Intraductal carcinoma of the prostate (IDCP) has recently attracted increasing interest owing to its unfavorable prognoses. To effectively identify the IDCP-specific gene expression profile, we took ...a novel approach of characterizing a typical IDCP case using spatial gene expression analysis. A formalin-fixed, paraffin-embedded sample was subjected to Visium CytAssist Spatial Gene Expression analysis. IDCP within invasive prostate cancer sites was recognized as a distinct cluster separate from other invasive cancer clusters. Highly expressed genes defining the IDCP cluster, such as
,
,
, and
, reflected the aggressive nature of high-grade prostate cancer. IDCP sites also showed increased hypoxia markers
,
,
, and
; decreased fibroblast markers
,
, and
; and decreased immune cell markers
and
. Overall, these findings indicate that the hypoxic tumor microenvironment and reduced recruitment of fibroblasts and immune cells, which reflect morphological features of IDCP, may influence the aggressiveness of high-grade prostate cancer.
Neuroendocrine prostate carcinoma (NEPC) accounts for less than 1% of prostate neoplasms and has extremely poorer prognosis than the typical androgen receptor pathway-positive adenocarcinoma of the ...prostate (ARPC). However, very few cases in which de novo NEPC and APRC are diagnosed simultaneously in the same tissue have been reported. We report herein a 78-year-old man of de novo metastatic NEPC coexisting with ARPC treated at Ehime University Hospital. Visium CytAssist Spatial Gene Expression analysis (10× genetics) was performed using formalin-fixed, paraffin-embedded (FFPE) samples. The neuroendocrine signatures were upregulated in NEPC sites, and androgen receptor signatures were upregulated in ARPC sites. TP53, RB1, or PTEN and upregulation of the homologous recombination repair genes at NEPC sites were not downregulated. Urothelial carcinoma markers were not elevated. Meanwhile, Rbfox3 and SFRTM2 levels were downregulated while the levels of the fibrosis markers HGF, HMOX1, ELN, and GREM1 were upregulated in the tumor microenvironment of NEPC. In conclusion, the findings of spatial gene expression analysis in a patient with coexisting ARPC and de novo NEPC are reported. The accumulation of cases and basic data will help with the development of novel treatments for NEPC and improve the prognosis of patients with castration-resistant prostate cancer.
Locally advanced prostate cancer is regarded as a very high‐risk disease with a poor prognosis. Although there is no definitive consensus on the definition of locally advanced prostate cancer, ...radical prostatectomy for locally advanced prostate cancer as a primary treatment or part of a multimodal therapy has been reported. Robot‐assisted radical prostatectomy is currently carried out even in high‐risk prostate cancer because it provides optimal outcomes. However, limited studies have assessed the role of robot‐assisted radical prostatectomy in patients with locally advanced prostate cancer. Herein, we summarize and review the current knowledge in terms of the definition and surgical indications of locally advanced prostate cancer, and the surgical procedure and perisurgical/oncological outcomes of robot‐assisted radical prostatectomy and extended pelvic lymphadenectomy for locally advanced prostate cancer.
Purpose
Management of metastatic renal cell cancer (mRCC) has undergone a paradigm shift with immune-checkpoint inhibitors (ICI) in the first-line setting. However, direct comparative data are ...inadequate to inform treatment decisions. Therefore, we aimed to assess first-line therapy for mRCC and indirectly compare the efficacy and safety of currently available treatments.
Materials and methods
Multiple databases were searched for articles published before June 2020. Studies that compared overall and/or progression-free survival (OS/PFS) and/or adverse events (AEs) in mRCC patients were considered eligible.
Results
Six studies matched our eligibility criteria. For OS, pembrolizumab plus axitinib hazard ratio (HR) 0.85, 95% credible interval (CrI) 0.73–0.98 and nivolumab plus ipilimumab (HR 0.86, 95% CrI 0.75–0.99) were significantly more effective than sunitinib, and pembrolizumab plus axitinib was probably the best option based on analysis of the treatment ranking. For PFS, pembrolizumab plus axitinib (HR 0.86, 95% CrI 0.76–0.97) and avelumab plus axitinib (HR 0.85, 95% CrI 0.74–0.98) were statistically superior to sunitinib, and avelumab plus axitinib was likely to be the preferred option based on analysis of the treatment ranking, closely followed by pembrolizumab plus axitinib. Nivolumab plus ipilimumab had significantly lower rates of serious AEs than sunitinib.
Conclusion
Pembrolizumab plus axitinib seemed to be the most efficacious first-line agents, while nivolumab plus ipilimumab had the most favorable efficacy–tolerability equilibrium. These findings may facilitate individualized treatment strategies and inform future direct comparative trials in an expanding treatment options without direct comparison between approved drugs.
This systematic review and meta-analysis aimed to assess the prognostic value of preoperative hematologic biomarkers in patients with urothelial carcinoma of the bladder treated with radical ...cystectomy. PUBMED, Web of Science, Cochrane Library, and Scopus databases were searched in September 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared cancer-specific survival in patients with urothelial carcinoma of the bladder with and without pretreatment laboratoryabnormalities. Formal meta-analyses were performed for this outcome. The systematic review identified 36 studies with 23,632 patients, of these, 32 studies with 22,224 patients were eligible for the meta-analysis. Several preoperative hematologic biomarkers were significantly associated with cancer-specific survival as follows: neutrophil − lymphocyte ratio (pooled hazard ratio HR: 1.20, 95% confidence interval CI: 1.11–1.29), hemoglobin (pooled HR: 0.87, 95% CI 0.82–0.94), C-reactive protein (pooled HR: 1.44, 95% CI 1.26–1.66), De Ritis ratio (pooled HR: 2.18, 95% CI 1.37–3.48), white blood cell count (pooled HR: 1.05, 95% CI 1.02–1.07), and albumin-globulin ratio (pooled HR: 0.26, 95% CI 0.14–0.48). Several pretreatment laboratory abnormalities in patients with urothelial carcinoma of the bladder were associated with cancer-specific mortality. Therefore, it might be useful to incorporate such hematologic biomarkers into prognostic tools for urothelial carcinoma of the bladder. However, given the study limitations including heterogeneity and retrospective nature of the primary data, the conclusions should be interpreted with caution.
Introduction
This systematic review and meta-analysis aimed to assess the prognostic value of testosterone in patients with castration-resistant prostate cancer (CRPC).
Materials and methods
PubMed, ...Web of Science, and Scopus databases were systematically searched until December 2019, according to the Preferred Reporting Items for Systemic Review and Meta-analysis statement. The endpoints were progression-free survival (PFS) and overall survival (OS).
Results
We identified 11 articles with 4206 patients for systematic review and nine articles with 4136 patients for meta-analysis. Higher testosterone levels were significantly associated with better OS (pooled HR 0.74, 95% CI 0.58–0.95) and better PFS (pooled HR 0.51, 95% CI 0.30–0.87). Subgroup analyses based on the treatment type revealed that higher testosterone levels were significantly associated with better OS in CRPC patients treated with androgen receptor-targeted agents (ARTAs) (pooled HR 0.64, 95% CI 0.55–0.75), but not in those treated with chemotherapy (pooled HR 0.78, 95% CI 0.53–1.14).
Conclusion
This meta-analysis demonstrated that the PFS and OS were significantly greater in patients with CRPC in those with higher testosterone levels than that of those with lower testosterone levels. In the subgroup analyses, lower testosterone levels were a consistently poor prognostic factor for OS in patients treated with ARTAs, but not in those treated with chemotherapy. Therefore, higher testosterone levels could be a useful biomarker to identify patient subgroups in which ARTAs should be preferentially recommended in the CRPC setting.
This systematic review and meta-analysis aimed to assess the prognostic value of sequential of abiraterone (ABI) and enzalutamide (ENZ) therapy in patients with castration-resistant prostate cancer ...(CRPC).
PUBMED, Web of Science, Cochrane Library, and Scopus databases were searched for articles published prior to December 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared overall survival (OS), combined progression-free survival (PFS), combined prostate specific antigen (PSA)-PFS, and PSA response rates in CRPC patients receiving sequential ABI/ENZ or vice versa. PSA response to both the first and second agents was defined as a >50% decrease in PSA achieved with each of these agents. Formal meta-analyses were performed for these outcomes.
Ten studies with 1096 patients were eligible for the systematic review and eight studies with 643 patients for the meta-analysis. The ABI-to-ENZ sequence was significantly associated with better PFS (pooled hazard ratio (HR): 0.62, 95% confidential interval (CI): 0.49-0.78, P < 0.001), and PSA-PFS (pooled HR: 0.48, 95% CI: 0.38-0.61, P < 0.001) than the ENZ-to-ABI sequence. PSA response rates of both agents were significantly better with the ABI-to-ENZ sequence (risk ratio: 0.21, 95% CI: 0.09-0.47, P < 0.001). In contrast, treatment sequence was not significantly associated with OS (pooled HR: 0.77, 95% CI: 0.59-1.01, P = 0.055).
ABI-to-ENZ sequential therapy in patients with CRPC was associated with better PFS, PSA-PFS, and PSA response rates. Regardless of sequencing, response to drug therapy was transient for both ABI and ENZ when either agent was used as a secondary therapy. Despite this, treatment sequencing is important to achieve the maximum possible benefit from available drugs in CRPC.
PURPOSEThis systematic review and meta-analysis aimed to assess the prognostic impact of intraductal carcinoma of the prostate in patients with prostate cancer. MATERIALS AND METHODSA systematic ...search was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. We searched PubMed®, Web of Science™, the Cochrane Library and Scopus® up to October 2019. The end points were biochemical recurrence-free, cancer specific and overall survival. RESULTSWe identified 32 studies with 179,766 patients. A total of 31 studies containing 179,721 patients with localized and advanced prostate cancer were eligible for meta-analysis. In localized prostate cancer intraductal disease was associated with adverse outcomes including lower biochemical recurrence-free survival (pooled HR 2.09, 95% CI 1.75-2.50) and cancer specific survival (pooled HR 2.93, 95% CI 2.25-3.81). In advanced prostate cancer overall survival was lower in patients with vs without intraductal disease (pooled HR 1.75, 95% CI 1.43-2.14). Subgroup analysis by specimen type revealed that intraductal carcinoma of the prostate is a significant negative prognostic factor in both biopsies and prostatectomy specimens. Moreover, subgroup analyses based on the histopathological definitions of intraductal carcinoma of the prostate indicated that intraductal disease was significantly associated with lower biochemical recurrence-free, cancer specific and overall survival for almost all definitions. CONCLUSIONSIntraductal disease is a histopathological feature of biologically and clinically aggressive prostate cancer. It confers worse oncologic outcomes in both localized and advanced prostate cancer, whether assessed in biopsy or prostatectomy specimen. The pathologist should assess for and report on the presence of intraductal disease in all prostate specimens. The urologist and radiation oncologist should consider this adverse feature in their clinical decision making.
SPOP, speckle-type POZ protein is a substrate adaptor protein of the Cullin-3/RING ubiquitin E3 complex. The
gene is the most commonly point mutated in human primary prostate cancers, but the ...pathological contribution of the SPOP mutations remains unclear. In this study, we investigated several known factors that are critical in the DNA--protein cross-link repair process. The depletion of SPOP or overexpression of a prostate cancer-associated SPOP mutant, F133V, in androgen receptor-positive prostate cancer cells increased the amount of topoisomerase 2A (TOP2A) in the nuclei together with the increased amount of γH2AX, an indication of DNA breaks. Tyrosyl-DNA phosphodiesterases (TDPs) and an endo/exonuclease MRE11 are enzymes that liberate TOP2A from the TOP2A-DNA cleavage complex, and thus is essential for the completion of the DNA repair process. We found that the amount of TDP1 and TDP2 was decreased in SPOP-depleted cells, and that of TDP2 and MRE11 was decreased in F133V-overexpressing cells. These results suggest that the F133V mutant exerts dominant-negative and gain-of-function effects in down-regulation of TDP2 and MRE11, respectively. We conclude that SPOP is involved in the DNA-protein cross-link repair process through the elimination of TOP2A from the TOP2A cleavage complex, which may contribute to the genome stability.
Obesity correlates with an increased risk of developing prostate cancer (PCa) and leptin plays an important role in PCa progression. Since leptin is produced by adipocytes, the serum leptin level is ...higher in obese than in non-obese individuals. However, the effects of leptin remain controversial and unclear. The aim of the present study was to investigate the effect of leptin on PCa cell aggressiveness. Three human PCa cell lines (LNCaP, DU145 and PC-3) were treated with recombinant leptin for 28 days. Cell proliferation, migration, and invasion were estimated using the WST assay, a wound-healing assay, and a BD Matrigel invasion assay, respectively. The mechanism underlying the proliferative effect of leptin was investigated by cell transfections with small interfering RNA (siRNA) against the leptin receptor (ObR) or forkhead box O1 (FOXO1), and by immunocytochemistry. Long-term exposure of PCa cells to leptin enhanced their proliferation, migration and invasion. Leptin increased ObR expression and enhanced Akt phosphorylation constitutively. Leptin also increased the phosphorylation of FOXO1 via PI3K signaling and FOXO1 gene silencing enhanced PCa cell proliferation. Leptin induced the translocation of FOXO1 from the nucleus to the cytoplasm. Furthermore, the PI3K inhibitor, LY294002 suppressed this translocation. These results suggested that leptin regulated the subcellular localization of FOXO1 and induced Akt phosphorylation. Additionally, we revealed that leptin increased the expression of cyclin D1 and decreased the expression of p21 protein. In conclusion, long-term exposure to leptin increased the cell proliferation, migration, and invasion of PCa cells through inactivation of FOXO1. This inactivation resulted from exclusion of FOXO1 from the nucleus and its restriction to the cytoplasm through PI3K/Akt signaling. Our findings contribute to an understanding of the association between obesity and PCa aggressiveness.
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