Ferroptosis and ferroptosis-inducing nanomedicine as a promising weapon in combination therapy of prostate cancer.

Incidence and mortality of prostate cancer (PCa) rank in the top five among male tumors. However, single treatment modalities are often restricted due to biochemical recurrence and drug resistance, necessitating the development of new approaches for the combination treatment of castration-resistant and neuroendocrine PCa. Ferroptosis is characterized by the accumulation of iron-overload-mediated lipid peroxidation and has shown promising outcomes in anticancer treatment, prompting us to present a review reporting the application of ferroptosis in the treatment of PCa. First, the process and mechanism of ferroptosis are briefly reviewed. Second, research advances combining ferroptosis-inducing agents and clinical treatment regimens, which exhibit a "two-pronged approach" effect, are further summarized. Finally, the recent progress on ferroptosis-inducing nanomaterials for combination anticancer therapy is presented. This review is expected to provide novel insights into ferroptosis-based combination treatment in drug-resistant PCa.

Hippo signaling modulation and its biological implications in urological malignancies.

Although cancer diagnosis and treatment have rapidly advanced in recent decades, urological malignancies, which have high morbidity and mortality rates, are among the most difficult diseases to treat. The Hippo signaling is an evolutionarily conserved pathway in organ size control and tissue homeostasis maintenance. Its downstream effectors, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), are key modulators of numerous physiological and pathological processes. Recent work clearly indicates that Hippo signaling is frequently altered in human urological malignancies. In this review, we discuss the disparate viewpoints on the upstream regulators of YAP/TAZ and their downstream targets and systematically summarize the biological implications. More importantly, we highlight the molecular mechanisms involved in Hippo-YAP signaling to improve our understanding of its role in every stage of prostate cancer, bladder cancer and kidney cancer progression. A better understanding of the biological outcomes of YAP/TAZ modulation will contribute to the establishment of future therapeutic approaches.

Assessment of Therapeutic Benefit and Option Strategy on Intravesical Instillation for Preventing Bladder Cancer Recurrence after Radical Nephroureterectomy in Patients with Upper Urinary Tract Urothelial Carcinoma.

Objective: Upper urinary tract urothelial carcinoma (UUT-UC) is a very aggressive disease, characterized by 22%-50% of patients suffering from subsequent bladder recurrence after radical nephroureterectomy (RNU). Although the therapy of intravesical instillation is reported to be effective in preventing bladder recurrence, no study had been reported in Northeast China. The findings relating to the clinical effectiveness of intravesical instillation after RNU are somewhat controversial, and the best efficacy and least adverse effects of instillation drugs have not been widely accepted. Here, we aimed at evaluating the efficacy of intravesical instillation for the prevention intravesical recurrence systematically. Methods: In this retrospective cohort study, from October 2006 to September 2017, 158 UUT-UC patients underwent RNU were divided into 4 groups: epirubicin (EPB) instillation group, hydroxycamptothecin (HCPT) instillation group, bacillus Calmette-Guerin (BCG) instillation group, and noninstillation group. Cox univariate and multivariate analyses were employed to identify the risk factors for intravesical recurrence-free survival (IVRFS). The nomogram model was also applied to predict patient outcomes. Subsequently, to evaluate the clinical significance of intravesical instillation comprehensively, several databases including PubMed, Ovid, and Embase were searched and data from published studies with our results were combined by direct meta-analysis. Moreover, a network meta-analysis comparing instillation therapies was conducted to evaluate the clinical efficacy of different instillation drugs. Results: In our retrospective cohort study, the Kaplan-Meier survival curve demonstrated noninstillation groups were associated with worsened IVRFS. Meanwhile, multivariate analysis indicated that intravesical instillation was independent protective factors for IVRFS (hazard ratio [HR] = 0.731). Moreover, calibration plots, receiver operating characteristic (ROC) curves, area under the curve (AUC) values, and the C-index showed the priority of nomogram's predictive accuracy. Next, direct meta-analysis including 19 studies showed that intravesical instillation could prevent the recurrence of bladder cancer with a pooled risk ratio (RR) estimate of 0.53. Subgroup analysis by study type, year of intravesical recurrence, first instillation time, and instillation times also confirmed the robustness of the results. Moreover, intraoperative instillation was associated with a decrease in the risk of bladder recurrence compared with postoperative instillation. Then, a network meta-analysis including 7 studies indicated that pirarubicin (THP) (surface under the cumulative ranking curve [SUCRA] = 89.2%) is the most effective therapy to reduce the risk of bladder recurrence, followed by BCG (SUCRA = 83.5%), mitomycin C (MMC) (SUCRA = 53.6%), EPB (SUCRA = 52.6%), and HCPT (SUCRA = 5.1%) after the analysis of the value ranking. Conclusions: A maintenance schedule of intravesical instillation prevents the recurrence of bladder cancer after RNU in UUT-UC patients effectively. Large, prospective trials are needed to further confirm its value. Compared with other chemotherapy regimens, THP may be a promising drug with favorable efficacy to prevent bladder recurrence. As included studies had moderate risk of bias, the results of network meta-analysis should be applied with caution.

Immunohistochemical analysis of PD-L1 and tumor-infiltrating immune cells expression in the tumor microenvironment of primary signet ring cell carcinoma of the prostate.

Primary signet ring cell carcinoma (SRCC) of the prostate is a rare neoplasm. However, its potential tumorigenic mechanism, clinicopathological features, and prognostic outcome have not been systematically described. To determine the pathogenic mechanism, we detected distributions of programmed cell death-ligand 1 (PD-L1), programmed death 1 (PD-1), and cellular components in the tumor microenvironment, including tumor-infiltrating lymphocytes (CD4 and CD8), tumor-associated macrophages (TAMs; CD163 and CD68), and tumor-associated fibroblasts (vimentin and alpha-smooth muscle actin [α-SMA]), in tumor tissues from four patients with primary prostatic SRCC compared with corresponding adjacent tissues and tumor tissues from 30 patients with prostate adenocarcinoma (PCa) by immunohistochemical staining. We found higher expression of PD-L1, CD163, and CD68 in primary SRCC specimens than that in both corresponding adjacent nontumor specimens and PCa specimens with different Gleason scores, indicating that TAMs may participate in the malignant biological behavior of primary SRCC of the prostate. For further analysis, we searched electronic journal databases and Surveillance, Epidemiology, and End Results (SEER) to identify 200 eligible patients including our four cases. According to Kaplan-Meier survival curve analysis, patients <68 years old, with radical prostatectomy (RP), Gleason score of 7-8, and lower clinical stage had longer overall survival (OS). Moreover, Cox multivariate analysis indicated that race (hazard ratio [HR] = 1.422), surgical approach (HR = 1.654), and Gleason score (HR = 2.162) were independent prognostic factors for OS. Therefore, primary SRCC of the prostate represents a distinct and aggressive subtype of prostate cancer associated with a higher distribution of PD-L1 and TAMs, which warrants further clinical investigation.

Primary adrenal tuberculosis infection in patients with Behcet's disease presenting as isolated adrenal metastasis by 18F-FDG PET/CT: a rare case report and literature review.

Primary adrenal tuberculosis (TB) is a rare type of extrapulmonary tuberculosis (EPTB). A pathological biopsy is usually required to make a definite diagnosis due to nonspecific symptoms. Antituberculous chemotherapy is the main treatment regimen, and cortisol replacement therapy should be added when adrenal insufficiency is involved. Here, we present a 59-year-old man who had recurrence of oral and genital aphthosis for 3 years and was diagnosed with Behcet's disease (BD), which was cured by thalidomide. After 10 days of admission, the patient had sudden abdominal pain in the right upper quadrant with high fever and was diagnosed with acute cholecystitis attack, which was treated by percutaneous transhepatic gallbladder drainage (PTGBD). Further contrast-enhanced CT showed a right adrenal mass with a diameter of 2.0 cm, and PET-CT indicated intense 18F-fluorodeoxyglucose (18F-FDG) uptake in the right adrenal mass with a maximum standardized uptake value (SUVmax) of 15.2. As a metastatic adrenal mass was suspected, the patient underwent retroperitoneal laparoscopic adrenalectomy. Histopathological and immunohistochemical analysis revealed primary adrenal TB. After routine anti-tuberculosis treatment with isoniazid, rifampin, pyrazinamide and ethambutol for six months, the patient was cured and discharged. In summary, primary unilateral adrenal TB without adrenal insufficiency is difficult to diagnose only on the basis of clinical manifestations and examinations. Further studies are needed to develop an easier and more accurate diagnostic examination.

Predictive Value of Preoperative Positive Urine Cytology for Development of Bladder Cancer After Nephroureterectomy in Patients With Upper Urinary Tract Urothelial Carcinoma: A Prognostic Nomogram Based on a Retrospective Multicenter Cohort Study and Systematic Meta-Analysis.

BACKGROUND: Upper urinary tract urothelial carcinoma (UUT-UC) is a rare and severe urinary malignancy. Several studies have explored the relationship between preoperative urine cytology and intravesical recurrence (IVR) in patients with UUT-UC. However, the results of these studies are controversial or even contradictory, and investigations with UUT-UC patients in northeast China are rare. METHODS: We first estimated the prognostic significance of preoperative urine cytology in the outcomes of intravesical recurrence in 231 UUT-UC patients (training cohort = 142, validation cohort = 89) after radical nephroureterectomy (RNU) by the nomogram model. Subsequently, we quantitatively combined our results with the published data after searching several databases to assess whether preoperative positive urine cytology was associated with poor intravesical recurrence-free survival and a high risk of tumor malignant biological behavior. RESULTS: Firstly, the multicenter retrospective cohort study demonstrated that preoperative positive urine cytology correlated with poor intravesical recurrence-free survival and can serve as significant independent predictors of IVR by Kaplan-Meier curves and Cox regression analysis. The construction of the nomogram demonstrated that predictive efficacy and accuracy were significantly improved when preoperative urine cytology was combined. Meanwhile, meta-analysis showed that preoperative positive urine cytology was associated with a 49% increased risk of IVR. In the subgroup analysis by region, study type, and sample size, the pooled hazard ratios (HRs) were statistically significant for the Japan subgroup (HR 1.32), China subgroup (HR 1.88), cohort study subgroup (HR 1.45), and the single-arm study subgroup (HR 1.63). CONCLUSIONS: Preoperative urine cytology was validated as a potential predictor of intravesical recurrence in patients with UUT-UC after RNU, although these results need to be generalized with caution. Large, prospective trials are required to further confirm its significance in prognosis and tumor malignant biological behavior.