Diagnosis and management of urinary bladder paragangliomas: A Sino-American-European retrospective observational study.

OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.

PD-L1 Expression is Linked to Tumor-Infiltrating T-Cell Exhaustion and Adverse Pathological Behavior in Pheochromocytoma/Paraganglioma.

Pheochromocytoma/paraganglioma (PPGL) is an endocrine-related tumor associated with excessive catecholamine release and has limited treatment options once metastasis occurs. Although recent phase 2 clinical trials of immune checkpoint inhibitors in the treatment of PPGL have preliminarily shown promising results, the fundamentals of immunotherapy for PPGL have not yet been established. In the early research, using bulk RNA sequencing of tumor samples from 7 PPGL patients, we found that PPGL tumor tissues exhibited high PD-L1 mRNA expression compared with adjacent normal adrenal medulla tissues, and this was related to T-cell exhaustion biomarkers. To further validate the association, in this study (n = 60), we first stratified all PPGL samples according to PD-L1 expression as determined by immunohistochemical staining, and then subjected 23 fresh PPGL tumor samples from the cohort to a quantitative polymerase chain reaction (n = 16), flow cytometry (n = 7), and multiplex-immunofluorescence staining. Subsequently, we evaluated the pathological manifestations of all 60 PPGL tumor samples and analyzed the correlation among PD-L1 expression, adverse pathological behavior, various clinicopathological data, and genotypes in PPGL. The results showed that PD-L1-positive expression correlated with the exhaustion of tumor-infiltrating T cells, preoperative abnormal elevation of plasma norepinephrine, high Ki67 index, and adverse pathological behavior in PPGL but not with genetic mutation or metastatic disease, possibly due to the limitation of the small number of patients with metastatic disease (n = 4) in the study cohort. In conclusion, our findings reveal that PD-L1 expression is associated with T-cell exhaustion and adverse pathological behavior in PPGL. These results are expected to provide a new theoretical basis and clinical guidance for the treatment of PPGL.

Nomogram for predicting hemodynamic instability and the association between preoperative 3D printing and hemodynamic instability during laparoscopic adrenalectomy for pheochromocytoma.

Laparoscopic adrenalectomy (LA) for resection of pheochromocytomas (PCCs) is associated with high risk of complications and morbidity due to intraoperative hemodynamic instability (HDI). This study aims to identify factors related to HDI during laparoscopic resection of pheochromocytoma and develop a scoring model for prediction of HDI. Data of a total of 119 patients with pathological confirmed PCCs were collected at a single center in China between 2010 and 2021. All patients underwent unilateral LA for PCCs. Clinical and biochemical variables were collected. Next-generation sequencing was performed in all PCCs patients for detection of mutations. Univariate and multivariable logistic regression analyses were used to select risk factors for constructing the nomogram. The area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the discrimination of the nomogram. The calibration curve was performed. Finally, four variables including 24 h urinary output of urine vanillylmandelic acid (VMA) ≥ 58 µmol/day, tumor size ≥ 4 cm, right-side tumor location, Cluster 2 mutations were independent risk factors for HDI during LA and were included in the nomogram. The nomogram demonstrated a good discrimination performance with an AUC of 0.784 [95% confidence interval (CI), 0.701-0.867]. The calibration curve showed a bias-corrected AUC of 0.758. Multivariable analysis revealed that preoperative 3D printing is an independent protective factor for HDI. Our study proposed a novel nomogram for prediction of HDI during LA for resection of PCCs. Preoperative 3D printing was associated with HDI in PCCs.

Somatic IDH1 Hotspot Variants in Chinese Patients With Pheochromocytomas and Paragangliomas.

CONTEXT: IDH1 is a pheochromocytoma/paraganglioma (PPGL) susceptibility gene; however, its role, especially in the Chinese population, has not been characterized. OBJECTIVE: To determine the prevalence of somatic IDH1 hotspot variants in a large cohort of Chinese patients with PPGLs and to summarize associated phenotypes. METHODS: This retrospective cross-sectional study was based on a main cohort of 1141 patients with PPGLs from 2 tertiary-care centers in China. We included 50 cases with urinary bladder paragangliomas (UBPGLs), of whom 29 were part of the main cohort and 21 were from other centers. Two additional cases with IDH1 hotspot variants not part of the main cohort were also included for summarizing IDH1-associated phenotypes. Next-generation sequencing of tumor DNA was used to analyze a customized panel of genes. RESULTS: The overall prevalence of IDH1 hotspot variants in the main cohort was 0.5% (6/1141). Among those PPGLs without mutations in 15 common driver genes, the prevalence of IDH1 variants was 0.9% (4/455). When restricted to paraganglioma (PGL) without mutations, the prevalence reached 4.7% (4/86). Among UBPGLs, IDH1 hotspot variants accounted for 8% (4/50). Together, all 10 patients (9 PGLs and 1 pheochromocytoma) with IDH1 hotspot variants, including 3 females with concurrent EPAS1 hotspot variants, had apparently sporadic tumors, without metastasis or recurrence. There were 3 patients with biochemical data, all showing a non-adrenergic phenotype. CONCLUSIONS: The somatic IDH1 hotspot variants cause PPGL development in some Chinese patients, especially among those apparently sporadic PGLs with a non-adrenergic phenotype and without mutations in major PPGL driver genes.

Impact of body composition and genotype on haemodynamics during surgery for pheochromocytoma and paraganglioma.

BACKGROUND: Maintaining intraoperative haemodynamic stability can reduce cardiovascular complications during surgery for pheochromocytoma and paraganglioma (PPGL). Risk factors such as tumour size and catecholamine levels are reported to predict haemodynamic responses during surgery for PPGL. We hypothesized that additional factors including body composition and genetic information could further improve prediction. METHODS: Consecutive patients with PPGL confirmed by surgical pathology between June 2010 and June 2019 were retrospectively included. Cross-sectional computed tomography images at the L3 level were used to assess body composition parameters including skeletal muscle area and visceral fat area. Next-generation sequencing was performed using a panel containing susceptibility genes of PPGL. Differences in clinical-genetic characteristics and body composition parameters were analysed and compared in patients with and without intraoperative haemodynamic instability (HDI). RESULTS: We included 221 patients with PPGL (median age 47 [38-56] years, and 52% male). Among them, 49.8% had Cluster 2 mutations (related to kinase signalling pathways), 44.8% had sarcopenia, and 52.9% experienced intraoperative HDI. Compared with patients without HDI, more patients with HDI had Cluster 2 mutations (59.8% vs. 38.5%, P = 0.002) and less had sarcopenia (35.9% vs. 54.8%, P = 0.005). Multivariate analysis showed that urine vanillylmandelic acid ≥ 58 µmol/day (adjusted odds ratio [OR] = 1.840, 95% confidence interval [CI] = 1.012-3.347, P = 0.046), tumour size ≥ 4 cm (adjusted OR = 2.278, 95% CI = 1.242-4.180, P = 0.008), and Cluster 2 mutations (adjusted OR = 2.199, 95% CI = 1.128-4.285, P = 0.021) were independent risk factors for intraoperative HDI, while sarcopenia (adjusted OR = 0.475, 95% CI = 0.266-0.846, P = 0.012) decreased the risk. CONCLUSIONS: Body composition and genotype were associated with intraoperative haemodynamics in patients with PPGL. Our results indicated that inclusion of body composition and genotype in the overall assessment of patients with PPGL helped to predict HDI during surgery, which could assist in implementing preoperative and intraoperative measures to reduce perioperative complications.

Surgical treatment of large pheochromocytoma (>6 cm): A 10-year single-center experience.

Objective: Clinical practice guidelines recommend open adrenalectomy (OA) for large pheochromocytoma (LPCC) > 6 cm in size. Although laparoscopic adrenalectomy (LA) for the treatment of LPCC has been reported, its role remains unclear. This study aimed to compare the effectiveness of LA and OA, and summary the surgical treatment experience. Methods: Data concerning LPCC, from January 2010 to June 2019 of a single institution, were retrospectively reviewed. Altogether 82 patients with a tumor larger than 6 cm were included (52 patients in LA group and 30 patients in OA group). Groups were balanced by propensity score matching (PSM) into 15 pairs. Patients' demographics, preoperative characteristics, and prognosis were analyzed. Results: Before PSM, the OA group had larger tumor sizes (median [interquartile range, IQR]: 8.9 [7.3-10.3] vs. 7.2 [6.7-8.0] cm; p=0.000) and higher vanillylmandelic acid level (median [IQR]: 114.3 [67.8-326.4] vs. 66.6 [37.8-145.8] µmol/24 h; p =0.004) and needed a higher cumulative dose of prazosin (median [IQR]: 83.5 [37.0-154.0] vs. 38.0 [21.0-81.0] mg; p=0.028). After PSM, the baseline data showed no significant differences between both groups. The LA group had relatively more stable blood pressure in surgery, with a lower fluctuation of systolic blood pressure (mean±standard deviation [SD]: 70.9±25.1 vs. 107.4±46.2 mmHg, p=0.012) and a lower percentage of hemodynamic instability (46.7% vs. 86.7%, p=0.020). The LA group had shorter postoperative hospital stays (mean±SD: 6.4±2.7 vs. 10.1±3.4 days; p=0.003) than the OA group. Differences regarding metastasis rate (6.7% vs. 0, p=1.000) were not statistically significant between LA and OA groups. The median (IQR) follow-up time of 82 patients was 72.5 (47.0-103.5) months. Binary logistic regression showed that right-side tumors or those >8 cm in size were independent risk factors of OA. Conclusion: LA is a safe, minimally invasive procedure for LPCC and has relatively better perioperative characteristics in large medical centers. Patients with tumors on the right side or larger than 8 cm are more likely to undergo OA initially.

Value of Immunohistochemical Expression of Apelin, Succinate Dehydrogenase B, Chromogranin B, Human Epidermal Growth Factor Receptor-2, Contactin 4, and Succinyl-CoA Synthetase Subunit Beta in Differentiating Metastatic From Non-Metastatic Pheochromocytoma and Paraganglioma.

Objective: We aimed to retrospectively collect pathologically identified pheochromocytoma and paraganglioma (PPGL) tumor tissues from our center and investigate the expression of apelin and succinyl-CoA synthetase subunit beta (SUCLG2), human epidermal growth factor receptor-2 (HER2 or ERBB-2), contactin 4 (CNTN4), chromogranin B (CHGB), and succinate dehydrogenase B (SDHB) in metastatic and non-metastatic PPGLs, for exploring their roles in the diagnosis of metastatic PPGLs. Methods: A total of 369 patients with pathologically and surgically confirmed PPGLs at Xiangya Hospital, Central South University, between June 2010 and June 2020 were retrospectively included. Sixty patients-12 patients with metastatic PPGLs and 48 patients with non-metastatic PPGLs-were selected through propensity score matching (1:4) to reduce the effect of PPGL type, sex, and age. We observed and quantified the expression of apelin, SDHB, CHGB, ERBB-2, CNTN4, and SUCLG2 in paraffin-embedded samples using immunohistochemical staining. Results: No significant differences were observed between the metastatic group and non-metastatic group with respect to the expression of CNTN4 and SUCLG2. The expression of apelin, SDHB, CHGB, and ERBB-2 was significantly different between the two groups. The expression of apelin, SDHB, and CHGB was significantly lower in the metastatic group than that in the non-metastatic group (P < 0.001). ERBB-2 expression was significantly higher in the metastatic group than in the non-metastatic group (P = 0.042). Kaplan-Meier analysis revealed that patients with negative expression of apelin, SDHB, and CHGB showed significantly lower metastasis-free survival than those with positive expression. Multivariate Cox analysis revealed that SDHB and CHGB levels were independently associated with metastasis-free survival. Conclusion: The expression levels of apelin, CHGB, SDHB, and ERBB-2 may be predictive biomarkers for the diagnosis of metastatic PPGLs. Patients with negative expression of apelin, CHGB, and SDHB should be subjected to frequent postoperative follow-up procedures.

Genetic Characteristics of Incidental Pheochromocytoma and Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are being increasingly discovered by imaging performed for unrelated conditions. The genetic landscape of incidental PPGLs remains to be elucidated. OBJECTIVE: We aimed to describe the genetic characteristics of PPGLs discovered incidentally in a large PPGL cohort. METHODS: This retrospective cross-sectional study included 697 patients with pathology confirmed PPGLs, including 283 incidentalomas and 414 nonincidentalomas, at 2 tertiary care centers in China in 2009-2019. Tumor DNA samples were sequenced by next-generation sequencing. Identified genetic mutations were confirmed by Sanger sequencing and tested in 277 available matched blood DNA samples. RESULTS: There was a lower proportion of patients with mutations identified (53% vs 63.3%; P = 0.0067) in incidental than nonincidental PPGLs. In incidental PPGLs, HRAS (11.7%), FGFR1 (11%), and RET (9.2%) were the top 3 mutated genes, whereas HRAS (17.9%), VHL (9.2%), and NF-1 (8.7%) exhibited the highest rate of mutations in nonincidental PPGLs. In incidental pheochromocytomas, the most frequently mutated genes were RET (10.9%), HRAS (10.4%), and VHL (8.6%), while in incidental paragangliomas, FGFR1 (32.8%), HRAS (16.4%), and EPAS1 (9.8%) topped the list. The frequency of NF-1 mutations was significantly lower in incidental than nonincidental pheochromocytomas (4.1% vs 11%; P = 0.0042), while FGFR1 mutations were far more common in incidental than nonincidental paragangliomas (32.8% vs 15.3%; P = 0.0076). CONCLUSION: More than half of patients with incidental PPGLs had mutations in common susceptibility genes. The search for susceptibility genes should take both the mode of discovery (incidental vs nonincidental) and tumor location (pheochromocytoma vs paraganglioma) into consideration.

Machine Learning: Applications and Advanced Progresses of Radiomics in Endocrine Neoplasms.

Endocrine neoplasms remain a great threat to human health. It is extremely important to make a clear diagnosis and timely treatment of endocrine tumors. Machine learning includes radiomics, which has long been utilized in clinical cancer research. Radiomics refers to the extraction of valuable information by analyzing a large amount of standard data with high-throughput medical images mainly including computed tomography, positron emission tomography, magnetic resonance imaging, and ultrasound. With the quantitative imaging analysis and model building, radiomics can reflect specific underlying characteristics of a disease that otherwise could not be evaluated visually. More and more promising results of radiomics in oncological practice have been seen in recent years. Radiomics may have the potential to supplement traditional imaging analysis and assist in providing precision medicine for patients. Radiomics had developed rapidly in endocrine neoplasms practice in the past decade. In this review, we would introduce the general workflow of radiomics and summarize the applications and developments of radiomics in endocrine neoplasms in recent years. The limitations of current radiomic research studies and future development directions would also be discussed.

Background, applications and challenges of radiogenomics in genitourinary tumor.

Genitourinary tumors are groups of tumors with high complexity and heterogeneity. For long-term monitoring, biomarkers that can be used in detection, grading and treatment response assessment are needed. With rapid development in imaging technology and cancer genomics, radiogenomics, the combination of "radiology" and "genomics", has emerged as a powerful tool in oncology practice in recent years because imaging can provide some information that genomic test cannot as gene expression and mutation status are usually evaluated on a small portion of the tumor and are usually not powerful enough to reflect tumor heterogeneity. Radiogenomics investigates the correlations between imaging features and gene expression of a disease, especially in oncologic diseases. It aims to detect the disease's mutation status and supplement genomic analysis based on imaging analysis, providing additional findings for diagnosis, treatment decisions, evaluation of treatment response and prognosis prediction of the disease. Recent years have seen an increase in the number of studies investigating the application of radiogenomics in genitourinary tumors. Many studies have shown promising results. However, there still exist limitations and challenges. In this review, we will summarize recent applications of radiogenomics in genitourinary tumors and discuss limitiations, challenges and future directions of radiogenomics.

Seven Novel Genes Related to Cell Proliferation and Migration of VHL-Mutated Pheochromocytoma.

Pheochromocytoma, as a neuroendocrine tumor with the highest genetic correlation in all types of tumors, has attracted extensive attention. Von Hipper Lindau (VHL) has the highest mutation frequency among the genes associated with pheochromocytoma. However, the effect of VHL on the proteome of pheochromocytoma remains to be explored. In this study, the VHL knockdown (VHL-KD) PC12 cell model was established by RNA interference (shRNA). We compared the proteomics of VHL-KD and VHL-WT PC12 cell lines. The results showed that the expression of 434 proteins (VHL shRNA/WT > 1.3) changed significantly in VHL-KD-PC12 cells. Among the 434 kinds of proteins, 83 were involved in cell proliferation, cell cycle and cell migration, and so on. More importantly, among these proteins, we found seven novel key genes, including Connective Tissue Growth Factor (CTGF), Syndecan Binding Protein (SDCBP), Cysteine Rich Protein 61 (CYR61/CCN1), Collagen Type III Alpha 1 Chain (COL3A1), Collagen Type I Alpha 1 Chain (COL1A1), Collagen Type V Alpha 2 Chain (COL5A2), and Serpin Family E Member 1 (SERPINE1), were overexpressed and simultaneously regulated cell proliferation and migration in VHL-KD PC12 cells. Furthermore, the abnormal accumulation of HIF2α caused by VHL-KD significantly increased the expression of these seven genes during hypoxia. Moreover, cell-counting, scratch, and transwell assays demonstrated that VHL-KD could promote cell proliferation and migration, and changed cell morphology. These findings indicated that inhibition of VHL expression could promote the development of pheochromocytoma by activating the expression of cell proliferation and migration associated genes.

Study Progression of Apelin/APJ Signaling and Apela in Different Types of Cancer.

Apelin is an endogenous ligand that binds to the G protein-coupled receptor angiotensin-like-receptor 1 (APJ). Apelin and APJ are widely distributed in organs and tissues and are involved in multiple physiological and pathological processes including cardiovascular regulation, neuroendocrine stress response, energy metabolism, etc. Additionally, apelin/APJ axis was found to play an important role in cancer development and progression. Apela is a newly identified endogenous ligand for APJ. Several studies have revealed the potential role of Apela in cancers. In this article, we review the current studies focusing on the role of apelin/APJ signaling and Apela in different cancers. Potential mechanisms by which apelin/APJ and Apela mediate the regulation of cancer development and progression were also mentioned. The Apelin/APJ signaling and Apela may serve as potential therapeutic candidates for treatment of cancer.

Applications of radiomics in genitourinary tumors.

Genitourinary tumors are heterogeneous groups of tumors with high morbidity and mortality rates. Confronted with existing problems in the management of genitourinary tumors, a personalized imaging method called radiomics shows great potential in areas including detection, grading, and treatment response assessment. Radiomics is characterized by extraction of quantitative imaging features which are not visible to the naked eye from conventional imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography-computed tomography (PET-CT), followed by data analysis and model building. It outperforms other invasive methods in terms of non-invasiveness, low cost and high efficiency. Recently, a number of studies have evaluated the application of radiomics in patients with genitourinary tumors with promising data. The combination of radiomics and clinical/laboratory factors provides added value in many studies. Despite this, there are limitations and challenges to be overcome before a more extensive clinical application in the future. In this article, we will introduce the concept, significance and workflow of radiomics, review their current applications in patients with genitourinary tumors and discuss limitations and future directions of radiomics. It would help multidisciplinary team involved in the treatment of patients with genitourinary tumors to achieve a better understanding of the results of radiomics study toward a personalized medicine.

Sino-European Differences in the Genetic Landscape and Clinical Presentation of Pheochromocytoma and Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are characterized by distinct genotype-phenotype relationships according to studies largely restricted to Caucasian populations. OBJECTIVE: To assess for possible differences in genetic landscapes and genotype-phenotype relationships of PPGLs in Chinese versus European populations. DESIGN: Cross-sectional study. SETTING: 2 tertiary-care centers in China and 9 in Europe. PARTICIPANTS: Patients with pathologically confirmed diagnosis of PPGL, including 719 Chinese and 919 Europeans. MAIN OUTCOME MEASURES: Next-generation sequencing performed in tumor specimens with mutations confirmed by Sanger sequencing and tested in peripheral blood if available. Frequencies of mutations were examined according to tumor location and catecholamine biochemical phenotypes. RESULTS: Among all patients, higher frequencies of HRAS, FGFR1, and EPAS1 mutations were observed in Chinese than Europeans, whereas the reverse was observed for NF1, VHL, RET, and SDHx. Among patients with apparently sporadic PPGLs, the most frequently mutated genes in Chinese were HRAS (16.5% [13.6-19.3] vs 9.8% [7.6-12.1]) and FGFR1 (9.8% [7.6-12.1] vs 2.2% [1.1-3.3]), whereas among Europeans the most frequently mutated genes were NF1 (15.9% [13.2-18.6] vs 6.6% [4.7-8.5]) and SDHx (10.7% [8.4-13.0] vs 4.2% [2.6-5.7]). Among Europeans, almost all paragangliomas lacked appreciable production of epinephrine and identified gene mutations were largely restricted to those leading to stabilization of hypoxia inducible factors. In contrast, among Chinese there was a larger proportion of epinephrine-producing paragangliomas, mostly due to HRAS and FGFR1 mutations. CONCLUSIONS: This study establishes Sino-European differences in the genetic landscape and presentation of PPGLs, including ethnic differences in genotype-phenotype relationships indicating a paradigm shift in our understanding of the biology of these tumors.

The systems of metastatic potential prediction in pheochromocytoma and paraganglioma.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors that arising from the adrenal medulla or extra-adrenal autonomic ganglia. Traditionally, PPGL was classified as benign or malignant based on the presence of distant metastasis at the time of initial surgery. However, according to WHO 2017 Classification of Tumors of Endocrine Organs, all PPGL has metastatic potential. The term "metastatic" is used, replacing "malignant" in this group of tumors. The prediction of PPGL's metastatic potential is a clinical concern, although many relevant indicators such as genetics, histology, pathology and molecular biology markers have been proved to be related to the metastasis of PPGL, but none of them is 100% predictive; various types of prediction systems had been created, but previous studies had demonstrated that they still need to be validated in multicenter studies. There is no unified clinical standard to differentiate metastatic from non-metastatic and a highly effective prediction system is of urgent need. In this review, we summarized all reported prediction systems, including the PASS system, the GAPP system, the COPPs system and the ASES system. Additional potential indicators that related to metastatic PPGL were also introduced.

A Comprehensive Analysis Identified the Key Differentially Expressed Circular Ribonucleic Acids and Methylation-Related Function in Pheochromocytomas and Paragangliomas.

We investigated differentially expressed circular RNAs (circRNAs) and their potential functions in pheochromocytomas and paragangliomas (PCC/PGLs). Expression levels of circRNAs in tumor and adjacent normal tissues from seven PCC/PGL patients were analyzed through RNA sequencing. Real-time PCR was conducted to verify the key candidates identified in the sequencing data. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the functions of these circRNAs. A total of 367 circRNAs were found differentially expressed between tumor and normal samples. The top three histone methylation-related circRNAs (hsa_circ_0000567, hsa_circ_0002897, and hsa_circ_0004473) and their target microRNAs (miRNAs) were identified and validated. We then mapped the circRNA-miRNA-messenger RNA (mRNA) coding-noncoding gene co-expression (CNC) networks to show the potential binding relationships between circRNAs and their targets in PCC/PGLs. The top five mRNAs, 88 miRNAs, and 132 circRNAs related to pathogenesis were utilized to map the CNC network, and we observed that the interactions of these candidates with their target miRNAs regulated histone methylation and further mediated PCC/PGL pathogenesis. This study is the first to provide the whole profile of differentially expressed circRNAs in PCC/PGLs. Our data indicate that altered circRNAs may control the pathogenesis of PCC/PGLs by regulating histone methylation processes, highlighting their role as potential biomarkers.

Validation of the World Health Organization/International Society of Urological Pathology grading for Chinese patients with clear cell renal cell carcinoma.

BACKGROUND: This study aimed to compare the World Health Organization/International Society of Urological Pathology (WHO/ISUP) grading system and the Fuhrman grading system and to verify the WHO/ISUP grade as a prognostic parameter of clear cell renal cell carcinoma (ccRCC) in a Chinese population. METHODS: The study consisted of 753 ccRCC patients treated with curative surgery between 2010 and 2018 at Xiangya Hospital Central South University (Changsha, China). All pathologic data were retrospectively reviewed by two pathologists. Cancer-specific survival (CSS) and recurrence-free survival (RFS) were examined as clinical outcomes. RESULTS: According to the WHO/ISUP grading system (ISUP group), nephrectomy type, pT stage and WHO/ISUP grade were independent risk factors for CSS (P<0.0001, P=0.0127 and P<0.0001, respectively) and RFS (P<0.0001, P=0.0077, and P<0.0001, respectively). In the Fuhrman group, nephrectomy type, pT stage and Fuhrman grade were independent risk factors for CSS (P<0.0001, P=0.0004, and P<0.0001, respectively) and RFS (P<0.0001, P=0.0001, and P<0.0001, respectively). The C-index for CSS and RFS using the Fuhrman grading system was 0.6323 and 0.6342, respectively, and that using the WHO/ISUP grading system was 0.6983 and 0.7005, respectively, both higher than the former (P=0.0185, and P=0.0172, respectively). In addition, upgrading from Fuhrman grade 2 to ISUP grade 3 resulted in worse CSS and RFS for ccRCC patients (P=0.0033 and P =0.0003, respectively). CONCLUSIONS: We first verified correlations between the postoperative prognosis and WHO/ISUP grade of ccRCC in a Chinese population and confirmed that the ability to predict clinical outcomes with the WHO/ISUP grading system was superior to that with the Fuhrman grading system.