Urothelial Tumors Research Articles

Abstract 1901: Disitamab vedotin, a clinical stage HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy in preclinical urothelial cancer models

Abstract Disitamab vedotin (DV, RC48-ADC) is an antibody-drug conjugate (ADC) that selectively delivers cytotoxic drug to HER2-expressing cancer cells. DV is composed of disitamab, a HER2-directed monoclonal antibody, and a vedotin linker-payload system, which enables conjugation of the microtubule-disrupting agent monomethyl auristatin E (MMAE) to the antibody via a protease-cleavable linker. The proposed mechanism of action (MOA) of DV occurs through direct cytotoxicity of HER2-expressing tumor cells following internalization of DV and intracellular release of MMAE. DV may also induce antitumor activity through bystander-mediated cytotoxicity of neighboring cells and via the inhibition of HER2 signaling pathways. Moreover, cellular response to MMAE includes the induction of immunogenic cell death and recruitment of immune cells to the tumor site. DV is currently being evaluated globally in subjects with HER2-expressing locally advanced or metastatic urothelial carcinoma (la/mUC) and has gained conditional approval in China following an overall response rate of 50.5% (pooled analysis from studies NCT03507166 and NCT03809013). RNA sequencing data from a large cohort of urothelial cancer patient tumors revealed expression of HER2 in many urothelial tumors; however, the relationship between HER2 expression and efficacy of DV is not well understood. Here, we sought to evaluate the antitumor activity of DV monotherapy in preclinical urothelial cancer models with varying levels of HER2 expression. Multiple patient-derived xenografts (PDX) and patient-derived 3D in vitro urothelial cancer models showed potent antitumor response to DV monotherapy in tumors with varying HER2 expression levels including HER2-low tumors. Overall, these findings support ongoing clinical trials in subjects with HER2-expressing la/mUC and provide scientific rationale to further explore DV monotherapy in HER2-positive and HER2-low urothelial cancer clinical settings. Citation Format: Renee Hein, Kelsi Willis, Gina LoMastro, Suhas Vasaikar, Vinita Gupta, Katie Snead, Sharsti Sandall, Anita Kulukian. Disitamab vedotin, a clinical stage HER2-directed antibody-drug conjugate, shows potent antitumor activity as a monotherapy in preclinical urothelial cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1901.

Abstract 1046: Prevalence of MTAP deficiencyin human cancer: A tissue microarray study on 17,078 cancers from 149 different tumor types

Abstract The S-methyl-5′-thioadenosine phosphorylase (MTAP) gene is located at 9p21 and is often co-deleted with CDKN2A. Because homozygous MTAP deletions result in a complete expression loss, MTAP immunohistochemistry (IHC) can be used for detection of homozygous deleted cells. MTAP IHC is of diagnostic utility for the distinction of mesotheliomas (often 9p21 deleted) from benign mesothelial proliferations. Moreover, evidence is emerging that MTAP deficiency results in a critical vulnerability of cancer cells towards drugs targeting several different pathways that depend on a functional MTAP gene and also causes resistance to immune checkpoint inhibitors. To determine the prevalence of complete MTAP expression loss and to assess the diagnostic utility of MTAP IHC, a tissue microarray containing 17,078 samples from 149 different tumor entities and 608 samples of 76 different normal tissue types was analyzed by IHC. All cases with complete MTAP loss were validated by fluorescence in situ hybridization (FISH). In normal tissues, MTAP was ubiquitously expressed resulting in a cytoplasmic and nuclear MTAP staining. At least one case with a complete MTAP expression loss was observed in 87 of 149 (58%) tumor categories. MTAP staining was most commonly lost in neuroendocrine neoplasms of various sites (up to 80%), Hodgkin’s lymphoma (38%), mesothelioma (24-30%), bilio-pancreatic adenocarcinomas (9-36%), urothelial neoplasms (19-29%), malignant melanoma (14-21%), mucinous carcinoma of the ovary (27%), squamous cell carcinomas of various organs of origin (up to 24%), various types of sarcomas (up to 20%), adenocarcinoma of the lung (11%), gastro-esophageal adenocarcinomas (2.6-11%), and in various types of non-Hodgkin’s lymphomas (up to 14%). FISH validation identified homozygous 9p21 deletions in 90-98% of cases with MTAP expression loss in most tumor categories including urothelial neoplasms, mesotheliomas, and pancreatic cancers, and others. There were, however, also tumor types such as neuroendocrine tumors and Hodgkin’s lymphomas that always lacked 9p21 deletions. In summary, our data provide a comprehensive overview on MTAP expression in cancer and show a strong link between MTAP expression loss and homozygous 9p21 deletions in most tumor entities. These cancers might most benefit from cancer drugs targeting MTAP deficiency. The absence of 9p21 deletions in other entities with frequent MTAP expression loss demonstrates that other mechanisms can cause significant MTAP downregulation. Whether these tumors benefit from targeting MTAT deficiency remains to be determined. Citation Format: Natalia Gorbokon, Maximilian Lennartz, Doris Hoeflmayer, Sebastian Dwertmann Rico, Simon Kind, Viktor Reiswich, Florian Viehweger, Florian Lutz, Christoph Fraune, Andreas M. Luebke, Claudia Hube-Magg, Franziska Büscheck, Anne Menz, Ria Schlichter, Till Krech, Andrea Hinsch, Eike Burandt, Guido Sauter, Ronald Simon, Stefan Steurer, Andreas H. Marx, Patrick Lebok, David Dum, Sarah Minner, Frank Jacobsen, Till S. Clauditz, Christian Bernreuther, Martina Kluth. Prevalence of MTAP deficiencyin human cancer: A tissue microarray study on 17,078 cancers from 149 different tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1046.

Abstract 4632: Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial bladder cancer

Abstract Bladder cancers display a wide spectrum of morphologies that frequently co-exist within individual tumors. Several histologic variants, including plasmacytoid, neuroendocrine, and micropapillary subtypes, are associated with an increased bladder cancer recurrence risk and cancer-specific mortality. The molecular basis and therapeutic implications of this phenotypical plasticity remain poorly understood. Enfortumab vedotin (EV), an antibody-drug conjugate targeting Nectin-4, has also emerged as a new standard-of-care for metastatic bladder cancer patients, but the association between lineage plasticity as manifested by morphologic heterogeneity in bladder cancer, Nectin-4 expression and ADC response remains poorly defined. Previous DNA-based molecular profiling studies of histologic variants revealed that CDH1 mutations were the pathognomonic molecular alteration in plasmacytoid urothelial carcinoma, but no recurrent driver mutations have been found to be unique to the aberrant histology regions of other mixed histology subtypes. Thus, to explore the molecular basis for the lineage plasticity of bladder cancers with aberrant histology and to define the association between lineage plasticity manifested as morphologic heterogeneity and the expression of Nectin-4, HER2 and other potential ADC targets, we performed RNA-seq of pure urothelial carcinomas (n=118, not otherwise specified, UC-NOS) and bladder tumors with divergent differentiation or histologic subtypes (n=199). Our cohort included a subset of tumors in which RNA-seq was performed on microdissected UC-NOS and variant histology regions of the same tumor. Tumors with neuroendocrine, sarcomatoid and squamous histology had the lowest Nectin-4 expression, whereas histologic subtypes that retained a luminal transcriptional profile such as micropapillary, plasmacytoid and nested histology had higher levels of Nectin-4 expression. In mixed histology tumors, Nectin-4 and/or HER2 expression was often restricted to only one of the two histologic components. Gene Set Enrichment Analysis noted enrichment of distinct oncogenic pathway gene sets in different histologic variants. Preliminary investigation into the mechanism(s) of Nectin-4 regulation using bladder cancer cell lines and patient-derived organoids (PDOs) has identified targetable pathways which when inhibited revert lineage plasticity and induce Nectin-4 expression. In sum, lineage plasticity manifested as heterogenous histomorphologies was associated with heterogeneous Nectin-4 expression in some but not all histologic variants of bladder cancer. Ongoing studies using PDOs from bladder cancer patients with mixed histology will seek to identify molecular pathways whose inhibition leads to increased expression of Nectin-4 or other ADC targets such as HER2 and thus increased sensitivity of ADCs targeting these cell surface proteins. Citation Format: Jiaqian Luo, Sizhi P. Gao, Fengshen Kuo, Gamze Gokturk Ozcan, Merve Basar, Florestan Koll, Jacob E. Tallman, Syed M. Alam, Carissa E. Chu, Ziyu Chen, Eugene J. Pietzak, Gopakumar Iyer, Jonathan E. Rosenberg, David B. Solit, Hikmat Al-Ahmadie. Lineage plasticity as a determinant of antibody-drug conjugate target expression in urothelial bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4632.

Abstract 1737: METTL3-mediated m6A modification promotes tumor progression in upper tract urothelial carcinoma

Abstract Upper tract urothelial carcinoma (UTUC), comprising 5% of urothelial neoplasms, is a rare malignancy arising from the transitional epithelium of the renal pelvis and ureter. Its rarity and diverse histology pose diagnostic and therapeutic challenges, often lead to delayed diagnoses. The absence of targeted therapies, coupled with a limited understanding of molecular pathogenesis, underscores the ongoing research in urological oncology for effective UTUC management. N6-methyladenosine (m6A) is the predominant RNA methylation in mammalian cells, with its inscription primarily orchestrated by METTL3, a crucial methyltransferase. METTL3 has been implicated in various cancers, affecting critical processes like proliferation, migration, and tumor progression. However, the specific mechanisms and biological function of how METTL3/m6A regulates the progression of UTUC remain unclear. In our study, we found that m6A modification and METTL3 expression were elevated in aggressive UTUC, both are negatively correlated with unfavorable clinical outcomes and poor patient survival. By overexpressing METTL3 in less aggressive UTUC cell lines BFTC909 and KTCC28, the abilities of cell proliferation, migration, invasion, and colony formation increased. Notably, overexpression of METTL3 also increased tumor growth and metastasis in the in vivo orthotopic mouse model. In contrast, knockdown of METTL3 decreases tumor progression in a highly aggressive UTUC cell line KTCC28M. Furthermore, our comparative analysis of RNA-seq and m6A MeRIP-seq datasets unveiled the regulation of 1660 genes by METTL3. This diverse set includes genes associated with tumor growth and metastasis (such as MYC, JAK2, and STAT3), as well as RNA processing-related genes which their critical roles in modulating mRNA stability and splicing (such as GEMIN5 and PABPC1L). Together, we noticed METTL3/m6A is a crucial protagonist in the oncogenic landscape of UTUC, which suggested that it can be used as a target for novel therapeutic strategy for UTUC treatment. Citation Format: LI-JIE LIN, PEI-HUA PENG, KAI-WEN HSU. METTL3-mediated m6A modification promotes tumor progression in upper tract urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1737.

Novel meriolin derivatives activate the mitochondrial apoptosis pathway in the presence of antiapoptotic Bcl-2

Meriolin derivatives represent a new class of kinase inhibitors with a pronounced cytotoxic potential. Here, we investigated a newly synthesized meriolin derivative (termed meriolin 16) that displayed a strong apoptotic potential in Jurkat leukemia and Ramos lymphoma cells. Meriolin 16 induced apoptosis in rapid kinetics (within 2–3 h) and more potently (IC50: 50 nM) than the previously described derivatives meriolin 31 and 36 [1]. Exposure of Ramos cells to meriolin 16, 31, or 36 for 5 min was sufficient to trigger severe and irreversible cytotoxicity. Apoptosis induction by all three meriolin derivatives was independent of death receptor signaling but required caspase-9 and Apaf-1 as central mediators of the mitochondrial death pathway. Meriolin-induced mitochondrial toxicity was demonstrated by disruption of the mitochondrial membrane potential (ΔΨm), mitochondrial release of proapoptotic Smac, processing of the dynamin-like GTPase OPA1, and subsequent fragmentation of mitochondria. Remarkably, all meriolin derivatives were able to activate the mitochondrial death pathway in Jurkat cells, even in the presence of the antiapoptotic Bcl-2 protein. In addition, meriolins were capable of inducing cell death in imatinib-resistant K562 and KCL22 chronic myeloid leukemia cells as well as in cisplatin-resistant J82 urothelial carcinoma and 2102EP germ cell tumor cells. Given the frequent inactivation of the mitochondrial apoptosis pathway by tumor cells, such as through overexpression of antiapoptotic Bcl-2, meriolin derivatives emerge as promising therapeutic agents for overcoming treatment resistance.

Primary mucinous adenocarcinoma of the ureter and renal pelvis: A case report.

Primary adenocarcinoma rarely occurs in the upper urinary tract and accounts for less than 1% of the urothelial tumors. Here we present a case report of a 45-year-old female patient who presented with a lump in the abdomen and pain in the right lumbar region for 2 months. Various radiological investigations revealed right-sided hydronephrosis with enhancing masses in the right proximal ureter and renal pelvis associated with multiple calculi. A gross examination of the right nephrectomy specimen revealed multiple cystic areas filled with mucinous material and papillary projections in the renal pelvis. A necrotic growth was observed in the right proximal ureter in association with the staghorn calculus in the renal pelvis. Histological examination of the ureteric mass and solid areas from the renal pelvis showed acini and papillary projections lined by pseudostratified columnar epithelium showing malignant changes. Surrounding areas also revealed intestinal metaplasia with moderate to marked dysplasia in some places. The ureteric malignancy was observed to infiltrate the inner two-thirds of the wall of the ureteric muscular layer and extend until the margin of excision. Thus, a diagnosis of mucinous adenocarcinoma of the ureter and renal pelvis with intestinal metaplasia and dysplasia that occurred in association with a large staghorn calculus was made.

The role of URO17® in diagnosis and follow up of bladder cancer patients

Objectiveto evaluate the role of urinary URO17® biomarker in the detection of urothelial tumors in haematuria patients and the detection of recurrence in non-muscle invasive bladder urothelial tumors.Materials and methodsOur study was formed of two cohorts of patients, group I represents patients presenting with haematuria (n = 98), while group II represents patients with known non-muscle invasive bladder cancers on their scheduled follow up cystoscopic investigation (n = 51). For both groups, patients were asked to provide urine samples before cystoscopy, either primary as part of the haematuria investigation or as a scheduled follow-up. Urine samples were sent anonymously for standard urine cytology and URO17® biomarker immunostaining. Results were compared to cystoscopic findings using Chi-square analysis and Fisher’s exact test (P < 0.05).ResultsGroup I was formed of 98 patients, with an average age of 60 years. URO17® showed 100% sensitivity and 96.15% specificity with a negative predictive value (NPV) of 100 and a positive predictive value (PPV) of 95.83. The results showed statistical significance with P value < 0.001. Group II was formed of 51 patients, with an average age of 75 years. URO17® was shown to have a sensitivity of 85.71% and NPV of 95.45. Eleven patients of group II were on scheduled BacillusCalmette-Guerin (BCG) and another 5 received Mitomycin C (MMC). The overall results of both groups combined (n = 149) showed statistical significance between flexible cystoscopy results and the results of urinary URO17® and urine cytology.ConclusionURO17® has a potential to be a reliable test for diagnosis and follow up of urothelial cancer patients and a screening tool adjunct to flexible cystoscopy.Trial RegistrationNot applicable as the current study is not a clinical trial, as per according to the National Institutes of Health, “studies that involve a comparison of methods and that do not evaluate the effect of the interventions on the participant do not meet the NIH clinical trial definition.”

Conservative management of an early abdominal complication during a Tullio percutaneous endoscopic excision of renal pelvis urothelial carcinoma: A case report

BACKGROUND Upper tract urothelial carcinoma (UTUC) representing only a small fraction of all urothelial tumors. It predominantly affects the renal pelvis in men, often coexisting with bladder carcinoma. UTUC displays a more aggressive genetic profile compared to bladder neoplasms, with the majority of patients presenting with advanced disease. Histologically, about a quarter of UTUC cases exhibit high-grade subtypes, associated with a worse prognosis. Tobacco use and past exposure to aromatic amines are significant risk factors for UTUC. Imaging modalities such as Uro-computed tomography and magnetic resonance imaging play crucial roles in diagnosis. Ureterorenoscopy is vital for direct visualization and biopsy sampling, but its limited sampling capacity presents challenges in determining tumor depth and staging. Traditionally, nephroureterectomy with bladder cuff excision has been the gold-standard treatment for UTUC. Endoscopic conservative treatment has recently emerged as a viable option for selected patients, offering comparable oncological outcomes to radical surgery. Percutaneous access is also feasible for larger intrarenal tumors. CASE SUMMARY We present a case of an 84-year-old woman who underwent percutaneous endoscopic excision of a renal pelvis neoplasm using the Tullio laser. Despite successful tumor removal, the patient experienced a postoperative complication with abdominal fluid leakage. Conservative management effectively resolved the complication. Given the patient's age and refusal for radical surgery, the conservative approach proved to be a valid therapeutic choice. CONCLUSION Overall, UTUC remains a diagnostic and therapeutic challenge due to its rarity. However, advances in endoscopic and percutaneous techniques provide valuable alternatives for selected patients, warranting further exploration in this evolving field.

La version 2022 du Système de Paris : quoi de neuf ?

The second version of the Paris System for reporting urine cytology was published in 2022. It follows the first version in 2016, which was very successful and widely adopted by many cytopathologists from different countries. Thus, numerous publications using the Paris system have made it possible to refine the criteria as well as discussing the limits. The diagnosis accuracy of urinary cytology is high for detection of high grade urothelial carcinoma, but not for low-grade where there are few cytological abnormalities. So, the chapter individualizing low-grade urothelial neoplasms was deleted, the latter were included in the category “negative for high-grade urothelial carcinoma‿. Indeed, the risk of malignancy is replaced by the risk of high-grade urothelial carcinoma. A new chapter has been devoted to urothelial tumors of the upper tract. Finally, the pitfalls linked to cellular degeneration are discussed for each category. The risk of high-grade malignancy associated with each category, will help communication with the clinician and patient care.

Loss of TROP2 and epithelial cell adhesion molecule expression is linked to grade progression in pTa but unrelated to disease outcome in pT2-4 urothelial bladder carcinomas.

Trophoblast cell surface antigen 2 (TROP2; EpCAM2) is a transmembrane glycoprotein which is closely related to EpCAM (EpCAM; EpCAM1). Both proteins share partial overlapping functions in epithelial development and EpCAM expression but have not been comparatively analyzed together in bladder carcinomas. TROP2 constitutes the target for the antibody-drug conjugate Sacituzumab govitecan (SG; TrodelvyTM) which has been approved for treatment of metastatic urothelial carcinoma by the United States Food and Drug administration (FDA) irrespective of its TROP2 expression status. To evaluate the potential clinical significance of subtle differences in TROP2 and EpCAM expression in urothelial bladder cancer, both proteins were analyzed by multiplex fluorescence immunohistochemistry in combination with a deep-learning based algorithm for automated cell detection on more than 2,700 urothelial bladder carcinomas in a tissue microarray (TMA) format. The staining pattern of TROP2 and EpCAM were highly similar. For both proteins, the staining intensity gradually decreased from pTa G2 low grade (TROP2: 68.8±36.1; EpCAM: 21.5±11.7) to pTa G2 high grade (64.6±38.0; 19.3±12.2) and pTa G3 (52.1±38.7; 16.0±13.0, p<0.001 each). In pT2-4 carcinomas, the average TROP2 and EpCAM staining intensity was intermediate (61.8±40.9; 18.3±12.3). For both proteins, this was significantly lower than in pTa G2 low grade (p<0.001 each) but also higher than in pTa G3 tumors (p=0.022 for TROP2, p=0.071 for EpCAM). Within pT2-4 carcinomas, the TROP2 and EpCAM staining level was unrelated to pT, grade, UICC-category, and overall or tumor-specific patient survival. The ratio TROP2/EpCAM was unrelated to malignant phenotype and patient prognosis. Our data show that TROP2 and EpCAM expression is common and highly interrelated in urothelial neoplasms. Despite of a progressive loss of TROP2/EpCAM during tumor cell dedifferentiation in pTa tumors, the lack of associations with clinicopathological parameters in pT2-4 cancer argues against a major cancer driving role of both proteins for the progression of urothelial neoplasms.

Clinical, Pathological Characteristics and Progression of Urothelial Bladder Cancer in Young Adult Patients. Our Experience and Literature Review.

Bladder cancer is highly prevalent even though its incidence is considerably lower in patients younger than 40 years, thus raising the issue of the influence of age at diagnosis on the natural history of this disease. This study aimed to evaluate the characteristics and progression of young patients with urothelial bladder carcinoma with at least 10 years of follow-up and to compare the results with those of previously reported studies. A retrospective study between 1990 and 2007 was conducted. The medical records and tissue samples of patients with urothelial bladder tumours were reviewed, and patients with a first diagnosis of urothelial carcinoma of the bladder at age 40 years or younger were selected. Their clinical and pathological data and disease-free survival were analysed. This study included 43 patients, with a median follow-up of 152 months (interquartile range (IQR): 96-222) and a mean age at diagnosis of 34 years (SD: 4.6). Thirty-five patients (81.4%) had non-muscle invasive tumours at diagnosis, and 53.5%, 27.9% and 18.6% had tumour grades of G1, G2 and G3, respectively. Fifteen patients (34.9%) experienced recurrence, and eight (18.6%) progressed. At 24 and 60 months, the recurrence-free survival rates were 84.8% (95% confidence interval (CI): 69.2%-92.9%) and 68.9% (95% CI: 51.7%-81%), respectively, and the progression-free survival rates were 94.9% (95% CI: 81%-98.7%) and 92.2% (95% CI: 77.8%-97.4%), respectively. Bladder cancer is an uncommon disease in young patients. In most cases, it consists of non-muscle-invasive tumours, with a low rate of recurrence and progression. The prognosis is based on the tumour's characteristics and not on the patient's age.

Correlation between urine cytology results on the day after overnight continuous saline irrigation following transurethral resection of bladder tumor and bladder tumor recurrence.

To investigate the relationship between urine cytology results after overnight continuous saline irrigation (OCSI) following transurethral resection of bladder tumor (TURBT) and bladder tumor recurrence in non-muscle invasive bladder cancer (NMIBC). A retrospective study was conducted on patients diagnosed with NMIBC between 2016 and 2020 after undergoing TURBT at our hospital. All patients received OCSI following TURBT and had urine cytology test at postoperative 1 day. Urine cytology was classified into three groups: Negative, low-grade urothelial neoplasm (LGUN)+atypical urothelial cells (AUC), and suspicious for high-grade urothelial carcinoma (SHGUC)+high-grade urothelial carcinoma (HGUC). Recurrence-free survival (RFS) in each group was compared using the Kaplan-Meier method. Univariable and multivariable Cox regression analyses were performed to evaluate independent prognostic factors. A total of 172 patients were included in this study. Based on urine cytology group (after OCSI), RFS did not reach the median value in the Negative group. In the LGUN+AUC group, the median RFS was 615.00 days. In the SHGUC+HGUC group, the median RFS was 377.00 days. In survival analysis, the Negative group had a longer RFS than the SHGUC+HGUC group (p=0.013). However, Cox regression analysis showed that SHGUC+HGUC was not an independent prognostic factor for recurrence. Urine cytology results after OCSI following TURBT in NMIBC were associated with bladder tumor recurrence. Specifically, SHGUC or HGUC in urine cytology after OCSI showed earlier recurrence than negative cases. However, further research is needed to accurately determine whether it is an independent prognostic factor.

Combined expression of JHDM1D/KDM7A gene and long non-coding RNA RP11-363E7.4 as a biomarker for urothelial cancer prognosis.

Bladder cancer is the tenth most frequently diagnosed cancer globally. Classification of high- or low-grade tumors is based on cytological differentiation and is an important prognostic factor. LncRNAs regulate gene expression and play critical roles in the occurrence and development of cancer, however, there are few reports on their diagnostic value and co-expression levels with genes, which may be useful as specific biomarkers for prognosis and therapy in bladder cancer. Thus, we performed a marker lesion study to investigate whether gene/lncRNA expression in urothelial carcinoma tissues may be useful in differentiating low-grade and high-grade tumors. RT-qPCR was used to evaluate the expression of the JHDM1D gene and the lncRNAs CTD-2132N18.2, SBF2-AS1, RP11-977B10.2, CTD-2510F5.4, and RP11-363E7.4 in 20 histologically diagnosed high-grade and 10 low-grade tumors. A protein-to-protein interaction network between genes associated with JHDM1D gene was constructed using STRING website. The results showed a moderate (positive) correlation between CTD-2510F5.4 and CTD2132N18.2. ROC curve analyses showed that combined JHDM1D and RP11-363E7.4 predicted tumor grade with an AUC of 0.826, showing excellent accuracy. In conclusion, the results indicated that the combined expression of JHDM1D and RP11-363E7.4 may be a prognostic biomarker and a promising target for urothelial tumor therapy.

Initial Experience of Robot-Assisted Nephroureterectomy without Intraoperative Repositioning Using a New Robotic Surgical System (KD-SR-01TM).

Robot-assisted nephroureterectomy (RANU) has been more and more applied since 21st century. However, the high cost limits the widespread use of robot system. A relatively low-cost new robotic surgical system (KD-SR-01™) has recently been developed in China. To assess the safety and efficacy of the KD-SR-01™ Surgical System in RANU. Patients with upper-tract urothelial tumor and undergoing RANU with the KD-SR-01™ Robotic System were prospectively included. Surgeries were all performed by a single surgeon. Patients' demographic and clinical characteristics, perioperative data, pathology findings, and follow-up data were collected. Key Findings. 9 patients were enrolled in this study, and the surgeries went smoothly with no conversion to open. The 1st docking time, the 2nd docking time, and the operation time were 222 s, 169 s, and 202 min respectively. No equipment-related adverse events occurred. All patients were followed up for at least 3 months, and one patient experienced bladder recurrences. Conclusions and Clinical Implications. This study is the first to verify that the KD-SR-01™ robot system is effective and safe in RANU and has advantages in terms of its rotation boom during redocking and its price. This trial is registered with ChiCTR2200056672.

Üreterde Cut-off İşareti

Obstructive uropathy occurs due to common causes such as kidney stones, vesicoureteral reflux, posterior urethral valve and urothelial tumors. In addition, there are rare causes such as solid tumors, retroperitoneal fibrosis, primary lymphomas (Non-Hodgkin lymphomas etc.). A 20-year old male with lower back pain underwent a bone scan for differential diagnosis of back pain. The bone scan findings were normal, except for the presence of unilateral renal stasis accompanied by a short segment ureteral stasis. Due to the abrupt termination of the ureteral activity, namely the “cutoff sign”, a subsequent SPECT/CT imaging was focused for differential diagnosis of ureteral stasis. Non-diagnostic CT sections revealed a para-aortic soft tissue mass compressing the ureter. This case underlines the added value of SPECT/CT imaging in subtle scintigraphic findings. The abrupt termination of stasis in the ureter may warrant the application of SPECT/CT in cases with no previous history of urinary tract pathology. SPECT / CT may provide additional benefits of clarifying the etiology.

The Relationship between Trop-2, Chemotherapeutic Drugs, and Chemoresistance.

Trop-2 is a highly conserved one-pass transmembrane mammalian glycoprotein that is normally expressed in tissues such as the lung, intestines, and kidney during embryonic development. It is overexpressed in many epithelial cancers but is absent in non-epithelial tumors. Trop-2 is an intracellular calcium signal transducer that participates in the promotion of cell proliferation, migration, invasion, metastasis, and probably stemness. It also has some tumor suppressor effects. The pro-tumoral actions have been thoroughly investigated and reported. However, Trop-2's activity in chemoresistance is less well known. We review a possible relationship between Trop-2, chemotherapy, and chemoresistance. We conclude that there is a clear role for Trop-2 in some specific chemoresistance events. On the other hand, there is no clear evidence for its participation in multidrug resistance through direct drug transport. The development of antibody conjugate drugs (ACD) centered on anti-Trop-2 monoclonal antibodies opened the gates for the treatment of some tumors resistant to classic chemotherapies. Advanced urothelial tumors and breast cancer were among the first malignancies for which these ACDs have been employed. However, there is a wide group of other tumors that may benefit from anti-Trop-2 therapy as soon as clinical trials are completed.

Significance of TERT promoter mutation in differential diagnosis of non-invasive inverted urothelial lesions of bladder

Objective: To investigate the gene mutation of telomerase reverse transcriptase (TERT) promoter in inverted urothelial lesions of the bladder and its significance in differential diagnosis. Methods: From March 2016 to February 2022, a total of 32 patients with inverted urothelial lesions diagnosed in Department of Pathology at Qingdao Chengyang People's Hospital and 24 patients at the Affiliated Hospital of Qingdao University were collected, including 7 cases of florid glandular cystitis, 13 cases of inverted urothelial papilloma, 8 cases of inverted urothelial neoplasm with low malignant potential, 17 cases of low-grade non-invasive inverted urothelial carcinoma, 5 cases of high-grade non-invasive inverted urothelial carcinoma, and 6 cases of nested subtype of urothelial carcinoma were retrospectively analyzed for their clinical data and histopathological features. TERT promoter mutations were analyzed by Sanger sequencing in all the cases. Results: No mutations in the TERT promoter were found in the florid glandular cystitis and inverted urothelial papilloma. The mutation rates of the TERT promoter in inverted urothelial neoplasm with low malignant potential, low grade non-invasive inverter urothelial carcinoma, high grade non-invasive inverted urothelial carcinoma and nested subtype urothelial carcinoma were 1/8, 8/17, 2/5 and 6/6, respectively. There was no significant difference in the mutation rate of TERT promoter among inverted urothelial neoplasm with low malignant potential, low-grade non-invasive inverted urothelial carcinoma, and high-grade non-invasive inverted urothelial carcinoma (P>0.05). All 6 cases of nested subtype of urothelial carcinoma were found to harbor the mutation, which was significantly different from inverted urothelial neoplasm with low malignant potential and non-invasive inverted urothelial carcinoma (P<0.05). In terms of mutation pattern, 13/17 of TERT promoter mutations were C228T, 4/17 were C250T. Conclusions: The morphology combined with TERT promoter mutation detection is helpful for the differential diagnosis of bladder non-invasive inverted urothelial lesions.

Clinical Outcomes of Patients With Variant Histology of Urothelial Carcinoma After Radical Cystectomy

Purpose: The efficacy of standard chemotherapy or radical cystectomy in patients who have urothelial tumors with variant histology (VH) is very limited in terms of their prognosis. This study aimed to investigate the prognosis of bladder cancer (BC) patients with VH who underwent radical cystectomy (RC).Materials and Methods: We retrospectively evaluated 327 BC patients who underwent RC at Pusan National University Yangsan Hospital between February 2010 and June 2021. VH was categorized into less and more aggressive types according to the patient’s mortality risk relative to pure urothelial carcinoma (PUC). More aggressive types included micropapillary, plasmacytoid, and sarcomatoid variants. Less aggressive types comprised other variant types, including squamous differentiation, glandular differentiation, lipoid, and nested. Small cell carcinoma, pure adenocarcinoma, pure squamous cell carcinoma, and lymphoma BC were excluded from analysis. The progression-free survival (PFS) and overall survival (OS) rates were evaluated using Kaplan-Meier analysis and Cox regression.Results: After the exclusion of nonurothelial tumors, data from 299 patients were available for analysis. We identified 244 (74.6%) and 55 patients (16.8%) with PUC and urothelial carcinoma with VH, respectively. VH patients were categorized as having less aggressive (n=35) and more aggressive (n=20) types. Univariate analysis identified significant differences in PFS (p=0.031) between patients with PUC (n=244) and more aggressive VH (n=20). Multivariate analysis showed that more aggressive VH was significantly associated with OS and PFS. In the Kaplan-Meier analysis, a statistically significant difference was observed between PUC and more aggressive VH in OS and PFS.Conclusions: VH patients with more aggressive types showed more advanced TNM stages at presentation than PUC patients. Pathological upstaging after RC was more common in VH patients. Among VH patients, the presence of a more aggressive VH type can be an independent predictor of progression after RC, with a worse prognosis than that of PUC patients.

TRPS1 is a highly sensitive marker for breast cancer: A tissue microarray study evaluating more than 19,000 tumors from 152 different tumor entities

Abstract Introduction/Objective TRPS1 (Trichorhinophalangeal syndrome 1) is a nuclear protein expressed in breast epithelial cells. TRPS1 immunohistochemistry (IHC) has thus been suggested as a marker for breast cancer. However, reports on TRPS1 positivity in other cancer types are piling up. Methods/Case Report To comprehensively determine the diagnostic utility of TRPS1 IHC, tissue microarrays containing 19,201 samples from 152 different tumor types and subtypes were analyzed. GATA3 IHC data were available from 11,891 of these tumors from a previous study. Results (if a Case Study enter NA) TRPS1 positivity occurred in 86 of 152 tumor categories of which 36 contained at least one strongly positive case. TRPS1 staining predominated in various types of breast carcinomas (51%-100%) and was also seen in various subtypes of soft tissue tumors (up to 100%), salivary gland tumors (up to 46%), squamous cell carcinomas (up to 35%), and gynecological cancers (up to 40%) as well as in other tumors. TRPS1 positivity occurred in only 1.8% of 1,083 urothelial neoplasms. Positivity for both TRPS1 and GATA3 occurred in 47.4%-100% of breast cancers, up to 30% of salivary gland tumors, but in only 29 (0.3%) of 9,835 tumors from 134 other cancer entities. Conclusion Although TRPS1 expression can be seen in many different tumor types, TRPS1 Immunohistochemistry has high utility for the identification of cancers of breast or salivary gland origin, especially in combination with GATA3. The virtual absence of TRPS1 positivity in urothelial neoplasms is useful for the distinction of GATA3 positive urothelial carcinoma from breast cancer.

Expression of Gata Binding Protein 3 as a Prognostic Factor in Urogenital Lesions and Its Association With Morphology.

Urogenital malignancies, encompassing urinary bladder cancer, prostate cancer, and renal cell carcinoma, pose significant diagnostic challenges due to overlapping histopathological features. GATA binding protein 3 (GATA3), a transcription factor associated with urothelial tissue, has shown promise as a potential diagnostic marker.This study aimed to investigate the incidence of these malignancies, explore GATA3's involvement in urothelial cancer (UC), and determine its role in distinguishing urogenital malignancies. A cross-sectional, retro-prospective, hospital-based study was conducted from May 2019 to April 2021. The surgical samples of patients who underwent transurethral resection of bladder tumour (TURBT), transurethral resection of the prostate (TURP), radical cystoprostatectomy, total and partial radical nephrectomy specimens during the study period were reviewed. Patients diagnosed with urinary bladder neoplasm and high-grade prostate neoplasm along with chromophobe, oncocytic, sarcomatoid variant and clear cell carcinoma, renalcell carcinoma were included. Immunohistochemical analysis of GATA3 expression was performed, with scoring based on nuclear staining intensity and percentage of tumor cells labeled. The study included 64 patients, predominantly males over 60 years. Personal habits revealed a high prevalence of smoking (85.9%). The most prevalent symptom was hematuria (75.0%), followed by hematuria with urgency (20.3%). The most common site of lesion was posterolateral (31.3%). Urothelial cancer was the most common malignancy, primarily high-grade. Strong positive GATA3 expression was significantly associated with high-grade UC (p=0.01) and invasion (p=0.01). However, low-grade UC and papillary urothelial neoplasm of low malignant potential exhibited moderate GATA3 expression. GATA3 demonstrated potential for distinguishing UC from other histological types. GATA3 expression correlates with high-grade urothelial cancer and invasive behavior, suggesting its utility as a diagnostic marker in challenging cases.