Real-life Data on First- and Second-Line Treatment of Metastatic Castration-Resistant Prostate Cancer With Abiraterone, Enzalutamide and Cabazitaxel - A multicentric Study From Portugal.

INTRODUCTION AND OBJECTIVES: New drugs for metastatic castrate resistant prostate cancer (mCRPC) were approved, first in the pos-docetaxel and then in the pre-docetaxel setting. We aim to assess the real daily practice benefit of abiraterone (Abi), enzalutamide (Enz) and cabazitaxel (Cab) in patients with mCRPC, compare it with RCT results and compare Abi vs Enz. MATERIALS AND METHODS: We retrospectively collected the data of all consecutive mCRPC patients treated with Abi, Enz or Cab in the six major oncological hospitals in the north of Portugal until December 2020. RESULTS: A total of 470 treatments pre-docetaxel (163 Abi and 307 Enz) and 373 pos-docetaxel (160 Abi, 148 Enz and 59 Cab) were included, with median follow-up time of 35 months. Mean age was 73.1, 84.4% had ECOG status < 2, ISUP grade was ≥ 4 in 59% and 28.0% had oligometastatic disease. In first line, for Abi and for Enz respectively, the proportion of patients with PSA reduction > 50% was 64.4% and 80.4% (P < .001), the mean duration of treatment (DT) was 10 and 14 months (P = .037) and the median overall survival (OS) was 25 months and 30 months (P = .17). In second line the results for Abi, Enz and Cab were respectively: proportion of patients with PSA reduction > 50% was 40.4%, 57.4% and 24.6% (p for Abi vs Enz=0.004); DT was 7, 8, and 3 months (p for Abi vs Enz = 0.27); OS was 17, 22 and 10 months (p for Abi vs. Enz = 0,07). CONCLUSION: These drugs have good efficacy in real-world evidence, similar to those reported in randomized clinical trials, with the expected exception of lower OS due to the inclusion of a broader sample of patients. Our results add to the evidence that Enz might have better efficacy in this setting compared with Abi.

Intraductal Prostate Cancer Affinity for Lymphatic-Predominant Metastases Through 18F-DCFPyL‒Prostate-Specific Membrane Antigen‒Positron Emission Tomography/CT Scans in Pretreatment Prostate Cancer Patients.

PURPOSE: Intraductal prostate cancer (IDC) is linked to unfavorable oncologic outcomes, marked by distinctive cellular intrinsic pathway changes and intricate immunosuppressive microenvironments that could impact the way cancer spreads. The aim of this study was to determine whether the presence of IDC in prostate biopsy specimens obtained from patients before primary prostate cancer (PCa) treatment is associated with a lymph node metastatic propensity in prostate-specific membrane antigen (PSMA)‒positron emission tomography (PET)/CT. MATERIALS AND METHODS: This was a cross-sectional analysis of all PCa patients undergoing a pretreatment 18F-DCFPyL-PSMA-PET/CT between January 1, 2016, and August 2021 at The Princess Margaret Cancer Centre. Outcomes were presence of any metastasis in the overall cohort, presence of lymphatic vs no metastases, and presence of lymphatic vs bone metastasis among patients who underwent PSMA-PET/CT as PCa primary staging. The associations between IDC presence on the prostate biopsy and the study outcomes were evaluated using univariable and multivariable logistic regression analyses. RESULTS: The cohort consisted of 120 patients. IDC and cribriform pattern were observed in 55 (46%) and 48 (40%) prostate biopsies, respectively. Overall, 52 patients (43%) had evidence of metastasis. Presence of IDC on biopsy was associated with increased odds of overall metastasis (odds ratio: 2.47, 95% CI: 1.09-5.61, P = .03). Of the 52 patients with evidence of metastasis, 41 (79%) had evidence of lymphatic metastasis. Presence of IDC on biopsy was associated with significantly increased odds of lymphatic metastasis vs nonmetastases (odds ratio: 3.03, 95% CI: 1.24-7.40, P = .01). CONCLUSIONS: The identification of IDC morphology in prostate biopsy specimens has been observed to be significantly linked with lymph node metastasis on 18F-DCFPyL-PET/CT imaging in a PCa pretreatment staging setting. We found that presence of IDC in prostate biopsy appears to be a marker for lymph node metastasis on 18F-DCFPyL-PET/CT.

Using active surveillance for Gleason 7 (3+4) prostate cancer: A narrative review.

The interest in broadening the application of active surveillance (AS) has been increasing, encompassing patients who may not strictly adhere to the conventional criteria for low-risk prostate cancer (PCa), particularly those diagnosed with small-volume Gleason grade group 2 disease. Nonetheless, accurately identifying individuals with low intermediate-risk PCa who can safely undergo AS without facing disease progression remains a challenge.This review aims to delve into the progression of this evolving trend specifically within this cohort of men, while also examining strategies aimed at minimizing irreversible disease advancement. Additionally, we address the criteria for patient selection, recommended followup schedules, and the indicators prompting intervention.

Limitations of Prostate Biopsy in Detection of Cribriform and Intraductal Prostate Cancer.

BACKGROUND: The presence of cribriform morphology and intraductal carcinoma (IDC) in prostate biopsies and radical prostatectomy specimens is an adverse prognostic feature that can be used to guide treatment decisions. OBJECTIVE: To assess how accurately biopsies can detect cribriform morphology and IDC cancer by examining matched biopsy and prostatectomy samples. DESIGN, SETTING, AND PARTICIPANTS: Patients who underwent radical prostatectomy at The Princess Margaret Cancer Centre between January 2015 and December 2022 and had cribriform morphology and/or IDC in the surgical specimen were included in the study. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used detection sensitivity to evaluate the level of agreement between biopsy and prostatectomy samples regarding the presence of cribriform morphology and IDC. RESULTS AND LIMITATIONS: Of the 287 men who underwent radical prostatectomy, 241 (84%) had cribriform morphology and 161 (56%) had IDC on final pathology. The sensitivity of prostate biopsy, using radical prostatectomy as the reference, was 42.4% (95% confidence interval [CI] 36-49%) for detection of cribriform morphology and 44.1% (95% CI 36-52%) for detection of IDC. The sensitivity of prostate biopsy for detection of either IDC or cribriform morphology was 52.5% (95% CI 47-58%). Among patients who underwent multiparametric magnetic resonance imaging-guided biopsies, the sensitivity was 54% (95% CI 39-68%) for detection of cribriform morphology and 37% (95% CI 19-58%) for detection of IDC. CONCLUSIONS: Biopsy has low sensitivity for detecting cribriform morphology and IDC. These limitations should be incorporated into clinical decision-making. Biomarkers for better detection of these histological patterns are needed. PATIENT SUMMARY: Prostate biopsy is not an accurate method for detecting two specific types of prostate cancer cells, called cribriform pattern and intraductal prostate cancer, which are associated with unfavorable prognosis.

Epigenetic alterations in urothelial bladder cancer associated with disease outcomes.

OBJECTIVES: Bladder cancer (BLCA) is a molecular heterogeneous disease with known genetic distinctive signatures. However, DNA methylation is highly prevalent across a wide range of tumors, suggesting its potential in oncogenesis. Here, we aimed to interrogate the role of nine epigenetic alterations as diagnostic and prognostic markers in BLCA. METHODS: DNA methylation, gene expression, and clinicopathological information were retrieved from The Cancer Genome Atlas data portal. Methylation values and gene expression were assessed to determine their association with normal and malignant tissue. Additionally, we studied the association between methylation values and clinicopathological variables. For the prognostic model, Kaplan-Meier Survival curves were generated. Lastly, univariate and multivariate analysis were performed to evaluate the simultaneous impact of methylation and clinicopathological variables on the risk of tumor progression and survival. RESULTS: Nine CpG sites' methylation ß -values involved in our study demonstrated different methylation signatures between normal and malignant urothelium. Hypermethylated CpGs were overrepresented in tumor tissue (p < 0.0001). Opposingly, 4 CpG sites showed lower methylation values in tumor samples (p < 0.0001). Cg12743248high and cg17192862low are risk factors for progression-free survival, whereas cg12374721high (HR:3.003 (1.283-7.030)) also demonstrated to be the most valuable independent risk factor for disease progression and a risk factor for overall survival. CONCLUSIONS: We have identified that methylated cg12374721 shows promise as a diagnostic and independent prognostic marker in BLCA progression.

Mesorectal nodal metastasis with seminal vesicle invasion in biochemically recurrent prostate cancer.

OBJECTIVES: To determine the prevalence and predictors of mesorectal lymph node (MLN) metastases on prostate-specific membrane antigen (PSMA)-based positron emission tomography/computed tomography (PET/CT) in patients with biochemically recurrent prostate cancer (PCa) following radical therapy. MATERIALS AND METHODS: This was a cross-sectional analysis of all PCa patients with biochemical failure following radical prostatectomy or radiotherapy who underwent an 18 F-DCFPyL-PSMA-PET/CT at the Princess Margaret Cancer Centre between December 2018 and February 2021. Lesions with PSMA scores ≥2 were considered positive for PCa involvement (PROMISE classification). Predictors of MLN metastasis were evaluated using univariable and multivariable logistic regression analyses. RESULTS: Our cohort consisted of 686 patients. The primary treatment method was radical prostatectomy and radiotherapy in 528 (77.0%) and 158 patients (23.0%), respectively. The median serum PSA level was 1.15 ng/mL. Overall, 384 patients (56.0%) had a positive scan. Seventy-eight patients (11.3%) had MLN metastasis, with 48/78 (61.5%) having MLN involvement as the only site of metastasis. On multivariable analysis, presence of pT3b disease (odds ratio 4.31, 95% confidence interval 1.44-14.2; P = 0.011) was significantly associated with increased odds of MLN metastasis, whereas surgical factors (radical prostatectomy vs radiotherapy; performance/extent of pelvic nodal dissection), surgical margin positivity, and Gleason Grade were not. CONCLUSIONS: In this study, 11.3% of PCa patients with biochemical failure had MLN metastasis on 18 F-DCFPyL-PET/CT. pT3b disease was associated with 4.31-fold significantly increased odds of MLN metastasis. These findings suggest alternate drainage routes for PCa cells, either via alternate lymphatic drainage from the seminal vesicles themselves or secondary to direct extension from posteriorly located tumours invading the seminal vesicles.

European Association of Urology Guidelines on Testicular Cancer: 2023 Update.

CONTEXT: Each year the European Association of Urology (EAU) produce a document based on the most recent evidence on the diagnosis, therapy, and follow-up of testicular cancer (TC). OBJECTIVE: To represent a summarised version of the EAU guidelines on TC for 2023 with a focus on key changes in the 2023 update. EVIDENCE ACQUISITION: A multidisciplinary panel of TC experts, comprising urologists, medical and radiation oncologists, and pathologists, reviewed the results from a structured literature search to compile the guidelines document. Each recommendation in the guidelines was assigned a strength rating. EVIDENCE SYNTHESIS: For the 2023 EAU guidelines on TC, a review and restructure were undertaken. The key changes incorporated in the 2023 update include: new supporting text regarding venous thromboembolism prophylaxis in males with metastatic germ cell tumours receiving chemotherapy; quality of life after treatment; an update of the histological classifications and inclusion of the World Health Organization 2022 pathological classification; inclusion of the revalidation of the 1997 International Germ Cell Cancer Collaborative Group prognostic risk factors; and a new section covering oncology treatment protocols. CONCLUSIONS: The 2023 version of the EAU guidelines on TC include the highest available scientific evidence to standardise the management of TC. Better stratification and optimisation of treatment modalities will continue to improve the high survival rates for patients with TC. PATIENT SUMMARY: This article presents a summary of the European Association of Urology guidelines on testicular cancer published in 2023 and includes the latest recommendations for management of this disease. The guidelines are a valuable resource that may help patients in understanding treatment recommendations.

THOR is a targetable epigenetic biomarker with clinical implications in breast cancer.

BACKGROUND: Breast cancer (BC) is the most frequently diagnosed cancer and a leading cause of death among women worldwide. Early BC is potentially curable, but the mortality rates still observed among BC patients demonstrate the urgent need of novel and more effective diagnostic and therapeutic options. Limitless self-renewal is a hallmark of cancer, governed by telomere maintenance. In around 95% of BC cases, this process is achieved by telomerase reactivation through upregulation of the human telomerase reverse transcriptase (hTERT). The hypermethylation of a specific region within the hTERT promoter, termed TERT hypermethylated oncological region (THOR) has been associated with increased hTERT expression in cancer. However, its biological role and clinical potential in BC have never been studied to the best of our knowledge. Therefore, we aimed to investigate the role of THOR as a biomarker and explore the functional impact of THOR methylation status in hTERT upregulation in BC. RESULTS: THOR methylation status in BC was assessed by pyrosequencing on discovery and validation cohorts. We found that THOR is significantly hypermethylated in malignant breast tissue when compared to benign tissue (40.23% vs. 12.81%, P < 0.0001), differentiating malignant tumor from normal tissue from the earliest stage of disease. Using a reporter assay, the addition of unmethylated THOR significantly reduced luciferase activity by an average 1.8-fold when compared to the hTERT core promoter alone (P < 0.01). To further investigate its biological impact on hTERT transcription, targeted THOR demethylation was performed using novel technology based on CRISPR-dCas9 system and significant THOR demethylation was achieved. Cells previously demethylated on THOR region did not develop a histologic cancer phenotype in in vivo assays. Additional studies are required to validate these observations and to unravel the causality between THOR hypermethylation and hTERT upregulation in BC. CONCLUSIONS: THOR hypermethylation is an important epigenetic mark in breast tumorigenesis, representing a promising biomarker and therapeutic target in BC. We revealed that THOR acts as a repressive regulatory element of hTERT and that its hypermethylation is a relevant mechanism for hTERT upregulation in BC.

Prevalence and Management of Incidental Testicular Masses-A Systematic Review.

Management of incidentally diagnosed small testicular masses (STM) is controversial. Although there is the risk of malignancy, it might be realistic to safely seek preservation of testicles bearing benign masses. This study aims to systematically evaluate the evidence regarding prevalence of STMs, their benign or malignant histology and their management. We conducted a systematic literature search for studies reporting small or incidental testicular masses and their management by radical orchiectomy, testis sparing surgery (TSS) or ultrasound (US) surveillance. We initially screened 2126 abstracts and from these, 57 studies met the inclusion criteria. Testicular masses were detected in 1.74% of patients undergoing US examination. Regarding STMs removed by surgery, 41.12% were benign. Intraoperative frozen section examination (FSE) is a reliable tool to discriminate between benign and malignant testicular masses (average 93.05% accuracy), supporting TSS. Benign lesions were associated with smaller diameter (<1 cm 68.78% benign), were often hypoechoic and exhibited regular margins on US. Conclusions: Small testicular masses are often benign. Clinical and US patterns are not accurate enough for including patients in surveillance protocols and TSS paired with FSE is pivotal for precluding the removal of testicles bearing benign lesions. Future research might unveil new imaging tools or biomarkers to support clinical management.

Laparoscopic treatment of entero-neobladder fistula after radical cystectomy.

Entero-neovesical fistula is a rare complication of orthotopic ileal neobladder after radical cystectomy occurring in <2% of cases. Surgical treatment is usually required and includes open resection of the affected bowel tract and reconstitution of bowel transit. Here we present a case of a laparoscopic treatment of entero-to-neobladder fistula 8 years after laparoscopic radical cystectomy to demonstrate the feasibility and safety of minimally invasive treatment (Supplementary Video). To the best of our knowledge, this is the first report of minimally invasive treatment of entero-neobladder fistula.

Salicylate activates KATP channels and reduces spontaneous firing in glycinergic cartwheel neurons in the dorsal cochlear nucleus of rats.

High doses of salicylate induce tinnitus in humans and experimental animals. The Dorsal Cochlear Nucleus is implicated with the genesis of tinnitus, and increased activity in this nucleus is seen in animal models of tinnitus. Incubation of brainstem slices containing the DCN with millimolar salicylate reduces the spontaneous firing of glycinergic cartwheel neurons and glycinergic neurotransmission on fusiform neurons, the principal neuron of this nucleus. However, the mechanism of salicylate mediating this effect is not known. Recently, we have shown that KATP channels strongly modulate the spontaneous firing of cartwheel neurons. We tested if KATP channels could mediate the effects of salicylate on cartwheel neurons. Perfusion of 1.4 mM salicylate hyperpolarizes the membrane of cartwheel neurons and stops firing. Salicylate produces an outward current similar to the KATP current seen in quiet cartwheel neurons. Activation of this current is occluded by the KATP agonist diazoxide, which is produced by the opening of KATP channels. The antagonist of AMP-kinase (AMPK), dorsomorphim, inhibited salicylate effects, suggesting that they could be mediated by activation of this kinase. Still, the AMPK agonist, AICAR, did not reproduce salicylate effects but occluded them. Additionally, inhibiting mitochondrial ATP synthesis with the protonophore CCCP reproduced, albeit with less efficacy, and inhibited the effects of salicylate. We concluded that salicylate in millimolar concentrations opens KATP channels in DCN cartwheel neurons, inhibiting spontaneous firing of these neurons, probably by activating AMPK and reducing mitochondrial ATP synthesis.

Extracellular Vesicle Proteome in Prostate Cancer: A Comparative Analysis of Mass Spectrometry Studies.

Molecular diagnostics based on discovery research holds the promise of improving screening methods for prostate cancer (PCa). Furthermore, the congregated information prompts the question whether the urinary extracellular vesicles (uEV) proteome has been thoroughly explored, especially at the proteome level. In fact, most extracellular vesicles (EV) based biomarker studies have mainly targeted plasma or serum. Therefore, in this study, we aim to inquire about possible strategies for urinary biomarker discovery particularly focused on the proteome of urine EVs. Proteomics data deposited in the PRIDE archive were reanalyzed to target identifications of potential PCa markers. Network analysis of the markers proposed by different prostate cancer studies revealed moderate overlap. The recent throughput improvements in mass spectrometry together with the network analysis performed in this study, suggest that a larger standardized cohort may provide potential biomarkers that are able to fully characterize the heterogeneity of PCa. According to our analysis PCa studies based on urinary EV proteome presents higher protein coverage compared to plasma, plasma EV, and voided urine proteome. This together with a direct interaction of the prostate gland and urethra makes uEVs an attractive option for protein biomarker studies. In addition, urinary proteome based PCa studies must also evaluate samples from bladder and renal cancers to assess specificity for PCa.

Dual role of allele-specific DNA hypermethylation within the TERT promoter in cancer.

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allele-specific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.

Circulating MicroRNAs, the Next-Generation Serum Biomarkers in Testicular Germ Cell Tumours: A Systematic Review.

CONTEXT: Clinical management of testicular germ cell tumours (GCTs) is hampered by low sensitivity and specificity of the biomarkers currently in use. Circulating microRNAs (miRs) might offer the potential to address areas of unmet clinical need. OBJECTIVE: To systematically evaluate the evidence for clinical applications of serum levels of miR302/367 and miR371-3 in adult testicular GCTs in terms of primary diagnosis, various clinical scenarios, and the costs of clinical implementation. EVIDENCE ACQUISITION: We performed a critical review of PubMed/Medline, Embase and the Cochrane Library in January 2021 in accordance with Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. EVIDENCE SYNTHESIS: Thirty-one manuscripts addressed miR performance and potential clinical use in testicular GCT. Of these, 23 evaluated the utility in primary diagnosis, seven in early-stage disease, and 13 in metastatic disease, and two addressed the costs of clinical implementation. Of the various miRs studied, miR-371a-3p appears the most useful and potentially the only one that needs to be assayed, with an area under the receiver operating characteristic curve >0.90, sensitivity of 89-96%, and specificity of >90% for both seminoma and nonseminoma, surpassing the classic serum tumour markers. The miRs studied to date are not elevated in cases with teratoma only. Levels of miR-371a-3p correlate with primary tumour mass, clinical stage, and International Germ Cell Cancer Collaborative Group risk groups. Serial measurements mirror treatment efficacy in all clinical stages. CONCLUSIONS: Circulating miRNA levels, particularly of miR-371a-3p, have potential for incorporation in clinical practice and may aid in clinical decision-making in various clinical scenarios in GCT. PATIENT SUMMARY: We analysed the current evidence on the usefulness of blood levels of molecules called microRNAs in the management of testicular tumours. The microRNA-371a-3p molecule has better sensitivity and specificity than the markers currently being measured. This new biomarker may soon have a place in clinical practice.

Liquid Biopsies in the Clinical Management of Germ Cell Tumor Patients: State-of-the-Art and Future Directions.

Liquid biopsies constitute a minimally invasive means of managing cancer patients, entailing early diagnosis, follow-up and prediction of response to therapy. Their use in the germ cell tumor field is invaluable since diagnostic tissue biopsies (which are invasive) are often not performed, and therefore only a presumptive diagnosis can be made, confirmed upon examination of the surgical specimen. Herein, we provide an overall review of the current liquid biopsy-based biomarkers of this disease, including the classical, routinely used serum tumor markers-the promising microRNAs rapidly approaching the introduction into clinical practice-but also cell-free DNA markers (including DNA methylation) and circulating tumor cells. Finally, and importantly, we also explore novel strategies and challenges for liquid biopsy markers and methodologies, providing a critical view of the future directions for liquid biopsy tests in this field, highlighting gaps and unanswered questions.

Recommendations to Balance Benefits and Risks Of Thromboprophylaxis and to Avoid Central Venous-access Devices During First-line Chemotherapy in Men with Metastatic Germ Cell Tumors: The European Association Of Urology Testicular Cancer Panel Position in 2021.

Men with metastatic germ cell tumors undergoing chemotherapy are at high risk of venous thromboembolic events and low risk of bleeding. A central venous-access device should be avoided whenever possible. Thromboprophylaxis may be prescribed after balancing the risks and benefits for each individual patient.

Loss of Brain-Derived Neurotrophic Factor Mediates Inhibition of Hippocampal Long-Term Potentiation by High-Intensity Sound.

Exposure to noise produces cognitive and emotional disorders, and recent studies have shown that auditory stimulation or deprivation affects hippocampal function. Previously, we showed that exposure to high-intensity sound (110 dB, 1 min) strongly inhibits Schaffer-CA1 long-term potentiation (LTP). Here we investigated possible mechanisms involved in this effect. We found that exposure to 110 dB sound activates c-fos expression in hippocampal CA1 and CA3 neurons. Although sound stimulation did not affect glutamatergic or GABAergic neurotransmission in CA1, it did depress the level of brain-derived neurotrophic factor (BDNF), which is involved in promoting hippocampal synaptic plasticity. Moreover, perfusion of slices with BDNF rescued LTP in animals exposed to sound stimulation, whereas BDNF did not affect LTP in sham-stimulated rats. Furthermore, LM22A4, a TrkB receptor agonist, also rescued LTP from sound-stimulated animals. Our results indicate that depression of hippocampal BDNF mediates the inhibition of LTP produced by high-intensity sound stimulation.