A multidisciplinary group for prostate cancer management: A single institution experience.

Increased knowledge regarding the heterogeneity of Prostate Cancer (PC) and its variable outcomes has generated controversy over the best clinical approach. Nowadays, it is well-known that patient outcomes and clinical management may be improved by an efficient organization of the national health care system. The Interdisciplinary Group for Oncological Care (GICO) for PC patients was created by our healthcare management company in September 2010. Since then, a multidisciplinary internal report was applied to PC patients. This report highlights our methodology and experience of planning a GICO, and illustrates the results obtained for the management of PC patients before and after the adopted GICO criteria in a single institution, the SS Annunziata Hospital (Chieti, Italy).

SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis.

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.

Time-domain analysis of scrotal thermoregulatory impairment in varicocele.

Varicocele is a common male disease defined as the pathological dilatation of the pampiniform plexus and scrotal veins with venous blood reflux. Varicocele usually impairs the scrotal thermoregulation via a hemodynamic alteration, thus inducing an increase in cutaneous temperature. The investigation of altered scrotal thermoregulation by means of thermal infrared imaging has been proved to be useful in the study of the functional thermal impairment. In this study, we use the Control System Theory to analyze the time-domain dynamics of the scrotal thermoregulation in response to a mild cold challenge. Four standard time-domain dynamic parameters of a prototype second order control system (Delay Time, Rise Time, closed poles locations, steady state error) and the static basal temperatures were directly estimated from thermal recovery curves. Thermal infrared imaging data from 31 healthy controls (HCS) and 95 varicocele patients were processed. True-positive predictions, by comparison with standard echo color Doppler findings, higher than 87% were achieved into the proper classification of the disease stage. The proposed approach could help to understand at which specific level the presence of the disease impacts the scrotal thermoregulation, which is also involved into normal spermatogenesis process.

A diagnostic dilemma: dystrophic calcified nodule of the testicle in a patient with no other symptoms - case report and review of the literature.

Dystrophic calcified nodule of the testicle represents an exceptional lesion with an unknown etiology and controversial diagnostic approach. There are very few reports in the literature that have examined this feature. Here, we report the fourth case of dystrophic testis nodule, identified in a 46-year-old man who presented the urologist with a palpable mass on his left testicle and no other symptoms. Histopathological findings were discussed and pooled with those of all previously published series. We believe that this description is particularly innovative because of the absence of symptoms and testicular pain associated with the lesion, and interesting as an attempt to determine the recognition of this rare entity.

Scrotal thermoregulatory model and assessment of the impairment of scrotal temperature control in varicocele.

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.

Androgen deprivation boosts prostatic infiltration of cytotoxic and regulatory T lymphocytes and has no effect on disease-free survival in prostate cancer patients.

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 IFNγ-inducible protein-10/CXCL10 in the glandular epithelium of normal prostate tissue, and restored the CD8(+) lymphocyte depletion occurring in PCa, whereas it significantly increased the CD4(+) lymphocyte infiltrate. Lymphocytes, mostly with CD8(+) 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)(+)CD25(+)CD127(-) T regulatory (Treg) cells. The χ(2) test disclosed the lack of association (P = 0.27) between NHT and the high intratumoral CD8(+)/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(+) and Treg infiltrates, leaves their intratumoral balance unchanged, and thus has no impact on disease-free survival.

The lack of epithelial interleukin-7 and BAFF/BLyS gene expression in prostate cancer as a possible mechanism of tumor escape from immunosurveillance.

PURPOSE: The human prostate is endowed with intraepithelial and stromal lymphocytes, which may develop lymphoid follicles (LF) and allow a local immune response. We sought to investigate whether interleukin (IL)-7 and BAFF/BLyS, two fundamental survival factors for T and B cells, are expressed in the normal and neoplastic prostate and affect intraprostatic lymphocyte homeostasis. EXPERIMENTAL DESIGN: We have used real-time reverse transcription-PCR of microdissected prostatic glands and confocal microscopy to detect cytokine production, combined with immunohistochemistry to characterize intraprostatic lymphocytes. RESULTS: Prostatic epithelia constitutively produce IL-7 and, to a lesser extent, BAFF/BLyS. Indeed, we show that IL-7 receptor alpha is expressed by intraepithelial T lymphocytes and parafollicular T cells, whereas BAFF-R is found on periglandular B lymphocytes and mantle zone B cells of LFs. Prostate-homing B and T lymphocytes are scarcely proliferating, whereas most of them express the antiapoptotic protein bcl-2 and reveal a low apoptotic index in the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. The transition from normal to neoplastic glands in prostate cancer (PCa) is marked by a dramatic decline of IL-7 and BAFF/BLyS production. Accordingly, PCa is characterized by a significant reduction of intraepithelial lymphocytes and loss of LFs. B-cell and T-cell expression of bcl-2 decrease, whereas the apoptotic events increase. The remaining PCa-infiltrating lymphocytes are mostly CD8(+) T cells that lack terminal differentiation and barely penetrate neoplastic glands. CONCLUSIONS: These results suggest that epithelial IL-7 and BAFF/BLyS production support intraprostatic lymphocyte survival. Its loss in PCa is associated with a severe depletion of prostate-associated lymphocytes and points to a novel tumor escape mechanism.

Quality of life evaluation by the EORTC QLQ-C30 questionnaire in patients treated with hormonal treatment in Italy. A QuABIOS group study.

OBJECTIVES: An observational study was planned by the QuABIOS group, to survey the hormonal treatment administered to prostate cancer patients in Italy within a time window of 12 months. We report here a prospective quality of life (QOL) evaluation over time and by hormonal treatment modalities. METHODS: Patients with diagnosis of prostate cancer and treated with hormonal therapy were eligible for this study. The EORTC QLQ-C30 v.3 questionnaire was administered at enrolment, after 6 months and after 12 months from enrolment. RESULTS: 587 patients were enrolled by 33 urological centers. When 1518 visits were considered together independently of time, antiandrogen monotherapy was associated with a significantly better QOL than LHRH-analogue containing treatment modalities in almost all functional scales; cyproterone acetate demonstrated a better physical function and general health status than bicalutamide. When QOL was analyzed in a prospective 12-month window, a worsening of physical function and general health status was observed, notwithstanding, antiandrogens remained significantly associated to a better QOL than LHRH-analogue therapies also over time: a favourable physical function and general health status appeared again to be related to cyproterone acetate than bicalutamide. CONCLUSIONS: Androgen deprivation therapy is associated with decline in QOL, particularly in the domains of physical function, energy, and general health status. This survey demonstrated that antiandrogens had a better QOL profile than LHRH-analogue containing therapies;furthermore, a more favourable tolerability for cyproterone acetate as compared to bicalutamide is suggested.

Dynamics of male sexual arousal: distinct components of brain activation revealed by fMRI.

The peripheral mechanisms of male sexual arousal are well known. Recently, neuroimaging techniques, such as PET or fMRI, allowed the investigation of the subjacent cerebral mechanisms. In ten healthy subjects, we have simultaneously recorded fMRI images of brain activation elicited by viewing erotic scenes, and the time course of penile tumescence by means of a custom-built MRI-compatible pneumatic cuff. We have compared activation elicited by video clips with a long duration, that led to sexual arousal and penile erection, and activation elicited by briefly presented still images, that did induce sexual arousal without erection. This comparison and the use of the time course of penile tumescence in video clips allowed to perform a time resolved data analysis and to correlate different patterns of brain activation with different phases of sexual response. The activation maps highlighted a complex neural circuit involved in sexual arousal. Of this circuit, only a few areas (anterior cingulate, insula, amygdala, hypothalamus, and secondary somatosensory cortices) were specifically correlated with penile erection. Finally, these areas showed distinct dynamic relationships with the time course of sexual response. These differences might correspond to different roles in the development and appraisal of the sexual response. These findings shed light on the psychophysiology of male sexuality and open new perspectives for the diagnosis, therapy, and possible rehabilitation of sexual dysfunction.

[Pathology of the gynecologic ureter]. / La patologia dell'uretere ginecologico.

OBJECTIVE: Ureteral lesions due to pelvic endometriosis, gynecological surgery and post-actinic are common findings in urology. Pelvic endometriosis can also be caused by a direct or indirect ureteral lesion after laparoscopic procedures. Stenosing ureteral lesions can be found after major gynecological surgery and after laparoscopic procedures. Many surgical techniques have been described to reduce the risks and to correct the complications. MATERIALS AND METHODS: In our experience (1985-2000) we registered 2 ureteral lesions due to pelvic endometriosis. The patients were treated with resection and end-to-end anastomosis. We also protected the site of suture with omentoplasty. 49 patients developed a post-actinic ureteral lesion (43 unilaterally and 6 bilaterally). In 20 cases we performed an end-to-end anastomosis, in 25 cases we re-implanted the ureter and in 10 cases we performed a psoas hitch. In 36 patients we performed an omentoplastic procedure. Ureteral lesions after gynecological surgery were registered in 44 patients (33 after trans-vaginal hysterectomy, 6 after colposuspension, 5 after Wertheim). 40 ureters underwent open air surgery (26 patients, resection + end-to-end anastomosis, 6 patients simple re-implantation, 4 psoas hitch). In 32 patients we performed an omentoplastic procedure. 4 patients were corrected with an endoscopic procedure. These patients had a fulgurating lesion of the ureter with a consequent urinary fistula. A long-term drainage with endoureteral stent avoided the operation. All patients with an acute ureteral lesion were treated with a nephrostomic drainage and a short term repair. RESULTS: In 2 patients with ureteral lesions due to pelvic endometriosis the results after corrective operation (3-4 years follow-up) were excellent with a good conservation of kidney function. In patients that underwent operation due to post-actinic ureteral stenosis, long-term results were: 78% complete preservation of kidney function without the need for permanent stents, 20% preservation of kidney function with need to conserve endoureteral stents, 2% loss of kidney function and consequent nephrectomy. Long-term results in patients that underwent an operation for ureteral lesions following surgical gynecological procedures were: 87% complete preservation of kidney function without the need of permanent stents, 13% conservation of kidney function but no need to preserve the endoureteral stent. DISCUSSION: Lower urinary tract lesions after gynecological surgery are present in every surgical study. Most authors describe that intraoperative cystoscopy can immediately enhance the problem avoiding a re-operation. The laparoscopic risk seems to be for the cardinal ligaments when they divide beneath the uterine veins. Most authors seem to agree with the immediate need for a nephrostomic drainage followed by a postponed intervention. These procedures seem to reduce morbidity and the risk for a re-operation. In extended ureteral lesions there is agreement that psoas hitch is the best procedure. In our experience a nephrostomic drainage and a postponed intervention (2 weeks) has given comparable results with the best in literature as far as kidney function is concerned. The worst results were registered in patients with chronic lesions and with a deteriorated kidney function at the moment of the corrective procedure.