Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study.

OBJECTIVES: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment-resistant advanced urothelial cancer in a real-world setting. PATIENTS AND METHODS: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression-free survival (PFS), and overall survival (OS), with treatment-related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median follow-up was 8.9 months (range, 0.1-16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7-9.8), and the median OS was 14.5 months (95% CI: 12.4-not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non-urothelial carcinoma histology, and 40 (38.3%) had at least one pre-existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. CONCLUSIONS: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti-tumor activity and had manageable safety profiles outside the clinical trial setting.

Aristolochic acid-containing Chinese herbal medicine and upper urinary tract urothelial carcinoma in Taiwan: a narrative review.

PURPOSE: The high incidence of upper urinary tract urothelial carcinoma (UTUC) in Taiwan is largely due to exposure to aristolochic acid (AA), a principal component of Aristolochia-based herbal medicines. Here we systematically review the molecular epidemiology, clinical presentation and biomarkers associated with AA-induced UTUC. METHODS: This is a narrative review. Medline, Embase, and Web of Science were searched from inception to December 31, 2021. Studies evaluating the association, detection, and clinical characteristics of AA and UTUC were included. RESULTS: A nationwide database revealed 39% of the Taiwanese population had been exposed to AA-containing herbs between 1997 and 2003. Epidemiological reports revealed AA posed a significantly higher hazard for renal failure and UTUC in herbalists and the general population who ingested AA-containing herbs. The presence of aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, located predominantly on the non-transcribed DNA strand, with a strong preference for deoxyadenosine in a consensus sequence (CAG), was observed in many UTUC patients. Clinically, AA-related UTUC patients were characterized by a younger age, female gender, impaired renal function and recurrence of contralateral UTUC. To date, there are no preventive measures, except prophylactic nephrectomy, for subjects at risk of AA nephropathy or AA-related UTUC. CONCLUSION: AA exposure via Aristolochia-based herbal medicines is a problem throughout Taiwan, resulting in a high incidence of UTUC. Aristolactam-DNA adducts and a distinctive signature mutation, A:T to T:A transversions, can be used as biomarkers to identify AA-related UTUC. AA-related UTUC is associated with a high recurrence rate of contralateral UTUC.

Significant impact of a history of prior or concomitant upper urinary tract cancer on the recurrence and progression of non-muscle invasive bladder cancer.

BACKGROUND: The objective of the present study was to evaluate the prognostic impact of the upper urinary tract cancer status on recurrence-free survival and progression-free survival, and to develop risk stratification systems that include the upper urinary tract cancer status for patients with non-muscle invasive bladder cancer. PATIENTS AND METHODS: The present study included 40 (upper urinary tract cancer-non-muscle invasive bladder cancer group) and 285 (non-muscle invasive bladder cancer alone group) patients with and without a history of prior or concomitant upper urinary tract cancer, respectively. Nine clinicopathological findings between the two groups were compared, and risk stratification systems for the recurrence and progression of non-muscle invasive bladder cancer were developed. RESULTS: Recurrence-free survival and progression-free survival in the upper urinary tract cancer-non-muscle invasive bladder cancer group were significantly inferior to those in the NMIBC alone group (P < 0.001 and P = 0.006, respectively). Multivariate analyses identified the following independent prognosticators: multiplicity and upper urinary tract cancer status for recurrence-free survival, and pT category and upper urinary tract cancer status for progression-free survival. Significant differences were noted by the risk stratification systems based on the positive number of independent predictors of recurrence-free survival and progression-free survival (P < 0.001 and P = 0.007, respectively). The concordance indices of recurrence-free survival were 0.627, 0.588 and 0.499 in this study stratification, EORTC risk table and CUETO model, respectively. Those of progression-free survival were 0.752, 0.740 and 0.714, respectively. CONCLUSION: The present results suggest the significant impact of a history of prior or concomitant UUTC on recurrence-free survival and progression-free survival in non-muscle invasive bladder cancer patients, and risk stratification systems that include the upper urinary tract cancer status for the recurrence and progression of non-muscle invasive bladder cancer are promising tools for predicting the outcomes of these patients.

Renal capsule metastasis from renal pelvic cancer: a case report.

BACKGROUND: Metastatic renal cancers are relatively common. Most are metastases to the renal parenchyma via a hematogenous route and are derived from lung, breast, and gastrointestinal cancer, malignant melanoma, and hematologic malignant cancer. However, little is known about renal capsule metastasis from other cancers. CASE PRESENTATION: We report a 71-year-old woman with breast cancer who was treated with endocrine therapy. She presented with gross hematuria and was diagnosed as having right renal pelvic cancer and renal cell cancer. She underwent right laparoscopic radical nephroureterectomy. Pathological findings revealed right pelvic cancer and renal capsule metastasis. CONCLUSION: Renal capsule metastasis derived from renal pelvic cancer is very rare. When diagnosing renal capsule cancer, we believe that renal capsule metastasis should also be taken into consideration. Clinical and radiological differential diagnosis of renal capsule metastasis from renal cell cancer and primary renal capsule cancer is difficult. Assessment of the histopathological findings of the surgical specimens seems to be the only realistic approach to achieving the correct diagnosis.

Tumour multifocality and grade predict intravesical recurrence after nephroureterectomy in patients with upper urinary tract urothelial carcinoma without a history of bladder cancer.

OBJECTIVE: Patients with upper urinary tract urothelial carcinoma (UUT-UC) without a history of bladder cancer have a different natural history of intravesical recurrence after nephroureterectomy compared with those with a history of bladder cancer. The aim of this study was to identify predictive factors for post-operative intravesical recurrence in patients with non-metastatic upper urinary tract-localized urothelial carcinoma without a history of bladder cancer and who were not taking medication during the perioperative period. METHODS: This retrospective study included 133 patients who were treated between 1995 and 2012. Univariate and multivariate analyses were used to evaluate the clinical and pathological factors associated with the cumulative incidence of bladder cancer. RESULTS: Of the 133 patients, 51 (38.3%) developed intravesical recurrence during a median follow-up of 71 months (range, 0.8-210.8). In the multivariate analysis, multifocality (P = 0.03) and high tumour grade (P = 0.007) were significantly associated with the cumulative incidence of bladder cancer. We constructed a prediction classification model on the basis of the total number of risk factors. The 2-year cumulative incidence rates were 5.6, 34.8 and 50.0% in individuals with no, one and two risk factors, respectively. There was a significant difference between patients with no risk factors and those with two risk factors (P = 0.01). CONCLUSIONS: Although this retrospective study had several limitations, tumour multifocality and tumour grade were found to be potential risk factors for intravesical recurrence in our cases.

Prognostic factors of recurrent disease in upper urinary tract urothelial cancer after radical nephroureterectomy: Subanalysis of the multi-institutional national database of the Japanese Urological Association.

OBJECTIVES: To explore predictive factors of disease recurrence after radical nephroureterectomy in patients with upper urinary tract urothelial cancer. METHODS: A multi-institutional national database promoted by the Japanese Urological Association including 293 institutions and 1172 patients was used for the present study. Patient with non-metastatic upper urinary tract urothelial cancer who underwent primary radical nephroureterectomy with curative intent were analyzed. Univariate analysis using the Kaplan-Meier method and multivariate Cox regression models with stepwise selection was used to evaluate time to recurrence after surgery. RESULTS: The median duration of follow up was 55.8 months, and disease recurred in 325 (27.7%) patients at a median of 11.4 months after radical nephroureterectomy. According to a Cox proportional hazards model, the Union International Contre le Cancer 2002 pathological stage of the primary tumor, lymph node status, presence of lymphatic and/or vascular invasion, infiltrative growth pattern, and age were independent predictors (P < 0.05) of recurrence-free survival. CONCLUSIONS: Despite several limitations, our analysis suggests that pathological tumor stage, lymph node status, lymphovascular invasion, infiltrative growth pattern and age represent important prognostic variables after radical nephroureterectomy in Japanese patients with upper urinary tract urothelial cancer. This information could be potentially used to select patients for adjuvant systemic therapy.

Oncological outcomes of renal pelvic and ureteral cancer patients registered in 2005: the first large population report from the Cancer Registration Committee of the Japanese Urological Association.

OBJECTIVES: To describe the clinical and pathological characteristics and the outcomes of renal pelvic and ureteral cancer patients diagnosed in 2005 in Japan. METHODS: In 2011, data were collected from renal pelvic and ureteral cancer patients diagnosed in 2005. A total of 1509 registered patients from 348 institutions were analyzed. Epidemiology and survival were analyzed based on each cancer location and on cancer multiplicity. RESULTS: The 5-year overall survival of the 1509 patients was estimated at 0.64. Open surgery was carried out in 409 renal pelvic cancer cases (66.9%) and 315 ureteral cancer cases (63.0%). The retroperitoneal approach was common, and lymph node dissection was carried out in approximately one-third of open surgery cases and one-fifth of laparoscopic cases. Approximately 60% of the operated unilateral renal pelvic or ureteral cancer was diagnosed as invasive, and just 14.6% was diagnosed as stage pTa. Distribution of the estimated worst tumor grade was significantly different for renal pelvic cancer and ureteral cancer. CONCLUSIONS: This article presents the first large population report of survival data in Japanese renal pelvic and ureteral cancer patients. In comparison with the Japanese bladder cancer database report in 1999-2001 from the Cancer Registration Committee of the Japanese Urological Association, the pathological characteristics of renal pelvic and ureteral cancer were diagnosed as aggressive.

Renal pelvic plasmacytoid subtype urothelial carcinoma accompanied with solitary mammary metastasis.

A 72-year-old female was referred to our institution for further evaluation of right renal tumor detected during work-up for macroscopic hematuria in other hospital. CT urography performed at our institution suggested renal pelvic tumor. Voiding cytology was atypical. CT also revealed a small mass in the right mammary gland. Percutaneous needle biopsies were performed on the right mammary gland and renal mass, leading to a pathological diagnosis of UC with plasmacytoid subtype, suggesting metastasis from the renal pelvic UC to the mammary gland. She had a favorable response to four cycles of dose-dense MVAC therapy; therefore, we performed nephroureterectomy. One month after nephroureterectomy, new intraperitoneal metastatic lesions were observed and pembrolizumab therapy was started. After seven doses of pembrolizumab, CT revealed a marked size reduction of intraperitoneal metastases and the mammary metastasis remained small.

Pancreatitis as immune-related adverse event during pembrolizumab therapy for multiple lung metastases from renal pelvic cancer.

Introduction: Pembrolizumab administration has become the standard of care for patients with urothelial carcinoma, though a variety of adverse events have been reported. Presented here is a rare case of pancreatitis that occurred as an immune-related adverse event. Case presentation: An 81-year-old man undergoing treatment with pembrolizumab for multiple lung metastases from renal pelvic cancer was presented with a fever and diagnosed with pancreatitis based on elevated pancreatic enzyme levels and imaging findings. There was no history of alcohol consumption or findings indicating gallstones, elevated liver enzymes, or abdominal complications. The patient was diagnosed with immune-related adverse event pancreatitis and treated with Lactate Ringer's solution (3000 mL/day) and steroids, during which his condition improved. Conclusion: Although pancreatitis is a rare complication, it should always be considered as a potential immune-related adverse event in patients treated with an immune checkpoint inhibitor such as pembrolizumab.

Advance renal pelvic cancer caused obstructive jaundice: A case report.

We report a case of advanced renal pelvic cancer in a 69-year-old woman who presented with fatigue, appetite loss, and yellow sclera. Contrast-enhanced computed tomography revealed a large lesion mass extending from the right renal pelvis to the duodenum and surrounding enlarged lymph nodes. Gastroduodenal endoscopy revealed a mass in the ampulla of Vater, and an endoscopic biopsy was performed. Histological and immunohistochemical examination of the biopsy specimen confirmed a diagnosis of urothelial carcinoma. To the best of our knowledge, this is the first report of advanced renal pelvic cancer causing obstructive jaundice.

Bladder and upper urinary tract cancers as first and second primary cancers.

BACKGROUND: Previous population-based studies on second primary cancers (SPCs) in urothelial cancers have focused on known risk factors in bladder cancer patients without data on other urothelial sites of the renal pelvis or ureter. AIMS: To estimate sex-specific risks for any SPCs after urothelial cancers, and in reverse order, for urothelial cancers as SPCs after any cancer. Such two-way analysis may help interpret the results. METHODS: We employed standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancer associated with urothelial cancers. Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015. RESULTS: We identified 46 234 urinary bladder cancers (75% male), 940 ureteral cancers (60% male), and 2410 renal pelvic cancers (57% male). After male bladder cancer, SIRs significantly increased for 9 SPCs, most for ureteral (SIR 41.9) and renal pelvic (17.2) cancers. In the reversed order (bladder cancer as SPC), 10 individual FPCs were associated with an increased risk; highest associations were noted after renal pelvic (21.0) and ureteral (20.9) cancers. After female bladder cancer, SIRs of four SPCs were significantly increased, most for ureteral (87.8) and pelvic (35.7) cancers. Female bladder, ureteral, and pelvic cancers associated are with endometrial cancer. CONCLUSIONS: The risks of recurrent urothelial cancers were very high, and, at most sites, female risks were twice over the male risks. Risks persisted often to follow-up periods of >5 years, motivating an extended patient follow-up. Lynch syndrome-related cancers were associated with particularly female urothelial cancers, calling for clinical vigilance.

A Case of Renal Pelvic Cancer with a Complete Duplication of the Renal Pelvis and Ureter.

This paper describes a case of renal pelvic cancer with a complete duplication of the renal pelvis and ureter, which is substantially rare. A 76-year-old man was referred to the hospital because of gross hematuria for 2 years. A tumor was detected in the upper right kidney using enhanced computed tomography and magnetic resonance imaging scan, and the downstream ureter was suspected to open into the prostate. Retrograde ureteroscopy via the ectopic ureter orifice showed a hemorrhagic papillary tumor consistent with imaging findings. Laparoscopic radical nephroureterectomy was performed and the prostate was preserved because the tumor was only in the renal pelvis. Histopathological examination showed the tumor as a high-grade urothelial carcinoma. There was no sign of recurrence at one and a half years after operation. Ureteroscopy was effective in detecting an upper urinary tract tumor, even via ectopic ureter orifice, and preserving the prostate was possible.

Delayed post-diuretic 18F-FDG PET/CT for preoperative evaluation of renal pelvic cancer.

Background: Application of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in urological oncology was relatively slowly due to the urinary elimination of 18F-FDG. We investigated whether delayed post-diuretic 18F-FDG PET/CT could be used for diagnosing renal pelvic cancer. Methods: 51 patients were included who underwent delayed post-diuretic 18F-FDG PET/CT for detecting renal pelvic space-occupying lesions. The comparations of delayed PET/CT parameters and clinical characteristics between renal pelvic cancer and benign polyp were investigated. Results: Among the 51 patients, 47 were found to have renal pelvic urothelial carcinoma, and 4 had benign polyp. ROC analysis identified the lesion maximum standardized uptake value (SUVmax) of 6.2 as the optimal cut-off value to distinguish from renal pelvic urothelial carcinoma to benign polyp. With the SUVmax cut-off of 6.2, the sensitivity, and specificity for predicting of renal pelvic urothelial carcinoma were 91.5% (43/47), and 100% (4/4). We also found a significant difference in tumor size between the positive (SUVmax > 6.2) and negative (SUVmax ≤ 6.2) PET groups in renal pelvic cancers. In patients with tumor size < 1.1 cm, the probability of being in the negative PET group was 75%. In such patients, a substantial proportion of renal pelvic cancer demonstrated negative SUVmax similar to that in patients with benign polyp. Conclusion: Delayed 18F-FDG PET/CT could be used for differentiating renal pelvic cancer from benign polyp. In patients with small tumor size, renal pelvic cancer may present low 18F-FDG uptake, mimicking the metabolic phenotypes of patients with benign polyp.

Successful pembrolizumab treatment in a patient with metastatic urothelial carcinoma and underlying overlap syndrome involving systemic sclerosis and systemic lupus erythematosus.

INTRODUCTION: The safety and efficacy of pembrolizumab administration in patients with urothelial carcinoma and underlying autoimmune disease (including overlap syndrome) is unknown. CASE PRESENTATION: We present the case of a 67-year-old woman with cT3N2M0 metastatic renal pelvic cancer who had been treated with prednisolone for overlap syndrome involving systemic sclerosis and systemic lupus erythematosus for 20 years. She had a remarkable response to pembrolizumab as a third-line systemic therapy, wherein the tumor reduced in size and all regional lymph node and pulmonary metastases disappeared. She did not develop any immune-related adverse events or autoimmune disease flare-ups during the treatment. CONCLUSION: This case report suggests that pembrolizumab could be beneficial to patients with urothelial carcinoma and underlying well-controlled overlap syndrome.

Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma.

An overview of epidemiological pattern of upper tract urothelial carcinoma (UTUC), including outcome of UTUC over past decades as well as factors responsible for observed epidemiological changes was performed. Gender and racial disparities influencing incidence of UTUC were reviewed. The incidence of multifocal urothelial carcinoma and relation of UTUC to urothelial carcinoma of bladder were examined.

Successful Resection of Cisplatin-Resistant Renal Pelvic Cancer after the Administration of Pembrolizumab as Second-Line Therapy.

Pembrolizumab has been used as a second-line systemic therapy for urothelial carcinoma. We herein report a case of cisplatin-resistant renal-pelvic urothelial carcinoma that was successfully resected after pembrolizumab treatment. A 74-year-old woman was referred to our hospital for further examination for gross hematuria and a renal-pelvis tumor. Retrograde pyelography showed a defect lesion in her renal pelvis and urinary cytology of the renal pelvis showed class V. Because staging CT could not deny lung metastasis, we planned to perform nephro-ureterectomy after evaluating the response to neoadjuvant chemotherapy. After three courses of gemcitabine and cisplatin chemotherapy, the original site showed progression; thus, nephro-ureterectomy was cancelled. We introduced pembrolizumab as a second-line therapy. After four courses of pembrolizumab treatment, the size of the original lesion was significantly decreased. During these therapies the lung tumor size was unchanged; thus, we determined that the lung tumor was not metastatic and performed nephro-ureterectomy. A pathological examination demonstrated that the tumor was completely resected with a negative surgical margin. We described the first case in which cisplatin-resistant renal pelvic tumor was successfully resected after pembrolizumab treatment.

Accuracy of High-Frequency Endoluminal Ultrasonography for Clinical Staging of Upper Tract Urothelial Carcinoma.

INTRODUCTION: Staging of upper tract urothelial carcinoma (UTUC) remains a dilemma due to imaging and biopsy limitations leading to understaging. We seek to determine the accuracy of endoluminal ultrasound (ELUS) for clinical staging of UTUC. MATERIALS AND METHODS: Patients evaluated for UTUC underwent retrograde pyelography, ureteroscopy, and ELUS. ELUS was performed using mechanical radial scanning at 20 MHz in B-mode with a 5F probe. Cine clips were evaluated by 2 radiologists blinded to ureteroscopic and pathology findings. Results were compared to pathology from nephroureterectomy. Inclusion criteria were patients who underwent nephroureterectomy without pretreatment or managed endoscopically for cTa-1 disease and were without recurrence for >1 year. RESULTS: From 2008 to 2013, 53 patients underwent ELUS without complication. Twenty-seven patients met inclusion criteria with conclusive ELUS imaging. ELUS accurately identified 16 of 21 patients with non-muscle invasive (MI) disease (18 pTa, 2 pT1, 1 CIS) and 1 of 6 patients with at least MI disease (2 pT2, 4 pT3). For MI disease, the positive predictive value (PPV), negative predictive value, and accuracy was 76.2%, 16.7%, and 63%, respectively, while for non-organ confined (OC) disease results were 0%, 81.8%, and 66.7%, respectively. CONCLUSIONS: With current technique and instrumentation, ELUS may prove useful in select cases to confirm findings of non-MI and OC disease. However, it has insufficient PPV for stage pT2-3 disease. Further studies and better instrumentation are needed before incorporation into clinical practice.

Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma.

BACKGROUND: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data. RESULTS AND LIMITATIONS: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade

Warfarin-related nephropathy in a patient with renal pelvic cancer.

An 83-year-old Japanese man had a history of chronic heart failure due to bradycardia-tachycardia syndrome. He was admitted to our hospital because of macrohematuria and acute kidney injury (AKI), which were detected by an urologist at an outpatient visit. He had a history of recurrent macrohematuria and transurethral resection of bladder tumors twice in the preceding 2 years. He had been on warfarin for 12 years, with a stable international normalized ratio (INR) that was usually less than 2.1. Urinalysis revealed numerous red blood cells (RBCs) and mild proteinuria without RBC casts. His serum creatinine level was elevated to 2.41 mg/dL from 0.96 mg/dL at 3 weeks before admission. INR was 1.44. Hydronephrosis was not observed. Ureteroscopy detected invasive urothelial carcinoma of the renal pelvis, and right laparoscopic nephroureterectomy was performed at 41 days after diagnosis of AKI. The background renal parenchyma displayed tubular obstruction by red blood cell casts and acute tubular injury, which were changes compatible with warfarin-related nephropathy (WRN). Warfarin was discontinued, and the serum creatinine level recovered to 1.66 mg/dL after 3 months. In the present patient with nephrosclerosis, WRN occurred at a therapeutic INR level after 12 years of uneventful warfarin therapy, and the coexisting urothelial malignancy was a unique feature.