Estimation of the tumor size at cure threshold among adult patients with adrenocortical carcinoma: A populational-based study.

Background: The prognostic significance of tumor size with adrenocortical carcinoma (ACC) patients has not yet been thoroughly evaluated. Our objective was to investigate the influence of tumor size on prognostic value in adult ACC patients. Methods: The Surveillance, Epidemiology and End Results Program (SEER) was employed to identify adult ACC patients who had been diagnosed from 2004 to 2015. The "X-Tile" program determined the optimal cutoff value of tumor size. Cancer-specific survival (CSS) and overall survive (OS) were estimated. The survival outcomes and risk factors were analyzed by the Kaplan-Meier methods and the multivariable cox regression respectively. Results: A total 426 adult ACC patients were included. Univariable and multivariable cox analysis revealed age, larger tumor size and metastasis as consistent predictors of lower CSS and OS. The optimal cutoff value of tumor size was identified as 8.5 cm using X-tile software, and Kaplan-Meier method showed dramatic prognostic difference between patients with larger tumors (＞8.5 cm) and smaller tumors (≤8.5 cm) (log-rank test, P < 0.001). Subgroup analyses revealed no statistical significance and a consistent proportionate effect of tumor size on CSS and OS across all eight pre-specified subgroups. Interestingly, an additional subgroup analysis showed that ACC patients could not benefit from chemotherapy in terms of CSS and OS. Conclusion: The study suggests that tumor size is a crucial prognostic factor in ACC patients and a cutoff value 8.5 cm might indicate a poor outcome. Given the limitations of the available data, it is challenging to conclusively determine the benefit of chemotherapy in adult ACC patients across different tumor size ranges.

Analysis of the origin and invasion of prostate cancer from autopsy and radical prostatectomy specimens.

Background: Without a pseudocapsule, prostate cancer is invasive in volume growth and has some regularity in spatial distribution. Our study aims to explore the specific origin location, invasive characteristics, and morphology of prostate cancer. Methods: Ninety-eight clinical specimens with tumor volume equal to or less than one-third of the organ volume and 111 autopsy specimens were retrospectively analyzed. The origin location and invasion of prostate cancer in four horizontal quadrants and 11 vertical slides were demonstrated. In addition, the median maximum anteroposterior, left-right, horizontal, and vertical diameters of lesions were compared, and the spatial morphology of lesions was described. Results: There were 335 lesions in the autopsy and clinical specimens. There was no significant difference in the distribution of lesions confined to the horizontal quarter quadrant (P=0.064). The number of lesions with a single positive slide above the apex 0.5-1.4 cm was 75 (49.7%). No significant difference was found when compared with the maximum vertical and horizontal diameters (P=0.421). However, the maximum left-right and horizontal diameters were longer than the maximum anteroposterior diameter (P=0.046 and P<0.001). The number of lesions with a tumor area that decreased from the center to both sides was 85 (46.2%) and decreased from the center to one side was 81 (44.0%). Conclusions: Approximately 50% of the lesions originated from the apex above 0.5-1.4 cm. The invasive tendency of prostate cancer was consistent in the horizontal and vertical dimensions but less so in the anteroposterior direction. About ninety percent of lesions with tumor area decreased from the center to both sides or one side.

Safety and feasibility of single-port nephroscopy combined with a needle electrode technique to treat dorsal SRCs.

Objective The aim of this study was to explore the safety and feasibility of single-port nephroscopy combined with a needle electrode technique to unroof single dorsal simple renal cysts (SRCs). Methods This was a retrospective analysis of the clinical data for 18 patients with single dorsal SRCs treated with single-port nephroscopy and a needle electrode technique at Zhongshan City People's Hospital from August 2021 to August 2022. The basic information included the cyst condition, surgical methods and recurrence rate, and follow-up was conducted with CT imaging. Results The surgery was successful in all 18 patients. The duration of surgery ranged from 24-46 minutes, with an average of 35.83±1.62 minutes; the intraoperative bleeding volume ranged from 2-20 ml, with an average of 9.0±1.3 ml; and the visual analog scale (VAS) score within 24 hours after surgery ranged from 1-6 points, with an average of 2.72±0.36 points. There were no significant postoperative complications, such as bleeding, urinary fistula, or infection. All drainage tubes were removed on the first day after surgery. After 1 year of postoperative follow-up, one patient experienced recurrence, for a recurrence rate of 5.6%. Conclusion Single-port nephroscopy combined with a needle electrode technique is a safe, feasible, and effective minimally invasive surgical approach for treating single dorsal SRCs.

N6-methyladenosine modified lncRNAs signature for stratification of biochemical recurrence in prostate cancer.

Nonmutational epigenetic reprogramming is a crucial mechanism contributing to the pronounced heterogeneity of prostate cancer (PCa). Among these mechanisms, N6-methyladenosine (m6A)-modified long non-coding RNAs (lncRNAs) have emerged as key players. However, the precise roles of m6A-modified lncRNAs in PCa remain to be elucidated. In this study, methylated RNA immunoprecipitation sequencing (MeRIP-seq) was conducted on primary and metastatic PCa samples, leading to the identification of 21 lncRNAs exhibiting differential methylation and expression patterns. We further established a PCa prognostic signature, named m6A-modified lncRNA score (mLs), based on 9 differential methylated lncRNAs in 4 multicenter cohorts. The high mLs score cohort exhibited a tendency for earlier biochemical recurrence (BCR) compared to the low mLs score cohort. Remarkably, the predictive performance of the mLs score surpassed that of five previously reported lncRNA-based signatures. Functional enrichment analysis underscored a negative correlation between the mLs score and lipid metabolism. Additionally, through MeRIP-qPCR, we pinpointed a hub gene, MIR210HG, which was validated through in vitro and in vivo experiments. These findings collectively illuminate the landscape of m6A-methylated lncRNAs in PCa tissue via MeRIP-seq and harness this information to prognosticate PCa outcomes using the mLs score. Furthermore, our study validates, both experimentally and mechanistically, the facilitative role of MIR210HG in driving PCa progression.

Biparametric MRI-based radiomics classifiers for the detection of prostate cancer in patients with PSA serum levels of 4∼10 ng/mL.

Purpose: To investigate the predictive performance of the combined model by integrating clinical variables and radiomic features for the accurate detection of prostate cancer (PCa) in patients with prostate-specific antigen (PSA) serum levels of 4-10 ng/mL. Methods: A retrospective study of 136 males (mean age, 67.3 ± 8.4 years) with Prostate Imaging-Reporting and Data System (PI-RADS) v2.1 category ≤3 lesions and PSA serum levels of 4-10 ng/mL were performed. All patients underwent multiparametric MRI at 3.0T and transrectal ultrasound-guided systematic prostate biopsy in their clinical workup. Radiomic features were extracted from axial T2-weighted images (T2WI) and apparent diffusion coefficient (ADC) maps of each patient using PyRadiomics. Pearson correlation coefficient (PCC) and recursive feature elimination (RFE) were implemented to identify the most significant radiomic features. Independent clinic-radiological factors were identified via univariate and multivariate regression analyses. Seven machine-learning algorithms were compared to construct a single-layered radiomic score (ie, radscore) and multivariate regression analysis was applied to construct the fusion radscore. Finally, the radiomic nomogram was further developed by integrating useful clinic-radiological factors and fusion radscore using multivariate regression analysis. The discriminative power of the nomogram was evaluated by area under the curve (AUC), DeLong test, calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC). Results: The transitional zone-specific antigen density was identified as the only independent clinic-radiological factor, which yielded an AUC of 0.592 (95% confidence interval [CI]: 0.527-0.657). The ADC radscore based on six features and Naive Bayes achieved an AUC of 0.779 (95%CI: 0.730-0.828); the T2WI radscore based on 13 features and Support Vector Machine yielded an AUC of 0.808 (95%CI: 0.761-0.855). The fusion radscore obtained an improved AUC of 0.844 (95%CI: 0.801-0.887), which was higher than the single-layered radscores (both P<0.05). The radiomic nomogram achieved the highest value among all models (all P<0.05), with an AUC of 0.872 (95%CI: 0.835-0.909). Calibration curve showed good agreement and DCA together with CIC confirmed the clinical benefits of the radiomic nomogram. Conclusion: The radiomic nomogram holds the potential for accurate and noninvasive identification of PCa in patients with PI-RADS ≤3 lesions and PSA of 4-10 ng/mL, which could reduce unnecessary biopsy.

Genome-Scale CRISPR-Cas9 Transcriptional Activation Screening in Metformin Resistance Related Gene of Prostate Cancer.

Metformin is a classic type II diabetes drug which possesses anti-tumor properties for various cancers. However, different cancers do not respond to metformin with the same effectiveness or acquire resistance. Thus, searching for vulnerabilities of metformin-resistant prostate cancer is a promising strategy to improve the therapeutic efficiency of the drug. A genome-scale CRISPR-Cas9 activation library search targeting 23,430 genes was conducted to identify the genes that confer resistance to metformin in prostate cancer cells. Candidate genes were selected by total reads of sgRNA and sgRNA diversity, and then a CCK8 assay was used to verify their resistance to metformin. Interestingly, we discovered that the activation of ECE1, ABCA12, BPY2, EEF1A1, RAD9A, and NIPSNAP1 contributed to in vitro resistance to metformin in DU145 and PC3 cell lines. Notably, a high level of RAD9A, with poor prognosis in PCa, was the most significant gene in the CCK8 assay. Furthermore, we discerned the tumor immune microenvironment with RAD9A expression by CIBERSORT. These results suggested that a high level of RAD9A may upregulate regulatory T cells to counterbalance metformin in the tumor immune microenvironment.

Ginsenoside Rh2 Inhibits Angiogenesis in Prostate Cancer by Targeting CNNM1.

To explore the molecular mechanism by which ginsenoside Rh2 (G-Rh2) inhibits prostate cancer by regulating vascular growth. Different concentrations of G-Rh2 with three prostate cancer cell lines (LNCaP, PC3 and DU145) were transplanted in nude mice, and tumor mass volume was measured over time. LNCaP, PC3 and DU145 were co-cultured with vascular endothelial cells to determine the optimal concentration of G-Rh2 by MTT assay. LNCaP, PC3 and DU145 were cultured under the selected concentration (0, 0.01, 0.05, 0.1, 0.5 and 1 mg/mL) of G-Rh2, and the expression levels of CD31, VEGF, PDGF and CNNM1 detected by qRT-PCR and western blot. The expression pattern of CD31 was detected in CNNM1 overexpressed and knockout LNCaP, PC3 and DU145 cells under G-Rh2. G-Rh2 significantly inhibited the growth of all three prostate cancer cell lines in the dorsum of nude mice (P <0.05), and the increment rate of vascular endothelial cells co-cultured with LNCaP, PC3 and DU145 (P <0.05). The expression of CD31, VEGF, PDGF and CNNM1 genes in LNCaP, PC3 and DU145 cells was inhibited by G-Rh2. Overexpression of CNNM1 reversed the inhibitory effect of G-Rh2 on the expression of CD31 in these cells (P <0.05), while the function of knockout of CNNM1 and the inhibitory effect of G-Rh2 appeared to be similar (P <0.05). In conclusion, G-Rh2 inhibited prostate cancer growth by inhibiting its angiogenesis through decreasing the expression of CNNM1 in the cancer cells.

miR­30c suppresses prostate cancer survival by targeting the ASF/SF2 splicing factor oncoprotein.

Our previous study revealed that microRNA (miR) ­30c represents a potential tumor suppressor gene, the expression of which is associated with decreased oncogenic potential in prostate cancer (PCa) cell lines. However, the functional role and underlying mechanisms of miR­30c in PCa remain to be fully elucidated. Reverse transcription­quantitative polymerase chain reaction and immunohistochemical analysis were used to detect the expression levels of alternative splicing factor/splicing factor 2 (ASF/SF2) in PCa tissues. A luciferase reporter assay was used to investigate whether ASF/SF2 may be a direct target gene of miR­30c. In addition, the effects of miR­30c on the proliferation and apoptosis of PCa cell lines were examined, following transfection with miR­30c mimics. Furthermore, correlation analysis was performed to investigate the relationship between the expression of miR­30c and ASF/SF2 and various clinicopathological parameters of patients with PCa. The present results demonstrated that PCa tissues exhibited higher levels of alternative splicing factor/splicing factor 2 (ASF/SF2), compared with normal tissues. In addition, miR­30c was revealed to targete the 3'­untranslated region of the ASF/SF2 gene, causing a decrease in the mRNA and protein levels of ASF/SF2. Furthermore, miR­30c was reported to decrease cell proliferation, increase the percentage of cells in the G1 cell cycle phase, and promote apoptosis through the inhibition of ASF/SF2. Following correlation analysis using patient samples, the expression of ASF/SF2 was revealed to be tightly correlated with the pathological stage of PCa and biochemical recurrence (BCR). In addition, patients with PCa exhibiting low expression levels of miR­30c and high expression of ASF/SF2 had significantly lower rates of BCR­free survival. In conclusion, the present study suggested that the tumor suppressor miR­30c may be involved in PCa tumorigenesis, possibly via targeting ASF/SF2. The combined analysis of the expression of ASF/SF2 and miR­30c may be a valuable tool for early prediction of BCR in patients with PCa following radical prostatectomy.

Overexpression of NIMA-related kinase 2 is associated with progression and poor prognosis of prostate cancer.

BACKGROUND: The NIMA-related kinase 2 (NEK2) is a serine/threonine kinase that is involved in regulation of centrosome duplication and spindle assembly during mitosis. Dysregulation of these processes causes chromosome instability and aneuploidy, which are hallmark changes of many solid tumors. However, whether aberrant expression of NEK2 is associated with outcome of prostate cancer (PCa) patients remains to be determined. METHODS: Expression of NEK2 in human PCa cells and primary PCa tissues was assessed by quantitative RT-PCR. Expression of NEK2 in human PCa cells was depleted with siRNA. Effects of the depletion on cell proliferation, survival, and tumorigenicity were assessed both in vitro with cell cultures and in vivo with subcutaneous implantation of xenografts. In silico analyses of the online Taylor dataset were carried out to determine whether the expression level of NEK2 correlated with the clinicopathological characteristics of prostate cancer. RESULTS: Compared with benign human prostatic epithelial cells and tissues, the expression of NEK2 was elevated in human PCa cells and primary PCa tissues. Depleting NEK2 expression inhibited human PCa cell proliferation in vitro and xenograft growth in vivo. Expression level of NEK2 in PCa positively correlated with the Gleason score and pathologic stage of the patient. CONCLUSION: The results suggest that overexpression of NEK2 has the potential to serve as a biomarker for PCa prognosis. Further validation with large sample pool is warrant.

MicroRNA-224 and its target CAMKK2 synergistically influence tumor progression and patient prognosis in prostate cancer.

We previously demonstrated that microRNA (miR)-224 expression was significantly reduced in human prostate cancer (PCa) tissues and predicted unfavorable prognosis in patients. However, the underlying mechanisms of miR-224 have not been fully elucidated. In this study, calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was identified as a target gene of miR-224. Then, we found that enforced expression of miR-224 could suppress PCa cell proliferation and cell cycle by regulating the expression of CAMKK2 in vitro. In addition, the expression levels of miR-224 in PCa tissues were negatively correlated with those of CAMKK2 mRNA significantly (Spearman's correlation: r = -0.66, P = 0.004). Moreover, combined low miR-224 expression and high CAMKK2 expression (miR-224-low/CAMKK2-high) was closely correlated with advanced clinical stage (P = 0.028). Furthermore, PCa patients with miR-224-low/CAMKK2-high expression more frequently had shorter overall survival than those in groups with other expression patterns of two molecules. In conclusion, our data offer the convincing evidence that miR-224 and its target gene CAMKK2 may synergistically contribute to the malignant progression of PCa. Combined detection of miR-224 and CAMKK2 expressions represents an efficient predictor of patient prognosis and may be a novel marker which can provide additional prognostic information in PCa.

Elevated expression of IMPDH2 is associated with progression of kidney and bladder cancer.

Novel molecular markers for cancer progression are valuable for the diagnosis and evaluation of treatment efficacies of the diseases. Expression of inosine 5'-monophosphate dehydrogenase type II (IMPDH2), a rate-limiting enzyme in the de novo guanine nucleotide biosynthesis, is up-regulated in various neoplasms, including prostate cancer and patient serum. However, whether IMPDH2 can serve as a biomarker for other urologic cancers is unknown. Paired patient tissue macroarrays were analyzed by immunohistochemistry, the IMPDH2 protein expression in these tissues was quantitated and expressed as immunoreactivity scores. Compared with non-cancerous tissues, IMPDH2 protein expression levels were significantly upregulated in kidney and bladder cancer, but no difference in testis cancer. In addition, expression of IMPDH2 was not associated with the disease clinical stages and pathological features. The findings suggest that overexpressed IMPDH2 can be used as a biomarker for kidney and bladder cancer diagnosis and is a potential therapeutic target for the diseases.

Combined overexpression of HIVEP3 and SOX9 predicts unfavorable biochemical recurrence-free survival in patients with prostate cancer.

BACKGROUND: To clarify the involvement of HIVEP3 and SOX9 coexpression in prostate cancer (PCa). METHODS: A small interfering RNA was used to knockdown SOX9 expression in a PCa cell line and to analyze the effects of SOX9 inhibition on the expression of HIVEP3 in vitro. Then, HIVEP3 and SOX9 expression patterns in the human PCa tissues were detected using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry. RESULTS: We found that the downregulation of SOX9 could inhibit the expression of HIVEP3 in the PCa cells in vitro. In addition, both HIVEP3 and SOX9 messenger RNA expression levels in the PCa tissues were significantly higher than those in the noncancerous prostate tissues (P=0.006 and P<0.001, respectively). Moreover, the immunohistochemical staining scores of HIVEP3 in the PCa tissues with PSA failure were significantly higher than those without (P=0.042); the increased SOX9 protein expression was more frequently found in the PCa tissues with a high Gleason score (P=0.045) and a high clinical stage (P=0.012). The tumors showing the HIVEP3-high/SOX9-high expression more frequently had PSA failure (P=0.024). When the patients with an HIVEP3 overexpression combined with the SOX9 overexpression, this group had a worse biochemical recurrence-free survival (P<0.001). Furthermore, the multivariate analysis showed that the HIVEP3/SOX9 coexpression was an independent predictor of an unfavorable biochemical recurrence-free survival. CONCLUSION: Our data offer the convincing evidence for the first time that a combined analysis of HIVEP3 and SOX9 may help to predict the tumor progression and prognosis of PCa patients. In particular, the overexpression of HIVEP3 in PCa might partly explain the poor prognosis of patients with an upregulation of SOX9.

MicroRNA-224 inhibits progression of human prostate cancer by downregulating TRIB1.

Our previous microarray data showed that microRNA-224 (miR-224) was downregulated in human prostate cancer (PCa) tissues compared with adjacent benign tissues. However, the underlying mechanisms by which miR-224 is involved in PCa remain unclear. In this study, we identified TRIB1 as a target gene of miR-224. Forced expression of miR-224 suppressed PCa cell proliferation, invasion and migration, and promoted cell apoptosis by downregulating TRIB1. Moreover, the expression level of miR-224 in PCa tissues was negatively correlated with that of TRIB1. miR-224 downregulation was frequently found in PCa tissues with metastasis, higher PSA level and clinical stage, whereas TRIB1 upregulation was significantly associated with metastasis. Both miR-224 downregulation and TRIB1 upregulation were significantly associated with poor biochemical recurrence-free survival of patients with PCa. In conclusion, these findings reveal that the aberrant expression of miR-224 and TRIB1 may promote PCa progression and have potentials to serve as novel biomarkers for PCa prognosis.

Decreased expression of myosin light chain MYL9 in stroma predicts malignant progression and poor biochemical recurrence-free survival in prostate cancer.

The aim of this study was to investigate the associations of myosin light chain (MYL9) downregulation with tumor progression and prognosis in patients with prostate cancer (PCa). MYL9 protein expression in human PCa and non-cancerous prostate tissues was detected by Western blot and immunohistochemistry analyses, which was validated by microarray-based Taylor data at mRNA level. Then, the associations of MYL9 expression with clinicopathological features and clinical outcome of PCa patients were statistically analyzed. Both Western blot and immunohistochemistry analyses found that MYL9 expression was significantly decreased (both P < 0.001) in PCa tissues compared with those in non-cancerous prostate tissues. In addition, MYL9 was mainly expressed in the cytoplasm of stromal cells of prostate tissues, and the decreased expression of MYL9 in PCa tissues was significantly correlated with the older age of patients (P = 0.011), the higher Gleason score (P < 0.001), the advanced pathological stage (P = 0.002), the presence of metastasis (P < 0.001) and PSA failure (P = 0.001). Furthermore, both univariate and multivariate analyses showed that the downregulation of MYL9 was an independent predictor of shorter overall survival (P = 0.026 and P = 0.009, respectively) and biochemical recurrence-free survival (P = 0.001 and P = 0.002, respectively). Our data strongly confirmed for the first time that the decreased expression of MYL9 may play an important role in tumor progression of PCa. More importantly, the downregulation of MYL9 may efficiently predict both overall and biochemical recurrence-free survivals in PCa patients.

Clinical performance of serum [-2]proPSA derivatives, %p2PSA and PHI, in the detection and management of prostate cancer.

Prostate-specific antigen (PSA) has been widely used as a serum marker for prostate cancer (PCa) screening or progression monitoring, which dramatically increased rate of early detection while significantly reduced PCa-specific mortality. However, a number of limitations of PSA have been noticed. Low specificity of PSA may lead to overtreatment in men who presenting with a total PSA (tPSA) level of < 10 ng/mL. As a type of free PSA (fPSA), [-2]proPSA is differentially expressed in peripheral zone of prostate gland and found to be elevated in serum of men with PCa. Two p2PSA-based derivatives, prostate health index (PHI) and %p2PSA, which were defined as [(p2PSA/fPSA) × âˆš tPSA] and [(p2PSA/fPSA) × 100] respectively, have been suggested to be increased in PCa and can better distinguish PCa from benign prostatic diseases than tPSA or fPSA. We performed a systematic review of the available scientific evidences to evaluate the potentials of %p2PSA and PHI in clinical application. Mounting evidences suggested that both %p2PSA and PHI possess higher area under the ROC curve (AUC) and better specificity at a high sensitivity for PCa detection when compare with tPSA and %fPSA. It indicated that measurements of %p2PSA and PHI significantly improved the accuracy of PCa detection and diminished unnecessary biopsies. Furthermore, elevations of %p2PSA and PHI are related to more aggressive diseases. %p2PSA and PHI might be helpful in reducing overtreatment on indolent cases or assessing the progression of PCa in men who undergo active surveillance. Further studies are needed before being applied in routine clinical practice.