Diagnostic performance of regional systematic biopsy for prostate cancer stratified by PI-RADS and histologic zones

Abstract Objectives To explore the diagnostic performance of targeted biopsy (TB) combined with regional systematic biopsy (RSB) in patients with different Prostate Imaging Reporting and Data System (PI-RADS) and histologic zones for prostate lesions. Methods This retrospective study included 1301 patients who underwent multiparametric MRI followed by combined MRI/US fusion-guided TB+systematic biopsy (SB) between January 2019 and October 2022. RSB was defined as the four perilesional SB cores adjacent to an MRI-positive lesion. Cancer detection rates were calculated for TB + SB, TB, SB, and TB + RSB, while the McNemar test was utilized for multiple comparisons among them. Subgroup analyses were performed based on different Pl-RADS and histologic zones. Results Of 1301 included participants (median age, 68 years; interquartile range, 63–74 years), 16,104 total biopsy cores were performed. TB + RSB detected clinically significant prostate cancer in 70.9% (922/1301) of patients, which was significantly higher than TB (67.4%, p < 0.001) or SB (67.5%, p < 0.001) but similar to TB + SB (71.0%, p = 0.50). Compared with TB + SB, TB + RSB required fewer median biopsy cores (6.3 vs. 12.4, p < 0.001) and had a higher proportion of positive cores (56.3% vs. 39.0%, p < 0.001). Subgroup analysis showed that TB had outstanding sensitivity for detecting PI-RADS 5 lesions in the PZ. Conclusions Compared with TB + SB, TB + RSB achieved a similar clinically significant prostate cancer detection rate while requiring fewer biopsy cores and exhibiting higher diagnostic efficiency. Critical relevance statement For MRI-positive prostate lesions, targeted biopsy combined with regional systematic biopsy could serve as an alternative diagnostic approach to targeted biopsy combined with systematic biopsy. Key Points The scheme of prostate biopsy needs to be optimized. Regional systematic biopsy decreases the total number of cores taken. Targeted biopsies combined with regional systematic biopsies improve prostate diagnostic efficiency. Graphical Abstrac

The Application of Internal Suspension Technique in Retroperitoneal Laparoscopic Partial Nephrectomy for Renal Ventral Tumors

Objective. To evaluate the feasibility of an internal suspension technique in retroperitoneal laparoscopic partial nephrectomy for the management of renal ventral tumors. Methods. Between January 2013 and July 2016, a total of 145 patients underwent retroperitoneal laparoscopic partial nephrectomy with or without internal suspension technique. For patients who underwent internal suspension technique, the surgeons preserved the external fat of the renal tumor as a suspension traction measure when separating the kidney. Propensity score matching (PSM) was performed according to age, gender, body mass index, tumor size, tumor location, and RENAL nephrometry score. Patient characteristics and intraoperative and postoperative outcomes were compared between the groups. Results. After PSM, 32 patients treated with the internal suspension technique were compared with 32 cases treated without such technique. Baseline characteristics were statistically similar for the cohorts. The use of our new technique resulted in shorter warm ischemia time (WIT: 15.0 versus 19.0 minutes, P=.002) and tumor resection time (4.0 versus 7.5 minutes, P25 minutes decreased (6.3% versus 25%, P=.04) and the trifecta outcomes were significantly improved (87.5% versus 62.5%, P=.02). Conclusion. Internal suspension technique is a feasible and safe procedure in retroperitoneal laparoscopic partial nephrectomy for renal ventral tumors

The Significance of Metastasectomy in Patients with Metastatic Renal Cell Carcinoma in the Era of Targeted Therapy

Objective. To investigate the efficacy of surgery in the treatment of metastatic renal cell carcinoma (mRCC) and to identify prognostic factors. Methods. A single center retrospective study of 96 patients with mRCC from December 2004 to August 2013. Results. The median follow-up time was 45 months. Thirty-one (32.3%) of the patients received complete resection of metastatic sites, 11 (11.5%) of the patients underwent incomplete resection of metastatic sites, and 54 (56.3%) of the patients received no surgery. In the univariate Kaplan-Meier analysis, the median overall survival times of the three groups were 52 months, 16 months, and 22 months, respectively (p<0.001). The difference in the overall survival time was statistically significant between complete resection and no surgery groups (HR = 0.43, p=0.009), while there was no significant difference between the incomplete metastasectomy and no surgery groups (HR = 1.80, p=0.102). According to the multivariate Cox regression analysis, complete metastasectomy (HR = 0.49, p=0.033), T stage > 3 (HR = 1.88, p=0.015), disease free interval <12 months (HR = 2.34, p=0.003), and multiorgan involvement (HR = 2.00, p=0.011) were significant prognostic factors. Conclusion. In the era of targeted therapy, complete metastasectomy can improve overall survival. Complete metastasectomy, T stage > 3, disease free interval <12 months, and multiorgan involvement are independent prognostic factors

Downregulation of CLDN7 due to promoter hypermethylation is associated with human clear cell renal cell carcinoma progression and poor prognosis

Abstract Background Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood. Methods A total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo. Results Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining. Conclusions We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC

Table_5_Identification of a claudin-low subtype in clear cell renal cell carcinoma with implications for the evaluation of clinical outcomes and treatment efficacy.xlsx

BackgroundIn bladder and breast cancer, the claudin-low subtype is widely identified, revealing a distinct tumor microenvironment (TME) and immunological feature. Although we have previously identified individual claudin members as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC), the existence of an intrinsic claudin-low subtype and its interplay with TME and clinical outcomes remains unclear.MethodsTranscriptomic and clinical data from The Cancer Genome Atlas (TCGA)- kidney clear cell carcinoma (KIRC) cohort and E-MTAB-1980 were derived as the training and validation cohorts, respectively. In addition, GSE40435, GSE53757, International Cancer Genome Consortium (ICGC) datasets, and RNA-sequencing data from local ccRCC patients were utilized as validation cohorts for claudin clustering based on silhouette scores. Using weighted correlation network analysis (WGCNA) and multiple machine learning algorithms, including least absolute shrinkage and selection operator (LASSO), CoxBoost, and random forest, we constructed a claudin-TME related (CTR) risk signature. Furthermore, the CTR associated genomic characteristics, immunity, and treatment sensitivity were evaluated.ResultsA claudin-low phenotype was identified and associated with an inferior survival and distinct TME and cancer immunity characteristics. Based on its interaction with TME, a risk signature was developed with robust prognostic prediction accuracy. Moreover, we found its association with a claudin-low, stem-like phenotype and advanced clinicopathological features. Intriguingly, it was also effective in kidney chromophobe and renal papillary cell carcinoma. The high CTR group exhibited genomic characteristics similar to those of claudin-low phenotype, including increased chromosomal instability (such as deletions at 9p) and risk genomic alterations (especially BAP1 and SETD2). In addition, a higher abundance of CD8 T cells and overexpression of immune checkpoints, such as LAG3, CTLA4 and PDCD1, were identified in the high CTR group. Notably, ccRCC patients with high CTR were potentially more sensitive to immune checkpoint inhibitors; their counterparts could have more clinical benefits when treated with antiangiogenic drugs, mTOR, or HIF inhibitors.ConclusionWe comprehensively evaluated the expression features of claudin genes and identified a claudin-low phenotype in ccRCC. In addition, its related signature could robustly predict the prognosis and provide guide for personalizing management strategies.</p

Table_6_Identification of a claudin-low subtype in clear cell renal cell carcinoma with implications for the evaluation of clinical outcomes and treatment efficacy.xlsx

BackgroundIn bladder and breast cancer, the claudin-low subtype is widely identified, revealing a distinct tumor microenvironment (TME) and immunological feature. Although we have previously identified individual claudin members as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC), the existence of an intrinsic claudin-low subtype and its interplay with TME and clinical outcomes remains unclear.MethodsTranscriptomic and clinical data from The Cancer Genome Atlas (TCGA)- kidney clear cell carcinoma (KIRC) cohort and E-MTAB-1980 were derived as the training and validation cohorts, respectively. In addition, GSE40435, GSE53757, International Cancer Genome Consortium (ICGC) datasets, and RNA-sequencing data from local ccRCC patients were utilized as validation cohorts for claudin clustering based on silhouette scores. Using weighted correlation network analysis (WGCNA) and multiple machine learning algorithms, including least absolute shrinkage and selection operator (LASSO), CoxBoost, and random forest, we constructed a claudin-TME related (CTR) risk signature. Furthermore, the CTR associated genomic characteristics, immunity, and treatment sensitivity were evaluated.ResultsA claudin-low phenotype was identified and associated with an inferior survival and distinct TME and cancer immunity characteristics. Based on its interaction with TME, a risk signature was developed with robust prognostic prediction accuracy. Moreover, we found its association with a claudin-low, stem-like phenotype and advanced clinicopathological features. Intriguingly, it was also effective in kidney chromophobe and renal papillary cell carcinoma. The high CTR group exhibited genomic characteristics similar to those of claudin-low phenotype, including increased chromosomal instability (such as deletions at 9p) and risk genomic alterations (especially BAP1 and SETD2). In addition, a higher abundance of CD8 T cells and overexpression of immune checkpoints, such as LAG3, CTLA4 and PDCD1, were identified in the high CTR group. Notably, ccRCC patients with high CTR were potentially more sensitive to immune checkpoint inhibitors; their counterparts could have more clinical benefits when treated with antiangiogenic drugs, mTOR, or HIF inhibitors.ConclusionWe comprehensively evaluated the expression features of claudin genes and identified a claudin-low phenotype in ccRCC. In addition, its related signature could robustly predict the prognosis and provide guide for personalizing management strategies.</p

Table_3_Identification of a claudin-low subtype in clear cell renal cell carcinoma with implications for the evaluation of clinical outcomes and treatment efficacy.xlsx

BackgroundIn bladder and breast cancer, the claudin-low subtype is widely identified, revealing a distinct tumor microenvironment (TME) and immunological feature. Although we have previously identified individual claudin members as prognostic biomarkers in clear cell renal cell carcinoma (ccRCC), the existence of an intrinsic claudin-low subtype and its interplay with TME and clinical outcomes remains unclear.MethodsTranscriptomic and clinical data from The Cancer Genome Atlas (TCGA)- kidney clear cell carcinoma (KIRC) cohort and E-MTAB-1980 were derived as the training and validation cohorts, respectively. In addition, GSE40435, GSE53757, International Cancer Genome Consortium (ICGC) datasets, and RNA-sequencing data from local ccRCC patients were utilized as validation cohorts for claudin clustering based on silhouette scores. Using weighted correlation network analysis (WGCNA) and multiple machine learning algorithms, including least absolute shrinkage and selection operator (LASSO), CoxBoost, and random forest, we constructed a claudin-TME related (CTR) risk signature. Furthermore, the CTR associated genomic characteristics, immunity, and treatment sensitivity were evaluated.ResultsA claudin-low phenotype was identified and associated with an inferior survival and distinct TME and cancer immunity characteristics. Based on its interaction with TME, a risk signature was developed with robust prognostic prediction accuracy. Moreover, we found its association with a claudin-low, stem-like phenotype and advanced clinicopathological features. Intriguingly, it was also effective in kidney chromophobe and renal papillary cell carcinoma. The high CTR group exhibited genomic characteristics similar to those of claudin-low phenotype, including increased chromosomal instability (such as deletions at 9p) and risk genomic alterations (especially BAP1 and SETD2). In addition, a higher abundance of CD8 T cells and overexpression of immune checkpoints, such as LAG3, CTLA4 and PDCD1, were identified in the high CTR group. Notably, ccRCC patients with high CTR were potentially more sensitive to immune checkpoint inhibitors; their counterparts could have more clinical benefits when treated with antiangiogenic drugs, mTOR, or HIF inhibitors.ConclusionWe comprehensively evaluated the expression features of claudin genes and identified a claudin-low phenotype in ccRCC. In addition, its related signature could robustly predict the prognosis and provide guide for personalizing management strategies.</p