Danilo Zani

Surgical treatment of adrenal metastasis from renal cell carcinoma: a single-centre experience of 45 patients

To report, in a retrospective study, the diagnostic problems and oncological results of surgery in patients with either synchronous or metachronous adrenal metastasis, which are uncommon in renal cancer, at 2–10% of patients.

The follow-up management of non-metastatic renal cell carcinoma: definition of a surveillance protocol

To define a follow‐up protocol based on the University of California Los Angeles Integrated Staging System (UISS) for patients undergoing surgery for N0M0 renal cell carcinoma (RCC).

GPNMB/OA protein increases the invasiveness of human metastatic prostate cancer cell lines DU145 and PC3 through MMP-2 and MMP-9 activity

Non-metastatic glycoprotein melanoma protein B (GPNMB), also known as osteoactivin (OA) is expressed in a wide array of tumors and represents an emerging target for drug development. In this study, we investigated the role of GPNMB/OA in the progression of human metastatic DU145 and PC3 prostate cancer cells. GPNMB/OA contribution in PCa malignant phenotype has been analyzed by small interfering RNA-induced GPNMB/OA silencing. We found that following GPNMB/OA silencing the migration capability of both DU145 and PC3 cells, evaluated by using in vitro invasivity assay, as well as the metalloproteinases MMP-2 and MMP-9 activity were equally strongly inhibited. By contrast knocking down GPNMB/OA weakly attenuated cell proliferation rate of DU145, an effect that paralleled with an increase number of apoptotic cells. However, PC3 cell growth seems to be not affected by GPNMB/OA. Together, these data reveal that GPNMB/OA acts as a critical molecular mediator promoting the acquisition of the more aggressive, pro-metastatic phenotype distinctive of human DU145 and PC3 cell lines.

Cytogenetic features, clinical significance and prognostic impact of type 1 and type 2 papillary renal cell carcinoma

The purpose of this paper is to evaluate the clinical, pathologic, and cytogenetic features, as well as the disease-free survival in patients with papillary renal cell carcinoma (PRCC) subdivided into types 1 and 2, according to the definition given by Delahunt and Eble. The clinical, surgical, and follow-up data for the PRCC cases treated since 1995 were taken from an institutional database. The samples were revised by an experienced pathologist, who subdivided them into types 1 and 2. The data from the cases in which the tumor karyotype was available were analyzed. Out of 1,150 patients surgically treated for renal cancer, 132 cases of PRCC were detected (prevalence 11.5%), 57 with type 1 and 75 with type 2, followed for a mean period of 50 months. Tumor diameter, peri-renal tissues, as well as venous invasion, lymphnodal, and distant metastasis were highlighted to be distributed with a significant difference between the two groups, which indicated higher aggressiveness in type 2 cases. Survival analysis has showed a significantly higher-progression risk and a shorter disease-free survival in type 2 cases. An evaluable tumoral karyotype was obtained in 26 cases. An overlapping distribution was detected in chromosomes 7, 17, 12, 16, and 20, while some alterations in chromosomes 10, 5, 6, 11, 15, 18, 22, and 8 appeared as typical of type 2 cases. In conclusion, types 1 and 2 PRCC have different pathologic and cytogenetic features and a radically different biologic behavior - indolent in type 1 and aggressive in type 2.

Nerve growth factor signaling in prostate health and disease

The prostate is one of the most abundant sources of nerve growth factor (NGF) in different species, including humans. NGF and its receptors are implicated in the control of prostate cell proliferation and apoptosis and it can either support or suppress cell growth. The co-expression of both NGF receptors, p75NGFR and tropomyosin-related kinase A (trkA), represents a crucial condition for the antiproliferative effect of NGF; indeed, p75NGFR is progressively lost during prostate tumorigenesis and its disappearance represents a malignancy marker of prostate adenocarcinoma (PCa). Interestingly, a dysregulation of NGF signal transduction was found in a number of human tumors. This review summarizes the current knowledge on the role of NGF and its receptors in prostate and in PCa. Conclusions bring to the hypothesis that the NGF network could be a candidate for future pharmacological manipulation in the PCa therapy: in particular the re-expression of p75NTR and/or the negative modulation of trkA could represent a target to induce apoptosis and to reduce proliferation and invasiveness of PCa.

Muscarinic receptors stimulate cell proliferation in the human urothelium-derived cell line UROtsa

The widespread non-neuronal synthesis of acetylcholine (ACh) has changed the paradigm of ACh acting solely as a neurotransmitter. Indeed, the presence of ACh in many types of proliferating cells suggests a role for this neurotransmitter in the control of cell division. The parasympathetic system is a major pathway regulating micturition, but ACh-mediated control plays a more complex role than previously described, acting not only in the detrusor muscle, but also influencing detrusor function through the activity of urothelial muscarinic receptors. Here we investigated the role of muscarinic receptors in mediating cell proliferation in the human UROtsa cell line, which is a widely used experimental model to study urothelium physiology and pathophysiology. Our results demonstrate that UROtsa cells express the machinery for ACh synthesis and that muscarinic receptors, with the rank order of M3>M2>M5>M1=M4, are present and functionally linked to their known second messengers. Indeed, the cholinergic receptor agonist carbachol (CCh) (1-100 μM) concentration-dependently raised IP(3) levels, reaching 66±5% over basal. The forskolin-mediated adenylyl cyclase activation was reduced by CCh exposure (forskolin: 1.4±0.14 pmol/ml; forskolin+100 μM CCh: 0.84±0.12 pmol/ml). CCh (1-100 μM) concentration-dependently increased UROtsa cell proliferation and this effect was inhibited by the non-selective antagonist atropine and the M(3)-selective antagonists darifenacin and J104129. Finally, CCh-induced cell proliferation was blocked by selective PI-3 kinase and ERK activation inhibitors, strongly suggesting that these intracellular pathways mediate, at least in part, the muscarinic receptor-mediated cell proliferation.

Gene expression profile of prostate cancer cell lines: Effect of nerve growth factor treatment

A dysregulation of the nerve growth factor (NGF)-mediated control of prostate cell growth is associated with the malignant progression of prostate epithelial cells. Exogenous NGF induced in prostate cancer (PCa) cell lines DU145 and PC3 the expression of p75(NGFR), accompanied by a reduction of the cell malignancy. The aim of this study was to analyze the profile of NGF-regulated genes the PCa cell line DU145 by using the cDNA microarray technique. NGF treatment of DU145 cells decreased the expression of 52 known genes, while the expression of 40 known genes was increased. NGF treatment of the DU145 cell line modified the expression profile of clusters of genes involved in invasion and metastasis, in cell proliferation and apoptosis, inflammation, cell metabolism and transcriptional activity. Interestingly, NGF induced the same pattern of gene modifications in both PCa cell lines. Data presented here may help to identify gene/proteins that dispose to PCa progression and to assess future markers that could allow the development of new clinic diagnostic and therapeutical approaches.

Different muscarinic receptor subtypes modulate proliferation of primary human detrusor smooth muscle cells via Akt/PI3K and map kinases

While acetylcholine (ACh) and muscarinic receptors in the bladder are mainly known for their role in the regulation of smooth muscle contractility, in other tissues they are involved in tissue remodelling and promote cell growth and proliferation. In the present study we have used primary cultures of human detrusor smooth muscle cells (HDSMCs), in order to investigate the role of muscarinic receptors in HDSMC proliferation. Samples were obtained as discarded tissue from men >65 years undergoing radical cystectomy for bladder cancer and cut in pieces that were either immediately frozen or placed in culture medium for the cell culture establishment. HDSMCs were isolated from samples, propagated and maintained in culture. [(3)H]-QNB radioligand binding on biopsies revealed the presence of muscarinic receptors, with a Kd of 0.10±0.02nM and a Bmax of 72.8±0.1fmol/mg protein. The relative expression of muscarinic receptor subtypes, based on Q-RT-PCR, was similar in biopsies and HDSMC with a rank order of M2≥M3>M1>M4>M5. The cholinergic agonist carbachol (CCh, 1-100μM) concentration-dependently increased [(3)H]-thymidine incorporation (up to 46±4%). This was concentration-dependently inhibited by the general muscarinic receptor antagonist atropine and by subtype-preferring antagonists with an order of potency of darifenacin >4-DAMP>AF-DX 116. The CCh-induced cell proliferation was blocked by selective PI-3 kinase and ERK activation inhibitors, strongly suggesting that these intracellular pathways mediate, at least in part, the muscarinic receptor-mediated cell proliferation. This work shows that M2 and M3 receptors can mediate not only HDSM contraction but also proliferation; they may also contribute bladder remodelling including detrusor hypertrophy.

Renal mass with caval thrombous as atypical presentation of xantogranulomatous pyelonephritis. A case report and literature review

Introduction Xantogranulomatous pyelonephritis is a rare, severe, chronic renal infection typically resulting in diffuse renal destruction. Enlarged kidney is typical radiological finding. In this work we describe an extremely rare case in which a clinically classified cT3b Tumor (level II IVC thrombus) was detected; at specimen analysis to be xantogranulomatous pyelonephritis with IVC extension. Material And Method U.V., female, 86 years old, we diagnosed with right renal mass, with extension to IVC. By pathological analysis, it was found that renal mass and the thrombus was not due to RCC, but by xantogranulomatus pyelonephritis. Discussion xantogranulomatous pyelonephritis with IVC thrombus is exceptional and has been described in 4 cases. Such a diagnosis could have anesthesiologic importance, in particular related to antimicrobial treatment. Xantogranulomatous pyelonephritis has its own classification, based on extension and organ involvement, but this case fall out of current classification Conclusion This possibility could be suspected and updating of diseases classification could be suggested.

Clinical features and prognosis of patients with renal cancer and a second malignancy

OBJECTIVE To evaluate the epidemiologic aspects, the clinical features, and the prognosis of patients with renal cancer affected by a second malignancy. MATERIALS AND METHODS Since 1983, at our institution, a database concerning all the patients who underwent surgery for renal neoplasia has been prospectively compiled. In the present study, we compared patients with renal cancer and a second primary malignancy, diagnosed before, at the same time, or after the renal cancer, to those affected only by a renal malignancy. RESULTS Out of 1,673 patients with renal cancer, 285 (17%) were diagnosed with a second malignancy. The follow-up lasted on average 71 months after the treatment of renal neoplasia. The second neoplasia was antecedent in 115 patients (average latency period 8.5 years), synchronous in 97 patients, and subsequent in 103 patients (average latency period 4.4 years). The sites of associated neoplasia were, in descending order of frequency, prostate, bladder, and bowel for men and breast, gynecologic organs, thyroid, and bladder for women. Compared with the patients not affected by a second neoplasm, those with multiple malignancies generally were older and had a smaller, low-grade, low-stage, and asymptomatic renal tumor. Comparing patients with associated neoplasia with a group without associated neoplasia matched for gender, mode of diagnosis, dimension, grade, stage, and histologic subtype of renal cancer, at survival analysis, no significant differences were noticed in renal cancer-related survival. However, among patients with multiple malignancies, the contemporaneous diagnosis of renal and associated cancer had an independent negative impact on survival. CONCLUSIONS The association between renal cancer and other malignancies is a frequent event with an unremarkable impact on prognosis, and it shall not limit surgical indication to treat renal cancer, even if the negative prognostic impact of synchronous occurrence of multiple neoplasias should be regarded, especially in older or unhealthy patients, since ablative therapies or active surveillance could be considered as viable alternative options.