Prediction of Clinically Significant Prostate Cancer by a Specific Collagen-related Transcriptome, Proteome, and Urinome Signature.

BACKGROUND AND OBJECTIVE: While collagen density has been associated with poor outcomes in various cancers, its role in prostate cancer (PCa) remains elusive. Our aim was to analyze collagen-related transcriptomic, proteomic, and urinome alterations in the context of detection of clinically significant PCa (csPCa, International Society of Urological Pathology [ISUP] grade group ≥2). METHODS: Comprehensive analyses for PCa transcriptome (n = 1393), proteome (n = 104), and urinome (n = 923) data sets focused on 55 collagen-related genes. Investigation of the cellular source of collagen-related transcripts via single-cell RNA sequencing was conducted. Statistical evaluations, clustering, and machine learning models were used for data analysis to identify csPCa signatures. KEY FINDINGS AND LIMITATIONS: Differential expression of 30 of 55 collagen-related genes and 34 proteins was confirmed in csPCa in comparison to benign prostate tissue or ISUP 1 cancer. A collagen-high cancer cluster exhibited distinct cellular and molecular characteristics, including fibroblast and endothelial cell infiltration, intense extracellular matrix turnover, and enhanced growth factor and inflammatory signaling. Robust collagen-based machine learning models were established to identify csPCa. The models outcompeted prostate-specific antigen (PSA) and age, showing comparable performance to multiparametric magnetic resonance imaging (mpMRI) in predicting csPCa. Of note, the urinome-based collagen model identified four of five csPCa cases among patients with Prostate Imaging-Reporting and Data System (PI-IRADS) 3 lesions, for which the presence of csPCa is considered equivocal. The retrospective character of the study is a limitation. CONCLUSIONS AND CLINICAL IMPLICATIONS: Collagen-related transcriptome, proteome, and urinome signatures exhibited superior accuracy in detecting csPCa in comparison to PSA and age. The collagen signatures, especially in cases of ambiguous lesions on mpMRI, successfully identified csPCa and could potentially reduce unnecessary biopsies. The urinome-based collagen signature represents a promising liquid biopsy tool that requires prospective evaluation to improve the potential of this collagen-based approach to enhance diagnostic precision in PCa for risk stratification and guiding personalized interventions. PATIENT SUMMARY: In our study, collagen-related alterations in tissue, and urine were able to predict the presence of clinically significant prostate cancer at primary diagnosis.

Addressing the unmet needs of women with breast cancer in Mexico: a non-randomised pilot study of the digital ePRO intervention.

OBJECTIVES: This study aimed to explore the acceptability, feasibility, usability, and preliminary effect of an electronic patient-reported outcome (ePRO) intervention for patients with breast cancer in Mexico. DESIGN: We conducted a multimethod non-randomised pilot study. We used a pre-test/post-test design for quantitative assessment of the intervention's effect on patients' supportive care needs and quality of life. We conducted in-depth interviews (IDIs) with participants and healthcare workers to explore the intervention's benefits and barriers and understand its feasibility. PARTICIPANTS: 50 women aged 20-75 diagnosed with stage I-III breast cancer were enrolled within 2 weeks of starting neoadjuvant or adjuvant treatment with chemotherapy or radiotherapy. We excluded illiterate women and those with visual impairment, cognitive disability or severe depression. IDIs were conducted with 18 participants and 10 healthcare providers. SETTING: Oncology services in three public hospitals of the Mexican Social Security Institute. INTERVENTION: The ePRO intervention consisted of a responsive web application for weekly symptom reporting combined with proactive follow-up by nurses guided by predefined clinical algorithms for 6 weeks. RESULTS: 50 women were enrolled out of 66 eligible patients approached (75.8%). All 50 completed the 4-week follow-up assessment (100% retention). Completion of the symptom registry declined from 100% in week 1 to 66% in week 6. Participants experienced decreases in supportive care needs and increased quality of life. The ePRO application was rated highly usable. Participants and health professionals both perceived intervention benefits. Drawbacks included poor fit for women receiving radiotherapy and challenges using the application for women with low digital literacy or experiencing severe symptoms. CONCLUSIONS: This pilot study provided evidence of the high usability and potential efficacy of a web-based ePRO intervention. We revised recruitment during the pilot to include multiple facilities, and we will further revise for the randomised trial to address barriers to successful ePRO implementation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov ID: NCT05925257.

Automatic Skeleton Segmentation in CT Images Based on U-Net.

Bone metastasis, emerging oncological therapies, and osteoporosis represent some of the distinct clinical contexts which can result in morphological alterations in bone structure. The visual assessment of these changes through anatomical images is considered suboptimal, emphasizing the importance of precise skeletal segmentation as a valuable aid for its evaluation. In the present study, a neural network model for automatic skeleton segmentation from bidimensional computerized tomography (CT) slices is proposed. A total of 77 CT images and their semimanual skeleton segmentation from two acquisition protocols (whole-body and femur-to-head) are used to form a training group and a testing group. Preprocessing of the images includes four main steps: stretcher removal, thresholding, image clipping, and normalization (with two different techniques: interpatient and intrapatient). Subsequently, five different sets are created and arranged in a randomized order for the training phase. A neural network model based on U-Net architecture is implemented with different values of the number of channels in each feature map and number of epochs. The model with the best performance obtains a Jaccard index (IoU) of 0.959 and a Dice index of 0.979. The resultant model demonstrates the potential of deep learning applied in medical images and proving its utility in bone segmentation.

Lower baseline testosterone level is related to earlier development of castration resistance in metastatic prostate cancer: a multi-center cohort study.

Purpose: In the era of concurrent combination therapy in metastatic hormone sensitive prostate cancer, the impact of the testosterone level before initiating androgen deprivation therapy on treatment outcome is still uncertain. We aimed to investigate its effect on time-to-castration-resistance in a metastatic hormone sensitive prostate cancer cohort. Methods: This is a multi-center retrospective study of 5 databases from China, Japan, Austria and Spain including 258 metastatic hormone sensitive prostate cancer patients with androgen deprivation therapy initiated between 2002 and 2021. Baseline testosterone was divided into high and low groups using 12 nmol/L as cutoff level. Primary outcome was time-to-castration-resistance. Secondary outcomes were survival functions. Kaplan-Meier method was employed to evaluate the correlation between baseline testosterone and time-to-castration-resistance. Subgroup analysis was performed to elucidate the effect of upfront combination-therapy and metastatic volume. Results: Median age was 72 years. Median follow-up time was 31 months. Median pre-treatment prostate-specific-antigen level was 161 ng/mL. Majority of case were graded as International-Society-of-Urological-Pathology grade 5 (63.6%). 57.8% patients had high volume disease and 69.0% received upfront combination treatment. 44.6% of the cohort developed castration-resistance. The low testosterone group demonstrated shorter mean-time-to-castration-resistance (19.0 vs 22.4 months, p=0.031). The variance was more significant in patients without combination therapy (13.2 vs 26.3 months, p=0.015). Cancer-specific and overall survival were inferior in the low baseline testosterone level group without receiving combination therapy (p=0.001). Conclusions: Lower pre-treatment testosterone level is correlated to shorter time-to-castration resistance and worse survival in metastatic prostate cancer patients without upfront combination therapy. Those with low baseline testosterone should be encouraged to adopt combination therapy to delay progression.

Cold Sintering Enables the Reprocessing of LLZO-Based Composites.

All-solid-state batteries have the potential for enhanced safety and capacity over conventional lithium ion batteries, and are anticipated to dominate the energy storage industry. As such, strategies to enable recycling of the individual components are crucial to minimize waste and prevent health and environmental harm. Here, we use cold sintering to reprocess solid-state composite electrolytes, specifically Mg and Sr doped Li7La3Zr2O12 with polypropylene carbonate (PPC) and lithium perchlorate (LLZO-PPC-LiClO4). The low sintering temperature allows co-sintering of ceramics, polymers and lithium salts, leading to re-densification of the composite structures with reprocessing. Reprocessed LLZO-PPC-LiClO4 exhibits densified microstructures with ionic conductivities exceeding 10-4 S/cm at room temperature after 5 recycling cycles. All-solid-state lithium batteries fabricated with reprocessed electrolytes exhibit a high discharge capacity of 168 mA h g-1 at 0.1 C, and retention of performance at 0.2 C for over 100 cycles. Life cycle assessment (LCA) suggests that recycled electrolytes outperforms the pristine electrolyte process in all environmental impact categories, highlighting cold sintering as a promising technology for recycling electrolytes.

A comparison of whole-mount and conventional sections for pathological mesorectal extension and circumferential resection margin assessment after total mesorectal excision.

INTRODUCTION: The objective of the study is to compare 2 techniques for histological handling of rectal cancer specimens, namely whole-mount in a large block vs conventional sampling using small blocks, for mesorectal pathological assessment of circumferential resection margin status and depth of tumor invasion into the mesorectal fat. METHODS: This is a prospective study including 27 total mesorectal excision specimens of rectal cancer from patients treated for primary rectal carcinoma between 2020 and 2022 in a specialized multidisciplinary Colorectal Unit. For each total mesorectal excision specimen, 2 contiguous representative tumoral slices were selected and comparatively analyzed with whole-mount and small blocks macroscopic dissection techniques, enabling comparison between them in the same surgical specimen. The agreement between the 2 techniques to assess the distance of the tumor from the circumferential resection margin as well as the depth of tumor invasion was evaluated with the Student's t-test for paired samples, Pearson's correlation coefficient, and the Bland-Altman method comparison analysis. RESULTS: Complete mesorectal excision was observed in 8% of cases. Circumferential resection margin involvement was observed in only one case (4 %). The whole-mount and small block techniques obtained similar results when we assessed the distance to the circumferential resection margin (t-test P = 0.8, r = 0.92) and the depth of mesorectal infiltration (t-test P = 0.6, r = 0.95). CONCLUSIONS: Both gross dissection techniques (whole-mount vs multiple small cassettes) are equivalent and reliable to assess the distance to circumferential resection margin and the depth of mesorectal infiltration in the mesorectal fat in rectal cancer staging.

Dysregulation of RNA-Exosome machinery is directly linked to major cancer hallmarks in prostate cancer: Oncogenic role of PABPN1.

Novel biomarkers and therapeutic strategies for prostate-cancer (PCa) are required to overcome its lethal progression. The dysregulation/implication of the RNA-Exosome-complex (REC; cellular machinery controlling the 3'-5'processing/degradation of most RNAs) in different cancer-types, including PCa, is poorly known. Herein, different cellular/molecular/preclinical approaches with human PCa-samples (tissues and/or plasma of 7 independent cohorts), and in-vitro/in-vivo PCa-models were used to comprehensively characterize the REC-profile and explore its role in PCa. Moreover, isoginkgetin (REC-inhibitor) effects were evaluated on PCa-cells. We demonstrated a specific dysregulation of the REC-components in PCa-tissues, identifying the Poly(A)-Binding-Protein-Nuclear 1 (PABPN1) factor as a critical regulator of major cancer hallmarks. PABPN1 is consistently overexpressed in different human PCa-cohorts and associated with poor-progression, invasion and metastasis. PABPN1 silencing decreased relevant cancer hallmarks in multiple PCa-models (proliferation/migration/tumourspheres/colonies, etc.) through the modulation of key cancer-related lncRNAs (PCA3/FALEC/DLEU2) and mRNAs (CDK2/CDK6/CDKN1A). Plasma PABPN1 levels were altered in patients with metastatic and tumour-relapse. Finally, pharmacological inhibition of REC-activity drastically inhibited PCa-cell aggressiveness. Altogether, the REC is drastically dysregulated in PCa, wherein this novel molecular event/mechanism, especially PABPN1 alteration, may be potentially exploited as a novel prognostic and therapeutic tool for PCa.

EASIER: A new model for online learning of minimally invasive surgery skills.

INTRODUCTION: Technology Enhanced Learning (TEL) can provide the tools to safely master minimally invasive surgery (MIS) skills in patient-free environments and receive immediate objective feedback without the constant presence of an instructor. However, TEL-based systems tend to work isolated from one another, focus on different skills, and fail to provide contents without a sound pedagogical background. OBJECTIVE: The objective of this descriptive study is to present in detail EASIER, an innovative TEL platform for surgical and interventional training, as well as the results of its validation. METHODS: EASIER provides a Learning Management System (LMS) for institutions and content creators that can connect and integrate TEL "external assets" (virtual reality simulators, augmented box trainers, augmented videos, etc.) addressing different skills. The platform integrates all skills under an Assessment Module that measures skills' progress in different courses. Finally, it provides content creators with a pedagogical model to scaffold contents while retaining flexibility to approach course design with different training philosophies in mind. Three courses were developed and hosted in the platform to validate it with end-users in terms of usability, performance, learning results in the courses and student self-perception on learning. RESULTS: In total 111 volunteers completed the validation. The study was limited due to the COVID-19 pandemic, which limited access to external assets (virtual reality simulators). Nevertheless, usability was rated with 73.1 in the System Usability Scale. Most positive aspects on performance were easiness to access the platform, easiness to change the configuration and not requiring additional plug-ins to use the platform. The platform was rated above average in the six scales of the User Experience Questionnaire. Overall, student results improved significantly across the three courses (p < 0.05). CONCLUSIONS: This study provides, within its limitations, evidence on the usefulness of the EASIER platform for distance learning of MIS skills. Results show the potential impact of the platform and are an encouraging boost for the future, especially in the aftermath of the COVID-19 pandemic.

LRP10, PGK1 and RPLP0: Best Reference Genes in Periprostatic Adipose Tissue under Obesity and Prostate Cancer Conditions.

Obesity (OB) is a metabolic disorder characterized by adipose tissue dysfunction that has emerged as a health problem of epidemic proportions in recent decades. OB is associated with multiple comorbidities, including some types of cancers. Specifically, prostate cancer (PCa) has been postulated as one of the tumors that could have a causal relationship with OB. Particularly, a specialized adipose tissue (AT) depot known as periprostatic adipose tissue (PPAT) has gained increasing attention over the last few years as it could be a key player in the pathophysiological interaction between PCa and OB. However, to date, no studies have defined the most appropriate internal reference genes (IRGs) to be used in gene expression studies in this AT depot. In this work, two independent cohorts of PPAT samples (n = 20/n = 48) were used to assess the validity of a battery of 15 literature-selected IRGs using two widely used techniques (reverse transcription quantitative PCR [RT-qPCR] and microfluidic-based qPCR array). For this purpose, ΔCt method, GeNorm (v3.5), BestKeeper (v1.0), NormFinder (v.20.0), and RefFinder software were employed to assess the overall trends of our analyses. LRP10, PGK1, and RPLP0 were identified as the best IRGs to be used for gene expression studies in human PPATs, specifically when considering PCa and OB conditions.

Prognostic impact of serum testosterone in metastatic hormone-naive prostate cancer: a systematic review and meta-analysis.

PURPOSE OF REVIEW: In daily practice, there is an unmet medical need for biomarkers that facilitate therapeutic decision-making in the metastatic hormone sensitive prostate cancer (mHSPC) scenario. Although recent studies have highlighted the potential of testosterone as a prognostic and predictive marker in prostate cancer, the evidence is controversial. The objective of this review was to summarize and analyze the scientific evidence regarding the prognostic role of basal testosterone levels in patients with mHSPC. METHODS: A systematic review was performed. Three authors selected the articles from Web of Science, PubMed, Scopus, and Cochrane Library electronic databases. Risk of bias was assessed by the Newcastle Ottawa Scale. RECENT FINDINGS: Most of the selected articles suggest that low testosterone levels before starting hormonal blockade imply a worse prognosis for patients with mHSPC. However, the quality of the evidence is poor, the studies are heterogeneous, and it is not possible to meta-analyze most of the published results. SUMMARY: Testosterone is an accessible and affordable biomarker. If it were correctly demonstrated that it harbors a prognostic and/or predictive role in the mHSPC setting, it could represent an advance in decision-making in these patients. Well designed prospective studies are needed to correctly answer this question.

ProsTAV, a novel blood-based test for biopsy decision management in significant prostate cancer.

BACKGROUND: Current pathways in early diagnosis of prostate cancer (PCa) can lead to unnecessary biopsy procedures. Here, we used telomere analysis to develop and evaluate ProsTAV®, a risk model for significant PCa (Gleason score >6), with the objective of improving the PCa diagnosis pathway. METHODS: This retrospective, multicentric study analyzed telomeres from patients with serum PSA 3-10 ng/mL. High-throughput quantitative fluorescence in-situ hybridization was used to evaluate telomere-associated variables (TAVs) in peripheral blood mononucleated cells. ProsTAV® was developed by multivariate logistics regression based on three clinical variables and six TAVs. The predictive capacity and accuracy of ProsTAV® were summarized by receiver operating characteristic (ROC) curves and its clinical benefit with decision curves analysis. RESULTS: Telomeres from 1043 patients were analyzed. The median age of the patients was 63 years, with a median PSA of 5.2 ng/mL and a percentage of significant PCa of 23.9%. A total of 874 patients were selected for model training and 169 patients for model validation. The area under the ROC curve of ProsTAV® was 0.71 (95% confidence interval [CI], 0.62-0.79), with a sensitivity of 0.90 (95% CI, 0.88-1.0) and specificity of 0.33 (95% CI, 0.24-0.40). The positive predictive value was 0.29 (95% CI, 0.21-0.37) and the negative predictive value was 0.91 (95% CI, 0.83-0.99). ProsTAV® would make it possible to avoid 33% of biopsies. CONCLUSIONS: ProsTAV®, a predictive model based on telomere analysis through TAV, could be used to increase the prediction capacity of significant PCa in patients with PSA between 3 and 10 ng/mL.

M-Health in lung cancer: A literature review.

The internet and digital technology have become an important resource for patients with cancer. Mobile health strategies permit patients and clinicians to interact via different tools to enrich the supplements to routine hospital visits or out-patient attendance. In this work, we have reviewed different mobile health platforms to support lung cancer patients in different areas: pre-surgery; post-surgery and on systemic treatment. We have also reviewed different digital tools used by long-term lung cancer survivors as well as the impact of these tools on the quality of life, and we tried to analyse according to literature the potential efficiency of these platforms in health system administration.

Radiomics analysis of bone marrow biopsy locations in [18F]FDG PET/CT images for measurable residual disease assessment in multiple myeloma.

The combination of visual assessment of whole body [18F]FDG PET images and evaluation of bone marrow samples by Multiparameter Flow Cytometry (MFC) or Next-Generation Sequencing (NGS) is currently the most common clinical practice for the detection of Measurable Residual Disease (MRD) in Multiple Myeloma (MM) patients. In this study, radiomic features extracted from the bone marrow biopsy locations are analyzed and compared to those extracted from the whole bone marrow in order to study the representativeness of these biopsy locations in the image-based MRD assessment. Whole body [18F]FDG PET of 39 patients with newly diagnosed MM were included in the database, and visually evaluated by experts in nuclear medicine. A methodology for the segmentation of biopsy sites from PET images, including sternum and posterior iliac crest, and their subsequent quantification is proposed. First, starting from the bone marrow segmentation, a segmentation of the biopsy sites is performed. Then, segmentations are quantified extracting SUV metrics and radiomic features from the [18F]FDG PET images and are evaluated by Mann-Whitney U-tests as valuable features differentiating PET+/PET- and MFC+ /MFC- groups. Moreover, correlation between whole bone marrow and biopsy sites is studied by Spearman ρ rank. Classification performance of the radiomics features is evaluated applying seven machine learning algorithms. Statistical analyses reveal that some images features are significant in PET+/PET- differentiation, such as SUVmax, Gray Level Non-Uniformity or Entropy, especially with a balanced database where 16 of the features show a p value < 0.001. Correlation analyses between whole bone marrow and biopsy sites results in significant and acceptable coefficients, with 11 of the variables reaching a correlation coefficient greater than 0.7, with a maximum of 0.853. Machine learning algorithms demonstrate high performances in PET+/PET- classification reaching a maximum AUC of 0.974, but not for MFC+/MFC- classification. The results demonstrate the representativeness of sample sites as well as the effectiveness of extracted features (SUV metrics and radiomic features) from the [18F]FDG PET images in MRD assessment in MM patients.

NMR and GPC Analysis of Alkyd Resins: Influence of Synthesis Method, Vegetable Oil and Polyol Content.

Alkyd resins are oil-based polymers that have been widely used for generations in the surface coating industry and beyond. Characterization of these resins is of high importance to understand the influence of its components on its behavior, compatibility with other resins, and final quality to ensure high durability. Here, NMR spectroscopy and GPC were used for characterizing differences in the chemical structure, molecular distribution, and dispersity between oil-based and fatty acid-based alkyd polymers made from sacha inchi and linseed oils. Sancha inchi (Plukentia volubilis L.) is a fruit-bearing plant native to South America and the Caribbean, and has a rich unsaturated fatty acid content. The effect of vegetable oil and polyol selection on the synthesis of alkyd resins for coating applications was analyzed. The influence of two different synthesis methods, monoglyceride and fatty acid processes, was also compared. Important structural differences were observed using NMR: one-dimensional spectra revealed the degree of unsaturated fatty acid chains along the polyester backbone, whereas, 2D NMR experiments facilitated chemical shift assignments of all signals. GPC analysis suggested that alkyd resins with homogeneous and high molecular weights can be obtained with the fatty acid process, and that resins containing pentaerythritol may have uniform chain lengths.

Clinical utility of checkpoint inhibitors against metastatic bladder cancer: overcoming challenges to find a way forward.

INTRODUCTION: Cisplatin-based chemotherapy is currently considered the gold-standard treatment for metastatic urothelial carcinoma (mUC). Nevertheless, most mUC patients develop resistance to chemotherapy. Immune checkpoint inhibitors (ICI) have emerged as a therapeutic option for mUC. ICI are used as both first- and second-line therapy for patients with mUC but also for maintenance following chemotherapy and durable responses may be expected in these settings. AREAS COVERED: Patients with mUC who experience progression after platinum-based chemotherapy regimens, those who are cisplatin-ineligible and have positive PD-L1 expression, and those who are platinum-ineligible, regardless of PD-L1 status, are the target population. The role of ICI monotherapy or drug combinations and newer proposals for mUC therapy are reviewed. The current status of biomarkers to guide ICI treatments in mUC is also provided, focusing on PD-L1, tumor mutational load, and liquid biopsies using ctDNA. EXPERT OPINION: Current challenges to improve the role of ICI in mUC could be summarized as i) development of better drugs; ii) advances in drug-combinations schemes; iii) development of novel biomarkers and techniques to better select patients for this treatment; iv) providing the drugs in the optimal clinical setting; v) promoting trials covering more demographic and clinical heterogeneity (i.e. wider age range, gender, and diverse clinical representation).

Risk Classification of Bladder Cancer by Gene Expression and Molecular Subtype.

This study evaluated a panel including the molecular taxonomy subtype and the expression of 27 genes as a diagnostic tool to stratify bladder cancer patients at risk of aggressive behavior, using a well-characterized series of non-muscle invasive bladder cancer (NMIBC) as well as muscle-invasive bladder cancer (MIBC). The study was conducted using the novel NanoString nCounter gene expression analysis. This technology allowed us to identify the molecular subtype and to analyze the gene expression of 27 bladder-cancer-related genes selected through a recent literature search. The differential gene expression was correlated with clinicopathological variables, such as the molecular subtypes (luminal, basal, null/double negative), histological subtype (conventional urothelial carcinoma, or carcinoma with variant histology), clinical subtype (NMIBC and MIBC), tumor stage category (Ta, T1, and T2-4), tumor grade, PD-L1 expression (high vs. low expression), and clinical risk categories (low, intermediate, high and very high). The multivariate analysis of the 19 genes significant for cancer-specific survival in our cohort study series identified TP53 (p = 0.0001), CCND1 (p = 0.0001), MKI67 (p < 0.0001), and molecular subtype (p = 0.005) as independent predictors. A scoring system based on the molecular subtype and the gene expression signature of TP53, CCND1, or MKI67 was used for risk assessment. A score ranging from 0 (best prognosis) to 7 (worst prognosis) was obtained and used to stratify our patients into two (low [score 0-2] vs. high [score 3-7], model A) or three (low [score 0-2] vs. intermediate [score 3-4] vs. high [score 5-7], model B) risk categories with different survival characteristics. Mean cancer-specific survival was longer (122 + 2.7 months) in low-risk than intermediate-risk (79.4 + 9.4 months) or high-risk (6.2 + 0.9 months) categories (p < 0.0001; model A); and was longer (122 + 2.7 months) in low-risk than high-risk (58 + 8.3 months) (p < 0.0001; model B). In conclusion, the molecular risk assessment model, as reported here, might be used better to select the appropriate management for patients with bladder cancer.

The role of multiparametric magnetic resonance in active surveillance of a low-risk prostate cancer cohort from clinical practice.

INTRODUCTION: Active surveillance (AS) is considered a suitable management practice for those patients with low-risk prostate cancer (PCa). At present, however, the role of multiparametric magnetic resonance imaging (mpMRI) in AS protocols has not yet been clearly established. OUTCOMES: To determine the role of mpMRI and its ability to detect significant prostate cancer (SigPCa) in PCa patients enrolled in AS protocols. MATERIALS AND METHODS: There were 229 patients enrolled in an AS protocol between 2011 and 2020 at Reina Sofía University Hospital. MRI interpretation was based on PIRADS v.1 or v.2/2.1 classification. Demographics, clinical, and analytical data were collected and analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for mpMRI in different scenarios. We defined SigPCa and reclassification/progression as a Gleason score (GS) ≥ 3 + 4, a clinical stage ≥T2b, or an increase in PCa volume. Kaplan-Meier and log-rank tests were used to estimate progression-free survival time. RESULTS: Median age was 69.02 (±7.73) at diagnosis, with a 0.15 (±0.08) PSA density (PSAD). Eighty-six patients were reclassified after confirmatory biopsy, with a suspicious mpMRI an indication for a clear reclassification and risk-predictor factor in disease progression (p < 0.05). During follow-up, 46 patients were changed from AS to active treatment mainly due to disease progression. Ninety patients underwent ≥2mpMRI during follow-up, with a median follow-up of 29 (15-49) months. Thirty-four patients had a baseline suspicious mpMRI (at diagnostic or confirmatory biopsy): 14 patients with a PIRADS 3 and 20 patients with ≥PIRADS 4. From 14 patients with a PIRADS 3 baseline mpMRI, 29% progressed radiologically, with a 50% progression rate versus 10% (1/10 patients) for those with similar or decreased mpMRI risk. Of the 56 patients with a non-suspicious baseline mpMRI (PIRADS < 2), 14 patients (25%) had an increased degree of radiological suspicion, with a detection rate of SigPCa of 29%. The mpMRI NPV during follow-up was 0.91. CONCLUSION: A suspicious mpMRI increases the reclassification and disease progression risk during follow-up and plays an important role in monitoring biopsies. In addition, a high NPV at mpMRI follow-up can help to decrease the need to monitor biopsies during AS.

Mass Spectrometry-Based Biomarkers to Detect Prostate Cancer: A Multicentric Study Based on Non-Invasive Urine Collection without Prior Digital Rectal Examination.

(1) Background: Prostate cancer (PCa) is the most frequently diagnosed cancer in men. Wide application of prostate specific antigen test has historically led to over-treatment, starting from excessive biopsies. Risk calculators based on molecular and clinical variables can be of value to determine the risk of PCa and as such, reduce unnecessary and invasive biopsies. Urinary molecular studies have been mostly focusing on sampling after initial intervention (digital rectal examination and/or prostate massage). (2) Methods: Building on previous proteomics studies, in this manuscript, we aimed at developing a biomarker model for PCa detection based on urine sampling without prior intervention. Capillary electrophoresis coupled to mass spectrometry was applied to acquire proteomics profiles from 970 patients from two different clinical centers. (3) Results: A case-control comparison was performed in a training set of 413 patients and 181 significant peptides were subsequently combined by a support vector machine algorithm. Independent validation was initially performed in 272 negative for PCa and 138 biopsy-confirmed PCa, resulting in an AUC of 0.81, outperforming current standards, while a second validation phase included 147 PCa patients. (4) Conclusions: This multi-dimensional biomarker model holds promise to improve the current diagnosis of PCa, by guiding invasive biopsies.

Pleomorphic giant cell carcinoma of the prostate: clinicopathologic analysis and oncological outcomes.

We report on the clinicopathologic features of 27 pleomorphic giant cell carcinoma (PGCC) cases of the prostate identified in 20 patients with an age range of 51 to 84 years (68 ± 9; median 71 years). Charlson comorbidity index ranged from 3 to 12. Serum PSA ranged from 4.30 to 662 ng/mL (median 13 ng/mL). On histologic examination, bizarre giant cells with pleomorphic nuclei characterized pleomorphic giant cell carcinoma of the prostate. PGCC component was present in 5% to 100%, with half of the patients presenting with ≥ 20%. Half of the patients initially presented with T4 and 26% with T3 disease. All patients were considered Gleason scores of 9 to 10 (ISUP grade 5). A combination of hormone therapy with chemotherapy with or without radiation therapy was applied in 68% of patients. On follow-up, 14 patients (52%) were alive with disease (1-69 months) or dead of disease (1-38 months). Patients diagnosed earlier with lower TNM stage had longer survival than those diagnosed at a later T-stage or with metastatic disease (p = 0.02). The percentage of PGCC was not related to survival in the current study. Molecular alterations in 3 samples showed a microsatellite-stable disease with low tumor mutation burden and variable PTEN, PTCH1, KDM6A, ARv7, and PIK3CA loss/alteration, TP53 mutation, TMPRSS2-ERG fusion, and MYC, PIK3CB, RICTOR, or IRS2 amplification. Our findings suggest that PGCC is a rare and aggressive subtype of prostate carcinoma whose recognition may steer clinicians to adopt more aggressive treatments and investigate new therapeutic strategies.

Tumor suppressor role of RBM22 in prostate cancer acting as a dual-factor regulating alternative splicing and transcription of key oncogenic genes.

Prostate cancer (PCa) is one of the leading causes of cancer-related deaths among men. Consequently, the identification of novel molecular targets for treatment is urgently needed to improve patients' outcomes. Our group recently reported that some elements of the cellular machinery controlling alternative-splicing might be useful as potential novel therapeutic tools against advanced PCa. However, the presence and functional role of RBM22, a key spliceosome component, in PCa remains unknown. Therefore, RBM22 levels were firstly interrogated in 3 human cohorts and 2 preclinical mouse models (TRAMP/Pbsn-Myc). Results were validated in in silico using 2 additional cohorts. Then, functional effects in response to RBM22 overexpression (proliferation, migration, tumorspheres/colonies formation) were tested in PCa models in vitro (LNCaP, 22Rv1, and PC-3 cell-lines) and in vivo (xenograft). High throughput methods (ie, RNA-seq, nCounter PanCancer Pathways Panel) were performed in RBM22 overexpressing cells and xenograft tumors. We found that RBM22 levels were down-regulated (mRNA and protein) in PCa samples, and were inversely associated with key clinical aggressiveness features. Consistently, a gradual reduction of RBM22 from non-tumor to poorly differentiated PCa samples was observed in transgenic models (TRAMP/Pbsn-Myc). Notably, RBM22 overexpression decreased aggressiveness features in vitro, and in vivo. These actions were associated with the splicing dysregulation of numerous genes and to the downregulation of critical upstream regulators of cell-cycle (i.e., CDK1/CCND1/EPAS1). Altogether, our data demonstrate that RBM22 plays a critical pathophysiological role in PCa and invites to suggest that targeting negative regulators of RBM22 expression/activity could represent a novel therapeutic strategy to tackle this disease.