Recent updates on the role of microRNAs in prostate cancer

MicroRNAs (miRNAs) are short non-coding RNAs that are involved in several important biological processes through regulation of genes post-transcriptionally. Carcinogenesis is one of the key biological processes where miRNAs play important role in the regulation of genes. The miRNAs elicit their effects by binding to the 3' untranslated region (3'UTR) of their target mRNAs, leading to the inhibition of translation or the degradation of the mRNA, depending on the degree of complementary base pairing. To-date more than 1,000 miRNAs are postulated to exist, although the field is moving rapidly. Currently, miRNAs are becoming the center of interest in a number of research areas, particularly in oncology, as documented by exponential growth in publications in the last decade. These studies have shown that miRNAs are deregulated in a wide variety of human cancers. Thus, it is reasonable to ask the question whether further understanding on the role of miRNAs could be useful for diagnosis, prognosis and predicting therapeutic response for prostate cancer (PCa). Therefore, in this review article, we will discuss the potential roles of different miRNAs in PCa in order to provide up-to-date information, which is expected to stimulate further research in the field for realizing the benefit of miRNA-targeted therapeutic approach for the treatment of metastatic castrate resistant prostate cancer (mCRPC) in the near future because there is no curative treatment for mCRPC at the moment

Loss of Let-7 Up-Regulates EZH2 in Prostate Cancer Consistent with the Acquisition of Cancer Stem Cell Signatures That Are Attenuated by BR-DIM

The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3′UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3′-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Metastatic carcinoma suggestive of urothelial carcinoma in the absence of known high-stage urothelial carcinoma: Analysis of clinical and pathologic parameters

Background: Urothelial carcinoma that is pT2 or higher is known to be an aggressive disease. However, we have encountered occasional biopsies of metastatic carcinoma with features suggestive of urothelial carcinoma in patients who have no known high-stage primary tumor. Design: We searched our pathology database for reports indicating metastatic carcinoma with findings suggesting urothelial carcinoma. Clinical and pathologic data were reviewed to identify patients without a known high-stage primary tumor. Results: Search identified 272 specimens showing metastatic carcinoma suggestive of urothelial carcinoma. Of these, 14 patients had no known primary tumor of pT2 or higher on comprehensive pathology and electronic medical record review, including 10 (71%) pT1, 3 (21%) carcinoma in situ, and 2 (14%) pTa. A substantial number (n=8, 57%) had tumors of the renal pelvis (n=5), ureter (n=1), or prostatic urethra (n=2). Metastatic sites included the lungs (n=4), liver (n=4), bone / soft tissue (n=3), brain (n=2), and lymph nodes (n=2). Unique patients included one with a renal pelvis high-grade papillary urothelial carcinoma concurrent with multiple sites of clear cell adenocarcinoma thought to be also of urinary tract origin. Another patient had prominent inflammatory / myxoid changes surrounding the ureter that was resected to relieve obstruction; however, no carcinoma was sampled in this specimen. Conclusions: A high proportion of patients with metastatic carcinoma suggestive of urothelial carcinoma in the absence of a high-stage primary tumor (pT2 or higher) have had a primary tumor in uncommon sites, including the renal pelvis, prostatic urethra, or ureter (57%). This raises the possibility that current staging parameters and pathologic evaluation for non-bladder primary tumors are not entirely adequate for assessing their risk

Myoepithelial carcinoma of the posterior mediastinum: An uncommon site for a rare tumor

Myoepithelial carcinoma (MC) is a rare tumor that arises from myoepithelial cells; most commonly in the salivary glands, but other infrequent body sites such as the breast, lung, lower limb, upper limb, head and neck, vulva, and vagina can be involved. We report the first case of myoepithelial carcinoma arising in the posterior mediastinum of a 51 year-old male who presented with a mediastinal mass and subsequently underwent tumor debulking surgery. Grossly, the specimen consisted of multiple tan–gray firm fragments of tissue with an overall measurement of 7.0 cm in greatest dimension. Histologic examination revealed an ill-defined, infiltrative lesion with a biphasic cell population. The tumor cells were diffusely positive for epithelial and myoepithelial markers, confirming the above diagnosis. Recognition of this entity at an uncommon site may present a diagnostic challenge due to its morphologic heterogeneity and the differential diagnosis includes benign and malignant tumors, which could lead to over or under-treatment, respectively

Histopathologic features of prostate cancer in patients who underwent seminal vesicle-sparing radical prostatectomy: A novel surgical approach

Background: Incontinence and erectile dysfunction are common complications of radical prostatectomy (RP). Seminal vesicle (SV) involvement is found in 5-23% of RP, frequently with grade group (GG) 3-5. At our institution a novel seminal vesicle-sparing approach (SVSRP) has been introduced, with preservation of either one or both seminal SVs in a select group of patients to improve functional outcomes. Here we report on the surgical pathology findings on SVSRP. Design: All SVSRP were reported by a specialist genitourinary pathologist. Detailed pathologic findings including grade, tumor size, number of tumor nodules, margin status, and pathologic stage were studied. Results: Specimens from 33 patients were studied with median age of 63 (range 51-80). In the diagnostic biopsy, 7 were Grade Group (GG) 1, 16 GG2, 6 GG3, 2 GG4, 1 GG5, and 1 not applicable (post hormonal therapy). Median number of biopsies taken was 12 (6-36) and median number positive biopsies was 3 (1-11). Half (16/33, 48%) had frozen section (FS) evaluation of the SV. Almost all (32/33) had bilateral sparing of SV, whereas in one FS of the SV base was positive and unilateral sparing of SV was performed. Median tumor percentage was 6% (1-30%). A dominant tumor nodule (DN) was identified in 31/33 (94%), whereas 2 had scattered microscopic tumor foci. Median size of the DN was 21 mm (11-30) and median number of secondary nodule(s) was 1 (1-6). Median GG of the DN was 2 (1-5). Positive margin was present in 20/33 (60%). However, only one (3%) had positive margin at the site of SVSRP. Median linear extent of positive margin was 3.5 mm (1-20 mm). Lymphovascular invasion was present in 2/33 (6%), 1/33 (3%) had bladder neck invasion, 1/33 (3%) had lymph node metastasis, 15/33 (45%) had extraprostatic extension, and 4/33 (12%) showed intraductal carcinoma. The case with positive margin at the SVSRP site was the case with unilateral (left) SV sparing. (Table). (Table presented) Conclusions: SVSRP is a promising surgical approach which may offer early return of continence compared to RP while allowing resection of clinically significant tumor. Although 60% of our cases had positive margins, only one case with aggressive disease had positive margin at the SVSRP site. The rest would have had positive margins with a conventional RP. Further refinement of selection criteria with additional pre-op or intra-op biopsies of the seminal vesicles may help to improve oncologic control in this surgical approach

Prognostic significance of histomorphologic features of lymph node metastases in prostate cancer patients treated with radical prostatectomy: A single center study

OBJECTIVE: We assessed the prognostic value of histomorphologic features of lymph node (LN) metastases in patients with prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: We evaluated the effect of the features of LN metastasis on the risk of biochemical recurrence (BCR) in 280 LN-positive patients who underwent radical prostatectomy between 2006 to 2018. LN specific parameters recorded included number of metastatic LNs, size of the largest metastatic focus, Gleason Grade (GG) of the metastatic focus, and extranodal extension (ENE). RESULTS: A solitary positive LN was found in 166/280 (59%), 95/280 (34%) patients had 2-4 positive LNs, and 19/280 (7%) had 5 or more positive LNs. The size of the largest metastatic focus \u3e 2 mm (macrometastasis) in 154/261 (59%). GG of the metastatic focus was as follows: GG 1-2: 29/224 (13%); GG 3: 27/224 (12%); and GG 4-5: 168/224 (75%). ENE was identified in 99/244 (41%). We found the number of LNs positive (2-4 vs. 1 Hazard ratio (HR) = 1.60; 95% CI: 1.02 to 2.5; P = 0.04) and GG of the metastatic focus (GG 4&5 vs. 1-3 HR = 1.90; 95% CI: 1.14-3.2; P= 0.014) to be independent predictors of the risk of BCR after surgery on multivariate analysis. CONCLUSIONS: Our study showed the number of LNs positive and GG of the LN metastatic focus to be significant independent predictors of BCR after radical prostatectomy. We recommend reporting histomorphologic parameters of LN metastasis as they may help in defining BCR risk categorization

The impact of histological subtypes on stage at presentation and overall survival of patients with upper tract urothelial carcinoma: A nationwide cohort analysis

Introduction & Objectives: The impact of urinary upper tract cancer histology on patient prognosis and outcomes has been poorly elucidated in literature. This might stem from the rarity of certain histological subtypes. To address this void, we set to examine the impact of cancer histology on stage at presentation and overall survival (OS) of patient with urinary upper tract cancer who were treated surgically within a large North American nationwide cohort. Materials & Methods: Our cohort included 9750 cM0 UTUC patients who underwent a radical nephroureterectomy (RNU), between 2004 and 2015, within the National Cancer Database (NCDB). These patients had either pathologically proven urothelial carcinoma (UC)/papillary urothelial carcinoma, or one of the following variant histology: pure squamous, sarcomatoid/spindle cell carcinoma, or micropapillary urothelial carcinoma (MPUC). Kaplan-Meier curves and log-rank test were used to depict and compare survival curves among the different histological subtypes. Cox regression analysis tested the impact of histological subtypes on OS after accounting for: age, sex, race, year of diagnosis Charlson Comorbidity Index, income, treatment center type, insurance status, pathological tumor stage, nodal stage, and pathological LVI status. Results: Mean (SD) age was 70.90 10.9 years. The histological subtype was UC, pure squamous, sacromatoid/spindle cell carcinoma, and MPUC in respectively 49.8%, 0.61%, 0.71%, and 48.9% of patients. For these histological subtypes, the rate of pT3/4 disease was respectively 46.5%, 48.6%, 68.2%, and 31.0% (p\u3c0.001), and the rate of pN1 or higher disease was 9.47%, 5.45%, 9.375%, and 3.98% (p\u3c0.001), respectively. The mean (SD) follow-up was 42.9 35.3 months. The 5-year OS rate for these histological subtypes was respectively 42.5%, 28.1%, 26.7%, and 56.8% (p\u3c0.001). On multivariate analysis, patients with pure squamous had a 1.94-fold higher risk of death (95% CI: 1.28-2.82, p\u3c0.001), those with sarcamatoid/spindle cell carcinoma had a 1.89-fold higher risk of death (95% CI: 1.41-2.53, P\u3c0.001), while those with MPUC were 27% less likely to die (HR 0.73; 95% CI: 0.67-079, p\u3c0.001) than their counterparts with UC. Conclusions: To the best of our knowledge, our report is the first to examine the impact of urinary upper tract cancer histological subtype on cancer control outcomes in a large North American cohort. Our results indicated that the sarcomatoid/spindle cell carcinoma have a higher tumor and nodal stage at presentations in comparison to the other subtype, and that this subtype along with pure squamous have the least favorable survival outcomes. On the other hand, MPUC seem to have most favorable survival outcomes