Opportunistic Prostate Cancer Screening with Biparametric Magnetic Resonance Imaging (VISIONING).

BACKGROUND: This study investigates the use of biparametric magnetic resonance imaging (bpMRI) as primary opportunistic screening for prostate cancer (PCa) without using a prostate-specific antigen (PSA) cut-off. OBJECTIVE: The primary endpoint was to assess the efforts and effectiveness of identifying 20 participants with clinically significant prostate cancer (csPCa) using bpMRI. DESIGN, SETTING, AND PARTICIPANTS: Biopsy-naïve men aged over 45 yr were included. All participants underwent 3 Tesla bpMRI, PSA, and digital rectal examination (DRE). Targeted-only biopsy was performed in participants with Prostate Imaging Reporting and Data System (PI-RADS) ≥3. Men with negative bpMRI but suspicious DRE or elevated PSA/PSA density had template biopsies. Preintended protocol adjustments were made after an interim analysis for PI-RADS 3 lesions: no biopsy and follow-up MRI after 6 mo and biopsy only if lesions persisted or upgraded. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Biopsy results underwent a comparison using Fisher's exact test and univariable logistic regression to identify prognostic factors for positive biopsy. RESULTS AND LIMITATIONS: A total of 229 men were enrolled in this study, of whom 79 underwent biopsy. Among these men, 77 displayed suspicious PI-RADS lesions. PCa was detected in 29 participants (12.7%), of whom 21 had csPCa (9.2%). Biparametric MRI detected 21 csPCa cases, while PSA and DRE would have missed 38.1%. Protocol adjustment led to a 54.6% biopsy reduction in PI-RADS 3 lesions. Overall, in this cohort of men with a median PSA value of 1.26 ng/ml, 10.9 bpMRI scans were needed to identify one participant with csPCa. A major limitation of the study is the lack of a control cohort undergoing systematic biopsies. CONCLUSIONS: Opportunistic screening utilising bpMRI as a primary tool has higher sensitivity in detecting csPCa than classical screening methods. PATIENT SUMMARY: Screening with biparametric magnetic resonance imaging (bpMRI) and targeted biopsy identified clinically significant prostate cancer in every 11th man, regardless of the prostate-specific antigen (PSA) levels. Preselecting patients based on PSA >1 ng/ml and a positive family history of prostate cancer, as well as other potential blood tests may further improve the effectiveness of bpMRI in this setting.

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer.

Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of a long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological, phenotypical, and transcriptional features of SARC and harbors somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53 (p53) and RB1 (pRB). High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and conventional urothelial carcinoma (UroCa) organoids, identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, including agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts and in organoid models, GR and its encoding gene NR3C1 were found to be significantly more expressed in SARC as compared to UroCa, suggesting that high GR expression is a hallmark of SARC tumors. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.

Prostate cancer patient-derived organoids: detailed outcome from a prospective cohort of 81 clinical specimens.

Patient-derived organoids (PDOs) represent promising preclinical models in various tumor types. In the context of prostate cancer (PCa), however, their establishment has been hampered by poor success rates, which impedes their broad use for translational research applications. Along with the necessity to improve culture conditions, there is a need to identify factors influencing outcomes and to determine how to assess success versus failure in organoid generation. In the present study, we report our unbiased efforts to generate PDOs from a cohort of 81 PCa specimens with diverse pathological and clinical features. We comprehensively analyzed histological features of each enrolled sample (Gleason score, tumor content, proliferation index) and correlated them with organoid growth patterns. We identified improved culture conditions favoring the generation of PCa organoids, yet no specific intrinsic tumor feature was broadly associated with sustained organoid growth. In addition, we performed phenotypic and molecular characterization of tumor-organoid pairs using immunohistochemistry, immunofluorescence, fluorescence in situ hybridization, and targeted sequencing. Morphological and immunohistochemical profiles of whole organoids altogether provided a fast readout to identify the most promising ones. Notably, primary samples were associated with an initial take-rate of 83% (n = 60/72) in culture, with maintenance of cancer cells displaying common PCa alterations, such as PTEN loss and ERG overexpression. These cancer organoids were, however, progressively overgrown by organoids with a benign-like phenotype. Finally, out of nine metastasis samples, we generated a novel organoid model derived from a hormone-naïve lung metastasis, which displays alterations in the PI3K/Akt and Wnt/ß-catenin pathways and responds to androgen deprivation. Taken together, our comprehensive study explores determinants of outcome and highlights the opportunities and challenges associated with the establishment of stable tumor organoid lines derived from PCa patients. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Laser Vaporization of the Prostate With the 180-W XPS-Greenlight Laser in Patients With Ongoing Platelet Aggregation Inhibition and Oral Anticoagulation.

OBJECTIVE: To characterize the safety and efficacy of the 180-W XPS-Greenlight laser in patients on systemic anticoagulation. MATERIALS AND METHODS: A retrospective analysis of 384 patients who underwent photoselective vaporization of the prostate with the 180-W XPS-laser between 2010 and 2013 at two centers in the United States and Switzerland was performed. The primary outcome was the intraoperative and postoperative complication rates for those on anticoagulation undergoing photoselective vaporization of the prostate. The secondary outcome was International Prostate Symptom Scores, postvoid residual, maximum flow rate, and prostate-specific antigen levels. RESULTS: Of 384 patients, aspirin, clopidogrel, and warfarin were used in 146 (38%), 34 (8.9%), and 57 (14.8%) patients, respectively. Single-drug, two-drug, and three-drug combinations were used in 142 (35.5%), 37 (9.3%), and 7 (1.7%) of the cases. Median lasing time (39 min vs 36 min; P = .99) and number of fibers used (1.0 vs 1.0; P = .63) were comparable between patients on vs off systemic anticoagulation. Postoperatively, urinary symptoms (International Prostate Symptom Score, quality of life) and objective voiding parameters (maximum flow rate, postvoid residual) improved in both groups of patients. During a maximum follow-up of 2 years, patients on vs off systemic anticoagulation did not show any significant differences in the rate of postoperative urinary tract infection (3.8% vs 5.1%; P = .71), retention (5.1% vs 5.9%; P = .71), urethral stricture (1.5% vs none, P = .05), and reoperation (2.2% vs 1.5%; P = .49). The primary limitation is the retrospective nature of the study. CONCLUSION: Photovaporization of the prostate with the 180-W XPS-laser is a safe and effective minimal-invasive treatment option for patients on systemic anticoagulation.

Early development of human lymphomas in a prostate cancer xenograft program using triple knock-out immunocompromised mice.

BACKGROUND: There is an urgent need for preclinical models of prostate cancer; however, clinically relevant patient-derived prostate cancer xenografts (PDXs) are demanding to establish. METHODS: Sixty-seven patients who were undergoing palliative transurethral surgery or radical prostatectomy for histologically confirmed, clinically relevant prostate cancer were included in the study. Fresh prostate cancer tissue was identified by frozen analysis in 48 patients. The cancer tissue was transplanted subcutaneously and under the renal capsule of NSG and NOG mice supplemented with human testosterone. All growing PDXs were evaluated by histology and immunohistochemistry. RESULTS: Early assessment of the animals at least three months after transplantation included 27/48 (56.3%) eligible PDX cohorts. PDX growth was detected in 10/27 (37%) mouse cohorts. Eight of the ten PDXs were identified as human donor derived lymphomas, including seven Epstein Barr virus (EBV)-positive diffuse large B-cell lymphomas and one EBV-negative peripheral T-cell lymphoma. One sample consisted of benign prostatic tissue, and one sample comprised a benign epithelial cyst. Prostate cancer was not detected in any of the samples. CONCLUSIONS: Tumors that arise within the first three months after prostate cancer xenografting may represent patient-derived EBV-positive lymphomas in up to 80% of the early growing PDXs when using triple knockout NSG immunocompromised mice. Therefore, lymphoma should be excluded in prostate cancer xenografts that do not resemble typical prostatic adenocarcinoma.