Increased Apolipoprotein A1 Expression Correlates with Tumor-Associated Neutrophils and T Lymphocytes in Upper Tract Urothelial Carcinoma.

An increased neutrophil-to-lymphocyte ratio (NLR) is a poor prognostic biomarker in various types of cancer, because it reflects the inhibition of lymphocytes in the circulation and tumors. In urologic cancers, upper tract urothelial carcinoma (UTUC) is known for its aggressive features and lack of T cell infiltration; however, the association between neutrophils and suppressed T lymphocytes in UTUC is largely unknown. In this study, we examined the relationship between UTUC-derived factors and tumor-associated neutrophils or T lymphocytes. The culture supernatant from UTUC tumor tissue modulated neutrophils to inhibit T cell proliferation. Among the dominant factors secreted by UTUC tumor tissue, apolipoprotein A1 (Apo-A1) exhibited a positive correlation with NLR. Moreover, tumor-infiltrating neutrophils were inversely correlated with tumor-infiltrating T cells. Elevated Apo-A1 levels in UTUC were also inversely associated with the population of tumor-infiltrating T cells. Our findings indicate that elevated Apo-A1 expression in UTUC correlates with tumor-associated neutrophils and T cells. This suggests a potential immunomodulatory effect on neutrophils and T cells within the tumor microenvironment, which may represent therapeutic targets for UTUC treatment.

Postoperative recurrence detection using individualized circulating tumor DNA in upper tract urothelial carcinoma.

Biomarkers that could detect the postoperative recurrence of upper tract urothelial carcinoma (UTUC) have not been established. In this prospective study, we aim to evaluate the utility of individualized circulating tumor DNA (ctDNA) monitoring using digital PCR (dPCR) as a tumor recurrence biomarker for UTUC in the perioperative period. Twenty-three patients who underwent radical nephroureterectomy (RNU) were included. In each patient, whole exome sequencing by next-generation sequencing and TERT promoter sequencing of tumor DNA were carried out. Case-specific gene mutations were selected from sequencing analysis to examine ctDNA by dPCR analysis. We also prospectively collected plasma and urine ctDNA from each patient. The longitudinal variant allele frequencies of ctDNA during the perioperative period were plotted. Case-specific gene mutations were detected in 22 cases (96%) from ctDNA in the preoperative samples. Frequently detected genes were TERT (39%), FGFR3 (26%), TP53 (22%), and HRAS (13%). In all cases, we obtained plasma and urine samples for 241 time points and undertook individualized ctDNA monitoring for 2 years after RNU. Ten patients with intravesical recurrence had case-specific ctDNA detected in urine at the time of recurrence. The mean lead time of urinary ctDNA in intravesical recurrence was 60 days (range, 0-202 days). Two patients with distal metastasis had case-specific ctDNA in plasma at the time of metastasis. In UTUC, tumor-specific gene mutations can be monitored postoperatively as ctDNA in plasma and urine. Individualized ctDNA might be a minimally invasive biomarker for the early detection of postoperative recurrence.

MicroRNA-299-3p inhibits cell proliferation, motility, invasion and angiogenesis via VEGFA in upper tract urothelial carcinoma.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a rare tumor with extraordinarily different features between Eastern and Western countries. Vascular endothelial growth factor-A (VEGFA) was originally identified as a secreted signaling protein and regulator of vascular development and cancer progression. In this study, we aimed to elucidate the molecular mechanisms underlying the regulation of VEGFA by microRNA in UTUC. METHODS: VEGFA expression was evaluated by immunohistochemistry in 140 human UTUC tissue samples. Next, we assessed the regulatory relationship between VEGFA and miR-299-3p by real-time PCR, western blotting, ELISA and dual-luciferase reporter assays using two UTUC cell lines. The role of miR-299-3p/VEGFA in cell proliferation, motility, invasion, and tube formation was analyzed in vitro. RESULTS: High VEGFA expression was significantly associated with tumor stage, grade, distant metastasis and cancer-related death and correlated with poor progression-free and cancer-specific survival. VEGFA knockdown repressed proliferation, migration, invasion and angiogenesis in UTUC cell lines. miR-299-3p significantly reduced VEGFA protein expression and miR-299-3p overexpression inhibited VEGFA mRNA and protein expression by directly targeting its 3'-UTR. Functional studies indicated that VEGFA overexpression reversed the miR-299-3p-mediated suppression of tumor cell proliferation, migration, invasion and angiogenesis. In addition, miR-299-3p/VEGFA suppressed cellular functions in UTUC by modulating the expression of P18 and cyclin E2. CONCLUSIONS: Our findings suggest that miR-299-3p possibly suppresses UTUC cell proliferation, motility, invasion and angiogenesis via VEGFA. VEGFA may act as a prognostic predictor, and both VEGFA and miR-299-3p could be potential therapeutic targets for UTUC.

Prognostic Impact of Preoperative Thrombocytosis on Recurrence-Free Survival in Patients with Upper Tract Urothelial Carcinoma.

BACKGROUND: The aim of this work was to evaluate the prognostic potential of preoperative thrombocytosis for recurrence-free survival (RFS) and cancer-specific survival (CSS) among patients subjected to radical nephroureterectomy (RNU) due to UTUC. PATIENTS AND METHODS: Analytical cohort was composed of a single-center series of 405 patients treated between January 1999 and December 2020. Thrombocytosis was defined as a platelet count exceeding the threshold value of 400 × 109 per L. Along with the Kaplan-Meier survival probability, Cox proportional hazard regression models were used. RESULTS: Preoperative thrombocytosis confirmed in 71 patients (17.5%) was significantly associated with the higher pathological tumor stage, lymph node metastasis, prior bladder cancer diagnosis, and preoperative anemia. With a median post-surgical follow-up period of 33.5 months, 125 patients (30.9%) experienced disease recurrence. The recurrence rate among patients with normal platelet levels was 13.6%, compared with 22.2% in those with preoperative thrombocytosis (p < 0.03). The 5-year RFS estimates reached 36.6% in the thrombocytosis-confirmed group. Multivariate analysis implied that preoperative thrombocytosis was a significant independent prognosticator of both poor RFS (HR 2.22, 95% CI 1.14-4.31, p = 0.02) and CSS (HR 2.48, 95% CI 1.14-3.09, p = 0.01). CONCLUSIONS: Patients with a clinically significant elevation of platelet count prior to RNU were more likely to have UTUC with advanced tumor stages and lymph node metastases. Preoperative thrombocytosis was an independent predictor of RFS and CSS in patients who underwent radical nephroureterectomy. Furthermore, preoperative thrombocytosis may complement and refine UTUC clinical prediction algorithms as an independent indicator of adverse survival outcomes.

The efficacy and safety of tislelizumab combined with gemcitabine plus cisplatin in the treatment of postoperative patients with muscle-invasive upper tract urothelial carcinoma.

BACKGROUND: A combination of immune checkpoint inhibitors (ICIs) and chemotherapy has demonstrated excellent clinical efficacy and safety in treating a variety of cancers, including urothelial carcinoma (UC). However, its efficacy and safety in patients with muscle-invasive upper tract urothelial carcinoma (UTUC) who are undergoing radical surgery remain uncertain. The purpose of this retrospective study was to examine the effectiveness and safety of tislelizumab combined with gemcitabine plus cisplatin (TGC) as a first-line postoperative adjuvant treatment in this population. METHODS: This single-center, real-world study retrospectively analyzed the data from 71 patients with muscle-invasive UTUC who had radical nephroureterectomy (RNU) at the Affiliated Hospital of Xuzhou Medical University between November 1, 2020, and November 1, 2023. Among the 71 patients, 30 received adjuvant therapy of TGC within 90 days after RNU and 41 underwent surveillance. No patients receive preoperative neoadjuvant therapy. The TGC therapy group received adjuvant therapy every 3 weeks postoperatively until the first recurrence, first metastasis, or death due to any reason, whichever occurred first. The patients were followed up telephonically and through outpatient visits to record and evaluate their disease-free survival (DFS) and treatment-related adverse events (TRAEs). RESULTS: This study assessed the DFS of 41 and 30 patients in the surveillance group and TGC therapy group, respectively. The median DFS of the surveillance group was 16.5 [95% confidence interval (CI), 14.7-18.3] months, while the median DFS of the TGC group has not yet reached [hazard ratio (HR) 0.367 (95% CI, 0.169-0.796); p = 0.008], with 21 patients still undergoing follow-up. Compared with the surveillance group, the TGC therapy group had dramatically improved DFS after RNU and reduced risk by 63.3%. Of the 30 patients receiving combination therapy, 28 experienced TRAEs; all TRAEs were consistent with the frequently reported events in the chemotherapy-alone regimens, and there were no treatment-related deaths. CONCLUSION: This study demonstrates that TGC therapy exhibits excellent clinical efficacy in patients undergoing radical surgery, significantly improving DFS and displaying great safety.

A urine-based liquid biopsy for detection of upper tract urothelial carcinoma: a self-matched study.

BACKGROUND: To establish the pathological diagnosis of UTUC before treatment is profitable. At present, the conventional pathological diagnostic methods have certain problems. Besides, the urine-based DNA methylation test have been already utilized to detect bladder cancer. OBJECTIVE: To evaluate the sensitivity and specificity of DNA methylation plus 17 genes mutation test and compare the combined test with cytology. MATERIALS AND METHODS: We included 45 patients from April 2019 to May 2022, all of whom underwent radical nephroureterectomy (RNU), nephrectomy, diagnostic ureteroscopy or tissue biopsy. Before surgery, the urine samples were collected for DNA methylation plus 17 genes mutation test and cytology. The test performance was calculated, and comparative ROC curves were drawn. RESULTS: The median age of the patients was 67 years. The Kappa value of the DNA methylation plus 17 genes mutation test and tissue pathology was 0.59 (p<0.001). The sensitivity/specificity/PPV/NPV of DNA methylation plus 17 genes mutation test was 86/80/94/62% compared with 29/100/100/29% for cytology. The AUC of DNA methylation plus 17 genes mutation test was 0.829 (p<0.001).The mutated gene proportion of UTUC patients was 51.43% for TERT and 25.71% for TP53. CONCLUSION: The test performance of DNA methylation plus 17 genes mutation test was satisfactory, which may replace cytology in the future. Further multicenter studies with larger samples are needed to confirm the clinical value of this promising method. NOVELTY & IMPACT STATEMENTS: We evaluated the diagnostic efficacy of a urine-based liquid biopsy for the detection of UTUC and compared the combined test with cytology. We found satisfactory results and concluded that the test could partly replace cytology. Further studies are needed.

A collaborative review of the microsatellite instability/deficient mismatch repair phenotype in patients with upper tract urothelial carcinoma.

OBJECTIVE: To perform a collaborative review of the literature exploring the microsatellite instability/deficient mismatch repair (MSI/dMMR) phenotype in patients with upper tract urothelial carcinoma (UTUC). METHOD: A collaborative review of the literature available on Medline was conducted by the Cancer Committee of the French Association of Urology to report studies describing the genetic mechanisms, investigation, prevalence and impact of the MSI/dMMR phenotype in UTUC patients. RESULTS: The predominant genetic mechanism leading to the MSI/dMMR phenotype in UTUC patients is related to the constitutional mutation of one allele of the MMR genes MLH1, MSH2, MSH6 and PMS2 within Lynch syndrome. Indications for its investigation currently remain limited to patients with a clinical suspicion for sporadic UTUC to refer only those with a positive testing for germline DNA sequencing to screen for this syndrome. With regard to technical aspects, despite the interest of MSIsensor, only PCR and immunohistochemistry are routinely used to somatically investigate the MSI and dMMR phenotypes, respectively. The prevalence of the MSI/dMMR phenotype in UTUC patients ranges from 1.7% to 57%, depending on the study population, investigation method and definition of a positive test. Younger age and a more balanced male to female ratio at initial diagnosis are the main specific clinical characteristics of UTUC patients with an MSI/dMMR phenotype. Despite the conflicting results available in the literature, these patients may have a better prognosis, potentially related to more favourable pathological features. Finally, they may also have lower sensitivity to chemotherapy but greater sensitivity to immunotherapy. CONCLUSION: Our collaborative review summarises the available data from published studies exploring the MSI/dMMR phenotype in UTUC patients, the majority of which are limited by a low level of evidence.

Role of neoadjuvant chemotherapy in patients with locally advanced and clinically positive nodes Upper Tract Urothelial Carcinoma treated with Nephroureterectomy: real-world data from the ROBUUST 2.0 Registry.

PURPOSE: To assess the impact of neoadjuvant and adjuvant chemotherapy on survival outcomes, within a large multicenter cohort of Upper tract urothelial carcinoma patients treated with Nephroureterectomy. METHODS: A multicenter retrospective analysis utilizing the Robotic surgery for Upper Tract Urothelial Cancer Study registry was performed. Baseline, preoperative, perioperative, and pathologic variables of three groups of patients receiving surgery only, neoadjuvant or adjuvant chemotherapy were compared. Categorical and continuous variables among the three subgroups were compared with Chi square and ANOVA tests. The impact of perioperative chemotherapy on survival outcomes was assessed with the Kaplan Meier method. Univariable and multivariable Cox regression analyses were performed to identify predictors of survival. RESULTS: Overall, 1,994 patients were included. Overall and Clavien grade ≥3 complications rates were comparable among the three subgroups (p = 0.65 and p = 0.92). At Kaplan Meier analysis, neoadjuvant chemotherapy significantly improved cancer-specific survival (p = 0.03) and overall survival (p = 0.03) probabilities of patients with cT ≥ 3 tumors and of those with positive cN (p = 0.03 and p = 0.02). On multivariable analysis, neoadjuvant chemotherapy was independently associated with an improvement of cancer-specific survival in cT ≥ 3 patients (HR 0.44; p = 0.04), and of both cancer-specific survival (HR 0.50; p = 0.03) and overall survival (HR 0.53; p = 0.02) probabilities in positive cN patients. CONCLUSIONS: This large multicenter retrospective analysis suggests significant survival benefit in Upper tract urothelial carcinoma patients with either locally advanced or clinically positive nodes disease receiving neoadjuvant chemotherapy. These findings can be regarded as "hypothesis generating", stimulating future trials focusing on such advanced stages.

Survival benefit of nephroureterectomy in systemic therapy exposed metastatic upper tract urinary urothelial carcinoma patients.

BACKGROUND: It is unknown whether the stage of the primary may influence the survival (OS) of metastatic upper tract urothelial carcinoma (mUTUC) patients treated with nephroureterectomy (NU) and systemic therapy (ST). We tested this hypothesis within a large-scale North American cohort. METHODS: Within Surveillance Epidemiology and End Results database 2000-2020, all mUTUC patients treated with ST+NU or with ST alone were identified. Kaplan-Maier plots depicted OS. Multivariable Cox regression (MCR) models tested for differences between ST+NU and ST alone predicting overall mortality (OM). All analyses were performed in localized (T1-T2) and then repeated in locally advanced (T3-T4) patients. RESULTS: Of all 728 mUTUC patients, 187 (26%) harbored T1-T2 vs 541 (74%) harbored T3-T4. In T1-T2 patients, the median OS was 20 months in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU independently predicted lower OM (HR 0.37, p < 0.001). Conversely, in T3-T4 patients, the median OS was 12 in ST+NU vs 10 months in ST alone. Moreover, in MCR analyses that also relied on 3 months' landmark analyses, the combination of ST+NU was not independently associated with lower OM (HR 0.85, p = 0.1). CONCLUSIONS: In mUTUC patients, treated with ST, NU drastically improved survival in T1-T2 patients, even after strict methodological adjustments (multivariable and landmark analyses). However, this survival benefit did not apply to patients with locally more advanced disease (T3-T4).

Investigation of eligibility for adjuvant therapy from real-world data of patients with urothelial carcinoma undergoing radical cystectomy and radical nephroureterectomy.

OBJECTIVE: Adjuvant nivolumab prolonged disease-free survival compared with placebo in patients at high risk of recurrence following radical cystectomy or radical nephroureterectomy in the CheckMate 274 trial. However, the ideal eligibility criteria for adjuvant therapy in real-world clinical practice remain controversial. METHODS: We retrospectively analyzed clinical data of 409 patients who underwent radical cystectomy (n = 252) or radical nephroureterectomy (n = 157) and validated the risk of recurrence based on the classification used in the CheckMate 274 trial. We also investigated the impact of perioperative chemotherapy, lymph node dissection and pathological factors on prognosis. RESULTS: The median follow-up time was 37.5 and 32.1 months in bladder cancer and upper tract urothelial carcinoma, respectively. Among the high-risk patients based on CheckMate 274 trial, disease-free survival was considerably shorter for bladder cancer and upper tract urothelial carcinoma patients than for low-risk patients (hazard ratios: 4.132 and 7.101, respectively). The prevalence of adjuvant chemotherapy in high-risk patients was low (24 and 38% for bladder cancer and upper tract urothelial carcinoma, respectively). The extent of lymph node dissection in bladder cancer and presence of lymph node dissection in upper tract urothelial carcinoma did not affect prognosis. Cox proportional multivariate analysis revealed CheckMate 274-high-risk as a poor prognostic factor in bladder cancer and upper tract urothelial carcinoma. CONCLUSIONS: This study validated the risk classification for recurrence following radical cystectomy and radical nephroureterectomy using the CheckMate 274 criteria in real-world practice. Further research would help assess the degree of benefit obtained from adjuvant nivolumab.

Associations between early changes in the neutrophil-to-lymphocyte ratio after radical nephroureterectomy and treatment outcomes.

OBJECTIVES: This study explored the impacts of peri-operative changes in the neutrophil-to-lymphocyte ratio (NLR) on the survival rate after radical nephroureterectomy. METHODS: This retrospective analysis included a multicentric cohort of patients diagnosed with upper tract urothelial carcinoma (UTUC) who had undergone radical nephroureterectomy from 2012 to 2021. We assessed the preoperative NLR, postoperative NLR, delta-NLR (difference between postoperative and preoperative NLRs), and NLR change (ratio of postoperative to preoperative NLR). Additionally, patients were categorized according to increases in their preoperative and/or postoperative NLRs. Associations of survival with peri-operative changes in the NLR were investigated using Cox multivariate regression models. RESULTS: A total of 488 patients were included in the study, with a median age of 73 years. Among the patients, 105 (21.5%) exhibited elevated preoperative and postoperative NLRs, 88 (18.0%) exhibited elevated preoperative NLR only, 53 (10.9%) exhibited elevated postoperative NLR only, and 242 (49.6%) exhibited normal NLRs. Multivariate analysis indicated significant negative correlations between both preoperative and postoperative increased NLRs and oncological outcomes, including nonurothelial tract recurrence-free survival and cancer-specific survival (hazard ratio [HR]: 1.65, P = 0.017; HR: 2.12, P = 0.014, respectively). CONCLUSION: This is the first study to evaluate the association between peri-operative changes in the NLR and the outcomes of patients with UTUC who underwent radical nephroureterectomy. Patients with elevated NLRs at both time points experienced considerably worse outcomes. Further research should explore whether increases in the NLR during long-term follow-up could indicate impending disease recurrence.

Perioperative management of upper tract urothelial carcinoma in the Nordic countries.

BACKGROUND: Upper tract urothelial carcinoma (UTUC) is a rare malignancy, with typically only few new cases annually per urological department. Adherence to European association of urology (EAU) guidelines on UTUC in the Nordic countries is unknown. The objective of this survey was to examine the implementation of EAU guidelines, the perioperative management and organization of the treatment of UTUC in the Nordic countries. METHODS: The electronic survey was distributed to 93 hospitals in the Nordic countries performing radical nephroureterectomy (NU). The survey consisted of 57 main questions and data was collected between December 1st, 2021 and April 23rd, 2022. RESULTS: Overall response rate was 47/93 (67%) with a completion rate of 98%. Five out of the 6 examined subjects on diagnostic practice are applied by ≥ 72% of the participating centers. NU as treatment for high-risk UTUC is performed by 37/47 (79%), and 91% include a bladder cuff excision. CONCLUSIONS: Adherence to EAU guidelines is high on diagnostic practice in the Nordic countries, whereas disease management is less coherent.

Outcomes of laparoscopic, robotic and open nephroureterectomy with bladder cuff excision in patients with T3T4 upper urinary tract urothelial carcinoma: a multi-center retrospective study.

BACKGROUND: Nephroureterectomy with bladder cuff excision is the standard treatment for high-risk upper urinary tract urothelial carcinoma (UTUC). The role of minimally invasive surgery in treating locally advanced UTUC remains controversial. This study aimed to compare the outcomes of open, laparoscopic, and robotic surgeries for managing locally advanced UTUC. METHODS: We retrospectively reviewed 705 patients with locally advanced UTUC from multiple institutions throughout Taiwan. Perioperative outcomes and oncological outcomes, such as cancer-specific survival, overall survival, disease-free survival and bladder-free survival, were compared between the open, laparoscopic and robotic groups. RESULTS: The minimally invasive group had better overall and cancer-specific survival (CSS) rates. The 2-year CSS rates of the open, laparoscopic and robotic groups were 71%, 83%, and 77% respectively (p < 0.001). The robotic group had similar outcomes to the laparoscopic group. (p = 0.061, 0.825, 0.341 for OS, CSS, DFS respectively.) More lymph node dissections were performed and more lymph nodes were harvested in the robotic group (p = 0.009). CONCLUSIONS: Our results demonstrated that minimally invasive surgery, including laparoscopic and robotic surgery, for locally advanced UTUC resulted in oncological outcomes that are non-inferior to those of open surgery.

Establishment and validation of a nomogram for predicting overall survival of upper-tract urothelial carcinoma with bone metastasis: a population-based study.

BACKGROUND: Bone metastasis (BM) carries a poor prognosis for patients with upper-tract urothelial carcinoma (UTUC). This study aims to identify survival predictors and develop a prognostic nomogram for overall survival (OS) in UTUC patients with BM. METHODS: The Surveillance, Epidemiology, and End Results database was used to select patients with UTUC between 2010 and 2019. The chi-square test was used to assess the baseline differences between the groups. Kaplan-Meier analysis was employed to assess OS. Univariate and multivariate analyses were conducted to identify prognostic factors for nomogram establishment. An independent cohort was used for external validation of the nomogram. The discrimination and calibration of the nomogram were evaluated using concordance index (C-index), area under receiver operating characteristic curve (AUC), calibration curve, and decision curve analysis (DCA). All statistical analyses were performed using SPSS 23.0 and R software 4.2.2. RESULTS: The mean OS for UTUC patients with BM was 10 months (95% CI: 8.17 to 11.84), with 6-month OS, 1-year OS, and 3-year OS rates of 41%, 21%, and 3%, respectively. Multi-organ metastases (HR = 2.21, 95% CI: 1.66 to 2.95, P < 0.001), surgery (HR = 0.72, 95% CI: 0.56 to 0.91, P = 0.007), and chemotherapy (HR = 0.37, 95% CI: 0.3 to 0.46, P < 0.001) were identified as independent prognostic factors. The C-index was 0.725 for the training cohort and 0.854 for the validation cohort, and all AUC values were > 0.679. The calibration curve and DCA curve showed the accuracy and practicality of the nomogram. CONCLUSIONS: The OS of UTUC patients with BM was poor. Multi-organ metastases was a risk factor for OS, while surgery and chemotherapy were protective factors. Our nomogram was developed and validated to assist clinicians in evaluating the OS of UTUC patients with BM.

Serum α-hydroxybutyrate dehydrogenase as a biomarker for predicting survival outcomes in patients with UTUC after radical nephroureterectomy.

PURPOSE: We aimed to determine the prognostic value of α-hydroxybutyrate dehydrogenase (α-HBDH) in upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). MATERIALS AND METHODS: We retrospectively enrolled the data of 544 UTUC patients at West China Hospital from May 2003 to June 2019. Cancer-specific survival (CSS) was the endpoint of interest. The optimal cutoff value of α-HBDH was identified by X-Tile program. After propensity score matching (PSM), we utilized Kaplan‒Meier curves to estimate survival and Cox proportional hazard model for risk assessment. A nomogram was built based on the results of multivariate analysis, and calibration curve, time-dependent receiver operating characteristic (ROC) curves and decision curve analysis were also performed to evaluate the predictive accuracy. RESULTS: Overall, 394 and 150 patients were divided into the α-HBDH-low group and α-HBDH -high group at the cutoff value of 158 U/L, respectively. After PSM, the two groups were well matched for all confounding factors. High α-HBDH was associated with inferior CSS (P = 0.006), and preoperative α-HBDH was an independent predictor for CSS (HR: 1.36; 95% CI:1.08, 1.80), especially in localized UTUC patients (HR: 2.04; 95% CI:1.11, 3.74). Furthermore, the nomogram based on α-HBDH achieved great predictive ability for CSS with areas under the curves of 0.800 and 0.778 for 3-year and 5-year CSS, respectively. CONCLUSION: Serum α-HBDH was a novel and reliable biomarker for predicting survival outcomes in UTUC patients after RNU but should be further explored.

Preoperative analysis of factors associated with prolonged pneumoretroperitoneum time during retroperitoneal laparoscopic nephroureterectomy for upper tract urothelial carcinoma.

BACKGROUND: Prolonged laparoscopic nephroureterectomy (LNU) for upper tract urothelial cancer (UTUC) can increase the frequency of intravesical recurrence after surgery. Therefore, it is important for urological surgeons to have knowledge on preoperative risk factors for prolonged LNU. However, few studies have investigated the risk factors for prolonged LNU. We hypothesized that the quantity of perirenal fat affects the pneumoretroperitoneum time (PRT) of retroperitoneal LNU (rLNU). This study aimed to investigate the preoperative risk factors for prolonged PRT during rLNU. METHODS: We reviewed the data of 115 patients who underwent rLNU for UTUC between 2013 and 2021. The perirenal fat thickness (PFT) observed on preoperative computed tomography (CT) images was used to evaluate the perinephric fat quantity. Preoperative risk factors for PRT during rLNU were analyzed using logistic regression models. The cutoff value for PRT was determined based on the median time.The cutoff values for fat-related factors influencing PRT were defined according to receiver operating characteristic curve analysis. RESULTS: The median PRT for rLNU was 182 min (interquartile range, 155-230 min). The cutoff values of posterior, lateral, and anterior PFTs were 15 mm, 24 mm, and 6 mm, respectively. Multivariate analysis revealed that a posterior PFT ≥ 15 mm (odds ratio [OR], 2.72; 95% confidence interval, 1.04-7.08; p = 0.0410) was an independent risk factor for prolonged PRT. CONCLUSIONS: Thick posterior PFT is a preoperative risk factor for prolonged PRT during rLNU. For patients with UTUC and thick posterior PFT, surgeons should develop optimal surgical strategies, including the selecting an expert surgeon as a primary surgeon and the selecting transperitoneal approach to surgery or open surgery.

Real-world outcomes of adjuvant immunotherapy candidates with upper tract urothelial carcinoma: results of a multicenter cohort study.

BACKGROUND: Recent clinical trials have reported improved disease-free survival rates of patients with stage pT3-4/ypT2-4 or pN + upper tract urothelial carcinoma (UTUC) on adjuvant nivolumab therapy. However, the appropriateness of the patient selection criteria used in clinical practice remains uncertain. METHODS: We retrospectively analyzed 895 patients who underwent nephroureterectomy to treat UTUC. The patients were divided into two groups: grade pT3-4 and/or pN + without neoadjuvant chemotherapy (NAC) or grade ypT2-4 and/or ypN + on NAC (adjuvant immunotherapy candidates) and others (not candidates for adjuvant immunotherapy). Kaplan-Meier curves were drawn to assess the oncological outcomes, including recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Cox proportional hazards models were used to identify significant prognostic factors for oncological outcomes. RESULTS: The Kaplan-Meier curves revealed notably inferior RFS, CSS, and OS of patients who were candidates for adjuvant immunotherapy. Multivariate analysis revealed that pathological T and N grade and lymphovascular invasion (LVI) status were independent risk factors for poor RFS, CSS, and OS. CONCLUSION: In total, 44.8% of patients were candidates for adjuvant immunotherapy. In addition to pathological T and N status, LVI was a significant predictor of survival, and may thus play a pivotal role in the selection of patients eligible for adjuvant immunotherapy.

Hydronephrosis severity as a predictor of postoperative renal function decline following laparoscopic radical nephroureterectomy.

BACKGROUND: This study aimed to investigate factors, including the degree of hydronephrosis, that may be associated with decreased renal function after radical nephroureterectomy (RNU). METHODS: This study included 252 patients who underwent laparoscopic RNU with an estimated glomerular filtration rate (eGFR) ≥ 30 ml/min/1.73 m2 in three institutions. We assessed the association between hydronephrosis grade and perioperative renal function and performed a stepwise multivariate linear regression analysis to identify factors associated with postoperative eGFR. Patients with preoperative eGFR ≥ 50 ml/min/1.73 m2 were divided into a training set and an independent external validation set to develop a predictive model for postoperative renal function. RESULTS: The median preoperative and postoperative eGFR were 61.1 and 46.4 ml/min/1.73 m2, respectively. The eGFR preservation rates were 66.9%, 66.6%, 88.1%, and 100.0% in groups without, with mild, moderate, and severe hydronephrosis, respectively, and this difference was statistically significant (p < 0.001). Multivariate analysis revealed that factors predictive of postoperative eGFR included sex, preoperative eGFR, clinical T stage (cT3-4), and the presence of moderate or severe hydronephrosis. Our predictive model, based on these factors, positively correlated with actual postoperative renal function, and the similarity in categories with or without renal function insufficiency between predicted and actual postoperative renal functions was 78% in both training and validation sets. CONCLUSION: Moderate or severe hydronephrosis is associated with a modest postoperative decline in renal function, while mild hydronephrosis is not. Our predictive model may be useful in predicting postoperative renal function insufficiency and guiding decision-making for perioperative medical treatment.

Cyclin A2 Expression as Predictive Biomarker in Muscle-Invasive Upper Tract Urothelial Carcinoma.

INTRODUCTION: The aim was to evaluate the prognostic value of altered Cyclin A2 (CCNA2) gene expression in upper tract urothelial carcinoma (UTUC) and to assess its predictive potential as a prognostic factor for overall survival (OS) and disease-free survival. METHODS: 62 patients who underwent surgical treatment for UTUC were included. Gene expression of CCNA2, MKI67, and p53 was analyzed by quantitative reverse transcriptase polymerase chain reaction. Survival analyses were performed using the Kaplan-Meier method and the log-rank test. For Cox regression analyses, uni- and multivariable hazard ratios were calculated. Spearman correlation was used to analyze correlation of CCNA2 expression with MKI67 and p53. RESULTS: The median age of the cohort was 73 years, and it consisted of 48 males (77.4%) and 14 females (22.6%). Patients with high CCNA2 expression levels showed longer OS (HR 0.33; 95% CI: 0.15-0.74; p = 0.0073). Multivariable Cox regression analyses identified CCNA2 overexpression (HR 0.37; 95% CI: 0.16-0.85; p = 0.0189) and grading G2 (vs. G3) (HR 0.39; 95% CI: 0.17-0.87; p = 0.0168) to be independent predictors for longer OS. CCNA2 expression correlated positively with MKI67 expression (Rho = 0.4376, p = 0.0005). CONCLUSION: Low CCNA2 expression is significantly associated with worse OS. Thus, CCNA2 might serve as a potential biomarker in muscle-invasive UTUC and may be used to characterize a subset of patients having an unfavorable outcome and for future risk assessment scores.

Adjuvant Chemotherapy after Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma with Variant Histology: A Systematic Review and Meta-Analysis of Survival Outcomes.

INTRODUCTION: The objective of this study was to determine effects of adjuvant chemotherapy (AC) on survival outcomes compared to surgery alone without AC for upper tract urothelial carcinoma (UTUC) patients with variant histology (VH). METHODS: We conducted a systematic review and meta-analysis of studies investigating AC for UTUC in Medline, Embase, the Cochrane Library up to January 2023. Population, intervention, comparator, and outcome were UTUC patients with VH, radical nephroureterectomy with AC, radical nephroureterectomy only, and oncological survival, respectively. RESULTS: Four retrospective studies were included. Regarding overall survival (OS), the pooled hazard ratio was 0.61 (95% confidence interval: 0.42-0.87; p = 0.007) across two studies. Regarding cancer-specific survival (CSS), the pooled hazard ratio was 0.46 (95% confidence interval: 0.25-0.84; p = 0.01) across three studies. All included studies had a high quality based on the Newcastle-Ottawa Scale. Certainty of evidence for OS was low. Certainty of evidence for CSS was moderate due to a strong association (hazard ratio <0.5). Publication bias was not significant for any studies. CONCLUSION: In UTUC patients with VH, administration of AC after surgery might have better survival outcomes than surgery alone. Our study provides evidence for decision-making of clinicians who treat UTUC patients with VH.