Prognostication in Lymph Node-Positive Prostate Cancer with No PSA Persistence After Radical Prostatectomy.

BACKGROUND: This study aimed to create a prognostic model to predict disease recurrence among patients with lymph node involvement but no prostate-specific antigen (PSA) persistence and to explore its clinical utility. METHODS: The study analyzed patients with lymph node involvement after pelvic lymph node dissection with radical prostatectomy in whom no PSA persistence was observed between 2006 and 2019 at 33 institutions. Prognostic factors for recurrence-free survival (RFS) were analyzed by the Cox proportional hazards model. RESULTS: Among 231 patients, 127 experienced disease recurrence. The factors prognostic for RFS were PSA level at diagnosis (≥ 20 vs. < 20 ng/mL: hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.09-2.52; P = 0.017), International Society of Urological Pathology grade group at radical prostatectomy (RP) specimen (group ≥ 4 vs. ≤ 3: HR, 1.63; 95% CI 1.12-2.37; P = 0.010), pathologic T-stage (pT3b/4 vs. pT2/3a: HR, 1.70; 95% CI 1.20-2.42; P = 0.0031), and surgical margin status (positive vs. negative: HR, 1.60; 95% CI 1.13-2.28; P = 0.0086). The prognostic model using four parameters were associated with RFS and metastasis-free survival. CONCLUSION: The prognostic model in combination with postoperative PSA value and number of lymph nodes is clinically useful for discussing treatment choice with patients.

Prognosis based on postoperative PSA levels and treatment in prostate cancer with lymph node involvement.

BACKGROUND: The therapeutic role of pelvic lymph node dissection (PLND) during radical prostatectomy (RP) for prostate cancer is not established. In clinical practice, PLND is primarily performed in cases of high-risk prostate cancer. The detection of lymph node metastasis plays a crucial role in determining the need for subsequent treatments. This study aims to evaluate the prognosis of prostate cancer patients with lymph node involvement (LNI) by stratifying them based on postoperative prostate-specific antigen (PSA) levels to identify biomarkers that can guide postoperative treatment strategies. METHODS: Analysis was conducted on 383 patients, selected from 572 initially eligible, who underwent RP with LNI across 33 Japanese Urological Oncology Group institutions from 2006 to 2019. Patients were grouped according to postoperative PSA levels and salvage treatments received. Follow-up focused on castration resistance-free survival (CRFS), metastasis-free survival (MFS), and overall survival (OS). RESULTS: In the persistent PSA group (PSA ≥ 0.1 ng/mL), CRFS and MFS were significantly shorter compared to the non-persistent PSA group (PSA < 0.1 ng/mL), and there was a tendency for shorter OS. In the persistent PSA group, patients with postoperative PSA values above the median (PSA ≥ 0.52 ng/mL) showed shorter CRFS and MFS. Furthermore, in the PSA ≥ 0.52 group, androgen deprivation therapy (ADT) plus radiotherapy (RT) combination had prolonged CRFS and MFS compared with ADT alone. CONCLUSIONS: This study provides valuable insights into stratifying patients based on postoperative PSA levels to tailor postoperative treatment strategies, potentially improving the prognosis of prostate cancer patients with LNI.

Prostate fibroblasts enhance androgen receptor splice variant 7 expression in prostate cancer cells.

BACKGROUND: Androgen receptor splice variant (AR-V) expression has been associated with prostate cancer (PCa) progression to castration-resistant PCa during androgen deprivation therapy, which reduces androgen production and inhibits androgen action in PCa cells. However, the mechanisms whereby aberrant AR-V expression is increased in PCa are still largely unknown. Fibroblasts in tumor stroma influence PCa initiation and aggressiveness, and which may play a crucial role in eliciting genetic changes during malignant transformation in human prostate epithelium. Here, our aim was to determine whether prostate fibroblasts in tumor stroma induce aberrant AR-V7 expression in PCa cells under low androgen concentration. METHODS: We performed in vitro experiments using androgen-sensitive, AR-positive PCa cell lines (LNCaP and 22Rv1 cells), commercially available prostate stromal cells (PrSC), and primary cultured prostate fibroblasts (pcPrF) from PCa specimens collected from biopsies of patients with advanced PCa. PCa cells were cocultured with each of the three fibroblast lines (PrSC, pcPrF-M37, and pcPrF-M48). RESULTS: The proliferation under low androgen concentration of LNCaP and 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48 was significantly increased compared to that of PCa cells cultured alone. Androgen receptor-full length (AR-FL) protein expression was increased in LNCaP and 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48. AR-V7 protein expression was increased in 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48. Under low androgen concentration, AR-V7 protein expression was slightly detected in LNCaP cells cocultured with PrSC or pcPrF-M37. Cytokine array analysis revealed that monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8) levels in the conditioned medium of 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48 were increased under low androgen concentration. High IL-8 concentration (30 ng/ml) resulted in significantly increased protein expression of AR-FL, AR-V7, and phospho-NF-κB p65 in 22Rv1 cells. In contrast, IL-8 antibody (1 µg/ml) decreased AR-V7 protein expression in 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48. CONCLUSIONS: pcPrF from PCa specimens increase the expression of aberrant AR-V7 in PCa cells. IL-8 may be a target for preventing the expression of aberrant AR-Vs in PCa.

[Idiopathic Thrombocytopenia Purpura After Pembrolizumab Treatment Against Locally Recurrent Bladder Cancer : A Case Report].

A man in his 70s visited our hospital for gross hematuria. He was diagnosed with invasive urothelial carcinoma (cT3N2M0) and underwent total cystectomy and ileum conduit construction after three courses of neoadjuvant chemotherapy. Eight months after the operation, the disease reoccurred in the pelvic lesion. He received pembrolizumab therapy but developed idiopathic thrombocytopenic purpura (ITP) immediately before the ninth course of administration; and, treatment was discontinued. Recovery of symptoms and normalization of blood test data were achieved 3.5months after starting steroid treatment. Reduction of recurrent disease has been maintained for 2 years.

Radiotherapy plus androgen deprivation therapy for prostate-specific antigen persistence in lymph node-positive prostate cancer.

The treatment for lymph node involvement (LNI) after radical prostatectomy (RP) has not been established. This study aimed to reveal the outcomes of various management strategies among patients with LNI after RP. Retrospectively, 561 patients with LNI after pelvic lymph node dissection (PLND) with RP treated between 2006 and 2019 at 33 institutions participating in the Japanese Urological Oncology Group were investigated. Metastasis-free survival (MFS) was the primary outcome. Patients were stratified by prostate-specific antigen (PSA) persistence after RP. Cox regression models were used to analyze the relationships between clinicopathological characteristics and survival. Survival analyses were conducted using the Kaplan-Meier method and log-rank test with or without propensity score matching. Prognoses, including MFS and overall survival, were prominently inferior among patients with persistent PSA compared with those without persistent PSA. In multivariate analysis, androgen deprivation therapy (ADT) plus radiotherapy (RT) was associated with better MFS than ADT alone among patients with persistent PSA (hazard ratio = 0.37; 95% confidence interval = 0.15-0.93; p = 0.034). Similarly, MFS and overall survival were significantly better for ADT plus RT than for ADT alone among patients with persistent PSA after propensity score matching. This study indicated that PSA persistence in LNI prostate cancer increased the risk of poor prognoses, and intensive treatment featuring the addition of RT to ADT might improve survival.

Impact of family history on clinicopathological variables and disease progression in Japanese prostate cancer patients undergoing robotic-assisted radical prostatectomy.

OBJECTIVE: We evaluated whether a first-degree family history (FH) of prostate cancer (PCa) in Japanese patients undergoing robotic-assisted radical prostatectomy (RP) is correlated with clinicopathological variables and disease progression. METHODS: We reviewed consecutive 392 localized PCa patients undergoing robotic-assisted RP at our institution between 2015 and 2020. Information on FH was obtained via a self-administered questionnaire. A positive FH was defined as having a first-degree FH: a father and/or one or more brothers with PCa prior to diagnosis. All patients had clinically localized PCa treated by robotic-assisted RP. We evaluated the relationship between clinical characteristics, pathological findings, and biochemical progression-free survival (bPFS) according to first-degree FH status. RESULTS: Median follow-up was 20.8 months. FH was identified in 42 (10.7%) patients. Patients in the FH group (median, 64.8 years) were diagnosed at a significantly younger age than patients in the non-FH (NFH) group (patients without FH) (median, 67.7 years) (p = 0.003). The 5-year bPFS in the FH and NFH groups was 72.0% and 78.1%, respectively (p = 0.90). A subgroup analysis revealed a significant difference in prostate-specific antigen (PSA) density between the FH group (median, 0.51 ng/ml/cm3 ) and the NFH group (median, 0.29 ng/ml/cm3 ) in patients younger than 60 years (p = 0.033). CONCLUSIONS: In this RP population, FH of PCa was not associated with worse clinical characteristics, pathological findings, or disease progression. Patients with a FH underwent surgery at a significantly younger age, and among patients <60 years, patients with a FH had significantly higher PSA density compared with patients without a FH.

Current experimental human tissue-derived models for prostate cancer research.

Scientists engaged in prostate cancer research have been conducting experiments using two-dimensional cultures of prostate cancer cell lines for decades. However, these experiments fail to reproduce and reflect the clinical course of individual patients with prostate cancer, or the molecular and genetic characteristics of prostate cancer, the basic requirement for most of the preclinical studies on prostate cancer. The use of human prostate cancer tissues in experiments has enabled the collection and verification of clinically relevant data, including chemical reactions, changes in proteins, and specific gene expression. Tissue recombination models have been employed for studying prostate development, the initiation and progression of prostate cancer, and the tumor microenvironment. Notably, the epithelial-stromal interaction, which might play a critical role in prostate cancer pathogenesis, can be reproduced in this model. Patient-derived xenograft models have been developed as powerful avatars comprising patient-derived prostate cancer tissues implanted in immunocompromised mice and could serve as a precision medicine approach for each prostate cancer patient. Spheroid and organoid assays, representative of modern three-dimensional cultures, can replicate the conditions in human prostate tumors and the prostate organ itself as a miniature model. Although an intact immune system against the tumor is missing from the models aimed at investigating immuno-oncological reagents in various malignancies, all these experimental models can help researchers in developing new drugs and selecting appropriate treatment strategies for prostate cancer patients.

[Initial Experience of Photodynamic Diagnosis-Assisted Transurethral Resection of Bladder Tumor (PDD-TURBT)].

Photodynamic diagnosis (PDD) using 5-aminolevulinic acid (5-ALA) is expected to be useful in preventing oversight of non-muscle-invasive bladder cancer (NMIBC) and in reducing the intravesical recurrence rate after transurethral resection of bladder tumor (TURBT). We report our initial experience with28 cases of PDD-assisted TURBT (122 samples) performed at our hospital from February 2018 to April 2019. The median age of the patients was 74.5 years, and 18 of the 28 were primary cases. Each patient underwent TURBT with oral administration of 5-ALA 20 mg/kg 3 hours before endoscopic examination. The sensitivity was 89.8% when both white light and blue light were used, which was superior to the sensitivity of 67.8% when using only white light (p＜0.01, McNemar's test). Among the first several cases, we experienced high false positivity, which suggested that some experience may be required to discriminate tumors from inflammatory lesions. In fact, the specificity and the positive likelihood ratio improved with experience. No grade 2 or higher adverse events were observed among our cases. The median follow-up period was 738 days, and 9 of 28 patients (32. 1%) had recurrence within the follow-up period. In conclusion, our initial experience with PDD-assisted TURBT demonstrated its excellent diagnostic sensitivity and safety, as previously reported.

[Presurgical Treatment with Axitinib and Pembrolizumab Reduced Operation Risk by Downsizing the Vena Cava Tumor Thrombus in Clear Cell Renal Cell Carcinoma : A Case Report].

A woman in her seventies complained of chest pain during exertion and visited a local hospital. Computed tomographic scan showed right renal cell carcinoma with inferior vena cava (IVC) tumor thrombus extending above the diaphragm, and the patient was referred to our hospital. She was diagnosed with right renal cell carcinoma cT3cN0M0, with level IV IVC thrombus by Mayo classification. Axitinib and pembrolizumab were administered against intractable advanced renal cell carcinoma. The dose of axitinib was reduced due to grade 3 liver dysfunction. Right nephrectomy together with IVC thrombectomy was performed because the primary lesion had shrunk, and the level of IVC thrombus had become level III. The pathological results were clear cell carcinoma, pT3c, G3, Fuhrman grade3, INFA, v1, and ly0. Axitinib and pembrolizumab might be a presurgical option against an intractable renal cell carcinoma with an IVC thrombus.

Castration-induced stromal remodeling disrupts the reconstituted prostate epithelial structure.

The normal prostate epithelial structure is maintained by homeostatic interactions with smooth muscle cells. However, structural alterations of the stroma are commonly observed in prostatic proliferative diseases, leading to the abnormalities of prostate epithelial structure. A decrease in the androgen level experimentally induces stromal remodeling, i.e., replacement of smooth muscle cells with fibroblasts or myofibroblasts. In this study, we investigated the effects of castration-induced stromal remodeling and subsequent aberrant activation of epithelial-stromal interactions on the reconstituted human prostate-like epithelial structure. We performed in vivo experiments using the human prostate epithelial cell line BPH-1 and fetal rat urogenital sinus mesenchyme to generate heterotypic tissue recombinants that form human prostate-like epithelial structure (i.e., solid- and canalized-epithelial cords). Host mice were castrated at 12 weeks post transplantation (castration) and implanted with a dihydrotestosterone pellet at 14 days post castration (androgen replacement treatment; ART). In the castration group, the percentages of fibrotic area and disrupted prostate epithelial structure without the basement membrane (BM) increased proportionally in a time-dependent manner, but were suppressed by ART. In the castration group, tenascin-C (TNC)-positive fibroblasts were abundant in the stroma surrounding disrupted prostate epithelial structure without the BM. TGF-ß1 secretion from BPH-1 cells was increased by co-culturing with human primary cultured prostate fibroblasts. TNC mRNA expression was increased in fibroblasts co-culturing with BPH-1 cells and was suppressed by treatment with a TGF-ß RI kinase inhibitor. Moreover, in the castration group, the percentage of p-Smad2-positive cells was significantly higher in the stroma surrounding disrupted prostate epithelial structure without the BM. Our results demonstrate that castration-induced stromal remodeling disrupted the reconstituted human prostate-like epithelial structure and induced the appearance of TNC-positive fibroblasts accompanied by activation of TGF-ß signaling. The alteration of prostate stromal structure may be responsible for loss of the BM and epithelial cell polarity.

Effects of itraconazole and rifampicin on the single-dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects.

AIMS: To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects. METHODS: Two open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed. RESULTS: Esaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUClast ) and AUC from zero until infinity (AUCinf ) were 1.13 (1.05, 1.20) ng mL-1 , 1.47 (1.40, 1.54) ng h mL-1 and 1.53 (1.45, 1.62) ng h mL-1 , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone Cmax , AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively. CONCLUSION: Itraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.

Pre-treatment ratio of periprostatic to subcutaneous fat thickness on MRI is an independent survival predictor in hormone-naïve men with advanced prostate cancer.

BACKGROUND: Epidemiological studies have shown an association between obesity and prostate cancer (PCa) aggressiveness. However, little is known about periprostatic fat (PPF) and its relationship with overall fat deposition in PCa. PPF is thought to contribute to PCa growth and migration via secreted factors and induction of chronic inflammation. We investigated if pre-treatment PPF thickness correlates with overall survival (OS). METHODS: We reviewed 85 hormone-naïve men with advanced PCa who had received androgen deprivation therapy (ADT). PPF thickness was measured by magnetic resonance imaging (MRI) and compared with subcutaneous fat (SCF) thickness as an internal control. Visceral fat (VF) area measured by computed tomography served as an additional control. We evaluated the relationship between laboratory data, pathology results, and obesity parameters and OS. RESULTS: Median follow-up was 50.6 months. Thirty-six patients died during follow-up. Univariate analysis revealed that nadir PSA titer, Gleason score, N stage, M stage, extent of disease by bone scan grade, hemoglobin, lactate dehydrogenase, alkaline phosphatase, and PPF/SCF ratio were associated with OS. Multivariate analysis revealed that nadir PSA titer, N stage, and PPF/SCF ratio were independent prognostic factors for survival. The 5-year OS in the patients with higher PPF/SCF ratio (≥ 1) and lower PPF/SCF ratio (< 1) was 49.5% and 66.5%, respectively (P = 0.039). CONCLUSIONS: Pre-treatment ratio of PPF-to-SCF thickness on MRI is an independent predictor of survival in hormone-naïve men with advanced PCa. This could be useful for predicting which patients are more likely to develop castration-resistant PCa.

[Neoajuvant Chemotherapy with Gemcitabine and Cisplatin Plus S-1 for Primary Female Urethral Adenocarcinoma].

A 67-year-old female presented for evaluation of a left inguinal mass. Contrast-enhanced computed tomography revealed a tumor surrounding the urethra. Magnetic resonance imaging showed that the tumor had invaded the bladder neck on the anterior aspect of the urethra. The serum carbohydrate antigen 19-9 level was elevated. The clinical diagnosis was a primary adenocarcinoma of the female urethra (cT4N2M0). The initial treatment consisted of gemcitabine plus cisplatin (GC) and oral fluoropyrimidine (S-1). A total cysto-urethrectomy with anterior vaginal wall resection, pelvic and inguinal lymphadenectomy, and urinary diversion with ileal conduit formation were performed. The final diagnosis was urethral adenocarcinoma (ypT4ypN2, stage IV). Twelve months post-operatively, there was no evidence of recurrence or distant metastases.

[A Case of Extragonadal Germ Cell Tumor Treated by Induction Therapy with A Reduced Bep Regimen].

A 21-year-old man with chief complaints of left hypochondriac and chest pain was shown to have multiple masses in the lung, a pleural effusion in the right cavum thoracis, a mediastinal mass, and lymphadenopathy detected by computed tomographic scan. He was diagnosed with an extragonadal germ cell tumor based on pathologic findings from lung biopsies and elevation of the serum total human chorionic gonadotropin. He underwent a reduced chemotherapy regimen consisting of bleomycin, cisplatin, and etoposide (reduced BEP) to lower the risk of acute respiratory distress syndrome (ARDS), a manifestation of choriocarcinoma syndrome, which occurs at induction chemotherapy with the full-dose BEP regimen. Choriocarcinoma syndrome did not develop during chemotherapy, and he has been disease-free since salvage chemotherapy and subsequent retroperitoneal lymph node dissection.

Interleukin-6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation.

BACKGROUND: The reduced androgen-sensitivity of prostate cancer (PCa) cells is an important clinical development because of its association with the cells' progression to castration-resistant prostate cancer (CRPC). During androgen deprivation therapy (ADT), stroma-derived growth factors and cytokines can activate the androgen receptor (AR). For example, IL-6 is a multifunctional cytokine that is involved in the malignancy of PCa cells through AR activation. In the present study, we used an androgen-sensitive human PCa cell line (LNCaP) and its sublines to investigate the relationship between the responsiveness of PCa cells to IL-6 treatment and the cellular AR signaling pathway. METHODS: The androgen-low-sensitive F10 and E9 cells were obtained from LNCaP cells by limiting dilution method in regular culture condition. In contrast, the androgen-insensitive AIDL cells were established from LNCaP cells by continuous passaging in hormone-depleted condition. Original carcinoma-associated fibroblasts (CAFs) PCaSC-8 and PCaSC-9 cells were isolated from needle biopsy samples of PCa patients. RESULTS: In fibroblasts derived from PCa patients, IL-6 secretion was generally higher than that observed with normal fibroblasts. In contrast, IL-6 secretion was not detected in LNCaP and its sublines. The soluble IL-6 receptor was detected in PCa cells but not in fibroblasts. IL-6 treatment suppressed cell growth of LNCaP, F10, and E9 cells but not AIDL cells and it was accompanied with neuroendocrine-like differentiation. Induction of PSA secretion was observed in IL-6-treated LNCaP and F10 cells. VEGF secretion was strongly induced in IL-6-treated LNCaP and AIDL cells. IL-6-induced VEGF secretion was significantly suppressed by a PI3K inhibitor (LY294002) and it was accompanied by inhibited phosphorylation of Akt. CONCLUSIONS: Our results suggest that IL-6 might induce VEGF secretion from PCa cells in a manner independent of AR activation. To prevent IL-6-induced VEGF secretion, inhibition of the PI3K/AKT signaling pathway could be an important pharmacological goal regardless of ADT.

Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects.

AIMS: To characterize the pharmacokinetics, pharmacodynamics and safety of esaxerenone, a mineralocorticoid receptor antagonist, in healthy adult Japanese men. METHODS: Double-blind, placebo-controlled, sequential, dose-escalation studies were conducted in subjects randomized to receive oral once-daily esaxerenone (ranges: 5-200 mg [single-dose]; 10-100 mg over 10 days [multiple-dose]) or placebo under fasting conditions. Plasma concentrations were analysed by liquid chromatograph-tandem mass spectrometry. Pharmacokinetic parameters were determined by noncompartment analysis. Plasma/urine levels of pharmacodynamic biomarkers for mineralocorticoid receptor activity were evaluated. RESULTS: In total, 48/48 and 39/40 subjects completed the single- and multiple-dose studies, respectively. Exposures were generally dose-proportional. The tmax , t1/2 and CL/F remained unchanged, independent of dose; the respective ranges were 1.5-4.0 h, 22.3-25.1 h, and 4.0-5.2 l h-1 (multiple-dose study). Vz /F ranged from 136.5 to 283.7 l in the multiple-dose study, and exposure reached steady state by day 4. The mean observed accumulation ratio, by dose, ranged from 1.36-1.98. The urinary Na+ /K+ ratio increased after single-dose administration; however, its relationship to the doses tested remains unclear. Plasma renin activity, active renin concentration and aldosterone concentration increased dose-dependently. Although blood potassium levels increased dose-dependently in the multiple-dose study (reaching a maximum mean ± standard deviation of 4.63 ± 0.354 mmol l-1 in the 100-mg group), no safety/tolerability-related problems were detected in either study. CONCLUSIONS: Exposure levels in healthy adults receiving esaxerenone were generally dose-proportional. Dose-dependent changes in plasma pharmacodynamic biomarkers for the mineralocorticoid receptor were identified during multiple-dose treatment and support the pharmacological activity of esaxerenone. No important safety concerns were identified.

Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer.

In patients with prostate cancer (PCa), serum prostate-specific antigen (PSA) is a useful marker for evaluating the effects of androgen deprivation therapy (ADT). Intuitively, most urologists expect that a more rapid PSA decline in response to ADT would be positively associated with extended survival. Recently, we have reported that prolonged gradual serum PSA decline after ADT is strongly associated with favorable prognosis in PCa patients, however, the mechanism remains unknown. We investigated the role of fibroblasts in serum PSA decline after ADT. We performed in vitro experiments using androgen-sensitive, androgen receptor (AR)-positive prostate epithelial cell lines (LNCaP, 22Rv1, and RWPE-1 cells), commercially available prostate stromal cells (PrSC), and primary cultures of prostate fibroblasts (pcPrFs). In LNCaP and 22Rv1 cells, PSA production was increased by co-culture with fibroblasts under androgen-deprived conditions. In an in vivo model using LNCaP cells, serum PSA declined rapidly after ADT becoming undetectable within 14 days in mice inoculated with LNCaP cells alone. In contrast, when LNCaP cells were co-inoculated with fibroblasts, serum PSA levels were still high on 14 days post ADT and did not drop to undetectable levels until 21 days post ADT. Tumor volumes and Ki67 labeling indices were not altered between days 14 and 21 post ADT in mice inoculated with LNCaP cells; however, those in mice inoculated with LNCaP cells plus fibroblasts decreased gradually. PSA protein was detected in all tumors on 21 days post ADT by immunohistochemical staining. Microvessel densities were higher on 14 days post ADT for tumors from mice inoculated with LNCaP cells plus fibroblasts as compared with LNCaP cells alone. In summary, co-inoculation of fibroblasts with LNCaP cells prolonged serum PSA decline after ADT and enhanced the efficacy of ADT. Prolonged serum PSA decline may indicate the presence of protective fibroblasts that preserve the AR dependence of PCa cells, improving treatment efficacy.