Purpose: The value of neoadjuvant hormone therapy (NHT) prior to radical prostatectomy as a means of restraining prostate cancer (PCa) and strengthening its immunotherapy is still uncertain. This article asks whether it subverts immunoregulatory pathways governing tumor microenvironments, and has an impact on patient outcome.Experimental Design: We microdissected epithelium and stroma from cancerous and normal prostate specimens from 126 prostatectomized patients, of whom 76 had received NHT, to detect cytokine/ chemokine gene expression levels by real-time reverse transcriptase PCR. Confocal microscopy was used to identify cytokine/chemokine cell sources, and immunostainings to characterize lymphocyte subsets whose prognostic effects were assessed by Kaplan-Meier analyses.Results: NHT boosted the expression of IL-7 in the stroma and that of IFNg-inducible protein-10/ CXCL10 in the glandular epithelium of normal prostate tissue, and restored the CD8 þ lymphocyte depletion occurring in PCa, whereas it significantly increased the CD4 þ lymphocyte infiltrate. Lymphocytes, mostly with CD8 þ phenotype, expressed the T-cell intracellular antigen-1, granzyme-B, and perforin, typical of cytotoxic-effector T cells. NHT also induced thymus and activation-regulated chemokine/CCL17 production by monocytes/macrophages in the prostate and draining lymph nodes, and increased the number of their Forkhead box P3 (Foxp3)the lack of association (P ¼ 0.27) between NHT and the high intratumoral CD8 þ /Treg ratio indicative of a good prognosis.Conclusions: Androgen withdrawal regulates cytokine/chemokine gene expression in normal prostate and lymphoid tissues, and this probably favors both CD8 þ and Treg infiltrates, leaves their intratumoral balance unchanged, and thus has no impact on disease-free survival.

Critical issues in prostate cancer (PC) are a. identification of molecular drivers of the highly aggressive neuroendocrine differentiation (NED) in adenocarcinoma, and b. early assessment of disease progression.The SRY (sex determining region Y)-box 2 gene, SOX2, is an essential embryonic stem cell gene involved in prostate tumorigenesis. Here we assessed its implications in NED and progression of PC and its diagnostic and prognostic value.Laser microdissection, qRT-PCR, quantitative Methylation-Specific PCR and immunohistochemistry were used to analyze SOX2 gene expression and regulation in 206 PC samples. Results were examined according to the patient's clinical pathological profile and follow-ups. Functional studies were performed using PC cells transfected to overexpress or silence SOX2.SOX2 was consistently downregulated in PC, except in cell clusters lying within lymph node (LN)-positive PC. Multivariate analysis revealed that SOX2 mRNA expression in the primary tumor was significantly associated with LN metastasis. When SOX2 mRNA levels were ≥1.00, relative to (XpressRef) Universal Total RNA, adjusted Odds Ratio was 24.4 (95% CI: 7.54–79.0), sensitivity 0.81 (95% CI: 0.61–0.93) and specificity 0.87 (95% CI: 0.81–0.91). Patients experiencing biochemical recurrence had high median levels of SOX2 mRNA.In both PC and LN metastasis, SOX2 and NED marker, Chromogranin-A, were primarily co-expressed. In PC cells, NED genes were upregulated by SOX2 overexpression and downregulated by its silencing, which also abolished SNAI2/Slug dependent NED. Moreover, SOX2 upregulated neural CAMs, neurotrophins/neurotrophin receptors, pluripotency and epithelial-mesenchymal transition transcription factors, growth, angiogenic and lymphangiogenic factors, and promoted PC cell invasiveness and motility.This study discloses novel SOX2 target genes driving NED and spread of PC and proposes SOX2 as a functional biomarker of LN metastasization for PC.

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Guidelines for management of patients with erectile dysfunction indicate that intraurethral and intracavernosal injection therapies represent the second-line treatment available. Efficacy of intracavernosal injections seems superior to that of the intraurethral delivery of drugs, and this may explain the current larger diffusion of the former modality. Safety of these two therapeutic options is well established; however, the attrition rate with these approaches is significant and most patients eventually drop out of treatment. Newer agents with better efficacy-safety profiles and using user-friendly devices for drug administration may potentially increase the long-term satisfaction rate achieved with these therapies. Topical therapy has the potential to become a firstline treatment for erectile dysfunction because it acts locally and is easy to use. At this time, however, the crossing of the barrier caused by the penile skin and tunica albuginea has limited the efficacy of the drugs used.

Varicocele is defined as the pathological dilatation of the pampiniform plexus and scrotal veins with venous blood reflux. Varicocele may impair scrotal thermoregulation and spermatogenesis, even when present in asymptomatic forms. In this study, we use the control system theory to model scrotal thermoregulation in response to a standardized cold challenge in order to study the functional thermal impairment secondary to varicocele. The proposed model is based on a homeostatic negative feedback loop, characterized by four distinct parameters, which describe how the control mechanisms are activated and maintained. Thermal infrared images series from 49 young patients suffering from left varicocele and 17 healthy controls were processed. With respect to healthy controls, left varicocele patients presented higher basal scrotal temperature and faster recovery of the left hemiscrotum. The model indicated that varicocele alters local heat exchange processes among cutaneous layers and inner structures. The estimated model parameters help in the assessment of the scrotal thermoregulatory impairment secondary to the disease.