Comparative efficacy of Bacillus Calmette-Guérin instillation and radical cystectomy treatments for high-risk non-muscle-invasive urothelial cancer classified as high-grade T1 in initial and repeat transurethral resection of bladder tumor.

Objective: To compare the differential therapeutic effects of Bacillus Calmette-Guérin (BCG) instillation and radical cystectomy (RC) for high-risk non-muscle-invasive urothelial cancer (NMIBC) classified as high-grade T1 in initial and repeat transurethral resection of bladder tumors (TURBT) and to construct a prediction model. Methods: We retrospectively analyzed the clinical data of patients with malignant bladder tumors treated at the First Affiliated Hospital of Soochow University from January 2016 to December 2017 and compared the differences in 1-year, 2-year, 3-year, 5-year, and comprehensive overall survival (OS) and progression-free survival (PFS) between BCG instillation treatment and RC treatment. Survival curves were drawn to show differences in OS and PFS between the two groups. Concurrently, univariate and multivariate COX analyses were performed to identify risk factors affecting OS and PFS, and a nomogram was created. Results: In total, 146 patients were included in the study, of whom 97 and 49 were in the BCG and RC groups, respectively. No statistical differences were observed in the 1- and 2-year OS and PFS between the two groups, whereas significant statistical differences were found in the 3-year, 5-year, and comprehensive OS and PFS. Survival curves also confirmed the statistical differences in OS and PFS between the BCG and RC groups. Multivariate COX analysis revealed that the treatment method, concomitant satellite lesions, and albumin-to-alkaline phosphatase ratio (AAPR) were independent risk factors affecting OS and PFS. The nomogram that was further plotted showed good predictive ability for OS and PFS. Conclusion: For patients who exhibit high-level T1 pathology after both initial and repeat TURBT, especially those with low AAPR, and concomitant satellite lesions, choosing RC as a treatment method offers a better prognosis.

Diagnostic performance of photodynamic diagnosis with oral 5-aminolevulinic acid for upper tract- and bladder urothelial carcinoma: a single-centre, retrospective analysis.

PURPOSE: To compare the diagnostic performance of photodynamic diagnosis (PDD) enhanced with oral 5-aminolaevulinic acid between the suspected upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BUC) cases. METHODS: This retrospective study included 18 patients with suspected UTUC who underwent ureteroscopy (URS) with oral 5-ALA in the PDD-URS cohort between June 2018 and January 2019; and 110 patients with suspected BUC who underwent transurethral resection of bladder tumour (TURBT) in the PDD-TURBT cohort between January 2019 and March 2023. Sixty-three and 708 biopsy samples were collected during diagnostic URS and TURBT, respectively. The diagnostic accuracy of white light (WL) and PDD in the two cohorts was evaluated, and false PDD-positive samples were pathologically re-evaluated. RESULTS: The area under the receiver operating characteristic curve (AUC) of PDD was significantly superior to that of WL in both cohorts. The per biopsy sensitivity, specificity, and positive and negative predictive values of PDD in patients in the PDD-URS and PDD-TURBT cohorts were 91.2 vs. 71.4, 75.9 vs. 75.3, 81.6 vs. 66.3, and 88.0 vs. 79.4%, respectively. The PDD-URS cohort exhibited a higher AUC than did the PDD-TURBT cohort (0.84 vs. 0.73). Seven of four false PDD-positive samples (57.1%) in the PDD-URS cohort showed potential precancerous findings compared with eight of 101 (7.9%) in the PDD-TURBT cohort. CONCLUSION: The diagnostic performance of PDD in the PDD-URS cohort was at least equivalent to that in the PDD-TURBT cohort.

Multidisciplinary management of sexual and gender minorities with bladder cancer.

Bladder cancer, a common urologic malignancy, has poor morbidity and mortality in sexual and gender minority (SGM) individuals, stemming from higher risk, poor access to care and lack of quality cancer care. To begin addressing this disparity, this review offers key considerations for evaluation, diagnosis and treatment of SGM individuals with bladder cancer. In addition to thorough medical and surgical history, initial evaluation should include discussion of patient goals for sexual function and organ preservation, as well as an evaluation of sexual function. Prior gender affirming surgery and patient specific sexual function goals will impact diagnosis and treatment approaches, including surgical and radiation therapy. Throughout care for SGM individuals with bladder cancer, it is critical to acknowledge the systemic discrimination that may be experienced by these individuals and approach conversations with sensitivity and humility and incorporate mental and social support as appropriate.

The value and safety of adjuvant radiotherapy (ART) after radical cystectomy in locally advanced urothelial bladder cancer: A controlled randomized study.

BACKGROUND: Adjuvant radiotherapy after radical cystectomy in locally advanced bladder cancer was revived after the advancement in precise radiotherapy that decreased the normal pelvic tissue radiation hazards. However, there are still scarce controlled randomized studies addressing this issue. PATIENTS AND METHODS: One hundred thirty-one cystectomized urothelial bladder cancer patients were enrolled; a hundred and twenty-two were randomized to receive adjuvant radiotherapy (ART) 50 Gy/25 fractions, 4 weeks' post-cystectomy or cystectomy alone (CY). Sixty-two were included in the ART arm and sixty in the CY arm. Twenty-four ART and 30 CY patients received Neoadjuvant chemotherapy. Eleven patients (9%) had cotenant neo-bladder diversion, 6 in ART, and 5 in CY arms. All ART patients were treated with intensity-modulated radiotherapy (IMRT) with daily verification cone-beam CT (CBCT). The median follow-up was 42.7 months. RESULTS: The 3-year adjusted Locoregional relapse-free survival (LRFS) rate was higher in the ART arm, measuring 81% (95%CI: 69-94) compared to 71% (95% CI: 60-80) (p=0.0457). ART significantly improved the locoregional relapse-free rate in the cystectomy bed and the pelvic side wall (p= 0.016 and 0.001, respectively). The overall survival, event-free, and distant metastasis-free survival did not rank to the level of statistical significance in the 2 arms. Even though the acute side effects were slightly higher in ART, the late toxicities were almost equal in the two groups. CONCLUSIONS: Adjuvant radiotherapy is safe and quite tolerable after radical cystectomy when using precise radiation techniques. These techniques significantly improved the LRFS but had insignificant improvement on the overall survival. ART did not affect the distant metastasis-free survival. Similar studies are performed in different centers around the world to confirm the value of ART in urothelial bladder cancer.

Enfortumab vedotin-related cutaneous toxicity correlates with overall survival in patients with urothelial cancer: a retrospective experience.

Introduction: Enfortumab vedotin (EV) is an antibody drug conjugate approved for advanced urothelial cancer, consisting of a monomethyl auristatin E payload linked to a human monoclonal antibody targeting nectin-4. No validated biomarker predictive of or correlated with response exists for EV. Cutaneous toxicity is among the most common EV-related toxicities and typically emerges in early cycles. This retrospective experience of patients with urothelial cancer treated with EV monotherapy evaluated whether EV-related cutaneous toxicity correlated with improved outcomes including progression-free (PFS) and overall (OS) survival and overall response rate (ORR). Patients and methods: Patients treated with EV monotherapy at Johns Hopkins were identified, and baseline characteristics, treatment, and toxicity details were extracted through chart review. Univariable Cox hazard ratios (HRs) were calculated for assessing the effect of baseline patient characteristics and cutaneous toxicity in PFS and OS. Based on the univariable analysis and known risk factors, all subsequent analyses were adjusted for: Eastern Cooperative Oncology Group performance status, visceral metastases at baseline, gender as well as EV dose, and weight to account for dosing differences. Multivariable Cox proportional HRs were used for comparing PFS and OS between patients with and without cutaneous toxicity, assessing toxicity and EV dose as a time-dependent variables. Adjusted p-values were calculated to compare ORR and disease control rate (DCR) between groups using the Poisson regression model. Results: Of the 78 patients analyzed, 42 (53.8%) experienced EV-related cutaneous toxicity that appeared early during treatment (median time to occurrence 0.5 months from EV initiation). Cutaneous toxicity correlated with significantly improved OS [HR, 0.48; 95% confidence interval (CI), 0.25, 0.9; P = 0.0235], ORR (68.3% vs. 20.7%, P = 0.0033) and DCR (82.9% vs. 48.3%, P = 0.0122). Median PFS was numerically longer in the cutaneous toxicity group (6.3 vs. 1.7 months), although no significance was achieved in the multivariable analysis (HR, 0.62; 95% CI: 0.35, 0.108; P = 0.0925). Conclusion: In this retrospective study, EV-related cutaneous toxicity was associated with improved patient outcomes. Confirming this observation and understanding its mechanism could lead to discovery of a new clinical biomarker of EV response that can emerge in the first cycle.

Latrophilin-3 as a downstream effector of the androgen receptor induces urothelial tumorigenesis.

Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.

Paraneoplastic dermatomyositis and Stevens-Johnson syndrome related to immunotherapy.

Paraneoplastic syndromes such as dermatomyositis, often emerge as the initial clinical manifestation across various cancer types and are characterized by the development of B-cell responses targeting cancer-cell antigens that cross-react with normal skin and muscle cells. While these syndromes may alleviate following antineoplastic intervention, their response to immunotherapy remains elusive due to the exclusion of patients with autoimmune phenomena from clinical trials. In this report, we present the case of a female patient with advanced urothelial cancer presenting with dermatomyositis, who subsequently underwent treatment with anti-PD1 immunotherapy and experienced the onset of Stevens-Johnson syndrome. We discuss these two autoimmune entities and provide a comprehensive review of the existing literature to elucidate similar associations.

Dermatomyositis, an inflammatory disorder that causes a skin rash, might be the first sign that someone has cancer. But when scientists test new cancer treatments, they often don't include people with this skin problem. So, we do not know much about how safe or effective these treatments are for them. Here's a story about someone who had bladder cancer and dermatomyositis. They received a treatment called immunotherapy, but it caused a serious problem called Stevens-Johnson syndrome. We also found similar cases in medical papers.

Stereotactic body radiation therapy is beneficial for a subgroup of patients with urothelial cancer and solitary metastatic disease: a single institution real-world experience.

BACKGROUND: Standard treatment options for patients with metastatic urothelial cancer (mUC) include systemic platinum-based chemotherapy, immunotherapy, antibody-drug-conjugates, and targeted therapy. Oligometastatic disease (OMD) may be an intermediate state between localized and generalized cancer. The best treatment strategy for OMD and oligoprogressive (OPD) disease is poorly studied in mUC but local stereotactic body radiation therapy (SBRT) could be an option to avoid or delay systemic treatment. The aim of this study was to assess the efficacy and feasibility of SBRT given in a real-world patient population. METHODS: All patients with mUC treated with SBRT at Karolinska University Hospital, Stockholm, Sweden between 2009 and 2022 were included in this study. Baseline clinical characteristics, treatment data, SBRT dosimetry data and treatment outcome were collected retrospectively. The study endpoints were local control rate (LCR), progression-free-survival (PFS), overall survival (OS) and feasibility of SBRT. RESULTS: In total 39 patients were treated with SBRT. The median follow-up was 25.6 months. The LCR was 82%. PFS and OS were 4.1 and 26.2 months, respectively. Treatment was well tolerated; all patients but one (treatment related pain) completed the planned SBRT. Number of metastases irradiated with SBRT was significantly associated with outcome; patients with only one irradiated lesion had more favourable PFS compared to individuals with 2 or more metastases (HR 4.12, 95% CI: 1.81-9.38, p = 0.001). A subgroup of patients (15%) achieved a sustained long-term survival benefit and never required systemic treatments after SBRT. CONCLUSIONS: SBRT was well tolerated and associated with high LCR. A subpopulation of patients with single metastatic lesion achieved long-term OS and never required subsequent systemic treatment after SBRT. Prospective randomized studies are warranted to discover treatment predictive biomarkers and to investigate the role of SBRT in oligometastatic UC.

From Detection to Cure - Emerging Roles for Urinary Tumor DNA (utDNA) in Bladder Cancer.

PURPOSE OF REVIEW: This review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care. RECENT FINDINGS: Recent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology. utDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management.

Frontline immune checkpoint inhibitors in patients ≥ 90 years with advanced urothelial cancer: a single center experience.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are approved for advanced urothelial cancer alone and as first-line in combination with enfortumab vedotin. Platinum based chemotherapy which is another frontline choice is often not a treatment option for older patients due to comorbidities that increase with age. Despite ICIs being better tolerated compared to traditional chemotherapy little is known about their efficacy and toxicity in patients ≥ 90 years due to the rarity of this population in clinical trials. Our objective was to analyze the efficacy and toxicity of immune checkpoint inhibitors in patients ≥ 90 years. MATERIALS AND METHODS: We conducted a single center retrospective review of patients ≥ 90 years treated between July 2019 and September 2023 with standard of care ICIs for advanced urothelial cancer. RESULTS: Six patients treated with pembrolizumab were identified. Four (66.7%) were male and mean age was 93.5 years at the time of treatment initiation. Response rate was 66.7% (4 patients) with 3 complete responses, which were durable off therapy. Median follow up was 18.2 months. Median progression free survival (PFS) was 10.2 months [95%confidence interval (95%CI): 1.77, not reached (NR)] and median overall survival (OS) was 18.2 months (95%CI: 12.1, NR). Side effects presented in 4 (66.7%) patients and included hypothyroidism, diarrhea, anemia, thrombocytopenia, rash, and bullous dermatitis. One patient developed grade 3 anemia and no patients experienced grade 4 events or required hospitalization due to treatment side effects. CONCLUSIONS: Our experience in a small cohort of patients ≥ 90 years indicate that ICIs are well tolerated and effective for the treatment of advanced urothelial carcinoma in this patient population.

Machine Learning and External Validation of the IDENTIFY Risk Calculator for Patients with Haematuria Referred to Secondary Care for Suspected Urinary Tract Cancer.

BACKGROUND: The IDENTIFY study developed a model to predict urinary tract cancer using patient characteristics from a large multicentre, international cohort of patients referred with haematuria. In addition to calculating an individual's cancer risk, it proposes thresholds to stratify them into very-low-risk (<1%), low-risk (1-<5%), intermediate-risk (5-<20%), and high-risk (≥20%) groups. OBJECTIVE: To externally validate the IDENTIFY haematuria risk calculator and compare traditional regression with machine learning algorithms. DESIGN, SETTING, AND PARTICIPANTS: Prospective data were collected on patients referred to secondary care with new haematuria. Data were collected for patient variables included in the IDENTIFY risk calculator, cancer outcome, and TNM staging. Machine learning methods were used to evaluate whether better models than those developed with traditional regression methods existed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The area under the receiver operating characteristic curve (AUC) for the detection of urinary tract cancer, calibration coefficient, calibration in the large (CITL), and Brier score were determined. RESULTS AND LIMITATIONS: There were 3582 patients in the validation cohort. The development and validation cohorts were well matched. The AUC of the IDENTIFY risk calculator on the validation cohort was 0.78. This improved to 0.80 on a subanalysis of urothelial cancer prevalent countries alone, with a calibration slope of 1.04, CITL of 0.24, and Brier score of 0.14. The best machine learning model was Random Forest, which achieved an AUC of 0.76 on the validation cohort. There were no cancers stratified to the very-low-risk group in the validation cohort. Most cancers were stratified to the intermediate- and high-risk groups, with more aggressive cancers in higher-risk groups. CONCLUSIONS: The IDENTIFY risk calculator performed well at predicting cancer in patients referred with haematuria on external validation. This tool can be used by urologists to better counsel patients on their cancer risks, to prioritise diagnostic resources on appropriate patients, and to avoid unnecessary invasive procedures in those with a very low risk of cancer. PATIENT SUMMARY: We previously developed a calculator that predicts patients' risk of cancer when they have blood in their urine, based on their personal characteristics. We have validated this risk calculator, by testing it on a separate group of patients to ensure that it works as expected. Most patients found to have cancer tended to be in the higher-risk groups and had more aggressive types of cancer with a higher risk. This tool can be used by clinicians to fast-track high-risk patients based on the calculator and investigate them more thoroughly.

Pediatric urothelial cancer: a cross-sectional descriptive analysis of the National Cancer Database.

Background: Urothelial cancer is a rare pediatric malignancy; previous analyses suggest lower rates of recurrence and death as compared to adults. We analyzed pediatric bladder cancer information in a national database, hypothesizing that survival would be better in children than adults. Methods: We analyzed the 2004-2016 National Cancer Database (NCDB) for children and adolescents (0-18 years) with urothelial bladder cancer. Rhabdomyosarcoma patients were excluded. Assessed variables included TNM staging, pathology, tumor size, surgical procedures, and post-operative re-admissions. Overall survival was defined as months since diagnosis as of last follow-up. Results: Of 140 urothelial tumors reported to NCDB between 2004-2016, 75.7% (N=106) were stage 0 at diagnosis, 6.4% (N=9) were stage I, 2.9% (N=4) were stage II and 3.6% (N=5) were stage IV, while 11.4% cases (N=16) were unknown. From available mortality data (121 patients), no patients died after definitive surgical resection. Only 1 mortality was reported at 90 days, although cause of death was reportedly unknown. Three (2.5%) patients were lost to follow-up, and most (96.7%) were alive at 90 days. Conclusions: Short-term survival outcomes among children and adolescents with urothelial bladder tumors captured in NCDB are reassuring. Future investigations focused on long-term outcomes and appropriate surveillance in this rare patient cohort are imperative to better guide management options.

Pembrolizumab in patients with advanced upper tract urothelial carcinoma: a real-world study from ARON-2 project.

Upper tract urothelial carcinoma (UTUC) accounts for the 5-10% of all urothelial carcinomas (UCs). In this analysis, we reported the real-world data from the ARON-2 study (NCT05290038) on the efficacy of pembrolizumab in patients with UTUC who recurred or progressed after platinum-based chemotherapy. Medical records of patients with metastatic UTUC treated with pembrolizumab as second-line therapy were reviewed from 34 institutions in 14 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 235 patients were included in our analysis. Median OS was 8.6 months (95% CI 6.6-12.1), the 1 year OS rate was 43% while the 2 years OS rate 29%. The median PFS was 5.1 months (95% CI 3.9-6.9); 46% of patients were alive at 6 months, 34% at 12 months and 25% at 24 months. According to RECIST 1.1, 18 patients (8%) experienced complete response (CR), 57 (24%) partial response (PR), 44 (19%) stable disease (SD), and 116 (49%) progressive disease (PD), with an ORR of 32%. Our study confirms the effectiveness of pembrolizumab in patients pretreated with a platinum-based combination, irrespective of their sensitivity to the first-line treatment and of their histology. In addition, we emphasized the limited benefit of the treatment with pembrolizumab in patients with hepatic metastases and poor ECOG performance status.

HER2 overexpression in urothelial carcinoma with GATA3 and PPARG copy number gains.

HER2, encoded by the ERBB2 gene, is an important druggable driver of human cancer gaining increasing importance as a therapeutic target in urothelial carcinoma (UC). The genomic underpinnings of HER2 overexpression in ERBB2 nonamplified UC are poorly defined. To address this knowledge gap, we investigated 172 UC tumors from patients treated at the University of California San Francisco, using immunohistochemistry and next-generation sequencing. We found that GATA3 and PPARG copy number gains individually predicted HER2 protein expression independently of ERBB2 amplification. To validate these findings, we interrogated the Memorial Sloan Kettering/The Cancer Genome Atlas (MSK/TCGA) dataset and found that GATA3 and PPARG copy number gains individually predicted ERBB2 mRNA expression independently of ERBB2 amplification. Our findings reveal a potential link between the luminal marker HER2 and the key transcription factors GATA3 and PPARG in UC and highlight the utility of examining GATA3 and PPARG copy number states to identify UC tumors that overexpress HER2 in the absence of ERBB2 amplification. In summary, we found that an increase in copy number of GATA3 and PPARG was independently associated with higher ERBB2 expression in patient samples of UC. This finding provides a potential explanation for HER2 overexpression in UC tumors without ERBB2 amplification and a way to identify these tumors for HER2-targeted therapies.

Management of urothelial cancer in patients with chronic kidney disease receiving platinum-based chemotherapy.

Despite recent advances in the management of urothelial cancer (UC), cisplatin-based combination chemotherapy regimens remain critical. However, their use can be complicated in patients with chronic kidney disease (CKD), which is not uncommon in UC patients. Based on the Galsky criteria for cisplatin ineligibility, most patients with CKD will be excluded from receiving cisplatin-based chemotherapy altogether. For patients with borderline kidney function, several strategies - such as the use of split-dose cisplatin, dose reductions, or extra hydration - may facilitate the use of cisplatin, but these need to be prospectively validated. This review highlights the critical need for a multidisciplinary team, including onco-nephrologists, to help manage renal complications and optimize delivery of cancer care in complex UC patients with CKD.

In patients with urothelial cancer, the presence of chronic kidney disease can significantly impact treatment options, eligibility for clinical trials, and overall patient outcomes. This review discusses key strategies and newer treatment options that can be used to optimize outcomes in patients who often can't receive standard treatments. Importantly, this article also highlights the critical importance and need for a multidisciplinary team of specialists, including kidney specialists with a focus on cancer patients, to help manage kidney function and deliver high-quality care to patients with urothelial cancer and chronic kidney disease.

Characterization of the dehydrogenase-reductase DHRS2 and its involvement in histone deacetylase inhibition in urological malignancies.

BACKGROUND: Being implicated during tumor migration, invasion, clonogenicity, and proliferation, the nicotinamide adenine dinucleotide (NAD)/-phosphate (NADP)-dependent dehydrogenase/reductase member 2 (DHRS2) has been considered to be induced upon inhibition of histone deacetylases (HDACi). In this study, we evaluated the current knowledge on the underlying mechanisms of the (epi)genetic regulation of DHRS2, as well as its function during tumor progression. METHODS: DHRS2 expression was evaluated on mRNA- and protein-level upon treatment with HDACi by means of qRT-PCR and western blot analyses, respectively. Re-analysis of RNA-sequencing data gained insight into expression of specific DHRS2 isoforms, while re-analysis of ATAC-sequencing data shed light on the chromatin accessibility at the DHRS2 locus. Further examination of the energy and lipid metabolism of HDACi-treated urologic tumor cells was performed using liquid chromatography-mass spectrometry. RESULTS: Enhanced DHRS2 expression levels upon HDACi treatment were directly linked to an enhanced chromatin accessibility at the DHRS2 locus. Particularly the DHRS2 ENST00000250383.11 protein-coding isoform was increased upon HDACi treatment. Application of the HDACi quisinostat only mildly influenced the energy metabolism of urologic tumor cells, though, the analysis of the lipid metabolism showed diminished sphingosine levels, as well as decreased S1P levels. Also the ratios of S1P/sphingosine and S1P/ceramides were reduced in all four quisinostat-treated urologic tumor cells. CONCLUSIONS: With the emphasis on urologic malignancies (testicular germ cell tumors, urothelial, prostate, and renal cell carcinoma), this study concluded that elevated DHRS2 levels are indicative of a successful HDACi treatment and, thereby offering a novel putative predictive biomarker.

Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer.

Cisplatin-based chemotherapy has been the standard of care for patients with locally advanced or metastatic urothelial cancer (la/mUC). Enfortumab vedotin, an antibody-drug conjugate directed to Nectin-4, and pembrolizumab, an immune checkpoint inhibitor, are two therapies that have individually provided a survival benefit in patients with la/mUC. The combination regimen of enfortumab vedotin plus pembrolizumab was evaluated in EV-302 (KEYNOTE-A39; NCT0422385), a phase 3 study that showed statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and a key secondary endpoint of overall response rate versus chemotherapy. Based on these results and those from the EV-103 (KEYNOTE-869; NCT03288545) Dose Escalation cohort, Cohort A, and Cohort K, enfortumab vedotin plus pembrolizumab was granted approval from the US Food and Drug Administration for the treatment of adults with la/mUC. While guidelines and recommendations for the management of adverse events (AEs) have been developed for immune checkpoint inhibitor monotherapy and enfortumab vedotin monotherapy, additional guidance is needed for managing AEs that occur with enfortumab vedotin plus pembrolizumab. As monotherapies, enfortumab vedotin and pembrolizumab are both associated with some of the AEs observed with the combination, such as skin reactions, pneumonitis, and diarrhea, which may confound the attribution of the AE to a specific agent and thereby complicate clinical management. In this manuscript, we aim to provide recommendations for best practice for patient care and the management of AEs of clinical interest for patients with la/mUC receiving enfortumab vedotin plus pembrolizumab, including skin reactions, peripheral neuropathy, hyperglycemia, and pneumonitis. These recommendations were developed based on published guidelines, expert opinions, and the clinical experience of the authors, which include oncologist, advanced practice provider, nursing, and pharmacy perspectives. In addition, guidance on patient education and communication is provided. With vigilant monitoring, early detection, and prompt intervention of treatment-emergent AEs based on recommended approaches described herein, it is the authors' experience that most AEs can be managed with supportive therapy and dose modification/interruptions, allowing patients to continue treatment.

Bacillus Calmette-Guérin (BCG) prostato-epididymitis in a patient treated for a non-invasive urothelial cancer: A case report.

Introduction: The Bacillus Calmette-Guérin (BCG) used as anti-tuberculous vaccine is also a well-known therapy for superficial urothelial cancer. Local or general side effects can occur, although it is generally well tolerated. Case: We present the case of a 65 year-old caucasian man consulting for gross hematuria and lower urinary tract symptoms. Magnetic resonance imaging (MRI) demonstrated a non-invasive urothelial carcinoma (NMIBC) and Prostate Imaging-Reporting and Data System (PIRADS) IV lesions. Transurethral resection of the bladder tumor revealed a non-invasive transitional cell carcinoma. Intravesical Bacillus Calmette Guerin (BCG) therapy was provided. After 6 intravesical instillations, the patient presented with prostato-epididymitis. Forthcoming BCG instillations were canceled, and cancer treatment was switched to epirubicine. Treatment with ethambutol, rifampicin and isoniazid was started with rapid resolution of the symptoms. Urinary and semen cultures grew Mycobacterium tuberculosis complex strain BCG. As prostate specific antigen (PSA) rose, prostate's biopsies were performed showing extensive necrosis boarded by granulomas without signs of malignancy. Discussion: BCGitis is a rare complication in patients treated for non-invasive urothelial cancer. Several risk factors, local and systemic, should be considered prior to this immunotherapy. BCGitis (local or disseminated) or hypersensitivity reactions to BCG must be included in the differential diagnosis even if therapy was administered several years before the symptoms. Adequate treatment must be started as fast as possible to avoid serious complications.

Double Primary Cancer of the Prostate and Urothelial Cancer: A Single Institution Experience.

Prostate cancer (PCa) ranks as the second most common cancer in Japanese males, while bladder cancer (BC) holds the tenth spot. Among double urological cancers, the incidence of synchronous or metachronous BC and PCa is the highest. Reports on upper urinary tract (UUT) urothelial cancer (UC) in PCa patients are limited. Here, we present three cases of metachronous PCa and BC, with subsequent diagnosis of ureteral and renal pelvic cancer during the course of the disease. In the follow-up of patients with urological cancers, it is important to be aware not only of the progression of the initial cancer but also the potential development of a second cancer.