An ex vivo Tissue Culture Model for the Assessment of Individualized Drug Responses in Prostate and Bladder Cancer

Urological malignancies, including prostate and bladder carcinoma, represent a major clinical problem due to the frequent occurrence of therapy resistance and the formation of incurable distant metastases. As a result, there is an urgent need for versatile and predictive disease models for the assessment of the individualized drug response in urological malignancies. Compound testing on ex vivo cultured patient-derived tumor tissues could represent a promising approach. In this study, we have optimized an ex vivo culture system of explanted human prostate and bladder tumors derived from clinical specimens and human cancer cell lines xenografted in mice. The explanted and cultured tumor slices remained viable and tissue architecture could be maintained for up to 10 days of culture. Treatment of ex vivo cultured human prostate and bladder cancer tissues with docetaxel and gemcitabine, respectively, resulted in a dose-dependent anti-tumor response. The dose-dependent decrease in tumor cells upon administration of the chemotherapeutic agents was preceded by an induction of apoptosis. The implementation and optimization of the tissue slice technology may facilitate the assessment of anti-tumor efficacies of existing and candidate pharmacological agents in the complex multicellular neoplastic tissues from prostate and bladder cancer patients. Our model represents a versatile “near-patient” tool to determine tumor-targeted and/or stroma-mediated anti-neoplastic responses, thus contributing to the field of personalized therapeutics

The aldehyde dehydrogenase enzyme 7A1 is functionally involved in prostate cancer bone metastasis

High aldehyde dehydrogenase (ALDH) activity can be used to identify tumor-initiating and metastasis-initiating cells in various human carcinomas, including prostate cancer. To date, the functional importance of ALDH enzymes in prostate carcinogenesis, progression and metastasis has remained elusive. Previously we identified strong expression of ALDH7A1 in human prostate cancer cell lines, primary tumors and matched bone metastases. In this study, we evaluated whether ALDH7A1 is required for the acquisition of a metastatic stem/progenitor cell phenotype in human prostate cancer. Knockdown of ALDH7A1 expression resulted in a decrease of the α2hi/αvhi/CD44+ stem/progenitor cell subpopulation in the human prostate cancer cell line PC-3M-Pro4. In addition, ALDH7A1 knockdown significantly inhibited the clonogenic and migratory ability of human prostate cancer cells in vitro. Furthermore, a number of genes/factors involved in migration, invasion and metastasis were affected including transcription factors (snail, snail2, and twist) and osteopontin, an ECM molecule involved in metastasis. Knockdown of ALDH7A1 resulted in decreased intra-bone growth and inhibited experimentally induced (bone) metastasis, while intra-prostatic growth was not affected. In line with these observations, evidence is presented that TGF-β, a key player in cancer invasiveness and bone metastasis, strongly induced ALDH activity while BMP7 (an antagonist of TGF-β signaling) down-regulated ALDH activity. Our findings show, for the first time, that the ALDH7A1 enzyme is functionally involved in the formation of bone metastases and that the effect appeared dependent on the microenvironment, i.e., bone versus prostate

The flare in alkaline phosphatase activity post-orchidectomy predicts which patient may benefit from early chemotherapy in metastatic prostate cancer

BACKGROUND: A flare in serum alkaline phosphatase (ALP) activity post-orchidectomy has been shown to be of negative prognostic value for progression-free survival (PFS) in patients with prostate cancer. The aim of this study was to investigate whether a flare in ALP may help identify patients in whom prognosis could be positively influenced by early chemotherapy. METHODS: A retrospective analysis of the database of a Dutch multicenter study was conducted to evaluate the prognostic value of the flare in ALP post-orchidectomy for survival and PFS in 112 patients treated with orchidectomy (previously reported) compared to 121 age- and stage-matched patients additionally treated with estramustine-phosphate (EMP) as first line therapy. RESULTS: There was no overall difference in PFS and survival between the two treatment regimen. Subgroup analysis of patients demonstrating a greater than 50% increase in ALP post-orchidectomy showed, however, a significant increase in PFS in patients additionally treated with EMP. CONCLUSIONS: Our data suggest that the simple measurement of ALP activity within 4 weeks of castration represents a useful adjunct in assessing which patients with prostate cancer undergoing androgen ablation may benefit from additional early chemotherap

‘Feeling Hot’: Exploring the feasibility of nocturnal erection detection through penile temperature measurements

Abstract Objectives The observational ‘Feeling Hot’ study aims to evaluate the feasibility of employing overnight penile temperature measurements for the detection of nocturnal erections, thereby contributing to the advancement and modernization of a non‐invasive diagnostic system for erectile dysfunction. Subjects/Patients and Methods In this proof‐of‐concept study, 10 healthy men aged 20–25 were recruited, following the methodology outlined in the ‘Staying Hot’ study by Torenvlied et al. Participants underwent ambulatory overnight penile temperature measurements concurrent with RigiScan recordings. Key outcome measures included baseline and peak penile temperatures during RigiScan‐annotated nocturnal erections. Reference measurements of the thigh temperature were also taken to assess nocturnal temperature variations. Results Statistically significant penile temperature increases (p = 0.008, n = 9) were observed during nocturnal erections, with an average elevation of 1.47°C noted during the initial erections. This underscores the practical utility of penile temperature measurements in detecting erection onset. Challenges arose in accurately determining erection duration and subsequent erection onsets due to the persistence of elevated temperatures following initial erections, termed the ‘Staying Hot effect’. Reference thigh temperature measurements aided in addressing this challenge. Conclusion Examining overnight penile temperature alongside simultaneous RigiScan recordings has yielded valuable insights into the viability of using the temperature methodology for detecting nocturnal erections. The ‘Feeling Hot’ study findings demonstrate significant penile temperature elevation during nocturnal erections in healthy young men, highlighting the potential of integrating this measurement methodology into the design of a modernized tool for ambulatory erectile dysfunction diagnostics. Further development of an advanced sensor system to comprehensively assess erection duration and quality is essential for enhancing clinical applicability

Pelvic floor physical therapy in patients with chronic anal fissure: a randomized controlled trial

Background: A chronic anal fissure is a common, painful condition with great impact on daily life. The exact pathogenesis has not been fully elucidated and treatment varies. A large percentage of patients experience pelvic floor dysfunction (dyssynergia and increased pelvic floor muscle tone). The aim of our study was to investigate the effect of pelvic floor physical therapy in patients with chronic anal fissure. Methods: Between December 2018 and July 2021, at the Proctos Clinic in the Netherlands, patients with chronic anal fissure and pelvic floor dysfunction were randomly assigned to an intervention group, receiving 8 weeks of pelvic floor physical therapy including electromyographic biofeedback or assigned to a control group receiving postponed pelvic floor physical therapy. The primary outcome was muscle tone at rest during electromyographic registration of the pelvic floor before and after pelvic floor physical therapy. Secondary outcomes contained healing of the fissure, pain ratings, improvement of pelvic floor function, and complaint reduction measured with a proctology-specific patient-reported outcome measurement. Endpoints were measured at 8- and 20-week follow-up. Results: One hundred forty patients were included in the study, 68 men (48.6%) and 72 women (51.4%) with a mean age of 44.5 ± 11.1 (range 19–79) years. Mean resting electromyographic values of the pelvic floor in the intervention group significantly improved from pre- to post-treatment (p < 0.001) and relative to controls (mean estimated difference between groups − 1.88 µV; 95% CI, − 2.49 to − 1.27 (p < 0.001) at first follow-up and remained significant from baseline at 20-week follow-up (p < 0.001). The intervention group performed better compared to the control group on all secondary outcomes, i.e., healing of the fissure (55.7% of the patients vs 21.4% in control, pain ratings (p < 0.001), diminished dyssynergia (p < 0.001), complaint reduction (p < 0.001), and decrease of pelvic floor muscle tone (p < 0.05) at first follow-up. Conclusions: The findings of this study provide strong evidence that pelvic floor physical therapy is effective in patients with chronic anal fissure and pelvic floor dysfunction and supports its recommendation as adjuvant treatment besides regular conservative treatment

How Do Continence Nurses Address Sexual Function and a History of Sexual Abuse in Daily Practice? Results of a Pilot Study

Introduction. There is a strong association between urological complaints, sexual dysfunction, and history of sexual abuse (SA), and it is unknown whether urological continence nurses integrate this knowledge in their daily practice. Aim. To evaluate how, in their daily practice, Dutch urological continence nurses address sexual dysfunction and possible SA. Methods. An anonymous 19-item questionnaire was distributed among all Dutch urinary continence nurses visiting their yearly congress. Main Outcome Measures. The survey results. Results. The response rate was 48.9% (93/190). Of the respondents, 11.8% did not ask their female patients about sexual function; 37.6% asked only rarely; 44.1% asked often; and 6.5% always asked. Sexual functioning in males was not evaluated by the majority of the nurses (13.2% never, and 46.2% rarely). A minority of continence nurses asked males about sexual functioning (36.3% often and 4.3% always). Important reasons for not asking were insufficient knowledge of how to adequately ask males (38.9%) and females (47.8%) about sexual problems, and because nurses assumed the urologist had addressed this issue (48.1% asking males, 39.1% asking females). Younger nurses found it particularly difficult to raise sexual issues with both male and female patients (P = 0.001 and P = 0.003, respectively). Screening for sexual dysfunction was stated to be important by almost all nurses (65.2% "quite important," and 31.5% "very important"). Within their patient population, both male and female, 28% of the nurses never asked about SA and 49.5% asked only rarely. Conclusion. Dutch urological incontinence nurses acknowledge the importance of sexual problems in their patient population, but asking about this issue was not part of routine care. The main reasons for not asking, according to the nurses' responses, were that they had insufficient knowledge and that they assumed the urologist had already asked about sexual problems. Bekker MD, Van Driel MF, Pelger RCM, Lycklama a Nijeholt GAB, and Elzevier HW. How do continence nurses address sexual function and a history of sexual abuse in daily practice? Results of a pilot study. J Sex Med 2011;8:367-375

Dual-mTOR Inhibitor Rapalink-1 Reduces Prostate Cancer Patient-Derived Xenograft Growth and Alters Tumor Heterogeneity.

Bone metastasis is the leading cause of prostate cancer (PCa) mortality, frequently marking the progression to castration-resistant PCa. Dysregulation of the androgen receptor pathway is a common feature of castration-resistant PCa, frequently appearing in association with mTOR pathway deregulations. Advanced PCa is also characterized by increased tumor heterogeneity and cancer stem cell (CSC) frequency. CSC-targeted therapy is currently being explored in advanced PCa, with the aim of reducing cancer clonal divergence and preventing disease progression. In this study, we compared the molecular pathways enriched in a set of bone metastasis from breast and prostate cancer from snap-frozen tissue. To further model PCa drug resistance mechanisms, we used two patient-derived xenografts (PDX) models of bone-metastatic PCa, BM18, and LAPC9. We developed in vitro organoids assay and ex vivo tumor slice drug assays to investigate the effects of mTOR- and CSC-targeting compounds. We found that both PDXs could be effectively targeted by treatment with the bivalent mTORC1/2 inhibitor Rapalink-1. Exposure of LAPC9 to Rapalink-1 but not to the CSC-targeting drug disulfiram blocked mTORC1/2 signaling, diminished expression of metabolic enzymes involved in glutamine and lipid metabolism and reduced the fraction of CD44+ and ALDEFluorhigh cells, in vitro. Mice treated with Rapalink-1 showed a significantly delayed tumor growth compared to control and cells recovered from the tumors of treated animals showed a marked decrease of CD44 expression. Taken together these results highlight the increased dependence of advanced PCa on the mTOR pathway, supporting the development of a targeted approach for advanced, bone metastatic PCa

Patients and physician satisfaction of Degarelix in androgen deprivation therapy for advanced hormone-dependent prostate cancer in the Netherlands

BACKGROUND: To explore the effectiveness and safety of the gonadotropin-releasing hormone antagonist, Degarelix, for the treatment of advanced hormone-dependent prostate cancer (PCa) in a real-world setting. METHODS: In this noninterventional study, patients with advanced hormone-dependent PCa were included. Primary endpoints were progression-free survival (PFS) failure defined as either prostate-specific antigen failure, additional therapy related to PCa, or death. Secondary endpoints included patient and physician satisfaction scores, urinary symptoms, and adverse events (AEs). RESULTS: Of 274 patients with PCa, 271 received at least 1 dose of Degarelix. At a median follow-up of 12.2 (interquartile range 6.2–22.0) months, 148 patients (60.2%) had PFS failure. Thirty-five patients (13%) withdrew from the study due to AEs, 23 patients (8.4%) died, and 36 patients (13%) completed 3 years’ follow-up. Urinary symptoms significantly decreased over time. In the safety population, 87.8% of patients reported AEs, with injection-site reactions commonly reported. The majority of physicians and patients considered the therapy satisfactory and well tolerated. CONCLUSIONS: In this observational study, Degarelix treatment was well accepted by men with advanced hormone-dependent PCa. Compared with phase III studies, a higher proportion of patients had PFS failure, possibly due to the inclusion of men with more advanced disease in the current study, and more men reported AEs