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.

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.

A new and practical surgical technique of transvaginal natural orifice specimen extraction surgery (NOSES) in laparoscopic nephroureterectomy-an initial clinical experience.

OBJECTIVE: To explore the safety, feasibility and clinical effect of transvaginal natural orifice specimen extraction surgery (NOSES) in 3D laparoscopic nephroureterectomy (LNU) for upper tract urothelial carcinoma (UTUC). METHODS: A retrospective analysis was made of 16 female patients who underwent 3D LNU and NOSES in the Department of Urology, Cancer Hospital, Chinese Academy of Medical Sciences from June 2019 to December 2020. The basic clinical data, perioperative related data, perioperative complications, visual analogue pain score (VAS), postoperative scar assessment questionnaire (PSAQ) at 3 months, female pelvic floor dysfunction questionnaire (PFDI-20) and female sexual function index questionnaire (FSFI) at preoperative and postoperative 3 months were analyzed and evaluated. RESULTS: The surgery was successfully completed in all 16 patients, and none of them was converted to open surgery. No postoperative complications, such as abdominal incision-related infection. No cases of local recurrence and distant metastasis were observed during follow-up of 3 to 21 months. The VAS scores at 24 h and 48 h after operation were 2.9 ± 0.7, 1.3 ± 0.6, respectively. PSAQ scores at 3 months after operation were 34.3 ± 3.3. PFDI-20 scores of women preoperative and postoperative 3 months were 6.25 ± 1.75, 6.3 ± 1.8, respectively, and the difference was not statistically significant (p = 0.924). There was no significant difference in FSFI scores between preoperative and postoperative 3 months (p = 0.892). CONCLUSION: Transvaginal NOSES in 3D LNU for UTUC is safe, feasible and practical. The successful development of this technique has laid a solid foundation for further clinical application and promotion.

Transvaginal natural orifice specimen extraction surgery (NOSES) in 3D laparoscopic partial or radical nephrectomy: a preliminary study.

BACKGROUND: With the development of minimally invasive technology, more and more people pay attention to aesthetics of the wound after operation. This study is aim to introduce a new surgical technique of transvaginal natural orifice specimen extraction surgery (NOSES) in 3D laparoscopic partial or radical nephrectomy and evaluate the safety, feasibility and clinical effect. METHODS: Eleven patients who underwent 3D laparoscopic partial nephrectomy (n = 7) or radical nephrectomy (n = 4) and NOSES were included in this study. The surgical procedures and techniques, especially the NOSES operation, are reported in detail. In addition, the basic clinical data, perioperative related data, perioperative complications were analyzed. RESULTS: All 11 patients were performed successfully without conversion to open surgery. The mean total operative time was 133 (84, 150) min. NOSES time was 15 (13, 16) min, and the postoperative hospital stay was 5 (5, 5) d. The mean visual analogue score (VAS) was 3 (2, 4) point and 1 (0, 1) point at 24 h and 48 h after operation, respectively. No patient had recurrence, metastasis and death during the follow-up period of 3 to 17 months. The median Vancouver Scar Scale (VSS) was 1 (1, 1) point. The mean of Female Sexual Function Index (FSFI) was 21.60 (20.20, 21.60), 21.80 (19.80, 21.80) respectively between preoperative and postoperative 3 months, which has no statistical difference (P = 0.179). There was no statistical difference in the Pelvic Floor Distress Inventory-short form 20 (PFDI-20) score between preoperative and postoperative 3 months (P = 0.142). CONCLUSIONS: Transvaginal NOSES is safe and feasible in 3D laparoscopic partial or radical nephrectomy. Furthermore, it results in low incision-related pain without affecting the pelvic floor and sexual function.

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.

[Lycopene combined with quercetin and curcumin for chronic prostatitis/chronic pelvic pain syndrome in rats: Effect and mechanism].

OBJECTIVE: To study the therapeutic effect of lycopene combined with quercetin and curcumin on chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS) in rats and its underlying mechanism. METHODS: Thirty-three 6-week-old SD male rats were randomly divided into six groups: normal control (n = 3), CP/CPPS model control (n = 6), quercetin (n= 6), curcumin (n = 6), lycopene (n = 6) and combination therapy (n = 6). CP/CPPS was induced by injection of complete Freund's adjuvant into the ventral lobe of the prostate in the latter five groups of rats. After modeling, the rats in the normal and CP/CPPS model control groups were given corn oil by gavage, and those in the latter four groups treated intragastrically with quercetin at 50 mg/kg/d, curcumin at 50 mg/kg/d, lycopene at 10 mg/kg/d, and quercetin + curcumin + lycopene, respectively, once daily for a course of 4 weeks. Then, cardiac blood and prostate tissue samples were collected from the rats for measurement of related indexes. RESULTS: Histopathological changes in the model rats were basically consistent with the characteristics of CP/CPPS. The expressions of the inflammatory factors IL-1ß, IL-2, IL-6, TNFα, MCP1 and MIP-1α in the prostate tissue were all dramatically decreased in the quercetin, curcumin, lycopene and combination therapy groups compared with those in the normal controls (P < 0.01), even lower in the combination therapy group than in the quercetin, curcumin and lycopene groups (P < 0.05). The activities of the oxides CAT, GSH-PX and T-SOD were significantly increased and that of MDA decreased in the four treatment groups (P < 0.05), even more significantly in the combination therapy group than in the other three (P < 0.01). The phosphorylation of MAPKs was inhibited, the activation of NF-kB blocked and the transcriptional activity of Nrf2 enhanced in the four treatment groups (P < 0.05), even more significantly in the combination therapy group (P < 0.01). Conclusions: Lycopene combined with quercetin and curcumin is more effective than any of the three drugs used alone in the treatment of CP/CPPS, which may be associated with its alleviation of inflammatory response and oxidative stress by interaction between the NF-κB, MAPKs and Nrf2 signaling pathways.?

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.

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.

The methods and techniques of identifying renal pedicle vessels during retroperitoneal laparoscopic radical and partial nephrectomy.

BACKGROUND: Retroperitoneal laparoscopic radical and partial nephrectomy (RLRN and RLPN) have become the preferred modes of management for renal malignancy. One of the most critical steps in the RLRN and RLPN process is to seek and control the renal pedicle. The current study focuses on introducing methods and techniques that can help quickly and accurately identify the renal pedicle vessels during RLRN and RLPN. METHODS: RLRNs and RLPNs were performed for 292 cases in our hospital from November 2014 to January 2017. Different measures were adopted to seek and manage bilateral renal pedicle vessels. All operation procedures were performed by the following three steps: dissection, opening, and clamping. For the left lateral, after the perirenal fat in the dorsal and lateral side was fully dissected, the kidney was pushed toward the ventral side. The renal artery was visible when opening the dense bulging connective tissue, which was located in the middle of the dorsal interior of the kidney. Then, the renal artery was clamped with a Hem-o-lok or the Bulldog clamp. For the right kidney pedicles, the inferior vena cava was first identified and then dissipated upward. When the inferior vena cava was not visible, it was often the location of the right renal artery. The treatment for the artery was the same as for the left renal artery. Relevant clinical characteristics of patients, such as operative time, intraoperative blood loss, and duration of postoperative drainage, were analyzed retrospectively. The three-step method of identifying renal pedicle vessels during retroperitoneal laparoscopic radical and partial nephrectomy was evaluated. RESULTS: All operations were successfully accomplished with satisfying results, during which the artery could be controlled quickly, and no cases were converted to open surgery due to severe bleeding of renal pedicle vessels. There were no complications involving renal vessels during the entire study. The mean operative times were (81.9 ± 19.71) min and (88.2 ± 21.28) min for RLRN and RLPN, with an average intraoperative blood loss of (91.7 ± 47.10) ml and (62.4 ± 47.45) ml, respectively. The warm ischemia time for RLPN was (19.3 ± 5.6) min. The postoperative drainage-tube was removed within (4.5 ± 1.29) d (RLRN) and (4.6 ± 1.98) d (RLPN); the mean postoperative hospital stay times were (7.0 ± 2.4) d and (5.9 ± 1.98) d, respectively. CONCLUSION: The three-step method of identifying renal pedicle vessels during RLRN and RLPN is direct and feasible, and it may help simplify the operating procedure and improve the safety of the surgery. It may be of great practical application value in the clinical field.

Comparison of intracorporeal and extracorporeal urinary diversions after laparoscopic radical cystectomy in females with bladder cancer.

PURPOSE: To compare the peri-operative outcomes of females undergoing laparoscopic intracorporeal urinary diversions (ICUD) and extracorporeal urinary diversions (ECUD) after laparoscopic radical cystectomies (LRC). PATIENTS AND METHODS: Thirty-eight females who underwent LRCs and urinary diversions from February 2008 to October 2018 were divided into two groups: the ECUD group (19 patients) and the ICUD group (19 patients). We retrospectively analysed the patients in terms of patients' demographics, peri-operative outcomes, and oncological follow-ups. RESULTS: There were significant differences in the mean operative times between ECUDs and ICUDs (364.6 vs. 297.1 min, p = 0.007), transfusion rates (37% vs. 5%, p = 0.042), time to flatus (5 vs. 3 days, p = 0.020), time to ambulation (2 vs. 1 days, p = 0.022), and duration of postoperative hospital stays (22 vs. 13 days, p = 0.002). The mean lymph node yield was 12.9 in the ECUD group and 18.6 in the ICUD group (p = 0.140). Seven out of 19 patients (37%) in the ECUD group and 6 out of 19 patients (32%) in the ICUD group had positive lymph nodes (p > 0.9). Two out of 19 ECUD patients (11%) and 4 of 19 ICUD patients (21%) had positive surgical margins (p = 0.660). Although there were no differences in major complications at 30 days and in all complications at 90 days, the Clavien grade II complications were significantly different at 30 days (ECUD 8, ICUD 2; p = 0.026). The mean follow-up times were 48.7 months (ECUD group) and 26.4 months (ICUD group). There were no statistically significant differences in estimated glomerular filtration rates postoperatively (p = 0.516). Seven patients had disease metastases (ECUD 2 out of 19, ICUD 5 out of 19; p = 0.405) and 5 died (ECUD 3 out of 19, ICUD 2 out of 19; p > 0.9). CONCLUSIONS: ICUDs benefit females by having smaller incisions, faster recoveries, and decreased complication rates.

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.

Galanin suppresses proliferation of human U251 and T98G glioma cells via its subtype 1 receptor.

Galanin is a neuropeptide with a widespread distribution throughout the nervous and endocrine systems, and recent studies have shown an anti-proliferative effect of galanin on several types of tumors. However, whether and how galanin and its receptors are involved in the regulation of cell proliferation in glioma cells remains unclear. In this study, the roles of galanin and its subtype 1 receptor (GAL1) in the proliferation of human U251 and T98G glioma cells were investigated. We found that galanin significantly suppressed the proliferation of U251 and T98G cells as well as tumor growth in nude mice. However, galanin did not exert apoptotic or cytotoxic effects on these two cell lines. In addition, we showed that galanin decreased the proliferation of U251 and T98G cells via its GAL1 receptor. Finally, we found that the GAL1 receptor was involved in the suppressive effects of galanin by activating ERK1/2.

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.

Targeting Hypoxia and Autophagy Inhibition via Delivering Sonodynamic Nanoparticles With HIF-2α Inhibitor for Enhancing Immunotherapy in Renal Cell Carcinoma.

Immune checkpoint blockers (ICBs) therapy stands as the first-line treatment option for advanced renal cell carcinoma (RCC). However, its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). Sonodynamic therapy (SDT) generates tumor cell fragments that can prime the host's antitumor immunity. Nevertheless, the hypoxic microenvironment and upregulated autophagy following SDT often lead to cancer cell resistance. In response to these challenges, a hypoxia-responsive polymer (Poly(4,4'-azobisbenzenemethanol-PMDA)-mPEG5k, P-APm) encapsulating both a HIF-2α inhibitor (belzutifan) and the ultrasonic sensitize (Chlorin e6, Ce6) is designed, to create the nanoparticle APm/Ce6/HIF. APm/Ce6/HIF combined with ultrasound (US) significantly suppresses tumor growth and activates antitumor immunity in vivo. Moreover, this treatment effectively transforms the immunosuppressive microenvironment from "immune-cold" to "immune-hot", thereby enhancing the response to ICBs therapy. The findings indicate that APm/Ce6/HIF offers a synergistic approach combining targeted therapy with immunotherapy, providing new possibilities for treating RCC.

Preliminary clinical practice of radical prostatectomy without preoperative biopsy.

BACKGROUND: At present, biopsy is essential for the diagnosis of prostate cancer (PCa) before radical prostatectomy (RP). However, with the development of prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) and multiparametric magnetic resonance imaging (mpMRI), it might be feasible to avoid biopsy before RP. Herein, we aimed to explore the feasibility of avoiding biopsy before RP in patients highly suspected of having PCa after assessment of PSMA PET/CT and mpMRI. METHODS: Between December 2017 and April 2022, 56 patients with maximum standardized uptake value (SUVmax) of ≥4 and Prostate Imaging Reporting and Data System (PI-RADS) ≥4 lesions who received RP without preoperative biopsy were enrolled from two tertiary hospitals. The consistency between clinical and pathological diagnoses was evaluated. Preoperative characteristics were compared among patients with different pathological types, T stages, International Society of Urological Pathology (ISUP) grades, and European Association of Urology (EAU) risk groups. RESULTS: Fifty-five (98%) patients were confirmed with PCa by pathology, including 49 (89%) with clinically significant prostate cancer (csPCa, defined as ISUP grade ≥2 malignancy). One patient was diagnosed with high-grade prostatic intraepithelial neoplasia (HGPIN). CsPCa patients, compared with clinically insignificant prostate cancer (cisPCa) and HGPIN patients, were associated with a higher level of prostate-specific antigen (22.9 ng/mL vs. 10.0 ng/mL, P = 0.032), a lower median prostate volume (32.2 mL vs. 65.0 mL, P = 0.001), and a higher median SUVmax (13.3 vs. 5.6, P <0.001). CONCLUSIONS: It might be feasible to avoid biopsy before RP for patients with a high probability of PCa based on PSMA PET/CT and mpMRI. However, the diagnostic efficacy of csPCa with PI-RADS ≥4 and SUVmax of ≥4 is inadequate for performing a procedure such as RP. Further prospective multicenter studies with larger sample sizes are necessary to confirm our perspectives and establish predictive models with PSMA PET/CT and mpMRI.

Transvaginal natural orifice specimen extraction surgery for 3D laparoscopic radical cystectomy: A cohort study.

Objective: Transvaginal natural orifice specimen extraction surgery (NOSES) has been widely used in laparoscopic surgery due to its benefits. However, laparoscopic radical cystectomy (LRC) with NOSES has rarely been reported. Materials and Methods: A retrospective analysis of 25 patients who underwent 3D LRC with NOSES from November 2014 to November 2019 was performed. The clinical and perioperative related data, peri and postoperative complications, and oncologic outcomes were recorded. Results: Surgery was successfully completed in 25 patients, and none were converted to open surgery. Mean total operative time was 294.1 ± 48.80 min. Mean NOSES time was12 ± 6.48 min. The median post-op hospital stay was 10.5 d (range 6-27 d). The median visual analog pain score on post-op day 1, 2, and 3 was 2, 2, and 1, respectively. Thirteen patients had 30-day complications (3 had Clavien grade I and 11 had Clavien grade II). Pelvic floor distress inventory-short form 20 (PFDI-20) was 9.8 ± 1.9 after three months (compared with pre-PFDI-20, P = 0.06) and 9.3 ± 1.2 after six months (compared with pre-PFDI-20, P = 0.15). At the mean follow-up of 24.7 ± 12.05 months (range 11-60 months), one patient (4%) had recurrence, two (8%) had metastasis, and one (4%) died. Conclusion: Transvaginal NOSES in 3D LRC is safe and feasible. Understanding the female vagina anatomy and comprehending the techniques is conducive to avoid incision-related complications. NOSES is minimally invasive with good cosmetic outcomes with few surgical complications or affecting pelvic floor function.