Corrigendum: Long non-coding RNA CCAT1 acts as an oncogene and promotes sunitinib resistance in renal cell carcinoma.

[This corrects the article DOI: 10.3389/fonc.2020.516552.].

Development and validation of a predictive model for major complications after extracorporeal shockwave lithotripsy in patients with ureteral stones: based on a large prospective cohort.

The risk factors of complications after SWL are not well characterized. Therefore, based on a large prospective cohort, we aimed to develop and validate a nomogram for predicting major complications after extracorporeal shockwave lithotripsy (SWL) in patients with ureteral stones. The development cohort included 1522 patients with ureteral stones who underwent SWL between June 2020 and August 2021 in our hospital. Five hundred and fifty-three patients with ureteral stones participated in the validation cohort from September 2020 to April 2022. The data were prospectively recorded. Backward stepwise selection was applied using the likelihood ratio test with Akaike's information criterion as the stopping rule. The efficacy of this predictive model was assessed concerning its clinical usefulness, calibration, and discrimination. Finally, 7.2% (110/1522) of patients in the development cohort and 8.7% (48/553) of those in the validation cohort suffered from major complications. We identified five predictive factors for major complications: age, gender, stone size, Hounsfield unit of stone, and hydronephrosis. This model showed good discrimination with an area under the receiver operating characteristic curves of 0.885 (0.872-0.940) and good calibration (P = 0.139). The decision curve analysis showed that the model was clinically valuable. In this large prospective cohort, we found that older age, female gender, higher Hounsfield unit, size, and grade of hydronephrosis were risk predictors of major complications after SWL. This nomogram will be helpful in preoperative risk stratification to provide individualized treatment recommendations for each patient. Furthermore, early identification and appropriate management of high-risk patients may decrease postoperative morbidity.

Prospective comparison of extracorporeal shock wave lithotripsy versus flexible ureterorenoscopy in patients with non-lower pole kidney stones under the COVID-19 pandemic.

Both shock wave lithotripsy (SWL) and flexible ureterorenoscopy (F-URS) are recommended as the first choice for non-lower pole kidney stones. Therefore, we conducted a prospective study to evaluate the efficacy, safety, and cost of SWL versus F-URS in patients with solitary non-lower pole kidney stones ≤ 20 mm under the COVID-19 pandemic. This prospective study was conducted in a tertiary hospital from June 2020 to April 2022. Patients who underwent lithotripsy (SWL or F-URS) for non-lower pole kidney stones were enrolled in this study. The stone-free rate (SFR), retreatment rate, complications, and cost were recorded. Propensity score-matched (PSM) analysis was performed. A total of 699 patients were finally included, of which 81.3% (568) were treated with SWL and 18.7% (131) underwent F-URS. After PSM, SWL showed equivalent SFR (87.9% vs. 91.1%, P = 0.323), retreatment rate (8.6% vs. 4.8%, P = 0.169), and adjunctive procedure (2.6% vs. 4.9%, P = 0.385) compared with F-URS. Complications were scarce and also comparable between SWL and F-URS (6.0% vs 7.7%, P > 0.05), while the incidence of ureteral perforation was higher in the F-URS group compared with the SWL group (1.5% vs 0%, P = 0.008). The hospital stay was significantly shorter (1 day vs 2 days, P < 0.001), and the cost was considerably less (1200 vs 30,083, P < 0.001) in the SWL group compared with the F-URS group. This prospective cohort demonstrated that SWL had equivalent efficacy with more safety and cost benefits than F-URS in treating patients with solitary non-lower pole kidney stones ≤ 20 mm. During the COVID-19 pandemic, SWL may have benefits in preserving hospital resources and limiting opportunity for virus transmission, compared to URS. These findings may guide clinical practice.

Development and Validation of a Nomogram for Predicting Blood Pressure Change Failure in Patients with Pheochromocytoma and Concomitant Hypertension after Adrenalectomy.

(1) Background: Pheochromocytoma is a common cause of secondary hypertension, which is considered curable; nevertheless, some patients still suffer from hypertension after adrenalectomy. Therefore, we developed and validated a nomogram for predicting blood pressure change failure in patients with pheochromocytoma and concomitant hypertension after adrenalectomy. (2) Methods: The development cohort of this study consisted of 259 patients with pheochromocytoma who underwent adrenalectomy at our center between 1 January 2007 and 31 December 2018. Each patient's clinicopathologic data were recorded. LASSO (the least absolute shrinkage and selection operator) regression was used to reduce and select the features of the data. Furthermore, we used multivariate logistic regression analysis to develop the prediction model. An independent cohort of 110 consecutive patients from 1 January 2019 to 31 December 2021 was used for validation. The performance of this nomogram was assessed with regard to discrimination, calibration, and clinical usefulness. (3) Results: 40.9% and 46.4% of patients experienced blood pressure change failure in the development and validation cohorts of this study, respectively. We found that older patients with a longer duration of hypertension and concomitant cardiovascular events were more likely to suffer from blood pressure change failure. In the validation cohort, the model manifested great discrimination with an AUROC (area under the receiver operating characteristic) of 0.996 (p < 0.001) and good calibration (unreliability test, p = 0.359). Decision curve analysis demonstrated that the model was clinically useful. (4) Conclusions: This study presented a reliable nomogram that facilitated individualized preoperative prediction of blood pressure change failure after adrenalectomy in patients with pheochromocytoma, which may help decision-making in perioperative treatment and follow-up strategies.

Comparison of shock wave lithotripsy and ureteroscopy in patients with proximal ureteral stones under the COVID-19 pandemic.

PURPOSE: To compare the effectiveness, safety, and cost between ultrasound-guided shock wave lithotripsy (SWL) with an early second session protocol and ureteroscopy (URS) in patients with proximal ureteral stones using the propensity score matching (PSM) method based on a large prospective study. METHODS: This prospective study was conducted in a tertiary hospital from June 2020 to April 2022. Patients who underwent lithotripsy (SWL or URS) for proximal ureteral stones were enrolled. The stone-free rate (SFR), complications, and cost were recorded. PSM analysis was performed. RESULTS: A total of 1230 patients were included, of whom 81.1% (998) were treated with SWL and 18.9% (232) were treated with URS. After PSM, the SWL group had an equivalent SFR at one month (88.7 vs. 83.6%, P = 0.114) compared with the URS group. Complications were rare and comparable between the two groups, while the incidence of ureteral injuries was higher in the URS group compared with the SWL group (1.4 vs. 0%, P = 0.011). The hospital stay was significantly shorter (1 day vs. 2 days, P < 0.001), and the cost was considerably less (2000 vs. 25,053, P < 0.001) in the SWL group compared with the URS group. CONCLUSION: This prospective PSM cohort demonstrated that ultrasound-guided SWL with an early second session protocol had equivalent effectiveness but better safety and lower cost compared with URS in the treatment of patients with proximal ureteral stones, whether the stones were radiopaque or radiolucent. These results will facilitate treatment decisions for proximal ureteral stones.

Development and validation of a predictive model for treatment outcome after emergency extracorporeal shockwave lithotripsy in patients with symptomatic ureteral stones during the COVID-19 pandemic: in a large prospective cohort.

The predictors of treatment outcome after emergency extracorporeal shockwave lithotripsy (SWL) are not well characterized. Therefore, based on a large prospective cohort, we aimed to develop and validate a nomogram for predicting treatment outcome after emergency SWL in patients with symptomatic ureteral stones. The development cohort included 358 patients with symptomatic ureteral stones who underwent emergency SWL between June 2020 and August 2021 in our hospital. One hundred and twenty-nine patients with symptomatic ureteral stones participated in the validation cohort from September 2021 to April 2022. The data were prospectively recorded. The backward stepwise selection was applied using the likelihood ratio test with Akaike's information criterion as the stopping rule. The efficacy of this predictive model was assessed concerning its clinical usefulness, calibration, and discrimination. Finally, 15.6% (56/358) of patients in the development cohort and 14.0% (18/129) of those in the validation cohort suffered from stone-free failure after emergency SWL. We identified four predictors for stone-free failure: stone size, stone density, skin to stone distance (SSD), and degree of hydronephrosis. This model showed good discrimination with an area under the receiver operating characteristic (AUROC) curves of 0.935 (0.899-0.971) and good calibration (P = 0.059). The decision curve analysis showed that the model was clinically valuable. In this large prospective cohort, we found that stone size, stone density, SSD, and degree of hydronephrosis were predictors of treatment outcome after emergency SWL. This nomogram will be helpful in preoperative risk stratification to provide individualized treatment recommendations for each patient. Furthermore, early identification and appropriate management of patients may increase the success rate of emergency SWL during the COVID-19 pandemic.

Prospective Comparison of Local Anesthesia with General or Spinal Anesthesia in Patients Treated with Microscopic Varicocelectomy.

It is unclear whether local anesthesia (LA) is a viable and safe alternative to general anesthesia (GA) or spinal anesthesia (SA) for microscopic varicocelectomy. As a result, we designed a prospective trial to compare the pain relief, complications, and cost of LA with GA or SA in subinguinal microscopic varicocelectomy (MSV), using the propensity score matching method (PSM). This prospective study was conducted in a tertiary hospital from February 2021 to April 2022. Patients who underwent subinguinal MSV for varicocele were enrolled. The perioperative visual analog scale (VAS) scores, anesthesia-associated side effects, and cost data were recorded, and PSM analysis was performed. Finally, 354 patients were included, of whom 61.0% (216) were treated with LA, and 39.0% (138) underwent GA or LA. After PSM, the patients in the LA group exhibited lower VAS scores both three hours and one day after surgery, and a lower incidence of postoperative analgesic requirement; a lower ratio of patients who experienced anesthesia-associated side effects was also observed in the LA group, compared with the GA or SA group (all p < 0.001). The rate of perioperative satisfaction for patients was higher, the hospital stays and days to return to normal activity were shorter, and the cost was less in the LA group than in the patients in the GA or SA group (all p < 0.001). This prospective PSM cohort demonstrated that LA has the advantages of perioperative pain relief, reduced anesthesia-associated side effects, and cost, compared with GA or SA. It indicated that LA is an effective and safe technique for subinguinal MSV, and may guide clinical practice.

Nomogram for predicting spontaneous pregnancy after microscopic varicocelectomy in infertile men with normal hormone.

INTRODUCTION: The current challenge for the treatment of varicocele is identifying patients who could benefit the most from surgery. We aimed to develop and validate a nomogram for predicting spontaneous pregnancy following microscopic varicocelectomy in infertile men, based on a large cohort. METHODS: Two hundred eighty-two consecutive patients who underwent microscopic varicocelectomy from January 2018 to December 2020 were enrolled as participants in the study. Xiang Hua center (206 patients) as a development cohort. Hu Nan center (76 patients) as a validation cohort. Patient clinicopathologic data were recorded. Multivariate logistic regression was used to build a predictive model with regression coefficients. Then, backward stepwise selection was applied, and the likelihood ratio test with Akaike's information criterion was used as the stopping rule. The performance of this predictive model was assessed for discrimination, calibration, and clinical usefulness. RESULTS: Predictors of this model included the age of female partners, diameter of veins, initial and increased total progressively motile sperm count. The model demonstrated good discrimination with an AUROC of 0.925 (p < 0.001) and calibration (Unreliability test, p = 0.522) in the validation cohort. Furthermore, the model was clinically useful, according to decision curve analysis. CONCLUSIONS: Our findings indicated that younger female partners, larger diameter of veins, higher initial and increased total progressively motile sperm count were significant predictors of spontaneous pregnancy in infertile men, post microscopic varicocelectomy. This nomogram may assist in individual decision-making on the treatment strategy of varicocele preoperatively and improve the treatment outcome.

Immune status for monitoring and treatment of bladder cancer.

The high recurrence rate of non-muscle invasive bladder cancer (BC) and poor prognosis of advanced BC are therapeutic challenges that need to be solved. Bacillus Calmette-Guerin (BCG) perfusion was the pioneer immunotherapy for early BC, and the discovery of immune checkpoint inhibitors has created a new chapter in the treatment of advanced BC. The benefit of immunotherapy is highly anticipated, but its effectiveness still needs to be improved. In this review, we collated and analysed the currently available information and explored the mechaisms by which the internal immune imbalance of BC leads to tumour progression. The relationship between immunity and progression and the prognosis of BC has been explored through tests using body fluids such as blood and urine. These analytical tests have attempted to identify specific immuyne cells and cytokines to predict treatment outcomes and recurrence. The diversity and proportion of immune and matrix cells in BC determine the heterogeneity and immune status of tumours. The role and classification of immune cells have also been redefined, e.g., CD4 cells having recognised cytotoxicity in BC. Type 2 immunity, including that mediated by M2 macrophages, Th2 cells, and interleukin (IL)-13, plays an important role in the recurrence and progression of BC. Pathological fibrosis, activated by type 2 immunity and cancer cells, enhances the rate of cancer progression and irreversibility. Elucidating the immune status of BC and clarifying the mechanisms of action of different cells in the tumour microenvironment is the research direction to be explored in the future.

Systematic Analysis of the Global, Regional and National Burden of Kidney Cancer from 1990 to 2017: Results from the Global Burden of Disease Study 2017.

BACKGROUND: Data on kidney cancer burden are valuable for health-related policy making. OBJECTIVE: To report the results of the Global Burden of Disease 2017 study on global kidney cancer burden estimates grouped by gender, age, region, country or territory, and sociodemographic index (SDI) from 1990 to 2017. DESIGN, SETTING, AND PARTICIPANTS: This study is based on the Global Burden of Disease database. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We report here detailed estimates and temporal trends of the burden estimates of kidney cancer from 1990 to 2017, stratified by gender and age, in 195 countries and territories. We further evaluated the relationship between these estimates and the SDI, a composite indicator of income per person, years of education, and fertility as a measurement of the socioeconomic level of a country/region. The percentage change and estimated annual percentage change of incidence, mortality, and disability-adjusted life years (DALYs) were calculated to quantify temporal trends. RESULTS AND LIMITATIONS: Globally, age-standardized incidence rates, age-standardized death rates, and DALYs of kidney cancer in males exhibited an increase of 0.387%/yr, 0.345%/yr, and 0.046%/yr, respectively, from 1990 to 2017. This trend was mainly due to the increase in middle and low-middle SDI quintile countries. However, in females, decreasing trends of -0.324%/yr, -0.330%/yr, and -0.669%/yr, respectively, were observed. These trends were mainly due to the decrease in high, high-middle, and middle SDI quintile countries. Study limitations included differences in data collection practices, coding systems, and quality of data sources. CONCLUSIONS: The burden estimate pattern of kidney cancer trends varies widely between genders and throughout the world. Low-middle and middle SDI quintile countries face the highest burden estimates, especially for males. Efforts to increase health care investment are needed in these countries. PATIENT SUMMARY: The global burden estimate of kidney cancer trends increased in males; however, it decreased in females.

LncRNA HAND2-AS1 exerts anti-oncogenic effects on bladder cancer via restoration of RARB as a sponge of microRNA-146.

BACKGROUND: Growing evidence has shown that long noncoding RNA: microRNA: mRNA is implicated in tumor initiation, development, and progression. Long noncoding RNA HAND2-AS1 exhibits anti-cancer effects in diverse cancers. However, the knowledge of HAND-AS1 in bladder cancer development remains unknown. METHODS: LncRNA and miRNA microarray was conducted to explore different expressed RNA in primary bladder cancer specimens. RNA-RNA interaction prediction tools miRcode ( http://www.mircode.org/ ), DIANA-lncBase v2 ( https://carolina.imis.athena-innovation.gr/diana_tools/web/index.php?r=lncbasev2%2Findex-experimental ), DIANA-TarBase v.8 ( https://carolina.imis.athena-innovation.gr/diana_tools/web/index.php?r=tarbasev8%2Findex ) and miRDB ( http://www.mirdb.org/ ) were employed to predict the interactions between RNA. Bladder cancer cell lines were used to perform cell proliferation and apoptosis assays. Western blot and quantitative Real-time Polymerase Chain Reaction were used to determine the expression of protein and RNA separately. Dual-luciferase assay was conducted to determine the activity of three prime untranslated region of retinoic acid receptor beta (RARB). Furthermore, 5637 human bladder cancer mouse models were established to investigate the interactions of lncRNA: miRNA: mRNA in vivo. RESULTS: Based on the RT2 lncRNA PCR Arrays analysis, we validated HAND2-AS1 declined in bladder cancer and negatively correlated with the depth of invasion and grades. The overexpression of HAND2-AS1 in human bladder cancer cells 5637 and RT4 hampered cell proliferation by provoking Caspase 3-triggered cell apoptosis. Besides, one of the HAND2-AS1 sponges, miR-146, elevated in bladder cancer and targeted the tumor suppressor, retinoic acid receptor beta (RARB). We further demonstrated that the HAND2-AS1: miR-146: RARB complex promoted Caspase 3-mediated apoptosis by suppressing COX-2 expression. Finally, the results gained in mouse xenografts suggested that HAND2-AS1 diminished miR-146 expression, thereby reversing the suppression of miR-146 on RARB-mediated apoptosis and contributing to bladder cancer regression. CONCLUSION: The present study sheds light on the fact that lncRNA HAND2-AS1 exerted as a tumor suppressor by releasing RARB from miR-146, leading to tumor proliferation and invasion inhibition. The findings expanded HAND2-AS-mediated regulatory networks' knowledge and provided novel insights to improve the RARB-targeted regimens against bladder cancer.

Weighted gene co-expression network analysis can sort cancer-associated fibroblast-specific markers promoting bladder cancer progression.

The role of cancer-associated fibroblasts (CAFs) has been thoroughly investigated in tumour microenvironments but not in bladder urothelial carcinoma (BLCA). The cell fraction of CAFs gradually increased with BLCA progression. Weighted gene co-expression network analysis (WGCNA) revealed a specific gene expression module of CAFs that are relevant to cancer progression and survival status. Fifteen key genes of the module were consistent with a fibroblast signature in single-cell RNA sequencing, functionally related to the extracellular matrix, and significant in survival analysis and tumour staging. A comparison of the luminal-infiltrated versus luminal-papillary subtypes and fibroblast versus urothelial carcinoma cell lines and immunohistochemical data analysis demonstrated that the key genes were specifically expressed in CAFs. Moreover, these genes are highly correlated with previously reported CAF markers. In summary, CAFs play a major role in the progression of BLCA, and the 15 key genes act as BLCA-specific CAF markers and can predict CAF changes. WGCNA can, therefore, be used to sort CAF-specific gene set in cancer tissues.

Long Non-coding RNA CCAT1 Acts as an Oncogene and Promotes Sunitinib Resistance in Renal Cell Carcinoma.

Although sunitinib contributes to prolonging the progression-free survival of metastatic renal cell carcinoma significantly, the universal presence of resistance limits the initial response rate and restricts durable responses. The mechanisms involved in sunitinib resistance vary and need further investigation. We found long non-coding RNA (lncRNA) colon cancer-associated transcript-1 (CCAT1) overexpressed in sunitinib-resistant cells while declined in the parental cells. Moreover, lncRNA CCAT1 increased significantly in samples with resistance to sunitinib compared with those with responses to sunitinib. The reduction of CCAT1 suppressed cell growth and colony formation while triggering apoptosis. Inversely, the ectopic expression of c-Myc reversed the inhibition of cell growth and enhancement of apoptosis by the knockdown of CCAT1. We also verified that anti-apoptosis protein B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1) decreased along with the deregulation of CCAT1, whereas the expression of Bcl-2 and Mcl-1 restored in cells that were transfected sh-CCAT1 and c-Myc simultaneously. Apart from the in vitro experiments, we demonstrated that knockdown of CCAT1 boosted response to sunitinib by performing sunitinib-resistant ACHN mouse models. Briefly, lncRNA CCAT1 conferred renal cell carcinoma resistance to sunitinib in a c-Myc-dependent manner, providing a novel target for improvement of sunitinib therapy.

Comparison of Hiraoka's Transurethral Detachment Prostatectomy and Transurethral Resection of the Prostate Effects on Postoperative Erectile Function in Patients With Benign Prostatic Hyperplasia: A Prospective Randomized Controlled Study.

BACKGROUND: Currently, no study has focused on the postoperative erectile function in patients with benign prostatic hyperplasia (BPH) by comparing Hiraoka's transurethral detachment of prostate (TUDP) and transurethral resection of prostate (TURP). AIM: To compare the effects of Hiraoka's TUDP and TURP on postoperative erectile function in patients with BPH after long-term follow-up. METHODS: A total of 104 consecutive patients with BPH treated in our hospital between September 2018 and February 2019 were included in the study. All patients who met the inclusion criteria were randomly divided into the Hiraoka's TUDP (n = 52) and TURP (n = 52) groups. Patient baseline data were collected. The international index of erectile function (IIEF-5), minimal clinically important difference (MCID), and quality of life scale (QOLS) were used to evaluate erectile function and quality of life 3, 6, and 12 months after surgery. Primary study endpoints were IIEF-5 and MCID. Secondary study endpoints were QOLS and independent prognostic factors for MCID. OUTCOMES: Hiraoka's TUDP experienced greater improvement in postoperative IIEF5 scores than patients who underwent TURP. RESULTS: Patients in the Hiraoka's TUDP group had significantly higher mean IIEF-5 scores than those in the TURP group 6 and 12 months after surgery (6 months: 18.9 vs 14.8, P < .001; 12 months: 18.1 vs 15.7, P < .001). The percentages of patients in the TUDP group who achieved an MCID were 88.5% and 80.8%, compared to 30.8% and 46.2% in the TURP group (P < .001 for both), 6 and 12 months after the operation, respectively. Patients in the TUDP group had lower QOLS scores than those in the TURP group after the surgery. The surgical method was an independent prognostic factor for MCID (odds ratio = 0.218). CLINICAL IMPLICATIONS: Until now, no study has focused on the postoperative erectile function in patients with BPH by comparing Hiraoka's TUDP and TURP. Our study addressed this issue, which can add a new paradigm in the management to BPH. STRENGTH & LIMITATIONS: The comparison between Hiraoka's TUDP and TURP using a statistically appropriate, adequately powered methodology is the strength of the study. The single center and less participants are the limitations of the study. We believe that multicenter and large-sample studies are needed to further verify these study conclusions. CONCLUSIONS: Among similar cohorts of patients with BPH who underwent TUDP and TURP, patients who underwent Hiraoka's TUDP experienced greater improvement in postoperative IIEF5 scores than patients who underwent TURP, while improvement in IPSS was similar among both groups. Pan C, Zhan Y, Zhao Y, et al. Comparison of Hiraoka's Transurethral Detachment Prostatectomy and Transurethral Resection of the Prostate Effects on Postoperative Erectile Function in Patients With Benign Prostatic Hyperplasia: A Prospective Randomized Controlled Study. J Sex Med 2020;17:2181-2190.

Identification of a Gene Signature for Renal Cell Carcinoma-Associated Fibroblasts Mediating Cancer Progression and Affecting Prognosis.

Background: Cancer-associated fibroblasts (CAFs) are mainly involved in cancer progression and treatment failure. However, the specific signature of CAFs and their related clinicopathological parameters in renal cell carcinoma (RCC) remain unclear. Here, methods to recognize gene signatures were employed to roughly assess the infiltration of CAFs in RCC, based on the data from The Cancer Genome Atlas (TCGA). Weighted Gene Coexpression Network Analysis (WGCNA) was used to cluster transcriptomes and correlate with CAFs to identify the gene signature. Single-cell and cell line sequencing data were used to verify the expression specificity of the gene signature in CAFs. The gene signature was used to evaluate the infiltration of CAFs in each sample, and the clinical significance of each key gene in the gene signature and CAFs was analyzed. We observed that the CAF infiltration was higher in kidney cancer and advanced tumor stage and grade than in normal tissues. The seven key genes of the CAF gene signature identified using WGCNA showed high expression of CAF-related characteristics in the cell clustering landscape and fibroblast cell lines; these genes were found to be associated with extracellular matrix function, collagen synthesis, cell surface interaction, and adhesion. The high CAF infiltration and the key genes were verified from the TCGA and Gene Expression Omnibus data related to the advanced grade, advanced stage, and poor prognosis of RCC. In summary, our findings indicate that the clinically significant gene signature may serve as a potential biomarker of CAFs in RCC, and the infiltration of CAFs is associated with the pathological grade, stage, and prognosis of RCC.

Bladder Cancer Exhibiting High Immune Infiltration Shows the Lowest Response Rate to Immune Checkpoint Inhibitors.

Background: Bladder urothelial cancer (BLCA) treatment using immune checkpoint inhibitors (IMCIs) can result in long-lasting clinical benefits. However, only a fraction of patients respond to such treatment. In this study, we aimed to identify the relationships between immune cell infiltration levels (ICILs) and IMCIs and identify markers for ICILs. Methods: ICILs were estimated based on single-sample gene set enrichment analysis. The response rates of different ICILs to IMCIs were calculated by combining the ICILs of molecular subtypes in BLCA with the response rates of different molecular subtypes of IMvigor 210 trials to a programmed cell death ligand-1 inhibitor. Weighted gene co-expression network analysis was used to identify modules of interest with ICILs. Functional enrichment analysis was performed to functionally annotate the modules. Screening of key genes and unsupervised clustering were used to identify candidate biomarkers. Tumor IMmune Estimation Resource was used to validate the relationships between the biomarkers and ICILs. Finally, we verified the expression of key genes in molecular subtypes of different response rates for IMCIs. Findings: The basal squamous subtype and luminal infiltrated subtype, which showed low response rates for IMCIs, had the highest levels of immune infiltration. The neuronal subtypes, which showed the highest response rates to IMCIs, had low ICILs. The modules of interest and key genes were determined based on topological overlap measurement, clustering results, and inclusion criteria. Modules highly correlated with ICILs were mainly enriched in immune responses and epithelial-mesenchymal transition. After screening the key genes in the modules, five candidate biomarkers (CD48, SEPT1, ACAP1, PPP1R16B, and IL16) were selected by unsupervised clustering. The key genes were inversely associated with tumor purity and were mostly expressed in the basal squamous subtype and luminal infiltrated subtypes. Interpretation: Patients with high ICILs may benefit the least from treatment with IMCIs. Five key genes could predict ICILs in BLCA, and their high expression suggested that the response rate to IMCIs may decrease.

Sulfated polysaccharide of Sepiella maindroni ink targets Akt and overcomes resistance to the FGFR inhibitor AZD4547 in bladder cancer.

Rapid appearance of resistance to fibroblast growth factor receptor (FGFR) inhibitors hampers targeted regimens in bladder cancer. In the present study, we evaluated whether SIP-SII, a sulphated derivative of the polysaccharide in Sepiella maindroni (spineless cuttlefish) ink used in traditional Chinese medicine, could attenuate resistance to FGFR inhibition in bladder cancer cells. In vitro assays indicated that SIP-SII reduced cell viability and migration, restricted cell cycle progression, and increased apoptosis in parallel with decreased AKT phosphorylation and downregulation of CDK4, MMP2, and Bcl-2 in RT112 and JMSU1 cells. Synergistic effects on cell viability were observed when SIP-SII was combined with the small-molecule FGFR inhibitor AZD4547. Specific Akt targeting by SIP-SII was suggested by the fact that neither Akt knockdown nor the selective PI3K inhibitor BKM120 enhanced the inhibitory effects of SIP-II, while expression of a constitutively active Akt mutant rescued SIP-SII effects. Furthermore, subcutaneous transplantation of RT112 xenografts confirmed the superiority and tolerability of combined SIP-SII and AZD4547 administration over monotherapy regimens. The present study thus provides pre-clinical evidence of the ability of SIP-SII to improve FGFR-targeted therapies for bladder cancer by inhibiting Akt.

Identification of Biomarkers for Controlling Cancer Stem Cell Characteristics in Bladder Cancer by Network Analysis of Transcriptome Data Stemness Indices.

Background: Stem cells characterized by self-renewal and therapeutic resistance play crucial roles in bladder cancer (BLCA). However, the genes modulating the maintenance and proliferation of BLCA stem cells are still unclear. In this study, we aimed to characterize the expression of stem cell-related genes in BLCA. Methods: The mRNA expression-based stemness index (mRNAsi) of The Cancer Genome Atlas (TCGA) was evaluated and corrected by tumor purity. Corrected mRNAsi were further analyzed with regard to muscle-invasive bladder cancer molecular subtypes, survival analysis, pathological staging characteristics, and outcomes after primary treatment. Next, weighted gene co-expression network analysis was used to find modules of interest and key genes. Functional enrichment analysis was performed to functionally annotate the modules and key genes. The expression levels of key genes in all cancers were validated using Oncomine and Gene Expression Omnibus (GEO) database containing molecular subtypes in BLCA. Protein interaction networks were used to identify upstream genes, and the relationships between genes were analyzed at the protein and transcription levels. Findings: mRNAsi was significantly upregulated in cancer tissues. Corrected mRNAsi in BLCA increased as tumor stage increased, with T3 having the highest stem cell characteristics. Lower corrected mRNAsi scores had better overall survival and treatment outcome. The modules of interest and key genes were determined based on topological overlap measurement clustering results and the inclusion criteria. For 13 key genes (AURKA, BUB1B, CDCA5, CDCA8, KIF11, KIF18B, KIF2C, KIFC1, KPNA2, NCAPG, NEK2, NUSAP1, and RACGAP1), enriched gene ontology terms related to cell proliferation (e.g., mitotic nuclear division, spindle, and microtubule binding) were determined. Their expression did not differ according to the pathological stages of BLCA, and these genes were clearly overexpressed in many types of cancers. In GEO database, the expression levels of 13 key genes were higher in basal subtype with the highest stem cell characteristics than in luminal and its subtypes. AURKB and PLK1 may be regulated upstream of other key genes, and the key genes were found to be strongly correlated with each other and with upstream genes. Interpretation: The 13 key genes identified in this study were found to play important roles in the maintenance of BLCA stem cells. Controlling the upstream genes AURKB and PLK1 may have applications in the treatment of BLCA. These genes may act as therapeutic targets for inhibiting the stemness characteristics of BLCA.

Laparoscopic ultrasonography: The wave of the future in renal cell carcinoma?

Laparoscopic or robotic surgery is the main method of treating renal cell carcinoma (RCC). Laparoscopic surgery can accurately target lesions and shorten patient recovery time. Renal endogenous tumors or inferior vena cava tumor thrombi are very difficult to remove using the laparoscopic approach. The emergence of laparoscopic ultrasonography (LUS) has solved this problem. LUS can assist in the detection of tumor boundaries and the extent of tumor thrombi. The lack of tactile feedback may hinder the development of laparoscopic surgery for the treatment of renal cancer. LUS has become an important tool that has improved the rates of successful surgery. LUS is applied in not only early and locally advanced RCC treatment but also in monitoring ablation therapy, testing renal blood perfusion, and exposing renal pedicles. Sonographic techniques used for LUS include initial B-mode, Doppler, and contrast-enhanced ultrasound (CEUS). Contrast agents applied for CEUS do not induce nephrotoxicity and can display renal perfusion more accurately than the regular color Doppler ultrasound. According to current literature, LUS is a promising technique for the treatment of RCC, especially for endogenous RCC or RCC with thrombosis, and for monitoring the effectiveness of radiofrequency ablation, although further well-designed studies are warranted.

miR-335 inhibits the proliferation and invasion of clear cell renal cell carcinoma cells through direct suppression of BCL-W.

Increasing evidence has demonstrated that small non-coding microRNAs (miRNAs) play important roles in cancer development and progression. Recent studies have shown that microRNA-335 (miR-335) functions as an oncogene or a tumor suppressor in various human cancer types, but its role in clear cell renal cell carcinoma (ccRCC) remains poorly understood. In our study, we firstly found that the expression level of miR-335 was significantly downregulated in ccRCC tissues versus corresponding non-tumor tissues and the low expression of miR-335 was significantly associated with lymph node metastasis, larger tumor size, and poor T stage. Then, we found that overexpression of miR-335 significantly suppressed the proliferation and invasion of 786-O and CaKi-1 ccRCC cell lines. We subsequently found that miR-335 could interact with the 3'-untranslated regions (3'UTR) of B-cell CLL/lymphoma 2 like 2 (BCL-W or BCL2L2) messenger RNA (mRNA) and repress its expression. In addition, re-expression of BCL-W (without the 3'UTR) could partially abrogate the miR-335-induced 786-O and CaKi-1 ccRCC cell proliferation and invasion inhibition. Furthermore, we found that expression patterns of miR-335 were inversely correlated with those of BCL-W mRNA in ccRCC tissues. Taken together, these results indicate that miR-335 acts as a novel tumor suppressor to regulate ccRCC cell proliferation and invasion through downregulation of BCL-W expression.