Synchronous bilateral testicular germ cell tumour: case report and review of the literature.

We report a case of a 30 years old male affected by synchronous bilateral germ cell tumor with a history of unilateral cryptorchidism; the patient underwent surgical treatment followed by adjuvant radiotherapy on paraaortic and iliac lymphnodes. Patients with synchronous tumors usually present with a higher stage disease in contrast to those with unilateral testicular carcinoma, yet the prognosis remains equally favorable.

Gender and cystectomy for bladder cancer: A high-volume tertiary urologic care center experience.

BACKGROUND: Differences have often been reported in the outcomes of bladder cancer (BC) patients according to gender. OBJECTIVE: This study aims to provide data on patients undergoing radical cystectomy (RC) in a high-volume tertiary urologic center and to assess whether gender discrepancies do exist in terms of surgical options and clinical outcomes. MATERIALS AND METHODS: Consecutive BC patients treated between 2016 and 2020 at a single center (Careggi University Hospital, Florence, Italy) were included in the study. The impact of gender on disease stage at diagnosis, overall survival (OS), and type of surgery was analyzed. RESULTS: The study series comprised 447 patients (85 females and 362 males). At a median follow-up of 28.3 months (IQR: 33.5), OS was 52.6% and cancer-specific survival was 67.6%. Significant differences in OS emerged for age, acute myocardial infarction (AMI), Charlson Comorbidity Index (CCI), pT, and pN. OS rates were higher in patients undergoing robot-assisted surgery and in those receiving open orthotopic neobladder (ONB) (p = 0.0001). No statistically significant differences were found between male and female patients regarding surgical offer in any age group, surgical time, early postoperative complications, pathologic stage, and OS. CONCLUSIONS: After adjustment for pathologic tumor stage and treatment modalities, female and male patients showed similar oncologic outcomes. Further studies should be undertaken to evaluate functional results in women subjected to RC.

Weekly administration of docetaxel and epirubicin as first-line treatment for hormone-refractory prostate carcinoma.

Androgen-independent prostate carcinoma (AICP) is one of the tumors that continue to respond poorly to chemotherapy. Recently, protocols based on the use of docetaxel have significantly improved survival for patients in this disease. In other types of neoplastic disease, combined therapy with taxanes and anthracycline derivatives has been shown to produce additive effects in terms of growth inhibition, and superior tolerability when associated with weekly administration schedules. These findings prompted us to examine the tolerability and efficacy of weekly treatment of AICP with docetaxel (DOX) plus epirubicin (EPI). We enrolled 35 chemotherapy-naive men with AICP (mean age 72 years, range 68-77) and normal hepatic, renal, and cardiac function. The chemotherapy protocol provided for the IV administration of DOX (30 mg/m2) and EPI (30 mg/m2) on days 1, 8, and 15 every 28 days. Treatment was continued for 6 months or until disease progression and/or unacceptable toxicity was observed. Serum levels of prostate-specific antigen (PSA) were monitored in all patients, and reductions from baseline values of >50% were considered indicative of positive responses to treatment. Thirty-four patients were included in the analysis of toxicity, and objective responses to treatment were assessed in the 28 patients with measurable lesions. Nineteen patients (56%) experienced PSA reductions of >50% that persisted for more than 4 weeks. The response to therapy was classified as complete in 1 of the 28 patients (4%) with measurable disease (at the lymph node level). Thirteen others (13/28, 46%) had partial responses, in nine (32%) the disease remained unchanged, and progression was observed in the remaining five (18%); overall response rate was 50% (CR + PR). Of the 27 patients with pain at the time of enrollment, 16 (59%) experienced pain reduction during treatment. The median time to disease progression was 11.7 months (95% CI: 7.7-15.7) while the median survival time was 18.7 months (95% CI: 12.3-25.1). During the study, four patients developed grade 3 anemia and leukopenia, which was reversible in all cases. Lower grades of asthenia, nausea, vomiting, diarrhea, and peripheral edema were also observed. There were no cases of cardiotoxic effects. Alopecia was frequent but reversible in all cases. The results of this preliminary study indicate that the combined administration of DOX and EPI for treatment of AIPC is effective and well tolerated. The weekly administration of the drug combination appears to be a promising approach to the treatment of these tumors.

The treatment of fistulae and ureteral stenosis after kidney transplantation.

INTRODUCTION: The incidence of urological complications after kidney transplantation varies from 3% to 14%, with a probable loss of the graft in 10% to 15% of cases and a mortality rate of up to 15%, despite improvements in prevention, diagnosis, and treatment as well as the use of new immunosuppressive therapies. Urinous fistulae, which are considered early complications of transplantation, are due to ischemic damage or necrosis generally occurring in the distal third of the ureter. Preservation of accessory arteries to the lower portion of the kidney is important, as they may constitute the blood supply of this segment of the collecting system or ureter. Their ligation may lead to necrosis and urinary fistulae. Ureteral stenosis, as late complication, is related to a pathology of the ureter itself, to infections, to abscesses, to fibrosis, and to ischemia. An early endoscopic approach permits resolution in 70% of cases. The aim of this retrospective study was to determine incidence and treatment of these complications. MATERIALS AND METHODS: From 1991 to 2004 we performed 453 kidney transplantations both from cadaveric and living donors. In 199 patients we performed a transvesical ureteroneocystostomy (UNCS), and in 260, an extravesical UNCS. RESULTS: The nine patients who showed fistulae (1.9%) underwent surgical treatment. In eight we used a direct ureteral reimplantation, and in one, a Boari flap technique. Nephrectomy was necessary in four patients, including two who died of septic complications. In all 26 cases of ureteral stenosis (5.6%), we used an endourological approach (anterograde or retrograde), with surgical treatment afterward in 11 patients (42%) nine direct reimplants, one anastomosis to the native ureter (transplantation from a living donor), and in one case a Boari flap technique four patients who underwent surgical treatment showed progressive damage to graft function. CONCLUSIONS: In all patients who showed fistulae we suggest surgical review: for patients with ureteral stenosis, we suggest first an endourological approach and only when it is not successful do we consider surgical treatment.

Inhibition of spontaneous and androgen-induced prostate growth by a nonhypercalcemic calcitriol analog.

We have recently found that analog V (BXL-353, a calcitriol analog) inhibits growth factor (GF)-stimulated human benign prostate hyperplasia (BPH) cell proliferation by disrupting signal transduction, reducing Bcl-2 expression, and inducing apoptosis. We now report that BXL-353 blocks in vitro and in vivo testosterone (T) activity. BPH cells responded to T and dihydrotestosterone (DHT) with dose-dependent growth and reduced apoptosis. Exposure of BPH cells to BXL-353 significantly antagonized both T- and DHT-induced proliferation and induced apoptosis, even in the presence of T. To verify whether BXL-353 reduced prostate growth in vivo, we administered it orally to either intact or castrated rats, supplemented with T enanthate. Nonhypercalcemic doses of BXL-353 time- and dose-dependently reduced the androgen effect on ventral prostate weight, similarly to finasteride. Comparable results were obtained after chronic administration of BXL-353 to intact rats. Clusterin (an atrophy marker) gene and protein were up-regulated by BXL-353 in rat prostate, and nuclear fragmentation was widely present. The antiandrogenic properties of BXL-353 did not interfere with pituitary and testis function, as assessed by serum determination of rat LH and T. BXL-353 did not compete for androgen binding to BPH homogenates and failed to inhibit 5alpha-reductase type 1 and type 2 activities. In conclusion, BXL-353 blocks in vitro and in vivo androgen-stimulated prostate cell growth, probably acting downstream from the androgen receptor, without affecting calcemia or sex hormone secretion. BXL-353 and other vitamin D(3) analogs might thus represent an interesting class of compounds for treating patients with BPH.

Loss of heterozygosity of the long arm of chromosome 7 in follicular and anaplastic thyroid cancer, but not in papillary thyroid cancer.

Papillary thyroid cancer (PTC), but neither the follicular nor the anaplastic histotype [follicular thyroid cancer (FTC), anaplastic thyroid cancer (ATC)], overexpresses simultaneously the protooncogene HGF (hepatocyte growth factor) and its receptor HGF-R (or c-met). Because 1) HGF and c-met map to chromosome 7q21 and 7q31, respectively, 2) FTC loses genetic material at multiple loci with a frequency much higher than PTC, and 3) loss of heterozygosity (LOH) on 7q has been previously found in various tumors, we tested the hypothesis that both FTC and ATC, but not PTC, could harbor LOH in segments of 7q encompassing the loci for HGF and c-met. We screened 6 normal thyroids, 10 colloid nodules, 10 follicular hyperplasias, 10 oncocytic adenomas, 10 follicular adenomas (FA), 10 FTC, 6 ATC, 12 PTC using two microsatellite markers for HGF, and two for c-met. LOH for all 4 markers was found in 100% of FTC, 100% of ATC, and (for only 1 or 2 markers) in 10-29% of FA. This is the first demonstration of an LOH that separates both FTC and ATC from PTC, in the best possible manner: 100% vs. 0%. Clearly, each of the two segments we have probed contains at least one tumor suppressor gene, whose inactivation is crucial for the establishment of the FTC (and ATC) phenotype. This loss of genetic material explains why FTC and ATC, but not PTC, fail to express both HGF and c-met. Our findings may also have immediate diagnostic application, in the context of assisting pathologists in the often difficult task of distinguishing FA from FTC.

Expression of sialic acid on the alveolar surface of adult and fetal human lungs.

Lung alveoli are coated by a thin layer of extracellular material rich in anionic charges. The nature of this acid layer and its relationship to the phospholipid surfactant are not known. We investigated the possible presence of sialic acid groups by light and electron microscopy in tissues from normal fetal and adult lungs, using neuraminidase treatment followed by staining with the galactose-binding lectin from peanut, labeled with peroxidase. Our results showed that adult lung does not bear peanut lectin-reactive sites but that a very thin and distinct reactive layer becomes evident after neuraminidase treatment, especially on type II pneumocytes. In fetal lung, the entire surface of the developing respiratory tree is outlined by a strongly peanut lectin-reactive layer even if neuraminidase digestion is not performed. We conclude that the acid coat of the alveolar lining is in part composed of sialic acid residues and that sialic acid is added to the fetal lung as the alveoli mature.

Des (1-3) IGF-I-stimulated growth of human stromal BPH cells is inhibited by a vitamin D3 analogue.

Prostate growth and differentiation is under the control of androgens not only during fetal life and childhood but also in adulthood, and it has been proposed that increased prostatic concentration of androgens, or increased androgen responsiveness, causes benign prostatic hyperplasia (BPH). However, different androgen ablation strategies such as treatment with GnRH agonists and finasteride resulted in a modest decrease of the hyperplastic prostate volume. In the last few years it became evident that both androgen-dependent and androgen-independent growth factors promote prostate enlargement by inducing cell proliferation or reducing apoptosis. Therefore, new therapeutic strategies, aimed at reducing intraprostatic growth factor signaling, are under investigation. In this study, we report further evidence that a non hypercalcemic-analogue of vitamin D(3), analogue (V) decreases growth factor-induced human BPH cell proliferation and survival. We found that Des (1-3) insulin-like growth factor [Des (1-3) IGF-I], an IGF-I analogue, which does not bind to IGF-binding proteins, is a potent mitogen for BPH stromal cells via a dual mechanism: stimulation of cell growth and inhibition of apoptosis. Similar results were previously reported for another growth factor for BPH cells, keratinocyte growth factor (KGF). Accordingly, we speculate that both KGF and IGF might be involved in the pathogenesis of BPH. We also found analogue (V) not only inhibits the mitogenic activity of growth factors on BPH cells, but even decreased the basal expression of bcl-2, and induced apoptosis. Therefore, vitamin D(3) analogues might be considered for the medical treatment of BPH.

Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia.

OBJECTIVE: Calcitriol analogues might represent an interesting new therapy for benign prostate hyperplasia (BPH). We here report the preclinical characterization of BXL-628, an analogue selected for an ongoing double-blind, randomized, placebo-controlled phase II trial in BPH. DESIGN: Experiments with BXL-628 were carried out in human BPH cells and in the ventral prostate of intact and castrated rats. METHODS: BPH cell and rat prostate growth were evaluated along with morphological and biochemical hallmarks of apoptosis. RESULTS: BXL-628 inhibited human BPH cell proliferation and induced apoptosis even in the presence of androgens or growth factors. It also decreased prostate growth to an extent similar to finasteride, inducing DNA fragmentation and apoptosis, both in intact and in testosterone-supplemented castrated rats. Accordingly, BXL-628, like finasteride, increased the expression of clusterin, a prostatic atrophy marker. However, BXL-628 did not inhibit 5 alpha-reductase 1 and 2, did not bind to the androgen receptor (AR) in BPH homogenates and did not affect AR-coupled luciferase activity. In addition, BXL-628 did not affect rat pituitary and testis activity or calcemia. CONCLUSIONS: BXL-628 inhibited in vitro and in vivo prostate cell proliferation, and therefore might represent a novel, interesting option for the treatment of BPH.

Hepatitis B E antigen detection in formalin-fixed liver biopsy specimens. A tool to investigate wild-type and E-minus variant HBV infection.

The aim of this study is to investigate whether hepatitis B e antigen (HBeAg) reactivity can be detected on formalin-fixed, paraffin-embedded liver tissue, and whether immunohistochemical detection of intrahepatic HBeAg may help to distinguish between "wild-type" and "eminus" hepatitis B virus (HBV) infection. Liver biopsy specimens were analyzed from 27 patients with chronic type B hepatitis: 12 patients had serum HBeAg (group A), and 15 patients were anti-HBe positive (group B). Part of each biopsy fragment was processed for histologic and immunohistochemical studies, and a part was used for HBV-DNA analysis. Dewaxed sections from each specimen were tested with a specific monoclonal anti-HBe antibody; then a Biotin-Streptavidin kit was used as detection system. HBeAg was revealed in 10 of 12 cases of group A and in 6 of the 15 cases of group B. Pre-core region of HBV genomes, isolated from each biopsy specimen, was analyzed by direct sequencing: 10 cases of group A were found to be infected by wild-type HBV alone and 2 cases by both wild and e-minus HBV types. In group B, all the 6 cases with intrahepatic HBeAg reactivity were found to be infected by mixed viral population, whereas the 9 cases negative for such reactivity were found to be infected by e-minus HBV alone. These results show that HBeAg can be detected in formalin-fixed, paraffin-embedded liver specimens, and the method is sensitive and specific. Because the presence of HBeAg in the liver indicates a wild-type HBV infection, and the lack of detection of such antigen in the hepatocytes of anti-HBe positive subjects correlates with unmixed e-minus HBV infection, the authors conclude that this technique is a useful tool for recognizing the viral strains that infect patients with chronic type B hepatitis.

Immunohistochemical evidence of lactoferrin in hepatic biopsies of patients with viral or cryptogenetic chronic liver disease.

Lactoferrin (Lf) expression has been immunohistochemically investigated in 117 formalin-fixed paraffin-embedded liver bioptic samples obtained from an equal number of patients affected by chronic hepatitis (HCV = 76; HBV = 17; HBV + HDV = 14; cryptogenetic = 10); in addition, 10 autoptic specimens of normal liver were studied as control. The Lf immunoreactivity was evaluated by an intensity-distribution (ID) score. The Lf immunoexpression was observed in 88 out of 117 (75%) cases of chronic hepatitis; interestingly, all liver specimens from HBV hepatitis showed a constant Lf reactivity with the highest ID-score, whereas the evidence of Lf was encountered in 54/76 (71.1%) HCV as well as in 11/14 (78.6%) HDV chronic hepatitis, thus documenting a variable degree of Lf immunostaining in relation to different viruses. Moreover, in 6/10 (60%) cases of cryptogenetic hepatitis Lf immunoexpression was documented, whereas all normal liver controls were unreactive. In HCV specimens, the Lf nuclear immunoreactivity appeared to increase with the progression of the disease, with a greater expression in genotype 1. In contrast, no relationship among Lf ID-scores and different stages or grades of HBV, HDV or cryptogenetic hepatitis was encountered. This fact may suggest a role for Lf as an unspecific defensive agent in chronic inflammatory liver diseases, similarly to that elsewhere reported in other inflammatory tissue injuries.

Bile ductopenia following therapy with sulpiride.

We report a case of ductopenia associated with cholestatic hepatitis in a 59-year-old woman treated for 41 years for temporal epilepsy. The patient developed jaundice, without any clinical or biochemical features of hypersensitivity, 10 months after the beginning of treatment with sulpiride. Liver biopsy showed ballooning and acidophilic degeneration of the hepatocytes, macrophages packed with lipofuscin, biliary pigment in Kupffer cells, some biliary plugs, confluent necrosis and absence of biliary ducts in all the portal tracts. These features and the presence of foci of cholangiolitis suggest a destructive cholangitis as the pathogenetic mechanism causing ductopenia. Other causes of ductopenia were excluded. Sulpiride is known to produce severe cholestatic jaundice, which we believe is due to ductopenia. The absence of hypersensitivity and the 10-month latency suggest that sulpiride may cause liver damage through a toxic mechanism in genetically susceptible subjects.

Hepatitis B-DNA replication and histological patterns in liver biopsy specimens of chronic HBsAg positive patients with and without hepatitis delta virus superinfection.

The role of active hepatitis B virus (HBV) infection in chronic HBsAg positive hepatitis with and without hepatitis delta virus (HDV) superinfection was analysed in percutaneous liver biopsy specimens from 50 patients. Each specimen was divided into two--one part for histological evaluation and for the detection of HBcAg and delta antigen; the other part was tested for HBV-DNA using Southern blotting. Ten cases were of chronic lobular hepatitis, 10 of chronic persistent hepatitis, and 30 of chronic active hepatitis. Ten cases were delta antigen positive and showed high grade lobular activity but no evidence of HBV-DNA episomal forms or HBcAg reactivity. Twenty one cases showed HBV-DNA replicative intermediate forms; 19 had high grade lobular activity, which occurred in five cases without evidence of free viral DNA. Of the 21 biopsy specimens with HBV-DNA episomal forms, 14 were positive for HBcAg; only one of the 19 cases without detectable viral DNA was positive for such antigen. These data indicate that the presence of HBV or HDV active infection correlates with the histological finding of prominent lobular necrosis. Moreover, intrahepatic HBV-DNA seems to be a more sensitive marker than the presence of viral antigens for indicating HBV replication.

Periurethral neurofibroma.

A periurethral neurofibroma presenting as a midline perineal mass was removed in a three-year-old boy. An immunohistochemical study of S-100 protein distribution within the tumor tissue was performed.

Retroperitoneal germ cell tumor in postmenopausal woman.

A fifty-four-year-old woman presented with right renal colic and three months later a retroperitoneal tumor was diagnosed. After explorative laparotomy with biopsy, which showed a germ cell tumor, the patient received external beam radiotherapy, but died of metastatic diffusion nine months later. We believe this is a rare occurrence of a germ cell tumor in a postmenopausal woman.

Expression of the hepatocyte growth factor and c-met in normal thyroid, non-neoplastic, and neoplastic nodules.

We have examined the coexpression of hepatocyte growth factor (HGF) and its receptor (HGF-R or c-met) in an archival series of 63 paraffin-embedded thyroid specimens plus one lymph node metastasis. By immunocytochemistry, we found undetectable expression of both the ligand and the receptor in 10 normal thyroids and 9 nonpapillary malignant nodules [5 follicular carcinomas, 1 poorly differentiated (insular) carcinoma, 3 undifferentiated (anaplastic) carcinomas]. Of 10 non-neoplastic nodules (colloid nodules) and 17 benign neoplastic nodules, 3 of 10 colloid nodules, 2 of 10 follicular adenomas, and 2 of 7 oncocytic adenomas showed a weak but distinct staining (1+ score in a scale from 0 to 4+) of both HGF and c-met in a modest proportion of cells (1% to 3%). In these 7 cases, expression of HGF was always stromal and expression of c-met limited to the membrane of the follicular cells. Of 3 malignant nodules derived from aberrant growth of the parafollicular C cells (medullary thyroid cancer or MTC), 2 were positive (6% of cells). In these 2 cases, the expression of HGF (3+) was not stromal, but in both the membrane and cytoplasm of the parafollicular cells, while that of c-met (3+) was restricted to the membrane. In contrast to all of the above, of 14 papillary carcinomas (PTC) encompassing 5 histological variants (conventional; follicular; oncocytic; with foci of solid growth; diffuse sclerosing) plus 1 neck lymph node metastasis of 1 conventional PTC, 12 (86%) expressed HGF, and 13 (93%) expressed c-met. With the exception of 2 negative cases, HGF was detected in 15% to 46% of the cells. The highest percentage (46%) pertained to conventional PTC cases with abundant peritumoral lymphocyte infiltration, indicating that some lymphokine(s) may recruit PTC cells for HGF expression in a paracrine fashion. With the exception of one negative case, c-met was found in 43% to 80% of the cells, both at levels from intense (3+) to very intense (4+). The immunostaining for HGF was stromal in 25%, membranous in 8%, cytoplasmic in 8%, and both membranous and cytoplasmic in 59% of the PTC-positive cases. The immunostaining for c-met was membranous in 43% and both membranous and cytoplasmic in 57% of the PTC-positive cases. In the lymph node metastasis and in the diffuse sclerosing variant of PTC (the most aggressive variant), the coexpression of HGF/c-met was lost, in that only c-met was expressed on membranes in both cases. We conclude that the HGF/c-met system is activated (by overexpression of both components) in the vast majority of PTC. In most PTC the interaction of HGF and its receptor (c-met) is autocrine, not paracrine.

Expression of CD30 ligand and CD30 receptor in normal thyroid and benign and malignant thyroid nodules.

Because the CD30 ligand (CD30L)/CD30 receptor (CD30) system is expressed in certain malignancies, but has not been studied in thyroid nodules, we investigated its immunohistochemical expression in 6 normal thyroids (NT) and 131 thyroid nodules: 28 colloid nodules (CN), 45 adenomas (15 oncocytic [OA], 30 follicular [FA]) and 58 carcinomas (15 follicular [FTC], 1 insular [ITC], 6 anaplastic [ATC], 30 papillary [PTC], and 6 medullary [MTC]). NT and CN expressed neither CD30L nor CD30 (CD30L-/CD30-). Forty percent of OA and 20% of FA showed epithelial coexpression of CD30L and CD30, and interstitial expression of CD30L, which was also observed in the surrounding normal tissue. Within malignancies, epithelial coexpression of CD30L and CD30 was observed in 7% of FTC, 33% of ATC, 67% of PTC, and 67% of MTC. Only PTC and MTC showed epithelial expression of CD30L in the perinodular tissue with similar frequency (80% PTC, 75% MTC). PTC and MTC had the highest proportion of CD30L+ or CD30+ cells, and together with OA, a thus far unreported nuclear location of CD30L. In PTC, the proportion of CD30L+ cells and the prevalence of nuclear location of CD30L correlated inversely and directly, respectively, with aggressiveness. In conclusion, CD30L/CD30 signaling is activated only past the colloid nodule stage, most frequently in an autocrine fashion.

Cyclophosphamide, epidoxorubicin and Carboplatin as treatment for advanced-carcinoma of the bladder - a phase-ii study.

In advanced carcinoma of the bladder, the M-VAC chemotherapy schedule can yield positive results, but at the cost of very high toxicity. Recent studies have shown epidoxorubicin and to a lesser degree, carboplatin to be active against urothelial tumors, with cardiac, haematological and renal toxicity lower than that observed with CISCA or M-VAC chemotherapy regimens. In this study, we determined the toxicity and efficacy of cyclophosphamide 400 mg/m(2), epidoxorubicin 75 mg/m(2) and carboplatin 300 mg/m(2) in a 28-day course. From February 1990 to December 1991, we enrolled 33 advanced bladder cancer patients (25 males, 8 females), mean age 63 years. 31 patients were evaluable for toxicity and response. The major disease localizations were: locoregional 15 (48%), lymph nodes 6 (20%), liver 5 (16%), lung 3 (10%) and bone 2 (6%). A total of 186 cycles of therapy were administered, with a mean of 5.4 per patient. Six patients (19%) had a complete response (CR): 2 locoregional, 3 lymph node and 1 lung. Eleven patients (36%) had a partial response (PR), for an overall response rate of 55%. The median duration of response was 53 weeks and median survival for the entire group of patients was 40 weeks. No delays or interruptions due to sepsis occurred during therapy; haematological, cardiac and renal toxicity were below WHO grade 3. The efficacy of this chemotherapy regimen proved to be comparable to that of more aggressive schedules, while its toxicity was markedly lower.