and altered microbial composition (PERMANOVA: Unweighted UniFrac, p = 0.011) in urine, but not fecal samples. The relative abundance of Fusobacterium was also increased, although not significantly, in urine and fecal samples of dogs with UC. A comparison of canine and human urine microbiota further revealed similarities in dominant microbial taxa across both host species. This study supports the value of dogs as a model for studies on bladder cancer and urine microbiota, and it provides a foundation for future work exploring host-microbe dynamics in UC carcinogenesis, prognosis, and treatment.