Trimethylamine-N-oxide (TMAO) and predicted risk of cardiovascular events after partial nephrectomy.

INTRODUCTION: Emerging evidence suggests that uremic toxins, in particular trimethylamine-N-oxide(TMAO), indoxyl-sulfate(IS), and p-cresyl-sulfate(PCS), may associate with increased risk of cardiovascular events(CVe). However, whether uremic toxins increase after partial nephrectomy(PN) and their correlation with risk for CVe remains unknown. METHODS: 100 patients managed with PN were retrospectively reviewed. TMAO/IS/PCS levels were examined by liquid chromatography-mass-spectrometry. Renal-parenchymal-volume-preservation(RPVP) was estimated from CT scans. Predicted risks for CVe were obtained using the Framingham score. Linear regression assessed association between uremic toxins, GFR and risk of CVe. Logistic regression evaluated factors associated with post-PN TMAO. RESULTS: TMAO, IS and PCS increased from 1.7, 3.7 and 3.5 µmol/L before PN to 3.6, 5.4 and 7.4 µmol/L at latest follow-up, respectively, while GFR declined from 102 to 93 ml/min/1.73 m2 (all p<0.001). TMAO, IS and PCS levels all negatively correlated with GFR(all p<0.001). Predicted 10-year risk of CVe increased from 1.1% pre-PN to 1.7% post-PN(p<0.001), primarily due to increased age(p<0.001), blood pressure(p = 0.002) and total cholesterol(p = 0.003). TMAO(ß = 0.038) and GFR (ß = -0.02) were independent predictors for predicted 10-year CVe risk on multivariable-analysis. Increased TMAO was an early and sustained finding maintained through 5 years, unlike IS, PCS and eGFR. On multivariable analysis, increased pre-PN TMAO(OR = 2.79) and decreased RPVP(OR = 3.23) were identified as independent risk factors for higher post-PN TMAO, while ischemia type/duration failed to correlate. CONCLUSION: Uremic toxin levels increased after PN correlating with reduced GFR. Higher TMAO independently associated with greater predicted 10-year CVe risk. Parenchymal mass preserved rather than ischemia time or type associated with increased TMAO.

Longitudinal changes in renal parenchymal volume and function status after partial nephrectomy: a retrospective cohort study.

BACKGROUND: The ipsilateral renal parenchymal volume (RPV) experiences a sharp decrease shortly after partial nephrectomy (PN), mainly due to surgical remove or devascularization of kidney tissue. However, the subsequent change of RPV and its association with glomerular filtration rate (GFR) fast decline remains unknown. Our objective was to investigate the change of ipsilateral RPV and renal function status from new baseline (1-12 months after PN) to latest follow-up (≥1 year) after PN, and to explore factors associated with ipsilateral RPV decrease rate and correlation between RPV decrease and GFR fast decline. MATERIALS AND METHODS: A retrospective review of 367 patients with PN was conducted. Three-dimensional reconstruction of computed tomography (CT)/MRI images was performed for RPV calculation. Spectrum score was used to assess the degree of acute kidney injury (AKI) in the operated kidney after PN. GFR decline greater than 3 ml/min/1.73 m 2 /year was defined as GFR fast decline. One hundred fourteen patients underwent abdominal surgery was used as control. Predictive factors for subsequent decrease of RPV rate and GFR fast decline were evaluated by linear and logistic regression, respectively. RESULTS: With a median interval time of 21.1 (interquartile range:13.8-35.5) months, median ipsilateral RPV significantly decreased from 118.7 (interquartile range:100.7-137.1) ml at new baseline to 111.8 (IQR: 92.3-131.3) ml at latest follow-up. The interval time [ß: 1.36(0.71-2.01), P <0.001] and spectrum score [ß: 5.83 (2.92-8.74), P <0.001] were identified as independent predictors of ipsilateral RPV decrease rate. GFR fast decline was observed in 101 (27.5%) patients. Annual ipsilateral RPV decrease rate [odds ratio:1.67 (1.05-2.67), P =0.03] and overweight [odds ratio:1.63 (1.02-2.60), P =0.04] were independent predictors of GFR fast decline. CONCLUSIONS: Ipsilateral RPV experienced a moderate but significant decrease during follow-up after PN, especially in those with severer acute kidney injury. The presence of GFR fast decline was found to be associated with reduction of ipsilateral RPV, particularly in overweight individuals.

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.

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

Sex differences in renal cell carcinoma: a single-cell analysis reveals exhausted CD8+ T-cells highly infiltrated in males.

BACKGROUND: Although sex bias has been reported in the development and progression of renal cell carcinoma (RCC), the underlying mechanisms remain enigmatic. Here, we investigated the sex differences in the tumor microenvironment (TME) of RCC and explored a promising combination drug regimen to enhance the efficacy of immunotherapy. METHODS: Single-cell RNA sequencing (scRNA-seq) data from four published datasets were analyzed to investigate the sex differences in RCC patients, and tumor tissues were collected to validate the sex differences using multiplex immunofluorescence (MxIF) and flow cytometry (FCM). The function of the androgen-androgen receptor axis in sex differences was explored in vivo and in vitro experiments. RESULTS: Our analysis of scRNA-seq data from 220,156 cells, as well as MxIF and FCM assays, revealed that CD8+ T-cells infiltrated highly in the TME of male RCC, but were mostly in an exhausted and dysfunctional state. In vitro and in vivo experiments indicated that the dysfunction and exhaustion of CD8+ T-cells in male TME were induced by androgen. Clinically, higher serum androgen was significantly associated with a worse prognosis in male RCC patients receiving immunotherapy. Androgen receptor inhibitors could activate tumor-infiltrating CD8+ T-cells and enhance the efficacy of immunotherapy of RCC in vivo. CONCLUSIONS: Our study delineated the difference in TME between male and female patients with RCC, and demonstrated that the androgen-androgen receptor axis plays an important role in immunosuppression in male RCC. Our findings suggest that androgen receptor inhibitors in combination with immunotherapy may be a promising treatment option for male RCC patients.

Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) with a poor prognosis lacks reliable biomarkers for stratifying patients. Fas-associated death domain (FADD) could regulate cell proliferation and has shown promising diagnostic and prognostic significance in multiple cancers. However, researchers have not determined how FADD exerts its effect on PSCC. In this study, we set out to investigate the clinical features of FADD and the prognostic impact of PSCC. Additionally, we also assessed the role of affecting the immune environment in PSCC. Immunohistochemistry was carried out to evaluate the protein expression of FADD. The difference between FADDhigh and FADDlow was explored by RNA sequencing from available cases. The immune environment evaluation of CD4, CD8, and Foxp3 was performed by immunohistochemical. In this study, we found that FADD was overexpressed in 19.6 (39/199) patients, and the overexpression of FADD was associated with phimosis (p=0.007), N stage (p<0.001), clinical stage (p=0.001), and histologic grade (p=0.005). The overexpression of FADD was an independent prognostic factor for both PFS (HR 3.976, 95% CI 2.413-6.553, p<0.001) and OS (HR 4.134, 95% CI 2.358-7.247, p<0.001). In addition, overexpression of FADD was mainly linked to T cell activation and PD-L1 expression combined with PD-L1 checkpoint in cancer. Further validation demonstrated that overexpression of FADD was positively correlated with the infiltration of Foxp3 in PSCC (p=0.0142). It is the first time to show that overexpression of FADD is an adjunct biomarker with poor prognosis in PSCC and could also serve as a tumor immune environment regulator.

Association of computed tomography-based body composition with survival in metastatic renal cancer patient received immunotherapy: a multicenter, retrospective study.

OBJECTIVES: To investigate the association of computed tomography-assessed body composition with survival outcomes of metastatic renal cell carcinoma (mRCC) received immunotherapy. METHODS: In this multicenter, retrospective study, we reviewed 251 mRCC patients who received anti-PD1 from five centers. We analyzed the relationship between BMI, skeletal muscle area (SM), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and subcutaneous adipose percentage (SAT%) with progression-free survival (PFS) and overall survival (OS). The spatial localization T cells was investigated by multiplex immunofluorescence. RESULTS: Among 224 evaluable patients, 23 (10.3%) patients were underweight, 118 (52.7%) had normal weight, 65 (29%) were overweight, and 18 patients (8%) were obese. The median age was 55 years and most patients were male (71%). No significant improvement in PFS (HR, 0.61; 95% CI, 0.27-1.42) or OS (HR, 1.09; 95% CI, 0.38-3.13) was observed for the obese patients. Besides, SM, VAT, and SAT were not associated with survival outcomes (all p > 0.05). Interestingly, SAT% independently predicted PFS (as continuous variable, HR: 0.02; 95% CI, 0.01-0.11) and OS (HR:0.05; 95% CI, 0.01-0.39), which remained significant in multivariate modeling (as continuous variable, adjusted HR for PFS, 0.01; 95% CI, 0.00-0.04; adjusted HR for OS, 0.08; 95% CI, 0.01-0.72). These associations were consistent in subgroup analysis of different gender, BMI, PD-L1 positive, and sarcopenia group. Tumor of high SAT% patients had a higher intratumoral PD1+ CD8+ T cell density and ratio. CONCLUSION: High SAT% predicts better outcomes in mRCC patients treated with anti-PD1 and T cell location may account for the better response. KEY POINTS: • CT-based subcutaneous adipose percentage independently predicted progression-free survival and overall survival. • Patients with a higher subcutaneous adipose percentage had a higher intratumoral PD1+ CD8+ T cell density and ratio.

Perirenal Fat Thickness Significantly Associated with Prognosis of Metastatic Renal Cell Cancer Patients Receiving Anti-VEGF Therapy.

Although high body mass index (BMI) was reported to associate with a better prognosis for metastatic renal cell cancer (mRCC) patients receiving anti-vascular endothelial growth factor (anti-VEGF) therapy, it is an imperfect proxy for the body composition, especially in Asian patients with a lower BMI. The role of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and perirenal fat thickness (PRFT) in mRCC patients was still unknown. Therefore, a multicenter retrospective study of 358 Chinese mRCC patients receiving anti-VEGF therapy was conducted and their body composition was measured via computed tomography. We parameterized VAT, SAT and PRFT according to their median value and BMI according to Chinese criteria (overweight: BMI ≥ 24). We found VAT, SAT, and PRFT (all p < 0.05) but not BMI, significantly associated with overall survival (OS) and progression-free survival (PFS). Multivariate Cox analysis identified PRFT was the independent predictor of OS and PFS, and IMDC expanded with PRFT showed the highest C-index in predicting OS (OS:0.71) compared with VAT, SAT, and BMI. PRFT could increase the area under the curve of the traditional International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in OS (70.54% increase to 74.71%) and PFS (72.22% increase to 75.03%). PRFT was introduced to improve the IMDC model and PRFT-modified IMDC demonstrated higher AIC in predicting OS and PFS compared with the traditional IMDC model. Gene sequencing analysis (n = 6) revealed that patients with high PRFT had increased angiogenesis gene signatures (NES = 1.46, p = 0.04) which might explain why better drug response to anti-VEGF therapy in mRCC patients with high PRFT. The main limitation is retrospective design. This study suggests body composition, especially PRFT, is significantly associated with prognosis in Chinese mRCC patients receiving anti-VEGF therapy. PRFT-modified IMDC model proposed in this study has better clinical predictive value.

Nkx2.8 promotes chemosensitivity in bladder urothelial carcinoma via transcriptional repression of MDR1.

Multidrug resistance gene 1 (MDR1), a key factor contributing to drug insensitivity, has been associated with treatment failure and poor prognoses in various cancers, including bladder urothelial carcinoma (UC). Here we show that positive Nkx2.8 expression was associated with better prognosis of UC patients received chemotherapy. Patients with positive Nkx2.8 expression had promising prognosis from adjuvant chemotherapy. Enforced expression of Nkx2.8 promotes drug sensitivity of UC cells. Mechanistic investigations showed that Nkx2.8 negatively regulated expression of MDR1 by binds directly to the MDR1 promoter and transcriptionally represses MDR1 expression. P-gp inhibitor reversed chemosensitivity inhibition by Nkx2.8 scilencing. In clinical UC specimens, expression of Nkx2.8 inversely correlated with P-gp expression, and UC patients with Nkx2.8 positivity and low P-gp expression displayed the best prognosis. Our findings uncovered a new mechanism of chemosensitivity in UC cells and proposing Nkx2.8-MDR1 axis as a novel candidate target for therapeutic intervention of UC.

Role of Sam68 in Sunitinib induced renal cell carcinoma apoptosis.

Sunitinib is one of the first-line targeted drugs for metastatic renal cell carcinoma (RCC) with dual effects of antiangiogensis and proapoptosis. Sam68 (Src-associated in mitosis, 68 KDa), is found being involved in cell apoptosis. This article reveals that Sam68 impacts the sensitivity to sunitinib by mediating the apoptosis of RCC cells. Immunohistochemical staining indicated that the Sam68 expression levels in sunitinib sensitive tumor tissues were markedly higher than those in sunitinib resistant tumor tissues. Sunitinib induced RCC cell apoptosis in a concentration-dependent manner and inhibited the expression of total and phosphorylated Sam68 (p-Sam68). Downregulation of Sam68 expression inhibited RCC cell apoptosis induced by sunitinib. While upregulation of Sam68 expression could enhance apoptosis induced by sunitinib. Xenograft models showed that tumors in the Sam68-knockdown group did not shrink as much as those in the control group after treatment with sunitinib for 4 weeks. Together, our results suggest that Sam68 expression is associated with the sensitivity of ccRCC patients to sunitinib. Sam68 may promote cell apoptosis induced by sunitinib, and the Sam68 expression level may be a biomarker for predicting sunitinib sensitivity in ccRCC patients.

Immune checkpoint inhibitors further aggravate proteinuria in patients with metastatic renal cell carcinoma after long-term targeted therapy.

Background: Increasing number of patients with metastatic renal cell carcinoma (mRCC) are receiving subsequent programmed cell death protein-1 (PD-1) inhibitor combination therapy following tyrosine-kinase inhibitor (TKI) resistance. To explore whether PD-1 inhibitor would further deteriorate proteinuria and renal function, we observed their proteinuria's and renal function's condition since the administration of PD-1 inhibitor. Methods: To assess the change in proteinuria and renal function, the data of 141 patients with mRCC treated with TKI were collected, 66 of whom were further prescribed PD-1 inhibitor. Proteinuria and estimated glomerular filtration rate (eGFR) were measured and analyzed. Logistic regression models were established to identify the predictors of proteinuria deterioration and significant eGFR decline (≥15%). Results: Of the 141 patients, 74 (52%) had an increase in proteinuria level after an average of 22.98 months of TKI treatment. In multivariate analysis, longer duration of TKI (>12 months) and administration of PD-1 inhibitor were independent predictors for proteinuria deterioration. The median eGFR decreased from 81.56 mL/min/1.73 m2 to 66.75 mL/min/1.73 m2 after TKI treatment. Logistic regression identified older age (>60 years old) and longer duration of TKI (>12 months) as independent predictors for significant eGFR decline. Finally, of the 66 patients who received subsequent PD-1 inhibitor, 34 had sufficient proteinuria and eGFR data at follow-up. The level of proteinuria increased further after the administration of PD-1 inhibitor, although the decrease in eGFR was not statistically significant (P=0.182). Log-rank analysis identified proteinuria deterioration and eGFR decline were both significantly associated with patent's survival (P<0.001). Conclusions: Targeted therapy was associated with an increase in proteinuria level and a decrease in eGFR in patients with mRCC. The administration of PD-1 inhibitor contributed to exacerbation in proteinuria, but no significant difference in a decrease of eGFR was observed.

Single-cell transcriptomics reveals a low CD8+ T cell infiltrating state mediated by fibroblasts in recurrent renal cell carcinoma.

PURPOSE: Recurrent renal cell carcinoma(reRCC) is associated with poor prognosis and the underlying mechanism is not yet clear. A comprehensive understanding of tumor microenvironment (TME) of reRCC may aid in designing effective anticancer therapies, including immunotherapies. Single-cell transcriptomics holds great promise for investigating the TME, however, this technique has not been used in reRCC. Here, we aimed to explore the difference in the TME and gene expression pattern between primary RCC (pRCC) and reRCC at single-cell level. EXPERIMENTAL DESIGN: We performed single-cell RNA sequencing analyses of 32,073 cells from 2 pRCC, 2 reRCC, and 3 adjacent normal kidney samples. 41 pairs of pRCC and reRCC samples were collected as a validation cohort to assess differences observed in single-cell sequencing. The prognostic significance of related cells and markers were studied in 47 RCC patients underwent immunotherapy. The function of related cells and markers were validated via in vitro and in vivo experiments. RESULTS: reRCC had reduced CD8+ T cells but increased cancer-associated fibroblasts (CAFs) infiltration compared with pRCC. Reduced CD8+ T cells and increased CAFs infiltration were significantly associated with a worse response from immunotherapy. Remarkably, CAFs showed substantial expression of LGALS1 (Gal1). In vitro, CAFs could induce CD8+ T cells apoptosis via Gal1. In vivo, knockdown of Gal1 in CAFs suppressed tumor growth, increased CD8+ T cells infiltration, reduced the proportion of apoptotic CD8+ T cells and enhanced the efficacy of immunotherapy. CONCLUSIONS: We delineated the heterogeneity of reRCC and highlighted an innovative mechanism that CAFs acted as a suppressor of CD8+ T cells via Gal1. Targeting Gal1 combined with anti-PD1 showed promising efficacy in treating RCC.

What Happens to the Preserved Renal Parenchyma After Clamped Partial Nephrectomy?

BACKGROUND: Most partial nephrectomies (PNs) are performed with hilar occlusion to reduce blood loss and optimize visualization. However, the histologic status of the preserved renal parenchyma years after PN is unknown. OBJECTIVE: To compare the histologic chronic kidney disease (CKD) score of renal parenchyma before and years after PN, and to explore factors associated with CKD-score increase and glomerular filtration rate (GFR) decline. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 147 renal cell carcinoma patients who underwent PN and subsequent radical nephrectomy (RN) due to tumor recurrence was performed in 19 Chinese centers and Cleveland Clinic. Macroscopic normal renal parenchyma was evaluated at least 5 mm away from the tumor in PN specimens and at remote sites in RN specimens. INTERVENTION: PN/RN and ischemia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Histologic CKD score (0-12) represents a summary of glomerular/tubular/interstitial/vascular status. Predictive factors for a substantial increase of CKD score (≥3) were evaluated by logistic regression. RESULTS AND LIMITATIONS: Sixty-five patients with all necessary data were analyzed. The median interval between PN and RN was 2.4 yr. Median durations of warm ischemia (n = 42) and hypothermia (n = 23) were both 23 min. The histologic CKD score was increased after RN in 47 (72%) patients, with 29 (45%) experiencing more substantial increase (≥3). There was no significant difference in the change of CKD score related to the type and duration of ischemia (p = 0.7 and p = 0.4, respectively) or interval from PN to RN (p > 0.9). However, patients with comorbidities of hypertension, diabetes, and/or pre-existing CKD (hypertension [HTN]/diabetes mellitus [DM]/CKD) demonstrated increased rate and extent of CKD-score increase. On univariate analysis, HTN/DM/CKD was the only predictor of a substantial CKD-score increase (odds ratio: 3.53 [1.12-11.1]). Decline of GFR was modest and similar between patients with/without a substantial CKD-score increase. CONCLUSIONS: Within the context of conventional, limited durations of ischemia, histologic deterioration of preserved parenchyma after PN appears to be primarily due to pre-existing medical comorbidities rather than ischemia. A subsequent decline in renal function was mild and independent of histologic changes. PATIENT SUMMARY: After clamped PN, the preserved renal parenchyma demonstrated histologic deterioration in many cases, which correlated with the presence of comorbidities such as hypertension, diabetes mellitus, or chronic kidney disease. In contrast, the type and duration of ischemia did not correlate with histologic changes after PN, suggesting that ischemia insult had only limited impact on parenchyma deterioration.

Ureteral stents cannot decrease the incidence of ureteroileal anastomotic stricture and leakage: A systematic review and meta-analysis.

BACKGROUND: The ileal conduit and ileal orthotopic neobladder were the most popular methods for urinary diversion following radical cystectomy. Stenting the anastomosis of ileo-ureter or ureter-neobladder was a common practice. However, it is still controversial if ureteral stents could prevent complications such as ureteroileal anastomosis stricture (UIAS) and ureteroileal anastomosis leakage (UIAL) after ureteral anastomosis. OBJECTIVES: This study aims to investigate the role of the ureteral stent in preventing UIAS and UIAL. DATA SOURCES: We systematically searched the related studies in PubMed, Embase, and Cochrane Library up to June 2020. STUDY ELIGIBILITY CRITERIA: Cohort studies that identified the use of stent and the incidence of UIAS or UIAL were recorded. DATA SYNTHESIS: Comparative meta-analysis was conducted on four cohort studies for comparison of UIAS and UIAL between the stented and nonstented groups. Besides, eleven studies which reported the events of UIAS and UIAL were used for meta-analysis of single proportion. RESULTS: A total of 11 studies were qualified for analysis. Comparative meta-analysis identified that the incidence of UIAS was higher in the stented group than that in the nonstented group, but this did not reach a significant difference (odds ratio [OR]: 1.64; 95% confidence interval [CI]: 0.88-3.05; P = 0.12). Besides, there was no difference in the incidences of UIAL between the stented and the nonstented groups. On meta-analysis of single proportion, the incidence of UIAS was 7% (95% CI: 3%-10%) in the stented group and 3% (95% CI: 1%-6%) in the nonstented group. The UIAL rate was 1% (95% CI, 0%-4%) in stented patients and 2% (95% CI, 1%-4%) in nonstented patients. CONCLUSION: Stenting the ureteroileal anastomosis resulted in a higher incidence of UIAS. There is no evidence to support ureteral stents could prevent the occurrence of UIAL after urinary diversion.

Neoadjuvant combination of pazopanib or axitinib and programmed cell death protein-1-activated dendritic cell-cytokine-induced killer cells immunotherapy may facilitate surgery in patients with renal cell carcinoma.

BACKGROUND: Radical/cytoreductive nephrectomy or nephron-sparing surgery may be thought to be not safe or unfeasible in some renal cell carcinoma (RCC) patients in which tumor is locally advanced or highly complicated. Neoadjuvant therapy may reduce the volume of the tumor, thus facilitates surgery. The aim the study is to evaluate the efficacy and safety of neoadjuvant combination of pazopanib or axitinib and PD-1-activated dendritic cell-cytokine-induced killer (PD-1/DC-CIK) cell immunotherapy in those patients. METHODS: Data from 16 RCC patients who received neoadjuvant pazopanib (Group P, n=9) or axitinib (Group A, n=7) plus PD-1/DC-CIK cells immunotherapy were reviewed retrospectively. A total of 9 participants that were potential candidates for radical/cytoreductive nephrectomy (RN/CN) had locally advanced tumor and 5 participants with partial nephrectomy (PN) absolute indications had highly complicated tumors. The efficacy outcomes were based on volume changes of the primary tumor, lymph nodes, and tumor thrombus in 13 participants with complete computed tomography (CT) imaging. The treatment-related toxicities and surgical complications were also reported. RESULTS: With a median of 2.1 months treatment, the overall volume of the tumors decreased by a median of 42.30% [interquartile range (IQR): 19.37-66.78%]. Specifically, the median reduction of tumor volume was 88.77 and 15.50 cm3 in group P and group A, respectively (P=0.014). However, participants in Group P were more likely to experience grade 3 or 4 treatment-related adverse events (AEs) than those in Group A (44.4% vs. 0). Finally, all participants were candidates for appropriate surgery after neoadjuvant therapy (as assessed by the surgeon), and 10 participants accepted surgery, including 5 PN, 4 RN/CN, and 1 lymph node dissection. A solitary participant had Clavien grade IV acute renal failure required dialysis and another had grade II lymphatic leakage. CONCLUSIONS: Neoadjuvant combination of pazopanib or axitinib and PD-1/DC-CIK cells immunotherapy was well-tolerated and could effectively reduce the volume of tumors in locally advanced or highly complicated RCC patients.

Prognostic significance of tumor-infiltrating immune cells in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) is a lethal disease with poor treatment response and a high death rate. Immune cells infiltrating the tumor tissues have been shown to play a vital role in tumorigenesis and tumor progression, but their prognostic significance in MIBC remains unclear. OBJECTIVES: To explore the landscape and prognostic significance of tumor-infiltrating immune cells (TIICs) in MIBC, and to develop a model to improve the prognostic predictions of MIBC. METHODS AND MATERIALS: The gene expression profile and clinical data of MIBC patients were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas portal. The fractions of 22 TIIC subtypes were calculated using the Cell Type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm. A TIICs-based model was constructed using least absolute shrinkage and selection operator (LASSO) Cox regression in a training cohort and validated in the validation cohort. RESULTS: Ten types of TIICs demonstrated different infiltration abundance between MIBC and normal tissue. We also found 11 types of TIICs that were significantly associated with overall survival (OS). A TIICs-based model was established, consisting of 15 types of immune cells, and an immunoscore was calculated. Significant differences in OS were found between the high and low immunoscore groups, in both training (n = 343) and validation (n = 146) cohorts. The model could identify patients who would have worse OS despite having similar clinical characteristics. Furthermore, multivariate analysis identified the immunoscore as an independent risk factor (hazard ratio, 3.23; 95% confidence interval; 2.22-4.70) for OS in MIBC patients. CONCLUSION: The landscape of immune infiltration is different between MIBC and normal tissue. The TIICs-based model could provide promising predictive value to complement the existing staging system for predicting the OS of MIBC patients.

Acetyl-11-keto-ß-boswellic acid attenuates titanium particle-induced osteogenic inhibition via activation of the GSK-3ß/ß-catenin signaling pathway.

Rationale: Peri-prosthetic osteolysis (PPO) is mainly induced by wear particles and represents the leading cause of implant failure and revision surgery. Previous studies have identified mitigation of wear particle-induced inflammation and bone resorption as the main approaches to treat PPO. Recently, wear particle-induced reduction of bone formation around the prosthesis was identified as a major factor in the development of PPO. Acetyl-11-keto-ß-boswellic acid (AKBA), a derivative of frankincense, has been shown to play a potential role in bone metabolism. However, whether AKBA enhances bone formation in wear particle-induced osteolysis remains unknown. In this study, we examined whether AKBA attenuates titanium particle-induced osteogenic reduction. Methods: Titanium particles were used to induce osteolysis in murine calvaria, and micro-CT and histological analyses were used to evaluate the results. Mouse osteoblast cells, MC3T3-E1 were co-cultured with titanium particles to determine their effect on osteoblast formation in vitro. Results: We demonstrated that AKBA treatment significantly inhibited titanium particle-induced osteogenic inhibition by enhancing osteogenesis both in vivo and in vitro. AKBA treatment also enhanced the phosphorylation of GSK-3ß, decreased the degradation of ß-catenin, and increased the translocation of ß-catenin from the cytoplasm to the nucleus. Taken together, these results showed that AKBA treatment attenuated titanium-induced osteogenic inhibition by activating the GSK-3ß/ß-catenin signaling pathway. Conclusion: These findings suggest that AKBA is a promising new target in the prevention and treatment of PPO.