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Cureus May 2024Most prostate cancers are adenocarcinomas. However, there is a rare and aggressive subtype known as small cell carcinoma of the prostate (SCCP). This variant of prostate...
Most prostate cancers are adenocarcinomas. However, there is a rare and aggressive subtype known as small cell carcinoma of the prostate (SCCP). This variant of prostate cancer is marked by its distinctive features, including high-grade malignancy, neuroendocrine differentiation, and a unique clinical presentation, often involving metastases. This report details the presentation and management of a 66-year-old African-American male who was originally diagnosed with high-risk adenocarcinoma of the prostate. At initial diagnosis, the patient was suboptimally treated with radiation alone without androgen deprivation therapy (ADT). On re-biopsy several years later, he was found to have localized recurrent disease with transformation into SCCP. The prognosis for SCCP is poor with a mean survival. Patients typically present with metastases, commonly to the brain, liver, bones, or bladder. SCCP after treatment for adenocarcinoma of the prostate is more common than de novo presentation. The amount of neuroendocrine differentiation of SCCP often increases with treatment, particularly after treatment with ADT. This report emphasizes the importance of timely and optimal care when treating prostate cancer and suggests potential consequences that inappropriate treatment or treatment delays may entail.
PubMed: 38903357
DOI: 10.7759/cureus.60790 -
Journal of Health, Population, and... Jun 2024According to our knowledge, the relationship between dietary patterns such as pro-healthy, pro-vegetarian, and non-healthy dietary patterns and prostate cancer risk has...
INTRODUCTION
According to our knowledge, the relationship between dietary patterns such as pro-healthy, pro-vegetarian, and non-healthy dietary patterns and prostate cancer risk has not been clearly investigated in Iranian men. Therefore, we aimed to investigate the relationship between adherence to a pro-healthy (PHDI), pro-vegetarian (PDP), and non-healthy dietary indices (NHDI) and the risk of prostate cancer.
METHOD
In this matched case-control study, 125 participants (62 cases and 63 hospital-based controls) were enrolled from April to September 2015. Participants' dietary intakes were evaluated using a valid and reliable 160-item semi-quantitative food frequency questionnaire. Dietary indices calculated based on previous studies. The relationship between dietary indices (PHDI, NHDI and PDP) and prostate cancer risk was assessed using binary regression models.
RESULTS
According to adjusted model, significant negative correlations were found between PHDI and PDP with prostate cancer (PHDI: OR = 0.31; 95% CI; 0.11-0.85; P = 0.023 - PDP: OR = 0.34; 95% CI; 0.15-0.75; P = 0.008). Also, a positive association was seen between NHDI and prostate cancer (OR = 3.01; 95% CI; 1.20-7.57; P = 0.019).
CONCLUSION
We found that adherence to healthy dietary indices which includes high amounts of fruits, vegetables, and whole grains reduces the risk of prostate cancer. While adherence to a dietary pattern high in red and processed meat, refined grains, and sweetened beverages increases the risk of prostate cancer.
Topics: Humans; Male; Prostatic Neoplasms; Case-Control Studies; Iran; Middle Aged; Diet, Healthy; Risk Factors; Aged; Diet; Diet, Vegetarian; Feeding Behavior; Adult; Diet Surveys
PubMed: 38902815
DOI: 10.1186/s41043-024-00578-4 -
Journal of Experimental & Clinical... Jun 2024The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL),...
BACKGROUND
The androgen receptor (AR) is a drug target used to inhibit AR and prostate cancer (PCa) growth. Surprisingly, treatment with supraphysiological androgen level (SAL), used in bipolar androgen therapy, inhibits growth of PCa suggesting a tumor-suppressive activity by SAL. SAL was shown to induce cellular senescence in PCa.
METHODS
RNA-seq and transcriptome analysis, ChIP-seq, human 3D PCa spheroids, mouse xenografted castration-resistant PCa, knockdown and overexpression, Co-immunoprecipitation (Co-IP), translocation analysis, immune detection, qRT-PCR, protein-protein interaction modelling.
RESULTS
Here, mice xenografts with castration-resistant PCa tumors show that SAL inhibits cancer growth in vivo suggesting that SAL activates a tumor-suppressive mechanism. RNA-seq and ChIP-seq revealed the clock gene BHLHE40 is a novel direct AR target. Compared to adjacent human prostate tissues, the expression of BHLHE40 is reduced in PCa tumors and associated with reduced survival. Knockdown suggests that BHLHE40 mediates SAL-induced cellular senescence including tumor spheroids. Interestingly, a large overlap of differentially expressed gene sets was identified between BHLHE40 and SAL leading to the identification of four classes of SAL-BHLHE40 transcriptome landscapes. Co-IP and modelling suggest binding of BHLHE40 to AR and their co-translocation into nucleus by SAL treatment. Further, RNA-seq and ChIP-seq analysis indicate that the atypical tumor suppressive cyclin G2 emerged as a novel downstream target of BHLHE40 and a mediator of SAL-induced cellular senescence.
CONCLUSIONS
The data provide evidence of the tumor suppressive activity of SAL and a novel signaling by the AR-BHLHE40-CCNG2 axis for androgen-induced cellular senescence, linking circadian rhythm factor to androgen signaling as a novel tumor suppressive pathway.
Topics: Male; Humans; Cellular Senescence; Mice; Animals; Prostatic Neoplasms; Basic Helix-Loop-Helix Transcription Factors; Androgens; Cell Line, Tumor; Homeodomain Proteins; Receptors, Androgen; Gene Expression Regulation, Neoplastic; Xenograft Model Antitumor Assays
PubMed: 38902772
DOI: 10.1186/s13046-024-03097-6 -
NPJ Digital Medicine Jun 2024The current prostate cancer (PCa) screen test, prostate-specific antigen (PSA), has a high sensitivity for PCa but low specificity for high-risk, clinically significant...
The current prostate cancer (PCa) screen test, prostate-specific antigen (PSA), has a high sensitivity for PCa but low specificity for high-risk, clinically significant PCa (csPCa), resulting in overdiagnosis and overtreatment of non-csPCa. Early identification of csPCa while avoiding unnecessary biopsies in men with non-csPCa is challenging. We built an optimized machine learning platform (ClarityDX) and showed its utility in generating models predicting csPCa. Integrating the ClarityDX platform with blood-based biomarkers for clinically significant PCa and clinical biomarker data from a 3448-patient cohort, we developed a test to stratify patients' risk of csPCa; called ClarityDX Prostate. When predicting high risk cancer in the validation cohort, ClarityDX Prostate showed 95% sensitivity, 35% specificity, 54% positive predictive value, and 91% negative predictive value, at a ≥ 25% threshold. Using ClarityDX Prostate at this threshold could avoid up to 35% of unnecessary prostate biopsies. ClarityDX Prostate showed higher accuracy for predicting the risk of csPCa than PSA alone and the tested model-based risk calculators. Using this test as a reflex test in men with elevated PSA levels may help patients and their healthcare providers decide if a prostate biopsy is necessary.
PubMed: 38902526
DOI: 10.1038/s41746-024-01167-9 -
Modern Pathology : An Official Journal... Jun 2024Nephrogenic adenoma is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with an antecedent inflammation, instrumentation, or...
Nephrogenic adenoma is a benign, reactive lesion seen predominantly in the urinary bladder and often associated with an antecedent inflammation, instrumentation, or operative history. Its histopathological diversity can create diagnostic dilemmas and pathologists utilize morphological evaluation along with available immunohistochemical markers to navigate these challenges. Immunohistochemical assays currently do not designate or specify nephrogenic adenoma's potential putative cell of origin. Leveraging single-cell RNA sequencing technology, we nominated a principal cell collecting duct marker, L1 cell adhesion molecule (L1CAM), as a potential biomarker for nephrogenic adenoma. Immunohistochemical characterization revealed L1CAM to be positive in all 35 (100%) patient samples of nephrogenic adenoma; negative expression was seen in the benign urothelium, benign prostatic glands, urothelial carcinoma in situ, prostatic adenocarcinoma, majority of high-grade urothelial carcinoma, and metastatic urothelial carcinoma. In the study, we also utilized single-cell RNA sequencing to nominate a novel compendium of biomarkers specific for proximal tubule, loop of Henle, and distal tubule (including principal and intercalated cells) which can be used to perform nephronal mapping utilizing RNA in situ hybridization and immunohistochemistry technology. Employing this technique on nephrogenic adenoma we found enrichment of both principal cell marker L1CAM and, the proximal tubule types-A and -B cells markers, PDZKI1P1 and PIGR respectively. The cell type markers for the intercalated cell of distal tubules (LINC01187 and FOXI1), and the loop of Henle (UMOD and IRX5), were found to be uniformly absent in nephrogenic adenoma. Overall, our findings show that based on cell type-specific implications of L1CAM expression, the shared expression pattern of L1CAM between distal tubule principal cell (P) cells and nephrogenic adenoma. L1CAM expression will be of potential value in assisting surgical pathologists towards a diagnosis of nephrogenic adenoma in challenging patient samples.
PubMed: 38901674
DOI: 10.1016/j.modpat.2024.100540 -
ESMO Open Jun 2024Prostate cancer (PCa) treatments are associated with a detrimental impact on bone health (BH) and body composition. However, the evidence on these issues is limited and...
BACKGROUND
Prostate cancer (PCa) treatments are associated with a detrimental impact on bone health (BH) and body composition. However, the evidence on these issues is limited and contradictory. This consensus, based on the Delphi method, provides further guidance on BH management in PCa.
MATERIALS AND METHODS
In May 2023, a survey made up of 37 questions and 74 statements was developed by a group of oncologists and endocrinologists with expertise in PCa and BH. In June 2023, 67 selected Italian experts, belonging to the Italian scientific societies Italian Association of Medical Oncology and Italian Network for Research in Urologic-Oncology (Meet-URO), were invited by e-mail to complete it, rating their strength of agreement with each statement on a 5-point scale. An agreement ≥75% defined the statement as accepted.
RESULTS
In non-metastatic hormone-sensitive PCa, the panel agreed that androgen deprivation therapy (ADT) alone implies sufficient fracture risk to warrant antifracture therapy with bone-targeting agents (BTAs) for cancer treatment-induced bone loss (CTIBL) prevention (79%). Therefore, no consensus was reached (48%) for the treatment with BTAs of patients receiving short-term ADT (<6 months). All patients receiving active treatment for metastatic hormone-sensitive PCa (75%), non-metastatic castration-resistant PCa (89%) and metastatic castration-resistant PCa (mCRPC) without bone metastases (84%) should be treated with BTAs at the doses and schedule for CTIBL prevention. All mCRPC patients with bone metastasis should be treated with BTAs to reduce skeletal-related events (94%). In all settings, the panel analyzed the type and timing of treatments and examinations to carry out for BH monitoring. The panel agreed on the higher risk of sarcopenic obesity of these patients and its correlation with bone fragility.
CONCLUSIONS
This consensus highlights areas lacking major agreement, like non-metastatic hormone-sensitive prostate cancer patients undergoing short-term ADT. Evaluation of these issues in prospective clinical trials and identification of early biomarkers of bone loss are particularly urgent.
PubMed: 38901175
DOI: 10.1016/j.esmoop.2024.103484 -
JCO Clinical Cancer Informatics Jun 2024Prostate cancer (PCa) represents a highly heterogeneous disease that requires tools to assess oncologic risk and guide patient management and treatment planning. Current...
PURPOSE
Prostate cancer (PCa) represents a highly heterogeneous disease that requires tools to assess oncologic risk and guide patient management and treatment planning. Current models are based on various clinical and pathologic parameters including Gleason grading, which suffers from a high interobserver variability. In this study, we determine whether objective machine learning (ML)-driven histopathology image analysis would aid us in better risk stratification of PCa.
MATERIALS AND METHODS
We propose a deep learning, histopathology image-based risk stratification model that combines clinicopathologic data along with hematoxylin and eosin- and Ki-67-stained histopathology images. We train and test our model, using a five-fold cross-validation strategy, on a data set from 502 treatment-naïve PCa patients who underwent radical prostatectomy (RP) between 2000 and 2012.
RESULTS
We used the concordance index as a measure to evaluate the performance of various risk stratification models. Our risk stratification model on the basis of convolutional neural networks demonstrated superior performance compared with Gleason grading and the Cancer of the Prostate Risk Assessment Post-Surgical risk stratification models. Using our model, 3.9% of the low-risk patients were correctly reclassified to be high-risk and 21.3% of the high-risk patients were correctly reclassified as low-risk.
CONCLUSION
These findings highlight the importance of ML as an objective tool for histopathology image assessment and patient risk stratification. With further validation on large cohorts, the digital pathology risk classification we propose may be helpful in guiding administration of adjuvant therapy including radiotherapy after RP.
Topics: Humans; Prostatic Neoplasms; Male; Deep Learning; Neoplasm Grading; Risk Assessment; Prostatectomy; Aged; Middle Aged; Image Processing, Computer-Assisted
PubMed: 38900978
DOI: 10.1200/CCI.23.00184 -
Oncotarget Jun 2024Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies,... (Review)
Review
Prostate cancer (PCa) poses significant challenges in treatment, particularly when it progresses to a metastatic, castrate-resistant state. Conventional therapies, including chemotherapy, radiotherapy, and hormonal treatments, often fail due to toxicities, off-target effects, and acquired resistance. This research perspective defines an alternative therapeutic strategy focusing on the metabolic vulnerabilities of PCa cells, specifically their reliance on non-essential amino acids such as cysteine. Using an engineered enzyme cyst(e)inase to deplete the cysteine/cystine can induce oxidative stress and DNA damage in cancer cells. This depletion elevates reactive oxygen species (ROS) levels, disrupts glutathione synthesis, and enhances DNA damage, leading to cancer cell death. The combinatorial use of cyst(e)inase with agents targeting antioxidant defenses, such as thioredoxins, further amplifies ROS accumulation and cytotoxicity in PCa cells. Overall, in this perspective provides a compressive overview of the previous work on manipulating amino acid metabolism and redox balance modulate the efficacy of DNA repair-targeted and immune checkpoint blockade therapies in prostate cancer.
Topics: Humans; DNA Damage; Immunotherapy; Prostatic Neoplasms; Reactive Oxygen Species; Male; Oxidative Stress; DNA Repair; Animals; Cysteine
PubMed: 38900609
DOI: 10.18632/oncotarget.28595 -
Journal of Radiation Research Jun 2024Small fractions of patients suffer from radiotherapy late severe adverse events (AEs Grade ≥ 3), which are usually irreversible and badly affect their quality of...
Small fractions of patients suffer from radiotherapy late severe adverse events (AEs Grade ≥ 3), which are usually irreversible and badly affect their quality of life. A novel functional DNA repair assay characterizing several steps of double-strand break (DSB) repair mechanisms was used. DNA repair activities of peripheral blood mononuclear cells were monitored for 1 week using NEXT-SPOT assay in 177 breast and prostate cancer patients. Only seven patients had Grade ≥ 3 AEs, 6 months after radiotherapy initiation. The machine learning method established the importance of variables among demographic, clinical and DNA repair data. The most relevant ones, all related to DNA repair, were employed to build a predictor. Predictors constructed with random forest and minimum bounding sphere predicted late Grade ≥ 3 AEs with a sensitivity of 100% and specificity of 77.17 and 86.22%, respectively. This multiplex functional approach strongly supports a dominant role for DSB repair in the development of chronic AEs. It also showed that affected patients share specific features related to functional aspects of DSB repair. This strategy may be suitable for routine clinical analysis and paves the way for modelling DSB repair associated with severe AEs induced by radiotherapy.
PubMed: 38899572
DOI: 10.1093/jrr/rrae047 -
IEEE Open Journal of Engineering in... 2024To develop patient-specific 3D models using Finite-Difference Time-Domain (FDTD) simulations and pre-treatment planning tools for the selective thermal ablation of...
PURPOSE
To develop patient-specific 3D models using Finite-Difference Time-Domain (FDTD) simulations and pre-treatment planning tools for the selective thermal ablation of prostate cancer with interstitial ultrasound. This involves the integration with a FDA 510(k) cleared catheter-based ultrasound interstitial applicators and delivery system.
METHODS
A 3D generalized "prostate" model was developed to generate temperature and thermal dose profiles for different applicator operating parameters and anticipated perfusion ranges. A priori planning, based upon these pre-calculated lethal thermal dose and iso-temperature clouds, was devised for iterative device selection and positioning. Full 3D patient-specific anatomic modeling of actual placement of single or multiple applicators to conformally ablate target regions can be applied, with optional integrated pilot-point temperature-based feedback control and urethral/rectum cooling. These numerical models were verified against previously reported ex-vivo experimental results obtained in soft tissues.
RESULTS
For generic prostate tissue, 360 treatment schemes were simulated based on the number of transducers (1-4), applied power (8-20 W/cm2), heating time (5, 7.5, 10 min), and blood perfusion (0, 2.5, 5 kg/m3/s) using forward treatment modelling. Selectable ablation zones ranged from 0.8-3.0 cm and 0.8-5.3 cm in radial and axial directions, respectively. 3D patient-specific thermal treatment modeling for 12 Cases of T2/T3 prostate disease demonstrate applicability of workflow and technique for focal, quadrant and hemi-gland ablation. A temperature threshold (e.g., Tthres = 52 °C) at the treatment margin, emulating placement of invasive temperature sensing, can be applied for pilot-point feedback control to improve conformality of thermal ablation. Also, binary power control (e.g., Treg = 45 °C) can be applied which will regulate the applied power level to maintain the surrounding temperature to a safe limit or maximum threshold until the set heating time.
CONCLUSIONS
Prostate-specific simulations of interstitial ultrasound applicators were used to generate a library of thermal-dose distributions to visually optimize and set applicator positioning and directivity during a priori treatment planning pre-procedure. Anatomic 3D forward treatment planning in patient-specific models, along with optional temperature-based feedback control, demonstrated single and multi-applicator implant strategies to effectively ablate focal disease while affording protection of normal tissues.
PubMed: 38899026
DOI: 10.1109/OJEMB.2024.3397965