Adenoid cystic carcinoma of the breast and intraoperative electron radiotherapy: single case report and review of literature.

Adenoid cystic carcinoma (ACC) of the breast is a very rare neoplasm. It presents a triple-negative phenotype in most cases, but its prognosis is generally considered to be better than other breast cancers with the same immunohistochemical pattern. Due to its controversial features, no data are available in the literature regarding a consensus approach for ACC treatment, especially for subtypes with worse prognosis like solid basaloid ACC. We present for the first time a rare case of ACC with multifocal presentation treated with breast-conservative surgery and intraoperative electron radiotherapy, thus supporting this treatment of ACC in selected patients like young women affected by the solid basaloid variant who commonly present a worse prognosis. In this case, no local or systemic recurrence was detected after 30 months of follow-up.

Plain language summary Breast cancer is a large group of tumors with different and specific features. Because of its variety, no univocal guidelines are available to medical doctors for the treatment of this disease, especially for the rarest presentations. This is the case for breast adenoid cystic carcinoma, a rare tumor which accounts for less than 0.1% of all breast cancers and about which few instructions for its therapeutic approach or prognosis are described in the literature. This case report describes our experience using partial breast resection in combination with a specific protocol of intraoperative radiation for the treatment of an aggressive variant of breast adenoid cystic carcinoma. Good cosmetic results and no recurrence of the disease were shown, suggesting that a conservative approach could avoid unnecessary total breast resection as supported by some previous authors.

Microsatellite Instability: From the Implementation of the Detection to a Prognostic and Predictive Role in Cancers.

Microsatellite instability (MSI) has been identified in several tumors arising from either germline or somatic aberration. The presence of MSI in cancer predicts the sensitivity to immune checkpoint inhibitors (ICIs), particularly PD1/PD-L1 inhibitors. To date, the predictive role of MSI is currently used in the selection of colorectal cancer patients for immunotherapy; moreover, the expansion of clinical trials into other cancer types may elucidate the predictive value of MSI for non-colorectal tumors. In clinical practice, several assays are used for MSI testing, including immunohistochemistry (IHC), polymerase chain reaction (PCR) and next-generation sequencing (NGS). In this review, we provide an overview of MSI in various cancer types, highlighting its potential predictive/prognostic role and the clinical trials performed. Finally, we focus on the comparison data between the different assays used to detect MSI in clinical practice.

Gene Copy Number and Post-Transductional Mechanisms Regulate TRAP1 Expression in Human Colorectal Carcinomas.

Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a heat shock protein 90 (HSP90) molecular chaperone overexpressed in 60-70% human colorectal carcinomas (CRCs) and the co-upregulation of TRAP1 and associated 6-related proteins identifies metastatic CRCs with poor prognosis. Since the molecular mechanisms responsible for TRAP1 regulation are still unknown, the significance of TRAP1 gene copy number (CN) and the role of post-transductional protein modifications were addressed. TRAP1 gene aneuploidy accounted for 34.5% of cases in a cohort of 58 human CRCs and TRAP1 CN correlated with its mRNA and protein expression, suggesting that transcriptional mechanisms are responsible for TRAP1 upregulation. Furthermore, the analysis of the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium/The Cancer Genome Atlas (CPTAC/TCGA) CRC database showed that TRAP1 polysomy significantly correlates with lymph node involvement. However, a subgroup of tumors showed TRAP1 protein levels independent from its CN. Of note, a direct correlation was observed between TRAP1 protein levels and the expression of S-nitrosoglutathione reductase (GSNOR), a denitrosylase involved in the regulation of protein S-nitrosylation. Furthermore, CRC cell lines exposed to hypoxia or dichloroacetate treatment showed the downregulation of TRAP1 upon GSNOR silencing and this resulted in increased TRAP1 mono/polyubiquitination. These data suggest that transcriptional and post-transductional mechanisms account for TRAP1 expression in human CRCs and GSNOR protects TRAP1 from S-nitrosylation and consequent proteasome degradation mostly in conditions of stress.

[F-18] FDG-PET/CT parameters as predictors of outcome in inoperable NSCLC patients.

BACKGROUND: We evaluated the prognostic significance of standardized uptake value (SUVmax), metabolic tumour volume (MTV), and total lesion glycolysis (TLG) in [F-18] FDG PET/CT findings in patients with inoperable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred and three patients (mean age, 65.6 ± 16 years) underwent [F-18] FDG PET/CT before the chemotherapy. The SUVmax value, the MTV (cm(3); 42% threshold) and the TLG (g) were registered. The patients were followed up to 18 months thereafter (range 12-55 months). Failure to respond without progression, progression and/or disease-related death constituted surrogate end-points. The optimal SUVmax, MTV and TLG cut-off to predict the patients' outcome were estimated. PET/CT results were then related to disease outcome (progression free survival; PFS). RESULTS: The Kaplan-Meier survival analysis for SUVmax showed a significant shorter PFS in patients presenting with lower values as compared to those with higher (p < 0.05, log-rank test). MTV and TLG were not suitable for predicting PFS apart from the subset of patients with mediastinal nodal involvement. CONCLUSIONS: Despite the availability of new tools for the quantitative assessment of disease activity on PET/CT, the SUVmax rather than MTV and TLG remains the only predictor for PFS in NSCLC patients. MTV holds a value only when concomitant nodal involvement occurs.

Pyrosequencing evaluation of low-frequency KRAS mutant alleles for EGF receptor therapy selection in metastatic colorectal carcinoma.

AIM: To evaluate whether pyrosequencing (PS) improves the KRAS mutational status predictive value. PATIENTS & METHODS: A retrospective analysis of KRAS mutations by PS and direct sequencing (DS) in 192 metastatic colorectal carcinomas (mCRCs), subgrouped in 51 KRAS mutated at PS and 141 KRAS wild-type at DS. RESULTS: DS failed to detect low-frequency KRAS mutations in four out of 51 mCRCs, whereas PS detected 12 additional low-frequency KRAS mutations in 141 mCRCs KRAS wild-type at DS. After reanalyzing by PS 97 KRAS wild-type tumors treated with anti-EGF receptor (EGFR) antibodies, nine additional mutations were revealed in nonresponders, whereas none of responders exhibited a KRAS-mutated genotype. Of note, KRAS-mutated tumors upon PS showed a worst progression-free survival after EGFR therapy. Finally, PS allowed the detection of additional NRAS, BRAF and exon 20 PIK3CA mutations mostly in KRAS wild-type mCRCs resistant to EGFR therapy. CONCLUSION: PS detection of low-frequency mutations may improve the KRAS predictive value for EGFR therapy selection.

Applications and limitations of oncogene mutation testing in clinical cytopathology.

In an increased number of settings, cytology represents the only source of sampling and it often substitutes histology as an independent diagnostic modality. Thus, DNA molecular targets to stratify patients for targeted therapy are often evaluated on cytology. In addition, DNA mutational tests may refine indeterminate thyroid and pancreas cytology. This review discusses the applications and limitations of DNA mutational testing on cytology. With respect to histology, most cytological samples have the advantages of a purer population of tumor cells, with low stromal component, a better preserved DNA, and assessing at the same time of sample collection cellular adequacy for DNA testing. However, since in vitro diagnostic tests are licensed only for paraffin-tissue, all mutational assays on cytology are "home brew," requiring a rigorous validation process. This should take into account not only the performance characteristics of the molecular assay but also features inherent to any given cytological samples, such as its source, preparation type, fixation and staining modalities, and the most effective tumor cell enrichment methods. This calls for a change of cytotechnologists and cytopathologists mentality to collect and process the cytological samples not only for microscopy but also to assess clinically relevant molecular markers.

NTRK gene aberrations in triple-negative breast cancer: detection challenges using IHC, FISH, RT-PCR, and NGS.

Triple-negative breast cancer (TNBC) is usually an aggressive disease with a poor prognosis and limited treatment options. The neurotrophic tyrosine receptor kinase (NTRK) gene fusions are cancer type-agnostic emerging biomarkers approved by the Food and Drug Administration (FDA), USA, for the selection of patients for targeted therapy. The main aim of our study was to investigate the frequency of NTRK aberrations, i.e. fusions, gene copy number gain, and amplification, in a series of TNBC using different methods. A total of 83 TNBCs were analyzed using pan-TRK immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR), and RNA-based next-generation sequencing (NGS). Of 83 cases, 16 showed pan-TRK positivity although no cases had NTRK-fusions. Indeed, FISH showed four cases carrying an atypical NTRK1 pattern consisting of one fusion signal and one/more single green signals, but all cases were negative for fusion by NGS and RT-PCR testing. In addition, FISH analysis showed six cases with NTRK1 amplification, one case with NTRK2 copy number gain, and five cases with NTRK3 copy number gain, all negative for pan-TRK IHC. Our data demonstrate that IHC has a high false-positive rate for the detection of fusions and molecular testing is mandatory; there is no need to perform additional molecular tests in cases negativity for NTRK by IHC. In conclusion, the NTRK genes are not involved in fusions in TNBC, but both copy number gain and amplification are frequent events, suggesting a possible predictive role for other NTRK aberrations.

Reference standards for gene fusion molecular assays on cytological samples: an international validation study.

AIMS: Gene fusions assays are key for personalised treatments of advanced human cancers. Their implementation on cytological material requires a preliminary validation that may make use of cell line slides mimicking cytological samples. In this international multi-institutional study, gene fusion reference standards were developed and validated. METHODS: Cell lines harbouring EML4(13)-ALK(20) and SLC34A2(4)-ROS1(32) gene fusions were adopted to prepare reference standards. Eight laboratories (five adopting amplicon-based and three hybridisation-based platforms) received, at different dilution points two sets of slides (slide A 50.0%, slide B 25.0%, slide C 12.5% and slide D wild type) stained by Papanicolaou (Pap) and May Grunwald Giemsa (MGG). Analysis was carried out on a total of 64 slides. RESULTS: Four (50.0%) out of eight laboratories reported results on all slides and dilution points. While 12 (37.5%) out of 32 MGG slides were inadequate, 27 (84.4%) out of 32 Pap slides produced libraries adequate for variant calling. The laboratories using hybridisation-based platforms showed the highest rate of inadequate results (13/24 slides, 54.2%). Conversely, only 10.0% (4/40 slides) of inadequate results were reported by laboratories adopting amplicon-based platforms. CONCLUSIONS: Reference standards in cytological format yield better results when Pap staining and processed by amplicon-based assays. Further investigation is required to optimise these standards for MGG stained cells and for hybridisation-based approaches.

Human- or object-like? Cognitive anthropomorphism of humanoid robots.

Across three experiments (N = 302), we explored whether people cognitively elaborate humanoid robots as human- or object-like. In doing so, we relied on the inversion paradigm, which is an experimental procedure extensively used by cognitive research to investigate the elaboration of social (vs. non-social) stimuli. Overall, mixed-model analyses revealed that full-bodies of humanoid robots were subjected to the inversion effect (body-inversion effect) and, thus, followed a configural processing similar to that activated for human beings. Such a pattern of finding emerged regardless of the similarity of the considered humanoid robots to human beings. That is, it occurred when considering bodies of humanoid robots with medium (Experiment 1), high and low (Experiment 2) levels of human likeness. Instead, Experiment 3 revealed that only faces of humanoid robots with high (vs. low) levels of human likeness were subjected to the inversion effects and, thus, cognitively anthropomorphized. Theoretical and practical implications of these findings for robotic and psychological research are discussed.

OSAHS Growth Impairment and Resolution after Adenotonsillectomy in Children.

Introduction: One of the most important complications of OSAHS in children is growth delay. The aim of this study was to investigate changes in clinical body growth, and laboratory growth in children with OSAHS after adeno-tonsillar surgery. Materials and Methods: In our study, among 102 children suffering from sleep-disordered breathing, 70 met the inclusion criteria because they were affected by OSAHS and adenotonsillar hypertrophy. In total, 96 children affected by adeno-tonsillar hypertrophy (55 males and 41 females) underwent nocturnal cardiorespiratory monitoring with Embletta MPR, monitoring for post-operative 24 hours. Patients underwent blood sampling to evaluate preoperative GH and IGF-1 serum levels, "placement" in Cacciari's growth charts and adenotonsillectomy and saturation monitoring for post-operative 24 hours. According to auxological parameters, 82.86% of the patients were below the fiftieth percentile of BMI Cacciari's growth charts and IGF-1 preoperative serum levels were below the normal range. All patients underwent adenotonsillectomy. Results: All 70 patients recovered from OSAHS according to the results of nocturnal cardiorespiratory monitoring after six months. IGF-1 serum levels significantly increased after three months and one year after. All the auxological parameters showed a significant increase after surgery. We calculated the average annual growth in height of the patients before and after adenotonsillectomy (AT): the growth rate was impaired by OSAHS (5.4±1.3 cm/year), while in the following year post-surgery we found a significant growth speed acceleration (9.9±1.7 cm/year, P=0.001). Conclusions: In conclusion, growth delay in children can be caused by OSAHS, and when it is due to adenotonsillar hypertrophy, adenotonsillectomy is to be considered as the therapy of choice.

Primary malignant melanoma of the esophagus: a clinicopathologic study of a case with comprehensive literature review.

Primary malignant melanoma originating in the digestive tract is particularly rare, mainly affecting the anorectum and oral cavity. Primary malignant melanoma of the esophagus has been the subject mostly of case reports. This tumor has a dismal prognosis with a frequency estimated to be approximately 0.1% to 0.2% of all esophageal malignancies. According to the review by Volpin et al of November 2002, 238 cases of primary malignant melanoma of the esophagus have been published up to early 2001. We present an additional case of primary malignant melanoma of the esophagus of the amelanotic variant in a 69-year-old man. The patient was preoperatively investigated by esophageal endoscopy and endoscopic ultrasound. The surgically resected tumor specimen was examined histologically and supplemented by immunohistochemical and ultrastructural analysis. Intra-abdominal relapse occurred after 8 months at the site of surgery, necessitating repeat resection. The patient died of advanced intra-abdominal disease 14 months after the primary diagnosis. A comprehensive computerized (PubMed/Medline) review of the world literature was also carried out and 99 additional cases (after the review by Volpin et al) were found, 9 of them from the 1990s which escaped previous tabulations, and 90 from the years 2000 to 2010, amounting to a grand total of 337 ever published.

Solitary fibrous tumor of the central nervous system: a 15-year literature survey of 220 cases (August 1996-July 2011).

We reviewed the world literature on solitary fibrous tumors of the central nervous system from August 1996 to July 2011, focusing on both clinicopathological features and diagnostic findings. The anatomical distribution of the 220 cases reported so far reveals that most are intracranial and just over one-fifth are intraspinal. In decreasing frequency, intracranial tumors involve the supratentorial and infratentorial compartments, the pontocerebellar angle, the sellar and parasellar regions, and the cranial nerves. Intraspinal tumors are mainly located in the thoracic and cervical segments. Although most solitary fibrous tumors of the central nervous system are dural based, a small subset presents as subpial, intraparenchymal, intraventricular, or as tumors involving the nerve rootlets with no dural connection. Preoperative imaging and intraoperative findings suggest meningioma, schwannoma or neurofibroma, hemangiopericytoma, or pituitary tumors. Immunohistochemistry is critical to establish a definitive histopathological diagnosis. Vimentin, CD34, BCL2, and CD99 are the most consistently positive markers. The usual histologic type generally behaves in a benign manner if complete removal is achieved. Recurrence is anticipated when resection is subtotal or when the tumor exhibits atypical histology. The proliferative index as assessed by MIB1 labeling is of prognostic significance. Occasionally, tumors featuring conventional morphology may recur, perhaps because of minimal residual disease left behind during surgical extirpation. Rare extracranial metastases and tumor-related deaths are on record. Surgery is the treatment of choice. Stereotactic and external beam radiation therapy may be indicated for postsurgical tumor remnants and for unresectable recurrences. Long-term active surveillance of the patients is mandatory.

Diffuse Leukoplakia of the Bladder Ostium-Sparing in Patient Treated with Leuprorelin for Breast Cancer.

CASE: A 55-year-old woman came to our attention in April 2020 referring haematuria, frequency and urgency. The patient referred previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer three years ago. Urine culture was performed and resulted always negative for pathogens. Cystoscopy revealed a whitish plaque lesion on the fundus, dome, trigone, and left lateral wall of the bladder. Histology of the biopsy confirmed the diagnosis of leukoplakia of the bladder. The plan is to follow her up repeating a cystoscopy every three months and biopsy in 6 months. Literature search revealed very little information on pathogenesis and prognosis of this condition due to its rare occurrence. The main objective of our case study was to describe individual situation of a woman affected by diffuse leukoplakia of the bladder ostium-sparing with a previous treatment with leuprorelin 3.75 mg/2 ml for breast cancer and to show safety of follow-up by cystoscopy and biopsy. CONCLUSIONS: We showed a case of a woman treated with leuprorelin and with diffuse leukoplakia of the bladder. We support the recommended long-term follow-up and surveillance based on the literature review by cystoscopy with or without biopsy.

Metaplastic breast cancer. A case series.

Special type breast cancers display a wide range of different histological types in which clear recommendations on clinical and therapeutic management still lack and most of the information available derive from case report and case studies. In particular metaplastic breast cancer (MBC) is a rare and aggressive type of breast cancer accounting for around 1% of breast malignancies. We reported our experience in the management of five patients with MBC diagnosed and treated in our institution during the last few years (2016-2020). KEY WORDS: Metaplastic breast cancer, Special type breast cancers.

Cationic Channel TRPV2 Overexpression Promotes Resistance to Cisplatin-Induced Apoptosis in Gastric Cancer Cells.

Gastric cancer (GC) is characterized by poor efficacy and modest clinical impact of current therapies, in which apoptosis evasion is relevant. Intracellular calcium homeostasis dysregulation is associated with apoptosis escaping, and aberrant expression of calcium regulator genes could promote GC drug resistance. Since we previously found a prognostic value for TRPV2 calcium channel expression in GC, we aimed to characterize the role of TRPV2 in cisplatin resistance. Using the TCGA-STAD dataset, we performed a differential gene expression analysis between GC samples in upper and lower tertiles of TRPV2 expression, and then through a gene set analysis, we highlighted the enriched ontology and canonical pathways. We used qRT-PCR to assess TRPV2 expression in three GC cell lines and flow cytometry to evaluate cisplatin-induced cell death rates. Calcium green-1-AM assay was used to estimate differences in intracellular Ca2+ concentrations after inhibition of TRPV2. We engineered AGS cell line to overexpress TRPV2 and used confocal microscopy to quantify its overexpression and localization and flow cytometry to evaluate their sensitivity to cisplatin. Consistent with our hypothesis, among enriched gene sets, we found a significant number of those involved in the regulation of apoptosis. Subsequently, we found an inverse correlation between TRPV2 expression and sensitivity to cisplatin in GC cell lines. Moreover, we demonstrated that inhibition of TRPV2 activity by tranilast blocks the efflux of Ca2+ ions and, in combination with cisplatin, induced a significant increase of apoptotic cells (p = 0.004). We also demonstrated that TRPV2 exogenous expression confers a drug-resistant phenotype, and that tranilast is able to revert this phenotype, restoring cisplatin sensitivity. Our findings consistently suggested that TRPV2 could be a potential target for overcoming cisplatin resistance by promoting apoptosis. Notably, our data are a prerequisite for the potential reposition of tranilast to the treatment of GC patients and anticipate the in vivo evaluation.

The relationship of testosterone to prostate-specific antigen in men with sexual dysfunction.

INTRODUCTION: Concern about a testosterone (T)-induced prostate-specific antigen (PSA) increase is often perceived as one of the main limitations in treating hypogonadism even when it is symptomatic, such as in subjects with sexual dysfunction (SD). AIM: The aim of this study was to evaluate the relationship between T and PSA levels in subjects with SD. Methods. We retrospectively evaluated the relationship between T and PSA in 2,291 subjects seeking medical care at our outpatient clinic for SD (sample A). The analysis was then repeated in a selected subpopulation of 1,421 subjects apparently free from prostatic diseases (sample B). MAIN OUTCOME MEASURES: The specific association between PSA levels, circulating androgens, and different clinical signs and symptoms of hypogonadism, as assessed by ANDROTEST structured interview, was evaluated. RESULTS: In both samples A and B, subjects with higher PSA levels reported a lower prevalence of hypogonadism-related symptoms and signs, as well as higher total testosterone (TT), and analogue and calculated free T. However, when the association between PSA and T was evaluated as a function of T deciles, the upper nine groups had similar PSA values, with the lowest demonstrated a significantly reduced PSA (the lowest vs. the rest of the sample: 0.61[0.38-1.23] ng/mL vs. 0.86[0.57-1.44] ng/mL, and 0.51[0.30-0.94] ng/mL vs. 0.73[0.52-1.10] ng/mL, respectively, for samples A and B; both P < 0.0001). Furthermore, when the relationship between hypogonadism (TT < 8 nmol/L) and PSA levels was evaluated according to age, it was significant only in younger subjects, but not in the older ones. CONCLUSIONS: Our data demonstrated that PSA is unrelated to T concentration across most of the T range, except for the most severely T deficient, and that a significant relationship between T and PSA is seen in younger but not in older men.

The effect of statin therapy on testosterone levels in subjects consulting for erectile dysfunction.

INTRODUCTION: Previous clinical studies on effect of statins treatment on testosterone (T) levels have produced mixed results. AIM: The aim of the present study is to evaluate the association between statin therapy and hormonal parameters in a large series of subjects seeking medical care at our unit for erectile dysfunction (ED). METHODS: A consecutive series of 3,484 (mean age 51.6 + or - 13.1 years) patients with ED was studied. MAIN OUTCOME MEASURES: Several hormonal and biochemical parameters were investigated, along with ANDROTEST structured interview measuring hypogonadism-related symptoms. RESULTS: Among the patients studied, 244 (7%) patients were being treated with statins. After adjustment for confounding factors (including body mass index and Progetto Cuore cardiovascular (CV) risk engine score), both total and calculated free testosterone levels were significantly lower in subjects taking statins, when compared to the rest of the sample (hazard ratio [HR] = 0.93 [0.90; 0.96] and 0.26 [0.01; 0.18] for each decrement of total T and calculated free T, respectively; both P < 0.0001). The use of statins was also associated with a reduced testis volume and a higher prevalence of hypogonadism-related symptoms and signs, as assessed by higher ANDROTEST score (HR = 1.12 [1.03; 1.21]; P < 0.01 after adjustment for confounders). Follicle-stimulating hormone levels were significantly higher in subjects treated with statins when compared to the rest of the sample, while there was a trend toward higher luteinizing hormone levels, but this did not reach statistical significance. The lower levels of total and calculated free T observed in subjects treated with statins were also confirmed comparing them with age-waist circumference and CV risk score matched controls. Finally, subjects being treated with statins showed lower prolactin levels when compared to the rest of the sample. CONCLUSIONS: Our data demonstrated that statin therapy might induce an overt primary hypogonadism and should be considered as a possible confounding factor for the evaluation of testosterone levels in patients with ED.

Low testosterone is associated with an increased risk of MACE lethality in subjects with erectile dysfunction.

INTRODUCTION: Although testosterone (T) has been suggested to play a protective role against the development of atherosclerosis, studies demonstrating an association between low T and incident major adverse cardiovascular events (MACE) are scanty in the general population and absent in subjects with erectile dysfunction (ED). AIM: To investigate whether low T in subjects with ED predict incident fatal or nonfatal MACE. METHODS: This is an observational prospective cohort study evaluating a consecutive series of 1687 patients attending our andrological unit for ED. Patients were interviewed using the structured interview on erectile dysfunction (SIEDY) and ANDROTEST structured interviews measuring components relative to ED and hypogonadal-related symptoms, respectively. MAIN OUTCOME MEASURES: Total T was evaluated at baseline. Information on MACE was obtained through the City of Florence Registry Office. RESULTS: Among the patients studied, 5.2, 13.8, and 22.4% were hypogonadal according to different thresholds (T < 8, 10.4 and 12 nmol/L or 230, 300 and 350 ng/dL, respectively). During a mean follow-up of 4.3 + or - 2.6 years, 139 MACE, 15 of which were fatal, were observed. Unadjusted incidence of MACE was not associated with T levels. Conversely, the proportion of lethal events among MACE was significantly higher in hypogonadal patients, using either 10.4 nmol/L (300 ng/dL) or 8 nmol/L (230 ng/dL) thresholds. However, after adjustment for age and Chronic Diseases Score in a Cox regression model, only the association between incident fatal MACE and T < 8 nmol/L (230 ng/dL) was confirmed (HR = 7.1 [1.8-28.6]; P < 0.001). Interestingly, measuring hypogonadal-related symptoms and signs through ANDROTEST, only fatal MACE were also associated with a higher score (HR = 1.2 [1.0-1.5] for each ANDROTEST score increment; P = 0.05 after adjustment for age and Chronic Diseases Score). CONCLUSIONS: T levels are associated with a higher mortality of MACE. The identification of low T levels should alert the clinician thus identifying subjects with an increased cardiovascular risk.

Male sexuality and cardiovascular risk. A cohort study in patients with erectile dysfunction.

INTRODUCTION: Although penile blood flow (PBF) has been recommended as an additional diagnostic test in identifying erectile dysfunction (ED) patients at risk for latent cardiovascular disease, no study has ever assessed the possible association of PBF and the relational component of sexual function with incident major cardiovascular events (MACE). AIM: The aim of this study is to investigate whether severity of ED, PBF, and other factors related to a couple's relationship predict incident MACE. METHODS: A consecutive series of 1,687 patients was studied. Different clinical, biochemical, and instrumental (penile flow at color Doppler ultrasound) parameters were evaluated. MAIN OUTCOME MEASURES: Information on MACE was obtained through the City of Florence Registry Office. RESULTS: During a mean follow-up of 4.3 +/- 2.6 years, 139 MACE, 15 of which were fatal, were observed. Cox regression analysis, after adjustment for age and Chronic Disease Score, showed that severe ED predicted MACE (hazard ratio [HR] 1.75; 95% confidence interval 1.10-2.78; P < 0.05). In addition, lower PBF, evaluated both in flaccid (before) and dynamic (after prostaglandin-E1 stimulation) conditions, was associated with an increased risk of MACE (HR = 2.67 [1.42-5.04] and 1.57 [1.01-2.47], respectively, for flaccid [<13 cm/second] and dynamic [<25 cm/second] peak systolic velocity; both P < 0.05). Reported high sexual interest in the partner and low sexual interest in the patient proved to have a protective effect against MACE. CONCLUSIONS: The investigation of male sexuality, and in particular PBF, and sexual desire, could provide insights not only into present cardiovascular status but also into prospective risk.

Characterization of phosphodiesterase type 5 expression and functional activity in the human male lower urinary tract.

INTRODUCTION: Phosphodiesterase type 5 (PDE5) inhibitors ameliorate low urinary tract (LUT) symptoms in men with ED and symptomatic benign prostatic hyperplasia (BPH). PDE5 is highly expressed in rat and human bladder, where it regulates cyclic guanosine monophosphate (cGMP) degradation, muscle tone, and proliferation. AIM: To investigate PDE5 tissue distribution and activity in human LUT tissues (urethra, prostate, and bladder). MAIN OUTCOME MEASURES: PDE5 expression and activity were analyzed and compared within the same BPH patient in LUT tissues and in smooth muscle cells (SMCs) cultured from urethra, prostate, and bladder. METHODS: In LUT tissues, PDE5 was localized by immunohistochemistry and mRNA expression by quantitative real-time polymerase chain reaction. Proliferation assay was used as readout of PDE5 activity, evaluated as ability of vardenafil to increase the antiproliferative effect of different nitric oxide (NO)/cGMP pathway activators [the PDE5-resistant cGMP analog Sp-8-Br-PET-cGMPS, the NO donor sodium nitroprusside (SNP), and the soluble guanylate cyclase (sGC) stimulator BAY 41-8543]. RESULTS: In all the LUT tissues, PDE5 was immunolocalized in blood vessels and in muscular fibres, but not in epithelium. PDE5 mRNA expression was higher in urethra and bladder than in prostate SMC. The antiproliferative effect of Sp-8-Br-PET-cGMPS was similar in all LUT SMC. In prostatic SMC, SNP and BAY 41-8543 show a dose-dependent antiproliferative effect that resulted marginally enhanced by vardenafil. Conversely, in urethra and bladder SMC the antiproliferative effect of SNP and BAY 41-8543 was lower than in prostatic SMC, but it was significantly enhanced by vardenafil. In urethral and bladder cells vardenafil half-maximal response inhibiting concentration was in the subnanomolar range, whereas in prostate cells it resulted significantly higher. CONCLUSIONS: The highest expression and biological activity of PDE5 was found in bladder. However, a consistent PDE5 expression and activity was also found in prostatic urethra. In contrast, the prostate gland showed the lowest PDE5 abundance and cultures derived from this tissue were less sensitive to vardenafil.