The Diagnostic Value of the Sentinel Node Procedure to Detect Occult Lymph Node Metastases in PSMA PET/CT Node-Negative Prostate Cancer Patients.

Our objective was to assess the diagnostic value of the sentinel node (SN) procedure for lymph node staging in primary intermediate- and high-risk prostate cancer patients with node-negative results on prostate-specific membrane antigen PET/CT (miN0). Methods: From 2016 to 2022, 154 patients with primary, miN0 PCa were retrospectively included. All patients had a Briganti nomogram-assessed nodal risk of more than 5% and underwent a robot-assisted SN procedure for nodal staging. The prevalence of nodal metastases at histopathology and the occurrence of surgical complications according to the Clavien-Dindo classification were evaluated. Results: The SN procedure yielded 84 (14%) tumor-positive lymph nodes with a median metastasis size of 3 mm (interquartile range, 1-4 mm). In total, 55 patients (36%) were reclassified as pN1. A complication of Clavien-Dindo grade 3 or higher occured in 1 patient (0.6%). Conclusion: The SN procedure classified 36% of patients with miN0 prostate cancer with an elevated risk of nodal metastases as pN1.

Is It the Load That Breaks You or the Way You Carry It: How Demanding Is Endourology?

Objective: Surgical outcomes are dependent on multiple factors. Besides patient-related or procedure-related factors, several surgeon-related factors contribute to surgical outcomes. The Surgery Task Load Index (SURG-TLX) questionnaire helps to assess the impact of several stressors on the perceived demands of surgeons during surgery. In this study, we evaluate the applicability of the SURG-TLX questionnaire for endourologic procedures and set a first point of reference. Materials and Methods: Between March and August 2022, 15 urologists and urology residents at a tertiary referral center for endourology completed the SURG-TLX questionnaire after endourologic procedures. After data acquisition, all participants were asked to evaluate the applicability of the questionnaire for endourologic procedures. Results: A total of 130 procedures were included between March and August 2022. Situational stress had the lowest median score (3.0/20; interquartile range [IQR] 2.0-7.0) and task complexity the highest (5.0/20; IQR 3.0-8.0). After weighing, the dimensions showed different proportions when compared with the nonweighted scores. Distractions received the highest score (15.0/100; IQR 7.5-32.8), temporal demands (6.0/100; IQR 3.0-12.5), and situational stress the lowest (6.0/100; IQR 2.0-21.0). This was caused by the higher weight that was attributed to distractions (3.4/5), as opposed to task complexity (2.6/5). In the questionnaire regarding applicability of the SURG-TLX, the overall satisfaction (6.0/10; IQR 5.0-7.0) and clarity (6.5/10; IQR 5.0-7.5) were moderate. The user-friendliness and applicability of the questionnaire were rated high (7.0/10; IQR 5.5-8.0 and 7.0/10; IQR 6.0-8.0, respectively) and task load (3.0/10; IQR 2.0-5.0) and time load (2.0/10; IQR 2.0-3.5) low. Conclusion: The SURG-TLX questionnaire is appropriate to assess the different dimensions of workload during endourologic procedures. Furthermore, the perceived workload during endourologic procedures is relatively low.

3D-Reconstructed Contact Surface Area and Tumour Volume on Magnetic Resonance Imaging Improve the Prediction of Extraprostatic Extension of Prostate Cancer.

This study is to determine whether the volume and contact surface area (CSA) of a tumour with an adjacent prostate capsule on MRI in a three-dimensional (3D) model that can predict side-specific extraprostatic extension (EPE) at radical prostatectomy (RP). Patients with localised prostate cancer (PCa) who underwent robot-assisted RP between July 2015 and March 2021 were included in this retrospective study. MRI-based 3D prostate models incorporating the PCa volume and location were reconstructed. The tumour volume and surface variables were extracted. For the prostate-to-tumour and tumour-to-prostate CSAs, the areas in which the distances were ≤ 1, ≤ 2, ≤ 3, ≤ 4, and ≤ 5 mm were defined, and their surface (cm2) were determined. Differences in prostate sides with and without pathological EPE were analysed. Multivariable logistic regression analysis to find independent predictors of EPE. Overall, 75/302 (25%) prostate sides showed pathological EPE. Prostate sides with EPE had higher cT-stage, higher PSA density, higher percentage of positive biopsy cores, higher biopsy Gleason scores, higher radiological tumour stage, larger tumour volumes, larger prostate CSA, and larger tumour CSA (all p < 0.001). Multivariable logistic regression analysis showed that the radiological tumour stage (p = 0.001), tumour volume (p < 0.001), prostate CSA (p < 0.001), and tumour CSA (p ≤ 0.001) were independent predictors of pathological EPE. A 3D reconstruction of tumour locations in the prostate improves prediction of extraprostatic extension. Tumours with a higher 3D-reconstructed volume, a higher surface area of tumour in contact with the prostate capsule, and higher surface area of prostate capsule in contact with the tumour are at increased risk of side-specific extraprostatic extension.

Development and clinical applicability of MRI-based 3D prostate models in the planning of nerve-sparing robot-assisted radical prostatectomy.

The interpretation of conventional MRI may be limited by the two-dimensional presentation of the images. To develop patient-specific MRI prostate-based virtual and three-dimensional (3D)-printed models. To assess the association between 3D imaging and the pathological outcome of RARP specimen. To assess the clinical applicability of 3D models to guide nerve-sparing robot-assisted radical prostatectomy (RARP). We created virtual 3D and 3D-printed 3D models of 20 prostate cancer patients retrospectively. A comparison was made between conventional MRI and 3D-reconstructed images. The concordance between tumour lesion location in 3D models and pathology reporting of RARP specimens was assessed. Seven urologists assessed the side-specific extent of nerve-sparing based on (1) conventional MR images, (2) virtual 3D models, and (3) 3D-printed models. Clinically relevant changes in nerve-sparing and the absolute agreement between observers was analyzed using the Chi-square test and intra-class correlation coefficient (ICC). The index lesion was correctly visualized in 19/20 (95%) 3D models and the expected location of extraprostatic extension was correctly visualized in all 3D models. Clinically relevant changes in the planned extent of nerve-sparing between MRI and virtual 3D models and MRI and 3D-printed models were found in 25% and 26%. The ICC of the planned extent of nerve-sparing between urologists was 0.40 (95% CI 0.28-0.55) for conventional MRI, 0.52 (95% CI 0.39-0.66) for virtual 3D models and 0.58 (95% CI 0.45-0.71) for 3D-printed models. 3D models of the MRI prostate to guide RARP could aid urologists in the planning of nerve-sparing surgery as shown by a higher inter-observer agreement.

An optimized prostate biopsy strategy in patients with a unilateral lesion on prostate magnetic resonance imaging avoids unnecessary biopsies.

Purpose: The introduction of magnetic resonance imaging (MRI)-targeted biopsy (TBx) besides systematic prostate biopsies has resulted in a discussion on what the optimal prostate biopsy strategy is. The ideal template has high sensitivity for clinically significant prostate cancer (csPCa), while reducing the detection rate of clinically insignificant prostate cancer (iPCa). This study evaluates different biopsy strategies in patients with a unilateral prostate MRI lesion. Methods: Retrospective subgroup analysis of a prospectively managed database consisting of patients undergoing prostate biopsy in two academic centres. Patients with a unilateral lesion (PI-RADS ⩾ 3) on MRI were included for analysis. The primary objective was to evaluate the diagnostic performance for different biopsy approaches compared with bilateral systematic prostate biopsy (SBx) and TBx. Detection rates for csPCa (ISUP ⩾ 2), adjusted csPCa (ISUP ⩾ 3) and iPCa (ISUP = 1) were determined for SBx alone, TBx alone, contralateral SBx combined with TBx and ipsilateral SBx combined with TBx. A subgroup analysis was performed for biopsy-naive patients. Results: A total of 228 patients were included from October 2015 to September 2021. Prostate cancer (PCa) detection rate of combined SBx and TBx was 63.5% for csPCa, 35.5% for adjusted csPCa, and 14% for iPCa. The best performing alternative biopsy strategy was TBx and ipsilateral SBx, which reached a sensitivity of 98.6% (95% CI: 95.1-99.6) for csPCa and 98.8% (95% CI: 96.3-99.9) for adjusted csPCa, missing only 1.4% of csPCa, while reducing iPCa detection by 15.6% compared with SBx and TBx. TBx or SBx alone missed a significant amount of csPCa, with sensitivities of 90.3% (95% CI: 84.4-94.2) and 86.8% (95% CI: 80.4-91.4) for csPCa. Subgroup analysis on biopsy-naive patients showed similar results as the overall group. Conclusion: This study shows that performing TBx with ipsilateral SBx and omitting contralateral SBx is the optimal biopsy strategy in patients with a unilateral MRI lesion. With this strategy, a very limited amount of csPCa is missed and iPCa detection is reduced.

Surgical and Functional Outcomes of Bladder Neck Incision for Primary Vesico-Urethral Anastomosis Stricture after Robot-assisted Radical Prostatectomy are Influenced by the Presence of Pre- or Postoperative Radiotherapy.

OBJECTIVE: To report the intermediate- to long-term outcomes of bladder neck incision (BNI) for vesico-urethral anastomosis stricture (VUAS) after robot-assisted radical prostatectomy (RARP) and the influence of pre- or post-RARP radiotherapy on these outcomes. METHODS: A retrospective cohort study was performed with patients who underwent BNI for VUAS after RARP in a high-volume prostatectomy centre between 2006 and July 2021. Data was collected from patient charts. The cohort was divided into 4 groups: VUAS after (1) RARP-only, (2) RARP, but before salvage radiotherapy (SRT) (VUAS pre-SRT), (3) RARP and after SRT (VUAS post-SRT), and (4) primary radiotherapy and salvage RARP (SRARP). The VUAS recurrence rates, the ability to perform functional transurethral micturition and the post-BNI urinary continence rates were reported. RESULTS: BNI was performed in 90 patients. The median time between first BNI and last follow-up was 32 months (interquartile range 10-58, range 0-171). The majority of VUAS occurred within 6 months after (S)RARP. In those who underwent BNI, recurrent VUAS was reported in 12%, 57%, 29%, and 50% of patients after RARP-only, VUAS pre-SRT, VUAS post-SRT, and SRARP, respectively. Ultimately, transurethral micturition was possible in 94%, 93%, 71%, and 80%, respectively. Severe urinary-incontinence rates (>1 pads/d) were 6%, 16%, 10%, and 29% for RARP-only, VUAS pre-SRT, VUAS post-SRT, and SRARP patients, respectively. CONCLUSION: Primary radiotherapy before RARP and SRT after RARP significantly influenced the success rates of BNI. Those who underwent BNI after SRARP had worse outcomes than patients who underwent RARP only.

Incidence of testicular cancer in trans women using gender-affirming hormonal treatment: a nationwide cohort study.

OBJECTIVE: To assess the incidence of testicular cancer in trans women (male sex assigned at birth, female gender identity) using gender-affirming hormonal treatment. PATIENTS AND METHODS: Data of trans women starting hormonal treatment at our gender identity clinic between 1972 and 2017 were linked to the national pathology database to obtain testicular cancer diagnoses. The standardised incidence ratio (SIR) was calculated using the number of observed testicular cancer cases in our cohort and the number of expected cases based on age-specific Dutch incidence rates. Subgroup analyses were performed in testicular tissues sent for histopathological analysis at the time of bilateral orchidectomy, and when follow-up exceeded 5 years. RESULTS: The cohort consisted of 3026 trans women with a median follow-up time of 2.3 interquartile range (IQR) (1.6-3.7) years. Two testicular cancer cases were identified whilst 2.4 cases were expected (SIR 0.8, 95% confidence interval 0.1-2.8). In addition, one testicular cancer case was encountered in an orchidectomy specimen (0.1%). In the 523 trans women with a follow-up time of >5 years (median [IQR] 8.9 [6.4-13.9] years), no testicular cancer was observed. CONCLUSION: Testicular cancer risk in trans women is similar to the risk in cis men. The testicular cancer cases occurred within the first 5 years after commencing hormonal treatment, and the percentage of cases encountered at the time of bilateral orchidectomy was low. As no testicular cancer was observed in trans women with a long follow-up period, long-term hormonal treatment does not seem to increase testicular cancer risk.

Intraoperative Strategies to Reduce Catheter-Related Bladder Discomfort in the Early Postoperative Period after Robot-Assisted Radical Prostatectomy.

PURPOSE: Catheter-related bladder discomfort occurs in up to 63% of patients following robot-assisted radical prostatectomy. The optimal intraoperative anesthesia regime to prevent patients from catheter-related bladder discomfort is unknown. MATERIALS AND METHODS: A prospective cohort analysis was conducted. Patients with biopsy-proven prostate cancer selected for robot-assisted radical prostatectomy were included between January 2017 and April 2020 from a high volume prostate cancer center. Eight different treatment regimens were compared, ie a combination of general anesthesia and a transversus abdominis plane block with either an additional dose of clonidine or an additional dose of ketamine, or perivesical infiltrations (with 20 ml ropivacaine), or periurethral infiltrations (with ropivacaine); or a dorsal penile nerve block (with 20 ml ropivacaine). Multiple logistic regression and linear mixed models were used to analyze differences in catheter-related bladder discomfort and pain (0-10) at the postoperative recovery unit between the treatment protocols. RESULTS: Of the 391 patients included, those with a combination transversus abdominis plane block, perivesical and periurethral block with ropivacaine had the lowest incidence of catheter-related bladder discomfort, clinically relevant and statistically significantly lower compared to our baseline protocol (transversus abdominis plane block only), ie 36% vs 70%, p=0.001. Overall, patients who were treated with periurethral and/or perivesical infiltrations reported a statistically significantly lower incidence of catheter-related bladder discomfort compared to patients who did not receive this local infiltration (46.5% vs 60.7%, p=0.001). CONCLUSIONS: Perivesical and periurethral injections with ropivacaine have the potential to reduce the incidence of early postoperative catheter-related bladder discomfort by up to 49%. Further randomized studies are necessary to determine the optimal treatment regime to prevent early postoperative catheter-related bladder discomfort.

Detection of Recurrent Prostate Cancer Using Prostate-specific Membrane Antigen Positron Emission Tomography in Patients not Meeting the Phoenix Criteria for Biochemical Recurrence After Curative Radiotherapy.

Biochemical recurrence of prostate cancer (PCa) after curative radiotherapy is defined as a prostate-specific antigen (PSA) rise of ≥2 ng/ml above the nadir ("Phoenix criteria", 2005). With the introduction of prostate-specific membrane antigen positron emission tomography (PSMA-PET), the ability to localise PCa recurrences has increased markedly. Here, we reviewed 315 patients scanned with PSMA-PET after curative radiotherapy in the Prostate Cancer Network Amsterdam (2015-2018). Sixty-three patients (20.3%) were scanned below the Phoenix threshold (PSA rise <2.0 ng/ml). In 53 of these patients (84.1%), PSMA-PET-avid lesions were detected nonetheless: 21 patients (33.3%) revealed a local recurrence as a single site of disease, 32 patients (50.8%) harboured metastatic PCa. Besides rising PSA, no predictors were identified that prompted early PSMA-PET imaging. In this communication, we report on the frequent detection of metastatic PCa with PSMA-PET in men below the Phoenix PSA threshold. These findings are a plea for re-evaluation of current diagnostic work-up for rising PSA values after radiotherapy, as early detection of recurrences might refine salvage and/or adjuvant therapies. PATIENT SUMMARY: This study reports on the unexpected detection of prostate cancer (PCa) recurrences with prostate-specific membrane antigen positron emission tomography in patients treated with radiotherapy. This calls for re-evaluation of the current criteria for recurrent PCa after radiotherapy.

Prostate Cancer Incidence under Androgen Deprivation: Nationwide Cohort Study in Trans Women Receiving Hormone Treatment.

CONTEXT: Trans women (male sex assigned at birth, female gender identity) mostly use antiandrogens combined with estrogens and can subsequently undergo vaginoplasty including orchiectomy. Because the prostate remains in situ after this procedure, trans women are still at risk for prostate cancer. OBJECTIVE: To assess the incidence of prostate cancer in trans women using hormone treatment. The incidence of prostate cancer in trans women using hormone treatment. DESIGN: In this nationwide retrospective cohort study, data of participants were linked to the Dutch national pathology database and to Statistics Netherlands to obtain data on prostate cancer diagnosis and mortality. SETTING: Gender identity clinic. PARTICIPANTS: Trans women who visited our clinic between 1972 and 2016 and received hormone treatment were included. MAIN OUTCOME MEASURES: Standardized incidence ratios (SIRs) were calculated using the number of observed prostate cancer cases in our cohort and the number of expected cases based on age-specific incidence numbers from the Netherlands Comprehensive Cancer Organization. RESULTS: The study population consisted of 2281 trans women with a median follow-up time of 14 years (interquartile range 7-24), and a total follow-up time of 37 117 years. Six prostate cancer cases were identified after a median 17 years of hormone treatment. This resulted in a lower prostate cancer risk in trans women than in Dutch reference males (SIR 0.20, 95% confidence interval 0.08-0.42). CONCLUSIONS: Trans women receiving androgen deprivation therapy and estrogens have a substantially lower risk for prostate cancer than the general male population. Our results support the hypothesis that androgen deprivation has a preventive effect on the initiation and development of prostate cancer.

Surgical Outcomes of Neoscrotal Augmentation with Testicular Prostheses in Transgender Men.

INTRODUCTION: Testicular prosthesis implantation may be used for neoscrotal augmentation in transgender men. AIM: Assess the clinical outcomes and risk factors for postoperative complications of this procedure in transgender men. METHODS: All transgender men who underwent neoscrotal augmentation with testicular implants between January 1992 and December 2018 were retrospectively identified. A retrospective chart study was performed that recorded surgical characteristics and postoperative complications. Risk factors on complications were identified using uni- and multivariate analyses. MAIN OUTCOME MEASURE: Surgical outcomes included explantation due to infection, extrusion, discomfort, or leakage. RESULTS: We identified 206 patients, and the following prostheses were placed: Dow Corning (n = 22), Eurosilicone (n = 2), Nagor (n = 205), Polytech (n = 10), Promedon (n = 105) , Prometel (n = 22), Sebbin (n = 44), and unknown (n = 2). The mean clinical follow-up time was 11.5 ± 8.3 years. In 43 patients (20.8%), one or both prostheses were explanted due to infection, extrusion, discomfort, prosthesis leakage, or urethral problems. Currently, scrotoplasty according to Hoebeke is the most frequently performed technique. Our review found that for this technique explantation occurred in 6 of 52 patients (11.5%). A history of smoking was a risk factor for postoperative infections and prosthesis explantation. In earlier years, larger prostheses were immediately placed at scrotal reconstruction; however, a trend can be seen toward smaller and lighter testicular prostheses and delayed implantation. CLINICAL IMPLICATIONS: Patients wanting to undergo this procedure can be adequately informed on postoperative outcomes. STRENGTHS & LIMITATIONS: Strengths of this study include the number of patients, long clinical follow-up time, and completeness of data. Weaknesses of this study include its retrospective nature and the high variability of prostheses and surgical techniques used. CONCLUSION: Over the years, scrotoplasty techniques and testicular prostheses preferences have changed. Explantation rates have dropped over the last decade. Pigot GLS, Al-Tamimi M, Ronkes B, et al. Surgical Outcomes of Neoscrotal Augmentation with Testicular Prostheses in Transgender Men. J Sex Med 2019;16:1664-1671.

Risk of disease flare with LHRH agonist therapy in men with prostate cancer: myth or fact?

OBJECTIVES: The traditional assumption of a linear relationship between serum testosterone and prostate cancer growth has been seriously challenged, as overwhelming evidence contradicts its basic principles. Luteinizing hormone-releasing hormone (LHRH) agonists are known to cause a peak in serum testosterone level in the initial weeks of treatment, and prevention of the clinical sequelae of testosterone flare by concomitant use of antiandrogens is recommended. Along the present biological concept that there appears to be a limit to the ability of androgens to stimulate prostate cancer growth, termed the saturation model, the use of antiandrogens to prevent this disease flare is questioned. The purpose of this review is to gain historical and modern evidence to provide an objective and up-to-date basis for clinical decision making. METHODS AND MATERIALS: We performed a comprehensive research of the electronic databases PubMed and Embase until April 1, 2014. Studies with the subject of disease flare in men with prostate cancer on LHRH agonist therapy were included, as were studies that assessed the efficacy of antiandrogens to prevent this flare. Case reports were included as well. RESULTS: Overall, 25 studies considering disease flare were included: 9 randomized clinical trials with an LHRH agonist and an LHRH agonist/antiandrogen arm, 14 observational studies evaluating LHRH agonists only, and 2 case reports. The incidence of disease flare was reported between 0% and 83% owing to a wide set of clinical, biochemical, and radiological factors evaluated. In some of the randomized clinical trials, a statistically significant reduction of the incidence of disease flare by concomitant use of antiandrogens was reported. Most of these historical studies report on subjective worsening of disease symptoms as outcome measure. More objective outcome measures such as the prostate-specific antigen level did not seem to increase to higher than the baseline values. CONCLUSIONS: At present, there is a lack of compelling data showing definite disease progression during the short period of testosterone flare after initiation of LHRH agonist therapy. Based on the saturation model, presence of disease flare and the need to prevent this flare by concomitant use of antiandrogens might well be a misconception.

Relationship between body mass index and serum testosterone concentration in patients receiving luteinizing hormone-releasing hormone agonist therapy for prostate cancer.

OBJECTIVE: To evaluate the relationship between the body mass index (BMI) and serum testosterone concentrations in men receiving luteinizing hormone-releasing hormone (LHRH) agonist therapy for prostate cancer. MATERIALS AND METHODS: A total of 66 white men were included in the present study. All subjects had received LHRH agonist therapy for ≥ 3 months. The BMI was calculated, and the subjects were classified as normal weight (i.e. BMI <25 kg/m(2)), overweight (BMI 25-30 kg/m(2)), or obese (BMI >30 kg/m(2)). The serum testosterone concentration was determined using the highly sensitive isotope dilution-liquid chromatography-tandem mass spectrometry technique. The sex hormone-binding globulin level was determined using an immunometric assay, and the free serum testosterone concentration was calculated. RESULTS: The median serum testosterone concentration of the patients with a BMI <25 kg/m(2) was 5.5 ng/dL. The patients with a BMI of 25-30 kg/m(2) had a median serum testosterone concentration of 3.8 ng/dL. Those patients with a BMI >30 kg/m(2) had a median concentration of 5.7 ng/dL. No significant difference in the serum testosterone concentrations among the 3 groups was found. The sex hormone-binding globulin levels declined with an increasing BMI. The concentration of free testosterone was significantly greater in the obese men. CONCLUSION: Using an ultrasensitive technique of serum testosterone measurement, the present data have shown that no difference exists in the serum testosterone concentration in the castrate range among normal weight, overweight, and obese patients receiving LHRH agonist therapy for prostate cancer. From our findings and current knowledge, more stringent follow-up or changes in dosage or dosage intervals of LHRH agonist therapy in those with a greater or high BMI is not warranted.

Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer.

PURPOSE: Prostate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings. METHODS: In vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration-resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily. RESULTS: Testosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth. CONCLUSIONS: Despite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted.

Lower testosterone levels with luteinizing hormone-releasing hormone agonist therapy than with surgical castration: new insights attained by mass spectrometry.

PURPOSE: Androgen deprivation therapy by bilateral orchiectomy (surgical castration) or luteinizing hormone-releasing hormone agonist therapy (medical castration) is recommended for advanced or metastatic prostate cancer. Both methods aim at reducing serum testosterone concentrations to a castrate level which is currently defined as less than 50 ng/dl. The results of previous studies are based on testosterone immunoassays that have insufficient accuracy in the low range. In this study we reevaluated serum testosterone concentrations in men on androgen deprivation therapy using isotope dilution-liquid chromatography-tandem mass spectrometry, an accurate method of measuring testosterone in the castrate range. MATERIALS AND METHODS: Subjects underwent surgical castration (34) or received a luteinizing hormone-releasing hormone agonist (32). Serum samples were obtained more than 3 months after surgery or initiation of luteinizing hormone-releasing hormone agonist therapy. Testosterone levels were determined using isotope dilution-liquid chromatography-tandem mass spectrometry. Dihydroepiandrosterone sulfate, androstenedione, sex hormone-binding globulin and inhibin B levels were determined. RESULTS: All subjects had serum testosterone values less than 50 ng/dl and 97% had testosterone concentrations less than 20 ng/dl. Medically castrated men had significantly lower testosterone levels (median 4.0 ng/dl, range less than 2.9 to 20.2) than those surgically castrated (median 9.2 ng/dl, range less than 2.9 to 28.8, p <0.001). No difference was found in dehydroepiandrosterone sulfate, androstenedione and sex hormone-binding globulin levels between the groups, whereas inhibin B levels were significantly higher in the luteinizing hormone-releasing hormone agonist treated group. CONCLUSIONS: Using an accurate technique for testosterone measurement, subjects on luteinizing hormone-releasing hormone agonist therapy had significantly lower testosterone concentrations than men who underwent surgical castration. The clinical relevance of these findings remains to be determined.

Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial.

BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4. We aimed to assess the safety of combined treatment with GVAX and ipilimumab in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: We did an open-labelled, single-centre, dose-escalation study of ipilimumab concurrent with a fixed dose of GVAX, with a subsequent expansion phase, both at the VU University Medical Centre (Amsterdam, Netherlands). Eligible patients had documented mCRPC and had not been previously treated with chemotherapy. All patients received a 5×10(8) cell priming dose of GVAX intradermally on day 1 with subsequent intradermal injections of 3×10(8) cells every 2 weeks for 24 weeks. The vaccinations were combined with intravenous ipilimumab every 4 weeks. We enrolled patients in cohorts of three; each cohort received an escalating dose of ipilimumab at 0·3, 1·0, 3·0, or 5·0 mg/kg. Our primary endpoint was safety. This study is registered with ClinicalTrials.gov, number NCT01510288. FINDINGS: We enrolled 12 patients into our dose-escalation cohort. We did not record any severe immune-related adverse events at the first two dose levels. At the 3·0 mg/kg dose level, one patient had grade 2 and two patients grade 3 hypophysitis; at the 5·0 mg/kg dose level, two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis (a dose-limiting toxic effect). Due to observed clinical activity and toxic events, we decided to expand the 3·0 mg/kg dose level, rather than enrol a further three patients at the 5·0 mg/kg level. 16 patients were enrolled in the expansion cohort, two of whom developed grade 2 hypophysitis, three colitis (one grade 1 and two grade 2), and one grade 3 hepatitis--all immune-related adverse events. The most common adverse events noted in all 28 patients were injection-site reactions (grade 1-2 events seen in all patients), fatigue (grade 1-2 in 20 patients, grade 3 in two), and pyrexia (grade 1-2 in 15 patients, grade 3 in one). 50% or greater declines in prostate-specific antigen from baseline was recorded in seven patients (25%); all had received 3·0 mg/kg or 5·0 mg/kg ipilimumab. INTERPRETATION: GVAX combined with 3·0 mg/kg ipilimumab is tolerable and safe for patients with mCRPC. Further research on the combined treatment of patients with mCRPC with vaccination and ipilimumab is warranted. FUNDING: Cell Genesys Inc, Prostate Cancer Foundation, Dutch Cancer Society (KWF-VU 2006-3697), and Foundation Stichting VUmc Cancer Center Amsterdam.

Intraprostatic testosterone and dihydrotestosterone. Part I: concentrations and methods of determination in men with benign prostatic hyperplasia and prostate cancer.

Owing to inconsistencies and methodological differences, the present peer-reviewed literature lacks conclusive data on the intraprostatic levels of androgens, in particular dihydrotestosterone (DHT), in untreated benign prostatic hyperplasia (BPH) and prostate cancer. To date, no difference has been shown between DHT concentrations in normal prostatic tissue and BPH, and nor has a difference been shown in DHT concentrations between the histologically distinct regions of the prostate. Recent literature has also failed to show a consistent difference in androgen level between BPH and prostate cancer. The role of intraprostatic DHT in the pathogenesis of BPH and in the initiation and progression of prostate cancer thus remains to be established. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels may lead to more optimized and more personalized forms of treatment, and probably new therapeutic targets as well.

Intraprostatic testosterone and dihydrotestosterone. Part II: concentrations after androgen hormonal manipulation in men with benign prostatic hyperplasia and prostate cancer.

Androgen deprivation therapy (ADT) and 5-α-reductase (5AR) inhibition are used in the treatment of men with advanced or metastatic prostate cancer and benign prostatic hyperplasia (BPH), respectively. These drugs exert their effect by lowering androgen levels in the serum and allegedly, the prostate gland. It is, however, unknown whether (increased) intraprostatic androgen levels are associated with the pathogenesis of BPH and with the initiation and progression of prostate cancer. Also, it is unclear whether intraprostatic dihydrotestosterone (DHT) levels correlate with a response to initial hormonal therapy or with patient outcome. These uncertainties have resulted from the finding that serum testosterone levels do not necessarily reflect those in the prostate gland. Intraprostatic DHT levels of men being treated with 5AR inhibition, of those treated with ADT for hormone-naive prostate cancer, and of those with castration-resistant prostate cancer are all altered in an equivalent manner because of hormonal manipulation. Increased knowledge of the mechanisms of the androgenic steroid pathways in prostatic diseases, with a special focus on intraprostatic androgen levels, may lead to treatment that is tailored to the needs of the individual patient, and probably to new therapeutic targets as well.