Giuseppe Carrieri

FK506 Rescue for resistant rejection of renal allografts under primary cyclosporine immunosuppression

Seventy-seven patients with ongoing acute rejection on initial CsA therapy were converted to FK506 to attempt graft salvage. Fifty-nine patients had undergone primary transplantation and 18 had been retransplanted; there were 52 cadaveric and 25 living-donor transplants. The indications for conversion to FK506 were ongoing, biopsy-confirmed rejection in all patients, including vascular rejection in 20. The median interval to rescue was 2 months (range 2 weeks to 36 months) after transplantation. Sixty-one of the 77 patients (79%) had already received one or more courses of an antilymphocyte preparation (OKT3: n=33; ALG or ATG: n=1; OKT3+ALG/ATG: n=27). Of the 77 patients, 57 (74%) have been successfully rescued and still have functioning grafts with a mean follow-up of 14 months, with a mean serum creatinine of 2.35±0.97 mg/dl. Eighteen patients were already dialysis-dependent at the time of conversion to FK506; of these, 9 (50%) were successfully salvaged and have a mean serum creatinine of 2.3 mg/dl. Of the 61 patients previously treated with antilymphocyte preparations, 48 (79%) were rescued. In those salvaged, prednisone doses have been lowered from 22.2±7.2 mg/day preconversion to 7.5±5.6 mg/day postconversion, and 12 patients are on FK506 monotherapy. In nondiabetics, mean serum glucose was 101.4±20.5 mg/dl preconversion and 93.2±22 postconversion (P=0.07), uric acid 7.3±2.3 and 7.1±1.5 mg/dl (P=0.53), and triglycerides 199.2±101.6 and 167.2±106.4 mg/dl (P=0.06). Cholesterol levels were significantly lower following FK conversion (207.7±46.5 mg/dl pre. vs. 188.3±39.7 post, P=0.007). FK506 is capable of salvaging renal allografts with ongoing acute rejection on CsA therapy, even when antilymphocyte preparations have been ineffective.

Tumor Size Does Not Predict Risk of Metastatic Disease or Prognosis of Small Renal Cell Carcinomas

PURPOSE We characterized the clinicopathological features and the prognosis of small solid renal tumors defined as tumors 4 cm or smaller. MATERIALS AND METHODS We identified 1,208 patients who were treated with nephrectomy at 5 international academic centers for small solid renal tumors. Clinicopathological parameters and outcome data were collected for each patient and analyzed. RESULTS Of the tumors 88% were renal cell carcinoma and 12% were benign. Of those with renal cell carcinoma 995 (93%) were localized (N0M0) and 72 (7%) presented with metastatic disease. Tumor size did not predict synchronous metastatic disease. The incidence of metastatic disease in the tumor size ranges 0.1 to 1.0, 1.1 to 2.0, 2.1 to 3.0 and 3.1 to 4.0 cm was 7%, 6%, 5% and 8%, respectively (p = 0.322). Survival rates were excellent. The majority of patients who died of renal cell carcinoma (54%) presented with synchronous metastatic disease, but 3% of patients with localized disease also died of renal cell carcinoma. In patients with localized disease there was a 7% chance of recurrence post nephrectomy at 5 years. Progression-free survival (28 months) was better than for patients with metastatic disease having a primary tumor greater than 4 cm (8 months). Tumor size was not retained as an independent prognostic factor of survival in multivariate analyses. The University of California Integrated Staging System and the Karakiewicz nomogram were the best predictors of cancer specific survival for all renal cell carcinoma stages (c-index 0.87). CONCLUSIONS More than 85% of small solid renal tumors are renal cell carcinoma. The majority of localized small renal tumors can be cured with existing surgical approaches. However, there is a small but not insignificant risk of synchronous and metachronous metastatic disease and cancer associated death. Patients considering experimental therapies such as ablation and surveillance should be aware of this. Tumor size alone is not sufficient to distinguish renal cell carcinoma with benign behavior from aggressive small renal cell carcinoma. Survival of patients with small metastatic renal cell carcinoma is better then expected. The biology of these unique tumors should be further studied.

Carbon monoxide ameliorates renal cold ischemia-reperfusion injury with an upregulation of vascular endothelial growth factor by activation of hypoxia-inducible factor.

Background. We have previously shown that carbon monoxide (CO) inhalation at a low concentration provides protection against cold ischemia-reperfusion (I/R) injury after kidney transplantation. As vascular endothelial growth factor (VEGF) may promote the recovery process of impaired vascular endothelial cells during I/R injury, we examined whether protective effects of CO involved VEGF induction and its upstream hypoxia-inducible factor (HIF)-1 activation. Methods. Lewis rat kidney graft, preserved in University of Wisconsin at 4°C for 24 hr, was orthotopically transplanted into syngeneic recipient. Recipients were continuously maintained in air or exposed to CO (250 ppm) for 1 hr before and 24 hr after transplant. Results. Prolonged cold preservation resulted in progressive impairment of kidney graft function with early inflammatory responses. Carbon monoxide significantly protected kidney grafts from cold I/R injury, improved renal function and enhanced recipient survival. Real-time reverse transcriptase-polymerase chain reaction revealed upregulation of HIF-1&agr; and VEGF in the CO-treated kidney grafts as early as 1 hr after reperfusion. Western blot showed CO significantly upregulated VEGF expression 1 to 3 hr after kidney transplantation. Considerably more VEGF-positive cells were observed mainly in tubular epithelial cells in CO-treated, but not air-exposed, kidney grafts at 3 hr after reperfusion. YC-1, HIF-1&agr; inhibitor, completely abrogated the actions of CO on VEGF induction and reversed the protective effects afforded by CO. Nitric oxide production in the grafts was increased by CO, however, abolished by YC-1. Conclusion. These results demonstrate that the protective effect of CO against renal cold I/R injury may involve VEGF upregulation through its upstream signal, HIF-1 activation.

Oral L-Citrulline Supplementation Improves Erection Hardness in Men With Mild Erectile Dysfunction

OBJECTIVES To test the efficacy and safety of oral L-citrulline supplementation in improving erection hardness in patients with mild erectile dysfunction (ED). L-arginine supplementation improves nitric oxide-mediated vasodilation and endothelial function; however, oral administration has been hampered by extensive presystemic metabolism. In contrast, L-citrulline escapes presystemic metabolism and is converted to L-arginine, thus setting the rationale for oral L-citrulline supplementation as a donor for the L-arginine/nitric oxide pathway of penile erection. METHODS In the present single-blind study, men with mild ED (erection hardness score of 3) received a placebo for 1 month and L-citrulline, 1.5 g/d, for another month. The erection hardness score, number of intercourses per month, treatment satisfaction, and adverse events were recorded. RESULTS A total of 24 patients, mean age 56.5 ± 9.8 years, were entered and concluded the study without adverse events. The improvement in the erection hardness score from 3 (mild ED) to 4 (normal erectile function) occurred in 2 (8.3%) of the 24 men when taking placebo and 12 (50%) of the 24 men when taking L-citrulline (P < .01). The mean number of intercourses per month increased from 1.37 ± 0.93 at baseline to 1.53 ± 1.00 at the end of the placebo phase (P = .57) and 2.3 ± 1.37 at the end of the treatment phase (P < .01). All patients reporting an erection hardness score improvement from 3 to 4 reported being very satisfied. CONCLUSIONS Although less effective than phosphodiesterase type-5 enzyme inhibitors, at least in the short term, L-citrulline supplementation has been proved to be safe and psychologically well accepted by patients. Its role as an alternative treatment for mild to moderate ED, particularly in patients with a psychologically fear of phosphodiesterase type-5 enzyme inhibitors, deserves further research.

Surgical Treatment of Peyronie's Disease by Plaque Incision and Grafting with Buccal Mucosa

BACKGROUND Plaque incision and tunical grafting is widely used to correct penile curvatures secondary to Peyronies disease (PD), but there is no consensus on the ideal graft to be used. OBJECTIVE To evaluate the efficacy, safety, and reproducibility of plaque incision and buccal mucosa grafting (BMG) in the correction of severe penile curvatures secondary to PD. DESIGN, SETTING, AND PARTICIPANTS Fifteen patients reporting normal erections and stable curvature (>12-mo duration) entered this prospective study carried out at two university hospitals. INTERVENTION All patients underwent plaque incision and BMG. MEASUREMENTS Preoperative evaluation included the International Index of Erectile Function (IIEF-5) and penile duplex ultrasounds with measurement of curvature and length of affected side. Follow-up visits were scheduled at 1, 3, 6, and 12 mo postoperatively, then yearly. Three-mo postoperative evaluation included IIEF-5, patient and partner satisfaction, and intracavernous injection test with evaluation of penile rigidity, straightness, and length; patient and partner satisfaction was recorded at all subsequent visits. RESULTS AND LIMITATIONS Mean patient age was 56.3 yr and mean penile curvature 72 degrees ; five patients had a two-sided curvature with mean second curvature of 37 degrees . There were no complications. All patients resumed unassisted intercourse 1 mo after surgery. Three-mo postoperative evaluation showed 100% penile straightening, 1.8-cm mean increase in length of affected side, no curvature recurrence or de novo erectile dysfunction, 1.6 mean increase in IIEF-5 score, and patient and partner satisfaction of 93.3% and 100%, respectively. Although results remained stable at subsequent follow-up (mean 13.1 mo), a greater number of patients and longer follow-up are needed before drawing any definite conclusions. CONCLUSIONS BMG provided excellent short-term results, probably because its prompt revascularisation, suggested by the fast return of spontaneous erections, prevented shrinkage, which is the main cause of graft failure. It also proved to be safe and reproducible, thus representing a valuable treatment option for PD.

TachoSil® Sealed Tubeless Percutaneous Nephrolithotomy to Reduce Urine Leakage and Bleeding: Outcome of a Randomized Controlled Study

PURPOSE We determined the efficacy and safety of TachoSil(®) in sealing the tract after percutaneous nephrolithotomy compared to nephrostomy tube placement. MATERIALS AND METHODS A total of 100 consecutive patients scheduled for percutaneous nephrolithotomy were randomized 1:1 to receive a 16Fr nephrostomy tube (group 1) or TachoSil in the tract (group 2). All patients received a mono-J ureteral catheter. The primary study end points were bleeding and urinary leakage rates. The secondary end points were pain as assessed by the 0 to 10-point visual analog scale, analgesic requirement and hospital stay. RESULTS The groups were comparable for preoperative and operative variables. In group 1, 3 patients were excluded intraoperatively because of relevant bleeding, and in group 2, 1 patient was excluded intraoperatively because of hydrothorax. Tract complications were significantly more frequent in group 1 than in group 2 (25.5% vs 2%, p <0.001). However, the difference in urinary leakage reached statistical significance (19.1% vs 2%, p = 0.007), whereas that in perirenal hematoma formation did not (6.4% vs 0%, p = 0.113). There was no difference between the groups in mean ± SD number of analgesic doses (1.17 ± 1.56 vs 1.20 ± 1.69, p = 0.791) and visual analogue scale scores (4.77 ± 2.28 vs 4.24 ± 2.32, p = 0.270). Postoperative hospital stay was significantly shorter in group 2 than in group 1 (5.15 ± 1.74 vs 2.75 ± 1.78 days, p <0.0001). CONCLUSIONS Although failing to reduce pain and analgesic requirement, TachoSil provided better tract control and a shorter hospital stay than nephrostomy tube placement, thus allowing the extension of indications for tubeless percutaneous nephrolithotomy to most procedures.

Pentraxin 3: A Novel Biomarker for Predicting Progression from Prostatic Inflammation to Prostate Cancer

Pentraxin-3 (PTX3) is a member of the pentraxin family of innate immune regulators, which includes C-reactive protein (CRP). PTX3 has been implicated in angiogenesis, proliferation, and immune escape in cancer. In the present study, we evaluated PTX3 tissue expression and serum concentration as a biomarker to discriminate prostatic inflammation and benign prostatic hyperplasia (BPH) from prostate cancer, and to determine whether PTX3 status may predict progression from BPH to prostate cancer. We analyzed 40 patients with biopsy-proven BPH who underwent a second prostate biopsy 12 to 36 months later when they were diagnosed with prostate cancer or inflammation/BPH (n = 20 patients each group). Furthermore, we evaluated PTX3 serum concentrations in an independent set of patients with biopsy-proven inflammation/BPH (n = 61) and prostate cancer (n = 56). We found reduced PTX3 tissue expression in patients with prostatic inflammation/BPH compared with patients who developed prostate cancer. In the latter group, there was an increase in PTX3 tissue expression between the first and second prostate biopsy. PTX3 serum levels were also higher in patients with prostate cancer than in patients with inflammation/BPH. In contrast, there was no difference in serum PSA or CRP levels in these two groups. ROC curve analysis confirmed the reliability of PTX3 serum levels in predicting prostate cancer development, identifying a cutoff value of 3.25 ng/mL with a sensitivity and a specificity of 89.3% and 88.5%, respectively. In summary, our results encourage further evaluation of PTX3 as a tissue biopsy and blood-borne biomarker to discriminate BPH from prostate cancer.

Predictive markers in bladder cancer: Do we have molecular markers ready for clinical use?

Abstract Bladder cancer (BC) is a heterogeneous disease. Approximately 75% of patients present with non-muscle-invasive BC (NMIBC), which has a high recurrence rate and a low but unpredictable progression rate. Conversely, patients with muscle-invasive BC (MIBC) are at high risk for progression and cancer-specific mortality, but, again, disease behavior is unpredictable. To date, risk assessment for tumor recurrence and progression is based on clinico-pathological factors only. A risk assessment calculator that is based on several such parameters is available for NMIBC, but it has been reported to have potential flaws. In the last two decades, great effort has been made to evaluate the prognostic and predictive role of several molecular markers in MIBC and, even more so, in NMIBC, where the need for more precise risk stratification is urgently needed. This review addresses current evidence for the role of several molecular markers easily assessable by immunohistochemical techniques in prognosticating/predicting the outcome of NMIBC and MIBC. To date, because of divergent results among the many studies, no molecular marker has yet entered routine clinical practice; however, some of them (e.g., p53, pRb, p21, and survivin) have proved their predictive value in studies that included a homogeneous patient population on standardized treatment, and, therefore, are probably ready for clinical validation on a larger scale. Even more interesting is the possibility of constructing multimarker panels that could be used in routine clinical practice, as all these markers can easily be evaluated by immunohistochemistry on routine surgical pathology specimens. The molecular markers described herein hold promise for becoming widely available and cost-effective tools for reliable risk assessment, which would represent a great advancement in counseling patients, in selecting them for neoadjuvant and adjuvant treatments, and in determining their eligibility for clinical trials.

Retinoblastoma protein expression predicts response to bacillus Calmette-Guérin immunotherapy in patients with T1G3 bladder cancer

OBJECTIVES Bacillus Calmette-Guérin (BCG) immunotherapy is regarded as the current treatment of choice for stage T1 grade 3 (T1G3) bladder cancer (BC), though its efficacy is limited by high recurrence and progression rate. Identification of molecular prognosticators that might be helpful in discriminating between responders and nonresponders to BCG treatment is therefore of major clinical importance; thus we focused on the cell-cycle related retinoblastoma protein (pRB), which had been already investigated in bladder cancer. The goal of our study was specifically to address whether its expression predicts the outcomes of BCG treatment for patients with T1G3 disease. MATERIALS AND METHODS To address this issue, paraffin-embedded specimens of 27 patients having undergone transurethral resection of T1G3 BC and intravesical instillations of BCG (induction + 1 year maintenance) were immunostained with pRB monoclonal antibody. Patients in whom the bladder muscle was not clearly visible, and healthy, as well as patients with TaG3 tumors or with concomitant carcinoma in situ were excluded. Mean follow-up was 60 months (range 15-135). RESULTS Thirteen tumors showed normal (1% to 50% labeling index) while 14 showed altered pRB expression, consisting of no expression (0% labeling index) in six and overexpression (>50% labeling index) in eight. Recurrence occurred in 10 (37%) patients and mean time to recurrence was 22.8 months (range 6-48). Recurrence rate was 57% in patients with altered and 15% in those with normal pRB expression, with a statistically significant difference in disease-free survival (P = 0.037). Progression occurred in five (18.5%) patients and mean time to progression was 24 months (range 6-48). Progression rate was 36% in patients with altered and 0% in patients with normal pRB expression, with a statistically significant difference in progression-free survival (P = 0.018). CONCLUSIONS In this homogeneous population of T1G3 bladder tumors, altered pRB expression predicted recurrence and progression after BCG treatment. These findings outline the potential role of pRB immunostaining in predicting T1G3 BC response to BCG immunotherapy.

The Combination of Dapoxetine and Behavioral Treatment Provides Better Results than Dapoxetine Alone in the Management of Patients with Lifelong Premature Ejaculation

INTRODUCTION It is not known whether the efficacy of dapoxetine, the only drug approved for the on-demand treatment of premature ejaculation (PE), can be increased by the addition of sexual behavioral treatment (SBTx). AIM To test the hypothesis that combined dapoxetine and SBTx provide better result than dapoxetine alone in the management of patient with lifelong PE. METHODS After a 4-week run-in period, 50 patients with lifelong PE entered a 24-week, open-label, prospective study with a 1:1 assignment. Twenty-five patients (group A) received on-demand dapoxetine 30 mg alone, and the remaining 25 patients (group B) combined on-demand dapoxetine 30 mg and SBTx. The CONSORT 2010 statement was adhered to where possible. MAIN OUTCOME MEASURES The intravaginal ejaculatory latency time (IELT), the premature ejaculation diagnostic tool (PEDT) score, and the treatment-emergent adverse events (TEAEs) were analyzed. RESULTS Mean age was 34.16 years in group A and 34.44y in group B. From baseline to 4-, 12- and 24-week evaluation, both groups experienced a significant (P < 0.0001) increase in mean IELT and decrease in mean PEDT score, but patients in group A showed a significantly lower increase in mean IELT (85.0; 84.8; 130.7; 160.0 vs. 92.0; 137.9; 232.7; 370.7 seconds, respectively; P < 0.0001) and a significantly lower decrease in mean PEDT score (20.4; 18.16; 15.88; 14.68 vs. 19.56; 16.0; 11.96; 7.92, respectively; P < 0.0001) than those in group B. At 24-week evaluation, no patient in group A reached a PEDT score ≤8 (absence of PE) as opposed to 80% of patients in group B. There was no difference between groups in TEAEs rate (16% vs. 16%; P = 1.00). Limitations included the absence of a group receiving SBTx alone or group crossover. CONCLUSIONS Combined dapoxetine and SBTx proved to be more effective than dapoxetine alone in treating patients with lifelong PE, up to restoring a normal ejaculatory function in most of them.