Clinical implications of single cell sequencing for bladder cancer.

Bladder cancer (BC) is the 10th most common cancer worldwide, with about 0.5 million reported new cases and about 0.2 million deaths per year. In this scoping review, we summarize the current evidence regarding the clinical implications of single-cell sequencing for bladder cancer based on PRISMA guidelines. We searched PubMed, CENTRAL, Embase, and supplemented with manual searches through the Scopus, and Web of Science for published studies until February 2023. We included original studies that used at least one single-cell technology to study bladder cancer. Forty-one publications were included in the review. Twenty-nine studies showed that this technology can identify cell subtypes in the tumor microenvironment that may predict prognosis or response to immune checkpoint inhibition therapy. Two studies were able to diagnose BC by identifying neoplastic cells through single-cell sequencing urine samples. The remaining studies were mainly a preclinical exploration of tumor microenvironment at single cell level. Single-cell sequencing technology can discriminate heterogeneity in bladder tumor cells and determine the key molecular properties that can lead to the discovery of novel perspectives on cancer management. This nascent tool can advance the early diagnosis, prognosis judgment, and targeted therapy of bladder cancer.

Comparison of different prediction tools for the risk of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma: a propensity-matched analysis.

OBJECTIVE: To compare the predictive performance of the current clinical prediction models for predicting intravesical recurrence (IVR) after radical nephroureterectomy (RNU) in patients with upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively analysed upper tract urothelial carcinoma patients who underwent radical nephroureterectomy in our centre from January 2009 to December 2019. We used the propensity score matching (PSM) method to adjust the confounders between the IVR and non-IVR groups. Additionally, Xylinas' reduce model and full model, Zhang's model, and Ishioka's risk stratification model were used to retrospectively calculate predictions for each patient. Receiver operating characteristic (ROC) curves were generated, and the areas under the curves (AUCs) were compared to identify the method with the highest predictive value. RESULTS: We included 217 patients with a median follow-up of 41 months, of which 57 had IVR. After PSM analysis, 52 pairs of well-matched patients were included in the comparative study. No significant difference was found in clinical indicators besides hydronephrosis. The model comparison showed that the AUCs of the reduced Xylinas' model for 12 months, 24 months, and 36 months were 0.69, 0.73, and 0.74, respectively, and those of the full Xylinas' model were 0.72, 0.75, and 0.74, respectively. The AUC of Zhang's model for 12 months, 24 months, and 36 months was 0.63, 0.71, and 0.71, respectively, the performance of Ishioka's model is that the AUC of 12 months, 24 months and 36 months was 0.66, 0.71, and 0.74, respectively. CONCLUSION: The external verification results of the four models show that more comprehensive data and a larger sample size of patients are needed to strengthen the models' derivation and updating procedure, to better apply them to different populations.

Exploratory analyses of treatment subgroup interaction by PD-L1 status and according to PD-L1 expression in the JAVELIN Bladder 100 trial.

PURPOSE: Post hoc analysis of the JAVELIN Bladder 100 trial of avelumab maintenance in locally advanced/metastatic urothelial carcinoma (la/mUC) to determine the interaction by programmed death ligand 1 (PD-L1) status for overall survival (OS), and additional analyses of survival per a different PD-L1 expression cutoff of ≥ 1% in tumor cells or immune cells (TC/IC). METHODS: JAVELIN Bladder 100 data were used for the analysis of the interaction by PD-L1 status (per cutoff used in the trial) for OS and, additionally, OS and progression-free survival (PFS) analyses per a different ≥ 1% TC/IC PD-L1 expression cutoff (Ventana SP263 assay). RESULTS: No significant interaction between treatment and PD-L1 status was observed for OS. Clinically meaningful and robust survival data were observed in favor of avelumab using the different ≥ 1% TC/IC PD-L1 expression cutoff. CONCLUSIONS: These results demonstrate the benefit of avelumab maintenance in la/mUC regardless of PD-L1 expression, consistent with approved labels.

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.

An iodine­labelled Antibody-drug conjugate PET probe for noninvasive monitoring of Nectin-4 expression in urothelial carcinoma.

BACKGROUND AND PURPOSE: Some kinds of antibody-drug conjugate (ADC) with high affinity to Nectin-4 have demonstrated breakthrough progress in the third-line setting for bladder cancer. However, many patients are still difficult to benefit from treatment based on the heterogeneity of tumour. As the most advanced auxiliary treatment technology, treatment visualization can most intuitively predict the effectiveness of drug treatment, and timely detect the occurrence of drug resistance. Among them, nuclear medicine molecular probes play an important role in this field. METHODS: 124/125I-EV was prepared by labelling Enfortumad Vedetin (EV), an ADC drugs widely used in clinic targeted Nectin-4, with Na124/125I using N-bromine succinimide as oxidant. The radiochemical purity was analyzed via radio-TLC and bioactivity was measured by enzyme-linked immunosorbent assay. Cell uptake assay and small-animal PET imaging were performed to verified the specificity and targeting. KEY RESULTS: 124/125I-EV was prepared with high labeling yield and radiochemical purity. ELISA assays demonstrated that 124I-EV maintained the same high bioactivity as EV with significantly higher uptake in SW780 cells (Nectin-4 positive, 4.05 ± 0.32 %IA/5 × 105 cells at 8 h) than that in T24 cells (Nectin-4 negative, 1.34 ± 0.18 %IA/5 × 105 cells, p < 0.001). In PET imaging, 124I-EV had a significantly higher accumulation in SW780 tumour than that in T24 tumour and the uptake in SW780 tumour could be specifically blocked when co-injected with cold EV. The signal-to-noise ratio at the tumour site gradually increased with time, and peaked at 72 h. CONCLUSION AND IMPLICATIONS: 124I-EV was successfully prepared with high specificity and binding affinity of Nectin-4. This radioactive probe completely simulates the internal circulation of ADC drugs and tumour uptake and retention, which will greatly improve the clinical application of ADC therapy.

Expression of tumoral GSK3-ß, PD-L1, and CD8 cell density in urothelial carcinomas, association with tumor grade and overall survival.

Bladder cancer is the most common malignancy in the urinary tract, and is biologically and clinically quite heterogeneous. Around 90% of diagnoses are made in the 6th decade, being more prevalent in males. The programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1) axis play a putative role in immune checkpoint and as a means through which cancer evades the immune system. Inhibition of the glicogênio synthase kinase (GSK) 3 leads to the downregulation of PD-1 via upregulation of the transcription factor Tbet. The use of biomarkers PD-L1 and GSK-3ß and evaluation of the immune infiltrate have very promising correlations with urothelial carcinoma prognosis and treatment prediction. OBJECTIVE: To investigate the protein expression of PD-L1 and GSK-3ß and the CD8-positive immune infiltrates in bladder carcinomas. MATERIALS AND METHODS: This was a cross-sectional study of 140 samples of urothelial carcinomas from 2015 to 2018. Automated digitally assisted scoring and conventional analyses of the markers of GSK-3ß (27C10), CD8 (7103ß) and PDL-1 (22c3), were reviewed by two pathologists independently and a histologic score was calculated. The density of CD8 was also measured. RESULTS: The immunoexpression of GSK-3ß (91%) was presented in most samples, PD-L1 in 62.9% and CD8 cells present in 46.3% of cases. When analyzed in conjunction, the levels of GSK-3ß and PD-L1 (P = 0.033), and CD8 and PD-L1 (P<0.002) showed significant correlations. No significant associations were observed between GSK-3ß and CD8. The positivity of GSK-3ß and PD-L1 was predominant in high-grade tumors. CONCLUSION: Despite the tumor microenvironment heterogeneity, the expression of CD8, GSK-3ß and PDL1 could be valuable and GSK-3ß could be a potential target in advanced bladder cancer, especially in the context of immunotherapy.

Hematuria macroscópica como signo inicial del cáncer primario de uretra. Reporte de caso / Macroscopic hematuria as an initial sign of primary urethral cancer. Case report

Fundamento: El cáncer primario de uretra se define como el tumor cuya primera lesión se localiza en la uretra; es infrecuente, el mismo representa menos del 1 % de los tumores malignos y el 5 % de los tumores malignos del sistema urinario. La extensión de este proceso a la glándula prostática genera sintomatología urinaria obstructiva e irritativa y cuadros agudos como la hematuria macroscópica. Objetivo: Presentar el caso de un paciente con cáncer primario de uretra en su variedad urotelial con hematuria macroscópica como forma clínica de presentación. Presentación del caso: Caso clínico de un paciente masculino de 75 años de edad, con hematuria macroscópica como forma clínica de presentación de cáncer primario de uretra en su variedad urotelial, el cual se diagnosticó anatomopatológicamente durante el estudio de la hematuria. Conclusiones: El caso que se presenta permite alertar a la comunidad científica que en pacientes que presentan hematuria macroscópica, sin manifestaciones urológicas obstructivas ni irritativas, también debe tenerse en cuenta el diagnóstico de cáncer uretral primario, aunque sea un signo infrecuente como forma clínica de presentación de esa enfermedad.

Background: Primary urethral cancer is defined as a tumor whose first lesion is located in the urethra; is very uncommon, represents less than 1% of malignant tumors and 5% of malignant tumors of the urinary system. The extension of this process to the prostate gland creates obstructive and irritative urinary symptoms and acute conditions such as macroscopic hematuria. Objective: To present the case of a patient with primary urethral carcinoma in its urothelial variety with macroscopic hematuria as clinical presentation. Case presentation: Clinical case of a 75-year-old male patient, with macroscopic hematuria as a clinical presentation of primary cancer of the urethra in its urothelial variety, diagnosed anatomopathologically during the hematuria study. Conclusions: The case presented alerts the scientific community that the diagnosis of primary urethral cancer should be considered in patients with macroscopic hematuria in the absence of obstructive or irritative urologic manifestations, although it is a rare sign as clinical presentation of this disease.

Prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitor treatment.

PURPOSE: We evaluated the prevalence of immune-related adverse events and anti-tumor efficacy in advanced/metastatic urothelial carcinoma following immune-checkpoint inhibitors (ICIs) treatment. METHODS: We conducted a multicenter retrospective study of patients with advanced/metastatic urothelial carcinoma treated with ICIs in four Spanish institutions. irAEs were classified using Common Terminology Criteria for Adverse Event (CTCAE) v.5.0 guidelines. The primary endpoint was overall survival (OS). Other endpoints were overall response rate (ORR) and progression-free survival (PFS). irAEs were evaluated as a time-dependent covariate to avoid immortal time bias. RESULTS: A total of 114 patients were treated with ICIs between May 2013 and May 2019, 105 (92%) of whom received ICIs as monotherapy. irAEs of any grade were experienced in 56 (49%) patients and 21 (18%) patients had grade ≥ 3 toxicity. The most frequent irAEs were gastrointestinal and dermatological toxicities, reported in 25 (22%) and 20 (17%) patients, respectively. Patients with grade 1-2 irAEs had significantly longer OS compared to those without grade 1-2 irAEs (median 18.2 vs. 8.7 months, HR = 0.61 [95% CI 0.39-0.95], p = 0.03). No association with efficacy was observed for patients with grade ≥ 3 irAEs. No difference in PFS was observed after adjusting for the immortal time bias. ORR was higher in patients who developed irAEs (48% vs 17%, p < 0.001). CONCLUSIONS: Our findings suggest that development of irAEs was associated with higher ORR, and patients who developed grade 1-2 irAEs had longer OS. Prospective studies are necessary to confirm our findings.

Emerging targets in upper tract urothelial carcinomas: the TERT gene.

INTRODUCTION: Urothelial carcinoma (UC) is the fourth most prevalent malignancy in adults, accounting for 2.1% of cancer-related deaths. We aimed to describe the most frequent telomerase reverse transcriptase (TERT) gene mutations in this type of cancer and their relationship with the prognosis and treatment of this disease. MATERIALS AND METHODS: We performed a search strategy in Medline and Embase with the following keywords: telomerase reverse transcriptase (TERT) gene and upper tract UC. We included reviews and observational studies to support the statements throughout the manuscript. RESULTS: The transcriptional activation of the TERT gene and subsequent telomerase activity is a prerequisite step in malignant transformation and progression. In advanced upper tract UC, TERT mutations are the most common genomic alterations in the Foundation Medicine database. C228T mutations predict distant metastasis in 60% of patients with renal pelvis cancer and 11% with ureteral cancer. Also, C228T and C250T mutations in urine DNA had a sensitivity of 87% and specificity of 94.7%. All TERT genomic alterations are inactivating short variant sequence mutations. There are no copy number gains or losses in TERT and no TERT gene rearrangements or fusions. CONCLUSIONS: Multiple markers, and mutations regarding the TERT gene and its promoter have been found in upper tract UC. The C250T and C228T mutations have shown promising results as diagnostic markers detected with urine tests.

Castration immunoregulates toll-like receptor-4 in male bladder cancer.

PURPOSE: Among diverse Pattern Recognition Receptors (PRRs), Toll-like receptor-4 (TLR-4) is a key urothelial trigger for innate immune response impacting urothelial bladder carcinoma (BC). Androgen activation promotes immunotolerance, playing an immunoregulatory role by unknown mechanisms. We explored the castration impact on urothelial TLR-4 modulation in carcinogenesis and immunotherapeutic scenario. METHODS: Intact (SHAM) versus castrated male Fisher-344 rats were evaluated in 2 scenarios: (A) Carcinogenesis: After randomization to SHAM (n = 5) and Castration (n = 5), carcinogenesis was induced by four intravesical doses of 1.5 mg/kg n-methyl-n-nitrosourea (MNU) every 15 days. (B) Treatment: After ultrasonographic confirmed MNU-induced papillary BC on week 8, rats were randomized to SHAM (n = 5) and Castration (n = 5) and offered 6 weekly intravesical treatment of 106 CFU of bacillus Calmette Guerin (BCG) in 0.2 ml saline. After 15 weeks the urinary bladders underwent histopathology. Urothelial cell proliferation was measured by Ki-67 immunohistochemistry (IHC), and TLR-4 expression was quantified by IHC and WB. RESULTS: Castration induced higher TLR-4 urothelial expression (p = 0.007) and anticarcinogenic effect with fewer urothelial tumors (60 vs. 80%) and lower urothelial cell proliferation compared to intact animals (p = 0.008). In the intravesical BCG treatment setting, castration has potentialized the BCG activation of TLR-4 (p = 0.007) with no residual in situ carcinoma compared to intact animals, suggesting the potential to amplify the BCG immune response. CONCLUSION: To our knowledge, this is the first description of TLR-4 urothelial expression hormonal modulation. The described castration-mediated immunomodulation will help to improve the knowledge of urothelial cancer gender diversities and PRRs modulations with treatment implications.

[Rectal metastasis of a resected urothelial bladder cancer]. / Metástasis rectal de carcinoma urotelial de vejiga resecado.

We present the case of a female patient with a history of high-grade urothelial carcinoma of the bladder with secondary lymph node and bone involvement, who presented with hematochezia, tenesmus and rectal pain one year after her oncological surgery. The abdomen and pelvis magnetic resonance image showed a 5 cm solid rectal lesion that stenosed the lumen and crossed the peritoneum, 6 cm away from the anal margin. The histology of this lesion reported an urothelial metastasis at the level of the lower rectum according to the patient's history. This case identifies an atypical evolution of urothelial carcinomas (UC), highlighting an unusual route of distant metastasis. UC can, on rare occasions, metastasize to the rectum, usually in advanced or recurrent cases of the disease. As the literature available on this topic is scarce, it is crucial to highlight the importance of maintaining high suspicion in patients with a history of urothelial carcinoma and urinary/rectal symptoms (rectal pain and urgency, suprapubic pain, urinary and fecal incontinence).

Se presenta el caso de una paciente con antecedentes de carcinoma urotelial de vejiga de alto grado con compromiso secundario ganglionar y óseo, la cual presentó cuadro de hematoquecia, tenesmo y dolor rectal un año después de su cirugía oncológica. La resonancia magnética de abdomen y pelvis, demostró una lesión sólida rectal de 5 cm de longitud que estenosaba la luz y atravesaba el peritoneo, a 6 cm del margen anal. La anatomía patológica de dicha lesión, informó una metástasis urotelial a nivel del recto inferior en concordancia con el antecedente de la paciente. Este caso identifica una evolución atípica de carcinomas uroteliales (CU), destacando una ruta inusual de metástasis a distancia. Los CU pueden, en raras ocasiones, hacer metástasis rectales, generalmente en casos avanzados o recurrentes de la enfermedad. Al ser escasa la bibliografía disponible sobre dicho tema, cabe destacar la importancia de mantener un alto índice de sospecha en pacientes con antecedentes de carcinoma urotelial y síntomas urinarios/rectales (dolor y tenesmo rectal, dolor suprapúbico, incontinencia urinaria y fecal).

Metástasis rectal de carcinoma urotelial de vejiga resecado / Rectal metastasis of a resected urothelial bladder cancer

Resumen Se presenta el caso de una paciente con antecedentes de carcinoma urotelial de vejiga de alto grado con compromiso secundario ganglionar y óseo, la cual presentó cuadro de hematoquecia, tenesmo y dolor rectal un año después de su cirugía oncológica. La resonancia magnética de abdomen y pelvis, demos tró una lesión sólida rectal de 5 cm de longitud que estenosaba la luz y atravesaba el peritoneo, a 6 cm del margen anal. La anatomía patológica de dicha lesión, informó una metástasis urotelial a nivel del recto inferior en concordancia con el antecedente de la paciente. Este caso identifica una evolución atípica de carcinomas uroteliales (CU), destacando una ruta inusual de metástasis a distancia. Los CU pueden, en raras ocasiones, hacer metástasis rectales, generalmente en casos avanzados o recurrentes de la enfermedad. Al ser escasa la bibliografía disponible sobre dicho tema, cabe destacar la importancia de mantener un alto índice de sospecha en pacientes con antecedentes de carcinoma urotelial y síntomas urinarios/rectales (dolor y tenesmo rectal, dolor suprapúbico, incontinencia urinaria y fecal).

Abstract We present the case of a female patient with a history of high-grade urothelial carcinoma of the bladder with secondary lymph node and bone involvement, who presented with hematochezia, tenesmus and rectal pain one year after her oncological surgery. The abdomen and pelvis magnetic resonance image showed a 5 cm solid rectal lesion that stenosed the lumen and crossed the peritoneum, 6 cm away from the anal margin. The histology of this lesion reported an urothelial metastasis at the level of the lower rectum according to the patient's history. This case identifies an atypical evolution of urothelial carcinomas (UC), highlighting an unusual route of distant metastasis. UC can, on rare occasions, metastasize to the rectum, usually in advanced or recurrent cases of the disease. As the literature available on this topic is scarce, it is crucial to highlight the importance of maintaining high suspicion in patients with a history of urothelial carcinoma and urinary/rectal symptoms (rectal pain and urgency, suprapubic pain, urinary and fecal incontinence).

Sarcomatoid Urothelial Carcinoma: A Population-Based Study of Clinicopathologic Characteristics and Survival Outcomes.

INTRODUCTION: Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive variant of bladder cancer with limited data regarding epidemiology and survival. In this study, we explored clinicopathologic factors and oncologic outcomes of patients with SUC derived from Survival, Epidemiology and End Results (SEER) database, in comparison to conventional UC (CUC). MATERIALS AND METHODS: SEER database was searched for patients with invasive (≥T1) SUC or CUC using the topography codes C67.0 to C67.9 for bladder cancer and the morphologic codes 8120/8122 for CUC/SUC respectively. Demographic/clinicopathologic/treatment/survival data were extracted. Disease-specific survival (DSS) was estimated with the Kaplan-Meier method. Chi-squared tests were used for comparative analysis and Cox proportional hazards model for identifying clinical covariates associated with DSS. RESULTS: A total of 569 patients with SUC and 37,740 with CUC were identified. Overall, there was a male predominant population in both cohorts, although a higher proportion of women were noted in the SUC cohort (32 vs. 25%). Patients with SUC had significantly higher incidence of non-bladder confined disease (T3/4, 37% vs. 22%) and nodal invasion (18% vs. 12%) in comparison to those with CUC (all P < .05). Median DSS was 16 months (95% CI: 12.4-19.6) in the SUC vs. 82 months (95% CI; 75.9-88.1) in the CUC cohort. Presence of SUC histology was independently associated with shorter DSS in the multivariate analysis, when adjusted for other significant clinicopathologic factors. CONCLUSION: SUC was associated with advanced stage and shorter DSS compared to CUC. Further studies are needed to better understand biological underpinnings behind its aggressive behavior and the role of novel systemic treatments.

Can increased expression of miR-Let-7c reduce the transition potential of high-grade urothelial carcinoma?

BACKGROUND: Bladder cancer is the leading transitional cell carcinoma affecting men and women with high morbidity and mortality rates, justifying the need to develop new molecular target therapies using microRNAs. This study aimed to evaluate the behavior of the T24 cell line after transfection with miR-Let-7c precursor mimic through invasion, migration, apoptosis, and cell cycle assays. METHODS AND RESULTS: T24 cell was transfected with the Let-7c mimic and its respective control and evaluated after 24 h. The expression levels of miR-Let-7c were analyzed by qPCR. We performed wound healing, Matrigel and flow cytometry, apoptosis, and cell cycle assays to determine its effect on cellular processes. Cells transfected with miR-Let-7c showed increased apoptosis rates (p = 0.019), decreased migration 24 h (p = 0.031) and 48 h (p = 0.0006), invasion potential (p = 0.0007), and cell proliferation (p = 0.002). CONCLUSIONS: Our results demonstrate that miR-Let-7c can act in different pathways of the carcinogenic cellular processes of muscle-invasive urothelial carcinoma cells, inhibiting cell proliferation and increasing apoptosis levels, consequently limiting their invasion potential. However, further studies should be carried out better to elucidate this microRNA's role in high-grade urothelial carcinomas and unveil which targets this microRNA may present, which are intrinsically related to the cancer survival pathways.

Perspective: Humanized Pig Models of Bladder Cancer.

Bladder cancer (BC) is the 10th most common neoplasia worldwide and holds expensive treatment costs due to its high recurrence rates, resistance to therapy and the need for lifelong surveillance. Thus, it is necessary to improve the current therapy options and identify more effective treatments for BC. Biological models capable of recapitulating the characteristics of human BC pathology are essential in evaluating the effectiveness of new therapies. Currently, the most commonly used BC models are experimentally induced murine models and spontaneous canine models, which are either insufficient due to their small size and inability to translate results to clinical basis (murine models) or rarely spontaneously observed BC (canine models). Pigs represent a potentially useful animal for the development of personalized tumors due to their size, anatomy, physiology, metabolism, immunity, and genetics similar to humans and the ability to experimentally induce tumors. Pigs have emerged as suitable biomedical models for several human diseases. In this sense, the present perspective focuses on the genetic basis for BC; presents current BC animal models available along with their limitations; and proposes the pig as an adequate animal to develop humanized large animal models of BC. Genetic alterations commonly found in human BC can be explored to create genetically defined porcine models, including the BC driver mutations observed in the FGFR3, PIK3CA, PTEN, RB1, HRAS, and TP53 genes. The development of such robust models for BC has great value in the study of pathology and the screening of new therapeutic and diagnostic approaches to the disease.

Erdafitinib treatment in Brazilian patients with metastatic urothelial carcinoma (mUC): real-world evidence from an Expanded Access Program.

BACKGROUND: Erdafitinib is the first targeted therapy approved for the treatment of patients with metastatic urothelial carcinoma (mUC). Approval was based on a phase II single-arm trial that demonstrated significant activity of erdafitinib in patients with tumors harboring FGFR2/3 alterations. In Brazil, an Expanded Access Program (EAP) provided patients with early access to erdafitinib prior to market authorization. The current report describes characteristics and outcomes of patients with mUC on erdafitinib therapy. METHODS: Patients with mUC that failed first- and second-line systemic therapies were screened for FGFR2/3 alterations in primary or metastatic tumor tissues. Patients with FGFR2/3 alterations were selected to receive erdafitinib at the standard dosing schedule and were followed prospectively to evaluate the efficacy and safety outcomes. RESULTS: From 19 April 2019, through 13 March 2020, 47 patients with mUC from 10 Brazilian centers were tested for FGFR2/3 alterations. Alterations in FGFR2/3 were found in 12 patients (25.5%) and all of them were eligible for the EAP. Four patients (33%) had partial response, while two patients (17%) had stable disease. Progressive disease, the best response, was observed in five patients (42%). At a median follow-up of 16.2 months, the median time to treatment failure (TTF) was 2.8 months. When considering only patients with objective response, the median TTF was 5.3 months. Adverse events (AEs) were reported for any grade and grade 3 or higher in 10 patients (83%) and 5 patients (42%), respectively. The most common AE was hyperphosphatemia. CONCLUSION: This first real-world evidence report of heavily treated patients with mUC confirms the efficacy and safety of erdafitinib in a disease setting with a lack of treatment options.

National trends in clinical and pathologic staging for upper tract urothelial carcinoma: Implications for neoadjuvant chemotherapy.

INTRODUCTION: With growing support of perioperative chemotherapy for upper tract urothelial carcinoma (UTUC), current biopsy methods are challenging, and little is known as to the degree to which patients would appropriately receive neoadjuvant chemotherapy (NAC) from biopsy alone. Herein, we sought to assess the rates of appropriate clinical use of NAC and identify clinicopathologic factors associated with aggressive UTUC amongst patients undergoing radical nephroureterectomy (RNU) for clinically localized disease. METHODS: From 2004 to 2013, we identified all treatment naïve patients diagnosed with clinically localized, high grade UTUC (cTa-4Nx) who underwent RNU from the National Cancer Database (NCDB). Pathologic criteria for NAC (pT2-4N0,x; pTanyN1) from RNU represented the primary outcome. Bivariate and multivariable analyses were utilized to identify covariates associated with primary outcome to determine appropriate use of NAC. RESULTS: During the study interval, 5,362 patients were diagnosed with clinically localized UTUC and underwent RNU. Overall, 49.1% of patients presented with an unknown primary tumor stage (Tx) and 24.5% had invasive UTUC from biopsy. On multivariable analysis, upper tract tumor size was associated with invasive UTUC eligible for NAC (all P < 0.05). Amongst patients with cTx UTUC from biopsy, half of patients had pathologic noninvasive UTUC (pTa,is,1) from RNU and would be overtreated with NAC. CONCLUSION: Significant uncertainty persists in assigning primary upper tract tumor depth and represents a key barrier to widespread implementation of NAC for patients with high grade UTUC. Further research is needed to more accurately determine clinical criteria to identify patients for NAC.

Diagnóstico de carcinoma urotelial durante estudio de bacteremia por Streptococcus gordonii / Diagnosis of uroepithelial carcinoma during bacteremia by Streptococcus gordonii

Resumen La bacteremia por Streptococcus gordonii es infrecuente. Su aislamiento en hemocultivo traduce alta significancia clínica y debe dirigir el abordaje diagnóstico hacia la búsqueda de entidades subyacentes como neoplasias hematológicas, cardiopatías valvulares, neumonía, alteraciones estructurales de cabeza y cuello, inmunosupresión, y otras condiciones asociadas. No se han identificado reportes en pacientes con neoplasia de vías urinarias como posible condicionante de bacteremia por este agente. Se describe el caso de un paciente que, durante el estudio de bacteremia por este microorganismo, fue diagnosticado de carcinoma urotelial de alto grado.

Abstract Streptococcus gordonii bacteremia is rare. Its isolation in blood culture translates into high clinical significance and the diagnostic approach should be directed towards the search for underlying entities such as hematologic malignancies, valvular heart disease, pneumonia, structural changes of the head and neck, immunosuppression and other related conditions. No reports have been identified in patients with urinary tract neoplasia as a possible condition of bacteremia by this agent. The case of a patient who was diagnosed with high-grade urothelial carcinoma during the study of bacteremia by this microorganism is described.

Patterns and timing of perioperative blood transfusion and association with outcomes after radical cystectomy.

BACKGROUND: Perioperative blood transfusion (PBT) has been associated with worse outcomes across tumor types, including bladder cancer. We report our institutional experience with PBT utilization in the setting of radical cystectomy (RC) for patients with bladder cancer, exploring whether timing of PBT receipt influences perioperative and oncologic outcomes. METHODS: Consecutive patients with bladder cancer treated with RC were identified. PBT was defined as red blood cell transfusion during RC or the postoperative admission. Clinicopathologic and peri and/or postoperative parameters were extracted and compared between patients who did and did not receive PBT using Mann Whitney U Test, chi-square, and log-rank test. Overall (OS) and recurrence-free survival (RFS) were estimated with the Kaplan Meier method. Univariate/multivariate logistic and Cox proportional hazards regression were used to identify variables associated with postoperative and oncologic outcomes, respectively. RESULTS: The cohort consisted of 747 patients (77% men; median age 67 years). Median follow-up was 61.5 months (95% CI 55.8-67.2) At least one postoperative complication (90-day morbidity) occurred in 394 (53%) patients. Median OS and RFS were 91.8 months (95% CI: 76.0-107.6) and 66.0 months (95% CI: 48.3-83.7), respectively. On multivariate analysis, intraoperative, but not postoperative, BT was independently associated with shorter OS (HR: 1.74, 95% CI: 1.32-2.29) and RFS (HR: 1.55, 95%CI: 1.20-2.01), after adjusting for relevant clinicopathologic variables. PBT (intra- or post- operative) was significantly associated with prolonged postoperative hospitalization ≥10 days. CONCLUSIONS: Intraoperative BT was associated with inferior OS and RFS, and PBT overall was associated with prolonged hospitalization following RC. Further studies are needed to validate this finding and explore potential causes for this observation.

Prospective evaluation of a urinary biomarker panel to detect and predict recurrence of non-muscle-invasive bladder cancer.

PURPOSE: To perform a feasibility phase study of a panel of putative protein biomarkers and determine whether it can identify and predict tumor recurrence in patients with non-muscle-invasive bladder cancer (NMIBC) on follow-up. METHODS: We prospectively analyzed the urine of 152 patients previously treated for NMIBC. Quantitative expression of plasminogen activator inhibitor-1 (PAI-1), DJ-1, apolipoprotein A-I (apoA-1), matrix metallopeptidase-9 (MMP-9), and interleukin-8 (IL-8) was assessed by enzyme-linked immunosorbent assay and compared amongst patients with and without bladder cancer recurrence at urine collection and during 3 years of follow-up. Tumor recurrence was confirmed by pathologic analysis. We performed a prediction analysis, excluding patients with recurrence at the start of the study, and assessed the influence of previous use of intravesical BCG on the level of biomarkers. RESULTS: Median follow-up time was 47 months (interquartile range 39-50 months). Sixteen patients (10.5%) were diagnosed with recurrence at the start of the study, and 21 (15.4%) were diagnosed during the study. Three biomarker proteins (apoA-1, MMP-9, and IL-8) appear to hold diagnostic potential [odds ratio (OR) = 12.9; 95% CI 3.5-47.4]; while, PAI-1 and IL-8 predict recurrence (OR = 4.1; 95% CI 1.4-11.4). Previous use of intravesical BCG did not affect biomarker levels. CONCLUSION: In the feasibility phase, the panel of urine biomarkers analyzed detected and predicted recurrence of NMIBC and provided reliable results in patients who had previously used intravesical BCG. Validation studies are required to confirm the panel clinical utility.