Survival after Radical Prostatectomy versus Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer.

PURPOSE: Our goal was to compare cancer-specific mortality (CSM) rates between radical prostatectomy (RP) vs external beam radiotherapy (EBRT) in National Comprehensive Cancer Network© (NCCN©) high risk (HR) patients, as well as in Johns Hopkins University (JH) HR and very high risk (VHR) subgroups. MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results database (2010-2016), we identified 24,407 NCCN HR patients, of whom 10,300 (42%) vs 14,107 (58%) patients qualified for JH HR vs VHR, respectively. Overall, 9,823 (40%) underwent RP vs 14,584 (60%) EBRT. Cumulative incidence plots and competing-risks regression addressed CSM after 1:1 propensity score matching (according to age, prostate specific antigen, clinical T and N stages, and biopsy Gleason score) between RP and EBRT patients. All analyses addressed the combined NCCN HR cohort, as well as in JH HR and JH VHR subgroups. RESULTS: In the combined NCCN HR cohort 5-year CSM rates were 2.3% for RP vs 4.1% for EBRT and yielded a multivariate hazard ratio of 0.68 (95% CI 0.54-0.86, p <0.001) favoring RP. In VHR patients 5-year CSM rates were 3.5% for RP vs 6.0% for EBRT, yielding a multivariate hazard ratio of 0.58 (95% CI 0.44-0.77, p <0.001) favoring RP. Conversely, in HR patients no significant difference was recorded between RP vs EBRT (HR 0.7, 95% CI 0.39-1.25, p=0.2). CONCLUSIONS: Our data suggest that RP holds a CSM advantage over EBRT in the combined NCCN HR cohort, and in its subgroup of JH VHR patients.

Pumpkin seed oil (Cucurbita pepo) versus tamsulosin for benign prostatic hyperplasia symptom relief: a single-blind randomized clinical trial.

BACKGROUND: Benign prostatic hyperplasia (BPH) is very common in aging men. We aimed to compare the effects of tamsulosin and pumpkin (Cucurbita pepo) seed oil on BPH symptoms. METHODS: This single-blind randomized clinical trial included patients with BPH aged ≥ 50 years referred to the Urology Clinic of Shahid Beheshti Hospital, Hamadan, Iran, from August 23, 2019 to February 19, 2020. Patients were randomized into two groups. One group received 0.4 mg tamsulosin every night at bedtime and the other received 360 mg pumpkin seed oil twice a day. Patients' age, weight, height, and body mass index (BMI) were recorded. The International Prostate Symptom Score (IPSS) was filled out by the patients at baseline and then 1 month and 3 months after the initiation of treatment. The BPH-associated quality of life (QoL), serum prostate-specific antigen, prostate and postvoid residual volume, and maximum urine flow were also assessed at baseline and 3 months later. Drug side effects were also noted. RESULTS: Of the 73 patients included in this study with a mean age of 63.59 ± 7.04 years, 34 were in the tamsulosin group and 39 in the pupkin seed oil group. Patients were comparable with respect to age, weight, height, BMI, and baseline principal variables in both groups. Also, there was no significant difference between groups in terms of principal variables at any time point. However, there was a significant decrease in IPSS and a significant improvement in QoL in both groups. Although the decrease in IPSS from baseline to 1 month and 3 months was significantly higher in the tamsulosin group compared to the pumpkin group (P = 0.048 and P = 0.020, respectively), the decrease in IPSS from 1 to 3 months was similar (P = 0.728). None of the patients in the pumpkin group experienced drug side effects, while dizziness (5.9%), headache (2.9%), retrograde ejaculation (2.9%), and erythema with pruritus occurred in the tamsulosin group. CONCLUSIONS: Pumpkin (Cucurbita pepo) seed oil relieved BPH symptoms with no side effects, but was not as effective as tamsulosin. Further studies are required to confirm the role of pumpkin seed oil as an option for the treatment of BPH symptoms. Trial registration Iranian Registry of Clinical Trials, IRCT20120215009014N340. Registered 19.02.2020. Retrospectively registered, https://en.irct.ir/trial/45335 .

Calcium mitigates fluoride-induced kallikrein 4 inhibition via PERK/eIF2α/ATF4/CHOP endoplasmic reticulum stress pathway in ameloblast-lineage cells.

OBJECTIVES: The present study aimed to investigated the effect and mechanism of Ca2+ treatment on fluoride in ameloblast-lineage cells (ALCs). MATERIALS AND METHODS: The effects of fluoride and different Ca2+ levels treatment on the proliferative activity, cell apoptosis, cell cycle, intracellular free Ca2+, were firstly determined. Kallikrein 4 (KLK4), glucose-responsive protein 78 (GRP78), Protein kinase R -like endoplasmic reticulum kinase (PERK), the α subunit of eukaryotic initiation factor 2 (eIF2α), activating transcription factor 4 (ATF4), CCAAT enhancer-binding protein homologous protein (CHOP), were investigated in ALCs. RESULTS: The proliferative activity was obviously inhibited under concentrations of single fluoride high than 1 mM, and indicated highest proliferation at single 2.5 mM Ca2+ concentration in ALC cells. In addition, we found that single fluoride markedly induced intracellular free Ca2+ increasing, G2/M phase arrest, apoptosis. GRP78 and endoplasmic reticulum stress pathway of PERK/eIF2α/ATF4/CHOP were significantly increased, while the proliferation and KLK4 were markedly reduced in ALCs. Ca2+ additional treatment can obviously reverse the effect of fluoride-induced apoptosis and inhibition of KLK4. The effect of GRP78 and endoplasmic reticulum stress pathway of PERK/eIF2α/ATF4/CHOP were also alleviated under Ca2+ additional treatment in ALCs. More important, the results of 2.5 mmol/L Ca2+ treatment on the proliferation, cell cycle and apoptosis suggest this concentration is relatively better to mediate the intracellular Ca2+ homeostasis in ALCs. CONCLUSIONS: In sum, Ca2+-supplementation exerts antagonistic the toxic effects on fluoride and this inhibitory effect suggests the potential implications for Ca2+-supplementation on fluorosis.

The effect of green tea on prostate specific antigen (PSA): A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Prostate cancer is a major malignancy, affecting men, worldwide. The protective effect of green tea consumption on prostate cancer has been reported in several studies; however, the findings are equivocal. OBJECTIVE: The aim of this study was to evaluate the effects of green tea on PSA level, by conducting a systematic review and meta-analysis of randomized controlled trials. METHODS: We searched online databases, including PubMed, Scopus, and Web of Science, up to 11 Aug 2020, to obtain relevant publications. The publication search was not limited by language or date. RESULTS: A total of 2488 records were identified in the systematic search; from these, seven were included in the meta-analysis. The overall analysis showed no significant changes in PSA levels in subjects treated with green tea, (WMD: ‒0.60 ng/mL; 95 % CI: ‒1.32, 0.12 ng/mL; P = 0.104, I2 = 93.80 %, P heterogeneity<0.001). Subgroup analysis based on geographical location showed that green tea significantly reduced PSA level in the USA population (WMD: ‒1.02 pg/mL, 95 % CI: ‒1.30, ‒0.73, P < 0.001) compared to non-USA populations (WMD: ‒0.22 pg/mL, 95 % CI: ‒0.95, 0.50, P = 0.539) (P < 0.001). CONCLUSION: The results of this review show that green tea has no significant effect on PSA level. However, due to the heterogeneity among studies more consistent clinical trials, with larger sample sizes are required.

The electrochemical immunosensor for detection of prostatic specific antigen using quince seed mucilage-GNPs-SNPs as a green composite.

Prostatic specific antigen (PSA) is known as a biomarker of prostate cancer. In males, prostate cancer is ranked second as leading cause of death out of more than 200 different cancer types1. As a result, early detection of cancer can cause a significant reduction in mortality. PSA concentration directly is related to prostate cancer, so normal serum concentrations in healthy means are 4 ng and above 10 ng as abnormal concentration. Therefore, PSA determination is important to cancer progression. In this study, a free label electrochemical immunosensor was prepared based on a new green platform for the quantitative detection of the PSA. The used platform was formed from quince seed mucilage containing green gold and silver nanoparticles and synthesized by the green method (using Calendula officinalis L. extract). The quince mucilage biopolymer was used as a sub layer to assemble nanoparticles and increase the electrochemical performance. This nanocomposite was used to increase the antibody loading and accelerate the electron transfer, which can increase the biosensor sensitivity. The antibodies of the PSA biomarker were successfully incubated on the green platform. Under the optimal conditions, the electrochemical impedance spectroscopy (EIS) was proportional to the PSA biomarker concentration from 0.1 pg mL-1 to 100 ng mL-1 with low limit of detection (0.078 pg mL-1). The proposed green immunosensor exhibited high stability and reproducibility, which can be used for the quantitative assay of the PSA biomarker in clinical analyses. The results of real sample analysis presented another tool for the PSA biomarker detection in physiologic models.

Active Surveillance for Men with Intermediate Risk Prostate Cancer.

PURPOSE: Optimal treatment of intermediate risk prostate cancer remains unclear. National Comprehensive Cancer Network® guidelines recommend active surveillance, prostatectomy or radiotherapy. Recent trials demonstrated no difference in prostate cancer specific mortality for men undergoing active surveillance for low risk prostate cancer compared to prostatectomy or radiotherapy. The use of active surveillance for intermediate risk prostate cancer is less clear. In this study we characterize U.S. national trends for demographic, clinical and socioeconomic factors associated with active surveillance for men with intermediate risk prostate cancer. MATERIALS AND METHODS: This retrospective cohort study examined 176,122 men diagnosed with intermediate risk prostate cancer from 2010 to 2016 in the National Cancer Database. Temporal trends in demographic, clinical and socioeconomic factors among men with intermediate risk prostate cancer and association with the use of active surveillance were characterized. The analysis was performed in April 2020. RESULTS: In total, 176,122 men were identified with intermediate risk prostate cancer from 2010 to 2016. Of these men 57.3% underwent prostatectomy, 36.4% underwent radiotherapy and 3.2% underwent active surveillance. Active surveillance nearly tripled from 1.6% in 2010 to 4.6% in 2016 (p <0.001). On multivariate analysis use of active surveillance was associated with older age, diagnosis in recent years, lower Gleason score and tumor stage, type of insurance, treatment at an academic center and proximity to facility, and attaining higher education (p <0.05). Race and comorbidities were not associated with active surveillance. CONCLUSIONS: Our findings highlight increasing active surveillance use for men with intermediate risk prostate cancer demonstrating clinical and socioeconomic disparities. Prospective data and improved risk stratification are needed to guide optimal treatment for men with intermediate risk prostate cancer.

A phase II randomized placebo-controlled trial of pomegranate fruit extract in men with localized prostate cancer undergoing active surveillance.

INTRODUCTION OR OBJECTIVE: Men with favorable-risk prostate cancer (PCa) on active surveillance may benefit from intervention strategies to slow or prevent disease progression and the need for definitive treatment. Pomegranate and its extracts have shown antiproliferative and proapoptotic effects in cell lines and animal models, but its effect on human prostate cancer as a target tissue remain unclear. Objectives of this trial include pomegranate's ability to alter serum and prostate tissue biomarkers and the ability of an active surveillance cohort to adhere to a chemoprevention trial for 1 year. METHODS: Men with organ-confined, favorable-risk PCa on AS were randomly assigned to receive pomegranate fruit extract (PFE) 1000 mg (n = 15) or placebo (n = 15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the 1-year intervention. Plasma and urinary biomarkers were analyzed utilizing immunoassays and HPLC. Tissue proteins were assessed by immunohistochemistry (IHC) and measured by automated quantitation. RESULTS: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the 1-year intervention. No differences in plasma insulin-like growth factor-1 (IGF-1) levels, prostate-specific antigen doubling time, or biopsy kinetics were observed. Metabolites including urolithin A and urolithin A-gluc were detected more frequently in the PFE arm in both urine and plasma (p < .001 and p = .006, respectively). IHC analyses revealed reductions from baseline in 8-OHdG (a DNA damage marker) (p = .01) and androgen receptor expression (p = .04) in prostate tumor associated with PFE treatment. CONCLUSION: PFE administration for 12-month was well-tolerated and the protocol followed in an active surveillance population. Analyses suggest that PFE contains bioactive compounds capable of altering biomarkers involving oxidative stress and androgen signaling in prostate tumor and normal-appearing adjacent tissue. No alterations in the IGF axis were noted. This finding of study adherence and target activity provides a rationale for the further investigation of PFE in the active surveillance population.

Coptis chinensis Franch Directly Inhibits Proteolytic Activation of Kallikrein 5 and Cathelicidin Associated with Rosacea in Epidermal Keratinocytes.

Rosacea is a common and chronic inflammatory skin disease that is characterized by dysfunction of the immune and vascular system. The excessive production and activation of kallikerin 5 (KLK5) and cathelicidin have been implicated in the pathogenesis of rosacea. Coptis chinensis Franch (CC) has been used as a medicinal herb in traditional oriental medicine. However, little is known about the efficacy and mechanism of action of CC in rosacea. In this study, we evaluate the effect of CC and its molecular mechanism on rosacea in human epidermal keratinocytes. CC has the capacity to downregulate the expression of KLK5 and cathelicidin, and also inhibits KLK5 protease activity, which leads to reduced processing of inactive cathelicidin into active LL-37. It was determined that CC ameliorates the expression of pro-inflammatory cytokines through the inhibition of LL-37 processing. In addition, it was confirmed that chitin, an exoskeleton of Demodex mites, mediates an immune response through TLR2 activation, and CC inhibits TLR2 expression and downstream signal transduction. Furthermore, CC was shown to inhibit the proliferation of human microvascular endothelial cells induced by LL-37, the cause of erythematous rosacea. These results demonstrate that CC improved rosacea by regulating the immune response and angiogenesis, and revealed its mechanism of action, indicating that CC may be a useful therapeutic agent for rosacea.

Acteoside as a potential therapeutic option for primary hepatocellular carcinoma: a preclinical study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common malignant tumor with characteristics of poor prognosis, high morbidity and mortality worldwide. In particular, only a few systemic treatment options are available for advanced HCC patients, and include sorafenib and the recently described atezolizumab plus bevacizumab regimen as possible first-line treatments. We here propose acteoside, a phenylethanoid glycoside widely distributed in many medicinal plants as a potential candidate against advanced HCC. METHODS: Cell proliferation, colony formation and migration were analyzed in the three human HCC cell lines BEL7404, HLF and JHH-7. Angiogenesis assay was performed using HUVESs. The BEL7404 or JHH-7 xenograft nude mice model was established to analyze the possible antitumor effects of acteoside. qRT-PCR and western blotting were used to reveal the potential antitumor mechanisms of acteoside. RESULTS: Acteoside inhibited cell proliferation, colony formation and migration in all the three human HCC cell lines BEL7404, HLF and JHH-7. The prohibition of angiogenesis by acteoside was revealed by the inhibition of tube formation and cell migration of HUVECs. The combination of acteoside and sorafenib produced stronger inhibition of cell colony formation and migration of the HCC cells as well as of angiogenesis of HUVECs. The in vivo antitumor efficacy of acteoside was further demonstrated in BEL7404 or JHH-7 xenograft nude mice model, with an enhancement when combined with sorafenib in inhibiting the growth of JHH-7 xenograft. Further treatment of JHH-7 cells with acteoside revealed an increase in the level of tumor suppressor protein p53 as well as a decrease of kallikrein-related peptidase (KLK1, 2, 4, 9 and 10) gene level with no significant changes of the rest of KLK1-15 genes. CONCLUSIONS: Acteoside exerts an antitumor effect possibly through its up-regulation of p53 levels as well as inhibition of KLK expression and angiogenesis. Acteoside could be useful as an adjunct in the treatment of advanced HCC in the clinic.

Radiotherapy of Prostate Carcinoma: A Comparison of the Predictive Role of EAU Versus NCCN Risk Stratification Systems.

BACKGROUND/AIM: To compare the predictive efficacy of National Comprehensive Cancer Network (NCCN) and European Association of Urology (EAU) risk stratification systems in radiotherapy of prostate cancer. PATIENTS AND METHODS: One-thousand-nine-hundred-nine patients treated with definitive (1,074), adjuvant (381), and salvage radiotherapy (454) were analysed. RESULTS: Both systems significantly predicted biochemical-relapse-free-survival, metastasis-free-survival, and disease-free-survival, while only the NCCN system correlated with local-control in the definitive radiotherapy group. In the adjuvant setting, both systems failed to predict all outcomes. In the salvage setting, only the NCCN system significantly predicted biochemical-relapse-free-survival, metastasis-free-survival and disease-free-survival. CONCLUSION: This analysis confirms the efficacy of both systems in definitive radiotherapy and suggests the utility of the NCCN also in salvage radiotherapy.

Design of the PROstate cancer follow-up care in Secondary and Primary hEalth Care study (PROSPEC): a randomized controlled trial to evaluate the effectiveness of primary care-based follow-up of localized prostate cancer survivors.

BACKGROUND: In its 2006 report, From cancer patient to cancer survivor: lost in transition, the U.S. Institute of Medicine raised the need for a more coordinated and comprehensive care model for cancer survivors. Given the ever increasing number of cancer survivors, in general, and prostate cancer survivors, in particular, there is a need for a more sustainable model of follow-up care. Currently, patients who have completed primary treatment for localized prostate cancer are often included in a specialist-based follow-up care program. General practitioners already play a key role in providing continuous and comprehensive health care. Studies in breast and colorectal cancer suggest that general practitioners could also consider to provide survivorship care in prostate cancer. However, empirical data are needed to determine whether follow-up care of localized prostate cancer survivors by the general practitioner is a feasible alternative. METHODS: This multicenter, randomized, non-inferiority study will compare specialist-based (usual care) versus general practitioner-based (intervention) follow-up care of prostate cancer survivors who have completed primary treatment (prostatectomy or radiotherapy) for localized prostate cancer. Patients are being recruited from hospitals in the Netherlands, and randomly (1:1) allocated to specialist-based (N = 195) or general practitioner-based (N = 195) follow-up care. This trial will evaluate the effectiveness of primary care-based follow-up, in comparison to usual care, in terms of adherence to the prostate cancer surveillance guideline for the timing and frequency of prostate-specific antigen assessments, the time from a biochemical recurrence to retreatment decision-making, the management of treatment-related side effects, health-related quality of life, prostate cancer-related anxiety, continuity of care, and cost-effectiveness. The outcome measures will be assessed at randomization (≤6 months after treatment), and 12, 18, and 24 months after treatment. DISCUSSION: This multicenter, prospective, randomized study will provide empirical evidence regarding the (cost-) effectiveness of specialist-based follow-up care compared to general practitioner-based follow-up care for localized prostate cancer survivors. TRIAL REGISTRATION: Netherlands Trial Registry, Trial NL7068 (NTR7266). Prospectively registered on 11 June 2018.

Performance of clinicopathologic models in men with high risk localized prostate cancer: impact of a 22-gene genomic classifier.

BACKGROUND: Prostate cancer exhibits biological and clinical heterogeneity even within established clinico-pathologic risk groups. The Decipher genomic classifier (GC) is a validated method to further risk-stratify disease in patients with prostate cancer, but its performance solely within National Comprehensive Cancer Network (NCCN) high-risk disease has not been undertaken to date. METHODS: A multi-institutional retrospective study of 405 men with high-risk prostate cancer who underwent primary treatment with radical prostatectomy (RP) or radiation therapy (RT) with androgen-deprivation therapy (ADT) at 11 centers from 1995 to 2005 was performed. Cox proportional hazards models were used to determine the hazard ratios (HR) for the development of metastatic disease based on clinico-pathologic variables, risk groups, and GC score. The area under the receiver operating characteristic curve (AUC) was determined for regression models without and with the GC score. RESULTS: Over a median follow-up of 82 months, 104 patients (26%) developed metastatic disease. On univariable analysis, increasing GC score was significantly associated with metastatic disease ([HR]: 1.34 per 0.1 unit increase, 95% confidence interval [CI]: 1.19-1.50, p < 0.001), while age, serum PSA, biopsy GG, and clinical T-stage were not (all p > 0.05). On multivariable analysis, GC score (HR: 1.33 per 0.1 unit increase, 95% CI: 1.19-1.48, p < 0.001) and GC high-risk (vs low-risk, HR: 2.95, 95% CI: 1.79-4.87, p < 0.001) were significantly associated with metastasis. The addition of GC score to regression models based on NCCN risk group improved model AUC from 0.46 to 0.67, and CAPRA from 0.59 to 0.71. CONCLUSIONS: Among men with high-risk prostate cancer, conventional clinico-pathologic data had poor discrimination to risk stratify development of metastatic disease. GC score was a significant and independent predictor of metastasis and may help identify men best suited for treatment intensification/de-escalation.

Silencing KLK12 expression via RGDfC-decorated selenium nanoparticles for the treatment of colorectal cancer in vitro and in vivo.

Short interfering RNA (siRNA) has been investigated as a promising modality of cancer treatment due to its capability to target specific target genes for downregulation. However, the successful application of this strategy depends on producing a safe and effective carrier system for delivering siRNA to the tumor. Thus, investigation of siRNA delivery carriers is a fundamental step in the field of siRNA-based therapeutics. In the current research, the surface of selenium nanoparticles (SeNPs) were modified with the tumor-targeted molecular RGDfC peptide with positive charge to synthetize the biocompatible siRNA carrier RGDfC-SeNPs. Subsequently, KLK12-siRNA was loaded onto the surface of RGDfC-SeNPs to create functionalized nanoparticles (RGDfC-Se@siRNA) that we tested for in vitro and in vivo antitumor efficacy. We measured significantly greater particle uptake in HT-29 colorectal cancer cells relative to HUVECs, providing evidence for the targeted delivery of RGDfC-Se@siRNA. We found that RGDfC-Se@siRNA could enter HT-29 cells primarily via clathrin-mediated endocytosis. Further, these particles experienced faster siRNA release in an acidic microenvironment compared to pH 7.4. The results from quantitative PCR and Western blot assays suggested that the target gene of KLK12 in HT-29 cells were obviously silenced by RGDfC-Se@siRNA. The further biological studies showed that treatment with RGDfC-Se@siRNA had ability to suppress the proliferation and migration/invasion of HT-29 cells, and triggered HT-29 cells apoptosis. RGDfC-Se@siRNA could induce the mitochondrial membrane potential (MMP) disruption and enhance the reactive oxygen species (ROS) generation in HT-29 cells, indicating that RGDfC-Se@siRNA induced the HT-29 cells apoptosis possibly by a ROS-mediated mitochondrial dysfunction pathway. Importantly, the in vivo antitumor study also verified that RGDfC-Se@siRNA could significantly suppress the growth of tumor in vivo. In addition, we did not observe any signs of systemic or tissue-specific toxicity after administration of RGDfC-Se@siRNA in mice. As a whole, these findings suggest that RGDfC-Se@siRNA has promising potential as a therapy for colorectal cancer.

Biological therapy in hereditary angioedema: transformation of a rare disease.

Introduction: Hereditary angioedema, a disabling condition, with high mortality when untreated, is caused by C1 inhibitor deficiency and other regulatory disorders of bradykinin production or metabolism. This review covers the remarkable progress made in biological therapies for this rare disorder.Areas covered: Over the past 10 years, several evidence-based parenteral treatments have been licensed, including two plasma-derived C1 inhibitor replacement therapies and one recombinant C1 inhibitor replacement for acute treatment of angioedema attacks and synthetic peptides for inhibition of kallikrein or bradykinin B2 receptors, with oral small molecule treatments currently in clinical trial. Moreover, recent advances in prophylaxis by subcutaneous C1 inhibitor to restore near-normal plasma function or by humanized antibody inhibition of kallikrein have resulted in freedom from symptoms for a high proportion of those treated.Expert opinion: This plethora of treatment possibilities has come about as a result of recent scientific advances. Collaboration between patient groups, basic and clinical scientists, physicians, nurses, and the pharmaceutical industry has underpinned this translation of basic science into treatments and protocols. These in their turn have brought huge improvements in prognosis, quality of life and economic productivity to patients, their families, and the societies in which they live.

Feasibility of freehand MRI/US cognitive fusion transperineal biopsy of the prostate in local anaesthesia as in-office procedure-experience with 400 patients.

BACKGROUND: Transrectal (TR) ultrasound-guided prostate biopsy is one of the most commonly performed urologic procedures worldwide. The major drawback of this approach is the associated risk for infectious complications. Sepsis rates are increasing due to rising antibiotic resistance, representing a global issue. The transperineal (TP) approach for prostate biopsy has recently been adopted at many centres as an alternative to the TR biopsy, and it was shown to be associated with a lower risk for sepsis. The aim of this study was to assess safety and tolerability of TP prostate biopsy performed in local anaesthesia. METHODS: We retrospectively analysed data of patients who had undergone office-based TP prostate biopsy in local anaesthesia, performed by a single surgeon between January 2015 and May 2019. We evaluated the patients' acceptance of the procedure by a pain score, as well as its safety and diagnostic performance. RESULTS: Four hundred patients were included. Median age was 66 years [range, 49-86]. Median prostate-specific antigen (PSA) concentration was 6.4 ng/ml [range, 0.3-1400], median PSA density was 0.15 ng/ml2 [range, 0-31.1] and median prostate volume was 40 ml [range, 6-150]. A total of 118 (29.5%) and 105 (26.2%) patients had orally received two and one doses of 500 mg fluoroquinolone, respectively, and 177 (44.3%) patients did not receive any antibiotic prophylaxis. No infectious complications occurred. Median pain score was 2.0 (range, 0-8). Overall cancer detection rate was 64.5% (258/400). CONCLUSIONS: Freehand TP prostate biopsy in local anaesthesia is a safe, effective and well-tolerated outpatient procedure with a high cancer detection rate. The elimination of infectious complications and its high accuracy make this technique a feasible alternative to the TR approach for the urological office. We assume that the single puncture and our trocar-like access sheath introduction technique diminish tissue trauma and bacterial exposition, and thus contribute to these promising results.

Benign Prostatic Hyperplasia Endoscopic Surgical Procedures in Kidney Transplant Recipients: A Comparison Between Holmium Laser Enucleation of the Prostate, GreenLight Photoselective Vaporization of the Prostate, and Transurethral Resection of the Prostate.

Purpose: The main objective of this multicentric retrospective pilot study was to evaluate the 1-year follow-up safety (i.e., minor [Clavien-Dindo I-II] and major [Clavien-Dindo ≥III] complications) of holmium laser enucleation of the prostate (HoLEP), GreenLight photoselective vaporization of the prostate (GL PVP), and transurethral resection of the prostate (TURP) performed after kidney transplantation (KT). The secondary objectives were to evaluate the efficacy and to assess the impact of these procedures on graft function. Materials and Methods: We retrospectively included all KT recipients who underwent a HoLEP or GL PVP or TURP for benign prostatic hyperplasia (BPH) in three French university centers. Results: From January 2013 to April 2018, 60 BPH endoscopic surgical procedures in KT recipients were performed: 17 HoLEP (HoLEP group), 9 GL PVP (GL PVP group), and 34 TURP (TURP group). Age, body mass index, preoperative serum creatinine, preoperative International Prostatic Symptom Score, preoperative Qmax, preoperative prostate-specific antigen, medical history of acute urinary retention (AUR), urinary tract infection (UTI), and indwelling urethral catheter were similar in all study groups. Mean preoperative prostate volume was higher in HoLEP group. The rate of overall postoperative complications was statistically higher in the HoLEP group (11/17 [64.7%] vs 1/9 [11.1%] vs 12/34 [35.3%] in HoLEP group, GL PVP group, and TURP group, respectively, p = 0.02), with higher rate of long-term UTI and AUR. Qmax improved in all groups after operation. Delta postoperative month 12-preoperative serum creatinine was similar in the all groups. Conclusions: Although our study is underpowered, the rate of postoperative complications is higher with HoLEP procedure, in comparison with GL PVP, for the treatment of BPH after KT. One-year efficacy is similar in HoLEP, GL PVP, and TURP groups. Further prospective randomized controlled trials are needed to confirm our results.

miR-191 promotes radiation resistance of prostate cancer through interaction with RXRA.

Radiation therapy is a common treatment for prostate cancer, however recurrence remains a problem. MicroRNA expression is altered in prostate cancer and may promote therapy resistance. Through bioinformatic analyses of TCGA and CPC-GENE patient cohorts, we identified higher miR-191 expression in tumor versus normal tissue, and increased expression in higher Gleason scores. In vitro and in vivo experiments demonstrated that miR-191 overexpression promotes radiation survival, and contributes to a more aggressive phenotype. Retinoid X receptor alpha, RXRA, was discovered to be a novel target of miR-191, and knockdown recapitulated radioresistance. Furthermore, treatment of prostate cancer cells with the RXRA agonist 9-cis-retinoic acid restored radiosensitivity. Supporting this relationship, patients with high miR-191 and low RXRA abundance experienced quicker biochemical recurrence. Reduced RXRA translated to a higher risk of distant failure after radiotherapy. Notably, this miR-191/RXRA interaction was conserved in a novel primary cell line derived from radiorecurrent prostate cancer. Together, our findings demonstrate that miR-191 promotes prostate cancer survival after radiotherapy, and highlights retinoids as a potential option to improve radiotherapy response.

Novel thulium fiber laser for endoscopic enucleation of the prostate: A prospective comparison with conventional transurethral resection of the prostate.

OBJECTIVE: To compare the efficacy and safety of a novel thulium fiber laser for endoscopic enucleation of the prostate with monopolar transurethral resection of the prostate in patients with smaller glands (<80 cc). METHODS: A total of 51 patients underwent thulium fiber laser enucleation of the prostate, and 52 patients underwent monopolar transurethral resection of the prostate. All patients were assessed preoperatively, and at 3, 6, and 12 months postoperatively (International Prostate Symptom Score, maximum urine flow rate, International Prostate Symptom Score-quality of life). Preoperative prostate volumes and prostate-specific antigen levels were comparable (P = 0.543 and P = 0.078, respectively). The complications were graded according to the Clavien classification. RESULTS: Mean surgery time was longer in the thulium fiber laser enucleation of the prostate group (46.6 ± 10.2 vs 39.9 ± 8.6 min, P < 0.001), while catheterization and hospital stay were greater in the transurethral resection of the prostate group (P < 0.001). At 12 months, there were no differences in functional outcomes (International Prostate Symptom Score, maximum urine flow rate). Despite comparable prostate volumes at 12 months (P = 0.864), the prostate-specific antigen level in the thulium fiber laser enucleation of the prostate group (0.5 ± 0.5 ng/mL) was lower than in the transurethral resection of the prostate group (1.1 ± 1.0 ng/mL; P < 0.001). Hemoglobin and serum sodium decrease was lower in the thulium fiber laser enucleation of the prostate group (1.01 ± 0.4 g/dL and 1.1 ± 1.1 mmol/L) than in the transurethral resection of the prostate group (1.8 ± 0.8 g/dL and 4.1 ± 1.1 mmol/L; P < 0.001). Urinary incontinence rates at 12 months were comparable (P = 0.316). CONCLUSIONS: Thulium fiber laser enucleation of the prostate with novel thulium fiber laser in patients with smaller prostate glands (<80 cc) is comparable to transurethral resection of the prostate in voiding parameters improvement and complication rates. At the same time, the technique allows for a more substantial prostate-specific antigen decrease, indicating more complete removal of adenoma.

Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors.

The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.

Identification of Prognostic Biomarkers and Drugs Targeting Them in Colon Adenocarcinoma: A Bioinformatic Analysis.

Objective: To identify prognostic biomarkers and drugs that target them in colon adenocarcinoma (COAD) based on the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus databases. Methods: The TCGA dataset was used to identify the top 50 upregulated differentially expressed genes (DEGs), and Gene Expression Omnibus profiles were used for validation. Survival analyses were conducted with the TCGA dataset using the RTCGAToolbox package in the R software environment. Drugs targeting the candidate prognostic biomarkers were searched in the DrugBank and herbal databases. Results: Among the top 50 upregulated DEGs in patients with COAD in the TCGA dataset, the Wnt signaling pathway and cytokine-cytokine receptor interactions and pathways in cancer Kyoto Encyclopedia of Genes and Genomes pathway analysis were enriched in DEGs. Tissue development and regulation of cell proliferation were the main Gene Ontology biological processes associated with upregulated DEGs. MYC and KLK6 were overexpressed in tumors validated in the TCGA, GSE41328, and GSE113513 databases (all P < .001) and were significantly associated with overall survival in patients with COAD (P = .021 and P = .047). Nadroparin and benzamidine were identified as inhibitors of MYC and KLK6 in DrugBank, and 8 herbs targeting MYC, including Da Huang (Radix Rhei Et Rhizome), Hu Zhang (Polygoni Cuspidati Rhizoma Et Radix), Huang Lian (Coptidis Rhizoma), Ban Xia (Arum Ternatum Thunb), Tu Fu Ling (Smilacis Glabrae Rhixoma), Lei Gong Teng (Tripterygii Radix), Er Cha (Catechu), and Guang Zao (Choerospondiatis Fructus), were identified. Conclusion: MYC and KLK6 may serve as candidate prognostic predictors and therapeutic targets in patients with COAD.