Tumor immune contexture predicts recurrence after prostatectomy and efficacy of androgen deprivation and immunotherapy in prostate cancer.

BACKGROUND: Prostate cancer is one of the most common cancers in men with notable interpatient heterogeneity. Implications of the immune microenvironment in predicting the biochemical recurrence-free survival (BCRFS) after radical prostatectomy and the efficacy of systemic therapies in prostate cancer remain ambiguous. METHODS: The tumor immune contexture score (TICS) involving eight immune contexture-related signatures was developed using seven cohorts of 1120 patients treated with radical prostatectomy (training: GSE46602, GSE54460, GSE70769, and GSE94767; validation: GSE70768, DKFZ2018, and TCGA). The association between the TICS and treatment efficacy was investigated in GSE111177 (androgen deprivation therapy [ADT]) and EGAS00001004050 (ipilimumab). RESULTS: A high TICS was associated with prolonged BCRFS after radical prostatectomy in the training (HR = 0.32, 95% CI 0.24-0.45, P < 0.001) and the validation cohorts (HR = 0.45, 95% CI 0.32-0.62, P < 0.001). The TICS showed stable prognostic power independent of tumor stage, surgical margin, pre-treatment prostatic specific antigen (PSA), and Gleason score (multivariable HR = 0.50, 95% CI 0.39-0.63, P < 0.001). Adding the TICS into the prognostic model constructed using clinicopathological features significantly improved its 1/2/3/4/5-year area under curve (P < 0.05). A low TICS was associated with high homologous recombination deficiency scores, abnormally activated pathways concerning DNA replication, cell cycle, steroid hormone biosynthesis, and drug metabolism, and fewer tumor-infiltrating immune cells (P < 0.05). The patients with a high TICS had favorable BCRFS with ADT (HR = 0.25, 95% CI 0.06-0.99, P = 0.034) or ipilimumab monotherapy (HR = 0.23, 95% CI 0.06-0.81, P = 0.012). CONCLUSIONS: Our study delineates the associations of tumor immune contexture with molecular features, recurrence after radical prostatectomy, and the efficacy of ADT and immunotherapy. The TICS may improve the existing risk stratification systems and serve as a patient-selection tool for ADT and immunotherapy in prostate cancer.

Effects of different diets used to induce obesity/metabolic syndrome on bladder function in rats.

Preclinical and human studies on the relationship between obesity/metabolic syndrome (MetS) and lower urinary tract dysfunction (LUTD) are inconsistent. We compared the temporal effects of feeding four different diets used to induce obesity/MetS, including 60% fructose, 2% cholesterol +10% lard, 30% fructose + 20% lard, or 32.5% lard diet, up to 42 wk, on metabolic parameters and bladder function in male Sprague-Dawley rats. Rats fed a 30% fructose + 20% lard or 32.5% lard diet consumed less food (grams), but only the 32.5% lard diet group took in more calories. Feeding rats a 60% fructose or 30% fructose + 20% lard diet led to glucose intolerance and increased blood pressure. Higher body weight and increased cholesterol levels were observed in the rats maintained on a 2% cholesterol +10% lard diet, whereas exposure to a 32.5% lard diet affected most of the above parameters. Voiding behavior measurement showed that voiding frequency and the total voided volume were lower in the experimental diet groups except for the 30% fructose + 20% lard group. The mean voided volume was lower in the 30% fructose + 20% lard and 32.5% lard groups compared with the control group. Cystometric analysis revealed a decreased bladder capacity, mean voided volume, intermicturition interval, and compliance in the 32.5% lard diet group. In conclusion, experimental diets including 60% fructose, 30% fructose + 20% lard, or 2% cholesterol + 10% lard diet differently affected physiological and metabolic parameters and bladder function to a limited extent, while exposure to a 32.5% lard diet had a greater impact.

The effect of 5-α reductase inhibitor on Th1, Th2, and Th17 cell-related inflammatory response in BPH.

OBJECTIVE: To investigate the effect of 5-α reductase inhibitor on the expression of inflammation-related cytokines in Benign prostatic hyperplasia (BPH) specimens after transurethral prostatic resection (TUR-P). METHODS: We prospectively examined the expression of inflammation-related cytokines with immunohistochemistry in the paraffin blocks of 60 patients who underwent TUR-P. 30 cases in the 5-α-reductase inhibitor group were treated with finasteride, 5 mg qd, for more than 6 months; 30 cases in the control group were not treated with medicine before operation. HE staining was used to analyze the difference of inflammation reaction between the two groups, and immunohistochemical staining was used to analyze the effect of 5-α reductase inhibitor on the expression of B-cell lymphoma-2 (Bcl-2), Interleukin-2 (IL-2), Interferon-γ (IFN-γ), Interleukin-4 (IL-4), Interleukin-6 (IL-6), Interleukin-17 (IL-17), Interleukin-21 (IL-21) and Interleukin-23 (IL-23) in prostatic tissue. RESULTS: There was no statistical difference in the location, range and degree of inflammation between the two groups (P > 0.05). When IL-17 expression was low, there was statistical difference between the two groups (P < 0.05). Bcl-2 expression was positively correlated with IL-2, IL-4, IL-6 and IFN-γ (P < 0.05). There was no statistical difference in the expression of IL-21, IL-23 and high expression of IL-17 between the two groups (P > 0.05). CONCLUSIONS: 5-α Reductase inhibitor can inhibit the expression of Bcl-2 in prostatic tissue and the inflammatory response related to T-helper cell 1 (Th1) and T-helper cell 2 (Th2) cells. However, it did not affect Th17 cell-related inflammatory response.

The potential biological effects of quercetin based on pharmacokinetics and multi-targeted mechanism in vivo.

Quercetin is a plant-derived polyphenol flavonoid that has been proven to be effective for many diseases. However, the mechanism and in vivo metabolism of quercetin remains to be clarified. It achieves a wide range of biological effects through various metabolites, gut microbiota and its metabolites, systemic mediators produced by inflammation and oxidation, as well as by multiple mechanisms. The all-round disease treatment of quercetin is achieved through the organic combination of multiple channels. Therefore, this article clarifies the metabolic process of quercetin in the body, and explores the new pattern of action of quercetin in the treatment of diseases.

Feasibility of single position laparoscopic radical nephrectomy and tumor thrombectomy for left renal cell carcinoma with high-risk Mayo grade 0 and 1 tumor thrombus.

BACKGROUND: To explore the feasibility of single-position laparoscopic radical nephrectomy (LRN) and tumor thrombectomy for left renal cell carcinoma with high-risk Mayo 0 and 1 tumor thrombus (TT). METHODS: All patients with left renal cell carcinoma and venous TT (high-risk Mayo grade 0 and 1) who were performed single-position LRN and tumor thrombectomy were involved. After the renal artery was controlled by Hem-o-lok, the left renal vein was dissected through descending colon mesentery. The left renal vein was divided by EndoGIA for high-risk Mayo grade 0 TT. For Mayo grade 1 TT, part of the inferior vena cava was blocked by a bulldog clamp after milking the TT into the left renal vein and the inferior vena cava was sutured after complete excision of the TT. RESULTS: 3 patients were involved and operations were performed successfully without conversion to open surgery. The mean operation time was 136 min and the mean estimated blood loss was 60 mL. No postoperative complications occurred. CONCLUSIONS: It is feasible to control left renal vein and partial inferior vena cava through descending colon mesentery in a single position during LRN and tumor thrombectomy for the treatment of high-risk Mayo grade 0 and 1 TT.

Toxicity of Ag+ on microstructure, biochemical activities and genic material of Trifolium pratense L. seedlings with special reference to phytoremediation.

The objective of this research was to evaluate Ag+ toxicity in Trifolium pratense L. seedlings subjected to increasing doses of Ag+ by determining photosynthetic pigment and malondialdehyde (MDA) contents, microstructure and hereditary substance alterations, changes in activities of antioxidase-superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) as well as the content of total Ag absorbed in vivo with evaluation of root growth. Doses of approximately 80 mg L-1 Ag+ severely affected photosynthetic efficiency in Trifolium pratense L. seedlings promoted by damages in photosynthetic apparatus evidenced by downward trend in photosynthetic pigment contents and obvious chlorosis. Alterations in enzymatic activity, lipid peroxidation, genic material damage and the presence of Ag+in vivo had impacted on photosynthetic machinery as well. A hormesis effect was observed at 60 mg L-1 Ag+ for the photosynthetic pigments and antioxidase for Trifolium pratense L. seedlings. Tissue changes (i.e., roots, stems and leaves) observed in fluorescence microscope with obvious chlorosis, roots blackening and formation of agglomerated black particles, were related to the lesion promoted by excessive ROS in vivo. Asynchronous change of antioxidase activity corresponded to the alteration in the MDA content, indicating the synchronization in the elimination of ROS. The changes occurred in RAPD profiles of treated samples following Ag+ toxicity containing loss of normal bands, appearance of new bands and variation in band intensity compared to the normal plants with a dose-dependent effect. On average, the roots of Trifolium pratense L. immobilized 92.20% of the total Ag absorbed as a metal exclusion response. Root growth was significantly sensitive to Ag+ stress with obvious hormesis, which corresponded to the changes in Ag uptake, demonstrating the functional alterations in plants. To sum up, we suggest that modulating the genotype of Trifolium pratense L. seedlings to bear higher proportion of pollutants is conducive to contamination site treatment.

New therapy with XLQ® to suppress chronic prostatitis through its anti-inflammatory and antioxidative activities.

Chronic prostatitis is a common urological disease. The etiology of this disease and effective therapy for its treatment are yet to be elucidated. We investigated the functions of XLQ® in chronic nonbacterial prostatitis using a complete Freund's adjuvant-induced rat model. Prostates and blood samples were collected for further evaluation after oral gavage with XLQ ® or a vehicle for 4 weeks. The results showed that XLQ ® significantly decreased the prostate index, ameliorated the histopathologic changes, and reduced CD3+ and CD45+ cell infiltration in the prostate stroma. Further study showed that XLQ ® suppressed the expression of proinflammatory cytokines, such as interleukin (IL)-1ß, IL-2, IL-6, IL-17A, monocyte chemoattractant protein-1, and tumor necrosis factor-α. XLQ ® showed a strong antioxidant capacity by enhancing the activities of antioxidative enzymes (e.g., total superoxide dismutase, catalase, and glutathione peroxidase) and decreasing the level of lipid peroxidation products (malondialdehyde). Moreover, XLQ ® can suppress the activation of nuclear factor-κB and P38-mitogen-activated protein kinase signaling pathways. In summary, XLQ ® has affirmative effects on chronic prostatitis, which could be attributed to its anti-inflammatory and antioxidative capacities. On the basis of these results, XLQ ® can be developed as an effective and safe therapy for chronic prostatitis.

New-onset metabolic risk factors and the incidence of kidney stones: a prospective cohort study.

OBJECTIVE: To examine the association of kidney stones with new-onset hypertension, diabetes and obesity. PARTICIPANTS AND METHODS: This prospective cohort study included participants in the Qingdao Port Cardiovascular Health Study who were aged ≥18 years and had abdominal ultrasonography results in 2013 that were negative for kidney stones. Multivariable Cox regression models with time-dependent covariates were used to estimate the effects of new-onset hypertension, diabetes and obesity on the incidence of kidney stones. RESULTS: There were 9667 participants without kidney stones in 2013 (mean age 46.2 years; 75.6% men). During a mean (range) follow-up of 33.5 (6-42) months, 676 (7.0%) incident cases of kidney stones were identified. Kidney stones were more frequent among those who had new-onset of a metabolic factor vs those who did not (hypertension: 7.7 vs 6.0%; diabetes: 8.4 vs 6.6%; obesity: 7.4 vs 6.8%). Adjusted Cox models identified that increased risk of kidney stones was associated with new-onset hypertension (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.25-2.27), new-onset diabetes (HR 1.78, 95% CI 1.07-2.96), and new-onset obesity (HR 1.78, 95% CI 1.15-2.74). CONCLUSIONS: New-onset of hypertension, diabetes and obesity were all strongly associated with an increased risk of kidney stones in this prospective cohort study. Results suggest that a substantial proportion of kidney stones are potentially preventable by appropriate control of these metabolic risk factors.

The long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy combined with radical cystectomy versus radical cystectomy alone for bladder cancer: a propensity-score matching study.

BACKGROUND: Bladder cancer is a complex disease associated with high morbidity and mortality. Management of bladder cancer before radical cystectomy continues to be controversial. We compared the long-term efficacy of one-shot neoadjuvant intra-arterial chemotherapy (IAC) versus no IAC (NIAC) before radical cystectomy (RC) for bladder cancer. METHODS: We performed a retrospective review of patients who underwent either one-shot IAC or NIAC before RC between October 2006 and November 2015. A propensity-score matching (1:3) was performed based on key characters. The Kaplan-Meier method was utilized to estimate survival probabilities, and the log-rank test was used to compare survival outcomes between different groups. A multivariable Cox proportional hazard model was used to estimate survival outcomes. RESULTS: Twenty-six patients were treated using IAC before RC, and 123 NIAC patients also underwent RC. After matching, there was no significant difference between groups in baseline characteristics, perioperative variables, complication outcomes or tumor characteristics. Compared with clinical tumor stages, pathological tumor stages demonstrated a significant decrease (P = 0.002) in the IAC group. There was no significant difference in overall survival (OS, p = 0.354) or cancer-specific survival (CSS, p = 0.439) between the groups. Among all patients, BMI significantly affected OS (p = 0.004), and positive lymph nodes (PLN) significantly affected both OS (p<0.001) and CSS (p = 0.010). CONCLUSIONS: One-shot neoadjuvant IAC before RC shows safety and tolerability and provides a significant advantage in pathological downstaging but not in OS or CSS. Further study of neoadjuvant combination therapeutic strategies with RC is needed.

Laparoscopic radical cystectomy with intracorporeal ileal conduit: one center experience and clinical outcomes.

PURPOSE: To introduce our experience with intracorporeal ileal conduit and evaluate the safety and feasibility of this endoscopic urinary diversion. MATERIALS AND METHODS: Between March 2014 and July 2017, thirty-six consecutive patients underwent laparoscopic radical cystectomy with intracorporeal ileal conduit. Patients' demographic data, perioperative data, 90-days postoperative outcomes and complications were collected. This cohort were divided into two groups of 18 patients each by chronological order of the operations to facilitate comparison of clinical data. Data were evaluated using the students' T test, Mann-Whitney test and Fisher's Exact test. RESULTS: All surgeries were completed successfully with no conversion. Median total operating time and median intracorporeal urinary diversion time were 304 and 105 minutes, respectively. Median estimated blood loss was 200 mL, and median lymph node yield was 21. Twenty-six Clavien grade < 3 complications occurred within 30-days and 9 occurred within 30-90 days. Five Clavien grade 3-5 complications occurred within 30 days. No statistically signifi cant differences were found between the two groups except for intracorporeal urinary diversion time. At median follow-up of 17.5 (range 3-42) months, 6 patients experienced tumor recurrence/metastasis and 4 of these patients died. CONCLUSIONS: Intracorporeal ileal conduit following laparoscopic radical cystectomy is safe, feasible and reproducible. With the accumulation of experience, the operation time can be controlled at a satisfactory level.

Quercetin protects against chronic prostatitis in rat model through NF-κB and MAPK signaling pathways.

BACKGROUND: Chronic Prostatitis/Chronic Pelvic Pain Syndrome (CP/CPPS) is a common disease of urology, of which the pathogenesis and therapy remain to be further elucidated. Quercetin has been reported to improve the symptoms of CP/CPPS patients. We aimed to verify the therapeutic effect of quercetin on CP/CPPS and identify the mechanism responsible for it. METHODS: A novel CP/CPPS model induced with Complete Freund Adjuvant in Sprague Dawley rats was established and the prostates and blood specimens were harvested for further measurement after oral administration of quercetin for 4 weeks. RESULTS: Increased prostate index and infiltration of lymphocytes, up-regulated expression of IL-1ß, IL-2, IL-6, IL-17A, MCP1, and TNFα, decreased T-SOD, CAT, GSH-PX, and increased MDA, enhanced phosphorylation of NF-κB, P38, ERK1/2, and SAPK/JNK were detected in CP/CPPS rat model. Quercetin was identified to ameliorate the histo-pathologic changes, decrease the expression of pro-inflammatory cytokines IL-1ß, IL-2, IL-6, IL-17A, MCP1, and TNFα, improve anti-oxidant capacity, and suppress the phosphorylation of NF-κB and MAPKs. CONCLUSIONS: Quercetin has specific protective effect on CP/CPPS, which is mediated by anti-inflammation, anti-oxidation, and at least partly through NF-κB and MAPK signaling pathways.

Surgical techniques for facilitating laparoscopic intracorporeal orthotopic neobladder: initial experience.

PURPOSE: To describe our technique and outcomes for laparoscopic intracorporeal ileal neobladder (ICNB) reconstruction. MATERIALS AND METHODS: From April 2014 to November 2016, 21 patients underwent laparoscopic ICNB at our tertiary referral centre. ICNB with bilateral isoperistaltic afferent limbs and several technique improvements were introduced. Demographics, clinical, and pathological data were collected. Perioperative, 1-year oncologic, 1-year Quality of life and 1-year functional outcomes were reported. RESULTS: ICNB was successfully performed in all 21 patients without open conversion and transfusion. Mean operative time was 345.6±66.9 min, including 106±22 min for LRC and PLND and 204±46.4 min for ICNB, respectively. Mean established blood loss was 192±146 mL. The overall incidence of 90-d complication was 33.3%, while major complication occurred in 4.8%. One-year daytime and night-time continence rates were 85.7% and 57.1%, respectively. One patient died from myocardial infarction six months postoperatively, and two patients had lung metastasis five months and six months respectively. CONCLUSIONS: We described our experience of 3D LRC with a novel intracorporeal orthotopic ileal neobladder, and the technique improvements facilitate the procedure. However, further studies are required to evaluate long-term outcomes of the intracorporeal neobladder with bilateral isoperistaltic afferent limbs.

Self-retaining barbed suture reduces warm ischemia time during laparoscopic partial nephrectomy.

OBJECTIVE: To evaluate the efficacy and safety of self-retaining barbed suture in renorrhaphy during laparoscopic partial nephrectomy by comparing surgical outcomes in a prospective randomized manner. MATERIAL AND METHODS: From July 2014 to July 2015, a total of 60 patients with T1 renal tumor were randomized into two equal groups: self-retaining barbed suture (SRBS) and conventional absorbable polyglactin suture (non-SRBS group). All patients were treated by retroperitoneal laparoscopic partial nephrectomy. One surgeon with high volume experience performed all procedures. The patient demographics and perioperative outcomes were compared. RESULTS: The patient demographics and tumor characteristics were comparable. The mean tumor size and R.E.N.A.L. scores were comparable between the two groups. LPN was successfully accomplished in all patients without open conversion. The warm ischemia and renorrhaphy times were significantly shorter in the SRBS group (18.8 ± 8.2 vs. 22.9 ± 7.3 min, P = .04; 10.4 ± 3.7 vs. 13.8 ± 5.6 min, P = .01). The minor complication rate was 13.3% vs. 10.0%, which was comparable. No major complication occurred. CONCLUSIONS: The randomized controlled trial demonstrates that SRBS for renorrhaphy during retroperitoneal laparoscopic partial nephrectomy is safe and efficient. Application of barbed suture simplifies the parenchymal repair procedure and reduces warm ischemia time in comparison with conventional suture.

[Plasmakinetic enucleation of the prostate versus holmium laser enucleation of the prostate for benign prostatic hyperplasia].

OBJECTIVE: To evaluate the clinical effects of plasmakinetic enucleation of the prostate (PKERP) and holmium laser enucleation of the prostate (HoLEP) in the treatment of BPH. METHODS: We retrospectively analyzed the clinical data on 78 BPH patients treated by PKERP (n = 38) or HoLEP (n = 40) from January 2016 to October 2017. We recorded the operation time, intraoperative hemoglobin level, catheter-indwelling time, bladder irrigation time, hospital stay, 6-month postoperative IPSS, quality of life (QOL), maximum urinary flow rate (Qmax), postvoid residual urine (PVR), PSA level, International Index of Erectile Function (IIEF) and postoperative complications, and compared the obtained parameters between the two groups and some of them with the baseline. RESULTS: In comparison with the baseline, both the PKERP and HoLEP groups showed statistically significant differences at 6 months after surgery in the QOL score (4.82 ± 0.56 and 4.70 ± 0.67 vs 2.44 ± 0.69 and 2.92 ± 0.49, P < 0.01), IPSS (19.52 ± 4.96 and 19.44 ± 4.08 vs 9.56 ± 2.5 and 9.81 ± 2.5, P < 0.01), Qmax (ï¼»4.54 ± 1.86ï¼½ and ï¼»4.42 ± 2.89ï¼½ ml/s vs ï¼»17.72 ± 3.46ï¼½ and ï¼»17.27 ± 4.42ï¼½ ml/s, P < 0.01), and PVR (ï¼»83.73±55.33ï¼½ and ï¼»109.65 ± 89.58ï¼½ ml vs ï¼»19.93 ± 11.07ï¼½ and ï¼»18.31 ± 15.03ï¼½ ml, P < 0.01). Statistically significant differences were also found between the PKERP and HoLEP groups in the reduced hemoglobin level (ï¼»21.04 ± 16.96ï¼½ vs ï¼»7.88 ± 6.65ï¼½ g/dl, P = 0.01), catheter-indwelling time (ï¼»7.67 ± 2.27ï¼½ vs ï¼»3.93 ± 2.18ï¼½ d, P = 0.01), bladder irrigation time (ï¼»1.67 ± 0.62ï¼½ vs ï¼»1.3 ± 0.54ï¼½ d, P = 0.05), hospital stay (ï¼»4.22 ± 1.55ï¼½ vs ï¼»3.26 ± 0.9ï¼½ d, P = 0.01), and 6-month postoperative QOL score (ï¼»2.44 ± 0.69ï¼½ vs ï¼»2.92 ± 0.49ï¼½, P = 0.05), but not in the other parameters. CONCLUSIONS: Both PKERP and HoLEP are safe and effective for the treatment of BPH, the former more feasible in primary hospitals, while the latter with the advantages of less bleeding, shorter catheterization and hospital stay, and higher 6-month postoperative QOL score.

Laparoscopic radical cystectomy with novel orthotopic neobladder with bilateral isoperistaltic afferent limbs: initial experience.

PURPOSE: To introduce a new method of constructing an orthotopic ileal neobladder with bilateral isoperistaltic afferent limbs, and to describe its clinical outcomes. MATERIALS AND METHODS: From January 2012 to December 2013, 16 patients underwent a new method of orthotopic ileal neobladder after laparoscopic radical cystectomy for bladder cancer. To construct the neobladder, an ileal segment 60cm long was isolated approximately 25cm proximally to the ileocecum. The proximal 20cm of the ileal segment was divided into two parts for bilateral isoperistaltic afferent limbs. The proximal 10cm of the ileal segment was moved to the distal end of the ileal segment for the right isoperistaltic afferent limb, and the remaining proximal 10cm ileal segment was reserved for the left isoperistaltic afferent limb. The remaining length of the 40cm ileal segment was detubularized along its antimesenteric border to form a reservoir. The neobladder was sutured to achieve a spherical configuration. RESULTS: All procedures were carried out successfully. The mean operative time was 330 min, mean blood loss was 328mL, and mean hospital stay was 12.5 days. The mean neobladder capacity 6 and 12 months after surgery was 300mL and 401mL, respectively. With a mean follow-up of 22.8 months, all patients achieved daytime continence and 15 achieved nighttime continence. The mean peak urinary flow rate was 11.9mL/s and 12.8mL/s at 6 and 12 months postoperatively, respectively. CONCLUSIONS: This novel procedure is feasible, safe, simple to perform, and provides encouraging functional outcomes. However, comparative studies with long-term follow-up are required to prove its superiority.

Rupture of ectopic renal arterial pseudoaneurysm after percutaneous nephrolithotomy.

A 35-year-old female patient presented with swelling pain at left waist for 1 month. Left renal pelvis stones were found and standard percutaneous nephrolithotomy was successfully performed. Two weeks later, the patient suddenly suffered massive bleeding presented with gross hematuria. Rupture of ectopic renal artery pseudoaneurysm was identified by computed tomography and angiography of the renal artery. Emergency selective angioembolization of one branch of the artery was performed. To our knowledge, this is the first report of ruptured ectopic renal arterial pseudoaneurysm.

Retroperitoneal Laparoscopic Nephroureterectomy for Tuberculous Nonfunctioning Kidneys: a single-center experience.

PURPOSE: To present our surgical techniques and experiences of retroperitoneal laparoscopic nephroureterectomy for the treatment of tuberculous nonfunctioning kidneys. MATERIALS AND METHODS: From March 2005 to March 2013, a total of 51 patients with tuberculous nonfunctioning kidney underwent retroperitoneal laparoscopic nephroureterectomy at our medical center. The techniques included early control of renal vessels and dissection of the diseased kidney along the underlying layer outside the Gerato's fascia. The distal ureter was dissected through a Gibson incision and the entire specimen was removed en bloc from the incision. Patient demographics, perioperative characteristics and laboratory parameters as well as postoperative outcome were retrospectively reviewed. RESULTS: Retroperitoneal laparoscopic nephroureterectomy was successfully performed in 50 patients, whereas one case required conversion to open surgery due to non-progression of dissection. The mean operating time was 123.0 minutes (107-160 minutes) and the mean estimated blood loss was 134 mL (80-650 mL).The mean postoperative hospital stay was 3.6 days (3-5 days) and the mean return to normal activity was 11.6 days (10-14 days). Most intra-operative and post-operative complications were minor complications and can be managed conservatively. After 68 months (12-96 months) follow-up, the outcome was satisfactory, and ureteral stump syndrome did not occur. CONCLUSIONS: Retroperitoneal laparoscopic nephroureterectomy as a minimally invasive treatment option is feasible for treatment of tuberculous nonfunctioning kidneys.

Pure conventional laparoscopic radical nephrectomy with level II vena cava tumor thrombectomy.

The surgical management with laparoscopic technique for renal cell carcinoma with inferior vena cava tumor thrombus (IVTT) remains challenging and technically demanding in urological oncology. We present two patients with level II IVTT that were managed with pure conventional laparoscopic radical nephrectomy and thrombectomy. Two patients were diagnosed with a renal tumor with level II IVTT from December 2011 to January 2012. They both underwent pure conventional laparoscopic radical nephrectomy with thrombectomy. During these operations, intraoperative laparoscopic ultrasonography was used to detect the thrombus and ensure complete removal. Two patients were operated through retroperitoneal approach for right renal tumor and transperitoneal approach for left renal tumor respectively. The demographics, perioperative and follow-up data were recorded for the study. Both operations were successfully performed without conversion. They both had no radiographic evidence of recurrence during follow-up. It is concluded that it is feasible to manage renal cell carcinoma with level II IVTT through pure conventional laparoscopic approach in carefully selected patients, which might expand the indication for laparoscopic surgery. The purê laparoscopic approach in the treatment of renal cell carcinoma with level II vena cava tumor thrombus is challenging and requires advanced laparoscopic skills. Multicenter prospective randomized control trials are needed to prove the benefits of this approach.

Targeting DNA Damage and Repair Machinery via Delivering WEE1 Inhibitor and Platinum (IV) Prodrugs to Stimulate STING Pathway for Maximizing Chemo-Immunotherapy in Bladder Cancer.

Both cisplatin-based chemotherapy and immune checkpoint blockers (ICBs)-based immunotherapy are the first-line treatments for patients with advanced bladder cancer. Cancer cells can develop resistance to cisplatin through extensive DNA repair, while a low response rate to ICBs is mostly due to the presence of an immunosuppressive microenvironment and low PD-L1 expression. Herein, a glutathione (GSH)-responsive nanoparticle (NP2) loaded with cisplatin prodrug (Pt (IV)) and WEE1 inhibitor (MK1775) is designed. NP2 can be triggered by GSH in cancer cells, and the released MK1775 can inhibit the activity of WEE1 protein, which ultimately increases DNA damage by cisplatin. Genome-wide RNA sequencing first reveals that NP2 can inhibit DNA repair machinery by interfering with the cell cycle and significantly activate the stimulator of interferon genes pathway. Tumor growth is significantly inhibited by NP2 in vivo. As innate and adaptive immune responses are stimulated, the immunosuppressive microenvironment is modified, and the "immune cold tumor" is transformed into an "immune hot tumor". In addition, NP2 can upregulate PD-L1 expression in tumor cells, thereby increasing the response rate of PD-L1 monoclonal antibody (αPD-L1) and eliciting long-term immune responses in both primary and metastatic tumors.

Notch activation defines immune-suppressive subsets of ccRCCs with unfavorable benefits from immunotherapy over VEGFR/mTOR inhibitors.

The evolutionarily conserved Notch pathway, involved in cancer stem cell capacity and cancer immunity, may predict the benefit from immune checkpoint inhibitors (ICIs) in clear cell renal cell carcinoma (ccRCC). In the TCGA dataset, mRNA expression of Notch pathway genes identified three clusters with different prognoses and molecular characteristics. Based on the differentially expressed Notch pathway genes between clusters, we constructed the Notch-score, correlated with Notch activation, angiogenesis, PI3K-AKT-mTOR activity, and sensitivities to VEGFR/mTOR inhibitors. A high Notch-score was linked with more "resting"/"anti-inflammatory" rather than "activated"/"pro-inflammatory" tumor-infiltrating immune cells, inactivated immune pathways, and scarce any benefits from ICI-based therapies over VEGFR/mTOR inhibitors in the JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib) and the CheckMate-009/010/025 trials (nivolumab vs. everolimus). For the Notch-activated ccRCCs, ICIs provide limited advantages and might not be strongly recommended, by which the cost-effectiveness of treatments in ccRCCs may be potentially improved.