A Prospective Randomized Trial of Neoadjuvant Chemohormonal Therapy vs Hormonal Therapy in Locally Advanced Prostate Cancer Treated by Radical Prostatectomy.

PURPOSE: Benefits of docetaxel-based neoadjuvant chemohormonal therapy (NCHT) before radical prostatectomy (RP) remain largely unknown. We explored whether docetaxel-based NCHT would bring pathological benefits and improve biochemical progression-free survival (bPFS) over neoadjuvant hormonal therapy (NHT) in locally advanced prostate cancer. MATERIALS AND METHODS: A randomized trial was designed recruiting 141 locally advanced, high-risk prostate cancer patients who were randomly assigned at the ratio of 2:1 to the NCHT group (75 mg/m2 body surface area every 3 weeks plus androgen deprivation therapy for 6 cycles) and the NHT group (androgen deprivation therapy for 24 weeks). The primary end point was 3-year bPFS. Secondary end points were pathological response including pathological downstaging and minimal residual disease rates. RESULTS: The NCHT group showed significant benefits in 3-year bPFS compared to the NHT group (29% vs 9.5%, P = .002). At a median follow-up of 53 months, the NCHT group achieved a significantly longer median bPFS time than the NHT group (17 months vs 14 months). No significant differences were found between the 2 groups in pathological downstaging and minimal residual disease rates. CONCLUSIONS: NCHT plus RP achieved significant bPFS benefits when compared with NHT plus RP in high-risk, locally advanced prostate cancer. A larger cohort with longer follow-up duration is essential in further investigation.

Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing.

PURPOSE: To explore the genomic profiles of Chinese patients with castration sensitive prostate cancer and those with metastatic castration resistant prostate cancer via germline and circulating tumor DNA sequencing. MATERIALS AND METHODS: A hybridization capture based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes including androgen receptor pathway genes, DNA damage repair pathway genes, TP53 and RB1. RESULTS: We successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer (8.9% vs 9.8%, p >0.05). There was a high consistency (90.9%) between metastatic tumor tissue and matched circulating tumor DNA. Among patients who were circulating tumor DNA positive we observed significantly higher alteration frequencies of CDK12 (27.2% vs 6.4%, p <0.001) and FOXA1 (36.8% vs 15.3%, p <0.001) in our metastatic castration resistant prostate cancer cohort compared with the SU2C-PCF (Stand Up to Cancer-Prostate Cancer Foundation) cohort. Alteration frequencies of DNA damage repair pathway genes (66.7% vs 41.5%, p=0.015) and androgen receptor pathway genes (71.9% vs 48.8%, p=0.018) in patients with metastatic castration resistant prostate cancer were higher than in patients with de novo metastatic castration sensitive prostate cancer. Androgen receptor alteration was selectively enriched in metastatic castration resistant prostate cancer. CONCLUSIONS: Through genomic profiling of prostate cancer across clinical states we identified a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer. We explored the genomic diversity of androgen receptor and DNA damage repair pathway genes between patients with metastatic castration sensitive prostate cancer and metastatic castration resistant prostate cancer. Higher alteration frequencies of CDK12 and FOXA1 were observed in our metastatic castration resistant prostate cancer cohort than in the SU2C-PCF cohort. Our findings support the view that circulating tumor DNA sequencing could guide clinical treatment for metastatic prostate cancer.

Distinct Response to Platinum-Based Chemotherapy among Patients with Metastatic Castration-Resistant Prostate Cancer Harboring Alterations in Genes Involved in Homologous Recombination.

PURPOSE: We aimed to explore the association between genomic status and clinical outcome of platinum-based chemotherapy among patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We conducted a retrospective study of 55 patients with mCRPC who received platinum-based chemotherapy after the progression to docetaxel chemotherapy and underwent genomic profiling of 14 homologous recombination (HR) pathway genes. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. RESULTS: Of 55 patients, 23 harbored genomic defects in HR pathway genes. Median prostate specific antigen (PSA)-PFS for the HR defect group was 6.7 months compared with 2.6 months for the no HR defect group (p=0.001). The patients harboring somatic HR defect displayed shorter PSA-PFS than those harboring germline HR defect (4.5 months vs not available; p=0.066). The PSA50 (patients who survived for 12 weeks and had a PSA decline over 50% from baseline) response rate displayed higher in patients harboring BRCA2 or ATM defect (6/8, 75.0%) than in those harboring CDK12 defect (2/9, 22.2%; p=0.06). Patients harboring BRCA2 or ATM defect displayed prolonged PSA-PFS, compared with those harboring CDK12 defect and those harboring other HR defect (p=0.038). In multivariate Cox regression analysis, HR defect and BRCA2 or ATM defect were independent significant factors associated with superior PAS-PFS to platinum-based chemotherapy. CONCLUSIONS: The patients with mCRPC harboring alterations in different HR genes displayed distinct response to platinum-based chemotherapy. Patients with mCRPC harboring genomic defects in crucial HR genes either in the germline or somatic, especially BRCA2 and ATM, might experience superior outcomes to platinum-based chemotherapy, compared with those harboring CDK12 defect.

Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study.

BACKGROUND: This study aimed to describe the aberrations of DNA damage repair genes and other important driving genes in Chinese patients with metastatic castration-resistant prostate cancer (mCRPC) using circulating tumor (ctDNA) sequencing and to evaluate the associations between the clinical outcomes of multiple therapies and key genomic alterations in mCRPC, especially DNA damage repair genes. PATIENTS AND METHODS: A total of 292 Chinese patients with mCRPC enrolled from 8 centers. Multigene targeted sequencing was performed on 306 ctDNA samples and 23 matched tumor biopsies. The frequency of genomic alterations were compared with the Stand Up to Cancer-Prostate Cancer Foundation (SU2C-PCF) cohort. The Kaplan-Meier method was used to evaluate progression-free survival (PFS) following standard systemic treatments for mCRPC. Cox regression analyses were performed to determine prognostic factors associated with PFS resulting from treatments for mCRPC. RESULTS: In total, 33 of 36 (91.7%) mutations were found consistently between ctDNA and paired biopsy samples. The most common recurrent genomic alterations were found in AR (34.6%), TP53 (19.5%), CDK12 (15.4%), BRCA2 (13%), and RB1 (5.8%). The frequency of CDK12 alterations (15.4%) in our cohort was significantly higher than that in Western populations (5%-7%). AR amplification and TP53 and/or RB1 alterations were associated with resistance to abiraterone or docetaxel. Patients with a CDK12 defect showed rapid disease progression after abiraterone treatment. However, the clinical outcome after docetaxel treatment was similar between patients with and without CDK12 defects. In multivariate Cox regression analysis, a CDK12 defect was significantly associated with inferior PFS after abiraterone treatment. Patients with a BRCA2 defect showed marked response to both PARP inhibitors and platinum-based chemotherapy. CONCLUSIONS: Our study explored the genomic landscape of Chinese patients with mCRPC at different treatment stages using minimally invasive methods and evaluated the clinical implications of the driver genomic alterations on patients' response to the most widely used therapies for mCRPC. We observed a significantly higher alteration frequency of CDK12 in our cohort compared with the SU2C-PCF cohort.

Upregulated KDM4B promotes prostate cancer cell proliferation by activating autophagy.

Castration-resistant prostate cancer (CRPC) causes most of the deaths in patients with prostate cancer (PCa). The androgen receptor (AR) axis plays an important role in castration resistance. Emerging studies showed that the lysine demethylase KDM4B is a key molecule in AR signaling and turnover, and autophagy plays an important role in CRPC. However, little is known about whether KDM4B promotes CRPC progression by regulating autophagy. Here we used an androgen-independent LNCaP (LNCaP-AI) cell line to assay aberrant KDM4B expression using qPCR and western blot analysis and investigated the function of KDM4B in regulating cell proliferation. We found that KDM4B was markedly increased in LNCaP-AI cells compared with LNCaP cells. KDM4B level was significantly correlated with the Gleason score in PCa tissues. In vitro, KDM4B overexpression in CRPC cells promoted cell proliferation, whereas knockdown of KDM4B significantly inhibited cell proliferation. Upregulated KDM4B contributed to activate Wnt/ß-catenin signaling and autophagy. Moreover, KDM4B activated autophagy by regulating the Wnt/ß-catenin signaling. Finally, we demonstrated that autophagy inhibition attenuated KDM4B-induced CRPC cell proliferation. Our results provided novel insights into the function of KDM4B-driven CRPC development and indicated that KDM4B may be served as a potential target for CRPC therapy.

Neuroendocrine differentiation markers guide treatment sequence selection in metastatic castration-resistant prostate cancer.

BACKGROUND: To evaluate the value of the serum neuroendocrine differentiation (NED) markers in helping to select the best treatment sequence of abiraterone acetate (AA) and docetaxel-prednisone (DP) in mCRPC. METHODS: Eighty-eight mCRPC patients were identified (42 in the DP-to-AA group and 46 in the AA-to-DP group). The serum levels of NED markers were measured before the first-line treatment in 88 patients and also before and after DP therapy in 38 patients. We determined their impact on OS, radiographic progression-free survival (rPFS), and PSA-PFS. RESULTS: In men with an elevation of at least one NED marker (n = 46) before the first-line treatment, those who received AA and then DP had significantly better worse OS (21.7 months [95% CI 21.0-22.4] vs 19.9 months (95% CI 15.3-24.5); P = 0.023. In a multivariate Cox regression analysis, treatment sequencing selection (selecting DP-AA rather than AA-DP) independently predicted OS (HR 0.4, 95% CI 0.2-0.9, P = 0.035) in patients with an elevation of at least one NED marker. However, in the subgroup without NED marker elevation, there was no significant difference in clinical outcomes between AA-DP and DP-AA groups (all P > 0.05). In the group with continued NED marker evaluation during DP treatment, patients with higher baseline NED markers and obtaining PSA response to DP were more inclined to experience NED markers decline. CONCLUSIONS: Elevated pretreatment serum NED markers might indicate mCRPC patients would get better clinical outcomes from DP-AA than AA-DP. In contrast, those without NED marker elevation had similar outcomes regardless of which agent was chosen first. mCRPC patients with elevated NED markers and chemotherapy response were more inclined to obtain NED markers decline during DP therapy, which could account for this phenomenon.

PRKAR2B promotes prostate cancer metastasis by activating Wnt/ß-catenin and inducing epithelial-mesenchymal transition.

Castration-resistant prostate cancers (CRPC) that occur after the failure of androgen-blocking therapies cause most of the deaths in prostate cancer (PCa) patients. In a previous study we identified that PRKAR2B expression is upregulated in CRPC and possesses potentials to develop CRPC. Here we further investigated the underlying mechanism of PRKAR2B in regulating prostate cancer metastasis. We established an androgen-independent LNCaPcell line (LNCaP-AI), and investigated the function of PRKAR2B on regulating cell invasion in vitro and in vivo. We found that PRKAR2B expression was markedly increased in LNCaP-AI cells and metastatic CRPC (mCRPC) tissues compared to LNCaP cells and primary PCa specimens, respectively. PRKAR2B level was significantly correlated with the Gleason score and lymph nodes metastasis in PCa. In vitro, PRKAR2B overexpression promoted cell invasion, whereas knockdown of PRKAR2B in CRPC cells inhibited cell invasion. PRKAR2B overexpression also promoted tumor metastasis in vivo. PRKAR2B resulted in a decreased expression of E-cadherin and an increased expression of Vimentin, N-cadherin, Fibronectin, indicating that PRKAR2B induced epithelial-mesenchymal transition (EMT). PRKAR2B activated Wnt/ß-catenin signaling in CRPC cells. More important, inhibition of Wnt/ß-catenin attenuated PRKAR2B-induced EMT and cancer cells invasion. Our results provided novel insights to PRKAR2B-driven CRPC cell invasion and indicated that PRKAR2B might be served as a potential target for CRPC therapy.

Systemic immune-inflammation index predicts the combined clinical outcome after sequential therapy with abiraterone and docetaxel for metastatic castration-resistant prostate cancer patients.

OBJECTIVE: To compare the antitumor effect of abiraterone (AA) followed by docetaxel-prednisone (DP) or vice versa in metastatic castration-resistant prostate cancer (mCRPC) patients, and explored factors that might predict combined PSA-PFS, combined rPFS and OS. PATIENTS AND METHODS: We retrospectively analyzed mCRPC patients treated with sequential therapy using DP followed by AA or vice versa. Patients who had received enzalutamide or cabazitaxel were excluded. The primary outcome measure was overall survival (OS). The combined PSA progression-free survival (PSA-PFS), combined radiographic PFS (rPFS), and OS of AA-to-DP were compared to the reverse sequence using Kaplan-Meier curves with log-rank statistics. Univariable and multivariable Cox regression analyses were performed to determine prognostic factors that were associated with combined PSA-PFS, combined rPFS and OS. RESULTS: A total of 104 mCRPC patients who began treatment between 2013 and 2017 were identified: 42 were in the DP-to-AA group and 62 were in the AA-to-DP group. There was no significant difference of baseline clinical characteristics between AA-to-DP and DP-to-AA group. In addition, there was no significant difference in combined PSA-PFS (AA-to-DP: 12.5 [11.4-13.6] vs DP-to-AA: 13.2 [10.9-15.5] months [P = 0.127]), combined rPFS (AA-to-DP: 12.2 [10.9-13.4] vs DP-to-AA: 11.2 [8.9-13.5] months [P = 0.183]) and OS (AA-to-DP: 23.3 [19.7-26.9] vs DP-to-AA: 22.9 [22.1-23.7] months [P = 0.213]) between the two treatment sequences in Kaplan-Meier analysis. In multivariate Cox regression analysis, high systematic Immune-Inflammation Index (SII) level, which was calculated by P (platelet) × N (neutrophil)/L(lymphocyte), remained significant predictors of OS, combined rPFS and combined PSA-PFS. CONCLUSION: In this study, we did not observe differences in clinical outcomes based on alternative sequencing of AA and DP in mCRPC patients. The ability to tolerate side effects and patient preference may be used to determine the treatment sequencing. In addition, high pretreatment SII level is a negative independent prognosticator of survival outcomes in mCRPC with sequential therapy using DP followed by AA or vice versa, which might guide clinicians select the best treatment.

Abiraterone acetate for chemotherapy-naive metastatic castration-resistant prostate cancer: a single-centre prospective study of efficacy, safety, and prognostic factors.

BACKGROUND: To evaluate the efficacy and safety of abiraterone acetate (AA) plus prednisone compared with prednisone alone in Asian patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC), and to identify predictive factors. METHODS: We reviewed the medical records of 60 patients with chemotherapy-naive mCRPC at Renji Hospital who were treated with AA plus prednisone (n = 43) or prednisone alone (n = 17). All patients were assessed for prostate-specific antigen (PSA) response, PSA progression-free survival (PSA PFS), radiographic progression-free survival (rPFS), and overall survival (OS). The ability of several parameters to predict PSA PFS, rPFS, and OS was studied. RESULTS: The median follow-up time was 14.0 months (range 7.0-18.5 months), at which time 19 death events had been reported: 11 in the AA + prednisone group and 8 in the prednisone group. The AA + prednisone group had significantly longer median PSA PFS (10.3 vs 3.0 months, P < 0.001), rPFS (13.9 vs 3.9 months, P < 0.001), and OS (23.3 vs 17.5 months, P = 0.016) than the prednisone-alone group. The most frequently reported grade 3 or 4 adverse event in both the AA + prednisone and prednisone-alone groups was elevated alanine aminotransferase level in 5 of 43 patients (11.6%) and 2 of 17 patients (11.8%), respectively. No adverse events led to discontinuation of therapy. In multivariate analysis, time from androgen deprivation therapy (ADT) to castration resistance of ≤18 months was a determinant of shorter OS (P = 0.007). CONCLUSIONS: These results support the favourable safety and efficacy profile of AA for the treatment of Asian patients with chemotherapy-naive mCRPC. Longer duration of ADT response was significantly associated with longer survival.

Green Light photoselective vaporization of the prostate: a safe and effective treatment for elderly high-risk benign prostate hyperplasia patients with gland over 80 ml.

To analyze the efficacy of Green Light photoselective vaporization of the prostate (PVP) in elderly high-risk benign prostatic hyperplasia (BPH) patients with glands over 80 ml. From December 2013 to February 2016, we allocated 84 elderly (age 71-97) high-risk patients who underwent preoperative transrectal ultrasound (TRUS) examination with glands over 80 ml and divided them into two groups to receive 120 W (n = 40) and 180 W (n = 44) PVP. All the patients have been observed at least one intraoperative comorbidity: hypertension, diabetes mellitus, NYHA II, or combined. They were followed up for 12 months. All the conventional parameters were compared in this study. All the patients received successful operations without severe complications, and no patient needed blood transfusion. The operation time and catheterization time of the 180 W patients were significantly shorter than that of the 120 W patients (p < 0.05). The International Prostate Symptom Scores (IPSS), quality of life (QoL) scores, maximum flow rate (Qmax), and residual urine volume (RUV) in both groups have been significantly improved. PVP is safe and effective for high-risk aging patients with gland over 80 ml. In addition, 180 W XPS system has a short operation time and catheterization time and less inflammatory response.

Prognostic nutritional index predicts initial response to treatment and prognosis in metastatic castration-resistant prostate cancer patients treated with abiraterone.

OBJECTIVE: To determine if prognostic nutritional index (PNI) and its variation could predict initial response to treatment and prognosis in metastatic castration-resistant prostate cancer (mCRPC) patients treated with Abiraterone (AA). PATIENTS AND METHODS: One-hundred-twelve chemotherapy pretreated or chemotherapy-naive patients were scheduled for systemic treatment with AA. PNI levels were measured before and after one month of AA treatment. Univariate and multivariate logistic regression analyses were used to identify predictive factors of initial response to AA treatment. Univariable and Multivariable Cox regression analyses were performed to determine prognostic factors that were associated with PSA progression-free survival (PSA-PFS), radiographic PFS (rPFS) and overall survival (OS). The Harrell concordance index with variables only or combined PNI data were used to evaluate the prognostic accuracy. RESULTS: Eighty-one (72.3%) of 112 patients showed initial response to AA treatment, in which 15 experienced PSA flare during AA treatment. In multivariate logistic regression analyses, high baseline PNI level, PSA level decrease during the first month of AA treatment and PNI level elevation during the first month of AA treatment were significantly correlated with initial response to AA treatment. In multivariate Cox regression analysis, low PNI level remained significant predictors of OS, rPFS and PSA-PFS. The estimated c-index of the multivariate model for OS increased from 0.82 without PNI to 0.83 when PNI added. CONCLUSION: Independent of PSA level variation, PNI level elevation during the first month of AA treatment and high baseline PNI level were significantly correlated with initial response to AA treatment. In addition, low pretreatment PNI level is a negative independent prognosticator of survival outcomes in mCRPC treated with AA and also increases the accuracy of established prognostic model.

Influence of abiraterone acetate on neuroendocrine differentiation in chemotherapy-naive metastatic castration-resistant prostate cancer.

BACKGROUND: To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted an analysis in 115 chemotherapy-naïve mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED. RESULTS: Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED. CONCLUSIONS: We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients.

Chromogranin A and neurone-specific enolase variations during the first 3 months of abiraterone therapy predict outcomes in patients with metastatic castration-resistant prostate cancer.

OBJECTIVE: To determine the prognostic utility of serum chromogranin A (CgA) and neurone-specific enolase (NSE) variations during the first 3 months of abiraterone acetate (AA) treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The serum levels of CgA, NSE were measured at baseline and after 3 months of AA treatment in 40 patients with mCRPC. Outcome measures were prostate-specific antigen progression-free survival (PSA-PFS), radiographic PFS (rPFS), and overall survival (OS). RESULTS: CgA levels were not correlated with NSE levels (P = 0.296). In multivariate analysis the combination of CgA and NSE (≥1 marker positive vs both markers negative) and the combination of CgA and NSE elevation during the first 3 months of AA treatment (≥1 marker positive vs both markers negative) remained significant predictors of OS, rPFS, and PSA-PFS. CONCLUSION: We found that CgA and NSE elevation during the first 3 months of AA treatment and elevated baseline CgA and NSE levels were independent prognostic factors for OS, rPFS and PSA-PFS in patients with mCRPC treated with AA. This suggests that serial CgA and NSE evaluation may help clinicians in distinguishing patients with mCRPC who would obtain the best survival benefit from AA treatment.

Transcriptomic signature defines two subtypes of locally advanced PCa with distinct neoadjuvant therapy benefits.

Background: Patients with locally advanced prostate cancer (LAPCa) received docetaxel-based neoadjuvant chemo-hormonal therapy (NCHT) had better clinical outcomes after surgery compared to neoadjuvant hormonal therapy (NHT) groups, but not all patients experienced favorable clinical outcomes with NCHT, raising the necessity for potential biomarker assessment. The transcriptomic profiling offers a unique opportunity to interrogate the accurate response to NCHT and NHT treatment and to identify the predictive biomarkers for neoadjuvant therapy. Methods: The whole transcriptomic profiling was performed on baseline biopsies and surgical tissue specimens from 64 patients with LAPCa at Renji Hospital between 2014 and 2018. Biochemical progression-free survival (bPFS)-based gene-by-treatment interaction effects were used to identify predictive biomarkers for guiding treatment selection. Results: Comparing the transcriptome profiling of pre- and post-treatment LAPCa specimens, NHT and NCHT shared 1917 up- and 670 down-regulated DEGs at least 2-fold. Pathway enrichment analysis showed up-regulated pathways in response to NHT and NCHT were both enriched in cytokine receptor interaction pathways, and down-regulated pathways in response to NCHT were enriched in cell cycle pathways. By comprehensive transcriptome profiling of 64 baseline specimens, ten predictive markers were identified. We integrated them into the signature to evaluate the relative benefits of neoadjuvant therapy, which categorizes patients into two subgroups with relative bPFS benefits from either NHCT or NHT. In the high-score (≥ -95.798) group (n = 37), NCHT treatment led to significantly longer bPFS (P< 0.0001), with a clear and early separation of the Kaplan-Meier curves. In the low-score (< -95.798) group (n = 27), NHT also led to significantly longer bPFS (P=0.0025). Conclusions: In this study, we proposed the first predictive transcriptomic signature might potentially guide the effective selection of neoadjuvant therapy in LAPCa and might provide precise guidance toward future personalized adjuvant therapy. Trial registration: The study was approved by the Ethics Committee of Renji Hospital affiliated to Shanghai Jiao Tong University (Ky2019-087).

Endoscopic combined intrarenal surgery in prone split-leg and inclined supine positions to treat renal cast and multiple calyx stones: An invited commentary.

This Invited Commentary discusses the following article: Mulay A, Mane D, Mhaske S, Shah AS, Krishnappa D, Sabale V. Supine versus prone percutaneous nephrolithotomy for renal calculi: Our experience. Curr Urol 2022;16 (1):25-29. doi: 10.1097/CU9.0000000000000076.

Efficacy of neoadjuvant docetaxel + cisplatin chemo-hormonal therapy versus docetaxel chemo-hormonal therapy in patients with locally advanced prostate cancer with germline DNA damage repair gene alterations.

Purpose: To assess the efficacy and safety of neoadjuvant docetaxel + cisplatin chemotherapy with androgen deprivation therapy for the treatment of locally advanced prostate cancer (PCa) in patients harboring germline DNA damage repair genes (gDDR) defects. Methods: We conducted a prospective observational study in patients with locally advanced PCa confirmed with gDDR defects through next-generation sequencing. All patients received either docetaxel + cisplatin (platinum-group) or docetaxel chemo-hormonal therapy (docetaxel group) followed by radical prostatectomy with extended lymphadenectomy. The primary end point was biochemical progression-free survival (bPFS) and secondary end points include postoperative pathological response and safety assessment during the study period. Results: A total of 36 patients were included in the study, among whom 14 and 22 patients received docetaxel + cisplatin and docetaxel treatment, respectively. Down-staging of Tumor (T), Nodes (N), and Metastasis (M) stages was observed in 11 (78.57%) and 9 (40.9%) patients (p = 0.041), respectively, in the docetaxel + cisplatin group and docetaxel group. The median bPFS was 7.76 months (95% CI 0.770-14.748) and not reached in the docetaxel group and docetaxel + cisplatin group, respectively. bPFS was significantly longer in the docetaxel + cisplatin group (p = 0.039) with a hazard ratio of 0.386 (95% CI 0.151-0.987, p < 0.05). Furthermore, one patient discontinued docetaxel + cisplatin after second cycle due to severe liver insufficiency which was confirmed as viral hepatitis A and no significant perioperative complications was observed in either group. Conclusion: This study suggests that cisplatin may increase docetaxel anticancer activity with tolerable safety profile in patients with locally advanced PCa carrying gDDR defects in the neoadjuvant setting, a hypothesis which will require prospective, randomized confirmation.

Erratum: Downregulation of circ-TRPS1 suppressed prostatic cancer prognoses by regulating miR-124-3p/EZH2 axis-mediated stemness.

[This corrects the article on p. 4372 in vol. 10, PMID: 33415005.].

Efficacy of Neoadjuvant Chemohormonal Therapy in Oligometastatic Hormone-Sensitive Prostate Cancer: A Prospective, Three-Arm, Comparative Propensity Score Match Analysis.

BACKGROUND: The study aimed to investigate the efficacy and safety outcomes in hormone-sensitive oligometastatic prostate cancer (OMPC) patients treated with docetaxel-based neoadjuvant chemohormonal therapy (NCHT) prior to radical prostatectomy (RP) compared with direct RP and standard androgen deprivation therapy (ADT) alone using propensity score match (PSM) analysis. PATIENTS AND METHODS: A single-center, prospective, three-arm study was conducted with hormone-sensitive OMPC patients. Eligible patients (N = 130) were divided into three groups-NCHT, RP, and standard treatment (ST)-and received their respective treatments. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were pathological response rate, radiographic progression-free survival (rPFS), and overall survival (OS). Further, propensity scores were calculated and group-wise comparisons were carried out: NCHT versus RP, ST versus RP, and ST versus NCHT. RESULTS: After PSM, in the NCHT group, two patients (11.76%) and four patients (23.52%) had complete and partial pathological responses, respectively. Univariate and multivariate Cox regression analysis showed that PFS and rPFS were significantly higher in the NCHT group. For NCHT versus RP, the PFS hazard ratio (HR) = 0.11 (95% confidence interval [CI], 0.02-0.51; P = .004) and HR = 0.016 (95% CI, 0.0015-0.17; P < .001); the rPFS HR = 0.088 (95% CI, 0.011-0.71; P = .023) and HR = 0.03 (95% CI, 0.0025-0.36; P = .006). Further, the median OS of the ST group was 44.6 months for ST versus RP, and it was 49.3 months for ST versus NCHT; it was not reached in either the NCHT or RP group. Furthermore, 17.65% and 47.06% patients had positive surgical margins in the NCHT and RP groups, respectively, and no therapy-related deaths were observed during the study period. CONCLUSIONS: PSM analysis revealed NCHT before RP in OMPC patients has potential therapeutic benefits with acceptable toxicities and lower incidence of postoperative positive surgical margins.

Transcriptional regulation of PRKAR2B by miR-200b-3p/200c-3p and XBP1 in human prostate cancer.

The cyclic adenosine monophosphate (cAMP)-activated protein kinase A (PKA) pathway is profoundly implicated in Prostate cancer (PCa) progression. Previously, we showed that PRKAR2B, the type II-beta regulatory subunit of PKA, is highly expressed in castration-resistant prostate cancer (CRPC) and can induce epithelial-mesenchymal transition by activating Wnt/ß-catenin signaling in PCa cells. However, the molecular mechanism of dysregulated PRKAR2B expression pattern is still largely unknown. In this study, we found that the mutation, copy number alteration, and methylation status of PRKAR2B gene have no correlation with its expression level in PCa. Then, we identified two microRNAs (miR-200b-3p and miR-200c-3p) to be critical regulators of PRKAR2B expression in PCa. Notably, miR-200b-3p and miR-200c-3p expression were significantly downregulated in metastatic CRPC and negatively correlated with the expression level of PRKAR2B in PCa tissues. Moreover, we characterized X-Box Binding Protein 1 (XBP1) as a key transcription factor responsible for PRKAR2B expression in PCa. Importantly, miR-200b-3p/200c-3p or XBP1 knockdown inhibited PCa cell proliferation and promoted cell apoptosis and these inhibitory roles could be largely restored by PRKAR2B, suggesting that PRKAR2B is a functional mediator of miR-200b-3p, miR-200c-3p, and XBP1 in PCa. Collectively, our study firstly identified miR-200b-3p/200c-3p and XBP1 as the critical upstream regulators of PRKAR2B in PCa and provided novel insights to PRKAR2B-driven PCa progression.