Long-term outcomes of pelvic exenterations for gynecological malignancies: a single-center retrospective cohort study.

BACKGROUND: Recently, with the advancement of medical technology, the postoperative morbidity of pelvic exenteration (PE) has gradually decreased, and it has become a curative treatment option for some patients with recurrent gynecological malignancies. However, more evidence is still needed to support its efficacy. This study aimed to explore the safety and long-term survival outcome of PE and the feasibility of umbilical single-port laparoscopic PE for gynecologic malignancies in a single medical center in China. PATIENTS AND METHODS: PE for gynecological cancers except for ovarian cancer conducted by a single surgical team in Sun Yat-sen University Cancer Center between July 2014 and December 2019 were included and the data were retrospectively analyzed. RESULTS: Forty-one cases were included and median age at diagnosis was 53 years. Cervical cancer accounted for 87.8% of all cases, and most of them received prior treatment (95.1%). Sixteen procedures were performed in 2016 and before, and 25 after 2016. Three anterior PE were performed by umbilical single-site laparoscopy. The median operation time was 460 min, and the median estimated blood loss was 600 ml. There was no perioperative death. The years of the operations was significantly associated with the length of the operation time (P = 0.0018). The overall morbidity was 52.4%, while the severe complications rate was 19.0%. The most common complication was pelvic and abdominal infection. The years of surgery was also significantly associated with the occurrence of severe complication (P = 0.040). The median follow-up time was 55.8 months. The median disease-free survival (DFS) was 17.9 months, and the median overall survival (OS) was 25.3 months. The 5-year DFS was 28.5%, and the 5-year OS was 30.8%. CONCLUSION: PE is safe for patient who is selected by a multi-disciplinary treatment, and can be a curative treatment for some patients. PE demands a high level of experience from the surgical team. Umbilical single-port laparoscopy was a technically feasible approach for APE, meriting further investigation.

Extraperitonealization of the ileal conduit decreases the risk of parastomal hernia: A single-center, randomized clinical trial.

Parastomal hernia (PSH) is a common complication in patients receiving ileal conduit urinary diversion after radical cystectomy. In this randomized controlled clinical trial, we validate our previous finding that extraperitonealization of ileal conduit decreases incidence of PSH. In total, 104 consecutive patients undergoing radical cystectomy at Sun Yat-sen University Cancer Center are randomized 1:1 to receive either modified (extraperitonealized) ileal conduit (n = 52) or conventional ileal conduit (n = 52). Primary endpoint is incidence of radiological PSH during follow-up. Incidence of radiological PSH is lower in the modified group than in the conventional group (11.5% vs. 28.8%; p = 0.028) after a median follow-up of 32 months, corresponding to a hazard ratio of 0.374 (95% confidence interval: 0.145-0.965, p = 0.034) in the modified conduit group. The results support our previous finding that extraperitonealization of the ileal conduit is effective for reducing risk of PSH in patients receiving ileal conduit diversion.

Regular gastroscopy and colonoscopy during the evaluation of urachal cancer: do we really need them?

PURPOSE: Urachal cancer is similar to gastrointestinal adenocarcinoma in histology, and gastroscopy/colonoscopy is often administered during perioperative evaluation. However, gastroscopy and colonoscopy have corresponding disadvantages. This study discusses whether gastroscopy/colonoscopy is truly necessary for patients with urachal cancer. PATIENTS AND METHODS: A total of 166 bladder adenocarcinoma cases diagnosed at Sun Yat-sen University Cancer Center were retrospectively reviewed and divided into two groups (urachal cancer and nonurachal cancer), and perioperative evaluations were retrieved. RESULTS: There were 78 patients with urachal cancer, the median age was 48 years, and 59 were male. Perioperative gastroscopy/colonoscopy revealed 5 intestinal polyps and 1 adenoma during these evaluations, and no primary gastrointestinal cancer was found. Meanwhile, preoperative imaging evaluation did not detect significant gastrointestinal lesions. For 88 patients with nonurachal cancer, including primary bladder adenocarcinoma and metastatic tumors from gastrointestinal cancer, the median age was 56 years, and 64 were male. Preoperative imaging evaluation demonstrated 36 cases of gastrointestinal lesions, and 32 were confirmed by gastroscopy/colonoscopy; the other 4 were negative. Another 4 cases of colon cancer were detected by regular colonoscopy for suspected primary bladder adenocarcinoma. In all, 35 cases of colon cancer and 1 case of gastric cancer were identified by endoscopic examination. The diagnostic consistency of imaging and gastrointestinal endoscopy was favorable (P < 0.001), and the negative predictive value and diagnostic efficiency of imaging were 96.9% and 94.6%, respectively. CONCLUSIONS: The vast majority of gastrointestinal cancer cases can be identified by assessment of the patient's clinical symptoms, meticulous physical examination, and imaging evaluation. We recommend that gastroscopy/colonoscopy only be applied to patients with urachal cancer when the above examinations are positive.

Optimal interval timing between transurethral resection of bladder tumors and Bacillus Calmette-Guerin perfusion.

OBJECTIVE: There is no consensus regarding the best interval time between transurethral resection of a bladder tumor and Bacillus Calmette-Guerin (BCG) perfusion. This study was to explore whether the interval time has an impact on the prognosis and adverse effects. METHODS: We retrospectively reviewed the clinical data of patients who received BCG intravesical perfusion at Sun Yat-sen University Cancer Center (SYSUCC) from September 2015 to October 2021. Recurrence-free survival (RFS) and progression-free survival were the primary endpoints. Cox regression was used to explore independent predictors. The association between interval time and adverse effect grade was detected by logistic regression. Propensity score matching (PSM) was performed. RESULTS: A total of 403 patients were enrolled, the median interval time was 24 days (6-163 days), and the follow-up was 28 months (7-82 months). Eighty-eight (20.9%) patients relapsed, and 40 patients (10.0%) suffered progression. The multivariate Cox regression analysis confirmed that interval time was an independent predictor of RFS (p = 0.017). Notably, when the interval time was less than or equal to 26 days, there was a trend toward better RFS, PSM resulted in 65 matched pairs in each group, and Kaplan-Meier analysis showed that there was a significant difference in RFS between groups (p = 0.009). The logistic regression analysis showed that there was no correlation between interval time and adverse effects and their grades (p > 0.05). CONCLUSIONS: We considered that the first BCG perfusion could be performed within 2-4 weeks after surgery.

Gemcitabine/nab-paclitaxel vs gemcitabine/carboplatin for advanced urothelial carcinoma.

OBJECTIVE: To compare in a phase III trial the efficacy and safety of nanoparticle albumin-bound (nab)-paclitaxel plus gemcitabine (GA) with that of carboplatin plus gemcitabine (GCb) as a first-line treatment for patients with cisplatin-ineligible metastatic urothelial cancer (mUC). PATIENTS AND METHODS: Treatment-naive, cisplatin-ineligible patients with mUC were assigned randomly to either the GA (both nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days) or GCb group (carboplatin area under the free carboplatin plasma concentration versus time curve of 4.5 on Day 1, gemcitabine 1000 mg/m2 on Days 1 and 8, every 21 days). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), safety, and patient-reported outcomes (PROs). RESULTS: The trial was terminated early because of slow accrual after 54 patients were enrolled: 26 in in the GA group and 28 in the GCb groups. The median PFS was 6.7 vs 5.9 months for the GA and GCb groups, respectively (P = 0.248). The median OS time was 12.1 vs 10.7 months for the GA and GCb groups, respectively (P = 0.837). The ORR and DCR were 40% vs 46.4% (P = 0.637) and 72% vs 68% (P = 0.188) in the GA and GCb groups, respectively. Patients treated with GA showed significantly lower incidence of Grade 3-4 thrombocytopenia and does reduction and delay. Although peripheral sensory neuropathy was higher in the GA arm, no Grade 3 neuropathy occurred. There was no difference in the PROs between the two groups. CONCLUSION: While not powered for comparison, first-line GA showed similar efficacy and better tolerability and might be considered a rational alternative to GCb.

SAVE Testis-sparing score: a multicenter retrospective study of a novel predictive tool for quantifying testicular tumors.

BACKGROUND: Testis-sparing surgery (TSS) is a safe treatment for patients with benign testicular tumors. Presently, assessments for evaluating the suitability of TSS are poorly standardized, partially because testicular anatomical elements cannot be quantitatively described. MATERIALS AND METHODS: The authors developed a scoring method known as the SAVE testis-sparing score based on four critical and accessible anatomical features of a testicular tumor. The SAVE score ranges from 0 to 8 and is divided into four risk classes ( low , medium , high , and extremely high ) to evaluate the feasibility of TSS, wherein low-risk indicates high feasibility and vice versa. This study included 444 testicular tumor patients from eight centers. Among them, 216 patients (model group: 151 patients, validation group: 65 patients) were included in the modeling analysis, and the other 228 patients from children's centers were included in the proportion analysis. Using retrospective data, patient characteristics associated with surgical methods were identified. Furthermore, a multivariate logistic regression model was built quantify the associations between these characteristics and the surgery method. The receiver operator characteristic curve was used to evaluate the classification efficiency of SAVE. RESULTS: The SAVE testis-sparing score includes size (tumor size as maximal diameter), available testicular tissue volume, volume ratio of the tumor to the testis, and the exophytic / endophytic properties of the tumor. The SAVE scoring system accurately classified the suitability of TSS based on the complexity of benign testicular tumors. CONCLUSION: The SAVE score is a reproducible and robust tool for quantitatively describing the anatomical characteristics of benign testicular tumors and guide the preoperative evaluation of TSS.

m5C-dependent cross-regulation between nuclear reader ALYREF and writer NSUN2 promotes urothelial bladder cancer malignancy through facilitating RABL6/TK1 mRNAs splicing and stabilization.

The significance of 5-methylcytosine (m5C) methylation in human malignancies has become an increasing focus of investigation. Here, we show that m5C regulators including writers, readers and erasers, are predominantly upregulated in urothelial carcinoma of the bladder (UCB) derived from Sun Yat-sen University Cancer Center and The Cancer Genome Atlas cohort. In addition, NOP2/Sun RNA methyltransferase family member 2 (NSUN2) as a methyltransferase and Aly/REF export factor (ALYREF) as a nuclear m5C reader, are frequently coexpressed in UCB. By applying patient-derived organoids model and orthotopic xenograft mice model, we demonstrate that ALYREF enhances proliferation and invasion of UCB cells in an m5C-dependent manner. Integration of tanscriptome-wide RNA bisulphite sequencing (BisSeq), RNA-sequencing (RNA-seq) and RNA Immunoprecipitation (RIP)-seq analysis revealed that ALYREF specifically binds to hypermethylated m5C site in RAB, member RAS oncogene family like 6 (RABL6) and thymidine kinase 1 (TK1) mRNA via its K171 domain. ALYREF controls UCB malignancies through promoting hypermethylated RABL6 and TK1 mRNA for splicing and stabilization. Moreover, ALYREF recognizes hypermethylated m5C site of NSUN2, resulting in NSUN2 upregulation in UCB. Clinically, the patients with high coexpression of ALYREF/RABL6/TK1 axis had the poorest overall survival. Our study unveils an m5C dependent cross-regulation between nuclear reader ALYREF and m5C writer NSUN2 in activation of hypermethylated m5C oncogenic RNA through promoting splicing and maintaining stabilization, consequently leading to tumor progression, which provides profound insights into therapeutic strategy for UCB.

Better specificity and less ischemia: three-dimensional reconstruction is superior to routine computed tomography angiography in navigation of super-selective clamping robot-assisted laparoscopic partial nephrectomy.

Background: Available technologies could be used to guide surgeons in controlling highly selective tumor-bearing arteries robot-assisted laparoscopic partial nephrectomy (RALPN). Methods: Patients undergoing RALPN (from September 2018 to January 2020) for intermediate-high complex renal tumor (R.E.N.A.L. score ≥7) who underwent abdominal computed tomography (CT) scan with angiography and hyper-accuracy 3-dimensional reconstruction (H3DR). All patients underwent high-resolution CT scan with angiography and H3DR with special software, based on which two kinds of highly selective arterial clamp protocols were made for each patient and analyzed independently by two urologists and two radiologists to confirm which renal arterial branch was supplying the tumor. We chose the optimized clamping protocol with the principle of the minimized ischemic regions. During the operation, meticulous microdissection and clip ligation of the specific vascular branch was guided by optimized protocol [H3DR or computed tomography angiography (CTA) reconstruction], according to the in vivo anatomy (identified by intraoperative ultrasound). Results: Of 82 patients, the minimum-ischemic regions planning completed rate (MIRPCR) of preoperative planning with H3DR (90.2%) was higher than that with CTA (34.1%) (P<0.01). H3DR identified 78 high-order arteries (70.3%), whereas CTA identified 33 (29.7%) high-order arteries (P<0.001). H3DR detected a more optimal blocking option in 51 cases that were either missed (n=13) or misclassified by CTA (n=38). A total of 18 cases (56.3%) were converted to H3DR-guided occurred in CTA-guided surgery [5 (10.0%) occurred in group H3DR to CTA, P<0.01]. Moreover, in the CTA-guided group, the separation of renal hilum was avoided in 14 of 19 (73.7%) cases, whereas in the H3DR-guided group, it was avoided in 60 of 63 (95.3%) cases. Conclusions: For patients undergoing RALPN, H3DR-guided surgery compared with standard CTA-guided surgery has higher accuracy and feasibility in controlling arterial branches supplying the tumor and intraoperative surgical navigation. Additionally, it reduces the ischemic lesion area and simplifies vascular isolation steps, thus decreasing procedural difficulty.

CircRNA_001895 promotes sunitinib resistance of renal cell carcinoma through regulation of apoptosis and DNA damage repair.

Sunitinib, an inhibitor of receptor tyrosine kinase, possesses anti-tumor activity in renal cell carcinoma (RCC) through its anti-angiogenic effects. However, patients with advanced RCC are resistant to sunitinib. Dysregulated circRNAs has been shown to be associated with drug resistance in various tumors. However, little is known about the effect of circRNA_001895 on sunitinib resistance of RCC. First, the expression of circRNA_001895 was found to be higher in sunitinib-resistant RCC tissues than chemosensitive tumor tissues. Half maximal inhibitory concentration of sunitinib-resistant RCC cells (786-O/R and ACHN/R) was higher than sunitinib-sensitive 786-O and ACHN cells. CircRNA_001895 was also upregulated in 786-O/R and ACHN/R cells. Second, data from colony formation and flow cytometry analysis showed that knockdown of circRNA_001895 suppressed cell proliferation and promoted cell apoptosis in 786-O/R and ACHN/R cells. Moreover, the protein expression of phosphorylated histone H2AX (γH2AX) was enhanced, while phosphorylated DNA-dependent protein kinase (p-DNA-PK) and Rad51 were reduced in 786-/R and ACHN/R by knockdown of circRNA_001895. Lastly, knockdown of circRNA_001895 conferred sensitivity of in vivo tumor growth to sunitinib. In conclusion, circRNA_001895 was implicated in the sunitinib resistance in RCC through regulation of apoptosis and DNA damage repair, suggesting that circRNA_001895 might be a potential therapeutic target for advanced RCC.

Complete transurethral resection of bladder tumor before radical cystectomy is not a risk factor for organ-confined bladder cancer: A case-control study.

Objectives: To investigate the role of complete transurethral resection of bladder tumor (TURBT) before radical cystectomy (RC) for organ-confined bladder cancer. Materials and methods: Data of patients who underwent RC in our center from January 2008 to December 2018 were retrospectively reviewed. Patients with >T2N0M0 disease and positive surgical margins and those who received neoadjuvant/adjuvant chemotherapy or radiotherapy were excluded. Complete TURBT was defined as no visible lesion under endoscopic examination after TURBT or in the bladder specimen after RC. Kaplan-Meier curves and log-rank tests assessed disease-free survival (DFS). Logistic and Cox regression analyses were performed to identify potential predictors. Results: A total of 236 patients were included in this review, including 207 males, with a median age of 61 years. The median tumor size was 3 cm, and a total of 94 patients had identified pathological T2 stage disease. Complete TURBT was correlated with tumor size (p = 0.041), histological variants (p = 0.026), and down-staging (p < 0.001). Tumor size, grade, and histological variants were independent predictors of complete TURBT. During a median follow-up of 42.7 months, 30 patients developed disease recurrence. Age and histological variants were independent predictors of DFS (p = 0.022 and 0.032, respectively), whereas complete TURBT was not an independent predictor of DFS (p = 0.156). Down-staging was not associated with survival outcome. Conclusions: Complete TURBT was correlated with an increased rate of down-staging before RC. It was not associated with better oncologic outcomes for patients with organ-confined bladder cancer.

Bladder paraganglioma: basic characteristics and new perspectives on perioperative management.

PURPOSE: Paraganglioma and pheochromocytoma are rare neuroendocrine tumors with severe metabolic and cardiovascular complications. Bladder PGLs are rare, and their clinical management is not precise. Here, we discuss the basic characteristics and perioperative management of bladder PGLs. METHODS: We retrospectively reviewed 20 bladder PGL cases diagnosed at Sun Yat-sen University Cancer Center. Case notes were reviewed, clinical presentations, therapies, and outcomes were collected, and data analysis was performed. RESULTS: Ten male and ten female patients with a median age of 47.5 years (range 14-69 years) were included. Most patients (65%) had no symptoms, and PGL was detected incidentally during medical checkups. All patients were treated surgically; 4 (20%) underwent transurethral resection of bladder tumor (TURBT), and 16 (80%) underwent partial cystectomy. Strong intraoperative blood pressure fluctuations were observed in 13 patients (65%). Two patients who were treated preoperatively with α-receptor blockers also experienced severe intraoperative blood pressure fluctuations. Postoperative measurements of troponin I were available for 3 patients, and all were significantly elevated. All patients were diagnosed with bladder PGL on postoperative pathological examination. The median follow-up time was 51 months (range 2-147 months), and 2 patients were lost to follow-up at 1 and 3 months; 16 (88.9%) survived without recurrence, 2 patients (11.1%) experienced recurrence, and 1 patient died. CONCLUSION: Most bladder paragangliomas are easily mistaken for bladder urothelial carcinoma, and robust hemodynamic instability during surgery might be a challenge for urologists. Postoperative monitoring of troponin I, regardless of the presence of clinical symptoms, is recommended for patients with bladder PGL.

Optimizing prediction of new-baseline glomerular filtration rate after radical nephrectomy: are algorithms really necessary?

INTRODUCTION: Radical nephrectomy (RN) is an important consideration for the management of localized renal-cell-carcinoma (RCC) whenever the tumor appears aggressive, although reduced renal function is a concern. Split-renal-function (SRF) in the contralateral kidney and postoperative renal functional compensation (RFC) are fundamentally important for the accurate prediction of new baseline GFR (NBGFR) post-RN. SRF can be estimated either from nuclear renal scans (NRS) or from preoperative imaging using parenchymal-volume-analysis (PVA). We compare two SRF-based models for predicting NBGFR after RN with a subjective prediction of NBGFR by an experienced urologic-oncologist. METHODS: 187 RCC patients managed with RN (2006-16) were included based on the availability of preoperative CT/MRI and NRS, and preoperative/postoperative eGFR. NBGFR was defined as the final GFR 3-12 months post-RN. For the SRF-based approaches, SRF was derived from either NRS or PVA, and RFC was estimated at 25% based on previous independent analyses. Thus, the formula (Global GFRPre-RN × SRFcontralateral) × 1.25 was used to predict NBGFR after RN. For subjective-assessment, a blinded, independent urologic oncologist provided NBGFR predictions based on preoperative eGFR, CT/MRI, and clinical/tumor characteristics. Predictive accuracies were assessed by correlation coefficients (r). RESULTS: The r values for subjective-assessment, NRS/SRF-based, and PVA/SRF-based approaches were 0.72/0.72/0.85, respectively (p < 0.05). The PVA/SRF-based model also demonstrated significant improvement across other performance parameters. CONCLUSIONS: The PVA/SRF-based model more accurately predicts NBGFR post-RN than NRS/SRF-based and Subjective Estimation. PVA software (Fujifilm-medical-systems) is readily available and affordable and provides accurate SRF estimations from routine preoperative imaging. This novel approach may inform clinical management regarding RN/PN for complex RCC cases.

Predicting GFR after radical nephrectomy: the importance of split renal function.

PURPOSE: To evaluate a conceptually simple model to predict new-baseline-glomerular-filtration-rate (NBGFR) after radical nephrectomy (RN) based on split-renal-function (SRF) and renal-functional-compensation (RFC), and to compare its predictive accuracy against a validated non-SRF-based model. RN should only be considered when the tumor has increased oncologic potential and/or when there is concern about perioperative morbidity with PN due to increased tumor complexity. In these circumstances, accurate prediction of NBGFR after RN can be important, with a threshold NBGFR > 45 ml/min/1.73m2 correlating with improved overall survival. METHODS: 236 RCC patients who underwent RN (2010-2012) with preoperative imaging (CT/MRI) and relevant functional data were included. NBGFR was defined as GFR 3-12 months post-RN. SRF was determined using semi-automated software that provides differential parenchymal-volume-analysis (PVA) from preoperative imaging. Our SRF-based model was: Predicted NBGFR = 1.24 (× Global GFRPre-RN) (× SRFContralateral), with 1.24 representing the mean RFC estimate from independent analyses. A non-SRF-based model was also assessed: Predicted NBGFR = 17 + preoperative GFR (× 0.65)-age (× 0.25) + 3 (if tumor > 7 cm)-2 (if diabetes). Alignment between predicted/observed NBGFR was assessed by comparing correlation coefficients and area-under-the-curve (AUC) analyses. RESULTS: The correlation-coefficients (r) were 0.87/0.72 for SRF-based/non-SRF-based models, respectively (p = 0.005). For prediction of NBGFR > 45 ml/min/1.73m2, the SRF-based/non-SRF-based models provided AUC of 0.94/0.87, respectively (p = 0.044). CONCLUSION: Previous non-SRF-based models to predict NBGFR post-RN are complex and omit two important parameters: SRF and RFC. Our proposed model prioritizes these parameters and provides a conceptually simple, accurate, and clinically implementable approach to predict NBGFR post-RN. SRF can be easily obtained using PVA software that is affordable, readily available (FUJIFILM-Medical-Systems), and more accurate than nuclear-renal-scans. The SRF-based model demonstrates greater predictive-accuracy than a non-SRF-based model, including the clinically-important predictive-threshold of NBGFR > 45 ml/min/1.73m2.

[Expressions of FOXO1/3a/4/6 in human testis and their roles in testicular aging].

OBJECTIVE: To investigate the expression rules of FOXO1a, FOXO3a, FOXO4 and FOXO6 proteins in the human testis, and explore their roles in the development and progression of testicular aging. METHODS: We collected the para-carcinoma testis tissue from 4 testis cancer patients aged 28, 31, 32 and 46 years, and the testis tissue from another 2 PCa patients aged 66 and 81 years after castration surgery from January 2018 to December 2020. We detected the expressions of FOXO1a, FOXO3a, FOXO4 and FOXO6 proteins in the testis tissue by Western blot, determined the locations of FOXO1a, FOXO3a, FOXO4 and FOXO6 in the testis cells by immunofluorescence staining, and performed semi-quantitative and statistical analyses using image J and SPSS 23.0 software, respectively. RESULTS: The expression levels of FOXO1a and FOXO3a proteins were significantly decreased in the testis tissue of the elderly patients (P < 0.01), with an age-dependent reduction in the proportion of the positive cells. No statistically significant difference was observed in the expression levels of FOXO4 and FOXO6 between different age groups. FOXO1a was mainly expressed at the base of the seminiferous tubules, FOXO3a and FOXO4 in the Leydig cells, and FOXO6 in the seminiferous tubules. In addition, FOXO4 underwent age-related nuclear translocation in the senescent Leydig cells, suggesting its involvement in the aging of Leydig cells. CONCLUSION: FOXO1a/3a/4 may be closely related to human testicular aging and corresponding pathological changes, but its underlying mechanism remains to be further explored.

Extraperitonealization of ileal conduit reduces parastomal hernia after cystectomy and ileal conduit diversion.

OBJECTIVE: Parastomal hernia (PSH) is a common complication of ileal conduit diversion after radical cystectomy. Novel surgical techniques for preventing PSH formation are needed. We aimed to evaluate surgical technique of extraperitonealizing the ileal conduit (modified ileal conduit) for preventing PSH. METHODS: A retrospective analysis of 375 consecutive patients who underwent ileal conduit after cystectomy at the Sun Yat-sen University Cancer Center between January 1, 2000 and June 31, 2019 was conducted. 214 patients had modified ileal conduit diversion and 161 patients conventional ileal conduit (Bricker) diversion. The demographic and clinicopathologic characteristics of patients in the 2 groups were compared using the t test and Chi square test. Univariable and multivariable Cox regression analyses were used to predict the risk of PSH formation. RESULTS: The 2 groups were comparable in regard to all demographic and clinicopathologic variables. The incidence of PSH diagnosed by CT scan was 7.5% in the modified group and 21.1% in the conventional group (P < 0.001). High BMI and history of prior abdominal surgery was identified by univariable analysis as risk factors of PSH formation. Multivariable analyses revealed that technique of extraperitonealizing ileal conduit significantly reduced incidence of PSH in patients with or without risk factors of PSH formation (OR = 0.29, 95% CI 0.16-0.54, P < 0.001). CONCLUSIONS: Technique of extraperitonealizing ileal conduit appeared to be effective in reducing PSH formation after ileal conduit diversion.

Long noncoding RNAs to predict postoperative recurrence in bladder cancer and to develop a new molecular classification system.

BACKGROUND: Reliable molecular markers are much needed for early prediction of recurrence in muscle-invasive bladder cancer (MIBC) patients. We aimed to build a long-noncoding RNA (lncRNA) signature to improve recurrence prediction and lncRNA-based molecular classification of MIBC. METHODS: LncRNAs of 320 MIBC patients from the Cancer Genome Atlas (TCGA) database were analyzed, and a nomogram was established. A molecular classification system was created, and immunotherapy and chemotherapy response predictions, immune score analysis, immune infiltration analysis, and mutational data analysis were conducted. Survival analysis validation was also performed. RESULTS: An eight-lncRNA signature classifed the patients into high- and low-risk subgroups, and these groups had significantly different (disease-free survival) DFS. The ability of the eight-lncRNA signature to make an accurate prognosis was tested using a validation dataset from our samples. The nomogram achieved a C-index of 0.719 (95% CI, 0.674-0.764). Time-dependent receiver operating characteristic curve (ROC) analysis indicated the superior prognostic accuracy of nomograms for DFS prediction (0.76, 95% CI, 0.697-0.807). Further, the four clusters (median DFS = 11.8, 15.3, 17.9, and 18.9 months, respectively) showed a high frequency of TTN (cluster 1), fibroblast growth factor receptor-3 (cluster 2), TP53 (cluster 3), and TP53 mutations (cluster 4), respectively. They were enriched with M2 macrophages (cluster 1), CD8+ T cells (cluster 2), M0 macrophages (cluster 3), and M0 macrophages (cluster 4), respectively. Clusters 2 and 3 demonstrated potential sensitivity to immunotherapy and insensitivity to chemotherapy, whereas cluster 4 showed potential insensitivity to immunotherapy and sensitivity to chemotherapy. CONCLUSIONS: The eight-lncRNA signature risk model may be a reliable prognostic signature for MIBC, which provides new insights into prediction of recurrence of MIBC. The model may help clinical decision and eventually benefit patients.

LRPPRC regulates redox homeostasis via the circANKHD1/FOXM1 axis to enhance bladder urothelial carcinoma tumorigenesis.

Reactive oxygen species (ROS) which are continuously generated mainly by mitochondria, have been proved to play an important role in the stress signaling of cancer cells. Moreover, pentatricopeptide repeat (PPR) proteins have been suggested to take part in mitochondrial metabolism. However, the mechanisms integrating the actions of these distinct networks in urothelial carcinoma of the bladder (UCB) pathogenesis are elusive. In this study, we found that leucine rich pentatricopeptide repeat containing (LRPPRC) was frequently upregulated in UCB and that it was an independent prognostic factor in UCB. We further revealed that LRPPRC promoted UCB tumorigenesis by regulating the intracellular ROS homeostasis. Mechanistically, LRPPRC modulates ROS balance and protects UCB cells from oxidative stress via mt-mRNA metabolism and the circANKHD1/FOXM1 axis. In addition, the SRA stem-loop interacting RNA binding protein (SLIRP) directly interacted with LRPPRC to protect it from ubiquitination and proteasomal degradation. Notably, we showed that LRPPRC modulated the tumorigenesis of UCB cells in a circANKHD1-FOXM1-dependent manner. In conclusion, LRPPRC exerts critical roles in regulating UCB redox homeostasis and tumorigenesis, and is a prognostic factor for UCB; suggesting that LRPPRC may serve as an exploitable therapeutic target in UCB.

BMI1 activates P-glycoprotein via transcription repression of miR-3682-3p and enhances chemoresistance of bladder cancer cell.

Chemoresistance is the most significant reason for the failure of cancer treatment following radical cystectomy. The response rate to the first-line chemotherapy of cisplatin and gemcitabine does not exceed 50%. In our previous research, elevated BMI1 (B-cell specific Moloney murine leukemia virus integration region 1) expression in bladder cancer conferred poor survival and was associated with chemoresistance. Herein, via analysis of The Cancer Genome Atlas database and validation of clinical samples, BMI1 was elevated in patients with bladder cancer resistant to cisplatin and gemcitabine, which conferred tumor relapse and progression. Consistently, BMI1 was markedly increased in the established cisplatin- and gemcitabine-resistant T24 cells (T24/DDP&GEM). Functionally, BMI1 overexpression dramatically promoted drug efflux, enhanced viability and decreased apoptosis of bladder cancer cells upon treatment with cisplatin or gemcitabine, whereas BMI1 downregulation reversed this effect. Mechanically, upon interaction with p53, BMI1 was recruited on the promoter of miR-3682-3p gene concomitant with an increase in the mono-ubiquitination of histone H2A lysine 119, leading to transcription repression of miR-3682-3p gene followed by derepression of ABCB1 (ATP binding cassette subfamily B member 1) gene. Moreover, suppression of P-glycoprotein by miR-3682-3p mimics or its inhibitor XR-9576, could significantly reverse chemoresistance of T24/DDP&GEM cells. These results provided a novel insight into a portion of the mechanism underlying BMI1-mediated chemoresistance in bladder cancer.

N6-Methyladenosine Modification of LncRNA DUXAP9 Promotes Renal Cancer Cells Proliferation and Motility by Activating the PI3K/AKT Signaling Pathway.

Most localized human renal clear cell carcinoma (ccRCC)-related deaths result from cancer recurrence and metastasis. However, the precise molecular mechanisms largely remain unknown. In recent years, an increasing number of long noncoding RNAs (lncRNAs) have been shown to be vital regulators of tumorigenesis. In this study, we characterized a lncRNA DUXAP9 and the upregulation of DUXAP9 was analyzed by quantitative real-time PCR in 112 pairs of localized ccRCC tumor tissues compared with adjacent normal tissues. Kaplan-Meier curves showed that patients of localized ccRCC with high DUXAP9 expression had poorer overall survival (P<0.01) and progression-free survival (P<0.05) than cases with low DUXAP9 expression. Multivariate Cox regression analysis also showed that high DUXAP9 expression was an independent risk factor for poor prognosis in localized ccRCC (p<0.05). DUXAP9 knockdown in renal cancer cells inhibited renal cancer cells proliferation and motility capacities in vitro and reversed epithelial-mesenchymal transition (EMT), whereas overexpression of DUXAP9 promoted renal cancer cells proliferation and motility capacities in vitro and induced EMT. Pull-down, RNA immunoprecipitation and RNA stability assays (involving actinomycin D) showed that DUXAP9 was methylated at N6-adenosine and binds to IGF2BP2, which increases its stability. DUXAP9 activate PI3K/AKT pathway and Snail expression in renal cancer cells. DUXAP9 may be useful as a prognostic marker and/or therapeutic target in localized ccRCC.