Androgen Blockade Research Articles

The prognostic value of the pretreatment lung immune prognostic index in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

The lung immune prognostic index (LIPI) was first reported to predict the effectiveness of immune checkpoint inhibitors in patients with metastatic non-small cell lung cancer and there are no studies investigating the predictive value of LIPI for patients with PCa. This study explores the prognostic value of the LIPI in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Data from 502 patients with mHSPC primarily treated with maximal androgen blockade (MAB; 89% of patients received MAB) and 158 patients with mCRPC who received abiraterone were retrospectively analyzed. All cases were classified into LIPI-good, LIPI-intermediate, and LIPI-poor groups based on their LIPI score as calculated with the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase level. The potential for LIPI to be used in predicting mCRPC-free survival (CFS), prostate-specific antigen (PSA) response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) was analyzed. A propensity score matching (PSM) methodology was performed to balance the baseline factors of the different groups. In the mHSPC cohort, patients of the LIPI-good (mCFS: 25.7 months; mOS: 93.3 months), LIPI-intermediate (mCFS: 14.8 months; mOS: 51.9 months), and LIPI-poor group (mCFS: 6.8 months; mOS: 18.5 months) had sequentially worse clinical outcomes (P<0.001 for all pairwise comparisons). The results remained consistent after PSM. Multivariate Cox regression further confirmed that LIPI was an independent predictor of survival outcomes. Subgroup analysis verified that LIPI was associated with an unfavorable prognosis in all subgroups except for cases with visceral metastases or those receiving abiraterone or docetaxel. As for patients with mCRPC receiving abiraterone, LIPI was also an indicator of poor prognosis. Specifically, cases in the LIPI-good, LIPI-intermediate, and LIPI-poor groups had a ladder-shaped worse PSA response [71.4% (50/70) vs. 56.5% (39/69) vs. 36.8% (7/19); P=0.015], PSA-PFS (14.9 vs. 9.3 vs. 3.1 months; P<0.001), and OS (14.6 vs. 32.3 vs. 53.4 months; P<0.001). The results were robust even after PSM. Multivariate Cox regression confirmed that LIPI was an independent prognosticator of PSA-PFS and OS in patients with mCRPC treated with abiraterone. This study demonstrated that the baseline LIPI was a significant prognostic biomarker for patients with both mHSPC and mCRPC and could potentially facilitate risk classification and clinical decision-making.

Prognostic value of pretreatment lung immune prognostic index in patients with metastatic hormone-sensitive and castration-resistant prostate cancer.

198 Background: The aim of this study was to explore the prognostic value of the lung immune prognostic index (LIPI) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC). Methods: We retrospectively analyzed data of 502 mHSPC patients primarily treated with maximal androgen blockade and 158 mCRPC patients receiving abiraterone. All cases were classified into the LIPI-Good, LIPI-Intermediate, and LIPI-Poor groups based on their LIPI score calculated by the derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase. The potential of LIPI in predicting mCRPC-free survival (CFS), PSA response, PSA-progression-free survival (PSA-PFS), and overall survival (OS) were analyzed. A propensity score matching (PSM) methodology was performed to balance the baseline factors of different groups. Results: In the mHSPC cohort, patients of the LIPI-Good (mCFS: 25.7 mo; mOS: 93.3 mo), LIPI-Intermediate (mCFS: 14.8 mo; mOS: 51.9 mo) and LIPI-Poor group (mCFS: 6.8 mo; mOS: 18.5 mo) had sequentially worse clinical outcomes (P&lt;0.001 for all pairwise comparisons). The results remain consistent after PSM. Multivariate Cox regression further confirmed that LIPI was an independent predictor of survival outcomes. Subgroup analysis verified that LIPI was associated with unfavorable prognosis in all subgroups except for cases with visceral metastases or receiving abiraterone/docetaxel. As for patients with CRPC receiving abiraterone, LIPI was also an indicator of poor prognosis. Specifically, cases in the LIPI-Good, LIPI-Intermediate and LIPI-Poor group had a ladder-shaped worse PSA response (71.4% [50/70] vs. 56.5% [39/69] vs. 36.8% [7/12], P=0.015), PSA-PFS (14.9- vs. 9.3 vs. 3.1 mo, P&lt;0.001) and OS (14.6- vs. 32.3- vs. 53.4 mo, P&lt;0.001). The results were robust even after PSM. Multivariate Cox regression confirmed that LIPI was an independent prognosticator of abiraterone. Conclusions: This study demonstrated that baseline LIPI was a significant prognostic biomarker for both mHSPC and mCRPC patients and could potentially facilitate risk classification and treatment-decision making in clinical practice.

Phase 2 randomized total eradication of metastatic lesions following definitive radiation to the prostate in de novo oligometastatic prostate cancer (TERPs) trial.

TPS275 Background: It is now recognized that some patients with “oligo,” or few sites of metastases, may have the potential to completely eradicate their disease with aggressive local therapy. There are recent encouraging randomized prospective data for total consolidation of macroscopic metastases through treatment intensification involving metastasis-directed therapy (MDT). Hypotheses include that radiation to primary prostate tumor and metastatic sites affects the natural history of metastasis by virtue of radiation effects on cancer cell autonomous pathways and tumor microenvironment/normal tissue pathways. This study aims to evaluate the utility of the addition of MDT to the evolving standard of care treatment for de novo low volume metastatic prostate cancer (PCa) patients. This study will evaluate the efficacy of best systemic therapy (BST) and primary prostate radiation (XRT) versus BST, XRT and stereotactic ablative radiation therapy (SABR) MDT. Discovery correlatives associated with clinical outcome will be assessed by collection of including, but not limited to: circulating tumor cells, immunologic biomarkers, microbiota and radiomics. Methods: This study is a multi-site, non-blinded, randomized Phase II trial in patients with oligometastatic PCa. Men with de novo histologically confirmed (at any site) oligometastatic PCa (&lt;3 metastases on standard imaging or &lt;5 on Axumin/Choline/PSMA-PET/CT) will be randomized (1:1) to BST + XRT versus BST + XRT + SABR MDT. BST and XRT will be administered for all men in the first 3-months, and radiation treatment will be completed within the first 150 days. A range of XRT treatment approaches are permitted but must deliver an EQD2 &gt;75.6 Gy to the prostate. BST will allow standard and intensified androgen blockade. The trial will evaluate the addition of SABR MDT and explore several translational and imaging correlatives. Subjects who meet eligibility criteria and qualify for enrollment will be stratified according to: (i) hormonal therapy vs intensified hormonal therapy; (ii) XRT vs XRT + primary prostate boost, and (iii) absence vs presence of bone metastasis. This study has been approved and began accrual on October 3rd, 2022, the Clinicaltrials.gov. Identifier: NCT05223803. We assume an accrual time of 24 months, with 24 months of additional follow-up time, and will randomize a total of 122 patients (61 patients in each arm). The primary endpoint with be to assess 2-year failure-free survival (FFS). Secondary endpoints will include toxicity, quality of life (QoL), time to locoregional progression, time to distant progression, time to new metastasis, radiographic progression-free survival, and duration of response. Clinical trial information: NCT05223803 .

Preclinical models of prostate cancer - modelling androgen dependency and castration resistance in vitro, ex vivo and in vivo.

Prostate cancer is well known to be dependent on the androgen receptor (AR) for growth and survival. Thus, AR is the main pharmacological target to treat this disease. However, after an initially positive response to AR-targeting therapies, prostate cancer will eventually evolve to castration-resistant prostate cancer, which is often lethal. Tumour growth was initially thought to become androgen-independent following treatments; however, results from molecular studies have shown that most resistance mechanisms involve the reactivation of AR. Consequently, tumour cells become resistant to castration - the blockade of testicular androgens - and not independent of AR per se. However, confusion still remains on how to properly define preclinical models of prostate cancer, including cell lines. Most cell lines were isolated from patients for cell culture after evolution of the tumour to castration-resistant prostate cancer, but not all of these cell lines are described as castration resistant. Moreover, castration refers to the blockade of testosterone production by the testes; thus, even the concept of "castration" in vitro is questionable. To ensure maximal transfer of knowledge from scientific research to the clinic, understanding the limitations and advantages of preclinical models, as well as how these models recapitulate cancer cell androgen dependency and can be used to study castration resistance mechanisms, is essential.

Perioperative Morbidity of Radical Prostatectomy After Intensive Neoadjuvant Androgen Blockade in Men With High-Risk Prostate Cancer: Results of Phase II Trial Compared to a Control Group.

Recent studies about intense neoadjuvant therapy followed by Radical Prostatectomy (RP) lack standardized criteria regarding surgical complications and comparison to a group of patients who underwent RP without the use of neoadjuvant therapy. The aim of this study is to describe and compare the perioperative complication rates. This was a prospective, single-center phase II trial in patients with high-risk prostate cancer (HRPCa). The control group included HRPCa patients who underwent RP outside the clinical trial during the same study recruitment period. The interventional group was randomized (1:1) to receive neoadjuvant androgen deprivation therapy plus abiraterone with or withoutapalutamide followed by RP. Complications observed up to 30 days of surgery were classified based on the Clavien-Dindo classification. Uni- and multivariate analyses were carried out to assess predictive factors associated with perioperative complications. In total, 124 patients with HRPCa were underwent to RP between May 27, 2019 and August 6, 2021, including 61 patients in the intervention group and 63 patients in the control group. The general and major complications in the intervention group reached 29.6% and 6.6%, respectively, and 39.7% and 7.9% in the control group, respectively. There was no significant difference between groups. We observed 4.9% of thromboembolic event in the neoadjuvant group. There was no significant increase in morbidity rate in RP after intense neoadjuvant therapy. The association of intense androgen deprivation neoadjuvant therapy with RP and extended pelvic lymphadenectomy may increase the risk of a perioperative thromboembolic events.

Prostate-specific Antigen Kinetics During Androgen-deprivation Therapy Predict Response to Enzalutamide in Metastatic Castration-resistant Prostate Cancer.

No practical predictive biomarkers exist to date for the response to androgen receptor-axis targeted (ARAT) therapies in metastatic castration-resistant prostate cancer (mCRPC). This study investigated whether prostate-specific antigen (PSA) kinetics in primary androgen-deprivation therapy for advanced hormone-sensitive prostate cancer may be associated with the response to ARAT agents in mCRPC. This study assessed 102 patients with mCRPC treated with enzalutamide or abiraterone to evaluate the associations between clinical outcomes and PSA kinetics, including the ratio of initial to nadir PSA (I/N PSA) level in primary combined androgen blockade. The PSA response was defined as a ≥50% decrease at 3 months from baseline in patients with mCRPC. In patients treated with enzalutamide, the optimal cut-off I/N PSA value for PSA response was 531 ng/ml (sensitivity=66.7%, specificity=88.2%, area under the curve=0.73, using a receiver operating characteristic curve). The PSA response was 83.3% and 25.0% in the high and low I/N PSA groups, respectively. The median overall survival and radiographic progression-free survival from enzalutamide initiation were longer for the high compared to the low I/N PSA group. Multivariate analysis revealed I/N PSA (hazard ratio=0.275, p=0.026) as an independent risk factor for overall survival in the patients treated with enzalutamide. In contrast, I/N PSA showed no predictive ability for PSA response in patients treated with abiraterone. In patients with mCRPC, I/N PSA can be a practical predictive biomarker for response to the ARAT agent enzalutamide.

Restored Thymic Output after Androgen Blockade Participates in Antitumor Immunity.

The thymus is a hormone-sensitive organ, which involutes with age in response to production of sex steroids. Thymic involution leads to a decrease in the generation of recent thymic emigrants (RTEs), resulting in a reduced response to immune challenges such as cancer. Interestingly, the standard of care for prostate cancer patients is androgen deprivation therapy (ADT), which leads to thymic regeneration and an increase in thymic output. It remains unknown whether these newly produced T cells can contribute to the antitumor immune response. This study defines the kinetics of thymic regeneration in response to ADT in mice, determining that thymic epithelial cell proliferation is critical for the increase in RTE output. Using a mouse model to track RTE in vivo, we demonstrate that these newly generated RTEs can traffic to tumors, where they become activated and produce effector cytokines at levels similar to more mature T cells. Collectively, these data suggest that RTEs produced from ADT-induced thymic regeneration could be harnessed for the antitumor immune response.

Prostate Cancer and DNA Genes Repair: What Should an Oncologist Know? – A Narrative Review

Prostate cancer is a very prevalent disease in men, especially in Western countries. The treatment of this neoplasm, both localized and locally advanced, is based on the clinical risk analysis (Gleason, tumor size, PSA, and other factors) and is founded on surgery and/or radiotherapy with or without androgen blockade with a GnRH analog (hormone gonadotropin releaser). However, in patients who invariably progress to a metastatic disease scenario, the tumors may present a heterogeneous behavior, depending on whether or not they are sensitive to androgen blockade therapy. Due to the poor prognosis of the metastatic castration-resistant scenario, current research carried out in the molecular biology and genetics field has identified several gene alterations associated with the development of prostate cancer, which correlate with clinical risk, therapeutic predictive responses, and prognosis. Among the associated gene alterations, the genes of the DNA repair pathway are correlated with diseases that present: a higher risk of recurrence; early metastasis; worse cancer-specific survival; familial risk, and predictive responses to new targeted therapies. Therefore, the breast cancer susceptibility genes, BRCA1 and BRCA2 (and other variants), present in the DNA repair machinery are being investigated to provide more (and better) therapeutic options for the treatment of the disease in the advanced scenario. This review was aimed to describe the malignant prostate disease, especially with regard to DNA repair mechanisms, genomic analysis of prostate cancer, predictive and prognostic implications, as well as on the development of poly-(ADP-ribose) polymerase (PARP) inhibitors, synthetic lethality mechanisms, and BRCAness phenomenon.

Identification of novel prognostic and predictive biomarkers in salivary duct carcinoma via comprehensive molecular profiling

Molecular targets and predictive biomarkers for prognosis in salivary duct carcinoma (SDC) have not been fully identified. We conducted comprehensive molecular profiling to discover novel biomarkers for SDC. A total of 67 SDC samples were examined with DNA sequencing of 464 genes and transcriptome analysis in combination with the clinicopathological characteristics of the individuals. Prognostic biomarkers associated with response to combined androgen blockade (CAB) treatment were explored using mRNA expression data from 27 cases. Oncogenic mutations in receptor tyrosine kinase (RTK) genes or genes in the MAPK pathway were identified in 55 cases (82.1%). Alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway were identified in 38 cases (56.7%). Interestingly, patient prognosis could be predicted using mRNA expression profiles, but not genetic mutation profiles. The risk score generated from the expression data of a four-gene set that includes the ADAMTS1, DSC1, RNF39, and IGLL5 genes was a significant prognostic marker for overall survival in the cohort (HR = 5.99, 95% confidence interval (CI) = 2.73–13.1, p = 7.8 × 10−6). Another risk score constructed from the expression of CD3E and LDB3 was a strong prognostic marker for progression-free survival for CAB treatment (p = 0.03). Mutations in RTK genes, MAPK pathway genes, and PI3K/AKT pathway genes likely represent key mutations in SDC tumorigenesis. The gene expression profiles identified in this study may be useful for stratifying patients who are good candidates for CAB treatment and may benefit from additional systemic therapies.

166P Comparative assessment of prognostic outcomes between vintage hormonal therapy and androgen deprivation therapy combined with novel androgen pathway inhibitor in Japanese patients with metastatic castration-sensitive prostate cancer

In recent years, therapeutic strategy for metastatic castration-sensitive prostate cancer (mCSPC) have been drastically changed since the introduction of combined treatment with conventional androgen-deprivation therapy (ADT) and novel androgen pathway inhibitor (ARPI). In Japanese real-world clinical practice, however, it remains common to perform vintage hormonal therapy (VHT) either by ADT alone or combined androgen blockade (CAB). The objective of this study was to analyze the impacts of upfront hormonal therapies on the prognostic outcomes in Japanese mCSPC patients. This study included 581 consecutive mCSPC patients consisting of 305 and 276 who received VHT (VHT group) and ADT plus ARPI (ARPI group), respectively, as first-line therapy. Potential parameters associated with PSA-progression free survival (PFS) and overall survival (OS) in these patients were investigated. Median PFS and OS of the 581 patients was 27 months and not reached, respectively. Multivariate analyses of several factors identified independent predictors associated with unfavorable PFS as follows: high alkaline phosphatase, high lactate dehydrogenase (LDH), number of bone metastasis ≥3, existence of symptoms, treatment with VHT, and those associated with unfavorable OS as follows: older age, poor performance status, high LDH, existence of symptoms. In LATITUDE low risk patients, the median PFSs were 36.6 months and not reached in the VHT and ARPI groups (P = 0.071), respectively, and the median OSs were not reached in both groups (P = 0.60). In LATITUDE high risk patients, the median PFSs were 12.4 months and not reached in the VHT and ARPI groups (P <0.001), respectively, and the median OSs were 40.2 months and not reached in the VHT and ARPI groups (P = 0.023), respectively. These findings suggest that it could be expected to achieve favorable prognostic outcomes in mCSPC patients, particularly those classified into LATITUDE high risk, by introducing ADT plus ARPI, rather than VHT, as first-line therapy.

Proteoglycans orchestrate remodeling of prostatic cytoarchitecture after androgenic blockade in old gerbils.

The aim of this study was to evaluate modifications in proteoglycan morphology and composition in the prostatic stroma of 18-month-old gerbils after surgical castration, in association or not with an androgenic blockade. The animals (n = 5) were sorted into groups subjected or not to antiandrogen treatment (flutamide 10 mg/kg/day) administered for the total postsurgery period and euthanized at 7- or 30-daypostcastration; the control group consisted of intact animals. Tissue analysis included immunohistochemical assessment (perlecan and chondroitin sulfate) and proteoglycan morphology was analyzed by transmission electron microscopy. Chondroitin sulfate frequency was increased 7 days postcastration with an androgenic blockade. The presence of these carbohydrates was rare after 30 days of androgenic blockade treatment. There was a significant increase in the amount of perlecan in the prostate stroma from groups subjected to castration plus flutamide for 7 or 30 days. Ultrastructural analysis showed that the incidence of areas occupied by proteoglycans and basement membrane was altered by treatment. In addition, androgenic blockade results in changes in the amount, thickness, and morphology of these structures. At 30 days postcastration, with or without flutamide treatment, larger proteoglycans were common. In this study, in particular, the decrease in chondroitin sulfate after the longer period might be understood as a prostatic response to androgenic deprivation, while the high frequency and permanence of perlecan led to the assumption that its modulation could be androgen-independent. Length and form alterations in proteoglycans as well as associations among them and with the basement membrane were dynamic events in the prostate microenvironment.

Preoperative endogenous testosterone density predicts disease progression from localized impalpable prostate cancer presenting with PSA levels elevated up to 10 ng/mL

ObjectiveTo investigate endogenous testosterone density (ETD) predicting disease progression from clinically localized impalpable prostate cancer (PCa) presenting with prostate-specific antigen (PSA) levels elevated up to 10 ng/mL and treated with radical prostatectomy.Materials and methodsIn a period ranging from November 2014 to December 2019, 805 consecutive PCa patients who were not under androgen blockade had endogenous testosterone (ET, ng/dL) measured before surgery. ETD was evaluated as the ratio of ET on prostate volume (PV). Unfavorable disease was defined as including ISUP ≥ 3 and/or seminal vesicle invasion in the surgical specimen. The risk of disease progression was evaluated by statistical methods.ResultsOverall, the study selected 433 patients, of whom 353 (81.5%) had available follow-up. Unfavorable disease occurred in 46.7% of cases and was predicted by tumor quantitation features that were positively associated with ETD. Disease progression, which occurred for 46 (13%) cases, was independently predicted only by ETD (hazard ratio, HR = 1.037; 95% CI 1.004–1.072; p = 0.030) after adjusting for unfavorable disease. According to a multivariate model, ETD above the third quartile was confirmed to be an independent predictor for PCa progression (HR = 2.479; 95% CI 1.355–4.534; p = 0.003) after adjusting for unfavorable disease. The same ETD measurements, ET mean levels were significantly lower in progressing cancers.ConclusionsIn this particular subset of patients, increased ETD with low ET levels, indicating androgen independence, resulted in a more aggressive disease with poorer prognosis.

PARP inhibitors in metastatic prostate cancer: When, who, and how?

Carcinoma prostate is among the most common cancers worldwide and is mainly treated in metastatic settings through androgen blockade or chemotherapy. Homologous repair deficiency is fairly common (germline and somatic) and allows targeted therapy through poly ADP-ribose polymerases (PARP) inhibitors. While data backing monotherapy is strong, recent evidence seems to support frontline combination therapy as well. Genetic testing of prostate cancer patients also needs personalization. Pre-clinical and early clinical data have provided insights into mechanisms and management of therapy resistance as well. This narrative review deals with the optimal patient selection and the evidence behind PARP inhibitor therapy in cases of metastatic carcinoma prostate.

Enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment in Japan (Japanese research for patients with non-metastatic castration-resistant prostate cancer-enzalutamide: JCASTRE-zero)—a prospective single-arm interventional study

BackgroundThe effect of enzalutamide in patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade, which represents a patient profile similar to real-world clinical practice in Japan, remains unknown. Therefore, we investigate the efficacy and safety of enzalutamide after combined androgen blockade for recurrence following radical treatment in Japanese patients with non-metastatic castration-resistant prostate cancer.MethodsWe analyzed 66 patients with non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical prostatectomy or radiation therapy who were prospectively enrolled from October 2015 to March 2018. They received enzalutamide 160 mg orally once daily until the protocol treatment discontinuation criteria were met. The primary endpoint was prostate-specific antigen-progression-free survival, defined as the time from enrollment to prostate-specific antigen-based progression or death from any cause. The secondary endpoints included overall survival, progression-free survival, metastasis-free survival, time to prostate-specific antigen progression, prostate-specific antigen response rate, chemotherapy-free survival, and safety assessment.ResultsThe median observation period was 27.3 months. The median prostate-specific antigen-progression-free survival was 35.0 months (95% confidence interval, 17.5 to not reached). The median overall survival, median progression-free survival, median metastasis-free survival, and chemotherapy-free survival were not reached, with the corresponding 2-year rates being 91.6%, 67.1%, 72.4%, and 85.8%, respectively. The 50% prostate-specific antigen response rate was 88.9%, with the median time being 2.8 months. In total, 42.2% of the patients experienced adverse events, with malaise being the most common.ConclusionsEnzalutamide effectively manages non-metastatic castration-resistant prostate cancer after combined androgen blockade for recurrence following radical treatment.Trialregistration: UMIN000018964, CRB6180007.

Bone Health Management in the Continuum of Prostate Cancer Disease.

Simple SummaryIn this review, we summarize the risk factors of prostate cancer (PCa), mechanism of PCa induced bone metastasis, current treatments for PCa induced bone metastasis, treatment induced side-effects, management of skeletal-related events and potential future therapeutic options for bone management in the continuum of PCa disease.Prostate cancer (PCa) is the second-leading cause of cancer-related deaths in men. PCa cells require androgen receptor (AR) signaling for their growth and survival. Androgen deprivation therapy (ADT) is the preferred treatment for patients with locally advanced and metastatic PCa disease. Despite their initial response to androgen blockade, most patients eventually will develop metastatic castration-resistant prostate cancer (mCRPC). Bone metastases are common in men with mCRPC, occurring in 30% of patients within 2 years of castration resistance and in >90% of patients over the course of the disease. Patients with mCRPC-induced bone metastasis develop lesions throughout their skeleton; the 5-year survival rate for these patients is 47%. Bone-metastasis-induced early changes in the bone that proceed the osteoblastic response in the bone matrix are monitored and detected via modern magnetic resonance and PET/CT imaging technologies. Various treatment options, such as targeting osteolytic metastasis with bisphosphonates, prednisone, dexamethasone, denosumab, immunotherapy, external beam radiation therapy, radiopharmaceuticals, surgery, and pain medications are employed to treat prostate-cancer-induced bone metastasis and manage bone health. However, these diagnostics and treatment options are not very accurate nor efficient enough to treat bone metastases and manage bone health. In this review, we present the pathogenesis of PCa-induced bone metastasis, its deleterious impacts on vital organs, the impact of metastatic PCa on bone health, treatment interventions for bone metastasis and management of bone- and skeletal-related events, and possible current and future therapeutic options for bone management in the continuum of prostate cancer disease.

A rare case report: testicular leydig cell tumor with gynecomastia

Gynecomastia is the most common definition of breast tissue growth. It is common in urology due to androgen blockade used in prostate cancers. Clinically insignificant gynecomastia is present in 50% of men and there is no proliferation of breast tissue in ductus epithelium. Gynecomastia is rarely seen in primary testicular tumors such as Leydig Cell Tumors (LCT). Leyındg Cell Tumors are one of the rare sex cord stromal cell tumors of the testis . Although it is usually with endocrine changes, it is a painless mass or incidentally occurring tumor in the testis. In this case report, we examined the left testicle cell tumor of the gynecomastia at the age of 43 years. He had been admitted to our clinic for gynecomastia and breast pain for 6 years. The patient was followed-up by endocrinology due to the aforementioned complaints. The patient was suspected of prolactinoma. Physical examination revealed no MRI. MRI, heterogenous hyperintense in T2A with mild lobulated contoured T2A with a hypointense capsule in T2A with well limited T2A in the left intratesticular area, and heterogeneous isohaphy hyperintense internal T1A in the form of a nodular lesion (testicular tumor) showing intense and heterogeneous contrast enhancement commented. The patient underwent left inguinal orchiectomy and the pathology report was negative for the leyding cell tumor and surgical margin.&#x0D; Leydig cell tumors are the most common spermatic cord / stromal tumors. About 30% of patients present with gynecomastia. Ultrasonography is accepted as the first research method for the diagnosis of leydic cell tumor, but MRI is superior to ultrasonography in diagnosis. The gold standard treatment option is radical inguinal orchiectomy. The mechanism of hormonal disorders may be an overproduction of testosterone and estrogens by the tumor. As in our case, it is necessary to consider the possibility of LCT which is rarely seen in patients with gynecomastia and to provide differential diagnosis by performing the tests in this direction.

Treatment strategies and outcomes in a long-term registry study of patients with high-risk metastatic hormone-naïve prostate cancer in Japan: An interim analysis of the J-ROCK study.

ObjectiveThe prognosis of high‐risk metastatic hormone‐naïve prostate cancer is poor, and real‐world evidence of therapeutic options and sequences is lacking. The J‐ROCK study aimed to evaluate the outcomes in a real‐world setting in Japan.MethodsPatients with high‐risk metastatic hormone‐naïve prostate cancer diagnosed after May 2019 were eligible. Based on their treatment within 3 months after diagnosis, patients were allocated to either cohort 1 (androgen deprivation therapy alone or combined androgen blockade with bicalutamide) or cohort 2 (androgen deprivation therapy with abiraterone acetate+prednisolone, docetaxel, enzalutamide, or apalutamide).ResultsIn this first interim analysis (cut‐off January 2021), 410 patients were enrolled, including 163 patients in cohort 1 and 247 in cohort 2. The median follow‐up period was 7.6 (range 0.1–20.5) months. A higher proportion of patients in cohort 2 (42.5%) achieved nadir prostate‐specific antigen levels ≤0.2 ng/ml within a year, compared with cohort 1 (22.1%). Prostate‐specific antigen‐progression‐free survival was also more favorable in cohort 2 (adjusted hazard ratio 0.629 [95% confidence interval 0.345–1.147]).ConclusionsThe higher proportion of cohort 2 suggest a paradigm shift has occurred in the real‐world treatment of high‐risk metastatic hormone‐naïve prostate cancer in Japan. Some factors including prostate‐specific antigen may affect treatment selection but need further observation. Most patients in cohort 2 received abiraterone acetate+prednisolone. The proportion of patients in cohort 1 receiving combined androgen blockade was lower than previously reported in Japan. This analysis suggest that more intensive therapy tends to prolong prostate‐specific antigen‐progression‐free survival in patients with high‐risk metastatic hormone‐naïve prostate cancer.

Case Report: A rare presentation of prostate cancer with peritoneal carcinomatosis and malignant ascites complicated by tumor lysis syndrome

Background: Only 32 cases of prostate cancer with peritoneal carcinomatosis and ascites have currently been reported in the literature. We present the first reported case of prostate cancer with peritoneal carcinomatosis and malignant ascites whose treatment was complicated by tumor lysis syndrome along with a literature review evaluating similar cases. Case: We present a rare case of a 78-year-old retired Caucasian male with recurrent metastatic prostate cancer and malignant ascites. He had previously received definitive radiotherapy for localized prostate cancer but presented with bilateral hydronephrosis and right-sided bladder wall thickening 10 years later. He had imaging evidence of locoregional recurrence with elevated prostate specific antigen (PSA) and was initiated on combined androgen blockade with intramuscular leuprolide and oral bicalutamide. After being transferred to Scripps Clinic, he was found to have a solitary right upper lobe pulmonary lesion for which he completed stereotactic body radiation therapy. Then, 10 months later, he developed new onset malignant ascites and was treated with two cycles of intravenous docetaxel. Treatment resulted in improvement in his ascites and reduction in PSA. Unfortunately, his course was complicated by tumor lysis syndrome, encephalopathy, Escherichia coli bacteremia, and a fatal saddle pulmonary embolism. Conclusions: (1) Occurrence of ascites in prostate cancer patients is associated with worse prognosis than non-ascitic variants. (2) More common etiologies of ascites must be evaluated for. (3) Ascitic fluid prostate specific antigen (PSA) measurement may aid in diagnosis of malignant ascites in cases with diagnostic uncertainty. (4) Patients with advanced disease may benefit from combined hormonal and cytotoxic therapies. (5) Awareness of the occurrence of tumor lysis syndrome (TLS) in patients treated for prostate cancer can help identify patients in whom prophylaxis would be beneficial.

EFFICACY OF SCHEDULED INTRAVENOUS OR ORAL ACETAMINOPHEN ADMINISTRATION AFTER ROBOTIC-ASSISTED LAPAROSCOPIC RADICAL PROSTATECTOMY

(Purpose) To determine the efficacy of scheduled intravenous or oral acetaminophen administration after robotic-assisted laparoscopic radical prostatectomy (RARP) in our hospital. (Subjects and methods) We retrospectively analyzed 173 patients who underwent RARP at our hospital between April 2019 and December 2020. The patients were divided into three groups (A, B, and C) according to the use of postoperative analgesia. Group A patients were administered acetaminophen only when needed. Group B patients were administered intravenous acetaminophen every 6 h from the day of surgery to postoperative day 2. Group C patients were prescribed oral acetaminophen from 3 to 7 days postoperatively in addition to being administered intravenous acetaminophen (similar to group B). Multivariate analysis was performed to determine whether scheduled intravenous or oral acetaminophen administration reduced unscheduled analgesic use. (Results) There were 110, 33, and 30 patients in groups A, B, and C, respectively. Significant differences in lymph node dissection rates were observed between groups A and B (70.9% vs 36.4%; P=0.001) and groups A and C (70.9% vs 33.3%; P< 0.001); furthermore, significant differences in the frequency of preoperative androgen blockade therapy were observed between groups A and C (20% vs 3.3%; P=0.029). Logistic regression analysis showed that only scheduled intravenous and oral administration of acetaminophen on postoperative days 0 to 2 was an independent factor for postoperative pain (group A vs group B: OR=0.127; 0.046-0.355; P< 0.001 and group A vs group C: OR=0.133; 0.046-0.390; P< 0.001). On postoperative days 3 to 7, there was no significant difference in the unscheduled use of analgesics between groups A and B. Only 1 of the 30 group C patients received unscheduled analgesia. (Conclusions) Scheduled intravenous or oral administration of acetaminophen may reduce unscheduled analgesic use after RARP.

Impact of Androgen Deprivation Therapy on Cardiovascular Outcomes in Prostate Cancer

Purpose: Substantial evidence indicates that men with prostate cancer are at an increased risk for cardiovascular disease, and medical and surgical androgen deprivation therapy is associated with further increased cardiovascular risk. There are conflicting reports of differences in cardiovascular safety between gonadotropin-releasing hormone (GnRH) agonists and antagonists. The purpose of this narrative review is to compare data on the cardiovascular risks and safety outcomes associated with different hormonal treatment options in prostate cancer patients and to provide guidance on how to manage the increased risk associated with the condition. Methods: A PubMed search was conducted for papers published in the last 15 years using the following MeSH terms: “prostate neoplasms,” “gonadotropin-releasing hormone,” “androgen agonist,” “androgen antagonists,” “cardiovascular disease,” “epidemiology.” Results: Evidence regarding the risk of cardiovascular events during treatment with GnRH agonists and antagonists is conflicting. Some retrospective studies have shown that agonists are associated with a greater risk of cardiovascular disease and cardiovascular mortality and morbidity, and a similar risk with agonists and combined androgen blockade. Some studies have reported that antagonists are associated with a decreased risk of cardiovascular mortality and morbidity compared with agonists. With respect to coronary heart disease, ischemic heart disease, myocardial infarction, stroke, or sudden cardiac death, current evidence has failed to demonstrate a significant difference between antagonists and agonists. Cardiovascular risks in patients should be mitigated by regular monitoring of blood pressure, blood glucose, and lipids, as well as counseling patients to abstain from alcohol and improve their diet and exercise. Statins, metformin, and aspirin should also be considered. Conclusions: The evidence for the increased cardiovascular risk of GnRH agonists over antagonists for androgen deprivation therapy is unclear. Differences in methodology, population sizes, risk stratification, and outcomes between studies make direct comparisons problematic. The single prospective, randomized prostate cancer trial with a primary cardiovascular end point in men with pre-existing cardiovascular disease comparing GnRH agonist to antagonist was stopped early due to an interim futility analysis. The results are inconclusive.