Development and Validation of a Preoperative Nomogram for Endoscopic Management Decision Making in Upper Urinary Tract Urothelial Carcinoma.

OBJECTIVE: We aimed to develop and validate a preoperative nomogram that predicts low-grade, non-muscle invasive upper urinary tract urothelial carcinoma (LG-NMI UTUC), thereby aiding in the accurate selection of endoscopic management (EM) candidates. METHODS: This was a retrospective study that included 454 patients who underwent radical surgery (Cohort 1 and Cohort 2), and 26 patients who received EM (Cohort 3). Utilizing a multivariate logistic regression model, a nomogram predicting LG-NMI UTUC was developed based on data from Cohort 1. The nomogram's accuracy was compared with conventional European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) models. External validation was performed using Cohort 2 data, and the nomogram's prognostic value was evaluated via disease progression metrics in Cohort 3. RESULTS: In Cohort 1, multivariate analyses highlighted the absence of invasive disease on imaging (odds ratio [OR] 7.04; p = 0.011), absence of hydronephrosis (OR 2.06; p = 0.027), papillary architecture (OR 24.9; p < 0.001), and lack of high-grade urine cytology (OR 0.22; p < 0.001) as independent predictive factors for LG-NMI disease. The nomogram outperformed the two conventional models in predictive accuracy (0.869 vs. 0.759-0.821) and exhibited a higher net benefit in decision curve analysis. The model's clinical efficacy was corroborated in Cohort 2. Moreover, the nomogram stratified disease progression-free survival rates in Cohort 3. CONCLUSION: Our nomogram ( https://kmur.shinyapps.io/UTUC_URS/ ) accurately predicts LG-NMI UTUC, thereby identifying suitable candidates for EM. Additionally, the model serves as a useful tool for prognostic stratification in patients undergoing EM.

Final Results of a Phase I Trial of WST-11 (TOOKAD Soluble) Vascular-targeted Photodynamic Therapy for Upper Tract Urothelial Carcinoma.

PURPOSE: Vascular-targeted photodynamic therapy with the intravascular photosensitizing agent padeliporfin (WST-11/TOOKAD-Soluble) has demonstrated therapeutic efficacy as an ablative treatment for localized cancer with potential adaptation for endoscopic management of upper tract urothelial carcinoma. This Phase I trial (NCT03617003) evaluated the safety of vascular-targeted photodynamic therapy with WST-11 in upper tract urothelial carcinoma. MATERIALS AND METHODS: Nineteen patients underwent up to 2 endoscopic vascular-targeted photodynamic therapy treatments, with follow-up for up to 6 months. Patients who had residual or recurrent upper tract urothelial carcinoma (any grade/size) failing prior endoscopic treatment or unable or unwilling to undergo surgical resection were eligible for inclusion. The primary endpoint was to identify the maximally tolerated dose of laser light fluence. A dose escalation model was employed, with increasing light fluence (100-200 mW/cm) using a modified continual reassessment method. The secondary endpoint was treatment efficacy, defined by absence of visible tumor and negative urine cytology 30 days posttreatment. RESULTS: Fourteen (74%) patients received the maximally tolerated dose of 200 mW/cm, 2 (11%) of whom experienced a dose-limiting toxicity. The initial 30-day treatment response rate was 94% (50% complete, 44% partial). Eight patients underwent a second treatment, with a final observed 68% complete response rate. Leading toxicities were flank pain (79%) and hematuria (84%), which were transient. No ureteral strictures associated with treatment were identified during follow-up. CONCLUSIONS: Vascular-targeted photodynamic therapy with WST-11 has an acceptable safety profile with strong potential as an effective, kidney-sparing endoscopic management option for upper tract urothelial carcinoma. The recently initiated multicenter Phase 3 ENLIGHTED trial (NCT04620239) is expected to provide further evidence on this therapy.

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.

Balkan Endemic Nephropathy and the Causative Role of Aristolochic Acid.

Balkan endemic nephropathy is a chronic tubulointerstitial disease with insidious onset, slowly progressing to end-stage renal disease and frequently associated with urothelial carcinoma of the upper urinary tract (UTUC). It was described in South-East Europe at the Balkan peninsula in rural areas around tributaries of the Danube River. After decades of intensive investigation, the causative factor was identified as the environmental phytotoxin aristolochic acid (AA) contained in Aristolochia clematitis, a common plant growing in wheat fields that was ingested through home-baked bread. AA initially was involved in the outbreak of cases of rapidly progressive renal fibrosis reported in Belgium after intake of root extracts of Aristolochia fangchi imported from China. A high prevalence of UTUC was found in these patients. The common molecular link between Balkan and Belgian nephropathy cases was the detection of aristolactam-DNA adducts in renal tissue and UTUC. These adducts are not only biomarkers of prior exposure to AA, but they also trigger urothelial malignancy by inducing specific mutations (A:T to T:A transversion) in critical genes of carcinogenesis, including the tumor-suppressor TP53. Such mutational signatures are found in other cases worldwide, particularly in Taiwan, highlighting the general public health issue of AA exposure by traditional phytotherapies.

Prognosis and risk factors of patients with upper urinary tract urothelial carcinoma and postoperative recurrence of bladder cancer in central China.

BACKGROUND: To investigate the prognostic risk factors and postoperative recurrence of bladder cancer in patients with upper urinary tract urothelial carcinomas (UTUCs). METHODS: Data of 439 UTUC patients were retrospectively analyzed. Follow-up and analysis of smoking effects, consumption of traditional Chinese medicine containing aristolochic acid, history of bladder cancer, age, sex, presence or absence of diabetes mellitus (DM), metformin use, tumor characteristics (number, location, stage, grade), and open or laparoscopic surgery on the prognosis of UTUCs were performed. Cox proportional hazard regression analysis was performed to analyze the relationship between various factors and the postoperative survival rate. The survival rate was analyzed using the Kaplan-Meier method. Moreover, logistic regression analysis was performed to analyze the relationship between the above mentioned factors and postoperative recurrence of bladder cancer. RESULTS: Overall, 439 patients met, including 236 males (53.7%) and 203 females (46.3%), the criteria for the final statistical analysis, and the average age was 66.7 years. The 1-, 3-, and 5-year overall survival rates of 439 UTUC patients were 90.0, 76.4, and 67.7%, respectively. The 5-year survival rates of T1, T2, T3, and T4 patients were 90.2%, 78%, 43.8%, and 18.5%, respectively. Factors influencing the long-term survival rate of UTUC patients were smoking, taking traditional Chinese medicine containing aristolochic acid, history of bladder cancer, age, tumor size, tumor stage, tumor grade, and lymph node metastasis. The risk factors related to postoperative bladder cancer recurrence were advanced tumor stage, high grade tumor, preoperative ureteroscopy, ureteral urothelial carcinoma, no postoperative bladder perfusion chemotherapy and DM without metformin use. CONCLUSIONS: Advanced tumor stage and presence of a high-grade tumor were risk factors for not only poor UTUC prognosis but also BC recurrence. In addition, preoperative ureteroscopy, ureteral urothelial carcinoma and DM without metformin use were high risk factors for BC recurrence, whereas regular postoperative bladder perfusion chemotherapy was a protective factor.

Recent advances in upper tract urothelial carcinomas: From bench to clinics.

Urothelial carcinoma in the upper tract is rare and often discussed separately. Many established risk factors were identified for the disease, including genetic and external risk factors. Radiographic survey, endoscopic examination and urine cytology remained the most important diagnostic modalities. In localized upper tract urothelial carcinomas, radical nephroureterectomy with bladder cuff excision are the gold standard for large, high-grade and suspected invasive tumors of the renal pelvis and proximal ureter, whereas kidney-sparing surgeries should be considered in patients with low-risk disease. Advances in technology have given endoscopic surgery an important role, not only in diagnosis, but also in treatment. Although platinum-based combination chemotherapy is efficacious in advanced or metastatic disease, current established chemotherapy regimens are toxic and lack a sustained response. Immune checkpoint inhibitors have led to a new era of treatment for advanced or metastatic urothelial carcinomas. The remarkable results achieved thus far show that immunotherapy will likely be the future treatment paradigm. The combination of immune checkpoint inhibitors and other agents is another inspiring avenue to explore that could benefit even more patients. With respect to the high incidence rate and different clinical appearance of upper tract urothelial carcinomas in Taiwan, a possible correlation exists between exposure to certain external risk factors, such as arsenic in drinking water and aristolochic acid in Chinese herbal medicine. As more gene sequencing differences between upper tract urothelial carcinomas and various disease causes are detailed, this has warranted the era of individualized screening and treatment for the disease.

Upper tract urothelial carcinoma topical issue 2016: treatment of metastatic cancer.

PURPOSE: To review the management of metastatic upper tract urothelial carcinoma (UTUC) including recent advances in targeted and immune therapies as an update to the 2014 joint international consultation on UTUC, co-sponsored by the Société Internationale d'Urologie and International Consultation on Urological Diseases. METHODS: A PubMed database search was performed between January 2013 and May 2016 related to the treatment of metastatic UTUC, and 54 studies were selected for inclusion. RESULTS: The management of patients with metastatic UTUC is primarily an extrapolation from evidence guiding the management of metastatic urothelial carcinoma of the bladder. The first-line therapy for metastatic UTUC is platinum-based combination chemotherapy. Standard second-line therapies are limited and ineffective. Patients with UTUC who progress following platinum-based chemotherapy are encouraged to participate in clinical trials. Recent advances in genomic profiling present exciting opportunities to guide the use of targeted therapy. Immunotherapy with checkpoint inhibitors has demonstrated extremely promising results. Retrospective studies provide support for post-chemotherapy surgery in appropriately selected patients. CONCLUSIONS: The management of metastatic UTUC requires a multi-disciplinary approach. New insights from genomic profiling using targeted therapies, novel immunotherapies, and surgery represent promising avenues for further therapeutic exploration.

Upper urinary tract urothelial cancers: where it is A:T.

Despite a ban on the use of plants of the Aristolochia genus in herbal medicine, as they contain known carcinogens, urothelial carcinoma attributable to the use of this plant seems to be more common than previously thought.

Aristolochic acid-associated urothelial cancer in Taiwan.

Aristolochic acid, a potent human carcinogen produced by Aristolochia plants, is associated with urothelial carcinoma of the upper urinary tract (UUC). Following metabolic activation, aristolochic acid reacts with DNA to form aristolactam (AL)-DNA adducts. These lesions concentrate in the renal cortex, where they serve as a sensitive and specific biomarker of exposure, and are found also in the urothelium, where they give rise to a unique mutational signature in the TP53 tumor-suppressor gene. Using AL-DNA adducts and TP53 mutation spectra as biomarkers, we conducted a molecular epidemiologic study of UUC in Taiwan, where the incidence of UUC is the highest reported anywhere in the world and where Aristolochia herbal remedies have been used extensively for many years. Our study involves 151 UUC patients, with 25 patients with renal cell carcinomas serving as a control group. The TP53 mutational signature in patients with UUC, dominated by otherwise rare A:T to T:A transversions, is identical to that observed in UUC associated with Balkan endemic nephropathy, an environmental disease. Prominent TP53 mutational hotspots include the adenine bases of (5')AG (acceptor) splice sites located almost exclusively on the nontranscribed strand. A:T to T:A mutations also were detected at activating positions in the FGFR3 and HRAS oncogenes. AL-DNA adducts were present in the renal cortex of 83% of patients with A:T to T:A mutations in TP53, FGFR3, or HRAS. We conclude that exposure to aristolochic acid contributes significantly to the incidence of UUC in Taiwan, a finding with significant implications for global public health.

[Sporadic upper urinary tract urothelial cell carcinomas: identification of interaction between toxic carcinogens and individuals genetic susceptibility]. / Tumeurs des voies excrétrices urinaires supérieures sporadiques: identification de l'interaction entre l'exposition aux carcinogènes environnementaux et la susceptibilité génétique des individus.

Upper urinary tract urothelial cell carcinomas (UUT UCC) are rare sporadic tumors. Recent epidemiologic and molecular data have shown a singular susceptibility of UUT UCCs for specific risk factors. The main exogenic factors involved in UUT UCCs carcinogenesis remain tobacco and occupational exposure (aromatic amines, polycyclic hydrocarbures and chlored solvents). Enzymatic variants of detoxification system may be responsible of carcinogenesis with these toxics. Tumors induced by phenacetine consumption are decreasing since it was banned in the 1970s. Also, acid aristolochic exposure (Balkan nephropathy, Chinese Herb nephropathy) has been demonstrated to specifically induce UUT UCCs. Familial genic polymorphism of detoxification system would explain geographic distribution in endemic areas. In Taiwan, chronic arsenic exposition would constitute the main risk factor of UUT UCC. However, theses mechanisms of carcinogenesis remain unclear. The knowledge of UUT UCC development mechanisms implying toxic detoxification systems is still incomplete. To date, there is a growing body of evidence supporting that the interaction between individual genetic susceptibilities and environmental toxic exposure is a key to explain carcinogenesis in the majority of sporadic UUT UCC occurrence.

[A case of upper urinary tract metastases from sigmoid colon cancer].

We report a case of colorectal cancer with metastasis to the upper urinary tract. A 56-year-old man had left flank pain. Ultrasonography and computed tomographic (CT) examination demonstrated left hydronephroureter and a soft-tissue structure within the left ureter. Urinary cytology of the left ureter showed class IIIb. We diagnosed him with ureteral cancer and performed left nephroureterectomy. Microscopic examination demonstrated adenocarcinoma located in ureteral and pelvic wall, especially in blood vessels, with intact mucosa and similar to adenocarcinoma of colon cancer. Therefore metastatic upper urinary tract tumor was suspected. Barium enema and positron emission tomography-CT demonstrated sigmoid colon cancer. Biopsy specimen of colon cancer demonstrated adenocarcinoma, which was consistent with the ureteral tumor. Finally we diagnosed him with metastatic upper urinary tract tumor of sigmoid colon cancer.

Prognostic value of apoptosis-related markers in urothelial cancer of the upper urinary tract.

We investigated the expression of apoptosis-related markers and their association with the clinical outcomes of patients with urothelial carcinoma of the upper urinary tract. A total of 112 patients with urothelial carcinoma of the upper urinary tract that had surgery from March 1998 to July 2005 were included in the study. Tissue microarray slides were used for immunohistochemistry, and immunohistochemical staining was performed to investigate the association of apoptosis-related markers with clinical outcome. Apoptosis was confirmed by the TdT-mediated DUTP nick-end labeling method to obtain the apoptotic index. Survival analysis was performed according to the Kaplan-Meier method, and the Cox proportional hazard regression model was used to compare the relative influence of different prognostic factors. Among the 112 patients, 32 (28.6%) had altered expression of p53, 30 (26.8%) of bcl-2, 62 (55.4%) of bax, 27 (24.1%) of caspase-3, and 23 (20.5%) of survivin. The expression of p53 and caspase-3 was associated with the pathologic grade (P = .035 and P = .004, respectively). Altered expression of caspase-3 was associated with the pathologic stage (P = .016). The multivariate analysis showed that the expression of survivin (hazard ratio 2.91, 95% confidence interval 1.07-7.90, P = .036) and the apoptotic index (AI) (3.35, 1.06-10.56, P = .039), as well as the T and N stages (P = .043 and P = .010, respectively) were significantly associated with the disease-specific survival. Our results suggest that survivin expression and a high apoptotic index were poor prognostic factors for survival in patients with urothelial carcinoma of the upper urinary tract. These results may help to identify a subset of patients who require adjuvant therapy or closer follow-up.

CKD as a risk factor for bladder recurrence after nephroureterectomy for upper urinary tract urothelial carcinoma.

BACKGROUND: The aim of this study is to examine chronic kidney disease (CKD) as a risk factor for bladder recurrence and cancer-specific and total mortality in a cohort of patients with upper urinary tract (UUT) urothelial carcinoma (UC) treated by means of nephroureterectomy. STUDY DESIGN: Cohort study. SETTINGS & PARTICIPANTS: 150 patients with primary UC of the ureter or renal pelvis treated by means of nephroureterectomy at a single center. PREDICTOR: Presence and severity of CKD according to preoperative markers of kidney damage, estimated glomerular filtration rate calculated using the Modification of Diet in Renal Disease Study equation, and other covariates. OUTCOMES & MEASUREMENTS: Subsequent bladder recurrences, cancer-specific survival, and overall survival. RESULTS: Of 150 patients, 37 (25%) had no CKD, 71 patients (47%) had CKD stages 1 to 4, and 42 patients (28%) had CKD stage 5. 41 (27%) and 31 patients (21%) reported exposure to herbal medicine or tobacco use, respectively. During a mean follow-up of 4 years, 53 patients (35%) developed bladder recurrence and 27 (18%) died, of whom 14 (9.3%) died of cancer. Overall 5-year bladder recurrence-free and cancer-specific survival rates were 62% and 89%, respectively (n = 150). Risks of bladder recurrence were 2.43 (95% confidence interval, 1.00 to 5.93) and 3.95 (95% confidence interval, 1.59 to 9.80), greater in patients with CKD stages 1 to 4 and CKD stage 5 compared with patients without CKD, respectively. Ureteral involvement of the primary tumor (hazard ratio, 1.97; 95% confidence interval, 1.12 to 3.48) also was associated significantly with an increased rate of bladder recurrence. The risk of death from all causes or UC was not significantly greater in patients with CKD stages 1 to 4 or CKD stage 5 compared with those without CKD. Higher tumor stage (pT2 to 4) was associated significantly with overall death (hazard ratio, 5.15; 95% confidence interval, 1.84 to 14.48). LIMITATIONS: A retrospective study in an area of high incidence of both UUT-UC and CKD. CONCLUSIONS: Advancing CKD stage of patients and positive ureteral involvement of the primary tumor (especially in the lower ureter) are associated with greater risk of subsequent bladder recurrence in patients with UUT-UC treated by means of radical surgery.

Prognostic factors for metastatic urothelial carcinoma treated with cisplatin and 5-fluorouracil-based regimens.

OBJECTIVES: We have previously shown that a combination of infusion cisplatin and high-dose 5-fluorouracil/leucovorin (P-HDFL) has moderate activity and acceptable toxicity in patients with metastatic urothelial carcinoma. The present study sought to identify factors that predict for patient survival after treatment with P-HDFL-based regimens. METHODS: The outcomes of 79 patients (median age 69 years) with metastatic urothelial cancer treated in two Phase II trials, including P-HDFL and paclitaxel plus P-HDFL, were updated. The log-rank test and multivariate Cox proportional hazard models were used to identify the prognostic factors predicting for survival. RESULTS: The median follow-up duration was 38.9 months (range 10.2 to 89.0). A Karnofsky performance status scale of less than 80% (hazard ratio 2.6, 95% confidence interval 1.5 to 4.6), presence of visceral metastasis (hazard ratio 2.3, 95% confidence interval 1.3 to 4.1), and alkaline phosphatase level of 220 U/L or greater (hazard ratio 2.5, 95% confidence interval 1.3 to 4.5) were three significant risk factors predicting for poor survival in the Cox proportional hazard model. The three factors weighted approximately the same and were independent of each other. The median survival for patients with three, one or two, and no risk factors was 4.6, 13.2, and greater than 81.8 months, respectively (P <0.001). CONCLUSIONS: The Karnofsky performance status scale, presence of visceral metastasis, and alkaline phosphatase level were independent risk factors for survival in patients with metastatic urothelial carcinoma treated with cisplatin and 5-fluorouracil-based regimens.

Ureteral mullerian carcinosarcoma (mixed mullerian tumor) associated with endometriosis occurring in a patient with a concentrated soy isoflavones supplementation.

Malignant transformation and particularly malignant mixed mullerian tumor arising in extragenital endometriosis is extremely rare and occurs in the majority of cases after estrogen replacement therapy. We present a case of a 75-year-old woman who developed a ureteral malignant mullerian carcinosarcoma in a context of florid endometriosis. The patient had a history of total hysterectomy with bilateral salpingo-oophorectomy 30 years earlier for extensive endometriosis. Since 5 years, the patient has been on phytoestrogen supplementation consisting of 72 mg/day of superconcentrated soy isoflavones. This is the first case of ureteral mullerian carcinosarcoma arising in endometriosis foci after extensive phytoestrogen supplementation. Our data suggest that phytoestrogens at least in concentrated form may play a role not only in maintenance of endometriosis but also in its malignant transformation. Given the extraordinary popularity and availability of these dietary supplements, several studies are indispensable regarding their safety particularly in women with extensive endometriosis.

DNA adducts and p53 mutations in a patient with aristolochic acid-associated nephropathy.

BACKGROUND: Aristolochic acid-associated nephropathy (AAN) is a specific type of renal disease that predisposes patients to a high risk of urothelial carcinoma. The authors have analyzed DNA from a patient who had urothelial malignancy 6 years after presenting with AAN and later had a breast carcinoma that metastasized to the liver. METHODS AND RESULTS: DNA was isolated from the primary breast tumor, the liver tumor, and the original urothelial malignancy and assayed for aristolochic acid (AA)-DNA adducts and mutations in the p53 gene. The adduct detected was the adenosine adduct of aristolochic acid I 7-(deoxyadenosin-N6-yl)aristolactam I (dA-AAI). In DNA from the breast and liver tumors the authors showed the same missense mutation in codon 245 (GGC-->GAC; Gly-->Asp) of exon 7 of p53. In contrast, DNA extracted from the urothelial tumor showed an AAG to TAG mutation in codon 139 (Lys-->Stop) of exon 5. CONCLUSION: A to T transversions, as observed here, are the typical mutations observed in the H-ras gene of tumors induced when rodents are treated with AA and correspond with DNA adduct formation at adenosine residues. These data indicate the probable molecular mechanism whereby AA causes urothelial malignancy.

Urothelial malignant disease and Chinese herbal nephropathy.

We have previously reported occurrence of a specific type of nephropathy due to ingestion of Chinese herbs (Chinese herbal nephropathy [CHN]) in two patients in the UK. These cases highlighted the role of aristolochic acid in causing this nephropathy, which was first described in a Belgian cohort. We now report development of invasive transitional cell carcinoma of the urinary tract associated with the presence of aristolochic acid-DNA adducts in one of these patients. This work clearly shows the carcinogenic potential of aristolochic acid in this new type of nephropathy.