Upper Urinary Tract Urothelial Carcinoma Patients Research Articles

Low Expression of GRIM-19 Correlates with Poor Prognosis in Patients with Upper Urinary Tract Urothelial Carcinoma

Purpose: This study aimed to clarify the expression of a gene associated with Retinoid- Interferon-Induced Mortality-19 (GRIM-19) in Upper Urinary Tract Urothelial Carcinoma (UUTUC) and its prognostic significance for UUTUC patients. Materials and Methods: Immunohistochemical (IHC) staining was used to determine the GRIM-19 expression in 70 paired samples. Progression-Free Survival (PFS) and Cancer-Specific Survival (CSS) were assessed using the Kaplan-Meier method. The independent prognostic factors for PFS and CSS were analyzed by multivariable Cox regression models. Results: IHC staining showed that GRIM-19 expression was significantly decreased in UUTUC, and its cellular location changed from being both cytoplasmic and nuclear to only cytoplasmic. Kaplan- Meier analysis revealed that the patients with tumors expressing low GRIM-19 had a significantly higher risk for tumor progression (P = 0.002) and cancer-specific mortality (P < 0.001) compared to those with high GRIM-19 levels. The Cox regression showed that both GRIM-19 expression (P = 0.025) and lymph node metastasis (LN) (P = 0.007) were independent predictors of progression in the muscle-invasive (MIC) subgroup. GRIM-19 expressions (entire cohort: P = 0.011; MIC subgroup: P = 0.025), LN (entire cohort: P = 0.019; MIC subgroup: P = 0.007), and progression (entire cohort: P < 0.001; MIC subgroup: P < 0.001) were independent predictors of cancer-specific survival. Conclusion: Low expression of GRIM-19 in patients with UUTUC had significantly shorter PFS or CSS compared to those with high GRIM-19-expressing tumors. High GRIM-19 expression was also strongly associated with longer PFS in MIC patients. It indicates that GRIM-19 might serve as a promising prognostic biomarker for UUTUC patients.

Association of Androgen Receptor and PD-L1 Expression in Upper Urinary Tract Urothelial Carcinoma.

The response to immune checkpoint inhibitors (ICIs) or enfortumab vedotin is limited in patients with upper urinary tract urothelial carcinoma (UTUC), and the development of new targeted therapy for UTUC is eagerly needed. Several biomarkers, including programmed cell death-ligand 1 (PD-L1), have already been reported as predictors of response to ICIs therapy for UTUC. Recently, several studies have shown that steroid hormone receptors, including the androgen receptor (AR), are associated with progression of urothelial carcinoma. We prepared tissue microarrays (TMA) from paraffin blocks of UTUC specimens in 99 non-metastatic UTUC patients who underwent radical nephroureterectomy. With these TMA sections, we performed immunohistochemical staining for PD-L1 and AR and examined PD-L1 and AR expression levels in tumor cells. In addition, we analyzed the correlation between these markers and clinical prognosis in UTUC cases. PD-L1 was positive in 24 (24%) of the 99 samples, whereas AR was positive in 20 (20%) patients. AR-negative samples had significantly higher PD-L1 expression level than that the AR-positive samples (mean value 4.70% versus 2.55%, p=0.0324). Among AR-positive cases, patients with absence of PD-L1 expression had significantly lower cancer-specific survival (CSS) than that in PD-L1 expression-positive cases (p=0.049), although PD-L1 expression had no significant impact on CSS in AR-negative cases (p=0.920). Our findings suggest that AR is the promising target for UTUC treatment, especially in PD-L1-negative cases.

Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: Results from a Prospective Phase 2 Clinical Trial

Background and objectiveThe possible negative impact of radical surgery on patients’ health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes. MethodsPatients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds. Key findings and limitationsBetween 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age >70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning. Conclusions and clinical implicationsUTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery. Patient summaryWe investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.

Influence of preoperative body mass index on prognosis for patients with upper urinary tract urothelial carcinoma treated with radical nephroureterectomy.

The impact of body mass index (BMI) on patients with upper urinary tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU) is controversial. Increasing evidence suggests an age-dependent relationship between obesity and outcomes for some solid organ tumors. Herein, we aimed to assess the prognostic value of preoperative BMI in UTUC patients treated with RNU in Taiwan. This was a retrospective single-center study of 468 UTUC patients undergoing RNU during January 2010-December 2017, with preoperative BMI classification and subgroup analysis based on ages of < or ≥ 70years. All UTUC patients underwent RNU and bladder cuff excision. Overall survival (OS), cancer-specific survival, and disease-free survival (DFS) were analyzed. Fisher's exact test, Mann-Whitney U test, Kaplan-Meier method, and Cox regression model were used for data analysis. The median follow-up duration was 36months. Patients with higher versus lower BMI (cutoff: 25kg/m2) showed no differences in OS; older patients had poor OS (hazard ratio [HR] 1.74; 95% confidence interval [CI] 1.24-2.40; p < 0.001). Older age was an independent predictor of poor OS in multivariate Cox regression analysis (p = 0.001). Younger patients with higher BMI (p = 0.02) had better DFS than older patients with no BMI-related survival differences. Higher BMI was an independent predictor of favorable DFS in younger patients in multivariate Cox regression analysis (HR, 0.53; 95% CI 0.28-0.99; p = 0.043). Younger UTUC patients with higher BMI were independently associated with a favorable DFS.

Patient-specific targeted analysis of circulating tumour DNA in plasma is feasible and may be a potential biomarker in UTUC

PurposeThe prognosis of upper urinary tract urothelial carcinoma (UTUC) is associated with tumour grade (G) and stage. Despite preoperative risk stratification and radical treatment, recurrence and progression are common. Thus, prognostic and monitoring biomarkers are needed. This feasibility study aimed to investigate if targeted analyses on circulating tumour DNA (ctDNA) in plasma could identify tumour-specific gene variants, and thus have potential for further evaluation as a biomarker in UTUC.MethodsNine UTUC patients with genetically characterised tumours were included in this prospective pilot study. Two tumour-specific variants were chosen for targeted analyses with multiplex droplet digital PCR on cell-free DNA (cfDNA) from plasma at diagnosis or from recurrence.ResultsOf six patients with diagnostic plasma samples, ctDNA was detected in four with G2 or G3 tumours and tumours > 300m2 in size. Three of these patients progressed in their disease and the fourth had the largest G3 tumour at sampling. In contrast, the two patients with undetectable ctDNA in diagnostic plasma had a G1 tumour and G3 carcinoma in situ (CIS), respectively. The patient with G3 CIS had detectable ctDNA later during follow-up and progressed thereafter with aggressive intravesical recurrence and CT-scan-verified CIS progression in the upper urinary tract. In three patients with small recurrent G1 or G2 tumours, none had detectable ctDNA in plasma and all were progression free.ConclusionOur early findings demonstrate that ctDNA in plasma can be detected by targeted analysis in patients with UTUC. However, further studies are needed to determine its role as a potential biomarker.

Risk factors for extraurothelial recurrence in upper tract urothelial carcinoma after radical nephroureterectomy: a retrospective study based on a Chinese population.

The risk factors for extraurothelial recurrence (EUR) after radical nephroureterectomy (RNU) in patients with upper urinary tract urothelial carcinoma (UTUC) are currently inconsistent and unclear. In this study, we aimed to identify these risk factors and develop a grading system for EUR. We retrospectively analyzed 220 patients who underwent RNU for UTUC in our center from January 2009 to December 2020. Overall survival (OS) and extraurothelial recurrence-free survival (EURFS) were compared using the Kaplan-Meier curve with a log-rank test. Univariate and multivariate Cox regression models were applied to identify the independent risk factors related to EUR. The median follow-up period was 42 (range: 2-143) months. Of the 220 patients, 61 patients developed EUR in our cohort, which had worse survival outcome. Multivariate Cox regression analysis showed pathologic stage, lymph node (LN) status, lymphovascular invasion (LVI), Ki-67, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were independent risk factors for EUR. The Kaplan-Meier curves revealed a significant difference in EUR among the three risk groups. Our study suggests that pathologic stage, LN status, LVI, Ki-67, NLR, and PLR are independent risk factors for EUR in UTUC patients after RNU. The development of a grading system for EUR risk stratification may assist urologists in making clinical decisions regarding the management of UTUC.

A novel nomogram for predicting extraurothelial recurrence in patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy.

We aimed to establish and validate a nomogram for extraurothelial recurrence (EUR) after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). The data of 521 patients with UTUC after RNU from 2 medical centers were retrospectively studied and were used as training cohort (n = 301) and external validation cohort (n = 220). We used the least absolute shrinkage and selection operator (LASSO) to select variables for multivariable Cox regression, and included independent risk factors into nomogram models predicting EUR-free survival (EURFS). Multiple parameters were used to validate the nomogram, including the concordance index (C-index), the calibration plots, the time-dependent receiver-operator characteristics curve (ROC), and the decision curve analysis (DCA). Patients were stratified into three risk groups according to total points calculated by nomograms. The differences of EURFS in each group were analyzed by the Kaplan-Meier analysis. Four variables were screened through LASSO regression. Bladder cancer history, Ki-67, lymphovascular invasion (LVI), and pathological T stage were shown to be independent predictive factors for EUR. The C-indexes of the model were 0.793 and 0.793 in training and validation cohorts, respectively. In comparison with prediction based on categorized pathological T stage, the DCA curves for 5-year EUR exhibited better performance. The 5-year EURFS rates were 92.2%, 63.8%, and 36.2% in patients stratified to the low-, medium-, and high-risk group. Our study provided a new nomogram to predict the probability of EUR in UTUC patients underwent RNU, with perfect performance in discrimination ability and clinical net benefit. The application of the model may help urologists to choose proper treatment and monitoring.

The Predictive Value of the Preoperative Systemic Inflammatory Response Indices in Non–Organ-Confined Disease in Upper Urinary Tract Urothelial Carcinoma

Purpose: This study aims to evaluate the systemic inflammatory response indices (SII) for the prediction of the non–organ-confined (non-OC) disease in upper urinary tract urothelial carcinoma (UTUC) patients.Materials and Methods: From March 2010 to March 2020, patients who underwent radical nephroureterectomy (RNU) in a single tertiary center were retrospectively reviewed. Tumor location, multifocality, hydronephrosis on preoperative imaging, and preoperative SII, including C-reactive protein-to-albumin ratio (CAR), neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were used for analysis. Non-OC defined by locally advanced (pT3-4) or node-positive disease (pN1-2) in pathologic examination. Multivariable logistic regression was used for determining independent predictive markers of non-OC disease. Factors associated with locally advanced (pT3-4), and node-positive (pN1-2) disease were also analyzed.Results: Overall, 711 UTUC patients who underwent RNU, without neoadjuvant chemotherapy, were analyzed. The average age was 68.6±9.9 years and 507 patients were male. Non-OC disease was 36.8% (262 of 711); specifically, 35.9% (255 of 711) was locally advanced and 7.2% (51 of 771) was node-positive disease. Multivariable analysis demonstrated hydronephrosis (odds ratio [OR], 1.46; 95%confidence interval [CI], 1.06–2.01; p=0.02), high PLR (OR, 1.45; 95% CI, 1.05–2.01; p=0.03), and high CAR (OR, 2.56; 95% CI, 1.79–3.66; p&lt;0.01) were independent predictive markers non-OC disease. Hydronephrosis (p=0.01), high PLR (p=0.02), and high CAR (p&lt;0.01) were predictive markers for locally advanced disease, and multifocal tumor (p&lt;0.01) and high CAR (p&lt;0.01) were predictive markers for node-positive disease.Conclusions: CAR is a novel important factor for predicting any subtype of non-OC disease among SII. Large scale, multicenter studies should validate the clinical role of CAR.

The prognostic impact of lymphovascular invasion for upper urinary tract urothelial carcinoma: A propensity score-weighted analysis.

Lymphovascular invasion (LVI) predicts poor survival in patients with pathologically localized or locally advanced upper urinary tract urothelial carcinoma (UT-UC). However, LVI is associated with high tumor grade, tumor necrosis, advanced tumor stage, tumor location, concomitant carcinoma in situ, lymph node metastasis, and sessile tumor architecture. These factors might interfere with the analysis of the impact of LVI on oncological prognosis. To address this, this study aimed to clarify the relationship between LVI and patient prognosis in UT-UC using propensity score weighting. Data were collected from 789 patients with UT-UC treated with radical nephroureterectomy without chemotherapy. We evaluated the significance of LVI in predicting metastasis-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS) using propensity score weighting. All weighted baseline characteristics included in the propensity score model were balanced between the LVI (+) and LVI (-) groups. The MFS, CSS, and OS were all significantly poorer in the LVI (+) group. For patients without LVI, the 5-year MFS, CSS, and OS rates were 65.3%, 73.1%, and 67.3%, respectively, whereas the corresponding rates were 50.2%, 63.8 %, and 54.6%, respectively, for patients with LVI. (all P < .001). For patients without LVI, the 10-year MFS, CSS, and OS rates were 61.5%, 69.6%, and 59.2%, respectively, whereas those for patients with LVI were 44.5%, 57.0%, and 42.7%, respectively (all P < .001). LVI is an important pathological feature that predicts metastasis development and worse survival outcome after radical surgery in UT-UC patients.

Predictive Factors of Intravesical Recurrence after Ureteroscopy in Upper Urinary Tract Urothelial Carcinoma Followed by Radical Nephroureterectomy

Objective: To investigate the risk factors of developing intravesical recurrence (IVR) in patients with upper urinary tract urothelial carcinoma (UTUC) who underwent ureterorenoscopy (URS) before radical nephroureterectomy with bladder cuff excision (RNU).&#x0D; Materials and Methods: This retrospective study collected data from the medical records of patients diagnosed with UTUC between January 2012 and December 2019. All the patients underwent ureteroscopy before radical surgery. Patients previously diagnosed with bladder cancer were excluded. A total of 63 patients were included in the study. Tumour factors, such as multiplicity, location, size, histologic grade, pathologic T-stage, and lymphovascular invasion status, were evaluated. The type of endoscopic procedure and time interval between URS and RNU were analysed to determine the factors affecting IVR.&#x0D; Results: The associated factors with IVR included multifocal tumours (HR = 4.8(1.9–11.9)), large size tumours greater than or equal to 4 cm (HR = 3.3(1.5–7.0)), and time interval greater than or equal to 5 weeks between URS and RNU (HR = 2.6(1.2–5.5)). Factors including tumour location (kidney or ureter), size, grading, T-stage, and lymphovascular invasion as well as the type of endoscopic procedure were not at high risk for IVR.&#x0D; Conclusion: The predictive factors of IVR for UTUC patients who underwent URS before RNU included a multiplicity of primary tumours and a tumour size greater than or equal to 4 cm, while a time interval between URS and RNU greater than or equal to 5 weeks increased the risk of IVR.

Prognostic nomogram for overall survival in upper urinary tract urothelial carcinoma (UTUC) patients treated with chemotherapy: a SEER-based retrospective cohort study

ObjectiveTo establish a prognostic nomogram among UTUC patients who received chemotherapy.Methods1195 UTUC patients who received chemotherapy were extracted from the Surveillance, Epidemiology, and End Results (SEER) database for the period between 2004 and 2015. Patients were randomly divided into a training and a validation set. Nomogram was constructed to predict 1-, 3-, and 5-year overall survival (OS) in those patients. Receiver-operating characteristic curves (ROCs), calibration plots, and Decision curve analysis (DCA) were applied to assess and compare the discrimination, accuracy, and practicability of the nomogram with 8th American Joint Committee on Cancer (AJCC) tumor node metastasis (TNM) staging system.ResultsSix clinical parameters were identified as independent prognostic factors for UTUC patients’ OS, including age, marital status, TNM stage, and surgical methods of the primary site. The ROC curves showed a satisfactory discrimination capacity of the nomogram, with 1-, 3-, and 5-year area under curve (AUC) values of 0.789, 0.772, and 0.763 in the training set and 0.772, 0.822, and 0.814 in the validation set, respectively. Calibration curves indicated a good agreement between actual observation and nomogram prediction. ROC and DCA curves showed our nomograms exhibited larger benefits than the 8th AJCC-TNM staging system.ConclusionsA prognostic nomogram was established and validated to present individual predictions of OS among chemotherapeutic UTUC patients. This nomogram may assist clinicians in accurate survival prognostication, treatment decision-making, and design of future clinical trials.

Prognostic impact of postoperative neutrophil-to-lymphocyte ratio on survival outcomes of patients treated with radical nephroureterectomy for upper urinary tract urothelial carcinoma: a single institution retrospective analysis using propensity score matching.

Purpose: To investigate the prognostic impact of postoperative neutrophil to lymphocyte ratio (NLR) on survival outcomes in upper urinary tract urothelial carcinoma (UTUC). Materials and methods: Data from 397 patients with UTUC who underwent radical nephroureterectomy (RNU) without a history of neoadjuvant chemotherapy between 2002 and 2017 were retrospectively analyzed. Based on a postoperative NLR cut-off of 3, patients were divided into low NLR (<3) or high NLR (≥ 3) groups. After 2:1 propensity score matching, a Kaplan-Meier with log-rank test was used to compare survival outcomes between the two groups. Univariate and multivariate Cox proportional hazard models were used to investigate the impact of the postoperative NLR on survival outcomes. Results: The matched cohort (n=176) consisted of 116 low NLR and 60 high NLR patients. The Kaplan-Meier curves showed significant differences in the 3- and 5-year overall and cancer-specific survival rates between the two groups (each p = 0.03). Multivariate Cox regression analysis revealed that a postoperative high NLR was an independent predictor of worse overall survival (hazard ratio [HR]:2.13; 95% confidence interval [CI]:1.18-3.85, p = 0.012) and cancer-specific survival (HR:2.16; 95% CI 1.11-4.21, p = 0.024). Conclusions: Propensity score matching analysis revealed postoperative high NLR can be considered a potential inflammatory biomarker for predicting survival outcomes of UTUC patients treated with RNU.

Immunohistochemical Analysis of HER2, EGFR, and Nectin-4 Expression in Upper Urinary Tract Urothelial Carcinoma.

Upper urinary tract urothelial carcinoma (UTUC) is a rare disease, often discovered at an advanced stage at diagnosis. Nectin-4 is expressed in a broad range of patients with UTUC and is associated with poor progression-free survival. The receptors of the erythroblastosis oncogene B (ErbB) family are potential therapeutic targets for urothelial carcinoma. Herein, we aimed to investigate the relationship of nectin-4 and ErbB family receptors, namely epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in patients with UTUC. Targeted therapies for these receptors could be used in sequence or in combination for increasing treatment efficiency. We performed immunohisto-chemical analysis for HER2, EGFR, and nectin-4 using tissue microarrays. A total of 98 UTUC patients were included in the study. We investigated the impact of EGFR and HER2 expression status on recurrence-free survival (RFS) and cancer-specific survival (CSS) of all patients. The percentages of patients positive for HER2, EGFR, and nectin-4 were 97%, 70%, and 65%, respectively. The co-expression rates of HER2-EGFR, HER2-nectin-4, and EGFR-nectin-4 were 69%, 64%, and 47%, respectively. The number of patients positive for all three receptors was 47%. Higher HER2 levels were significantly associated with worse CSS and RFS. Higher EGFR levels were associated with a worse CSS. HER2, EGFR, and nectin-4 were highly expressed in UTUC. Combination of HER2-, EGFR-, and nectin-4-targeted therapy may be an effective option for the treatment of patients with UTUC.

Diagnostic performance of an immunoassay based on urine exfoliated cell enrichment nanotechnology for upper tract urothelial carcinoma: a retrospective, monocentric study

BackgroundNoninvasively urine-based diagnostic modalities for upper urinary tract urothelial carcinoma (UTUC) were still lacking. We evaluated the diagnostic value of our previously developed urine-based assay (UTC assay) in UTUC.MethodsWe retrospectively analyzed 90 patients with suspected UTUC and 40 donors without UTUC. Voided urine specimens were analyzed by UTC assay and fluorescence in situ hybridization (FISH). The performance of UTC assay and FISH was compared among the 60 histologically proven UTUC patients and the 40 donors with benign disease.ResultsOf the 60 UTUCs, there were 8 low-grade and 52 high-grade cases. Overall sensitivity for UTC assay and FISH were 85% and 73.3%, respectively (P = 0.116). Specificities for UTC assay and FISH were 92.5% and 95%, respectively (P = ns.). By grade, sensitivities of UTC assay and FISH were 87.5% vs. 37.5% for low-grade (P = 0.119), and 84.6% vs. 78.8% for high- grade UTUC (P = 0.446), respectively. By stage, UTC assay showed significantly higher sensitivity than FISH for detecting non-muscle-invasive UTUC, which were 88.5% vs. 61.5%, respectively (P = 0.025).ConclusionUTC assay has good performance for the non-invasive diagnosis of UTUC. UTC assay may improve the diagnosis and surveillance of low-grade or superficial UTUC.

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

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. 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. 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. 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.

Prognostic Value of HPV E6 and APOBEC3B in Upper Urinary Tract Urothelial Carcinoma.

Background APOBEC mutation signature is common in upper urinary tract urothelial carcinoma (UTUC). When virus infection occurs, upregulated APOBEC plays an antiviral role by deoxycytidine deaminase activity. However, the carcinogenic roles of HPV E6 protein and APOBEC mutation signature in UTUC have not been investigated. Aims This study explored the relationship among HPV E6, APOBEC, and clinicopathological characteristics in patients with UTUC and impacts of their expression on the prognosis. Methods The expression of HPV E6 and APOBEC3B of 78 patients with UTUC was detected by immunohistochemistry. Correlation of HPV E6 and APOBEC3B expression levels with clinicopathological characteristics was statistically analyzed. Univariate and multivariate Cox regression analyses were used to evaluate the prognosis of HPV E6 and APOBEC3B for disease-free survival (DFS); survival analysis was performed using Kaplan-Meier methods. Results The expression of APOBEC3B was positively correlated with the expression of HPV E6 (r = 0.383, P = 0.001). HPV E6 was significantly increased in patients with stage I (χ2 = 4.938, P = 0.026) and low-grade urothelial carcinoma (χ2 = 3.939, P = 0.047), as well as in patients without LVI (χ2 = 4.064, P = 0.044). Meanwhile, APOBEC3B was highly expressed in patients with stage I (χ2 = 4.057, P = 0.044) and low-grade urothelial carcinoma (χ2 = 7.153, P = 0.007). Multivariate Cox regression analysis revealed the APOBEC3B expression was the independent prognostic factor for DFS, Kaplan-Meier survival analysis showed that low expression of APOBEC3B and HPV E6 was significantly associated with the poor prognosis of UTUC patients. Conclusion HPV E6 expression is positively associated with APOBEC3B expression, and the high expression of HPV E6 and APOBEC3B is associated with favorable prognosis of patients with UTUC.

Long-term survival of upper tract urothelial carcinoma patients in a tertiary care hospital

Objective: Upper urinary tract urothelial carcinoma (UTUC) is an uncommon but rapidly progressive disease associated with a high mortality rate. Despite the advancement in surgical and medical treatment during the last decade, long-term clinical data pertinent to UTUC are still limited in Thailand. The objectives of this study were to identify the long-term survival rate and factors affecting the survival of UTUC patients. Materials and Methods: We reviewed medical records of UTUC patients treated at King Chulalongkorn Memorial Hospital from 2004 to 2019. We calculated 5-year survival rate using the Kaplan-Meier method and investigated its correlation with various clinicopathological factors through the Cox hazard regression model. Results: One hundred and twenty-seven UTUC patients were included in this study. There was a slight predominance of females (55.1%), and the mean age at diagnosis was 68.2 years. The majority of patients were TNM stage I (43.3%) followed by stage III (26.9%). The 5-year overall and cancer-specific survival rates were 62.2% and 75.6%, respectively. Based on univariable analysis, TNM stage, pathological T stage, pathological N stage, and lymph node dissection status were associated with the overall survival and cancer-specific survival. However, none of these factors remained statistically significant in the multivariate analysis. Conclusion: The 5-year overall survival rate of UTUC patients was 62.2%. TNM stage, pathological T stage, pathological N stage, and lymph node dissection status were associated with the overall survival. A further study with a higher population number is warranted to add weight to these findings and investigate their potential clinical use further.

Upregulation of Cartilage Oligomeric Matrix Protein Predicts Poor Prognosis in Urothelial Carcinoma.

PurposeCartilage oligomeric matrix protein (COMP) is known as a large pentameric glycoprotein, which interacts with various extracellular matrix proteins in tissues. COMP has been reported to play a role in multiple connective tissue disorders. Recently, elevated COMP levels have been found to be associated with increased tumor size, metastases, faster recurrence of cancer, and overall poorer survival in several cancers. However, the clinical importance of COMP in urothelial carcinoma remains unclear. We investigated the association between COMP expression and clinical outcomes in urothelial carcinoma.Patients and MethodsIn this retrospective study, we collected urothelial carcinoma (UC) tissue from 340 upper urinary tract UC (UTUC) patients and 295 urinary bladder UC (UBUC) patients. Pearson’s chi-square test, Kaplan–Meier analysis, and the multivariate Cox proportional hazards model was used to examine the relationship between COMP expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MFS) and disease-specific survival (DSS).ResultsA total of 295 UBUC patients and 340 UTUC patients were recruited. The COMP mRNA level was significantly higher among invasive tumors (pT2–pT4) than in noninvasive tumors (pTa-T1) in UBUC groups (P < 0.01). COMP overexpression was associated with advanced T stage, nodal metastases, vascular invasion, perineural invasion, high histological grade, and high mitotic rate in both UBUC and UTUC cohorts. COMP overexpression was predictive of shorter DSS (hazard ratio [HR] in UBUC, 3.986, P < 0.001; in UTUC, 2.283, P = 0.027] and MFS (HR in UBUC, 6.813, P < 0.001; in UTUC, 4.070, P < 0.001). Kaplan–Meier analysis demonstrated high COMP expression associated with poor DSS and MFS in UTUC and UBUC groups (all P < 0.0001).ConclusionCOMP overexpression was linked to poor clinical prognosis and poor pathological features in UC. These results suggest COMP as a biomarker for UC.

Assessment of Therapeutic Benefit and Option Strategy on Intravesical Instillation for Preventing Bladder Cancer Recurrence after Radical Nephroureterectomy in Patients with Upper Urinary Tract Urothelial Carcinoma.

Objective Upper urinary tract urothelial carcinoma (UUT-UC) is a very aggressive disease, characterized by 22%–50% of patients suffering from subsequent bladder recurrence after radical nephroureterectomy (RNU). Although the therapy of intravesical instillation is reported to be effective in preventing bladder recurrence, no study had been reported in Northeast China. The findings relating to the clinical effectiveness of intravesical instillation after RNU are somewhat controversial, and the best efficacy and least adverse effects of instillation drugs have not been widely accepted. Here, we aimed at evaluating the efficacy of intravesical instillation for the prevention intravesical recurrence systematically. Methods In this retrospective cohort study, from October 2006 to September 2017, 158 UUT-UC patients underwent RNU were divided into 4 groups: epirubicin (EPB) instillation group, hydroxycamptothecin (HCPT) instillation group, bacillus Calmette–Guerin (BCG) instillation group, and noninstillation group. Cox univariate and multivariate analyses were employed to identify the risk factors for intravesical recurrence-free survival (IVRFS). The nomogram model was also applied to predict patient outcomes. Subsequently, to evaluate the clinical significance of intravesical instillation comprehensively, several databases including PubMed, Ovid, and Embase were searched and data from published studies with our results were combined by direct meta-analysis. Moreover, a network meta-analysis comparing instillation therapies was conducted to evaluate the clinical efficacy of different instillation drugs. Results In our retrospective cohort study, the Kaplan–Meier survival curve demonstrated noninstillation groups were associated with worsened IVRFS. Meanwhile, multivariate analysis indicated that intravesical instillation was independent protective factors for IVRFS (hazard ratio [HR] = 0.731). Moreover, calibration plots, receiver operating characteristic (ROC) curves, area under the curve (AUC) values, and the C-index showed the priority of nomogram's predictive accuracy. Next, direct meta-analysis including 19 studies showed that intravesical instillation could prevent the recurrence of bladder cancer with a pooled risk ratio (RR) estimate of 0.53. Subgroup analysis by study type, year of intravesical recurrence, first instillation time, and instillation times also confirmed the robustness of the results. Moreover, intraoperative instillation was associated with a decrease in the risk of bladder recurrence compared with postoperative instillation. Then, a network meta-analysis including 7 studies indicated that pirarubicin (THP) (surface under the cumulative ranking curve [SUCRA] = 89.2%) is the most effective therapy to reduce the risk of bladder recurrence, followed by BCG (SUCRA = 83.5%), mitomycin C (MMC) (SUCRA = 53.6%), EPB (SUCRA = 52.6%), and HCPT (SUCRA = 5.1%) after the analysis of the value ranking. Conclusions A maintenance schedule of intravesical instillation prevents the recurrence of bladder cancer after RNU in UUT-UC patients effectively. Large, prospective trials are needed to further confirm its value. Compared with other chemotherapy regimens, THP may be a promising drug with favorable efficacy to prevent bladder recurrence. As included studies had moderate risk of bias, the results of network meta-analysis should be applied with caution.

Survival and Long-term Effects of Kidney-sparing Surgery Versus Radical Nephroureterectomy on Kidney Function in Patients with Upper Urinary Tract Urothelial Carcinoma

BackgroundCurrent European Association of Urology (EAU) guidelines discriminate between high- and low-risk upper urinary tract urothelial carcinoma (UTUC) to determine treatment by means of radical nephroureterectomy (RNU) or kidney-sparing surgery (KSS). ObjectiveTo compare long-term oncological outcomes and renal function for patients with UTUC treated by RNU versus KSS. Design, setting, and participantsA retrospective cohort study, including 186 renal units with nonmetastatic UTUC treated in a tertiary referral centre between 2010 and 2021, was conducted. InterventionRNU, ureterorenoscopy, percutaneous tumour resection, and segmental ureteral resection. Outcome measurements and statistical analysisRecurrence-free survival, metastasis-free survival (MFS), overall survival (OS), cancer-specific survival (CSS), and renal function were analysed by means of the log-rank test and the independent-sample t test. Results and limitationsOS was 71.1% for the RNU group and 81.9% for the KSS group. In a cohort matched for propensity weight based on EAU risk stratification progression-free survival (PFS; RNU 96.0%; KSS 86.0%), MFS (RNU 72.0%; KSS 84.0%), CSS (RNU 84.0%; KSS 86.0%), and OS (RNU 76.0%; KSS 76.0%) were all similar between both groups. No significant differences in renal function were seen at 2 and 5 yr after the intervention. Although this series represents the largest cohort of (high-risk) UTUC patients treated by means of KSS to date, it is not suitable for performing a multivariate analysis. ConclusionsPFS, MFS, CSS, and OS were all comparable when analysing the RNU and KSS groups. Similar results for groups with evenly distributed risk factors and a large percentage of high-risk disease suggest that current risk stratification might not be accurate in discriminating low-risk from high-risk disease. Patient summaryIn this report, we looked at outcomes for upper urinary tract urothelial carcinoma in a specialised hospital. We conclude that kidney-sparing surgery and radical nephroureterectomy have comparable outcomes and that risk factors for worse outcome might not be identified correctly.