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BackgroundCurrently, there is no efficacious treatment method for chronic prostatitis type IIIb/chronic pelvic pain syndrome (CP/CPPS). Aim of the study was to investigate and compare the efficacy and safety of low-intensity shockwave therapy (LiST) vs. sham treatment in CP/CPPS patients.MethodsPatients with CP/CPPS diagnosis were randomized in this prospective, sham-controlled, double-blind study either to the active groups (Group B, C) who received 5000 shockwaves per session with energy flux density 0.1 mJ/mm2 or to the sham group (Group A) who received 5000 shockwaves from a visually identical sham probe. All groups underwent six sessions (once/week). LiST effects on pain, micturition, quality of life (QoL), and erectile function were evaluated at 4, 12, and 24 weeks after treatment. The parameters were investigated using validated questionnaires. Uroflowmetry and post void residual calculation were performed at baseline and at 4- and 12-week FU visit. Prostate mpMRI and PSA measurement were performed at baseline and 12-week FU visit.ResultsOverall, 45 men were randomized to the active (n = 30) and sham groups (n = 15). Regarding impact of LiST in National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) total, pain, and QoL subdomains scores a clear and persistent in all FU timepoints improvement was found compared to sham treatment. NIH-CPSI urinary subdomain, International Prostate Symptom Score [IPSS], PSA, and mpMRI-PIRADS scores did not differ between the two groups. The mean difference between the LiST and sham group in the change of the NIH-CPSI pain-domain score (Q1–4) from baseline to 12 weeks after final treatment which was 3.3 (95% CI, 1.8, 4.7). Perineal LiST was easy and safe to perform without anesthesia or any side-effects.ConclusionsLiST seems to be a safe and effective treatment option for CP/CPPS, considerably improving pain and quality of life. Lack of any side-effects, and the potential for repetition make LiST a promising treatment choice for CP/CPPS patients.

Chronic inflammation promotes the development of several types of solid cancers and might contribute to prostate carcinogenesis. This hypothesis partly originates in the frequent observation of inflammatory cells in the prostate microenvironment of adult men. Inflammation is associated with putative prostate cancer precursor lesions, termed proliferative inflammatory atrophy. Inflammation might drive prostate carcinogenesis via oxidative stress and generation of reactive oxygen species that induce mutagenesis. Additionally, inflammatory stress might cause epigenetic alterations that promote neoplastic transformation. Proliferative inflammatory atrophy is enriched for proliferative luminal epithelial cells of intermediate phenotype that might be prone to genomic alterations leading to prostatic intraepithelial neoplasia and prostate cancer. Studies in animals suggest that inflammatory changes in the prostate microenvironment contribute to reprogramming of prostate epithelial cells, a possible step in tumour initiation. Prostatic infection, concurrent with epithelial barrier disruption, might be a key driver of an inflammatory microenvironment; the discovery of a urinary microbiome indicates a potential source of frequent exposure of the prostate to a diverse number of microorganisms. Hence, current evidence suggests that inflammation and atrophy are involved in prostate carcinogenesis and suggests a role for the microbiome in establishing an inflammatory prostate microenvironment that might promote prostate cancer development and progression.

Inflammation is inherent in prostatic diseases and it is now accepted that it may facilitate cellular proliferation in both benign and malignant conditions. The strong relationship between prostatic inflammation and pathogenesis of benign prostatic hyperplasia (BPH) is supported by epidemiologic, histopathologic and molecular evidence. Contrariwise, the role of inflammation in prostate carcinogenesis is still controversial, although current data indicate that the inflammatory microenvironment can regulate prostate cancer (PCa) growth and progression. Knowledge of the complex molecular landscape associated with chronic inflammation in the context of PCa may lead to the introduction and optimization of novel targeted therapies. In this perspective, evaluation of the inflammatory component in prostate specimens could be included in routine pathology reports.

Prostate cancer (PCa) is a major cause of death since ancient time documented in Egyptian Ptolemaic mummy imaging. PCa detection is critical to personalized medicine and varies considerably under an MRI scan. 172 patients with 2,602 morphologic images (axial 2D T2-weighted imaging) of the prostate were obtained. A deep learning with deep convolutional neural network (DCNN) and a non-deep learning with SIFT image feature and bag-of-word (BoW), a representative method for image recognition and analysis, were used to distinguish pathologically confirmed PCa patients from prostate benign conditions (BCs) patients with prostatitis or prostate benign hyperplasia (BPH). In fully automated detection of PCa patients, deep learning had a statistically higher area under the receiver operating characteristics curve (AUC) than non-deep learning ( P  = 0.0007 < 0.001). The AUCs were 0.84 (95% CI 0.78–0.89) for deep learning method and 0.70 (95% CI 0.63–0.77) for non-deep learning method, respectively. Our results suggest that deep learning with DCNN is superior to non-deep learning with SIFT image feature and BoW model for fully automated PCa patients differentiation from prostate BCs patients. Our deep learning method is extensible to image modalities such as MR imaging, CT and PET of other organs.

Prostate adenocarcinoma is the second most commonly diagnosed cancer in men worldwide, and the initiating factors are unknown. Oncogenic TMPRSS2:ERG (ERG+) gene fusions are facilitated by DNA breaks and occur in up to 50% of prostate cancers. Infection-driven inflammation is implicated in the formation of ERG+ fusions, and we hypothesized that these fusions initiate in early inflammation-associated prostate cancer precursor lesions, such as proliferative inflammatory atrophy (PIA), prior to cancer development. We investigated whether bacterial prostatitis is associated with ERG+ precancerous lesions in unique cases with active bacterial infections at the time of radical prostatectomy. We identified a high frequency of ERG+ non–neoplastic-appearing glands in these cases, including ERG+ PIA transitioning to early invasive cancer. These lesions were positive for ERG protein by immunohistochemistry and ERG messenger RNA by in situ hybridization. We additionally verified TMPRSS2:ERG genomic rearrangements in precursor lesions using tricolor fluorescence in situ hybridization. Identification of rearrangement patterns combined with whole-prostate mapping in three dimensions confirmed multiple (up to eight) distinct ERG+ precancerous lesions in infected cases. We further identified the pathogen-derived genotoxin colibactin as a potential source of DNA breaks in clinical cases as well as cultured prostate cells. Overall, we provide evidence that bacterial infections can initiate driver gene alterations in prostate cancer. In addition, our observations indicate that infection-induced ERG+ fusions are an early alteration in the carcinogenic process and that PIA may serve as a direct precursor to prostate cancer.

BackgroundThe human microbiome may influence prostate cancer initiation and/or progression through both direct and indirect interactions. To date, the majority of studies have focused on direct interactions including the influence of prostate infections on prostate cancer risk and, more recently, on the composition of the urinary microbiome in relation to prostate cancer. Less well understood are indirect interactions of the microbiome with prostate cancer, such as the influence of the gastrointestinal or oral microbiota on pro- or anti-carcinogenic xenobiotic metabolism, and treatment response.MethodsWe review the literature to date on direct and indirect interactions of the microbiome with prostate inflammation and prostate cancer.ResultsEmerging studies indicate that the microbiome can influence prostate inflammation in relation to benign prostate conditions such as prostatitis/chronic pelvic pain syndrome and benign prostatic hyperplasia, as well as in prostate cancer. We provide evidence that the human microbiome present at multiple anatomic sites (urinary tract, gastrointestinal tract, oral cavity, etc.) may play an important role in prostate health and disease.ConclusionsIn health, the microbiome encourages homeostasis and helps educate the immune system. In dysbiosis, a systemic inflammatory state may be induced, predisposing remote anatomical sites to disease, including cancer. The microbiome’s ability to affect systemic hormone levels may also be important, particularly in a disease such as prostate cancer that is dually affected by estrogen and androgen levels. Due to the complexity of the potential interconnectedness between prostate cancer and the microbiome, it is vital to further explore and understand the relationships that are involved.

Previous studies have shown that various dietary components may be implicated in the aetiology of prostate cancer, although the results remain equivocal. The possible relationship of inflammation derived from dietary exposures with prostate cancer risk has not been investigated. We examined the ability of a newly developed dietary inflammatory index (DII) to predict prostate cancer risk in a case–control study conducted in Italy between 1991 and 2002. A total of 1294 patients aged < 75 years with incident, histologically confirmed carcinoma of the prostate served as cases. A total of 1451 subjects aged < 75 years who were admitted to the same hospitals as cases for a wide spectrum of acute, non-neoplastic conditions served as controls. The DII was computed based on dietary intake assessed using a previously validated seventy-eight-item FFQ. Logistic regression models were used to estimate multivariable OR adjusted for age, study centre, years of education, social class, BMI, smoking status, family history of prostate cancer and total energy intake. Men with higher DII scores had a higher risk of prostate cancer when analysed using the DII as both continuous (OR 1·06, 95 % CI 1·00, 1·13) and categorical, i.e. compared with men in the lowest quartile of the DII, men in the third and fourth quartiles were at elevated risk (ORQuartile 3 v. 1 1·32, 95 % CI 1·03, 1·69 and ORQuartile 4 v. 1 1·33, 95 % CI 1·01, 1·76; P trend= 0·04). These data suggest that a pro-inflammatory diet, as indicated by the increasing DII score, is a risk factor of prostate cancer in Italian men.

SignificanceInflammation promotes the initiation of various malignancies by inducing genetic and epigenetic changes. Here we show that bacterial infection-induced prostatitis results in microenvironmental changes that enhance the differentiation of prostate basal cells into luminal cells, a cellular process that rarely occurs under normal physiological conditions. Previously, we showed in a mouse model that disease initiation for prostate cancer with a basal cell origin requires and is limited by basal-to-luminal differentiation and that prostatic inflammation induced by bacterial infection accelerates disease initiation by enhancing basal-to-luminal differentiation. Collectively, our results show that inflammation-induced microenvironmental changes alter the prostate epithelial lineage differentiation program, and we propose this alteration as a distinct and complementary process through which inflammation promotes tumor initiation. Chronic inflammation has been shown to promote the initiation and progression of diverse malignancies by inducing genetic and epigenetic alterations. In this study, we investigate an alternative mechanism through which inflammation promotes the initiation of prostate cancer. Adult murine prostate epithelia are composed predominantly of basal and luminal cells. Previous studies revealed that the two lineages are largely self-sustained when residing in their native microenvironment. To interrogate whether tissue inflammation alters the differentiation program of basal cells, we conducted lineage tracing of basal cells using a K14-CreER;mTmG model in concert with a murine model of prostatitis induced by infection from the uropathogenic bacteria CP9. We show that acute prostatitis causes tissue damage and creates a tissue microenvironment that induces the differentiation of basal cells into luminal cells, an alteration that rarely occurs under normal physiological conditions. Previously we showed that a mouse model with prostate basal cell-specific deletion of Phosphatase and tensin homolog (K14-CreER;Ptenfl/fl) develops prostate cancer with a long latency, because disease initiation in this model requires and is limited by the differentiation of transformation-resistant basal cells into transformation-competent luminal cells. Here, we show that CP9-induced prostatitis significantly accelerates the initiation of prostatic intraepithelial neoplasia in this model. Our results demonstrate that inflammation results in a tissue microenvironment that alters the normal prostate epithelial cell differentiation program and that through this cellular process inflammation accelerates the initiation of prostate cancer with a basal cell origin.

Background Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common disorder associated with voiding symptoms and pain in the pelvic or perineal area. Macrophages, particularly the pro-inflammatory M1 subtype, are crucial initiating of CP/CPPS. Interferon regulatory factor 7 (Irf7) has been implicated in promoting M1 polarization, contributing to the onset and progression of autoimmunity. However, the role of Irf7 in the etiology and progression of CP/CPPS remains unclear. Method We established the experimental autoimmune prostatitis (EAP) mouse model by subcutaneous injection of prostate antigen combined with complete Freund’s adjuvant. Six weeks after the first immunization, we analyzed the prostates, spleen, and blood to assess the degree of prostate inflammation, Irf7 expression levels, glycolysis, and M1 polarization to evaluate whether Irf7 could exacerbate the development of EAP by enhancing Hif-1α transcription, thereby increasing glycolysis and M1 polarization. Further investigations included sh-Irf7 intervention, Dimethyloxalylglycine (a Hif-1α agonist), and in vitro M1 polarization experiments. We also employed ChIP assays, dual-luciferase reporter assays, and q-PCR to explore if Irf7 could directly interact with the Hif-1α promoter in macrophages. Results In the EAP mouse and cell models, elevated Irf7 expression was observed in inflamed tissues and cells. Reducing Irf7 expression decreased M1 cell glycolysis by inhibiting the nuclear translocation of Hif-1α, thus mitigating M1 cell polarization. Additionally, Irf7 was identified as a transcription factor that regulates Hif-1α transcription by interacting with its promoter in macrophages, confirmed through ChIP and dual-luciferase assays. Co-culturing macrophage cells with 3T3 fibroblasts with reduced Irf7 levels resulted in decreased fibrosis, and a significant reduction in prostate tissue fibrosis was noted in mice with Irf7 knockdown. Conclusion Our findings indicate that Irf7 can contribute to the development and progression of CP/CPPS by promoting glycolysis, which can enhance both M1 polarization as well as interstitial fibrosis in the prostate. This process was found to be mediated by the upregulation of Hif-1α transcription, presenting new potential therapeutic targets for managing CP/CPPS.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a urinary disorder that affects youthful to middle-aged men most frequently. It has been revealed that Th17/Treg imbalance is a crucial factor in the pathophysiological mechanisms behind this disease. However, this imbalance’s mechanisms are unknown. In the experimental autoimmune prostatitis (EAP) mouse model, the NLRP3 inflammasome was turned on, IL-1β levels went up. Moreover, there exists a discernible positive association between the upsurge in IL-1β and the perturbation of Th17/Treg equilibrium. Additionally, we have revealed that IL-1β plays a vital role in promoting the differentiation of Naïve CD4+ T cells into the Th17 cells and enhances the conversion of Treg cells into Th17 cells. Further studies revealed that IL-1β promotes STAT3 phosphorylation, which is what causes Treg cells to become Th17 cells. All data strongly suggest that the NLRP3 inflammatory influence Th17 cell development and the conversion of Treg cells into Th17 cells through IL-1β, disrupting the Th17/Treg balance and exacerbating EAP inflammation. In this article, we provide new theories for the pathogenesis of CP/CPPS and propose new prevention and therapy methods.