MarR-Dependent Transcriptional Regulation of mmpSL5 Induces Ethionamide Resistance in Mycobacterium abscessus.

Mycobacterium abscessus (Mabs) is an emerging nontuberculosis mycobacterial (NTM) pathogen responsible for a wide variety of respiratory and cutaneous infections that are difficult to treat with standard antibacterial therapy. Mabs has a high degree of both innate and acquired antibiotic resistance to most clinically relevant drugs, including standard anti-mycobacterial agents. Ethionamide (ETH), an inhibitor of mycolic acid biosynthesis, is currently utilized as a second-line agent for treating multidrug-resistant tuberculosis infections. Here, we show that ETH displays activity against clinical strains of Mabs in vitro at concentrations that are >100× lower than other mycolic acid targeting drugs. Using transposon mutagenesis followed by transposon sequencing (Tn-Seq) and whole-genome sequencing of spontaneous ETH-resistant mutants, we identified MAB_2648c as a genetic determinant of ETH sensitivity in Mabs. MAB_2648c encodes a MarR family transcriptional regulator of the TetR class of regulators. We show that MAB_2648c represses expression of MAB_2649 (mmpS5) and MAB_2650 (mmpL5). Further, we show that derepression of these genes in MAB_2648c mutants confers resistance to ETH, but not other antibiotics. To identify determinants of resistance that may be shared across antibiotics with distinct mechanisms of action, we also performed Tn-Seq during treatment with amikacin and clarithromycin, drugs currently used clinically to treat Mabs. We found very little overlap in genes that modulate the sensitivity of Mabs to all three antibiotics, suggesting a high degree of specificity for resistance mechanisms in this emerging pathogen.

The Role of Mesenchymal Stem Cells and Exosomes in Tumor Development and Targeted Antitumor Therapies.

Mesenchymal stem cells (MSCs) can be isolated from various tissues in adults and differentiated into cells of the osteoblasts, adipocytes, chondrocytes, and myocytes. Recruitments of MSCs towards tumors have a crucial contribution to tumor development. However, the role of MSCs in the tumor microenvironment is uncertain. In addition, due to its tropism to the tumor and low immunogenic properties, more and more pieces of evidence indicate that MSCs may be an ideal carrier for antitumor biologics such as cytokines, chemotherapeutic agents, and oncolytic viruses. Here, we review the existing knowledge on the anti- and protumorigenic effect of MSCs and their extracellular vesicles and exosomes, the role of MSCs, and their extracellular vesicles and exosomes as antitumor vectors.

Patency outcomes of primary inferior vena cava repair in radical nephrectomy and tumor thrombectomy.

OBJECTIVE: The reconstruction of inferior vena cava (IVC) during radical nephrectomy and venous tumor thrombectomy (RN-VTT) is mostly performed with primary repair or with a patch/graft. We sought to systematically evaluate the outcomes of IVC patency over short- to intermediate-term follow-up for patients undergoing primary repair of IVC and to assess the association with survival. METHODS: A retrospective review of patients undergoing RN-VTT between January 2013 and August 2018 was conducted. Patients were followed until death, last available follow-up, or March 2022. The patency outcomes and IVC diameters were studied using follow-up cross-sectional imaging. The χ2 test, Student t test, and Kaplan-Meier survival analysis were used. RESULTS: Seventy-seven patients were included. The mean age was 59.2 ± 12.2 years and 45.4% had Mayo classification level III thrombus or higher. At a median follow-up of 36.5 months (13.3-60.7 months), the 3-year overall survival (OS) was 64%. Sixty patients underwent primary repair of the IVC and 48 of these patients were assessed for IVC patency. Ten patients (20.8%) developed caval occlusion, either from recurrent tumor (8.3%), new-onset bland thrombus (8.3%), or stenosis (4.2). The IVC patency seemed to be a significant predictor of OS (hazard ratio, 2.85; P = .021). Although the IVC diameters decreased significantly at the 3-month postoperative scan at the infrarenal (P = .019), renal (P < .001), and suprarenal (P < .001) levels, they did not decrease further on long-term follow-up imaging. CONCLUSIONS: IVC reconstruction with primary repair results in an overall patency rate of 80.2% with only a 4.0% rate of stenosis. Recurrence of tumor thrombus (8.3%) or bland thrombus (8.3%) are the predominant reasons for IVC occlusion after RN-VTT, and this outcome is associated with poor OS.

Corrigendum: Mini-percutaneous nephrolithotomy with an endoscopic surgical monitoring system for the management of renal stones: A retrospective evaluation.

[This corrects the article DOI: 10.3389/fsurg.2022.773270.].

Mini-Percutaneous Nephrolithotomy With an Endoscopic Surgical Monitoring System for the Management of Renal Stones: A Retrospective Evaluation.

Purpose: To compare the outcomes and postoperative quality of life of patients with renal calculi who underwent standard percutaneous nephrolithotomy (sPNL), mini-invasive percutaneous nephrolithotomy (mPNL) or mPNL with an endoscopic surgical monitoring system (ESMS) using a retrospective clinical trial. Methods: Eighty-six adult patients with renal stones who were treated with sPNL were retrospectively compared to ninety-two patients who were treated with mPNL between July 2014 and December 2017. Next, further studies were retrospectively conducted using a matched paired method. The ninety-two patients treated with mPNL were divided into two groups based on whether the endoscopic surgical monitoring system (ESMS) was used (ESMS-mPNL vs. non-ESMS-mPNL). The ESMS used strain gauge transducers to measure the inflow and outflow of irrigation solution. Bleeding and fluid absorption during endoscopic surgery could be accurately calculated by computer program in ESMS. Results: The fluoroscopy time, complication rate, stone-free status and clinically insignificant residual fragment (CIRF) rate were not significantly different between the two groups (sPNL vs. mPNL). The mPNL group had a significantly longer operation time than the sPNL group, and the mPNL group exhibited a markedly reduced 12-h postoperative visual analogue pain scale (VAS) score, mean hospitalization time, and return to work time, had slightly reduced haemoglobin loss, and underwent more tubeless operations. Moreover, among the 92 patients who underwent mPNL, the operation time (P = 0.090), complication rate (P = 0.996), stone-free status (P = 0.731), CIRF rates (P = 0.125) and number of tubeless operations (P = 0.760) were not significantly different between the two subgroups (non-ESMS-mPNL vs. ESMS-mPNL); however, the patients in the ESMS-mPNL group had significantly longer operation times than those in the non-ESMS-mPNL subgroup, along with marked reductions in irrigation fluid absorption, blood loss, haemoglobin loss, 12 h postoperative VAS score, mean hospitalization time, and return to work time. Conclusions: mPNL is less painful than sPNL in patients undergoing treatment for 20-40 mm renal stones. Similar stone-free rates were achieved by the two procedures, but mPNL was superior to sPNL in terms of blood loss, discomfort, hospitalization time and return to work time. We think that ESMS-mPNL is less painful for patients and more efficacious than non-ESMS-mPNL, and ESMS-mPNL achieves a stone-free rate that is similar to non-ESMS-mPNL in patients receiving treatment for 20-40 mm kidney stones.

The Latinx Disparity in Surgery for Kidney Cancer: Data from The South Texas Region.

The South Texas region, with a predominantly Latinx population, has a very high incidence of renal cell carcinoma (RCC), including those with tumor extending into the major blood vessels called venous tumor thrombus (VTT). There is currently no data on outcomes of Latinx patients with VTT as most published studies are from predominantly Caucasian population. Therefore, we performed this study to fill an urgent, unmet need. We reviewed patients who underwent radical nephrectomy with removal of VTT (called tumor thrombectomy) between 2015 and 2020. We collected data on demographics, clinical, pathological characteristics and outcomes of patients. Univariate and multivariate Cox regression analyses were used to evaluate the associations between ethnicity and disease progression or survival. We identified 112 patients, of which 67 (62%) were Latinx, and 41 (38%) were non-Latinx. Approximately 60% of patients had Level II-IV VTT; Latinx presented with a higher level of tumor thrombus (p=0.046). Latinx patients had a higher rate of no insurance (11% vs. 27%, p=0.04) and were more likely to lost to follow-up after surgery (22.4% vs. 13.3%, p=0.23) compared to non-Latinx. Fewer Latinx received systemic therapy (28% vs. 42%; p=0.13). Ninety-day mortality for the entire cohort was 3.8%. The Latinx population in the South Texas region present late, with advanced thrombus level, and do not have access to systemic therapy. Given symptomatic disease, surgical treatment, if feasible, is their only option. Our results highlight disparate treatment patterns which require further investigation and health-care policy changes.

Homologous Recombination Related Signatures Predict Prognosis and Immunotherapy Response in Metastatic Urothelial Carcinoma.

Objective: This study used homologous recombination (HR) related signatures to develop a clinical prediction model for screening immune checkpoint inhibitors (ICIs) advantaged populations and identify hub genes in advanced metastatic urothelial carcinoma. Methods: The single-sample gene enrichment analysis and weighted gene co-expression network analysis were applied to identify modules associated with immune response and HR in IMvigor210 cohort samples. The principal component analysis was utilized to determine the differences in HR-related module gene signature scores across different tissue subtypes and clinical variables. Risk prediction models and nomograms were developed using differential gene expression analysis associated with HR scores, least absolute shrinkage and selection operator, and multivariate proportional hazards model regression. Additionally, hub genes were identified by analyzing the contribution of HR-related genes to principal components and overall survival analysis. Finally, clinical features from GSE133624, GSE13507, the TCGA, and other data sets were analyzed to validate the relationship between hub genes and tumor growth and mutation. Results: The HR score was significantly higher in the complete/partial response group than in the stable/progressive disease group. The majority of genes associated with HR were discovered to be involved in the cell cycle and others. Genomically unstable, high tumor level, and high immune level samples all exhibited significantly higher HR score than other sample categories, and higher HR scores were related to improved survival following ICIs treatment. The risk scores for AUNIP, SEPT, FAM72D, CAMKV, CXCL9, and FOXN4 were identified, and the training and verification groups had markedly different survival times. The risk score, tumor neoantigen burden, mismatch repair, and cell cycle regulation were discovered to be independent predictors of survival time following immunotherapy. Patients with a high level of expression of hub genes such as EME1, RAD51AP1, and RAD54L had a greater chance of surviving following immunotherapy. These genes are expressed at significantly higher levels in tumors, high-grade cancer, and invasive cancer than other categories, and are associated with TP53 and RB1 mutations. Conclusion: HR-related genes are upregulated in genomically unstable samples, the survival time of mUC patients after treatment with ICIs can be predicted using a normogram model based on HR signature.

Aldehyde dehydrogenase 6 family member A1 negatively regulates cell growth and to cisplatin sensitivity in bladder cancer.

Aldehyde dehydrogenase 6 family member A1 (ALDH6A1) is a highly conserved member of aldehyde dehydrogenase (ALDHs) family. Recent studies reveal that it broadly involved in tumorigenesis and drug metabolism in kinds of cancer. However, the critical role of ALDH6A1 in bladder cancer progression and cisplatin resistance of cancer cells are still poorly understood. In this study, we researched the significant function of ALDH6A1 in bladder cancer. Our results showed that ALDH6A1 exhibited a decreased expression in clinical bladder cancer tissues and bladder cancer cell lines. Stable ALDH6A1 knockdown not only could promote cell growth and colony formation in bladder cancer cells, but also enhance drug resistance to cisplatin treatment. On the contrary, we found the active transcript factor hepatocyte nuclear factor 4α (HNF4α, NR2A1) by alveriene could upregulate ALDH6A1 expression, significantly inhibit the cell growth and colony formation of bladder cancer cells, and improve cisplatin sensitivity of bladder cancer cells. Together, our results show that ALDH6A1 plays as a tumor suppressor in bladder cancer, which regulated by HNF4a. ALDH6A1 could be a promising diagnostic marker and treatment target in bladder cancer.

Survival after minimally invasive vs. open radical nephrectomy for stage I and II renal cell carcinoma.

BACKGROUND: A recently reported phase III randomized trial comparing open and minimally invasive hysterectomy showed significantly higher rates of local recurrence after minimally invasive surgery (MIS) for cervical cancer. This raised concerns regarding patterns of recurrences and survival after MIS in general. This study aims to determine the effect of MIS on all-cause mortality among patients undergoing radical nephrectomy for Stage I and II renal cell carcinoma (RCC). METHODS: We utilized the National Cancer Database to identify patients diagnosed with clinical stage I-II RCCs between 2010 and 2013. Patients for whom a laparoscopic or robotic radical nephrectomy was attempted were compared to patients who underwent open radical nephrectomy (ORN). Adjusted regression models with inverse probability propensity score weighting (IPW) were utilized to identify independent predictors of receiving MIS. All-cause mortality rates were compared using IPW survival functions and log-rank tests. Adjusted Cox proportional hazard models were fitted to determine independent predictors of OS. RESULTS: 27,642 patients were identified; 11,524 (41.7%) had MIS, while 16,118 (58.3%) had ORN. Kaplan-Meier survival curves in the IPW cohort showed significant OS advantage for patients who underwent MIS (p < 0.001). Furthermore, length of hospital stays (3 vs. 4 days), 30 day readmission rates (2.4 vs. 2.87%), 30 day (0.53 vs. 0.96%) and 90 day mortality rates (1.04 vs. 1.77%) were significantly higher in the ORN group (p < 0.001). CONCLUSIONS: MIS was associated with better OS outcomes compared to ORN for stage I and II RCC. In addition, MIS had lower post-operative readmission, 30- and 90 day mortality rates.

RNA sequencing in a penile cancer cohort: an investigation of biomarkers of cisplatin resistance and potential therapeutic drug targets.

OBJECTIVE: Chemoresistance in distant micrometastatic lesions may account for diminished durable response rates in advanced penile cancer. However, there are limited studies on new therapeutic targets and the identification of biomarkers that predict chemotherapy response in this population. Thus, we examine the expression of candidate biomarkers of cisplatin resistance, ERCC1 and E2F1, and perform next-generation sequencing on the cancer transcriptome in a penile cancer cohort. MATERIALS AND METHODS: In this retrospective cohort study, we identified 71 patients treated for penile squamous cell carcinoma between 2009 and 2019. Immunohistochemistry staining for ERCC1 and E2F1 was performed. H-scores were measured for patient specimens obtained from adjacent normal skin, primary tumor and metastatic lymph node specimens and correlated with RNA expression data obtained through next-generation sequencing. RESULTS: Of the 71 patients identified, 51 and 8 had available surgical specimens for immunohistochemistry and RNA sequencing, respectively. Median H-scores for ERCC1 in adjacent normal skin, primary and metastatic tumors were 17.04, 3.15, and 7.9 respectively compared to E2F1 (43.95, 15.54, 7.9). The median H-score for E2F1 was higher in poorly differentiated primary tumors (24.86) compared to well (7.62) and moderately differentiated (9.55, p = 0.055). Next generation sequencing showed no difference in RNA expression of E2F1 nor ERCC1 between primary tumors and metastatic lesions however did demonstrate elevated RNA expression of genes such as MMP1, and MMP10 in primary tumors compared to adjacent normal skin. CONCLUSION: We identify potential drug targets for metastatic penile cancer through next-generation RNA sequencing.

Impact of facility type and volume on survival in patients with metastatic renal cell carcinoma.

INTRODUCTION: To investigate the impact of facility type and volume on survival in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: We investigated the National Cancer Database for patients with mRCC. Patients were stratified according to treatment facility type (academic vs. non-academic) and facility volume (high, intermediate, and low). Kaplan-Meier survival estimates and Cox proportional hazard models were fitted to evaluate overall survival (OS) as a function of facility type, volume, and different treatment modalities. RESULTS: A total of 27,598 patients were identified, of which 10,938 (40%) were treated at academic centers (AC) and 16,131 (60%) at non-academic centers (non-AC). Overall, 19,904 patients (72%) were treated in high-volume hospitals (HVH). Among patients treated at AC, 94% were treated at HVHs. Patients treated at AC were more likely to receive immunotherapy, undergo cytoreductive nephrectomy (CN) and metastasectomy. The 2 and 5 year OS rates for patients treated in AC were 29.7% (CI 28.8%-30.6%) and 13% (CI 12%-14%) vs. 21.7% (CI 21%-22.4%) and 8.4% (CI %7.91-%8.99) in the Non-AC, respectively (p < 0.001). Multivariate Cox regression analysis identified treatment at AC as an independent predictor of survival (HR 0.85, 95% CI 0.81-0.91, p < 0.001). Undergoing CN and receipt of immunotherapy was also associated with a survival benefit (HR 0.41, CI 0.40-0.43 and HR 0.63, CI 0.59-0.68 respectively, p < 0.001). CONCLUSIONS: Treatment at ACs and HVHs was associated with a survival benefit in patients with mRCC. Patients treated at AC were more likely to receive immunotherapy, undergo CN and metastasectomy.

Y-Box Binding Protein 1 Regulates Angiogenesis in Bladder Cancer via miR-29b-3p-VEGFA Pathway.

Angiogenesis plays a vital role in the development of bladder cancer (BC). The Y-box-binding protein 1 (YB-1) is a well-known oncoprotein which is closely related to angiogenesis of tumors, but the relationship and mechanism of YB-1 and angiogenesis in BC remain unclear. Based on 56 clinical BC specimens, this study found that high expression of YB-1 samples demonstrated a higher expression of vascular endothelial growth factor A (VEGFA) than those of YB-1 low expression. Subsequently, the expression of YB-1 and miR-29b-3p was regulated in the BC cell lines where we noted that YB-1 promoted VEGFA expression by downregulating the expression of miR- 29b-3p. The ability of BC cells to induce angiogenesis decreased after YB-1 was knocked down. Moreover, the in vivo study further confirmed that YB-1 promotes angiogenesis in BC. Our findings enhance the understanding of how YB-1 promotes angiogenesis in BC and provide evidence for YB-1 as a therapeutic target of BC. Moreover, this may provide new inspiration for miRNAs replacement therapies.

Prognostic value of preoperative inflammation-based predictors in patients with bladder carcinoma after radical cystectomy.

AIMS: Emerging evidence has related inflammation-based biomarkers to numerous carcinomas, including bladder carcinoma (BC). However, the role of inflammatory biomarkers in the prognosis of BC remains inconclusive. This study aimed to compare preoperative plasma fibrinogen (PF) and other inflammatory biomarkers such as the platelet-lymphocyte ratio (PLR), neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), C-reactive protein (CRP) level, and serum albumin level to predict the prognosis of patients with BC. METHODS: This article focused on a retrospective analysis of 175 patients with newly diagnosed BC who were admitted to our hospital from March 2005 to March 2016. Of these BC patients, 136 had undergone radical cystectomy (RC). RESULTS: According to multivariate analysis, high PF level was an independent predictor of overall survival (OS) in 136 BC patients receiving RC (HR = 3.759; P = 0.011), but not for all 175 BC patients. Combining the NLR and PF values showed higher predictive accuracy for OS than NLR or PF alone (P < 0.05). Additionally, for 136 BC patients who had undergone RC, a close relationship was found between high PF levels (≥3.39 g/L) and lymph node metastasis (P = 0.011) and clinical T stage (P = 0.015). Furthermore, PF was a superior prognostic factor compared with the LMR, PLR, CRP, and albumin values in 136 BC patients who had undergone RC (P < 0.001). CONCLUSIONS: The preoperative PF level may be a prognostic biomarker; and when combined with the NLR, it can improve the predictive ability of the survival of BC patients, particularly of BC patients who underwent RC.

FOXO3A Expression in Upper Tract Urothelial Carcinoma.

BACKGROUND: Epidemiological studies have reported various results regarding whether FOXO3A is related to various carcinomas. However, the prognostic significance of FOXO3A in upper tract urothelial carcinoma (UTUC) remains unclear. The purpose of this study was to validate the correlation between FOXO3A expression and oncological outcomes in UTUC. METHODS: The expression levels of FOXO3A in 107 UTUC patients were examined by immunohistochemistry (IHC). We examined the prognostic role of FOXO3A by using the Cox proportional hazard model. RESULTS: The results indicated that FOXO3A expression was notably decreased in UTUC tissue compared with control tissue. Decreased expression of FOXO3A was also related to advanced pathologic stage (P = 0.026), lymph node metastasis (P = 0.040), lymphovascular invasion (P < 0.001), and adjuvant therapy (P = 0.048). In addition, UTUC patients with low FOXO3A expression had a significantly shorter survival time, including both overall survival (OS) [hazard ratio (HR) 2.382, P = 0.004] and recurrence-free survival (RFS) (HR 2.385, P = 0.004), than those with high expression. Multivariate analyses showed that FOXO3A was a significant predictor for OS (HR 2.145, P = 0.014) and RFS (HR 2.227, P = 0.010) in UTUC patients. CONCLUSION: Our results indicate that FOXO3A may be involved in the recurrence of UTUC and that it has certain clinical value in the therapeutic targeting and prognostic evaluation of UTUC.

Association of TERT gene polymorphisms with clinical benign prostatic hyperplasia in a Chinese Han population of the Northwest region.

BACKGROUND: To investigate the association between single nucleotide polymorphisms (rs10078761, rs12696304, rs2853669, rs16847897, rs2736100, rs10069690) of telomerase gene (TERT) and the risk clinical benign prostatic hyperplasia (BPH) in a Chinese Han population of the Northwest region. METHODS: A total of 150 BPH patients and 150 healthy older males from the northwest Chinese Han population were included in this study. The sample size for this unmatched case-control study was estimated by the look-up table method. Meanwhile, the general information and disease data of patients were collected. Age was only collected in healthy control subjects for statistical correction. Genotypes were detected using a multiplex PCR + ligase detection reaction (LDR). Typing results and clinical data were statistically analyzed using multiple linear regression and logistic regression. Pearson correlation was used for Hardy-Weinberg equilibrium. RESULTS: The included population is in Hardy-Weinberg equilibrium. There was no significant association between SNP and the risk of BPH by correlation analysis. However, 4 haplotypes (TCTGGT, TCTGTC, TGCCTC, and TGTGTC) were identified as risk factors of BPH by haplotype analysis. The SNP rs2853669 is an independent risk factor for smooth muscle type of hyperplasia. Besides, rs2736100, rs10078761, and rs10069690 which are in linkage disequilibrium are associated with the severity of BPH. CONCLUSIONS: Polymorphism of the TERT gene determines the different disease development and pathological manifestations of BPH in the Chinese Han population the Northwest region.

Diagnostic and prognostic role of BTA, NMP22, survivin and cytology in urothelial carcinoma.

BACKGROUND: Cytology is a recommended noninvasive urine test for the detection and surveillance of bladder cancer and upper-tract urothelial carcinoma. It is however characterized by poor sensitivity in low-grade tumors. This study aims to determine the diagnostic and prognostic role of BTA, BTA-stat, NMP22, and Survivin. METHODS: Urine samples were collected from a total of 105 patients (bladder cancer (n=61), upper-tract urothelial carcinoma (n=44), and controls (n=52). The samples were directly assessed using cytology, BTA-stat (Qualitative test), BTA (chemiluminescence test), NMP22 (Qualitative test), and Survivin (enzyme-linked immunosorbent assay). Cancer progression and recurrence were assessed after a median follow-up of 32 months (4-47 months). Univariate and multivariate analyses were performed using Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: The triple combination of Survivin + BTA + Cytology was the most promising model for discriminating bladder cancer or upper-tract urothelial carcinoma from controls (UTUC group: the area under the curve value 0.97, sensitivity 86%, specificity 96%; BC group: the area under the curve value 0.86 sensitivity 67%, specificity 96%). Univariate survival analysis, showed Cytology (P=0.02; HR=5.35) and Survivin (HR=3.24; P=0.03) to have a significant association with the progression-free survival, while Survivin (HR=4.15; P=0.04) was statistically associated with cancer-specific survival in the bladder cancer group. The multivariable analysis did not show any of these markers as independent prognostic factors. CONCLUSIONS: These biomarkers showed a higher sensitivity than cytology, but a poorer specificity. All biomarkers exhibited good diagnostic performance in both bladder cancer and upper-tract urothelial carcinoma. Combining Survivin + BTA + Cytology was superior to the use of a single marker or combining other biomarkers.

The utilization status of neoadjuvant chemotherapy in muscle-invasive bladder cancer: a systematic review and meta-analysis.

INTRODUCTION: To give a comprehensive depiction of the utilization status of neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC) worldwide. EVIDENCE ACQUISITION: Potential relevant research papers of Pubmed, Embase, Web of Science, and the Cochrane Library were reviewed to identify eligible studies. Primary outcomes of this meta-analysis were utilization rate of NAC and its utility distribution in different genders, races, ages, countries and temporal trends. The utilization rates of NAC were calculated as 'Proportion (s)' with 95% confidence intervals (CIs) and pooled estimates were calculated by using a random-effect model. EVIDENCE SYNTHESIS: A total of thirteen studies and 35,738 patients were included. The total proportion of NAC applied in MIBC populations prior to radical cystectomy (RC) was 17.2% (95% CI: 12.5-21.9%, I2=99.7%). The comparative analyses showed there were no significant differences existing in different genders or races on NAC utilization rates. In terms of age distribution, <60 age group conferred higher utilization rate of NAC than the older (OR=1.919, 95% CI: 1.671-2.202, P=0.0001). As for regional distribution, our meta-analysis showed that Japan (Proportion: 44.0%, 95% CI: 6.5-81.5%, I2=99.6%) and Sweden (37.9%, 95% CI: 34.9-40.8%) were the top two leading countries which contributed to the most frequent application of NAC. In respect of pathologic responses after NAC, complete, partial and down-staged pathologic responses were achieved in 16.6% (95% CI: 7.4-25.9%, I2=89.7%), 14.6% (95% CI: 0.8-28.5%, I2=89.7%) and 45.0% (95% CI: 17.8-72.2%, I2=98.8%) patients, respectively. CONCLUSIONS: The present study shows the low utilization rate of NAC in MIBC patients. Standardization of the treatment modality of MIBC and promotion of guidelines might be necessary to expedite the adoption of NAC in near future.

Analyzing National Incidences and Predictors of Open Conversion During Minimally Invasive Partial Nephrectomy for cT1 Renal Masses.

Objectives: To analyze predictors of open conversion during minimally invasive partial nephrectomy (MIPN) for cT1 renal masses. Methods: The National Cancer Database (NCDB) was investigated for kidney cancer patients who underwent partial nephrectomy (PN) between 2010 and 2015. Patients who underwent MIPN were stratified into converted and nonconverted groups. Sociodemographics, facility characteristics, and surgical outcomes were compared between the two groups, and multivariate logistic regression model was fitted to identify independent predictors of open conversion. Results: In total, 54,246 patients underwent PN for kidney cancer during the 6-year period. Of those, 18,994 (35%) were open partial nephrectomies (OPNs) and 35,252 (64%) were MIPN. Overall, 1010 (2.87%) of MIPNs were converted to OPN. There was an increasing utilization of MIPN from 50.35% in 2010 to 74.73% in 2015. Patients who had open conversion had more 30-day readmissions (5.95% vs 3.31%, p < 0.01). On multivariate analysis; high-volume facility (>30 MIPNs/year), year of surgery (2015 vs 2010), and robotic approach predicted a lower likelihood of conversion (odds ratio [OR] 0.52, confidence interval [CI] 0.44-0.62; OR 0.59, CI 0.47-0.73; and OR 0.31, CI 0.27-0.35; respectively, p < 0.001 for all). Conversely, Medicaid (vs private insurance; OR 1.75, CI 1.39-2.19, p < 0.001) and male sex (OR 1.26, CI 1.11-1.44, p < 0.001) were independent predictors of conversion. Conclusions: Open conversion in MIPN occurred in 2.87% of cases. There was an increasing utilization of MIPN associated with decreased conversion rates. Higher volume hospitals and progressing year of surgery were associated with less likelihood of conversion.

Teratogenic Toxicity Evaluation of Bladder Cancer-Specific Oncolytic Adenovirus on Mice.

BACKGROUND: In our previous studies, we had demonstrated the efficiency and specificity of constructed bladder tissue-specific adenovirus Ad-PSCAE-UPII-E1A-AR (APU-EIA-AR) on bladder cancer. The virus biodistribution and body toxicity in nude mice have also been investigated. However, the safety of the bladder cancer-specific oncolytic adenovirus on fetal mice and F1 mice should be under intense investigation. OBJECTIVE: In order to evaluate the teratogenic toxicity of bladder cancer-specific oncolytic adenovirus APU-EIA-AR on mice, in this study, we investigated the fetal mice weight, fetal body length and tail length, fetal skeleton development, as well as the F1 mice weight, growth curve, and major organ pathology. These teratogenic toxicity data of bladder tissue-specific adenovirus Ad-PSCAE- UPII-E1A-AR (AD) would provide safe information prior to embarking on clinical trials. METHODS: On the sixth day of being fertilized, the pregnant mice began to be intramuscularly administrated with AD (1×107VP, 1×108VP, 1×109VP) every other day for ten days. The pregnant mice were then divided into two groups. One group was euthanized on the seventeenth day; the fetal mice were taken out, and the bone structure of the infants was observed. The other group was observed until natural childbirth. The Filial Generation (F1) is fed for 30 days; the variations in the growth progress and development were assessed. The mice were then euthanized; The tissues from major organs were harvested and observed under the microscope. RESULTS: In the process of teratogenic toxicity test, the Placenta weight, fetal mice weight, body length, and a tail length of mice fetal in adenovirus treated group did not reveal any alteration. Meanwhile, comparing with the PBS group, there is no obvious change in the skeleton of fetal mice treated with adenovirus. During the development process of F1 mice treated with adenovirus, the changes in mice weight show statistical significance. However, in the progress of the growth curve, this difference is not very obvious. Furthermore, the pathological section showed no obvious alteration in major organs. CONCLUSION: Our study demonstrated that bladder cancer-specific adenovirus Ad-PSCAE-UPII- E1A-AR appears safe in pregnant mice without any discernable effects on fetal mice and F1 development. Hence, it is relatively safe for tumor gene therapy.

Comparative Efficacy of Combined Radiotherapy, Systemic Therapy, and Androgen Deprivation Therapy for Metastatic Hormone-Sensitive Prostate Cancer: A Network Meta-Analysis and Systematic Review.

Background: Recent randomized clinical trials have examined the efficacy of different combinations of systemic and local treatment approaches for metastatic hormone-sensitive prostate cancer (mHSPC). We compared the efficacy of these combined regimens in order to identify the optimal therapy for specific patient subgroups. Methods: The treatments were abiraterone (ABI), apalutamide (APA), docetaxel (DOC), enzalutamide (ENZ), and radiotherapy (RT) combined with androgen-deprivation therapy (ADT). Five electronic databases were searched up to May 7, 2020 for relevant trials. The risk of bias in the included trials was evaluated with the Cochrane tool. The hazard ratio (HR) with 95% confidence interval (CI) was determined for the included trials and indirect comparisons were performed using the R software. Results: In total, 10 randomized, controlled trials with 11,194 patients were included in the meta-analysis. ADT + RT was superior to ADT monotherapy in terms of overall survival (HR = 0.96, 95% CI: 0.85-1.1) and conferred a survival benefit in a subgroup of low-volume patients (HR = 0.68, 95% CI: 0.54-0.87). Combined systemic treatments were significantly superior to ADT monotherapy in comparisons of survival and prostate-specific antigen response, including in the high-volume subgroup; meanwhile, in the low-volume subgroup only ADT + ENZ (HR = 0.38, 95% CI 0.21-0.69) showed a significant clinical benefit. In the Gleason score <8 subgroup, all combined systemic treatments were superior to ADT monotherapy, but the results were only significant for ADT + APA (HR = 0.56, 95% CI: 0.33-0.95) and ADT + DOC (HR = 0.71, 95% CI: 0.54-0.92). In the Gleason score ≥8 subgroup, ADT monotherapy was inferior (albeit not significantly) to combined treatments. In a ranking of performed comparisons, ADT + ENZ was the optimal regimen, although this was non-significant. Combined therapies also demonstrated superiority in quality-of-life indicators such as time to skeletal events and pain progression. Conclusion: ADT + radiotherapy led to superior outcomes in mHSPC patients with low-volume disease. While all combined systemic regimens confer a survival advantage over ADT monotherapy, the optimal treatment approach for certain mHSPC patient subgroups remains to be determined.