From Myo-inositol to D-chiro-inositol molecular pathways.

OBJECTIVE: Inositol is a carbocyclic sugar polyalcohol. By epimerization of its hydroxyl groups, nine possible stereoisomers can be generated, two of major physiological and clinical relevance: myo-inositol and D-chiro-inositol. Myo-inositol and D-chiro-inositol are normally stored in kidney, brain and liver and are necessary for functions, such as signal transduction, metabolic flux, insulin signaling, regulation of ion-channel permeability, stress response and embryo development. In this narrative review, we summarize the mechanisms by which myo-inositol and D-chiro-inositol can be synthesized and absorbed and their possible role in the etiopathogenesis of neural tube defects. MATERIALS AND METHODS: We performed an online search in the PubMed database using the following keywords: "inositol", "D-chiro-inositol", "myo-inositol", "neural tube defects and inositol". RESULTS: Inositol requirements are partly met by dietary intake, while the rest is synthesized endogenously. Inositol deficiency may be involved in the pathogenesis of diseases, such as metabolic syndrome, spina bifida (a neural tube defect), polycystic ovary syndrome and diabetes. Supplementation of the two inositol stereoisomers, D-chiro-inositol and myo-inositol is important to prevent these conditions. CONCLUSIONS: Inositol is fundamental for signal transduction in the brain, kidneys, reproductive organs and other tissues in response to neurotransmitters, hormones and growth factors. Various genes are involved in inositol metabolism and associated pathways. Altered inositol concentrations are observed in several diseases. Analysis of the genes involved in inositol metabolism may provide important information for the clinical management of these conditions.

Effect of metabolic and antioxidant supplementation on sperm parameters in oligo-astheno-teratozoospermia, with and without varicocele: A double-blind placebo-controlled study.

Since sperm require high energy levels to perform their specialised function, it is vital that essential nutrients are available for spermatozoa when they develop, capacitate and acquire motility. However, they are vulnerable to a lack of energy and excess amounts of reactive oxygen species, which can impair sperm function, lead to immotility, acrosomal reaction impairment, DNA fragmentation and cell death. This monocentric, randomised, double-blind, placebo-controlled trial investigated the effect of 6 months of supplementation with l-carnitine, acetyl-l-carnitine and other micronutrients on sperm quality in 104 subjects with oligo- and/or astheno- and/or teratozoospermia with or without varicocele. In 94 patients who completed the study, sperm concentration was significantly increased in supplemented patients compared to the placebo (p = .0186). Total sperm count also increased significantly (p = .0117) in the supplemented group as compared to the placebo group. Both, progressive and total motility were higher in supplemented patients (p = .0088 and p = .0120, respectively). Although pregnancy rate was not an endpoint of the study, of the 12 pregnancies that occurred during the follow-up, 10 were reported in the supplementation group. In general, all these changes were more evident in varicocele patients. In conclusion, supplementation with metabolic and antioxidant compounds could be efficacious when included in strategies to improve fertility.

Geometrical modified nesbit corporoplasty to correct different types of penile curvature: description of the surgical procedure based on geometrical principles and long-term results.

We present the use of a modified corporoplasty, based on geometrical principles, to determine the exact site for the incision in the tunica or plaque and the exact amount of albuginea for overlaying to correct with extreme precision the different types of congenital or acquired penile curvature due to Peyronie's disease. To describe our experience with a new surgical procedure for the enhancement of penile curvature avoiding any overcorrection or undercorrection. Between March 2004 and April 2013, a total of 74 patients underwent the geometrical modified corporoplasty. All patients had congenital curvature until 90° or acquired stable penile curvature 'less' than 60°, that made sexual intercourse very difficult or impossible, normal erectile function, absence of hourglass or hinge effect. Preoperative testing included a physical examination, 3 photographs (frontal, dorsal and lateral) of penis during erection, a 10 mcg PGE1-induced erection and Doppler ultrasound, administration of the International Index of Erectile Function (IIEF-15) questionnaire. A follow-up with postoperative evaluation at 12 weeks, 12 and 24 months, included the same preoperative testing. Satisfaction rates were better assessed with the use of validated questionnaire such as the International Erectile Dysfunction Inventory of the Treatment Satisfaction (EDITS). Statistical analysis with Student's t-test was performed using commercially available, personal computer software. A total of 25 patients had congenital penile curvature with a mean deviation of 46.8° (range 40-90), another 49 patients had Peyronie's disease with a mean deviation of 58.4 (range 45-60). No major complications were reported. Postoperative correction of the curvature was achieved in all patients (100%). Neither undercorrection nor overcorrection were recorded. No significant relapse (curvature>15°) occurred in our patients. Shortening of the penis was reported by 74% but did not influence the high overall satisfaction of 92% (patients completely satisfied with their sexual life). The erectile function was analyzed in both groups, Student's t-test showed a significant improvement in erectile function, preoperative average IIEF-15 scores were 17.43±4.67, whereas postoperatively it was 22.57±4.83 (P=0.001). This geometrical modified Nesbit corporoplasty is a valid therapy which allows penile straightening. The geometric principles make the technique reproducible in multicentre studies.

Minimally invasive infrapubic inflatable penile prosthesis implant for erectile dysfunction: evaluation of efficacy, satisfaction profile and complications.

Erectile dysfunction (ED), the second most common male sexual disorder, has an important impact on man sexuality and quality of life affecting also female partner's sexual life. ED is usually related to cardiovascular disease or is an iatrogenic cause of pelvic surgery. Many non-surgical treatments have been developed with results that are controversial, while surgical treatment has reached high levels of satisfaction. The aim is to evaluate outcomes and complications related to prosthesis implant in patients suffering from ED not responding to conventional medical therapy or reporting side effects with such a therapy. One hundred eighty Caucasian male suffering from ED were selected. The patient population were divided into two groups: 84 patients with diabetes and metabolic syndrome (group A) and 96 patients with dysfunction following laparoscopic radical prostatectomy for prostate cancer (group B). All subjects underwent primary inflatable penile prosthesis implant with an infrapubic minimally invasive approach. During 12 months of follow-up, we reported 3 (1.67%) explants for infection, 1 (0.56%) urethral erosion, 1 (0.56%) prosthesis extrusion while no intraoperative complications were reported. Mean International Index of Erectile Function-5 (IIEF-5) was 8.2 ± 4.0 and after the surgery (12 months later) was 20.6 ± 2.7. The improvement after the implant is significant in both groups without a statistically significant difference between the two groups (P-value 0.65). Mean Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) score 1 year after the implant is 72.2 ± 20.7, and there was no statistically significant difference between groups A and B (P-value 0.55). Implantation of an inflatable prosthesis, for treatment of ED, is a safe and efficacious approach; and the patient and partner satisfaction is very high. Surgical technique should be minimally invasive and latest technology equipment should be implanted in order to decrease after surgery common complications (infection and mechanical failure).

Prognostic value of circulating tumor cells in nonmuscle invasive bladder cancer: a CellSearch analysis.

BACKGROUND: Circulating tumor cells (CTCs) provide prognostic information in patients with metastatic tumors. Recent studies have shown that CTCs are released in circulation in an early phase of cancer disease so that their presence is under investigation in the adjuvant setting. Few studies investigated the prognostic significance of CTCs enumeration in patients with metastatic and advanced bladder cancer. The current study has analyzed the presence of CTC in patients with nonmuscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Forty-four NMIBC patients were enrolled and included in a 24-month follow-up program. Blood drawings were carried out in all patients at the first diagnosis. CellSearch system (Veridex; LLC, Raritan, NJ) was used for CTCs enumeration. RESULTS: CTC were detectable in 8/44 patients (18%). Presence of CTC was found significantly associated to shorter time to first recurrence (6.5 versus 21.7 months, P < 0.001). Median time to progression was not reached, due to the short follow-up period. CTC presence was found associated to concomitant carcinoma in situ and higher T category. CONCLUSION: The detection of CTC in this setting of disease may allow to distinguish patients with high risk of recurrence from those with high risk of progression, as well as to early identify patients candidate for adjuvant treatment.

Primary metastatic neuroendocrine small cell bladder cancer: a case report and literature review.

Small cell carcinoma of the urinary bladder (SCCUB) is a rare variant of neuroendocrine nonepithelial tumor. Clinically, SCCUB appears like a flat or ulcerated lesion and microscopically can cause microvascular invasion and necrosis. Small cell cancer, rarely found in the urogenital tract in a primitive form, usually coexists with urothelial bladder cancers. It has an incidence of 0.35-0.7% of all bladder neoplasms and survival at 5 years is estimated to be around 8%. A 60-year-old man who was a smoker was referred to our department with episodes of gross hematuria and pain in the lumbar region. After an extensive transurethral resection of the bladder, including of the muscular layer, the diagnosis of small cell carcinoma of the bladder was made. The neoplastic cells were positive with immunohistochemical staining for chromogranin A, paranuclear reactivity to cytokeratin and neuron-specific enolase. A total-body CT scan revealed lymph node involvement and hepatic, adrenal and lung metastases. Because of the advanced stage it was decided to avoid radical cystectomy and perform chemotherapy. The patient underwent two different cycles of cisplatin chemotherapy following international recommendations, but unfortunately without any response. After palliative therapy, the patient died in January 2010.

T1G3 high-risk NMIBC (non-muscle invasive bladder cancer): conservative treatment versus immediate cystectomy.

BACKGROUND: The management of stage T1 poorly differentiated G3 bladder cancer invading the lamina propria continues to be debated. These tumours are associated with a high risk of recurrence and progression; concomitant carcinoma in situ and/or multifocality are negative prognostic factors. Choosing between a preserving approach such as trans-urethral resection of the bladder (TURB) followed by maintenance bacillus Calmette-Guerin (BCG) and an invasive approach like cystectomy is critical. PATIENTS AND METHODS: Overall, 80 patients underwent TURB and RE-TURB followed by intra-vesical induction treatment with BCG plus maintenance (Group A) while 72 patients underwent immediate radical cystectomy with extended lymphadenectomy (Group B). Patients were divided into 3 subgroups: uni-focal tumours, multi-focal tumours and carcinoma in situ associated lesions. In Group A, time to first recurrence and time to progression were analysed. A comparison was made between Group A and Group B regarding progression-free survival, cancer-specific survival and overall survival with a median follow-up time of 8.3 years. RESULTS: As far as concerns Group A patients, 42 recurrences (52.5%) were reported in a median time of 10.4 months (range 3-26) and 25 progressions (31.2%) in a median time of 25 months (range 3-68). As far as concerns time to first recurrence and time to progression, both the Kaplan-Meier survival curves obtained are significant and P values are, respectively, 0.0263 and 0.0011. Comparing Groups A and B patients, 25 progressions (31.2%) in a median time of 25 months (range 3-68) and 18 progressions (25%) in a median time of 25.9 months (range 4-72), respectively, were recorded. Regarding overall survival, at 10 years, 24 deaths (42.5%) occurred in a median time of 55.4 months (range 12-94) in Group A and 42 deaths (58.3%) in a median time of 54.9 months (10-100) in Group B. Cancer-specific survival was evaluated in Group A with a total of 18 deaths (22.5%) in a median time of 47.5 months (range 16-78), and in Group B with a total of 16 deaths (22.2%) in a median time of 45.7 months (range 16-88). The progression-free survival Kaplan-Meier curve is not significant, the P value being 0.3801; the overall survival curve is significant with a P value of 0.0487 while the cancer-specific survival curve is not significant with a P value of 0.9762. DISCUSSION: In Group A, considering "time to first recurrence", the difference is greater between unifocal lesions and multifocal or Cis-associated lesions. Conversely, for "time to progression", there is a greater difference between unifocal and multifocal tumours and Cis-associated tumours. Looking at "progression-free survival" in Group A and Group B patients, there is no statistically significant difference, like in cancer-specific survival. A statistically significant difference was observed in overall survival being in favour of conservative treatment thus reflecting that conservative treatment is not burdened by all the surgical and post-operative complications of cystectomy. CONCLUSIONS: Although NMIBC invading the lamina propria, stage G3, with or without Cis-associated lesions are burdened both by a high volume of recurrences and progressions, cystectomy could be considered an aggressive approach. New biological markers are now needed which are able to predict the behaviour of the cancer and to guide the decision-making process between conservative or aggressive treatment.

Intravesical administration of gemcitabine in superficial bladder cancer: a phase I study with pharmacodynamic evaluation.

OBJECTIVE: To determine, in a phase I trial, the local and systemic toxicity and pharmacodynamics of intravesical gemcitabine in patients with superficial bladder cancer. PATIENTS AND METHODS: Twelve patients with histologically confirmed carcinoma localized to the bladder wall (stage T1 or Ta) resistant to previous administration of anticancer drugs and/or of bacille Calmette-Guérin were enrolled. They initially received intravesical gemcitabine starting at 500 mg and increased in 500 mg increments to 2000 mg. Three patients were treated at each dose level. RESULTS: There was no evidence of systemic toxicity and local toxicity was minimal. A pharmacological evaluation showed that gemcitabine was undetectable in plasma and its inactive metabolite (2',2'-difluorodeoxyuridine) was present at a mean (SD) concentration of 1.39 (1.05) mumol/L Deoxycytidine kinase was present in tumour tissue samples, and its activity was 27.3 (12.6) pmol/h/mg tissue; deoxycytidine deaminase activity varied from undetectable to 616 pmol/h/mg tissue. CONCLUSION: Intravesical gemcitabine appears to be well tolerated with no systemic and minimal local toxicity even at the highest dose (2000 mg). A phase II trial of intravesical gemcitabine at 2000 mg given weekly for six consecutive weeks is now in progress in patients with superficial bladder cancer.

Prognostic role of flow cytometry in superficial bladder cancer.

Prognostic factors in superficial transitional cell carcinoma of the bladder were assessed with histopathological and flow cytometry analysis in a series of 61 patients operated transurethrally between 1988 and 1990. In particular, we evaluated the usefulness of flow cytometry in order to identify patients who require a more accurate clinical follow-up or a more aggressive therapy. A multivariate analysis was done in 61 cases, considering patient age and sex, stage, grade and number of lesions (unifocal or multifocal), post-TUR therapy (therapy or not), and DNA ploidy (diploid/aneuploid). DNA pattern and number of recurrences were determinant for selecting risk cases for progression.

[Partial and multiple correlations between 4 types of enzymuria in 2 groups of chronic nephropathic patients]. / Aspetti di correlazione parziale e multipla tra quattro enzimurie in due gruppi di nefropatici cronici.

The urinary activity of four enzymes (NAG, GLU, GRS and GAL) was studied in two groups of patients suffering respectively from interstitial nephritis and chronic glomerulonephritis with the aim of further investigating enzyme variability through the theory of partial and multiple correlation. This study permitted the effects of two enzymes on the known correlations between the remaining two enzyme types to be studied. It was established that very stable relationships exist between each enzyme and the group composed of the remaining three. In particular, in patients with interstizial nephritis, correlations with GAL were all highly significant even if the effect of the other two enzymes was ignored. Similarly, correlations with GRS were strongly significant in patients with chronic glomerulonephritis. In the two groups studied, each enzyme appears to have a highly stable relationship with the other three. Accurate estimates may probably be achieved for GAL and GRS in both groups and for NAG in the glomerulonephritis sufferers. This is further evidence that the enzyme procedure may be used to differentiate between interstitial and glomerular nephritis.

[Behavior of 4 urinary enzymes in healthy subjects in relation to age, sex, body weight and height]. / Il comportamento di 4 enzimurie nei soggetti sani secondo l'età, il sesso, il peso corporeo e la statura.

105 healthy subjects were studied in order to verify results obtained on a smaller sample and revealed some correlations between NAG and GLU and age. It was also found that in male subjects, GAL tended to vary in relation to body weight and in females in relation to age.

[Stage P-1 primary neoplasia of the bladder. Critical evaluation of results obtained with the use of adriamycin and mitomycin C in the prevention of recurrences]. / Neoplasie primitive della vescica allo stadio P1. Valutazione critica dei risultati ottenuti con l'impiego dell'adriamicina e della mitomicina C nella profilassi delle recidive.

However adequately treated, surface carcinomas of the bladder recur sooner or later with infiltration found in about 10% of cases. Any development that may offer therapeutic progress and reduce the incidence of recurrences is therefore of primary importance. Two homogeneous groups of patients were selected for the present study: 35 were given Adriamycin and 25 Mitomycin C. In evaluating results, the incidence of recurrences in relation to the primary neoplasia and the existence of single or multiple tumors was analysed. It is concluded that Mitomycin C in association with either T.U.R. or T.V.R. is a particularly useful and indubitably effective form of topical chemotherapy in cases of single or multiple primary neoplasias.