OBJECTIVES: Radical prostatectomy (RP) is a common intervention in patients with localized prostate cancer (PCa), with nerve-sparing RP recommended to reduce adverse effects on patient quality of life. Accurate pre-operative detection of extraprostatic extension (EPE) remains challenging, often leading to the application of suboptimal treatment. The aim of this study was to enhance pre-operative EPE detection through multimodal data integration using explainable machine learning (ML). METHODS: Patients with newly diagnosed PCa who underwent [68Ga]Ga-PSMA-11 PET/MRI and subsequent RP were recruited retrospectively from two time ranges for training, cross-validation, and independent validation. The presence of EPE was measured from post-surgical histopathology and predicted using ML and pre-operative parameters, including PET/MRI-derived features, blood-based markers, histology-derived parameters, and demographic parameters. ML models were subsequently compared with conventional PET/MRI-based image readings. RESULTS: The study involved 107 patients, 59 (55%) of whom were affected by EPE according to postoperative findings for the initial training and cross-validation. The ML models demonstrated superior diagnostic performance over conventional PET/MRI image readings, with the explainable boosting machine model achieving an AUC of 0.88 (95% CI 0.87-0.89) during cross-validation and an AUC of 0.88 (95% CI 0.75-0.97) during independent validation. The ML approach integrating invasive features demonstrated better predictive capabilities for EPE compared to visual clinical read-outs (Cross-validation AUC 0.88 versus 0.71, p = 0.02). CONCLUSION: ML based on routinely acquired clinical data can significantly improve the pre-operative detection of EPE in PCa patients, potentially enabling more accurate clinical staging and decision-making, thereby improving patient outcomes. CRITICAL RELEVANCE STATEMENT: This study demonstrates that integrating multimodal data with machine learning significantly improves the pre-operative detection of extraprostatic extension in prostate cancer patients, outperforming conventional imaging methods and potentially leading to more accurate clinical staging and better treatment decisions. KEY POINTS: Extraprostatic extension is an important indicator guiding treatment approaches. Current assessment of extraprostatic extension is difficult and lacks accuracy. Machine learning improves detection of extraprostatic extension using PSMA-PET/MRI and histopathology.
- Publikační typ
- časopisecké články MeSH
Purpose: This study aims to assess whole-mount Gleason grading (GG) in prostate cancer (PCa) accurately using a multiomics machine learning (ML) model and to compare its performance with biopsy-proven GG (bxGG) assessment. Materials and Methods: A total of 146 patients with PCa recruited in a pilot study of a prospective clinical trial (NCT02659527) were retrospectively included in the side study, all of whom underwent 68Ga-PSMA-11 integrated positron emission tomography (PET) / magnetic resonance (MR) before radical prostatectomy (RP) between May 2014 and April 2020. To establish a multiomics ML model, we quantified PET radiomics features, pathway-level genomics features from whole exome sequencing, and pathomics features derived from immunohistochemical staining of 11 biomarkers. Based on the multiomics dataset, five ML models were established and validated using 100-fold Monte Carlo cross-validation. Results: Among five ML models, the random forest (RF) model performed best in terms of the area under the curve (AUC). Compared to bxGG assessment alone, the RF model was superior in terms of AUC (0.87 vs 0.75), specificity (0.72 vs 0.61), positive predictive value (0.79 vs 0.75), and accuracy (0.78 vs 0.77) and showed slightly decreased sensitivity (0.83 vs 0.89) and negative predictive value (0.80 vs 0.81). Among the feature categories, bxGG was identified as the most important feature, followed by pathomics, clinical, radiomics and genomics features. The three important individual features were bxGG, PSA staining and one intensity-related radiomics feature. Conclusion: The findings demonstrate a superior assessment of the developed multiomics-based ML model in whole-mount GG compared to the current clinical baseline of bxGG. This enables personalized patient management by identifying high-risk PCa patients for RP.
- MeSH
- genomika metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- magnetická rezonanční tomografie metody MeSH
- multiomika MeSH
- nádory prostaty * chirurgie patologie genetika diagnostické zobrazování MeSH
- pilotní projekty MeSH
- pozitronová emisní tomografie metody MeSH
- prospektivní studie MeSH
- prostatektomie * metody MeSH
- retrospektivní studie MeSH
- senioři MeSH
- strojové učení * MeSH
- stupeň nádoru * MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
Current standard-of-care systemic therapy options for locally advanced and metastatic bladder cancer (BC), which are predominantly based on cisplatin-gemcitabine combinations, are limited by significant treatment failure rates and frailty-based patient ineligibility. We previously addressed the urgent clinical need for better-tolerated BC therapeutic strategies using a drug screening approach, which identified outstanding antineoplastic activity of clofarabine in preclinical models of BC. To further assess clofarabine as a potential BC therapy component, we conducted head-to-head comparisons of responses to clofarabine versus gemcitabine in preclinical in vitro and in vivo models of BC, complemented by in silico analyses. In vitro data suggest a distinct correlation between the two antimetabolites, with higher cytotoxicity of gemcitabine, especially against several nonmalignant cell types, including keratinocytes and endothelial cells. Accordingly, tolerance of clofarabine (oral or intraperitoneal application) was distinctly better than for gemcitabine (intraperitoneal) in patient-derived xenograft models of BC. Clofarabine also exhibited distinctly superior anticancer efficacy, even at dosing regimens optimized for gemcitabine. Neither complete remission nor cure, both of which were observed with clofarabine, were achieved with any tolerable gemcitabine regimen. Taken together, our findings demonstrate that clofarabine has a better therapeutic window than gemcitabine, further emphasizing its potential as a candidate for drug repurposing in BC. PATIENT SUMMARY: We compared the anticancer activity of clofarabine, a drug used for treatment of leukemia but not bladder cancer, and gemcitabine, a drug currently used for chemotherapy against bladder cancer. Using cell cultures and mouse models, we found that clofarabine was better tolerated and more efficacious than gemcitabine, and even cured implanted tumors in mouse models. Our results suggest that clofarabine, alone or in combination schemes, might be superior to gemcitabine for the treatment of bladder cancer.
- MeSH
- deoxycytidin * analogy a deriváty farmakologie terapeutické užití MeSH
- gemcitabin * MeSH
- klofarabin * terapeutické užití farmakologie MeSH
- lidé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory močového měchýře * farmakoterapie patologie MeSH
- protinádorové antimetabolity terapeutické užití farmakologie MeSH
- xenogenní modely - testy protinádorové aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
BACKGROUND: Depending on the risk of LN metastasis ePLND at RP is recommended. As ePLND has potential side effects, and diagnostics have improved substantially, our objective was to evaluate the performance of the Briganti 2019 nomogram in a contemporary cohort with preoperative negative PSMA-PET. METHODS: Patients with intermediate- and high-risk prostate cancer (CaP), undergoing RP and ePND at our center with preoperative negative [68Ga]Ga-PSMA-11 PET were included. The Accuracy of the nomogram was assessed using ROC analysis. The association of clinical parameters with the presence of LN metastasis was assessed using logistic regression. Specimen of prostate and LNs in patients with false negative PSMA-PET were additionally stained for AR and PSMA expression and assessed by IHC. RESULTS: The study included 108 patients, 28% intermediate- and 72% high-risk. Twelve patients harbored occult LN metastasis. Accuracy of the nomogram was 0.62. [68Ga]Ga-PSMA-11 PET showed a NPV of 89%. IHC showed expression of PSMA and AR in the primary and LN metastasis in all patients. On logistic regression analysis only DRE (OR 2.72; 95%CI 1.01-7.35; P = 0.05) and percentage of cores with significant CaP (OR 1.29; 95%CI 1.05-1.60; P = 0.02) showed a significant association with LN metastasis. CONCLUSION: The currently used nomogram is suboptimal in detecting patients with occult LNM. While the cut-off value to perform ePLND can be increased slightly following a negative PSMA-PET scan, more accurate methods of identifying these patients are needed. Whether ePLND can have a therapeutic benefit, as opposed to a diagnostic only, needs to be re-evaluated in the PSMA-PET era.
PURPOSE OF REVIEW: The most common prostatic cancers (PCa) are acinary adenocarcinomas. Histological subtypes have been variably defined. The purpose of this review is to discuss unusual histological patterns and subtypes of acinar adenocarcinoma, as well as other types of PCa and their prognostic and therapeutic relevance. RECENT FINDINGS: The new term 'subtype' for morphologically defined tumor entities replaced the term 'variant' in the new 2022 classification of the WHO to allow for clear terminological distinction from genetic variants. The 2022 WHO classification mentions prostatic intraepithelial neoplasia (PIN)-like carcinoma, signet-cell-like adenocarcinoma, sarcomatoid carcinoma and pleomorphic-giant-cell adenocarcinoma of the prostate as true subtypes of acinary PCa. Other forms of acinary PCa are termed unusual histological patterns and include atrophic, foamy-cell, microcystic, pseudohyperplastic and mucinous patterns. Nonacinar forms of prostate cancer include other glandular PCa, the ductal adenocarcinoma and the treatment-associated neuroendocrine carcinoma, and nonglandular PCa, the adenosquamous carcinoma, the squamous cell carcinoma and the adenoid cystic (basal cell) carcinoma of the prostate. SUMMARY: True subtypes of acinary PCa and other forms of glandular and nonglandular PCa show relevant differences in prognosis and treatment approach compared with classic acinary PCa. The relevance of unusual histological patterns mainly lies in their deceptive benign appearance and the need for pathologists to know about these entities for accurate and timely diagnosis.
- MeSH
- adenokarcinom * patologie MeSH
- lidé MeSH
- nádory prostaty * patologie terapie MeSH
- prostata patologie MeSH
- prostatická intraepiteliální neoplazie * patologie MeSH
- spinocelulární karcinom * patologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
PURPOSE OF REVIEW: Due to the limited number of cases, there are no guidelines for basal cell carcinoma (BCC) of the prostate. This review combines an unpublished case report of a 55-year-old patient with BCC with an assessment of the latest literature. RECENT FINDINGS: BCC of the prostate has previously been described in only approximately 140 cases. We describe the diagnostic process, including the uropathological and DNA-sequencing results, which allowed us to start an experimental treatment with pemigatinib. BCC of the prostate is associated with an aggressive biological and clinical behavior, such as recurrence and metastasis. Several immunohistochemical stainings are available to differentiate BCC from adenocarcinoma of the prostate. Based on pathology and results from next-generation sequencing (NGS), patients can be offered targeted therapies. SUMMARY: With the aid of histological work-up and immunostaining, prostatic BCC can be accurately diagnosed. Our patient underwent radical prostatectomy and staged extended lymphadenectomy due to lymph node recurrence. The patient subsequently developed progressive disease and was treated with the FGFR-inhibitor pemigatinib. The patient's liver metastasis significantly responded. The present case confirms the possibility of aggressive behavior of prostatic BCC and highlights the importance of a thorough uropathological and molecular biological analysis with a precision medicine strategy.
- MeSH
- bazocelulární karcinom * diagnóza patologie chirurgie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfadenektomie MeSH
- morfoliny MeSH
- nádory kůže * chirurgie MeSH
- nádory prostaty * diagnóza farmakoterapie genetika MeSH
- prostata patologie MeSH
- prostatektomie MeSH
- pyrimidiny MeSH
- pyrroly MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- přehledy MeSH
BACKGROUND: The heterogeneity of bladder cancers (BCs) is a major challenge for the development of novel therapies. However, given the high rates of recurrence and/or treatment failure, the identification of effective therapeutic strategies is an urgent clinical need. OBJECTIVE: We aimed to establish a model system for drug identification/repurposing in order to identify novel therapies for the treatment of BC. DESIGN, SETTING, AND PARTICIPANTS: A collection of commercially available BC cell lines (n = 32) was comprehensively characterized. A panel of 23 cell lines, representing a broad spectrum of BC, was selected to perform a high-throughput drug screen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Positive hits were defined as compounds giving >50% inhibition in at least one BC cell line. RESULTS AND LIMITATIONS: Amongst >1700 tested chemical compounds, a total of 471 substances exhibited antineoplastic effects. Clofarabine, an antimetabolite drug used as third-line treatment for childhood acute lymphoblastic leukaemia, was amongst the limited number of drugs with inhibitory effects on cell lines of all intrinsic subtypes. We, thus, reassessed the substance and confirmed its inhibitory effects on commercially available cell lines and patient-derived cell cultures representing various disease stages, intrinsic subtypes, and histologic variants. To verify these effects in vivo, a patient-derived cell xenograft model for urothelial carcinoma (UC) was used. Well-tolerated doses of clofarabine induced complete remission in all treated animals (n = 12) suffering from both early- and late-stage disease. We further took advantage of another patient-derived cell xenograft model originating from the rare disease entity sarcomatoid carcinoma (SaC). Similarly to UC xenograft mice, clofarabine induced subcomplete to complete tumour remissions in all treated animals (n = 8). CONCLUSIONS: The potent effects of clofarabine in vitro and in vivo suggest that our findings may be of high clinical relevance. Clinical trials are needed to assess the value of clofarabine in improving BC patient care. PATIENT SUMMARY: We used commercially available cell lines for the identification of novel drugs for the treatment of bladder cancer. We confirmed the effects of one of these drugs, clofarabine, in patient-derived cell lines and two different mouse models, thereby demonstrating a potential clinical relevance of this substance in bladder cancer treatment.
- MeSH
- akutní lymfatická leukemie * farmakoterapie metabolismus MeSH
- časná detekce nádoru MeSH
- karcinom z přechodných buněk * MeSH
- klofarabin terapeutické užití MeSH
- lidé MeSH
- myši MeSH
- nádory močového měchýře * patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
