In vitro angiogenesis inhibition with selective compounds targeting the key glycolytic enzyme PFKFB3.

Abnormal glycolytic metabolism contributes to angiogenic sprouting involved in atherogenesis. We investigated the potential anti-angiogenic properties of specific 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3) inhibitors in endothelial cells (ECs). ECs were treated with PFKFB3 inhibitors (named PA-1 and PA-2) and their effects on metabolic and functional characteristics of ECs were investigated. The anti-glycolytic compound 3-(pyridinyl)- 1-(4-pyridinyl)- 2-propen-1-one (3PO) was used as reference compound. PFKFB3 expression and activity (IC50 about 3-21 nM) was inhibited upon treatment with both compounds. Glucose uptake and lactate export were measured using commercial assays and showed a partial reduction up to 40%. PFKFB3 inhibition increased intracellular lactate accumulation, and reduced expression of monocarboxylate transporters-1 (MCT1) and MCT4. Furthermore, endothelial cell migration and proliferation assays demonstrated significant reduction upon treatment with both compounds. Matrix- metalloproteinase (MMP) activity, measured by gelatin zymography, and expression was significantly reduced (up to 25%). In addition, PA compounds downregulated the expression of VCAM-1, VE-cadherin, VEGFa, VEGFR2, TGF-ß, and IL-1ß, in inflamed ECs. Finally, PA-1 and PA-2 treatment impaired the formation of angiogenic sprouts measured by both morphogenesis and spheroid-based angiogenesis assays. Our data demonstrate that the anti-glycolytic PA compounds may affect several steps involved in angiogenesis. Targeting the key glycolytic enzyme PFKFB3 might represent an attractive therapeutic strategy to improve the efficacy of cancer treatments, or to be applied in other pathologies where angiogenesis is a detrimental factor.

The role of nutraceutical medications in men with non bacterial chronic prostatitis and chronic pelvic pain syndrome: A prospective non blinded study utilizing flower pollen extracts versus bioflavonoids.

INTRODUCTION: Chronic prostatitis (CP)/chronic pelvic pain syndrome (CPPS) represents a challenge for the urologist, since the therapeutic efficacy does not always result in a satisfactory quality of life for the patients. Often the side effects of the medications used (antiinflammatories, antibiotics, alpha blockers) far outweighs the benefits gained with their admission. The choice of nutraceutical medications is preferred for their effectiveness, that has been accepted and proven by the scientific community, and for the low incidence of side effects. The objective of this study to compare the therapeutic efficacy of the flower pollen extracts (Deprox®) versus Bioflavonoids in terms of reduction of symptoms, and in the average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and to evaluate the quality of life improvement of the patients affected by CP/CPPS. METHODS: Among the 68 patients presented with prostatic symptoms to the Hospital "Umberto I" in Rome, Italy between March 2016 and June 2016, 54 patients met the clinical diagnosis of CP/CPPS (class IIIa or IIIb according to the NIH classification). The patients were assigned to either treatment with Deprox® or quercetin based on a randomization scheme previously determined.The NIH- CPSI, IPSS, QoL questionnaires were administered. Every patient underwent bacterial cultures and trans-rectal ultrasound. RESULTS: There was a statistically significant improvement of the NIH-CPSI score and QoL in the Deprox® group (p = < 0.0001 and p = 0.003 respectively). The average waiting time of the variation of the National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI) was statistically significant (p = 0.0019). In the absence of efficacy of the "conventional" medications, which also carries significant side effects, the dietary supplements may represent a valid alternative. CONCLUSIONS: DEPROX® has demonstrated a significant improvement of the symptoms and quality of life of patients diagnosed with by CP/CPPS. Furthermore, there was a statistical difference in the average waiting time of the variation of the NIH-CPSI) score without side effects as compared to the bioflavonoids complex with quercetin.

Total phallic reconstruction after penile amputation for donkey bite: Case report and review of the literature.

There are very few reported cases of traumatic amputation of the male genitalia due to animal bite. The management involves thorough washout of the wounds, debridement, antibiotic prophylaxis, tetanus and rabies immunization followed by immediate reconstruction or primary wound closure with delayed reconstruction, when immediate reconstruction is not feasible. When immediate reconstruction is not feasible, long-term good functional and cosmetic results are still possible in the majority of cases by performing total phallic reconstruction. In particular, it is now possible to fashion a cosmetically acceptable sensate phallus with incorporated neourethra, to allow the patient to void while standing and to ejaculate, and with enough bulk to allow the insertion of a penile prosthesis to guarantee the rigidity necessary to engage in penetrative sexual intercourse.

Malignant priapism due to penile metastases: Case series and literature review.

Malignant priapism secondary to penile metastases is a rare condition. This term was originally used by Peacock in 1938 to describe a condition of painful induration and erection of the penis due to metastatic infiltration by a neoplasm. In the current literature there are 512 case reports. The primary tumor sites are bladder, prostate and rectum. The treatment has only palliative intent and consists of local tumor excision, penectomy, radiotherapy and chemotherapy. We present one case of malignant priapism originated from prostate cancer, and two from urothelial carcinoma of the bladder. Different approaches in diagnosis and therapy were performed. The entire three patient reported a relief of the pain following the treatment, with an improvement of their quality of life, even though it was only temporary as a palliative. Malignant priapism is a rare medical emergency. Penile/pelvis magnetic resonance imaging (MRI) scan and corporal biopsies are considered an effective method of diagnosis of the primary organ site.

When to perform bone scan in patients with newly diagnosed prostate cancer: external validation of a novel risk stratification tool.

PURPOSE: To externally validate the performance characteristics of the Briganti's risk stratification tool for baseline staging bone scan in patients with newly diagnosed prostate cancer (PCa). METHODS: From 2009 onwards, a consecutive series of patients with PCa were enrolled. All patients were staged to evaluate the presence of bone metastasis (BM) with a conventional total-body Tc 99 m MDP scintigraphy performed regardless of baseline PCa characteristics. The area under the curve (AUC) estimates were used to test the accuracy of the Briganti's risk stratification tool that recommended staging baseline bone scan for patients with a biopsy Gleason score >7 or with a prostate-specific antigen (PSA) >10 ng/ml and palpable disease (cT2/T3). The new tool was compared to the European Association of Urology (EAU) guideline. RESULTS: A total of 313 patients were consecutively enrolled. Median age was 68 (range 49-95 years), and median PSA was 7 ng/ml (range 0.81-2,670). Twenty (6.4 %) patients presented BMs. Patients with BMs were significantly older, with higher PSA and a higher Gleason score (p = 0.001). The novel Briganti's model was significantly (p = 0.001) more accurate (AUC: 0.75; CI: 0.632-0.859) than the EAU guideline (AUC: 0.64; CI: 0.52-0.761) for the prediction of BMs. CONCLUSIONS: Our study validated in a group of patients with PCa the novel risk stratification tool proposed by Briganti, which presented a higher accuracy for baseline staging bone scan when compared with the EAU guideline. In our experience, this approach would further reduce (about 60 %) the use of staging baseline bone scan without compromising the ability to detect BMs in patients with PCa.

Ultrasound assessment of intravesical prostatic protrusion and detrusor wall thickness--new standards for noninvasive bladder outlet obstruction diagnosis?

PURPOSE: We evaluated the accuracy of detrusor wall thickness and intravesical prostatic protrusion, and the association of each test to diagnose bladder prostatic obstruction in patients with lower urinary tract symptoms. MATERIALS AND METHODS: We enrolled in the study 100 consecutive patients with lower urinary tract symptoms due to benign prostatic hyperplasia. Baseline parameters were International Prostate Symptom Score, prostate volume, urinary flow rate, intravesical prostatic protrusion, detrusor wall thickness, Schaefer obstruction class, minimal urethral opening pressure and the urethral resistance algorithm bladder outlet obstruction index. A ROC curve was produced to calculate AUC and evaluate the diagnostic performance of intravesical prostatic protrusion, detrusor wall thickness and prostate volume for bladder prostatic obstruction. RESULTS: We noted a highly significant correlation between intravesical prostatic protrusion and the bladder outlet obstruction index (Spearman's rho = 0.49, p = 0.001), and Schaefer obstruction class (Spearman's rho = 0.51, p = 0.001). A highly significant correlation was also observed for detrusor wall thickness and the bladder outlet obstruction index (Spearman's rho = 0.57, p = 0.001), detrusor wall thickness and Schaefer obstruction class (Spearman's rho = 0.432, p = 0.02). On multivariate analysis intravesical prostatic protrusion and detrusor wall thickness were the only parameters associated with bladder prostatic obstruction (p = 0.015). The AUC for intravesical prostatic protrusion was 0.835 (95% CI 0.756-0.915) and for detrusor wall thickness it was 0.845 (95% CI 0.78-0.91). The association of intravesical prostatic protrusion and detrusor wall thickness produced the best diagnostic accuracy (87%) when the 2 tests were done consecutively. CONCLUSIONS: Suprapubic ultrasound of detrusor wall thickness and intravesical prostatic protrusion is a simple, noninvasive, accurate system to assess bladder prostatic obstruction in patients with lower urinary tract symptoms due to benign prostatic hyperplasia.

[18F]ZCDD083: A PFKFB3-Targeted PET Tracer for Atherosclerotic Plaque Imaging.

PFKFB3, a glycolysis-related enzyme upregulated in inflammatory conditions and angiogenesis, is an emerging target for diagnosis and therapy of atherosclerosis. The fluorinated phenoxindazole [18F]ZCDD083 was synthesized, radiolabeled in 17 ± 5% radiochemical yield and >99% radiochemical purity, and formulated for preclinical PET/CT imaging in mice. In vivo stability analysis showed no significant metabolite formation. Biodistribution studies showed high blood pool activity and slow hepatobiliary clearance. Significant activity was detected in the lung 2 h postinjection (pi) (11.0 ± 1.5%ID/g), while at 6 h pi no pulmonary background was observed. Ex vivo autoradiography at 6 h pi showed significant high uptake of [18F]ZCDD083 in the arch region and brachiocephalic artery of atherosclerotic mice, and no uptake in control mice, matching plaques distribution seen by lipid staining along with PFKFB3 expression seen by immunofluorescent staining. In vivo PET scans showed higher aortic region uptake of [18F]ZCDD083 in atherosclerotic ApoE-/-Fbn1C1039G+/- than in control mice (0.78 ± 0.05 vs 0.44 ± 0.09%ID/g). [18F]ZCDD083 was detected in aortic arch and brachiocephalic artery of ApoE-/- (with moderate atherosclerosis) and ApoE-/-Fbn1C1039G+/- (with severe, advanced atherosclerosis) mice, suggesting this tracer may be useful for the noninvasive detection of atherosclerotic plaques in vivo.

Bacillus Calmette-Guérin unresponsiveness in non-muscle-invasive bladder cancer patients: what the urologists should know.

Transurethral resection of bladder (TURB) with adjuvant intravesical bacillus Calmette-Guérin (BCG) remains the gold standard therapy for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC). However, this disease is burdened with a high risk of recurrence or progression. For this reason, we sought to review and summarize the current evidence with a non-systematic Medline/PubMed literature search, regarding optimal treatment in BCG failure patients. Radical cystectomy (RC) should be considered as the preferred option in patients who experience a BCG-failure, especially in case of Ta or T1 high grade recurrence which occurred within 3 months of start-date of induction or in early-intermediate BCG relapsing tumors or in case of recurrence after ≥1 maintenance course with a maintenance exposure ≤6 months. However, in BCG-intolerant patients and in patients unfit or who refuse RC, alternative treatments can be proposed. In particular in BCG intolerant patients a reduction of dwell-time, an increase of length of intervals between the doses, use of anti-inflammatory drugs and antibiotics can be practiced for reducing symptoms. In patients with a low-intermediate grade recurrence for primary intermediate-risk tumor or for CIS disease after a single course of induction, a second induction course of BCG (but not further) can be performed. Intravesical chemotherapeutic agents are considered suboptimal but can be proposed in patients unfit or who refuse RC. On the contrary, combination chemotherapy is not indicated in BCG failure patients. Several ongoing trials are testing with promising prospects the efficacy of cytotoxic agents, immunotherapeutic agents, target therapies, devices and other molecules in BCG-failure patients.

The new Epstein gleason score classification significantly reduces upgrading in prostate cancer patients.

PURPOSE: To evaluate the differences between the old and the new Gleason score classification systems in upgrading and downgrading rates. MATERIALS AND METHODS: Between 2012 and 2015, we identified 9703 patients treated with retropubic radical prostatectomy (RP) in four tertiary centers. Biopsy specimens as well as radical prostatectomy specimens were graded according to both 2005 Gleason and 2014 ISUP five-tier Gleason grading system (five-tier GG system). Upgrading and downgrading rates on radical prostatectomy were first recorded for both classifications and then compared. The accuracy of the biopsy for each histological classification was determined by using the kappa coefficient of agreement and by assessing sensitivity, specificity, positive and negative predictive value. RESULTS: The five-tier GG system presented a lower clinically significant upgrading rate (1895/9703: 19,5% vs 2332/9703:24.0%; p = .001) and a similar clinically significant downgrading rate (756/9703: 7,7% vs 779/9703: 8%; p = .267) when compared to the 2005 ISUP classification. When evaluating their accuracy, the new five-tier GG system presented a better specificity (91% vs 83%) and a better negative predictive value (78% vs 60%). The kappa-statistics measures of agreement between needle biopsy and radical prostatectomy specimens were poor and good respectively for the five-tier GG system and for the 2005 Gleason score (k = 0.360 ± 0.007 vs k = 0.426 ± 0.007). CONCLUSIONS: The new Epstein classification significantly reduces upgrading events. The implementation of this new classification could better define prostate cancer aggressiveness with important clinical implications, particularly in prostate cancer management.

Biparametric versus Multiparametric MRI with Non-endorectal Coil at 3T in the Detection and Localization of Prostate Cancer.

AIM: To assess the sensitivity of biparametric magnetic resonance imaging (bpMRI) with non-endorectal coil in the detection and localization of index (dominant) and non-index lesions in patients suspected of having prostate cancer. PATIENTS AND METHODS: We carried-out a retrospective analysis of multiparametric MRI (mpMRI) of 41 patients who underwent radical prostatectomy. Results of MRI for detection and localization of index and non-index lesions were correlated with those of histology. RESULTS: No statistically significant difference in size was seen between tumor lesion at histology and index lesion at MRI. In 41 patients, a total of 131 tumors were identified at histology, while bpMRI (T2-weighted and diffusion-weighted MRI) approach detected 181 lesions. bpMRI gave 27.6% false-positives and 3.3% false-negatives. Sensitivity in lesion detection by bpMRI increased with lesion size assuming high values for lesions ≥10 mm. For bpMRI and mpMRI, the sensitivity for detecting index lesions was the same and equal: 100% in the peripheral zone 97.6% and 94.7% in the entire prostate and transitional zone, respectively. CONCLUSION: bpMRI can be used alternatively to mpMRI to detect and localize index prostate cancer.

Preoperative staging of resectability of colon cancer using virtual colonoscopy: correlation with surgical results. Our experience.

PURPOSE: To evaluate the clinical usefulness of preoperative computed tomography colonography (CTC) in locoregional staging in patients with abdominal pain secondary toocclusive colorectal cancer (CRC). MATERIALS AND METHODS: 80 patients with abdominal pain underwent CTC initially without contrast and after diagnosis with contrast. 47 patients had distal CRC and 33 had proximal CRC. CTimages were analyzed independently by two radiologists, using MPR reconstruction and VR images. Depending on the anatomical depth of wall invasion primary tumor (T) was classified ≤ T2, T3 and T4. The definition of node disease (N) was based on the number of involved regional lymph nodes. Metastases (M) were characterized by the presence and location of distant disease. Pre treatment stage (cT cN) was compared with pathologic stage (pT pN). Accuracy of CTC was also evaluated. RESULTS: The overall accuracy values for T staging of reviewer 1, reviewer 2 and consensus reading were 91.6%, 86.2% and 92.8% respectively; 92.2%, 79.8% and 92.5% for T2; 88.1%, 85.5%, and 89.7% for T3; and 94.5%, 93.5% and 96.2% for T4. The accuracy values for N staging and M staging were 81,.8%, 94.0% for reviewer 1; 78.2% and 88.1% for reviewer 2; 81.8% and 94.0% for consensus reading, respectively. CONCLUSION: In our experience CTC is not only useful in the evaluation of the proximal bowel, but can also provide surgeons with accurate information about staging and tumor localization. CTC is recommended for better evaluation of preoperative staging. KEY WORDS: CT colonography, Colorectal cancer, Extracolonic findings, Staging.

[Surgery of male infertility: an update]. / Chirurgia dell'infertilità maschile: update.

Surgery for male infertility includes three main areas: varicocele surgery, recanalization of seminal tract, sperm retrieval.Varicocele treatment in infertily is still controversial. Recent scientific evidence appears to demonstrate that in selected cases varicocele treatment is beneficial in improving semen parameters and pregnancy rate. The key for the success of treatment seems to be a correct indication. It is our opinion that varicocele should be treated in presence of abnormal semen parameters, when clinically significant, and in adolescents with atrophy of the affected testis. So far, no specific technique, either surgical, microsurgical or sclerotherapic, can be considered the gold standard. Good results in our hands have been obtained with the microsurgical lymphatic sparing high ligation of internal spermatic vein.Innovations in surgery for seminal tract obstructions include the new tubular invagination techniques for epididimovasostomy, which showed excellent results with a simplified and time-saving microsurgical approach. In distal obstructions, a new transperineal ultrasound-guided approach has been proposed for the diagnostic work-up and treatment. Advantages of this technique and of the TURED must be balanced with those of immediate sperm retrieval for ART.In sperm retrieval, microTESE represents the most important surgical evolution in non-obstructive azoospermia. We have recently proposed a new stepwise approach starting with a minimal equatorial incision for conventional testicular biopsy which is extended to perform microTESE only when no sperm is retrieved. In this way microTESE is offered only to patients who really need it. Another field of innovation is sperm retrieval for ICSI in patients with Klinefelter Syndrome.

Real-time magnetic resonance-guided high-intensity focused ultrasound focal therapy for localised prostate cancer: preliminary experience.

Five patients with unifocal, biopsy-proven prostate cancer (PCa) evident on multiparametric magnetic resonance imaging (MRI) were treated with magnetic resonance-guided focused ultrasound (MRgFUS) ablation before radical prostatectomy (RP). An endorectal probe featuring a phased-array focused ultrasound transducer was positioned for lesion ablation under MRI guidance. The tissue temperature and accumulation of thermal damage in the target zone was monitored during the procedure by MRI thermometry. Overlap between the ablation area and the devascularisation of the target lesion was evaluated by contrast-enhanced MRI performed immediately after treatment. The procedure was uneventful, and no adverse events were observed. RP was safely performed without significant surgical difficulties in relation to the previous MRgFUS treatment. The histopathology report showed extensive coagulative necrosis, with no residual tumour in the ablated area. Significant bilateral residual tumour, not evident on pretreatment MRI, was observed outside the treated area in two patients. MRgFUS ablation of focal localised PCa is feasible and, if confirmed in appropriate studies, could represent a valid option for the focal treatment of localised PCa.

Salvage laparoscopic radical prostatectomy following high-intensity focused ultrasound for treatment of prostate cancer.

OBJECTIVE: To test the feasibility and safety of salvage laparoscopic radical prostatectomy (sLRP) for recurrent prostate cancer after high-intensity focused ultrasound (HIFU) treatment. METHODS: Thirteen men (median age 61.3 years) fulfilled the criteria of recurrent prostate cancer after HIFU undergoing sLRP with HIFU performed using Ablatherm devices (EDAP TMS, Lyon, France). The median interval from primary treatment and biochemical recurrence was 38 months, and the median serum PSA nadir after primary therapy was 1.05 ng\mL. Perioperative data and functional outcome were recorded for each patient. Complications were recorded and graded according to Clavien scale. The prostatectomy specimens were analyzed for Gleason score, extracapsular extension, and surgical margins. Mean follow-up was 14 months. RESULTS: There was no perioperative mortality and no conversion to open surgery was necessary. Mean operation time was 220 minutes, mean blood loss was 150 mL, and none of the patients received any transfusion. On histopathologic evaluation, 8 patients had extracapsular extension (pT3a) and 5 patients had intracapsular disease (pT2b). Positive surgical margins (PSMs) were detected in 2 patients in the pT3a group. Gleason score was 7 (3 + 4) in 6 patients and (4 + 3) in 5 patients. Two patients had a Gleason score of 8. The median time to achieve continence was 6 months. Four patients showed mild incontinence and used 2 pads per day. None of the patients in our series were potent after sLRP. CONCLUSION: sLRP is feasible for men in whom HIFU has failed but has a higher morbidity rate than primary surgery.

Dysregulation of emotions and premature ejaculation (PE): alexithymia in 100 outpatients.

INTRODUCTION: There is still a lack of agreement on etiology, definition, and mechanisms that underlie premature ejaculation (PE) as well as on the different role and interaction between psychological and biological factors. Alexithymia is a deficit in identifying and communicating emotions that is presumed to play an important role in psychosomatic diseases. The influences of alexithymic features on sexuality are still understudied. AIM: Following a previous report on the relationship between alexithymia and erectile dysfunction, the objective of this study was the investigation of alexithymic features in patients with lifelong PE compared with controls, and the relationship between alexithymia level and PE severity. METHODS: We assessed 100 consecutive outpatients with lifelong PE (age range 20-60). A control group of 100 male volunteers was recruited for the control group. The two groups were comparable in age, marital status, and socioeconomic characteristics. MAIN OUTCOME MEASURES: The Toronto Alexithymia Scale (TAS-20) was employed for the assessment of alexithymia. The premature ejaculation severity index was used as self-report measure of PE severity on a multidimensional perspective. RESULTS: Our data show significantly higher scores of alexithymia in patients with PE than in the control group (P < 0.001), and a positive correlation between alexithymia level and PE severity (P < 0.002). With regard to TAS-20 subfactors, an externally oriented cognitive style shows the highest correlation with PE severity (P < 0.001) and the most significant difference in the comparison between PE and control group (P < 0.001). CONCLUSION: These findings suggest that alexithymic features, and in particular, an externally oriented cognitive style, can be seen as possible risk and/or maintenance factors for PE, and may contribute to a more serious manifestation of this condition. Alexithymia could represent an important variable for an integrated diagnosis and treatment of PE in a modern somatopsychic and holistic viewpoint.