Androgen deprivation therapy (ADT) for metastatic and high-risk prostate cancer (PC) inhibits growth pathways driven by the androgen receptor (AR). Over time, ADT leads to the emergence of lethal ...castrate-resistant PC (CRPC), which is consistently caused by an acquired ability of tumors to re-activate AR. This has led to the development of second-generation anti-androgens that more effectively antagonize AR, such as enzalutamide (ENZ). However, the resistance of CRPC to ENZ develops rapidly. Studies utilizing preclinical models of PC have established that inhibition of the Jak2-Stat5 signaling leads to extensive PC cell apoptosis and decreased tumor growth. In large clinical cohorts, Jak2-Stat5 activity predicts PC progression and recurrence. Recently, Jak2-Stat5 signaling was demonstrated to induce ENZ-resistant PC growth in preclinical PC models, further emphasizing the importance of Jak2-Stat5 for therapeutic targeting for advanced PC. The discovery of the Jak2V617F somatic mutation in myeloproliferative disorders triggered the rapid development of Jak1/2-specific inhibitors for a variety of myeloproliferative and auto-immune disorders as well as hematological malignancies. Here, we review Jak2 inhibitors targeting the mutated Jak2V617F vs. wild type (WT)-Jak2 that are currently in the development pipeline. Among these 35 compounds with documented Jak2 inhibitory activity, those with potency against WT-Jak2 hold strong potential for advanced PC therapy.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Prostate cancer (PCa) is the most diagnosed cancer in men, accounting for 27% of male new cancer diagnoses in 2022. If organ-confined, removal of the prostate through radical prostatectomy is ...considered curative; however, distant metastases may form resulting in poor patient prognosis. This study sought to determine whether quantitative pathomic features of prostate cancer differ in patients who biochemically recur following surgery. Whole mount prostate histology from 78 patients was analyzed for this study. In total, 614 slides were hematoxylin and eosin (H&E) stained and digitized to produce whole slide images (WSI). Regions of differing Gleason patterns were digitally annotated by a GU-fellowship trained pathologist (KAI), and high-resolution tiles were extracted from each annotated region of interest (ROI) for further analysis. Individual glands within the prostate were identified using automated image processing algorithms, and histomorphometric features were calculated on a per-tile basis as well as across WSI and averaged by patient. Tiles were organized into cancer and benign tissue. Logistic regression models were fit to assess the predictive value of the calculated pathomic features across tile groups and WSI, as well as models using clinical information for comparison. Logistic regression classified each pathomic feature model at accuracies >80% with areas under the curve (AUC) of 0.82, 0.76, 0.75, and 0.72 for all tiles, cancer only, noncancer only, and across WSI. This was comparable to standard clinical information, Gleason Grade Groups, and CAPRA score, which achieved similar accuracies but AUCs of 0.80, 0.77, and 0.70, respectively. This study demonstrates that the use of quantitative pathomic features calculated from digital histology of prostate cancer may provide clinicians with additional information beyond the traditional qualitative pathologist assessment. Further research is warranted to determine possible inclusion in treatment guidance.
Enhancer of Zeste 2 (EZH2), a methyltransferase and an upregulated gene is an adverse prognosticator in prostate cancer. It catalyzes histone H3 lysine 27 trimethylation (H3K27me3) leading to ...repressive chromatin status (heterochromatin). Following demethylation and acetylation of H3 protein (H3K27ac) the result is transcriptionally activated status (euchromatin), a key metastasis facilitator being targeted by ongoing clinical trials, as with palbociclib. Here, we performed the first immunohistochemical study of H3K27ac expression in prostatic tissue and cancer metastasis, and determined a possible correlation with EZH2 expression.
Tissue microarrays were made and immunohistochemistry was performed for EZH2 and H3K27ac. Slides were scanned and image data utilized a software-assisted, unbiased quantification method. The software captured diaminobenzidine positive regions, and tissue areas.
Benign prostate tissue expressed almost no EZH2 but showed strong H3K27-Ac positivity. Tumor was EZH2 positive (p < 0.05 vs. benign) with strongest staining in lymph node metastasis. H3K27-Ac was decreased in tumors, yet paradoxically had stagewise and gradewise progressive increases (both p < 0.05), with the strongest staining in lymph nodes. The overall relationship of EZH2 and H3K27ac was weakly correlated (r = 0.28, p < 0.05).
EZH2 and H3K27ac had an inverse correlation in benign versus (especially) low-grade and low-stage prostate cancers; however, in high-stage and high-grade cancers and metastases, H3K27ac increased significantly. Findings support EZH2 and H3K27ac as targets for cancer prevention in localized or low-grade prostate cancer, but we now note that their inverse relationship becomes uncoupled in advanced prostate cancer.
•EZH2 is an upregulated gene and adverse prognosticator in prostate cancer.•EZH2 contains a domain that catalyzes H3K27-Ac which is a key metastasis facilitator.•EZH2 and H3K27-Ac had an inverse correlation in benign versus especially low-grade and low-stage prostate cancers.•In high-stage and high-grade cancers and metastases, H3K27-Ac increased significantly.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pathological heterogeneity is common in clinical tissue specimens and complicates the interpretation of molecular data obtained from the specimen. As a typical example, a kidney biopsy specimen often ...contains glomeruli and tubulointerstitial regions with different levels of histological injury, including some that are histologically normal. We reasoned that the molecular profiles of kidney tissue regions with specific histological injury scores could provide new insights into kidney injury progression. Therefore, we developed a strategy to perform small RNA deep sequencing analysis for individually scored glomerular and tubulointerstitial regions in formalin-fixed, paraffin-embedded kidney needle biopsies. This approach was applied to study focal segmental glomerulosclerosis (FSGS), the leading cause of nephrotic syndrome in adults. Large numbers of small RNAs, including microRNAs, 3′-tRFs, 5′-tRFs, and mitochondrial tRFs, were differentially expressed between histologically indistinguishable tissue regions from patients with FSGS and matched healthy controls. A majority of tRFs were upregulated in FSGS. Several small RNAs were differentially expressed between tissue regions with different histological scores in FSGS. Notably, with increasing levels of histological damage, miR-21-5p was upregulated progressively and miR-192-5p was downregulated progressively in glomerular and tubulointerstitial regions, respectively. This study marks the first genome scale molecular profiling conducted in histologically characterized glomerular and tubulointerstitial regions. Thus, substantial molecular changes in histologically normal kidney regions in FSGS might contribute to initiating tissue injury or represent compensatory mechanisms. In addition, several small RNAs might contribute to subsequent progression of glomerular and tubulointerstitial injury, and histologically mapping small RNA profiles may be applied to analyze tissue specimens in any disease.
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There is a need to develop a novel analgesic for pain associated with interstitial cystitis/painful bladder syndrome (IC/PBS). The use of the conventional μ-opioid receptor agonists to manage IC/PBS ...pain is controversial due to adverse CNS effects. These effects are attenuated in benzylideneoxymorphone (BOM), a low-efficacy μ-opioid receptor agonist/δ-opioid receptor antagonist that attenuates thermal pain and is devoid of reinforcing effects. We hypothesize that BOM will inhibit bladder pain by attenuating responses of urinary bladder distension (UBD)-sensitive afferent fibers. Therefore, the effect of BOM was tested on responses of UBD-sensitive afferent fibers in L6 dorsal root from inflamed and non-inflamed bladder of rats. Immunohistochemical (IHC) examination reveals that following the induction of inflammation there were significant high expressions of μ, δ, and μ-δ heteromer receptors in DRG. BOM dose-dependently (1–10 mg/kg, i.v) attenuated mechanotransduction properties of these afferent fibers from inflamed but not from non-inflamed rats. In behavioral model of bladder pain, BOM significantly attenuated visceromotor responses (VMRs) to UBD only in inflamed group of rats when injected either systemically (10 mg/kg, i.v.) or locally into the bladder (0.1 ml of 10 mg/ml). Furthermore, oxymorphone (OXM), a high-efficacy μ-opioid receptor agonist, attenuated responses of mechanosensitive bladder afferent fibers and VMRs to UBD. Naloxone (10 mg/kg, i.v.) significantly reversed the inhibitory effects of BOM and OXM on responses of bladder afferent fibers and VMRs suggesting μ-opioid receptor-related analgesic effects of these compounds. The results reveal that a low-efficacy, bifunctional opioid-based compound can produce analgesia by attenuating mechanotransduction functions of afferent fibers innervating the urinary bladder.
•Cystitis enhances the expressions of μ-, δ-, and μ-δ- heteromer receptors in L6 DRGs.•BOM, μ-opioid receptor agonist and δ-opioid receptor antagonist, attenuates mechanotransduction properties of bladder afferent fibers.•In objective bladder pain measurement model, BOM significantly inhibits bladder distension-evoked pain.•Results clearly indicate that BOM produces analgesic effect in cystitis.•BOM produces antinociception by modulating the functions primary sensory neurons innervating the urinary bladder.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZRSKP
Prostate cancer (PCa) is the most diagnosed non-cutaneous cancer in men. Despite therapies such as radical prostatectomy, which is considered curative, distant metastases may form, resulting in ...biochemical recurrence (BCR). This study used radiomic features calculated from multi-parametric magnetic resonance imaging (MP-MRI) to evaluate their ability to predict BCR and PCa presence. Data from a total of 279 patients, of which 46 experienced BCR, undergoing MP-MRI prior to surgery were assessed for this study. After surgery, the prostate was sectioned using patient-specific 3D-printed slicing jigs modeled using the T2-weighted imaging (T2WI). Sectioned tissue was stained, digitized, and annotated by a GU-fellowship trained pathologist for cancer presence. Digitized slides and annotations were co-registered to the T2WI and radiomic features were calculated across the whole prostate and cancerous lesions. A tree regression model was fitted to assess the ability of radiomic features to predict BCR, and a tree classification model was fitted with the same radiomic features to classify regions of cancer. We found that 10 radiomic features predicted eventual BCR with an AUC of 0.97 and classified cancer at an accuracy of 89.9%. This study showcases the application of a radiomic feature-based tool to screen for the presence of prostate cancer and assess patient prognosis, as determined by biochemical recurrence.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Our understanding of genomic pathology and biomarkers for prostate cancer is continually growing. Some promising and useful tissue markers are GSTP1, HOXD3, cell cycle proteins, chromatin remodeling ...proteins, androgen receptor, Stat5a/b, ERG, and PTEN. Serum and urine markers are mostly either prostate-specific antigen or newer tests using one or more other kallikreins or sarcosine. The data and evidence for all of these markers and the commercial tests using them are reviewed here.
Among four sub-patterns of Gleason grade 4 prostate cancer, voluminous evidence supports that the cribriform pattern holds an unfavorable prognostic impact, as compared with poorly-formed, fused, or ...glomeruloid. The International Society of Urological Pathology (ISUP) recommends specifying whether invasive grade 4 cancer is cribriform. Recently, ISUP experts published a consensus definition of cribriform pattern highlighting criteria that distinguish it from mimickers. The current study aimed to analyze morphologic features separately to identify those that define the essence of the cribriform pattern. Thirty-two selected photomicrographs were classified by 12 urologic pathologists as: definitely cribriform cancer, probably cribriform, unsure, probably not cribriform, or definitely not cribriform. Consensus was defined as 9/12 agree or disagree, with ≤1 strongly supporting the opposite choice. Final consensus was achieved in 21 of 32 cases.
Generalized estimating equation (GEE) model with logit link was fitted to estimate effect of multiple morphologic predictors. Fisher exact test was used for categorical findings.
Presence of intervening stroma precluded calling cribriform cancer (p = 0.006). Mucin presence detracted (p = 0.003) from willingness to call cribriform cancer (only 3 cases had mucin). Lumen number was associated with cribriform consensus (p = 0.0006), and all consensus cases had ≥9 lumens. Predominant papillary pattern or an irregular outer boundary detracted (p = NS).
Invasive cribriform carcinoma should have absence of intervening stroma, and usually neither papillary pattern, irregular outer boundary, nor very few lumens. Setting the criteria for cribriform will help prevent over- or undercalling this important finding.
•12 ISUP prostate pathologists rated 32 cancer images.•Certain assessed morphologic features contraindicated a diagnosis of cribriform.•Absence of intervening stroma was the most significant.•Mucin, irregular outer boundary, and papillary pattern were the others.•At least 10 lm were present in most glands that had consensus for cribriform.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Metastases from visceral malignancies to subcutaneous soft tissues are relatively rare and their diagnosis requires a high level of suspicion. It is even more challenging if a metastatic lesion shows ...non‐specific high‐grade spindle cell morphology overlapping with various primary cutaneous and soft tissue tumors. We describe a unique case of subcutaneous metastasis of sarcomatoid renal cell carcinoma which was the first manifestation of the occult malignancy. The patient had a history of lipomas and dysplastic nevi and presented with an upper back mass. The mass, located superficially within the subcutis, was composed of atypical spindle cells arranged in a storiform pattern. By immunohistochemistry, the tumor cells were strongly diffusely positive for cytokeratin AE1/AE3 and vimentin and negative for Melan‐A, S‐100 protein, SOX10, melanoma cocktail, epithelial membrane antigen (EMA), p63, CK7, CK18, CK20, smooth muscle actin (SMA), desmin, CD34, TTF‐1, CD21, CD99 and bcl‐2. Scattered tumor cells were positive for MDM2 immunostain, but MDM2 amplification was not detected using fluorescent in situ hybridization (FISH). Co‐expression of cytokeratin and vimentin by the tumor raised the possibility of metastatic renal cell carcinoma and positivity of the tumor for PAX8 supported this hypothesis. A large renal mass was detected radiologically and the subsequent nephrectomy specimen showed high‐grade clear cell renal cell carcinoma with sarcomatoid features.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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