Tumor-neutrophil cross talk orchestrates the tumor microenvironment to determine the bladder cancer progression.

The immune landscape of bladder cancer progression is not fully understood, and effective therapies are lacking in advanced bladder cancer. Here, we visualized that bladder cancer cells recruited neutrophils by secreting interleukin-8 (IL-8); in turn, neutrophils played dual functions in bladder cancer, including hepatocyte growth factor (HGF) release and CCL3highPD-L1high super-immunosuppressive subset formation. Mechanistically, c-Fos was identified as the mediator of HGF up-regulating IL-8 transcription in bladder cancer cells, which was central to the positive feedback of neutrophil recruitment. Clinically, compared with serum IL-8, urine IL-8 was a better biomarker for bladder cancer prognosis and clinical benefit of immune checkpoint blockade (ICB). Additionally, targeting neutrophils or hepatocyte growth factor receptor (MET) signaling combined with ICB inhibited bladder cancer progression and boosted the antitumor effect of CD8+ T cells in mice. These findings reveal the mechanism by which tumor-neutrophil cross talk orchestrates the bladder cancer microenvironment and provide combination strategies, which may have broad impacts on patients suffering from malignancies enriched with neutrophils.

Deubiquitination of CDC6 by OTUD6A promotes tumour progression and chemoresistance.

BACKGROUND: CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated. METHODS: The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6. RESULTS: OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer. CONCLUSIONS: We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.

Prognostic value of Controlling Nutritional Status score for postoperative complications and biochemical recurrence in prostate cancer patients undergoing laparoscopic radical prostatectomy.

Background: Controlling Nutritional Status (CONUT) score was used for screening the preoperative nutritional status. The correlation between the CONUT score and the prognosis of patients with prostate cancer (PCa) has yet to be elucidated. Herein, we analyzed the prognostic value of CONUT scores in patients with PCa who underwent laparoscopic radical prostatectomy. Materials and methods: Data of 244 patients were retrospectively evaluated. Perioperative variables and follow-up data were analyzed. The patients were categorized into 2 groups according to their preoperative CONUT scores. Postoperative complication and incontinence rates were also compared. The Kaplan-Meier method was used to estimate the median biochemical recurrence-free survival (BCRFS) between the 2 groups. Univariate and multivariate Cox regression analyses were performed to identify the potential prognostic factors for BCRFS. Results: Patients were categorized into the low-CONUT group (CONUT score <3, n = 207) and high-CONUT group (CONUT score ≥3, n = 37). The high-CONUT group had a higher overall complication rate (40.5% vs.19.3%, p = 0.004), a higher major complication rate (10.8% vs. 3.9%, p = 0.013), and longer postoperative length of stay (8 days vs. 7 days, p = 0.017). More fever, urinary infection, abdominal infection, scrotal edema, rash, and hemorrhagic events (all p values < 0.05) were observed in the high-CONUT group. A higher rate of urinary incontinence was observed in the high-CONUT group at 1 (34.4% vs. 13.2%, p = 0.030) and 3 months (24.1% vs. 8.2%, p = 0.023) postoperatively. The high-CONUT group had shorter medium BCRFS (23.8 months vs. 54.6 months, p = 0.029), and a CONUT score ≥3 was an independent risk factor for a shorter BCRFS (hazards ratio, 1.842; p = 0.026). Conclusions: The CONUT score is a useful predictive tool for higher postoperative complication rates and shorter BCRFS in patients with PCa who undergo laparoscopic radical prostatectomy.

Adaptive ultra-hypofractionated whole-pelvic radiotherapy in high-risk and very high-risk prostate cancer on 1.5-Tesla MR-Linac: Estimated delivered dose and early toxicity results.

Background: Magnetic resonance (MR)-guided ultra-hypofractionated radiotherapy with whole-pelvic irradiation (UHF-WPRT) is a novel approach to radiotherapy for patients with high-risk (HR) and very high-risk (VHR) prostate cancer (PCa). However, the inherent complexity of adaptive UHF-WPRT might inevitably result in longer on-couch time. We aimed to estimate the delivered dose, study the feasibility and safety of adaptive UHF-WPRT on a 1.5-Tesla MR-Linac. Methods: Ten patients with clinical stage T3a-4N0-1M0-1c PCa, who consecutively received UHF-WPRT, were enrolled prospectively. The contours of the target and organ-at-risks on the position verification-MR (PV-MR), beam-on 3D-MR(Bn-MR), and post-MR (after radiotherapy delivery) were derived from the pre-MR data by deformable image registration. The physician then manually adjusted them, and dose recalculation was performed accordingly. GraphPad Prism 9 (GraphPad Prism Software Inc.) was utilized for conducting statistical analyses. Results: In total, we collected 188 MR scans (50 pre-MR, 50 PV-MR, 44 Bn-MR, and 44 post-MR scans). With median 59 min, the mean prostate clinical target volume (CTV)-V100% was 98.59% ± 2.74%, and the mean pelvic CTVp-V100% relative percentages of all scans was 99.60% ± 1.18%. The median V29 Gy change in the rectal wall was -2% (-18% to 20%). With a median follow-up of 9 months, no patient had acute Common Terminology Criteria for Adverse Events (CTCAE) grade 2 or more severe genitourinary (GU) or gastrointestinal (GI) toxicities (0%). Conclusion: UHF-RT to the prostate and the whole pelvis with concomitant boost to positive nodes using an Adapt-To-Shape (ATS) workflow was technically feasible for patients with HR and VHR PCa, presenting only mild GU and GI toxicities. The estimated target dose during the beam-on phase was clinically acceptable based on the 3D-MR-based dosimetry analysis. Clinical trial registration: Chinese Clinical Trial Registry ChiCTR2000033382.

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.

High and selective cytotoxicity of ex vivo expanded allogeneic human natural killer cells from peripheral blood against bladder cancer: implications for natural killer cell instillation after transurethral resection of bladder tumor.

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is treated with transurethral resection of bladder tumor (TURBT) followed by intravesical instillation of chemotherapy or Bacillus Calmette-Guérin therapy. However, these treatments have a high recurrence rate and side effects, emphasizing the need for alternative instillations. Previously, we revealed that expanded allogeneic human natural killer (NK) cells from peripheral blood are a promising cellular therapy for prostate cancer. However, whether NK cells exhibit a similar killing effect in bladder cancer (BCa) remains unknown. METHODS: Expansion, activation, and cryopreservation of allogeneic human NK cells obtained from peripheral blood were performed as we previously described. In vitro cytotoxicity was evaluated using the cell counting kit-8. The levels of perforin, granzyme B, interferon-γ, tumor necrosis factor-α, and chemokines (C-C-motif ligand [CCL]1, CCL2, CCL20, CCL3L1, and CCL4; C-X-C-motif ligand [CXCL]1, CXCL16, CXCL2, CXCL3, and CXCL8; and X-motif ligand 1 and 2) were determined using enzyme-linked immunosorbent assay. The expression of CD107a, major histocompatibility complex class I (MHC-I), MHC-I polypeptide-related sequences A and B (MICA/B), cytomegalovirus UL16-binding protein-2/5/6 (ULBP-2/5/6), B7-H6, CD56, CD69, CD25, killer cell Ig-like receptors (KIR)2DL1, KIRD3DL1, NKG2D, NKp30, NKp46, and CD16 of NK cells or BCa and normal urothelial cells were detected using flow cytometry. Cytotoxicity was evaluated using lactate dehydrogenase assay in patient-derived organoid models. BCa growth was monitored in vivo using calipers in male NOD-scid IL2rg-/- mice subcutaneously injected with 5637 and NK cells. Differential gene expressions were investigated using RNA sequence analysis. The chemotaxis of T cells was evaluated using transwell migration assays. RESULTS: We revealed that the NK cells possess higher cytotoxicity against BCa lines with more production of cytokines than normal urothelial cells counterparts in vitro, demonstrated by upregulation of degranulation marker CD107a and increased interferon-γ secretion, by MICA/B/NKG2D and B7H6/NKp30-mediated activation. Furthermore, NK cells demonstrated antitumor effects against BCa in patient-derived organoids and BCa xenograft mouse models. NK cells secreted chemokines, including CCL1/2/20, to induce T-cell chemotaxis when encountering BCa cells. CONCLUSIONS: The expanded NK cells exhibit potent cytotoxicity against BCa cells, with few toxic side effects on normal urothelial cells. In addition, NK cells recruit T cells by secreting a panel of chemokines, which supports the translational application of NK cell intravesical instillation after TURBT from bench to bedside for NMIBC treatment.

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.

Analysis of risk factors for positive surgical margin after laparoscopic radical prostatectomy with and without neoadjuvant hormonal therapy.

Background: Positive surgical margins (PSM) is not only an independent risk factor for recurrence, metastasis, and prognosis, but also an important indicator of adjuvant therapy for prostate cancer (PCa) patients treated with radical prostatectomy (RP). At present, there are few reports analyzing risk factors of PSM in laparoscopic RP (LRP), especially for those PCa cases who accepted neoadjuvant hormonal therapy (NHT). Hence, the aim of the current study was to explore risk factors for PSM after LRP in PCa patients with and without NHT. Methods: The clinicopathological data of patients who underwent LRP from January 2012 to July 2020 was retrospectively analyzed. Risk factors for PSM after LRP in NHT and non-NHT groups were respectively explored. Results: The overall PSM rate was 33.3% (90/270), PSM rate was 39.3% (64/163) in patients without NHT and 24.3% (26/107) in those with NHT. The apex was the most common location of PSM in non-NHT group (68.8%, 44/64), while the fundus was the most common location of PSM in NHT group (57.7%, 15/26). Multiple logistic regression revealed that body mass index (BMI), PSA, ISUP grade after LRP, pathological stage T (pT) and pathological lymph node status (pN) were independent factors affecting the PSM for patients without NHT (OR=1.160, 95%CI:1.034-1.301, p=0.011; OR=3.385, 95%CI:1.386-8.268, p=0.007; OR=3.541, 95%CI:1.008-12.444, p=0.049; OR=4.577, 95%CI:2.163-9.686, p<0.001; OR=3.572, 95%CI:1.124-11.347, p=0.031), while pT, pN, and lymphovascular invasion (LVI) were independent risk factors affecting PSM for patients with NHT (OR=18.434, 95%CI:4.976-68.297, p<0.001; OR=7.181, 95%CI:2.089-24.689, p=0.002; OR=3.545, 95%CI:1.109-11.327, p=0.033). Conclusions: The apex was the most common location in NHT group, and BMI, PSA, ISUP after LRP, pT and pN were independent risk factors affecting PSM for NHT patients; while the fundus was the most common location in non-NHT group, and pT, pN, and LVI were independent risk factors affecting PSM for non-NHT patients.

siRNA-based approaches for castration-resistant prostate cancer therapy targeting the androgen receptor signaling pathway.

Androgen deprivation therapy is a common treatment method for metastatic prostate cancer through lowering androgen levels; however, this therapy frequently leads to the development of castration-resistant prostate cancer (CRPC). This is attributed to the activation of the androgen receptor (AR) signaling pathway. Current treatments targeting AR are often ineffective mostly due to AR gene overexpression and mutations, as well as the presence of splice variants that accelerate CRPC progression. Thus there is a critical need for more specific medication to treat CRPC. Small interfering RNAs have shown great potential as a targeted therapy. This review discusses prostate cancer progression and the role of AR signaling in CRPC, and proposes siRNA-based targeted therapy as a promising strategy for CRPC.

In Situ Photoacoustic Visualization of Pneumonia Induced by MRSA and Specific Identifying Tumor-Homing Bacteria.

Optical imaging holds great promise for monitoring bacterial infectious processes and drug resistance with high temporal-spatial resolution. Currently, the diagnosis of deep-seated bacterial infections in vivo with fluorescence imaging, including near-infrared (NIR) fluorescence imaging technology, remains a significant challenge due to its limited tissue penetration depth. In this study, we developed a highly specific targeting probe, Cy7-Neo-NO2, by conjugating a bacterial 16S rRNA-targeted moiety, neomycin, with a bacterial nitroreductase (NTR)-activated NIR photoacoustic (PA) scaffold using our previously developed caged photoinduced electron transfer (a-PeT) approach. This conjugation effectively resolved probe aggregation issues in physiological conditions and substantially enhanced its reactivity toward bacterial NTR. Notably, Cy7-Neo-NO2 enabled the first in situ photoacoustic imaging of pneumonia induced by methicillin-resistant Staphylococcus aureus (MRSA), as well as the detection of bacteria within tumors. Furthermore, upon NIR irradiation, Cy7-Neo-NO2 successfully inhibited MRSA growth through a synergistic effect combining photothermal therapy and photodynamic therapy. Our results provided an effective tool for obtaining exceptional PA agents for accurate diagnosis, therapeutic evaluation of deep-seated bacterial infections in vivo, and intratumoral bacteria-specific recognition.

Sequential liquid-based cytology based on exfoliative cells of 18-gauge core needle groove to improve renal mass core needle biopsy yield: a real-world observational study.

Background: Renal mass biopsy (RMB) has regained clinical interest in recent years due to the pursuit of individualized and precision medicine. Renal mass core needle biopsy (RMCNB) for histopathology (HP), with or without liquid-based cytology (LBC), has been used increasingly in our hospital. This study investigated factors influencing the HP diagnostic yield of RMCNB, and compared the diagnostic rate between HP alone and HP plus LBC. Methods: In this retrospective cross-sectional study, a total of 134 patients who underwent ultrasound-guided percutaneous RMCNB in the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 2015 and May 2022 were enrolled. All biopsies were performed using an 18-gauge core needle biopsy gun, and the sampling tissues and exfoliative cells of 18-gauge core needle groove were delivered for HP and LBC diagnosis, respectively. The patient demographics, clinical indications, tumor characteristics, number of biopsies, final pathological diagnosis, and follow-up data were reviewed. Univariate and multivariate logistic regression analyses were performed to evaluate the association between variables and HP diagnostic yield of RMCNB. The diagnostic rate between HP and HP plus LBC was compared using McNemar's test and agreement was evaluated using the Kappa score. Results: The most common indication of RMCNB was renal masses with a radiological diagnosis of locally advanced disease or distant metastasis (86.6%). The HP diagnostic yield was established in 88.1% (118/134) of cases, and the diagnostic rate of HP plus LBC was 94.0% (126/134). Logistic regression analyses revealed that non-enhanced area exceeding 50% [odds ratio (OR): 0.021, 95% confidence interval (CI): 0.003-0.134, P<0.001] and number of core biopsies (OR: 9.479, 95% CI: 1.528-58.794, P=0.016) were associated with the HP diagnostic yield of RMCNB. The diagnostic rate of HP plus LBC was significantly higher than that of HP alone (94.0% vs. 88.1%, P=0.008), and they showed substantial agreement (Kappa =0.638, P<0.001). Meanwhile, in the non-enhanced area ≥50% subgroup, the diagnostic rate between HP plus LBC and HP alone was significantly different (86.7% vs. 60%, P=0.008), and the agreement was fair (Kappa =0.375, P=0.009). Conclusions: RMCNB has a high diagnostic yield with a minimum of two high-quality core biopsies, LBC can improve the diagnostic yield of HP alone, especially in masses with large non-enhanced area.

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.

TIGIT immune checkpoint blockade enhances immunity of human peripheral blood NK cells against castration-resistant prostate cancer.

Castration-resistant prostate cancer (CRPC) patients have a 14-month median survival, emphasizing the need for alternative treatments. Previously, we demonstrated that expanded high-dose natural killer (NK) cells derived from human peripheral blood exhibit therapeutic efficacy against CRPC. However, which immune checkpoint blockade promotes NK cell antitumor immunity against CRPC remains unknown. Here, we explored immune checkpoint molecule expression in NK and CRPC cells during their interactions, and identified that the T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) monoclonal antibody (mAb), vibostolimab, significantly enhanced NK cell cytotoxicity against CRPC cells and cytokine production in vitro, demonstrated by upregulation of degranulation marker CD107a and Fas-ligand (Fas-L) and increased interferon-gamma (IFN-γ) and tumor necrosis factor-alpha secretion. TIGIT blockade increased Fas-L expression and IFN-γ production via the NF-κB signaling pathway and restored degranulation via the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase) kinase/ERK pathway in activated NK cells. Vibostolimab significantly enhanced NK cell antitumor effects against CRPC in two xenograft mouse models. Vibostolimab also increased T cell chemotaxis induced by activated NK cells in vitro and in vivo. Overall, blocking TIGIT/CD155 signaling enhances the antitumor effect of expanded NK cells against CRPC; this finding supports the translational application of TIGIT mAb and NK cell combination strategies from bench to bedside for CRPC treatment.

Single-cell RNA sequencing reveals the cellular and molecular characteristics of high-grade and metastatic bladder cancer.

PURPOSE: Metastatic bladder cancer (BC) has the highest somatic mutation frequency and recurrence rate of all tumors. However, the cellular and molecular characteristics of BC remain unclear. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on the samples of paracancerous normal tissue (PNT), primary tumor (PT) and lymph node metastasis (LNM). The proportions and gene expression profiles of different cell types in the tumor microenvironment (TME) were investigated. RESULTS: In total, 50,158 cells were classified into six populations. Malignant cells of PT and LNM exhibited large mutant DNA fragments, while the cell phenotypes and gene expression profiles differed during differentiation. Metastasis was associated with a poorer prognosis than PT. Tumor-associated stromal cells and inhibitory immune cells were the main cell populations in PT and LNM. Cell-cell communication analysis revealed the roles of signaling pathways of inflammatory cancer-associated fibroblast (iCAF) and tumor-associated macrophage (TAM) in exhaustion of T cells. In addition, iCAF may recruit TAM to promote formation of the TME earlier than the differentiation of tumor cells. CONCLUSION: This study through scRNA-seq enhanced our understanding of new features about the cellular and molecular similarities and differences of high-grade and metastatic bladder cancer, which might provide potential therapeutic targets in future treatment.

Abiraterone acetate and prednisone in metastatic castration-resistant prostate cancer: a real-world retrospective study in China.

Background: This research work was aimed at evaluating the incidence and risk factors of adverse events (AEs) occurring in patients treated with abiraterone acetate (AA) and prednisone (PDN) outside clinical trials. These associations were assessed regarding the survival outcomes. Methods: The study included 191 patients aged ≥18 years of confirmed metastatic castration-resistant prostate cancer (mCRPC) between March 2017 and April 2022. AE incidences were descriptively summarized from the whole cohort. Baseline characteristics, safety (treatment-emergent AEs and severe AEs), and efficacy [progression-free survival (PFS)] were analyzed. Multi-variable Cox proportional hazards models were employed to assess the factors linked with PFS. Results: Overall, the median PFS was 17.16 months (range, 0.5-57.58). Patient baseline prostate-specific antigen (PSA) ≧̸10 ng/ml (p = 0.000), multiple organ metastasis (p = 0.007), hypertension (p = 0.004), and coronary heart disease (p = 0.004) were associated with worse PFS; however, radiotherapy (p = 0.028) was linked to better PFS at univariate analysis in the overall cohort. Baseline multiple organ metastasis, hypertension, and radiotherapy remained statistically significant in multivariable models (p = 0.007, p= 0.005, and p = 0.011, respectively).Incidence of AEs showed increased bilirubin (BIL) (55/191 patients, 28.8%) followed by increased alanine aminotransferase/aspartate aminotransferase (ALT/AST) (48/191 patients, 25.09%). The most common grade 3 AEs were increased ALT (3/191, 1.57%) followed by elevated BIL, hypercholesterolemia, and hypokalemia. Anemia had shorter PFS. There were no unexpected AEs in any patient. Conclusion: AA is effective and tolerated in asymptomatic or slightly symptomatic mCRPC in "real-life" setting. The survival outcomes are influenced by multiple organ metastasis, hypertension, and radiotherapy.

Neoadjuvant therapy with camrelizumab plus gemcitabine and cisplatin for patients with muscle-invasive bladder cancer: A multi-center, single-arm, phase 2 study.

BACKGROUND: Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes are suboptimal. Camrelizumab, a PD-1 blockade, has shown benefits in several tumors. This study aimed to investigate the efficacy and safety of neoadjuvant camrelizumab in combination with gemcitabine plus cisplatin (GC) followed by RC for MIBC patients. METHODS: This was a multi-center, single-arm study that enrolled MIBC patients with a clinical stage of T2-4aN0-1M0, and scheduled for RC. Patients received three 21-day cycles of camrelizumab 200 mg on day 1, gemcitabine 1000 mg/m2 on day 1 and 8, and cisplatin 70 mg/m2 on day 2, followed by RC. The primary endpoint was pathologic complete response (pCR, pT0N0). RESULTS: From May 2020 to July 2021, 43 patients were enrolled and received study medications at nine centers in China. Three of them were deemed ineligible and excluded from efficacy analysis but included in safety analysis. In total 10 patients were unevaluable as they declined RC (two due to adverse events [AEs] and eight due to patient's willingness). Among 30 evaluable patients, 13 patients (43.3%) achieved pCR, and 16 patients (53.3%) achieved pathologic downstaging. No AEs leading to death were observed. The most common AEs were anemia (69.8%), decreased white blood cell count (65.1%), and nausea (65.1%). Immune-related AEs were all grade 1 or 2. Pathologic response was not correlated with PD-L1 expression status or tumor mutation burden. Individual genes as a biomarker for pathologic response were not identified. CONCLUSIONS: Neoadjuvant treatment with camrelizumab and GC regimen demonstrated preliminary anti-tumor activity for MIBC patients with manageable safety profiles. The study met its primary endpoint, and the following randomized trial is ongoing.

Pan-cancer analysis and experimental validation of DTL as a potential diagnosis, prognosis and immunotherapy biomarker.

BACKGROUND: DTL has been found to be related with multiple cancers. However, comprehensive analyses, which identify the prediction value of DTL in diagnosis, prognosis, immune infiltration and treatment, have rarely been reported so far. METHODS: Combined with the data online databases, the gene expression, gene mutation, function enrichment and the correlations with the immunity status and clinical indexes of DTL were analyzed. Expression of DTL and the degree of immune cell infiltration were examined by immunofluorescence (IF) and immunohistochemistry (IHC) and analyzed by statistical analysis. Furthermore, the influences of DTL on the cell cycle, cell proliferation and apoptosis were detected by live cell imaging, IF and flow cytometric (FC) analysis. Genomic stability assays were conducted by chromosome slide preparation. RESULTS: DTL was widely expressed in various cells and tissues, while it was overexpressed in tumor tissues except acute myeloid leukemia (LAML). Pan-cancer bioinformatics analysis showed that the expression of DTL was correlated with the prognosis, immunotherapy, and clinical indexes in various cancers. In addition, gene set enrichment analysis (GSEA) uncovered that DTL was enriched in oocyte meiosis, pyrimidine metabolism, the cell cycle, the G2M checkpoint, mTORC1 signaling and E2F targets. Furthermore, the overexpression of DTL, and its association with immune cell infiltration and clinical indexes in liver hepatocellular carcinoma (LIHC), bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD) were verified in our study. It was also verified that overexpression of DTL could regulate the cell cycle, promote cell proliferation and cause genomic instability in cultured cells, which may be the reason why DTL plays a role in the occurrence, progression and treatment of cancer. CONCLUSIONS: Collectively, this study suggested that DTL is of clinical value in the diagnosis, prognosis and treatment of various cancers, and may be a potential biomarker in certain cancers.

MRI-measured periprostatic adipose tissue volume as a prognostic predictor in prostate cancer patients undergoing laparoscopic radical prostatectomy.

In this study, we evaluated the association between the PPAT volume and the prognosis of PCa patients after LRP. We retrospectively analysed data of 189 PCa patients who underwent LRP in Beijing Chaoyang Hospital. Volumes of PPAT and prostate were measured by magnetic resonance imaging (MRI), and normalized PPAT volume was computed (PPAT volume divided by prostate volume). Patients were then stratified into the high-PPAT group (n = 95) and low-PPAT group (n = 94) by the median of normalized PPAT volume (73%). The high-PPAT group had significantly higher Gleason score (total score 8 or more, 39.0% vs. 4.3%, p < 0.001) and pathological stage (stage T3b, 28.4% vs. 13.8%, p = 0.048). No significant correlation between normalized PPAT volume and body mass index (ρ = -0.012, p = 0.872) was observed. Kaplan-Meier curve analysis showed the high-PPAT group had significantly shorter biochemical recurrence (BCR) interval (median progression-free survival time 15.9 months vs. 32.7 months, p = 0.001). Univiarate and multivariate Cox regression analyses showed high normalized PPAT volume (>73%) (hazard ratio 1.787 [1.075-3.156], p = 0.002) were independent risk factors for BCR post-operatively. In conclusion, MRI-measured PPAT volume is of significant prognostic value for PCa patients undergoing LRP.

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.

Search for the optimized and key nephrometry elements combination in retroperitoneal laparoscopic partial nephrectomy: A retrospective study.

Background: The nephrometry scoring system plays a key role in the preoperative evaluation of partial nephrectomy, and scoring systems based on anatomical characteristics have high similarity in scoring elements. Currently, there is little research on scoring systems related to retroperitoneal laparoscopic partial nephrectomy, and there is a lack of research on the combination of scoring elements, which requires further investigation. Methods: We retrospectively analyzed the clinical records of 107 patients who underwent retroperitoneal laparoscopic partial nephrectomy conducted by a single operator at a single center. The score and scoring elements were generated based on imaging. The scoring elements of each scoring system and all combinations of two to five elements were extracted. The predictive ability of different score combinations was evaluated by AUC value, and the key parameters of the score were found by taking the intersection. A nomogram was constructed and evaluated. Results: We observed that with an increase in scoring elements, the strongest combination of elements did not significantly increase the predictive ability of warm ischemia time (P>0.05), postoperative complications (P>0.05), and trifecta achievement (P>0.05). The combination of the maximum tumor diameter and the distance between tumor and collecting system or renal sinus had a good comprehensive predictive ability, and there is no significant difference with the traditional score (P>0.05). The nomogram generated according to this combination has an excellent prediction ability for predicting whether obtain trifecta of partial nephrectomy. Conclusions: Within the range of two to five elements, the critical degree of elements is more important than the number of elements. The maximum tumor diameter and the distance between the tumor and the collecting system or renal sinus was the key element of the prediction ability.