A population-based propensity score matching analysis of risk factors and the impact on survival associated with refusal of cancer-directed surgery in patients with prostate cancer.

Cancer-directed surgeries (CDS) play a crucial role in prostate cancer (PCa) management along with possible survival and therapeutic benefits. However, barriers such as socioeconomic factors may affect patients' decision of refusing recommended CDS. This study aimed to uncover risk factors and the impact on survival associated with CDS refusal. We retrospectively reviewed the Surveillance, Epidemiology, and End Results database for patients diagnosed with PCa between 2000 and 2019. Multiple sociodemographic and clinical characteristics were extracted to assess predictors for physicians' surgical recommendations and patients' surgical refusal, respectively. Propensity score matching was performed to balance the covariates. The impact of surgical refusal on mortality risk was also investigated. A total of 185,540 patients were included. The physician's recommendation of CDS was significantly influenced by the patient's age, race, income, home location, diagnosis year, Gleason score, prostate-specific antigen (PSA), and TNM stage. About 5.6% PCa patients refused CDS, most of whom were older, non-White race, lack of partners, living outside of metropolitan areas, with higher PSA or lower clinical TNM stage. Patients who refused CDS had an increased risk of cancer-specific mortality and overall mortality than those who performed CDS. Physicians may weigh a host of sociodemographic and clinical factors prior to making a CDS recommendation. Patients' refusal of recommended CDS affected survival and was potentially modifiable by certain sociodemographic factors. Physicians should fully consider the hindrances behind patients' CDS refusal to improve patient-doctor shared decision-making, guide patients toward the best alternative and achieve better outcomes.

UBC Mediated by SEPT6 Inhibited the Progression of Prostate Cancer.

BACKGROUND: Prostate cancer is one of the most common malignancies in men. Protein ubiquitination is an important mechanism for regulating protein activity and level in vivo. We aimed to study the mechanism of SEPT6 and UBC action in prostate cancer to identify new targets. METHODS: The ubiquitin-protein and the ubiquitin coding gene UBA52, UBA80, UBB, and UBC expressions were detected in clinical tissues and cells. Overexpression and knockdown of UBC were performed in prostate cancer DU145 cells. Cell Counting Kit 8 (CCK-8) assay was performed to detect cell proliferation. Cell cycle at 24 h was detected by flow cytometry. Clonal formation assay was used to measure cell clone number. Immunofluorescence (IF) was performed to detect the colocalization of SEPT6 and UBC in prostate cancer cells. Next, we overexpressed or knocked down SEPT6 expression in DU145 cells. Pearson correlation coefficient was applied to analyze the relationship between SEPT6 and UBC in prostate cancer tissue. oe-SEPT6+oe-UBC coexpressing cells were constructed to detect the upstream and downstream relationship between SEPT6 and UBC on prostate cancer cells. The tumor formation experiment was performed to explore SEPT6/UBC effect on prostate cancer. RESULTS: UBC was upregulated in prostate cancer tissues and cells. Overexpression of UBC promoted cell survival and proliferation. IF revealed the colocalization of SEPT6 and UBC in prostate cancer cells. UBC expression decreased after oe-SEPT6, while increased after sh-SEPT6, indicating that UBC was downstream of SEPT6. Pearson correlation coefficient analysis showed that SEPT6 was negatively correlated with UBC in prostate cancer tissues. SEPT6 as an upstream gene of UBC regulated prostate cancer cell behavior through UBC. The tumor formation experiment showed that SEPT6 could inhibit tumor growth. CONCLUSION: In general, SEPT6 inhibited UBC expression, thereby reducing the overall ubiquitination level, affecting the expression level of downstream cell proliferation-related genes, and then affecting the progression of prostate cancer.

Efficacy and Safety of Individualized Schedule of Sunitinib by Drug Monitoring in Patients with Metastatic Renal Cell Carcinoma.

PURPOSE: To investigate the survival benefit and safety of individualized schedules for sunitinib in patients with metastatic renal cell carcinoma (mRCC) through plasma concentration monitoring. METHODS: A total of 105 patients with mRCC were enrolled. The schedule was adjusted in two ways: therapeutic drug monitoring (TDM) and toxicity-adjusted schedule (TAS). One group of patients were without any schedule adjustment (maintained schedule, MAS). Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared. The relationship between AEs and steady-state concentration or consecutive monitoring curves was explored. Further monitoring of individualized schedules was also conducted. RESULTS: Based on the plasma concentration, the schedules of 18 patients were adjusted in the TDM group. The schedules were adjusted in 37 patients due to severe AEs in the TAS group, while 50 patients were without any schedule adjustment. The median PFS and OS were better in the TDM group than the other two groups (p = 0.001 and p = 0.004, respectively). Univariate and multivariate analyses indicated that TDM could decrease the risk of death independently (p = 0.026). Moreover, the incidence of grades 3/4 AEs decreased from 88.9% to 33.3% in the TDM group (p = 0.001). Sunitinib concentration in 150-200ng/mL was regarded as a "transitional zone" due to severe AEs mainly happened when concentration elevated over it. After TDM, further plasma concentration monitoring indicated that individualized schedules enabled sunitinib concentration to fluctuate in a much safer range. CONCLUSION: Treatment-related toxicities could be minimized through plasma concentration monitoring. Patients with adjusted schedules by therapeutic drug monitoring could achieve better survival benefits.

The validation of the 2014 International Society of Urological Pathology (ISUP) grading system for patients with high-risk prostate cancer: a single-center retrospective study.

INTRODUCTION: Since the new 2014 grading system was recommended by the International Society of Urological Pathology (ISUP), it has been validated in patients with localized prostate cancer (PCa) and it has shown excellent prognostic value. However, its predictive power in high-risk PCa remains unclear. METHODS: A total of 420 patients with high-risk PCa who underwent radical prostatectomy (RP) were included in this study. Biochemical recurrence-free survival (BRFS) was set as the endpoint. RESULTS: Biochemical recurrence occurred in 84/420 (20.0%) patients at the end of follow-up. Compared to the three-tier grouping system, the five-tier grouping system could more effectively distinguish the BRFS of patients with higher predictive accuracy (C-index: 0.599 vs 0.646). The BRFS of patients with grade group (GG) 1 and GG 2 was similar (P=0.593). Also, the prognosis between those with GG 2 and GG 3 could be clearly distinguished (P=0.001). However, the discrimination capacity between patients with GG 3 and GG 4 was limited (P=0.681). When tertiary Gleason pattern (TGP5) and intraductal carcinoma of the prostate (IDC-P) were excluded, the HR value of the GG 4 group vs the GG 3 group increased from 1.15 (95% CI: 0.59-2.22) to 1.49 (95% CI: 0.72-3.10) and 1.36 (95% CI:0.65-2.83), respectively. CONCLUSIONS: This study is the first to validate the new 2014 ISUP grading system in patients with high-risk PCa who underwent RP. The 2014 system could effectively classify patients into five groups with high predictive accuracy. Notably, the existence of TGP5 and IDC-P needs to be routinely reported in clinical practice, which could help to support the predictive value of the new grading system.

Differential expressions of PD-1, PD-L1 and PD-L2 between primary and metastatic sites in renal cell carcinoma.

BACKGROUND: In clinical practice, the detection of biomarkers is mostly based on primary tumors for its convenience in acquisition. However, immune checkpoints may express differently between primary and metastatic tumor. Therefore, we aimed to compare the differential expressions of PD-1, PD-L1 and PD-L2 between the primary and metastatic sites of renal cell carcinoma (RCC). METHODS: Patients diagnosed with RCC by resection or fine needle aspiration of metastasis were included. Immunohistochemistry (IHC) was applied to detect PD-1, PD-L1 and PD-L2 expressions. SPSS 22.0 was applied to conduct Chi-square, consistency tests and Cox's proportional hazards regression models. GraphPad Prism 6 was used to plot survival curves and R software was used to calculate Predictive accuracy (PA). RESULTS: In the whole cohort (N = 163), IHC results suggested a higher detection rate of PD-L1 in the metastasis than that of the primary site (χ2 = 4.66, p = 0.03), with a low consistent rate of 32.5%. Among different metastatic tumors, PD-1 was highly expressed in the lung/lymph node (65.3%) and poorly expressed in the brain (10.5%) and visceral metastases (12.5%). PD-L1 was highly expressed in lung/lymph node (37.5%) and the bone metastases (12.2%) on the contrary. In terms of survival analysis, patients with PD-1 expression either in the primary or metastasis had a shorter overall survival (OS) (HR: 1.59, 95% CI 1.08-2.36, p = 0.02). Also, PD-L1 expression in the primary was associated with a shorter OS (HR 2.55, 95% CI 1.06-6.15, p = 0.04). In the multivariate analysis, the predictive accuracy of the whole model for PFS was increased from 0.683 to 0.699 after adding PD-1. CONCLUSION: PD-1, PD-L1 and PD-L2 were differentially expressed between primary and metastatic tumors. Histopathological examination of these immune check points in metastatic lesions of mRCC should be noticed, and its accurate diagnosis may be one of the effective ways to realize the individualized treatment.

Differential expression of TIM-3 between primary and metastatic sites in renal cell carcinoma.

BACKGROUND: Due to the significant heterogeneity of renal cell carcinoma (RCC), immune checkpoints may express differently between primary and metastatic tumor. We aimed to evaluate the differential expression of TIM-3 between the primary and metastatic sites of RCC. METHODS: Cases of RCC with metastases resected or biopsied at West China Hospital between January 2009 and November 2016 were included. Clinicopathological parameters were retrospectively extracted. SPPS 22.0, GraphPad Prism 6 and R statistical software were applied for data analysis. RESULTS: A total of 163 cases were included. Immunohistochemical results showed that the overall detection rate of TIM-3 was 56.4% (92/163). The detection rate of TIM-3 in the primary (53.0%, 44/83) was numerically higher than that of the metastasis (42.6%,79/174). Although the concordance rate of TIM-3 between the primary and metastasis was as high as 66.3% (55/83) in the paired cohort, a significant statistically difference of TIM-3 expression between the primary and metastasis was observed (χ2 = 4.664, p = 0.002), with a poor consistency (Kappa = 0.331, p = 0.002). Subsequent survival analysis suggested that TIM-3 expression either in the primary or metastatic tumor was associated with longer progression-free survival (PFS) (HR: 0.67, 95% CI 0.45-0.99, P = 0.02) and overall survival (OS) (HR: 0.52, 95% CI 0.33-0.82, P < 0.001). The expressions of TIM-3 in the primary, metastatic tumors and patients treated with targeted agents all played as favorable factors for PFS and OS. Further multivariate analysis showed that, in the whole cohort, TIM-3 expression in metastatic tumor increased the predicted accuracy (PA) of the whole model of PFS from 74.7 to 75.6% (P = 0.02). For OS, the PA of whole model was increased from 78.1 to 81.1% by adding TIM-3 expression in the metastasis (P = 0.005). The same trends were also observed in paired patients and patients treated with targeted agents. In conclusion, the expression difference between the primary and metastatic tumor of TIM-3 was significant. Biopsy or resection of the metastases may provide a more accurate biological information for clinician's decision-making and the patient's prognosis. What's more, the role of TIM-3 in the RCC still remains controversy, further study are needed to verify the conclusion.

What kind of patients with castration-naïve prostate cancer can benefit from upfront docetaxel and abiraterone: A systematic review and a network meta-analysis.

We conducted a systematic network meta-analysis to review the relevant literature evaluating the therapeutic efficacy of upfront docetaxel (Doc) or abiraterone (Abi) plus androgen deprivation therapy (ADT) on oncological outcome in patients with castration-naïve prostate cancer (CNPC). An attempt to identify subgroups of patients who would benefit most either from Doc or Abi plus ADT and further compare the efficacy and safety between these two combination therapies was made. A comprehensive search of the PubMed/Medline, Embase databases, International Clinical Trial Registration Platform (ICTRP), Clinical Trial, and Cochrane Central Register of Controlled Trials to December 2017 was performed. Six studies, involving 6480 patients, were included in this meta-analysis, consisting of over 60% (4462/6480) of patients with metastatic CNPC (mCNPC, M1), and 31.1% (2018/6480) of patients with non-metastatic CNPC (M0). In total, combination therapies (ADT plus Doc or Abi) significantly improved overall survival (OS) and failure-free survival (FFS) for all CNPC patients. For M1 patients, combination therapies were dramatically associated with improved OS and FFS, but for M0 patients, only with moderate improvement in FFS. M1 patients < 70 years old, Eastern Cooperative Oncology Group (ECOG) performance status (ECOG PS) 0-1, Gleason score (< 8), or visceral metastases could realize better survival benefit from either combination therapy. In indirect comparisons among M1 patients with younger age (< 70 years), ECOG PS 0-1 or aggressive Gleason score (GS ≥ 8), upfront Abi showed superiority to Doc in prolonging FFS. The incidence of severe adverse events (AEs ≥ 3) was comparable between these two therapeutic regimens. In conclusion, upfront Doc or Abi plus ADT should be considered a standard of care in selected patients with mCNPC. For a subset of populations, Abi may be the first choice for men who start treatment for the first time.

Improved Long-Term Clinical Outcomes And Safety Profile Of Sunitinib Dosing Schedule With 4/2 Switched To 2/1 In Patients With Metastatic Renal Cell Carcinoma.

Purpose: This study aimed to identify the survival benefit and safety of alternative dosage schedules for sunitinib in metastatic renal cell carcinoma. Materials and Methods: Clinicopathologic and survival data of patients treated with sunitinib as first-line therapy were retrospectively reviewed. Patients were classified into three groups: a standard dosing schedule (4/2 schedule), alternative dosing schedule (2/1 schedule), and switched dosing schedule (4/2-2/1 schedule). Results: Ninety-nine patients were retrospectively included. Seventy-five (75.8%) patients were initially administrated with a 4/2 schedule of sunitinib, while 24 were started with the 2/1 schedule. During treatment, 45 (60.0%) patients with an initial 4/2 schedule switched to a 2/1 schedule (4/2-2/1 schedule) due to severe adverse events (AEs) or poor tolerance. Compared to that with a 4/2 schedule, patients with a 2/1 schedule had a much lower incidence of grade 3/4 AEs (69.6% vs. 40.6%, p=0.001). Overall, the 4/2-2/1 schedule was associated with the best survival benefits. Among the 4/2, 2/1, and 4/2-2/1 schedule groups, the median PFS was 12.5, 11.0, and 25.0 months, respectively (p=0.003), and the median OS was 21.0, 28.0, and 52.0 months, respectively (p=0.03). Multivariate analysis identified the 4/2-2/1 schedule as an independent factor predicting favorable PFS. Although without statistical significance, 4/2-2/1 schedule could decrease 55% risk of death. Furthermore, patients with unfavorable IMDC risk seemed to have more opportunity to achieve better survival from the 4/2-2/1 dosing schedule. Conclusion: Patients with a 4/2-2/1 schedule could minimize treatment-related toxicities; more importantly, patients with 4/2-2/1 schedule could achieve a superior survival benefit.

Novel nomograms for castration-resistant prostate cancer and survival outcome in patients with de novo bone metastatic prostate cancer.

OBJECTIVES: To develop nomograms predicting the incidence of castration-resistant prostate cancer (CRPC) and overall survival (OS) for de novo metastatic prostate cancer (PCa). PATIENTS AND METHODS: Data from 449 patients with de novo metastatic PCa were retrospectively analysed. Patients were randomly divided into a training (n = 314, 70%) and a validation cohort (n = 135, 30%). Predictive factors were selected using a Cox proportional hazards model and were further used for building predictive models. The outcomes were incidence of CRPC and OS. RESULTS: Predictive factors included: Gleason score (GS), intraductal carcinoma of the prostate (IDC-P), Eastern Cooperative Oncology Group status, and alkaline phosphatase, haemoglobin and prostate-specific antigen levels. IDC-P and GS were the strongest prognosticators for both the incidence of CRPC and OS. Nomograms for predicting CRPC and OS had an internal validated concordance index of 0.762 and 0.723, respectively. Based on the ß coefficients of the final model, risk classification systems were constructed. For those with favourable, intermediate and poor prognosis, the median time to CRPC was 62.6, 28.0 and 13.0 months (P < 0.001), respectively; and the median OS was not reached, 55.0 and 33.0 months, respectively (P < 0.001). CONCLUSIONS: We developed two novel nomograms to predict the incidence of CRPC and OS for patients with de novo metastatic PCa. These tools may assist in physician decision-making and the designing of clinical trials.

The association between SPINK1 and clinical outcomes in patients with prostate cancer: a systematic review and meta-analysis.

Evidence of the prognostic role of serine peptidase inhibitor Kazal type 1 (SPINK1) in prostate cancer (PCa) is controversial. The aim of this study was, therefore, to evaluate the association between SPINK1 and clinical outcomes in PCa. Searches were made of PubMed, Medline, Embase, and the China Biology Medicine disc (CBMdisc) up to January 2017. The Newcastle-Ottawa Scale was used to assess the risk of bias of included studies. RevMan software was used to perform meta-analysis, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method was employed for assessing the quality of the evidence. Ten studies with 17,161 patients were included in the analysis. Random-effect models were adopted for all outcomes with significant heterogeneities. In patients treated with radical prostatectomy, SPINK1 was associated with biochemical recurrence (BCR) (hazard ratio [HR] =1.41, 95% confidence interval [CI]: 1.01-1.97; P=0.04), but not PCa-specific mortality (HR =0.93, 95% CI: 0.33-2.57; P=0.88), and overall survival (OS) (HR =0.89, 95% CI: 0.58-1.35; P=0.57). In metastatic PCa, SPINK1 was significantly associated with castration-resistant PCa-free survival (HR =3.87, 95% CI: 1.87-8.00; P=0.0003) and OS (HR =2.59, 95% CI: 1.16-5.78; P=0.02). However, the quality of the evidence was very low for all study outcome measures. In conclusion, although SPINK1 was not a predictor of PCa mortality or OS among patients who underwent radical prostatectomy, it may have prognostic value in metastatic PCa.

Predictive efficacy of the 2014 International Society of Urological Pathology Gleason grading system in initially diagnosed metastatic prostate cancer.

We compared the predictive ability of the 2014 and 2005 Gleason grading systems in 568 patients initially diagnosed with metastatic prostate cancer (PCa). Outcomes included the duration of castration-resistant prostate cancer-free survival (CFS) and overall survival (OS). Univariate analyses and log-rank tests were used to identify prognosis indicators and assess univariable differences in CFS and OS in Gleason score (GS) groups. Cox proportional hazards and area under the curves of receiver operator characteristics methods were used to evaluate the predictive efficacy of the 2005 and 2014 ISUP grading systems. Univariate analyses showed that the 2005 and 2014 grading systems were prognosticators for CFS and OS; both systems could distinguish the clinical outcome of patients with GS 6, GS 7, and GS 8-10. Using the 2014 criteria, no statistical differences in patient survival were observed between GS 3 + 4 and GS 4 + 3 or GS 8 and GS 9-10. The predictive ability of the 2014 and 2005 grading systems was comparable for CFS and OS (P = 0.321). However, the 2014 grading system did not exhibit superior predictive efficacy in patients initially diagnosed with PCa and bone metastasis; trials using larger cohorts are required to confirm its predictive value. To the best of our knowledge, ours is the first study to compare the 2005 and 2014 grading systems in initially diagnosed PCa with bone metastasis. At present, we recommend that both systems should be used to predict the prognosis of patients with metastatic PCa.

Different lasers in the treatment of benign prostatic hyperplasia: a network meta-analysis.

All available surgical treatments for benign prostatic hyperplasia (BPH) have their individual advantages or disadvantages. However, the lack of head-to-head studies comparing different surgeries makes it unavailable to conduct direct analysis. To compare the efficacy and safety among different lasers and transurethral resection of prostate (TURP) for BPH, randomized controlled trials were searched in MEDLINE, EMBASE, Cochrane library, WHO International Clinical Trial Registration Platform, and Clinical Trial.gov by 2015.5; and the effectiveness-, perioperation- and complication-related outcomes were assessed by network meta-analysis. 36 studies involving 3831 patients were included. Holmium laser through resection and enucleation had the best efficacy in maximum flow rate. Thulium laser through vapo-resection was superior in improving international prostate symptom score and holmium laser through enucleation was the best for post-voiding residual volume improvement. Diode laser through vaporization was the rapidest in removing postoperative indwelling catheter, while TURP was the longest. TURP required the longest hospitalization and thulium laser through vapo-resection was relatively shorter. Holmium and thulium lasers seem to be relatively better in surgical efficacy and safety, so that these two lasers might be preferred in selection of optimal laser surgery. Actually, more large-scale and high quality head-to-head RCTs are suggested to validate the conclusions.