Investigating the causal associations between metabolic biomarkers and the risk of kidney cancer.

Metabolic reprogramming plays an important role in kidney cancer. We aim to investigate the causal effect of 249 metabolic biomarkers on kidney cancer from population-based data. This study extracts data from previous genome wide association studies with large sample size. The primary endpoint is random-effect inverse variance weighted (IVW). After completing 249 times of two-sample Mendelian randomization analysis, those significant metabolites are included for further sensitivity analysis. According to a strict Bonferrion-corrected level (P < 2e-04), we only find two metabolites that are causally associated with renal cancer. They are lactate (OR:3.25, 95% CI: 1.84-5.76, P = 5.08e-05) and phospholipids to total lipids ratio in large LDL (low density lipoprotein) (OR: 0.63, 95% CI: 0.50-0.80, P = 1.39e-04). The results are stable through all the sensitivity analysis. The results emphasize the central role of lactate in kidney tumorigenesis and provide novel insights into possible mechanism how phospholipids could affect kidney tumorigenesis.

Association between physical activity and the prevalence of kidney stones in American adults: results from a multi-year national survey.

OBJECTIVE: To investigate the association between physical activity and the prevalence of kidney stones. METHODS: A cross-section study was conducted using data from National Health and Nutrition Examination Survey 2007-2018. Physical activity was evaluated based on the Global Physical Activity Questionnaire. Multivariable logistic regression was performed to elucidate the association between physical activity (patterns, intensity, duration and frequency of moderate and vigorous physical activity) and the prevalence of kidney stones after adjusting for potential confounders. Stratified and interaction analyses were conducted to detect potential effect modifiers. In addition, physical activity was assessed using metabolic equivalent and physical volume, and followed the regression above. Water intake was obtained from the day 2 dietary recall and was included in the sensitivity analysis. RESULTS: A total of 34,390 participants were included in the analysis. The multivariable logistic regression revealed that individuals who engaged in moderate physical activity for 30-60 minutes per day had a significant inverse association with the prevalence of kidney stones in the fully-adjusted model (OR=0.804, 95%CI 0.700 to 0.923), while no more significant finding was observed for other physical activity parameters. Interaction and stratified analyses indicated no covariate modifying the association. The results above were robust in the sensitivity analysis. CONCLUSION: The duration of moderate physical activity (30-60 mins/day) is inversely associated with the prevalence of kidney stones, while no more significant association was observed between other physical activity parameters (including patterns, intensity, duration and frequency of vigorous physical activity, frequency of moderate physical activity) and kidney stones. DATA AVAILABILITY: Data available in a publicly accessible repository that does not issue DOIs. Publicly available datasets were analyzed in this study. These data can be found here: https://www.cdc.gov/nchs/nhanes/index.htm.

Clinicopathologic characteristics and outcomes of prostate cancer incidentally discovered at the time of radical cystoprostatectomy: a population-based cohort study.

OBJECTIVE: This study aimed to comprehensively analyze the clinical characteristics and prognosis of patients with concomitant bladder cancer (BCa) and prostate cancer (PCa) using a large population-based database. METHODS: Within the Surveillance, Epidemiology, and End Results (SEER) database (2000-2019), we identified patient with concomitant PCa at the time of radical cystoprostatectomy (RCP). Logistic regression and propensity score matching (PSM) analyses were employed to identify risk factors and mitigate confounders, respectively. Kaplan-Meier survival curves were used to estimate cancer-specific survival (CSS). RESULTS: A total of 14,199 BCa patients undergoing RCP were identified, with 28.8% incidentally discovered to have concurrent PCa. Among them, 89.9% exhibited organ-confined (T1-2) PCa. An increased risk of concomitant tumors was observed among older age, white race, and high tumor grade of BCa. Survival analysis revealed no significant difference in CSS between patients with BCa alone and those with concurrent PCa (5-year CSS rate: 71.3% vs. 67.2%, P =0.076). Subgroup analysis and multivariable analysis, however, indicated that concurrent high-risk PCa adversely impacted survival (5-year CSS rate: 71.3% vs. 63.4%, HR 1.27, 95% CI 1.01-1.58, P =0.038) compared to solitary BCa. Notably, the presence of low/intermediate-risk PCa did not affect survival outcomes ( P =0.584). CONCLUSION: In conclusion, incidentally discovered PCa in RCP specimens is frequent and characterized by organ-confined presentation, lower PSA levels, and Gleason scores. Patients with concurrent high-risk PCa have a worse prognosis compared to those with solitary BCa, while the presence of low/intermediate-risk PCa does not influence oncological prognosis.

Predictors of trimodality therapy in patients with muscle-invasive bladder cancer and effect on survival

Background Due to its unique advantages over radical cystectomy (RC), trimodality therapy (TMT) is increasingly being utilized by patients diagnosed with muscle-invasive bladder cancer (MIBC) who are not suitable for or refuse RC. However, achieving a satisfactory oncological outcome with TMT requires strict patient selection criteria, and the comparative oncological outcomes of TMT versus RC remain controversial. Methods Patients diagnosed with non-metastatic MIBC who underwent TMT or RC were identified from the SEER database during 2004–2015. Before one-to-one propensity score matching (PSM), logistic regression was utilized to identify predictors of TMT. After matching, K-M curves were generated to estimate cancer-specific survival (CSS) and overall survival (OS) with log-rank to test the significance. Finally, we conducted univariate and multivariate Cox analyses to identify independent prognostic factors for CSS and OS. Results The RC and TMT groups included 5812 and 1260 patients, respectively, and the TMT patients were significantly older than the RC patients. Patients with advanced age, separated, divorced, or widowed (SDW) or unmarried marital status (married as reference), and larger tumor size (< 40 mm as reference) were more likely to be treated with TMT. After PSM, TMT was found to be associated with worse CSS and OS, and it was identified as an independent risk factor for both CSS and OS. Conclusion MIBC patients may not be carefully evaluated prior to TMT, and some non-ideal candidates underwent TMT. TMT resulted in worse CSS and OS in the contemporary era, but these results may be biased. Strict TMT candidate criteria and TMT treatment modality should be required (AU)

Predictors of trimodality therapy in patients with muscle-invasive bladder cancer and effect on survival.

BACKGROUND: Due to its unique advantages over radical cystectomy (RC), trimodality therapy (TMT) is increasingly being utilized by patients diagnosed with muscle-invasive bladder cancer (MIBC) who are not suitable for or refuse RC. However, achieving a satisfactory oncological outcome with TMT requires strict patient selection criteria, and the comparative oncological outcomes of TMT versus RC remain controversial. METHODS: Patients diagnosed with non-metastatic MIBC who underwent TMT or RC were identified from the SEER database during 2004-2015. Before one-to-one propensity score matching (PSM), logistic regression was utilized to identify predictors of TMT. After matching, K-M curves were generated to estimate cancer-specific survival (CSS) and overall survival (OS) with log-rank to test the significance. Finally, we conducted univariate and multivariate Cox analyses to identify independent prognostic factors for CSS and OS. RESULTS: The RC and TMT groups included 5812 and 1260 patients, respectively, and the TMT patients were significantly older than the RC patients. Patients with advanced age, separated, divorced, or widowed (SDW) or unmarried marital status (married as reference), and larger tumor size (< 40 mm as reference) were more likely to be treated with TMT. After PSM, TMT was found to be associated with worse CSS and OS, and it was identified as an independent risk factor for both CSS and OS. CONCLUSION: MIBC patients may not be carefully evaluated prior to TMT, and some non-ideal candidates underwent TMT. TMT resulted in worse CSS and OS in the contemporary era, but these results may be biased. Strict TMT candidate criteria and TMT treatment modality should be required.

Prognostic value of preoperative microscopic hematuria in patients with non-metastatic renal cell carcinoma who underwent nephrectomy.

BACKGROUND: Microscopic hematuria is associated with various urinary system diseases and is commonly used for the diagnosis of these conditions. Its prognostic role in non-metastatic renal cell carcinoma (RCC) patients who underwent nephrectomy remains unclear. PATIENTS AND METHODS: A retrospective analysis of non-metastatic RCC patients who underwent nephrectomy in West China Hospital of Sichuan University from 2011 to 2013 was performed. Significant microscopic hematuria (SMH), defined as a threshold with a significant impact on disease-free survival (DFS) and overall survival (OS), was determined by Kaplan-Meier curves and the Maximally Selected Log-Rank Statistic. Kaplan-Meier curves were then used to estimate patients' DFS and OS, and the log-rank test was used to examine statistical significance. Logistic regression was utilized to identify clinical-pathological factors associated with SMH, while Cox regression was employed to determine independent factors of survival. RESULTS: A total of 773 patients were included, and 20 red blood cells per high-power field was identified as the cutoff of SMH, of which 90 patients had preoperative SMH (11.6%) and 683 patients (88.4%) did not. Larger tumor size (OR = 1.10 [per cm], 95% CI 1.01-1.19, p = 0.036) and higher Fuhrman grade (grade 3 vs. grade 1-2, OR = 1.76, 95% CI 1.09-2.83, p = 0.02; grade 4 vs. grade 1-2, OR = 2.15, 95% CI 0.73-6.31, p = 0.164) were predictors of SMH. Compared to non-SMH patients, SMH patients had poorer DFS (HR = 3.16, 95% CI 2.07-4.83, p < 0.001) and OS (HR = 2.11, 95% CI 1.34-3.32, p = 0.001). CONCLUSION: In summary, preoperative SMH is associated with larger tumor size and higher Fuhrman grade, and it is also independently correlated with poorer DFS and OS in non-metastatic RCC patients who underwent nephrectomy.

Validation and comparison of prognostic value of different preoperative systemic inflammation indices in non-metastatic renal cell carcinoma.

BACKGROUND: Several preoperative systemic inflammation indices have been proven to be correlated with the prognosis of patients diagnosed with non-metastatic renal cell carcinoma (RCC). However, these indices are currently not included in the main prognostic models, and few studies have compared the prognostic efficacy of different preoperative systemic inflammation indices. PATIENTS AND METHODS: This retrospective study reviewed patients diagnosed with non-metastatic RCC who underwent nephrectomy at West China Hospital of Sichuan University from 2011 to 2013. Different preoperative systemic inflammation indices (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], monocyte-to-lymphocyte ratio [MLR], systemic immune-inflammation index [SII], and systemic inflammation response index [SIRI]) were calculated. Logistic regression was used to explore the relationship between systemic inflammation indices and clinical characteristics, and Cox regression was used to identify independent prognostic factors of overall survival (OS). The concordance index (c-index) was also calculated. RESULTS: A total of 820 patients were included in the study, with a median follow-up of 78 months. Higher levels of NLR (> 3.04), PLR (> 147), MLR (> 0.32), SII (> 700), and SIRI (> 1.27) were found to be associated with more advanced tumor stage, higher Furman grade, and larger tumor size. In multivariate Cox regression, NLR, PLR, MLR, SII, and SIRI were identified as independent prognostic factors, and SII had the highest and most significant hazard ratio and the largest c-index. CONCLUSION: In conclusion, various systemic inflammation indices were found to be associated with poorer OS. Among them, SII exhibited the highest predictive efficacy, suggesting its potential inclusion as a component in future prognostic models.

Relationship between weight-adjusted-waist index and erectile dysfunction in the United State: results from NHANES 2001-2004.

Objective: The purpose of this study is to examine the association between a novel adiposity parameter, the weight-adjusted-waist index (WWI), and erectile dysfunction (ED). Methods: According to National Health and Nutrition Examination Survey (NHANES) 2001-2004, a total of 3884 participants were categorized as ED and non-ED individuals. WWI was calculated as waist circumference (WC, cm) divided by the square root of weight (kg). Weighted univariable and multivariable logistic regression models were conducted to assess the correlation between WWI and ED. Smooth curve fitting was utilized to examine the linear association. The receiver operating characteristic (ROC) curve and DeLong et al.'s test were applied to compare the area under curve (AUC) value and predictive power among WWI, body mass index (BMI), and WC for ED. Results: WWI was positively related to ED with the full adjustment [odds ratio (OR)=1.75, 95% confidence interval (95% CI): 1.32-2.32, p=0.002]. After converting WWI to a categorical variable by quartiles (Q1-Q4), compared to Q1 the highest WWI quartile was linked to an obviously increased likelihood of ED (OR=2.78, 95% CI: 1.39-5.59. p=0.010). Subgroup analysis revealed the stability of the independent positive relationship between WWI and ED. It was shown that WWI had a stronger prediction for ED (AUC=0.745) than BMI (AUC=0.528) and WC (AUC=0.609). Sensitivity analysis was performed to verify the significantly positive connection between WWI and stricter ED (OR=2.00, 95% CI: 1.36-2.94, p=0.003). Conclusion: An elevated WWI was related to higher risks of ED in the United State adults, and a stronger predictive power of WWI for ED was observed than BMI and WC.

Radical versus partial nephrectomy for T1 non-clear cell renal cell carcinoma.

INTRODUCTION: Nephron-sparing surgery is the recommended surgical management of T1 renal cell carcinoma (RCC). However, non-clear cell RCC (nccRCC) is heterogeneous and included many histological types. Therefore, the present study was performed to compare radical nephrectomy (RN) versus partial nephrectomy (PN) in nccRCC. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results registry (2000-2019), the patients with nccRCC were identified. Kaplan-Meier survival curve and the log-rank test were conducted. Univariate analysis and multivariate Cox regression analysis were performed to explore the prognostic factors. RESULTS: A total of 7575 patients with nccRCC were included, of which papillary RCC (n = 5219) is the major histology. Kaplan-Meier plots and log-rank tests showed that nccRCC patients who underwent RN had significantly worse overall survival (OS) and cancer-specific survival (CSS) than those who received PN (all P < 0.05). Multivariate analysis also revealed that RN was significantly associated with poor OS and CSS in nccRCC patients. Stratified by histological types, the multivariate analysis also revealed that RN was significantly associated with poor OS in papillary and chromophobe (all P < 0.05). Besides, the multivariable analysis indicated that RN was associated with poor CSS in papillary RCC (P < 0.05). For other histology, the patients who received RN had a comparable survival to those who received PN. CONCLUSION: For patients with T1 nccRCC, our findings revealed that PN was not inferior to RN in OS and CSS. PN may be also the preferred option for T1 nccRCC, but more prospective studies are required to validate this finding.

Survival benefit stratification of partial nephrectomy versus non-surgical treatment in elderly patients with T1a renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) of stage T1a has been proven to be of low-grade malignancy and mostly affects elderly individuals with relatively limited life expectancy. However, research on the survival benefit of surgery relative to non-surgical treatment (NST) is limited. The aim of the study was to investigate the survival difference between partial nephrectomy (PN) and NST and to establish a benefit stratification model for elderly patients (≥70 years) diagnosed with T1a RCC. PATIENTS AND METHODS: Patients diagnosed with non-metastatic T1a RCC who received PN or NST were identified from the SEER database during 2004-2015. Before survival analysis, propensity score matching (PSM) was performed. Overall survival (OS) was estimated by the Kaplan-Meier method, and subgroup analyses were used to identify favorable factors of PN. Independent factors of survival were recognized by multivariate Cox regression analysis. RESULTS: Patients diagnosed with non-metastatic T1a RCC who received PN or NST were identified from the SEER database during 2004-2015. Before survival analysis, propensity score matching (PSM) was performed. Overall survival (OS) was estimated by the Kaplan-Meier method, and subgroup analyses were used to identify favorable factors of PN. Independent factors of survival were recognized by multivariate Cox regression analysis. CONCLUSIONS: Our findings suggest that the survival benefit of PN could be stratified based on the clinical characteristics in patients with stage T1a RCC aged 70 years or older, which may help physicians and patients optimize clinical decisions.

Immune landscape and immunotherapy for penile cancer.

Penile cancer is a rare malignancy and usually refers to penile squamous cell carcinoma (PSCC), which accounts for more than 95% of all penile malignancies. Although organ-sparing surgery is an effective treatment for early-stage PSCC, surgical intervention alone is often not curative for advanced PSCC with metastases to the inguinal and/or pelvic lymph nodes; thus, systemic therapy is required (usually platinum-based chemotherapy and surgery combined). However, chemotherapy for PSCC has proven to be of limited efficacy and is often accompanied by high toxicity, and patients with advanced PSCC usually have poor prognosis. The limited treatment options and poor prognosis indicate the unmet need for advanced PSCC. Immune-based therapies have been approved for a variety of genitourinary and squamous cell carcinomas but are rarely reported in PSCC. To date, several studies have reported high expression of PDL1 in PSCC, supporting the potential application of immune checkpoint inhibitors in PSCC. In addition, human papillomavirus (HPV) infection is highly prevalent in PSCC and plays a key role in the carcinogenesis of HPV-positive PSCC, suggesting that therapeutic HPV vaccine may also be a potential treatment modality. Moreover, adoptive T cell therapy (ATC) has also shown efficacy in treating advanced penile cancer in some early clinical trials. The development of new therapeutics relies on understanding the underlying biological mechanisms and processes of tumor initiation, progression and metastasis. Therefore, based on the interest, we reviewed the tumor immune microenvironment and the emerging immunotherapy for penile cancer.

Contemporary use trends and effect on survival of pelvic lymph node dissection for non-muscle-invasive bladder cancer.

Background: Patients diagnosed with non-muscle-invasive bladder cancer (NMIBC) who are at a very high risk of disease progression and failure of Bacillus Calmette-Guerin treatment are recommended to undergo immediate radical cystectomy (RC). The role and optimal degree of pelvic lymph node dissection (PLND) during RC for NMIBC patients, however, have not been well investigated. Patients and methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients. Overall survival (OS) was assessed with the Kaplan-Meier technique. Multivariable Cox regression analysis was conducted to determine independent factors of OS. Results: A total of 1,701 patients were identified in the SEER database from 2004 to 2015. Any level of PLND (>0 lymph nodes examined) was performed in 1,092 patients (64.2%). The median number of lymph nodes examined was 8 (interquartile range, 0-20) in T1, 0 (interquartile range, 0-11) in Ta, and 0 (interquartile range, 0-14) in Tia patients. Compared with non-PLND, any level of PLND improved OS in T1 but not in Ta or Tis patients. Compared to limited (1-9 lymph nodes examined) and non-PLND, extensive PLND (lymph nodes examined ≥10) resulted in better OS only in T1 patients (all p < 0.001, adjusted significance level = 0.017). PLND was identified as a independent protective factor for OS. Conclusion: Based on the SEER database, we found that PLND during RC led to better OS and extensive PLND was associated with better OS in T1 but not in Ta or Tis patients. The implementation of PLND was insufficient both in population proportions and scope.

Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits bladder cancer cell growth via the mitochondrial apoptosis and JNK pathways.

Erianin, a component extracted from the traditional Chinese herbal medicine Dendrobium, has shown significant anti-tumour activity in various cancers but not in bladder cancer. In this study, we assessed the effects of Erianin on bladder cancer growth and elucidated the related mechanisms. First, Erianin was synthesized with high yields, and markedly suppressed EJ and T24 cell proliferation. It induced G2/M-phase arrest in vitro. Furthermore, Erianin triggered apoptosis via caspase cascades activation and the mitochondrial-mediated apoptotic pathway. Bim up-regulation and Bcl-2 down-regulation as the symbol of apoptosis which were found to play the dominant role in the effects of Erianin. We further showed that JNK pathway activation is necessary for the Erianin-mediated anti-proliferation and apoptotic response. Finally, Erianin exhibited anti-tumour activity and induced apoptosis in tumour tissue in vivo. Collectively, these results suggest that Erianin induced cell cycle G2/M-phase arrest and apoptosis via the JNK signalling pathway in bladder cancer, indicating the potential usefulness of Erianin for the therapy of bladder cancer.

The Antiresection Activity of the X Protein Encoded by Hepatitis Virus B.

Chronic infection of hepatitis B virus (HBV) is associated with an increased incidence of hepatocellular carcinoma (HCC). HBV encodes an oncoprotein, hepatitis B x protein (HBx), that is crucial for viral replication and interferes with multiple cellular activities including gene expression, histone modifications, and genomic stability. To date, it remains unclear how disruption of these activities contributes to hepatocarcinogenesis. Here, we report that HBV exhibits antiresection activity by disrupting DNA end resection, thus impairing the initial steps of homologous recombination (HR). This antiresection activity occurs in primary human hepatocytes undergoing a natural viral infection-replication cycle as well as in cells with integrated HBV genomes. Among the seven HBV-encoded proteins, we identified HBx as the sole viral factor that inhibits resection. By disrupting an evolutionarily conserved Cullin4A-damage-specific DNA binding protein 1-RING type of E3 ligase, CRL4WDR70 , through its H-box, we show that HBx inhibits H2B monoubiquitylation at lysine 120 at double-strand breaks, thus reducing the efficiency of long-range resection. We further show that directly impairing H2B monoubiquitylation elicited tumorigenesis upon engraftment of deficient cells in athymic mice, confirming that the impairment of CRL4WDR70 function by HBx is sufficient to promote carcinogenesis. Finally, we demonstrate that lack of H2B monoubiquitylation is manifest in human HBV-associated HCC when compared with HBV-free HCC, implying corresponding defects of epigenetic regulation and end resection. Conclusion: The antiresection activity of HBx induces an HR defect and genomic instability and contributes to tumorigenesis of host hepatocytes.

(-)-Gochnatiolide B, synthesized from dehydrocostuslactone, exhibits potent anti-bladder cancer activity in vitro and in vivo.

With limited success achieved in bladder cancer patient management, novel agents are in urgent need for the purpose of therapy and prevention. As a sesquiterpenoid dimmer isolated from Gochnatia pomculat, (-)-gochnatiolide B has been bio-mimetically synthesized in multiple steps with a poor yield, which heavily limited the further research and clinical application. Herein, (-)-gochnatiolide B was synthesized beginning with dehydrocostuslactone in four steps with a total yield of 26%. MTT assays showed that (-)-gochnatiolide B inhibited the growth of vast majority of human cancer cells especially bladder cancer cells. Mechanistically, (-)-gochnatiolide B induced the increased expression of pro-apoptotic proteins and the decreased expression of anti-apoptosis proteins and further resulted in apoptosis of T24 cells. (-)-Gochnatiolide B induced G1 arrest which associated with SKP2 downregulation, leading to p27/Kip1 accumulation and downregulation of cyclin D1 in T24 cells. Furthermore, in vivo studies showed that (-)-gochnatiolide B remarkably inhibited tumor growth by 81% compared with vehicle control. Taken together, (-)-gochnatiolide B exhibits inhibitory activity against bladder cancer cells both in vitro and in vivo by inducing apoptosis, which suggests that (-)-gochnatiolide B could be an important candidate compound for prevention and treatment of bladder cancer.