Androgen deprivation therapy in advanced prostate cancer: insights from a real-world patient survey on health-related quality of life and information and communication sources.

PURPOSE: Androgen deprivation therapy (ADT) is a cornerstone treatment for advanced and metastatic prostate cancer. Real-world and patient-reported insights into ADT's impact on health-related quality of life (HRQoL) and communication experiences in healthcare settings remain underexplored. This patient organisation-initiated online survey aimed to assess these aspects. METHODS: Between December 2022 and August 2023, the patient organisation Think Blue Vlaanderen and the AZ Sint-Jan Hospital (Bruges, Belgium) invited ADT-treated patients to participate in a prospective, online, cross-sectional, patient-reported outcome survey. Demographic, clinical, HRQoL (FACT and EPIC-26), communication sources and information modality data were collected. Descriptive statistics and comparative analyses were applied. RESULTS: A total of 276/312 (88.5%) participating patients were on ADT at time of survey administration and completion, with the majority receiving a 3-monthly regimen. Sexual HRQoL was low and narrowly distributed (median (IQR): 16.7 (16.7-16.7)), with 84% of patients having erectile dysfunction (ED). Patients finding their ED problematic were more likely to seek pharmaceutical treatment. Hormonal HRQoL was widely distributed (median (IQR): 65 (45-85)), which improved with prolonged ADT duration. Physically active patients reported less lack of energy, but increased hot flashes. Within consistent FACT-G summary scores (median (IQR): 64.50 (54.75-77.00)), improved emotional wellbeing with prolonged ADT was noted. Multidisciplinary communication and multimodal information provision improved patient satisfaction. CONCLUSION: Patient organisation-initiated surveys offer real-world and patient-reported insights. Patient-tailored HRQoL assessments and longitudinal follow-up, physical activity, and multidisciplinary and multimodal communication approaches are warranted to improve patient-centred care in patients receiving ADT.

Phase II open-label study investigating apalutamide in patients with biochemical progression after radical prostatectomy.

Apalutamide, a competent inhibitor of the androgen receptor, has shown promising clinical efficacy results for patients with advanced prostate cancer. Here, we describe the rationale and design for the SAVE trial, a multi-center, Phase II study, wherein 202 men with biochemical progression after radical prostatectomy are randomly assigned 1:1 to apalutamide plus salvage radiotherapy (SRT) or androgen-deprivation therapy with an luteinizing hormone-releasing hormone agonist or antagonist plus SRT. The primary objective is to compare sexual function between the two treatment arms based on the expanded prostate cancer index-26 sexual domain score at nine months after start of hormonal treatment. The key secondary objectives are to assess quality of life, to evaluate the safety profile and the short-term efficacy of apalutamide in combination with SRT. ClinicalTrials.gov identifier: NCT03899077.

Circulating tumor cells and survival in abiraterone- and enzalutamide-treated patients with castration-resistant prostate cancer.

BACKGROUND: The outcome to treatment administered to patients with metastatic castration-resistant prostate cancer (mCRPC) greatly differs between individuals, underlining the need for biomarkers guiding treatment decision making. OBJECTIVE: To investigate the prognostic value of circulating tumor cell (CTC) enumeration and dynamics, in the context of second-line endocrine therapies (ie, abiraterone acetate or enzalutamide), irrespective of prior systemic therapies. DESIGN, SETTINGS, AND PARTICIPANTS: In a prospective, multicentre study blood samples for CTC enumeration were collected from patients with mCRPC at baseline (n = 174). In patients who responded for minimally 10-12 weeks a follow-up sample was collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For baseline analysis, patients were stratified in <5 or ≥5 CTCs/7.5 mL, whereas for the analysis of CTC dynamics at 10-12 weeks, in patients with stable, increasing or decreasing CTC counts. Progression-free survival (PFS), overall survival (OS), and PSA changes at 10-12 weeks were compared between groups. RESULTS: Patients demonstrating increasing CTCs on therapy had a shorter median PFS (4.03 vs 12.98 vs 13.67 months, HR 3.6, 95%CI 1.9-6.8; P < 0.0001) and OS (11.2 months vs not reached, HR 9.5, 95%CI 3.7-24; P < 0.0001), compared to patients with decreasing or stable CTCs. Multivariable Cox regression showed that prior chemotherapy (HR 4.1, 95%CI 1.9-8.9; P = 0.0003), a high baseline CTC count (HR 1.5, 95%CI 1.2-1.9; P = 0.002) and increasing CTCs at follow-up (HR 3.3, 95%CI 1.4-7.6; P = 0.005) were independent predictors of worse PFS. Previous chemotherapy (HR 7, 95%CI 1.9-25; P = 0.003), high baseline CTC counts (HR 2.2, 95%CI 1.4-3.7; P = 0.002) and increasing CTCs during therapy (HR 4.6, 95%CI 1.4-15; P = 0.01) were independently associated with shorter OS. ≥30% and ≥50% PSA responses less frequently occurred in patients with CTC inclines at 10-12 weeks on therapy (χ2 test: P < 0.01). CONCLUSIONS: CTC dynamics during therapy are associated with PSA response and provide independent clinical prognostication over PSA declines. Hence the study demonstrates the pharmacodynamic properties of CTCs.

Androgen receptor pathway inhibitors and taxanes in metastatic prostate cancer: an outcome-adaptive randomized platform trial.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician's choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician's choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or 'all' patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician's choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2-ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53-altered patients. In summary, ARPIs outperform taxanes and physician's choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 .

Fluorescence guidance during robotic resection of bladder wall endometriosis: case report and technique.

The application of indocyanine green (ICG) has recently been reported to aid in the resection of endometriosis in the bladder wall and/or involving the ureters. A symptomatic 41-year-old patient with dysmenorrhea and pollakisuria was referred to our tertiary center. Imaging revealed a 1.5-2 cm intramural endometriotic nodule in the posterior bladder wall. She was planned for robotic resection of the endometriotic nodule, under ICG guidance, together with a hysterectomy. After placement of double-J ureteral stents and clamping the bladder, perforation of the bladder mucosa could be avoided whilst performing a circumferential resection of the nodule. By clamping the bladder catheter after instillation of ICG, both the bladder wall thickness and ureters could be visualized with near-infrared imaging during robotic resection of the endometriotic nodule and hysterectomy. With the surgical approach described here, endometriotic nodules/tissue can be removed precisely with enlarged vision at the robot console, safely, and completely without damaging adjacent tissues.

Primary leiomyosarcoma of the uterine cervix: an unusual case and critical appraisal.

Leiomyosarcomas of the uterine cervix are rare, mostly occurring in perimenopausal women. Diagnosis is based on pathology and immunohistochemistry. Surgery with a total abdominal hysterectomy and bilateral salpingo-oophorectomy remains the standard. A female patient in her 60s presented with heavy postmenopausal bleeding. Vaginal ultrasound scan and magnetic resonance imaging showed a large strongly vascularized cervical mass with features suspicious of sarcomatous degeneration. Positron Emission Tomography-Computed Tomography (PET-CT) did not reveal any evidence of metastases nor lymphadenopathy, but presence of right hydronephrosis. An abdominal hysterectomy with bilateral salpingo-oophorectomy, and end-to-end anastomosis of the right ureter, was performed. Pathology showed an International Federation of Gynecology and Obstetrics (FIGO)-stage 1B leiomyosarcoma of the uterine cervix. No adjuvant treatment was given. Adjuvant radiotherapy reduces the risk of recurrence but no survival impact. The benefit of adjuvant chemotherapy is questionable given the lack of randomized trials. Multidisciplinary research concerning molecular alterations of the disease is required to determine optimal management strategies with potential novel molecular therapies.

Increased Pathway Complexity Is a Prognostic Biomarker in Metastatic Castration-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease, characterized by common and rare driver gene alterations that provide a selective growth advantage for progressing tumour cells. We hypothesized that the number of distinct gene driver alteration-affected pathways or gene classes was associated with poor prognosis in patients initiating androgen receptor signalling inhibitors (ARSi). We performed a post hoc analysis of an amalgamated baseline circulating tumour DNA (ctDNA) mutational landscape dataset of ARSi-treated men with mCRPC (n = 342). We associated the detected hotspot, pathogenic, and/or high impact protein function-affecting perturbations in 39 genes into 13 pathways. Progression-free (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and multivariate Cox regression models. Driver gene alterations were detected in 192/342 (56.1%) evaluable patients. An increased number of affected pathways, coined pathway complexity index (PCI), resulted in a decremental PFS and OS, and was independently associated with prognosis once ≥3 pathway or gene classes were affected (PFS HR (95%CI): 1.7 (1.02-2.84), p = 0.04, and OS HR (95%CI): 2.5 (1.06-5.71), p = 0.04). Additionally, visceral disease and baseline PSA and plasma ctDNA levels were independently associated with poor prognosis. Elevated PCI is associated with poor ARSi outcome and supports comprehensive genomic profiling to better infer mCRPC prognosis.

Long-term efficiency of skin stretching and a topical corticoid cream application for unretractable foreskin and phimosis in prepubertal boys.

OBJECTIVES: To evaluate the long-term efficacy of topical application of a potent corticoid cream and skin stretching in the treatment of unretractable foreskin, pinpoint phimosis, balanopreputial adhesions and lichen sclerosus in prepubertal boys. METHODS: 462 prepubertal boys (mean age 4.7 years) with unretractable foreskin applied a topical potent corticoid cream together with skin stretching twice daily for 6 weeks. Follow-up interview of all patients was performed to evaluate long-term results (median 22 months). Short- and long-term results were compared and evaluated. RESULTS: 400/462 boys (86%) had a retractable prepuce after 6 weeks of treatment. 62/462 boys had no or only a partial response. After a median follow-up of 22 months, the treatment continued to be successful in 383/462 boys (83%). In 76/462 boys the foreskin was unretractable, of which 35 preferred surgical treatment. 12/462 boys presented with lichen sclerosus and the non-surgical treatment appeared efficient in 9/12 (67%). CONCLUSIONS: This study has shown that local application of a potent corticoid cream and skin stretching is a safe, simple and effective long-term treatment for all types of unretractable foreskin in prepubertal boys. The efficiency of the treatment was not related to the age of the patient or the type of unretractable foreskin.

TP53 Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi).Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. RESULTS: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). CONCLUSIONS: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis.See related commentary by Rebello et al., p. 1699.

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.

The use of a Meckel's diverticulum in the creation of an orthotopic neobladder in case of a short mesoileum: a case report.

A 72-year-old patient was treated in our department for an invasive bladder TCC by cystoprostatectomy with the intention to create an orthotopic neobladder. During surgery it appeared to be impossible to mobilize part of the preterminal ileum into the small pelvis to make an anastomosis with the urethral stump. However, incidentally, a Meckel's diverticulum of about 8 cm was found on the preterminal ileum which could easily be mobilized onto the urethral stump. The intestinal insertion of the diverticulum served as the lowest point of the pouch. Above the diverticulum, we created a modified Studer-pouch. No major postoperative complications occurred and during the follow-up period of more than 12 months micturition was good.