Gerardo Flammia

Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients

A double-blind placebo-controlled study was performed in 35 benign prostatic hypertrophy (BPH) patients never treated before. The patients were randomized into two groups, the 1st (18 cases) receiving Serenoa repens extract (160 mg t.d.) for 3 months up to the day before the operation of transvesical adenomectomy and the 2nd (17 cases) receiving placebo. Steroid receptors were evaluated in the nuclear (n) and cytosolic (c) fraction using the saturation analysis technique (Scatchard analysis or single saturating-dose assay) for androgen (AR) and estrogen (ER) receptors and the enzyme immunoassay (EIA) for ER and progesterone receptors (PgR). Scatchard analysis of ERc and ERn revealed the presence of two classes of binding sites, one with high-affinity low-capacity binding and the other with low-affinity high-capacity binding. In the untreated BPH group, ER were higher in the n than in the c fraction: ERn were positive in 14 cases and ERc in 12 of 17 cases. In the BPH group treated with S. repens extract on the contrary, ERn were negative for both binding classes in 17 cases and ERc in 6 of 18 cases. Using EIA, ERn and ERc were detected in all 15 samples examined, but in the treated group, ERn were significantly (p less than 0.01) lower than in the untreated group, whilst ERc remained almost unchanged. Similar results were obtained measuring PgR: the n fraction of the treated group prostatic samples was significantly (p less than 0.01) lower than that of the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Sensitive detection of transitional cell carcinoma of the bladder by microsatellite analysis of cells exfoliated in urine

Transitional cell carcinoma (TCC) is the most common bladder tumor. Urine cytology can identify most high‐grade tumors but sensitivity is lower if one includes lesions of all grades. Microsatellite marker alterations have been found in many tumor types including bladder cancer and have been used to detect cancer cells in body fluids including urine. The aim of our study is to further evaluate feasibility and sensitivity of microsatellite analysis to detect bladder cancer cells in urine. We studied 55 individuals: 21 with symptoms suggestive of bladder cancer, 23 patients with previous history of TCC and 11 healthy subjects. Genomic DNA was extracted from blood lymphocytes, urine sediment, bladder washings and tumor or normal bladder mucosa. Twenty highly informative microsatellite markers were analyzed for loss of heterozigosity (LOH) and microsatellite instability (MIN) by polymerase chain reaction. Microsatellite analysis of urine identified 33 of 34 (97%) patients with either primary or tumor recurrence, whereas urine cytology identified 27 of 34 (79%) patients (p = 0.0001). Detection of microsatellite abnormalities improved the sensitivity of detecting low‐grade and/or stage bladder tumor: from 75–95% for grades G1–G2 and from 75–100% for pTis–pTa tumors. Bladder washings from 25 patients were also analyzed, and in all cases results were identical to those obtained from voided urine. None of the 16 patients without evidence of TCC showed LOH and/or MIN in urine samples or bladder washings. Interestingly, in a patient with persistent bladder mucosa abnormalities, microsatellite alterations were demonstrated 8 months before the histopathologic diagnosis of tumor recurrence. These results further indicate that microsatellite marker analysis is more sensitive than conventional urine cytology in detecting bladder cancer cells in urine and represents a potential clinical tool for monitoring patients with low‐grade/stage TCC.

Mutations of the D310 mitochondrial mononucleotide repeat in primary tumors and cytological specimens

A mononucleotide repeat (D310) in mitochondrial DNA has been recently identified as a mutational hot spot in primary tumors. We analyzed 56 tumors for insertion/deletion mutations in the D310 repeat. A total of 13 mutations were detected. The highest frequency of mutations was found for cervical cancer, followed by bladder tumors, breast cancer and endometrial neoplasia. No alterations were observed in four patients suspected of malignancy but without evidence of malignant tumor. We detected identical changes in four of four urine sediments from patients with bladder cancer and in three of three fine needle aspirates of patients with breast cancer. Our results indicate that D310 abnormalities are detectable in cytology specimens from patients with cancer and support the notion that D310 analysis may represent a new molecular tool for cancer detection.

Bacteriuria in patients with an orthotopic ileal neobladder: Urinary tract infection or asymptomatic bacteriuria?

To investigate the prevalence of asymptomatic bacteriuria (ABU) and urinary tract infection (UTI), and the local and systemic inflammatory response, in patients with ileal neobladder.

Acquired cystic kidney disease : the hormonal hypothesis

Based on the reported sex difference in the incidence of acquired cystic kidney disease (ACKD) in patients with chronic renal failure, it is hypothesized that the hormonal derangement, well documented in male and female uremic patients on long-term dialysis, could be responsible for the pathogenesis of ACKD. The decreased androgen/estrogen ratio, and the increased estrogen value could be responsible for an estrogen receptor mediated effect on the tubular epithelial cell proliferation, an event further potentiated by the action of regulatory peptides like epidermal growth factor (EGF). The epithelial stimulation is more pronounced in men because male tissues are less adapted than female tissues to high estrogen values. Furthermore the androgen reduction, more remarkable in male than female patients, is responsible for an up-regulation of EGF-R. Therefore hormones and growth factors, by means of their own receptor in renal tissue (homologous to the two oncogenes c-erb A and c-erb B), may be responsible for the development of ACKD, and may play an important role in the pathogenesis of multiple adenomas and renal carcinomas reported with high incidence among uremic patients with ACKD.

Reelin expression in human prostate cancer: a marker of tumor aggressiveness based on correlation with grade

Reelin is a glycoprotein that plays a critical role in the regulation of neuronal migration during brain development and, since reelin has a role in the control of cell migration, it might represents an important factor in cancer pathology. In this study, 66 surgical specimens of prostate cancer were analyzed for reelin expression by immunohistochemical method. The reelin expression was correlated with Gleason score and individual Gleason patterns. Reelin expression was found in 39% prostate cancers. Stromal tissues, normal epithelial cells and prostate intraepithelial neoplasia (PIN) of any grade around and distant from cancer were always negative for reelin. Reelin was found in malignant prostatic epithelial glands of 50% cases Gleason score 10, 52% Gleason score 9, 56% Gleason score 8, 18% Gleason score 7, while no sample of prostate cancers with Gleason score 6 showed reelin expression (P=0,005). As reelin staining is frequently found in high Gleason score prostate cancers, we explored whether reelin expression is influenced by single Gleason patterns. While Gleason 3 pattern did not show reelin immunoreactivity, reelin expression was found in 35% Gleason 4 patterns and 45% Gleason 5 patterns (P<0.001). Our results demonstrated for the first time that reelin is expressed in prostate cancer and not in benign prostate tissue and its expression occurs in higher Gleason score and correlates significantly with increasing of single Gleason patterns. This suggests reelin may behave as a specific histological marker and may represent a useful biomarker to predict aggressive phenotypic behavior of prostatic cancer cells.

Fibrin glue for refractory hemorrhagic cystitis after unrelated marrow, cord blood, and haploidentical hematopoietic stem cell transplantation.

BACKGROUND: Patients undergoing hematopoietic stem cell transplant (HSCT) are particularly exposed to the risk of developing hemorrhagic cystitis (HC), which is characterized by symptoms ranging from macroscopic hematuria to renal failure. Although HC significantly affects the quality of life and in a few cases becomes intractable leading to patient death, its therapeutic management has not been established. Fibrin glue (FG), a hemostatic agent derived from human plasma, has been largely employed in different surgical settings including urologic procedures.

Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma

The Keap1/Nrf2 pathway is a master regulator of the cellular redox state through the induction of several antioxidant defence genes implicated in chemotherapeutic drugs resistance of tumor cells. An increasing body of evidence supports a key role for Keap1/Nrf2 pathway in kidney diseases and renal cell carcinoma (RCC), but data concerning the molecular basis and the clinical effect of its deregulation remain incomplete. Here we present a molecular profiling of the KEAP1 and NFE2L2 genes in five different Renal Cell Carcinoma histotypes by analysing 89 tumor/normal paired tissues (clear cell Renal Carcinoma, ccRCCs; Oncocytomas; Papillary Renal Cell Carcinoma Type 1, PRCC1; Papillary Renal Cell Carcinoma Type 2, PRCC2; and Chromophobe Cell Carcinoma). A tumor-specific DNA methylation of the KEAP1 gene promoter region was found as a specific feature of the ccRCC subtype (18/37, 48.6%) and a direct correlation with mRNA levels was confirmed by in vitro 5-azacytidine treatment. Analysis of an independent data set of 481 ccRCC and 265 PRCC tumors corroborates our results and multivariate analysis reveals a significant correlation among ccRCCs epigenetic KEAP1 silencing and staging, grading and overall survival. Our molecular results show for the the first time the epigenetic silencing of KEAP1 promoter as the leading mechanism for modulation of KEAP1 expression in ccRCCs and corroborate the driver role of Keap1/Nrf2 axis deregulation with potential new function as independent epigenetic prognostic marker in renal cell carcinoma.

Multiple primary tumors: 17 cases of renal-cell carcinoma associated with primary tumors involving different steroid-hormone target tissues

The aim of this study was to analyze the characteristics of 17 women with renal-cell carcinoma (RCC) associated with other primary neoplasms occurring in steroid-hormone target tissues. The reproductive history of these patients and the use of exogenous hormones were taken into consideration. In all, 10 RCCs were associated with breast carcinoma; 4, with endometrial carcinoma; and 3, with ovarian carcinoma. The presentation of a second primary tumor was described as synchronous or metachronous by evaluation of the interval between the discovery of the two neoplasms. Hormone and surgical treatment as well as pathologic findings for each primary tumor were also reported. In these 17 RCCs the overall rate of disease-specific survival recorded after a mean follow-up period of 32.7 months (range 9–66 months) was 58.8%; 7 patients died of metastatic disease after surviving for a mean of 14.7 months. In terms of the pathologic stage of RCC, a significant difference in mean survival was found between pN0 (mean survival 22.1 ± 3.4 months) and pN 1 RCCs (mean survival 13.7 ± 3.5 months). A total of 13 (76.4%) women were postmenopausal at the time of diagnosis of the first primary tumor; the mean age of these women at menopause was 51.7 ± 1.2 years. No prior use of oral contraceptives was reported by 12 (70.5%) of the 17 patients. Plasma 17-beta-estradiol and estrone levels were determined in only 7 patients at the diagnosis of each of the primary tumors. High plasma estrogen levels were found in 4 women with RCC and breast carcinoma and in 1 patient with RCC and endometrial carcinoma; in the remaining 2 patients low-normal values were found. A relationship appears to exist between certain reproductive and hormone-related factors and the risk of developing these tumor associations. Data emerging from the present study do not provide strong support for the hypothesis of hormone dependency of RCC; however, a role for estrogens in cases in which RCC is associated with other primary tumors involving steroid-hormone target tissues can be hypothesized.

Early and Late Urodynamic Assessment of Padua Ileal Bladder

OBJECTIVES To report the data from a single series of 46 patients who underwent cystectomy and Padua ileal bladder (PIB) substitution during a 48-month period. Data are lacking concerning the changes in urodynamic characteristics of the orthotopic ileal neobladder. METHODS From January 2002 to April 2003, 46 consecutive male patients underwent radical cystectomy and PIB substitution for muscle-invasive bladder cancer. Uroflowmetry, cystometry, and urethral pressure profilometry were analyzed at 12 and 48 months after surgery. All patients were asked to complete a questionnaire regarding quality of life (the European Organization for Cancer Research and Treatment of Cancer Quality of Life Questionnaire and the bladder cancer-specific module). RESULTS Of the 46 patients, 8 were lost to follow-up because of cancer-related death. When comparing the 12- and 48-month urodynamic characteristics, no significant changes were observed in cystometric capacity or urethral closing pressure. However, the end-filling pressure, peak flow pressure, and postvoid residual urine volume were significantly lower at the 48-month evaluation (P = .0005, P = .0007, and P = .013, respectively). The number of involuntary contractions at 48 months had increased significantly (P = .0012), and the amplitude of the contractions was comparable (P = .084). The daytime continence rate was 96% and 90% at 12 and 48 months, respectively. The nighttime continence rate was 60% at the 48-month evaluation. The questionnaires about the quality of life highlighted the excellent results. CONCLUSIONS An ileal tone is maintained despite detubularization and most likely prevents enlargement of the neobladder. PIB was revealed to maintain an adequate capacity and low pressure during a 48-month period. The urodynamics results and quality of life support this urinary diversion as a valid treatment option for muscle-invasive bladder cancer.