Outcomes of Cytoreductive Radical Prostatectomy for Oligometastatic Prostate Cancer on Prostate-specific Membrane Antigen Positron Emission Tomography: Results of a Multicenter European Study.

BACKGROUND: De novo oligometastatic prostate cancer (omPCa) on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is a new disease entity and its optimal management remains unknown. OBJECTIVE: To analyze the outcomes of patients treated with cytoreductive radical prostatectomy (cRP) for omPCa on PSMA-PET. DESIGN, SETTING, AND PARTICIPANTS: Overall, 116 patients treated with cRP at 13 European centers were identified. Oligometastatic PCa was defined as miM1a and/or miM1b with five or fewer osseous metastases and/or miM1c with three or fewer lung lesions on PSMA-PET. INTERVENTION: Cytoreductive radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Thirty-day complications according to Clavien-Dindo, continence rates, time to castration-resistant PCa (CRPC), and overall survival (OS) were analyzed. RESULTS AND LIMITATIONS: Overall, 95 (82%) patients had miM1b, 18 (16%) miM1a, and three (2.6%) miM1c omPCa. The median prebiopsy prostate-specific antigen was 14 ng/ml, and 102 (88%) men had biopsy grade group ≥3 PCa. The median number of metastases on PSMA-PET was 2; 38 (33%), 29 (25%), and 49 (42%) patients had one, two, and three or more distant positive lesions. A total of 70 (60%) men received neoadjuvant systemic therapy, and 37 (32%) underwent metastasis-directed therapy. Any and Clavien-Dindo grade ≥3 complications occurred in 36 (31%) and six (5%) patients, respectively. At a median follow-up of 27 mo, 19 (16%) patients developed CRPC and eight (7%) patients died. The 1-yr urinary continence rate was 82%. The 2-yr CRPC-free survival and OS were 85.8% (95% confidence interval [CI] 78.5-93.7%) and 98.9% (95% CI 96.8-100%), respectively. The limitations include retrospective design and short-term follow-up. CONCLUSIONS: Cytoreductive radical prostatectomy is a safe and feasible treatment option in patients with de novo omPCa on PSMA-PET. Despite overall favorable oncologic outcomes, some of these patients have a non-negligible risk of early progression and thus should be considered for multimodal therapy. PATIENT SUMMARY: We found that patients treated at expert centers with surgery for prostate cancer, with a limited number of metastases detected using novel molecular imaging, have favorable short-term survival, functional results, and acceptable rates of complications.

Changes in bone and mineral homeostasis after short-term androgen deprivation therapy with or without androgen receptor signalling inhibitor - substudy of a single-centre, double blind, randomised, placebo-controlled phase 2 trial.

BACKGROUND: Prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT) have an increased fracture risk. Exploring biomarkers for early bone loss detection is of great interest. METHODS: Pre-planned substudy of the ARNEO-trial (NCT03080116): a double blind, randomised, placebo-controlled phase 2 trial performed in high-risk PCa patients without bone metastases between March 2019 and April 2021. Patients were 1:1 randomised to treatment with gonadotropin-releasing hormone antagonist (degarelix) + androgen receptor signalling inhibitor (ARSI; apalutamide) versus degarelix + matching placebo for 12 weeks prior to prostatectomy. Before and following ADT, serum and 24-h urinary samples were collected. Primary endpoints were changes in calcium-phosphate homeostasis and bone biomarkers. FINDINGS: Of the 89 randomised patients, 43 in the degarelix + apalutamide and 44 patients in the degarelix + placebo group were included in this substudy. Serum corrected calcium levels increased similarly in both treatment arms (mean difference +0.04 mmol/L, 95% confidence interval, 0.02; 0.06), and parathyroid hormone and 1,25-dihydroxyvitamin D3 levels decreased. Bone resorption markers increased, and stable calcium isotope ratios reflecting net bone mineral balance decreased in serum and urine similarly in both groups. INTERPRETATION: This exploratory substudy suggests that 12 weeks of ADT in non-metastatic PCa patients results in early bone loss. Additional treatment with ARSI does not seem to more negatively influence bone loss in the early phase. Future studies should address if these early biomarkers are able to predict fracture risk, and can be implemented in clinical practice for follow-up of bone health in PCa patients under ADT. FUNDING: Research Foundation Flanders; KU Leuven; University-Hospitals-Leuven.

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients.

Prostate cancer (PCa) is the most common cancer in men worldwide. Despite better and more intensive treatment options in earlier disease stages, a large subset of patients still progress to metastatic castration-resistant PCa (mCRPC). Recently, poly-(ADP-ribose)-polymerase (PARP)-inhibitors have been introduced in this setting. The TALAPRO-2 and PROpel trials both showed a marked benefit of PARPi in combination with an androgen receptor signaling inhibitor (ARSI), compared with an ARSI alone in both the homologous recombination repair (HRR)-mutated, as well as in the HRR-non-mutated subgroup. In this review, we present a comprehensive overview of how maximal AR-blockade via an ARSI in combination with a PARPi has a synergistic effect at the molecular level, leading to synthetic lethality in both HRR-mutated and HRR-non-mutated PCa patients. PARP2 is known to be a cofactor of the AR complex, needed for decompacting the chromatin and start of transcription of AR target genes (including HRR genes). The inhibition of PARP thus reinforces the effect of an ARSI. The deep androgen deprivation caused by combining androgen deprivation therapy (ADT) with an ARSI, induces an HRR-like deficient state, often referred to as "BRCA-ness". Further, PARPi will prevent the repair of single-strand DNA breaks, leading to the accumulation of DNA double-strand breaks (DSBs). Due to the induced HRR-deficient state, DSBs cannot be repaired, leading to apoptosis.

Penile metastasis in prostate cancer patients: Two case reports, surgical excision technique, and literature review.

Two cases of penile metastasis from primary prostate cancer in a single center are presented, along with a literature review and description of the excision technique. Despite its rich vascularization, penile metastasis is rare, with 72 new cases from September 2006 to March 2021. There is a wide variety of diagnoses, treatments, and prognoses for penile metastatic lesions. Ga-68 prostatespecific membrane antigen positron emission tomography/computed tomography is the most sensitive imaging tool for detecting metastasis from primary prostate cancer. Magnetic resonance imaging of the penis is the most reliable technique for differentiating penile lesions. Histological diagnosis is mostly performed using fine-needle biopsy aspiration. Metastasis-directed treatment is not considered to contribute to prolonged survival. Local treatment is feasible and can be offered to symptomatic patients. Owing to a heterogeneous group, defining overall survival is difficult. Survival until 46months after detecting penile metastases is described.

Predictors of Recurrence After Metastasis-directed Therapy in Oligorecurrent Prostate Cancer Following Radical Prostatectomy.

BACKGROUND: Metastasis-directed therapy (MDT) is performed to delay systemic treatments for oligorecurrent disease after primary prostate cancer (PCa) treatment. OBJECTIVE: The aim of this study was to identify the predictors of therapeutic response of MDT for oligorecurrent PCa. DESIGN, SETTING, AND PARTICIPANTS: bicentric, retrospective study, including consecutive patients who underwent MDT for oligorecurrent PCa after radical prostatectomy (RP; 2006-2020) was conducted. MDT encompassed stereotactic body radiation therapy (SBRT), salvage lymph node dissection (sLND), whole-pelvis/retroperitoneal radiation therapy (WP[R]RT), or metastasectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ndpoints were 5-yr radiographic progression-free survival (rPFS), metastasis-free survival (MFS), palliative androgen deprivation treatment (pADT)-free survival, and overall survival (OS) together with prognostic factors for MFS following primary MDT. Survival outcomes were studied by Kaplan-Meier survival and univariable Cox regression (UVA). RESULTS AND LIMITATIONS: A total of 211 MDT patients were included; 122 (58%) developed a secondary recurrence. Salvage lymph node dissection was performed in 119 (56%), SBRT in 48 (23%), and WP(R)RT in 31 (15%) of the cases. Two patients received sLND + SBRT and one received sLND + WPRT. Eleven (5%) patients received metastasectomies. The median follow-up since RP was 100 mo, while follow-up after MDT was 42 mo. The 5-yr rPFS, MFS, androgen deprivation treatment(-free survival, castration-resistant prostate cancer-free survival, CSS, and OS after MDT were 23%, 68%, 58%, 82%, 93%, and 87% respectively. There was a statistically significant difference between cN1 (n = 114) and cM+ (n = 97) for 5-yr MFS (83% vs 51%, p < 0.001), pADT-free survival (70% vs 49%, p = 0.014), and CSS (100% vs 86%, p = 0.019). UVA was performed to assess the risk factors (RFs) for MFS in cN1 and cM+. Alpha was set at 10%. RFs for MFS in cN1 were lower initial prostate-specific antigen (PSA) at the time of RP (hazard ratio [95% confidence interval] 0.15 [0.02-1.02], p = 0.053], pN stage at RP (2.91 [0.83-10.24], p = 0.096), nonpersisting PSA after RP (0.47 [0.19-1.12], p = 0.089), higher PSA at primary MDT (2.38 [1.07-5.24], p = 0.032), and number of positive nodes on imaging (1.65 [1.14-2.40], p < 0.01). RFs for MFS in cM+ were higher pathological Gleason score (1.86 [0.93-3.73], p = 0.078), number of lesions on imaging (0.77 [0.57-1.04], p = 0.083), and cM1b/cM1c (non-nodal metastatic recurrence; 2.62 [1.58-4.34], p < 0.001). CONCLUSIONS: Following MDT, 23% of patients were free of a second recurrence at 5-yr follow-up. Moreover, cM+ patients had significantly worse outcomes in terms of MFS, pADT-free survival, and CSS. The RFs for a metastatic recurrence can be used for counseling patients, to inform prognosis, and potentially select candidates for MDT. PATIENT SUMMARY: In this paper, we looked at the outcomes of using localized, patient-tailored treatment for imaging-detected recurrent prostate cancer in lymph nodes, bone, or viscera (maximum five recurrences on imaging). Our results showed that targeted treatment of the metastatic lesions could delay the premature use of hormone therapy.

Defining the optimal template of salvage lymph node dissection for unilateral pelvic nodal recurrence of prostate cancer following radical prostatectomy.

OBJECTIVES: Several retrospective studies have shown that salvage bilateral pelvic lymph node dissection (sLND) is a valid treatment option in the setting of oligorecurrent nodal prostate cancer following radical prostatectomy. Little is known about the optimal template of such sLND in patients with strictly unilateral pelvic recurrence on PET-CT imaging. In this study, we investigated whether a unilateral pelvic sLND could be sufficient in such a setting. METHODS: We retrospectively collected data of patients treated with sLND between 2010 and 2019 at the University Hospitals, Leuven. Patients were included if they developed recurrence following radical prostatectomy, characterized by ≤3 unilateral pelvic lymph node metastases on Choline or PSMA PET-CT and received a super-extended bilateral pelvic sLND as first metastasis-directed therapy. As a primary endpoint, we investigated in how many cases a unilateral sLND would have been sufficient. RESULTS: In total, 44 patients with strictly unilateral pelvic recurrence were treated with super-extended bilateral pelvic sLND. In 5 out of 44 (11%) patients, histological examination showed presence of prostate cancer in the contralateral hemi-pelvis. In the group with a single positive node on imaging prior to sLND, only 1 out of 27 (3%) patients had contralateral disease at final pathology. No one (0%) in this group subsequently developed recurrence in the contralateral hemi-pelvis following sLND. CONCLUSIONS: In conclusion, this study suggests that unilateral pelvic sLND could be sufficient in patients with a single unilateral pelvic lymph node recurrence on PET/CT imaging.

ARNEO: A Randomized Phase II Trial of Neoadjuvant Degarelix with or Without Apalutamide Prior to Radical Prostatectomy for High-risk Prostate Cancer.

BACKGROUND: High-risk prostate cancer (PCa) patients have a high risk of biochemical recurrence and metastatic progression following radical prostatectomy (RP). OBJECTIVE: To determine the efficacy of neoadjuvant degarelix plus apalutamide before RP compared with degarelix with a matching placebo. DESIGN, SETTING, AND PARTICIPANTS: ARNEO was a randomized, placebo-controlled, phase II neoadjuvant trial before RP performed between March 2019 and April 2021. Eligible patients had high-risk PCa and were amenable to RP. INTERVENTION: Patients were randomly assigned at a 1:1 ratio to degarelix (240-80-80 mg) + apalutamide (240 mg/d) versus degarelix + matching placebo for 3 mo followed by RP. Prior to and following neoadjuvant treatment, pelvic 18F-PSMA-1007 positron emission tomography (PET)/magnetic resonance imaging (MRI) was performed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the difference in proportions of patients with minimal residual disease (MRD; = residual cancer burden (RCB) ≤0.25 cm3 at final pathology). Secondary endpoints included differences in prostate-specific antigen responses, pathological staging, and change in TNM stage on prostate-specific membrane antigen (PSMA) PET/MRI following hormonal treatment. Biomarkers (immunohistochemical staining on prostate biopsy [PTEN, ERG, Ki67, P53, GR, and PSMA] and PSMA PET/MRI-derived characteristics) associated with pathological response (MRD and RCB) were explored. RESULTS AND LIMITATIONS: Patients were randomized to neoadjuvant degarelix + apalutamide (n = 45) or degarelix + matching placebo (n = 44) for 12 wk and underwent RP. Patients in the degarelix + apalutamide arm achieved a significantly higher rate of MRD than those in the control arm (38% vs 9.1%; relative risk [95% confidence interval] = 4.2 [1.5-11], p = 0.002). Patients with PTEN loss in baseline prostate biopsy attained significantly less MRD (11% vs 43%, p = 0.002) and had a higher RCB at final pathology (1.6 vs 0.40 cm3, p < 0.0001) than patients without PTEN loss. Following neoadjuvant hormonal therapy, PSMA PET-estimated tumor volumes (1.2 vs 2.5 ml, p = 0.01) and maximum standardized uptake value (SUVmax; 4.3 vs 5.7, p = 0.007) were lower in patients with MRD than in patients without MRD. PSMA PET-estimated volume and PSMA PET SUVmax following neoadjuvant treatment correlated significantly with RCB at final pathology (both p < 0.001). CONCLUSIONS: In high-risk PCa patients, neoadjuvant degarelix plus apalutamide prior to RP results in a significantly improved pathological response (MRD and RCB) compared with degarelix alone. Our trial results provide a solid hypothesis-generating basis for neoadjuvant phase 3 trials, which are powered to detect differences in long-term oncological outcome following neoadjuvant androgen receptor signaling inhibitor therapy. PATIENT SUMMARY: In this study, we looked at the difference in pathological responses in high-risk prostate cancer patients treated with degarelix plus apalutamide or degarelix plus matching placebo prior to radical prostatectomy. We demonstrated that patients treated with degarelix plus apalutamide achieved a significantly better tumor response than patients treated with degarelix plus matching placebo. Long-term follow-up is required to determine whether improved pathological outcome translates into better oncological outcomes.

Combining PSA and PET features to select candidates for salvage lymph node dissection in recurrent prostate cancer.

Objective: To evaluate the relationship between pre-operative PSA value, 68Ga-prostate-specific-membrane-antigen (PSMA) PET performance and oncologic outcomes after salvage lymph node dissection (sLND) for biochemical recurrent prostate cancer (PCa). Patients and methods: The study included 164 patients diagnosed with ≤2 pelvic lymph-node recurrence(s) of PCa documented on 68Ga-PSMA PET scan and treated with pelvic ± retroperitoneal sLND at 11 high-volume centres between 2012 and 2019. Pathologic findings were correlated to PSA values at time of sLND, categorized in early (<0.5 ng/ml), low (0.5-0.99 ng/ml), moderate (1-1.5 ng/ml) and high (>1.5 ng/ml). Clinical recurrence (CR)-free survival after sLND was calculated using multivariable analyses and plotted over pre-operative PSA value. Results: Median [interquartile range (IQR)] PSA at sLND was 1.1 (0.6, 2.0) ng/ml, and 131 (80%) patients had one positive spot at PET scan. All patients received pelvic sLND, whereas 91 (55%) men received also retroperitoneal dissection. Median (IQR) number of node removed was 15 (6, 28). The rate of positive pathology increased as a function of pre-operative PSA value, with highest rates for patients with pre-operative PSA > 1.5 ng/ml (pelvic-only sLNDs: 84%; pelvic + retroperitoneal sLNDs: 90%). After sLND, PSA ≤ 0.3 ng/ml was detected in 67 (41%) men. On multivariable analyses, pre-operative PSA was associated with PSA response (p < 0.0001). There were 51 CRs after sLND. After adjusting for confounders, we found a significant, non-linear relationship between PSA level at sLND and the 12-month CR-free survival (p < 0.0001), with the highest probability of freedom from CR for patients who received sLND at PSA level ≥1 ng/ml. Conclusions: In case of PET-detected nodal recurrences amenable to sLND, salvage surgery was associated with the highest short-term oncologic outcomes when performed in men with PSA ≥ 1 ng/ml. Awaiting confirmatory data from prospective trials, these findings may help physicians to optimize the timing for 68Ga-PSMA PET in biochemical recurrent PCa.

Pictograms to aid laypeople in identifying the addictiveness of gambling products (PictoGRRed study).

The structural addictive characteristics of gambling products are important targets for prevention, but can be unintuitive to laypeople. In the PictoGRRed (Pictograms for Gambling Risk Reduction) study, we aimed to develop pictograms that illustrate the main addictive characteristics of gambling products and to assess their impact on identifying the addictiveness of gambling products by laypeople. We conducted a three-step study: (1) use of a Delphi consensus method among 56 experts from 13 countries to reach a consensus on the 10 structural addictive characteristics of gambling products to be illustrated by pictograms and their associated definitions, (2) development of 10 pictograms and their definitions, and (3) study in the general population to assess the impact of exposure to the pictograms and their definitions (n = 900). French-speaking experts from the panel assessed the addictiveness of gambling products (n = 25), in which the mean of expert's ratings was considered as the true value. Participants were randomly provided with the pictograms and their definitions, or with a standard slogan, or with neither (control group). We considered the control group as representing the baseline ability of laypeople to assess the addictiveness of gambling products. Each group and the French-speaking experts rated the addictiveness of 14 gambling products. The judgment criterion was the intraclass coefficients (ICCs) between the mean ratings of each group and the experts, reflecting the level of agreement between each group and the experts. Exposure to the pictograms and their definition doubled the ability of laypeople to assess the addictiveness of gambling products compared with that of the group that read a slogan or the control group (ICC = 0.28 vs. 0.14 (Slogan) and 0.14 (Control)). Laypeople have limited awareness of the addictive characteristics of gambling products. The pictograms developed herein represent an innovative tool for universally empowering prevention and for selective prevention.

An empirical investigation of the Pathways Model of problem gambling through the conjoint use of self-reports and behavioural tasks.

Background and aims: Blaszczynski and Nower (2002) conceptualized their Pathways Model by postulating the existence of three subtypes of problem gamblers who share common characteristics, but also present specific ones. Methods: This study investigated how the psychological mechanisms postulated in the Pathways Model predict clinical status in a sample that combined treatment-seeking gamblers (n = 59) and non-problematic community gamblers (n = 107). To test the Pathways Model, we computed a hierarchic logistic regression in which variables associated with each postulated pathway were entered sequentially to predict the status of the treatment-seeking gambler. Self-report questionnaires measured gambling-related cognitions, alexithymia, emotional reactivity, emotion regulation strategies and impulsivity. Behavioural tasks measured gambling persistence (slot machine task), decision-making under uncertainty (Iowa Gambling Task) and decision-making under risk (Game of Dice Task). Results: We showed that specific factors theorized as underlying mechanisms for each pathway predicted the status of clinical gambler. For each pathway, significant predictors included gambling-related cognitive distortions and behaviourally measured gambling persistence (behaviourally conditioned pathway), emotional reactivity and emotion regulation strategies (emotionally vulnerable pathway), and lack of premeditation impulsivity facet (impulsivist-antisocial pathway). Discussion and conclusions: Our study adds to the body of literature confirming the validity of the Pathways Model and hold important implications in terms of assessment and treatment of problem gambling. In particular, a standardized assessment based on the Pathways Model should promote individualized treatment strategies to allow clinicians to take into account the high heterogeneity that characterizes gambling disorder.

Definition and Impact on Oncologic Outcomes of Persistently Elevated Prostate-specific Antigen After Salvage Lymph Node Dissection for Node-only Recurrent Prostate Cancer After Radical Prostatectomy: Clinical Implications for Multimodal Therapy.

BACKGROUND: The optimal definition and prognostic significance of persistently elevated prostate-specific antigen (PSA) after salvage lymph node dissection (sLND) for node-only recurrent prostate cancer (PCa) remain unknown. OBJECTIVE: To assess the definition and clinical implications of persistently elevated PSA after sLND for node-only recurrent PCa after radical prostatectomy. DESIGN, SETTING, AND PARTICIPANTS: The study included 579 patients treated with sLND at 11 high-volume centers between 2000 and 2016. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the linear relationship between the first PSA after sLND and death from PCa. Different definitions of PSA persistence were included in a multivariable model predicting cancer-specific mortality (CSM) after surgery to identify the best cutoff value. We investigated the association between PSA persistence and oncologic outcomes using multivariable regression models. Moreover, the effect of early androgen deprivation therapy (ADT) after sLND was tested according to PSA persistence status and estimated risk of CSM. RESULTS AND LIMITATIONS: We found an inverse relationship between the first PSA after sLND and the probability of cancer-specific survival. PSA persistence defined as first postoperative PSA ≥0.3 ng/ml provided the best discrimination accuracy (C index 0.757). According to this cutoff, 331 patients (57%) experienced PSA persistence. The median follow-up for survivors was 48 mo (interquartile range 27-74). After adjusting for confounders, men with persistently elevated PSA had higher risk of clinical recurrence (hazard ratio [HR] 1.61), overall mortality (HR 2.20), and CSM (HR 2.59; all p < 0.001) after sLND. Early ADT administration after sLND improved survival only for patients with PSA persistence after surgery (HR 0.49; p = 0.024). Similarly, when PSA persistence status was included in multivariable models accounting for pathologic features, early ADT use after sLND was beneficial only for patients with a predicted risk of CSM at 5 yr of >10%. CONCLUSIONS: PSA persistence after sLND independently predicts adverse prognosis, with the best discrimination accuracy for CSM provided by a definition of PSA ≥ 0.3 ng/ml. We showed that when stratifying patients by final pathology results and PSA persistence status, early ADT use after sLND was beneficial only for patients with PSA persistence or with a calculated 5-yr risk of CSM of >10%, which could be useful as we await results from ongoing prospective trials. PATIENT SUMMARY: We found that for patients with prostate cancer who had lymph nodes removed after their cancer recurred, persistently elevated prostate-specific antigen (PSA) levels predict poorer prognosis. We showed that a PSA level of ≥0.3 ng/ml provides the best accuracy in identifying patients with worse prognosis. This may help to improve risk stratification after lymph node removal and allow physicians to optimize treatment strategies after surgery.

Radium-223 in patients with prostate specific antigen (PSA) progression and without clinical metastases following maximal local therapy: A pilot study.

BACKGROUND: Despite the curative intent of radical prostatectomy (RP) (+/- radiotherapy (RT)), 30% of the clinically localized prostate cancer (CaP) patients will develop rising PSA (prostate specific antigen). In absence of clinical recurrence, there is a lack of effective treatment strategies in order to control the disease at its earliest (micro)metastatic stage. The aim of this study was to assess safety, tolerability, and biochemical response of off-label Radium-223 (Xofigo) treatment in CaP patients with PSA relapse following maximal local therapy. METHODS: We conducted a prospective, single arm, single center open-label, pilot study with Radium-223 in CaP patients with rising PSA (>0.2 ng/ml) following RP + adjuvant/salvage RT. Negative staging with 68Ga-PSMA-11 PET/CT and whole-body MRI was mandatory at time of inclusion. Patients were eligible if they exhibited adverse clinico-pathological features predictive of significant recurrence. Safety, tolerability, biochemical progression (defined as PSA increase >50% from PSA nadir) and clinical recurrence were assessed. RESULTS: In total, 23 patients were screened of whom 8 patients were included is the study. Radium-223 treatment was safe with no serious treatment related adverse events. One patient developed grade 3 lymphopenia. All patients rapidly developed PSA progression (median PSA progression-free survival: 5.5 months). Eventually all patients experienced clinical recurrence (median clinical recurrence-free survival 11.0 months) of whom only 2 patients developed skeletal recurrence. CONCLUSIONS: Radium-223 in patients with PSA relapse following maximal local treatment without clinical metastases is safe. However, the clinical benefit of Ra-223 in this setting is doubtful as significant oncological benefit is lacking.

Neoadjuvant hormonal therapy before radical prostatectomy in high-risk prostate cancer.

Patients with high-risk prostate cancer treated with curative intent are at an increased risk of biochemical recurrence, metastatic progression and cancer-related death compared with patients treated for low-risk or intermediate-risk disease. Thus, these patients often need multimodal therapy to achieve complete disease control. Over the past two decades, multiple studies on the use of neoadjuvant treatment have been performed using conventional androgen deprivation therapy, which comprises luteinizing hormone-releasing hormone agonists or antagonists and/or first-line anti-androgens. However, despite results from these studies demonstrating a reduction in positive surgical margins and tumour volume, no benefit has been observed in hard oncological end points, such as cancer-related death. The introduction of potent androgen receptor signalling inhibitors (ARSIs), such as abiraterone, apalutamide, enzalutamide and darolutamide, has led to a renewed interest in using neoadjuvant hormonal treatment in high-risk prostate cancer. The addition of ARSIs to androgen deprivation therapy has demonstrated substantial survival benefits in the metastatic castration-resistant, non-metastatic castration-resistant and metastatic hormone-sensitive settings. Intuitively, a similar survival effect can be expected when applying ARSIs as a neoadjuvant strategy in high-risk prostate cancer. Most studies on neoadjuvant ARSIs use a pathological end point as a surrogate for long-term oncological outcome. However, no consensus yet exists regarding the ideal definition of pathological response following neoadjuvant hormonal therapy and pathologists might encounter difficulties in determining pathological response in hormonally treated prostate specimens. The neoadjuvant setting also provides opportunities to gain insight into resistance mechanisms against neoadjuvant hormonal therapy and, consequently, to guide personalized therapy.

Positive and negative urgency as a single coherent construct: Evidence from a large-scale network analysis in clinical and non-clinical samples.

AIMS: Negative and positive urgency are emotion-related impulsivity traits that are thought to be transdiagnostic factors in psychopathology. However, it has recently been claimed that these two traits are closely related to each other and that considering them separately might have limited conceptual and methodological value. The present study aimed to examine whether positive and negative urgency constructs constitute separate impulsivity traits. METHODS: In contrast to previous studies that have used latent variable approaches, this study employed an item-based network analysis conducted in two different samples: a large sample of non-clinical participants (N = 18,568) and a sample of clinical participants with psychiatric disorders (N = 385). RESULTS: The network analysis demonstrated that items denoting both positive and negative urgency cohere as a single cluster of items termed "general urgency" in both clinical and non-clinical samples, thereby suggesting that differentiating positive and negative urgency as separate constructs is not necessary. CONCLUSION: These findings have important implications for the conceptualization and assessment of urgency and, more broadly, for future research on impulsivity, personality, and psychopathology.

Preclinical Models in Prostate Cancer: Resistance to AR Targeting Therapies in Prostate Cancer.

Prostate cancer is an androgen-driven tumor. Different prostate cancer therapies consequently focus on blocking the androgen receptor pathway. Clinical studies reported tumor resistance mechanisms by reactivating and bypassing the androgen pathway. Preclinical models allowed the identification, confirmation, and thorough study of these pathways. This review looks into the current and future role of preclinical models to understand resistance to androgen receptor-targeted therapies. Increasing knowledge on this resistance will greatly improve insights into tumor pathophysiology and future treatment strategies in prostate cancer.

Neoadjuvant treatment with androgen receptor signaling inhibitors prior to radical prostatectomy: a systematic review.

CONTEXT: There is an urgent need to develop novel treatment strategies in patients with unfavorable intermediate- and high-risk localized prostate cancer (PCa) to optimize the outcome of these patients. Androgen receptor signaling inhibitors (ARSI) have demonstrated a survival benefit in metastatic hormonesensitive and castration-resistant PCa. A similar benefit might be expected in the localized setting. OBJECTIVE: To perform a systematic review about the role of neoadjuvant ARSI in unfavorable intermediate and high-risk localized PCa. EVIDENCE ACQUISITION: We performed a systematic review of the following databases: MEDLINE (PubMed), EMBASE, Cochrane Library and Web of Science. Publications of ASCO were consulted to identify meeting abstract with early results of ongoing trials. This systematic review was performed and reported in accordance with the PRISMA guidelines. EVIDENCE SYNTHESIS: Pathological complete response (pCR) following neoadjuvant ARSI treatment was observed in 4%-13% of the patients. Minimal residual disease response ranged from 36% to 73.9% when defined as residual cancer burden < 0.25 cm3 at final pathology and from 8% to 20% when defined as the diameter of the remaining tumor < 5 mm. Despite intense neoadjuvant ARSI treatment, residual pT3 disease was observed in 48%-76% of the patients. In contrast, positive surgical margins (PSM) were present in only 5%-22%. Only one trial reported BCR following neoadjuvant ARSI therapy (44% BCR at a median follow-up of 4 years). CONCLUSION: Despite intense neoadjuvant ARSI therapy, pCR is rarely attained and high proportions of pT3 disease are still observed at final pathology. In contrast, promising results are obtained in terms of PSMs. Long-term survival outcomes are eagerly awaited.