Osteoclasts Are Active in Bone Forming Metastases of Prostate Cancer Patients

BACKGROUND: Bone forming metastases are a common and disabling consequence of prostate cancer (CaP). The potential role of osteoclast activity in CaP bone metastases is not completely explained. In this study, we investigated ex vivo whether the osteolytic activity is present and how it is ruled in CaP patients with bone forming metastases. METHODOLOGY: Forty-six patients affected by newly diagnosed CaP and healthy controls were enrolled. At diagnosis, 37 patients had a primary tumour only, while 9 had primary tumour and concomitant bone forming metastases. In all patients there was no evidence of metastasis to other non-bone sites. For all patients and controls we collected blood and urinary samples. We evaluated patients' bone homeostasis; we made peripheral blood mononuclear cell (PBMC) cultures to detect in vitro osteoclastogenesis; we dosed serum expression of molecules involved in cancer induced osteoclatogenesis, such as RANKL, OPG, TNF-alpha, DKK-1 and IL-7. By Real-Time PCR, we quantified DKK-1 and IL-7 gene expression on micro-dissected tumour and healthy tissue sections. PRINCIPAL FINDINGS: CaP bone metastatic patients showed bone metabolism disruption with increased bone resorption and formation compared to non-bone metastatic patients and healthy controls. The CaP PBMC cultures showed an enhanced osteoclastogenesis in bone metastatic patients, due to an increase of RANKL/OPG ratio. We detected increased DKK-1 serum levels and tissue gene expression in patients compared to controls. IL-7 resulted high in patients' sera, but its tissue gene expression was comparable in patients and controls. CONCLUSIONS: We demonstrated ex vivo that osteoclastogenesis is an active mechanism in tumour nesting of bone forming metastatic cancer and that serum DKK-1 levels are increased in CaP patients, suggesting to deeply investigate its role as tumour marker

Rassegna storica salernitana. N.s. A.1, n.1(1984)

La Società Salernitana di Storia Patria aderisce al progetto EleA e autorizza la pubblicazione del fascicolo.N.s., A.1, n.1(1984) : Gallo I., Un cinquantennio di cultura storica a Salerno, P. 9 ; Johannowsky W., Risultati e problemi della ricerca archeologica nel Salernitano, P. 53 ; Salvati C., Gli archivi monastici amalfitani. Contributo alla ri-costruzione, P. 63 ; Mauro D., Aspetti culturali e religiosi della pittura di Michele Ricciardi (1672-1753), P. 83 ; Leone A., Ancora per una storia sociale del notariato, P. 105 ; Capone A., Sul pensiero politico di Francesco De Sanctis, P. 111 ; Amarotta A.R., Michele De Angelis, P.127 ; Vita della «società salernitana di storia patria », statuto, p. 177 ; Mangieri G. Libero, L'attività numismatica della soprintendenza ar-cheologica, p. 179 ; De Cunzo M.A., Gli interventi della soprintendenza ai B.A.A.A.S. nel Salernitano, P. 18

Characteristics of patients and healthy controls.

<p>Bone turnover marker values are shown as mean±SD, the p values were calculated by one way ANOVA and the Bonferroni post-hoc correction. * and ° indicates the values significantly different between patients with/ without bone metastases (* <i>p</i> = 0.001, ° <i>p</i> = 0.000).</p

DKK-1 expression is higher in CaP patients.

<p>DKK-1 levels were dosed in serum patients with/without bone metastases and in healthy controls by ELISA. Bone metastatic (<i>p</i><0.004) and non-bone metastatic patients (<i>p</i><0.01) had significantly higher DKK-1 serum levels compared to healthy controls (A). CaP and healthy tissues were analyzed by Real-Time PCR in order to quantify DKK-1gene expression. The DKK-1 quantization was expressed as DKK-1 on β-Actin (the control gene) plasmid copy number. The histogram showed higher DKK-1 expression levels in CaP than in healthy tissues, <i>p</i><0.001 (B).</p

Prognostic significance of the Ki-67 labeling index in growth hormone-secreting pituitary adenomas.

CONTEXT: Ki-67 is a marker of proliferation activity associated with invasiveness and prognosis in human tumors. OBJECTIVE: The aim of the study was to evaluate the Ki-67 index prognostic relevance in a group of acromegalic patients who underwent transsphenoidal surgery for a GH-secreting pituitary adenoma. MATERIAL AND METHODS: We selected 68 consecutive acromegalic patients referred to our hospital during a 5-yr period. The Ki-67 index was determined by immunohistochemistry on tissue samples obtained from each adenoma after surgery. Those patients who were not completely cured after surgery began medical therapy with somatostatin analogs (SSAs). Periodical pituitary magnetic resonance imaging and hormonal evaluation were performed during the follow-up. RESULTS: Twenty-eight of 68 patients were cured after surgery (41%). Among the 40 patients treated with SSAs, 13 were considered uncontrolled. Pituitary magnetic resonance imaging showed residual/recurrent disease in 25 of 68 patients after 6 months. No correlation was found between Ki-67 index and age, tumor size, GH, or IGF-I plasma levels. Tumors described as having cavernous sinus invasion had a higher mean Ki-67 index as compared with noninvasive tumors (P < 0.01). The Ki-67 index was significantly lower in tumors in patients cured after surgery as compared with patients considered not cured (P < 0.01) and in tumors in patients controlled by SSA therapy as compared with patients considered as uncontrolled (P < 0.05). CONCLUSION: The Ki-67 labeling index may predict clinical outcome in postsurgical management of acromegalic patients. We suggest routine Ki-67 evaluation in GH-secreting pituitary adenomas

Factors predicting pasireotide responsiveness in somatotroph pituitary adenomas resistant to first-generation somatostatin analogues: an immunohistochemical study

INTRODUCTION: there is no available data regarding factors predicting responsiveness to pasireotide in acromegaly. PATIENTS AND METHODS: SSTR2a, SSTR3, SSTR5, AIP, Ki-67 and the adenoma subtype were evaluated in somatotroph adenomas from 39 patients treated post-operatively with somatostatin analogues (SSAs). A standardized SSTR scoring system was applied (scores 0 to 3). All patients received first generation SSAs, and 11 resistant patients were subsequently treated with pasireotide LAR. RESULTS: None of the patients with negative or cytoplasmic only SSTR2a expression (scores 0-1) were responsive to first generation SSAs, as opposed to 20% (score 2) and 50% of patients with a score of 3 (P=0.04). None of the patients with SSTR5 score 0-1 were responsive to pasireotide, as opposed to 5/7 cases with a score of 2 or 3 (P=0.02). SSTR3 expression did not influence first generation SSAs or pasireotide responsiveness. Tumours with low AIP were resistant to first generation SSAs (100 vs 60%; P=0.02), while they had similar responsiveness to pasireotide compared to tumours with conserved AIP expression (50 vs 40%; P=0.74). Tumours with low AIP displayed reduced SSTR2 (SSTR2a scores 0-1 44.4 vs 6.7%; P=0.006) while no difference was seen in SSTR5 (SSTR5 scores 0-1 33.3 vs 23.3%; P=0.55). Sparsely granulated adenomas responded better to pasireotide compared to densely granulated ones (80 vs 16.7%; P=0.04). CONCLUSIONS: The expression of SSTR5 might predict responsiveness to pasireotide in acromegaly. AIP deficient and sparsely granulated adenomas may benefit from pasireotide treatment. These results need to be confirmed in larger series of pasireotide-treated patients

Radically resected pituitary adenomas: prognostic role of Ki67 labeling index in monocentric retrospective series and literature review

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Treatment with octreotide LAR in clinically non-functioning pituitary adenoma: results from a case-control study

Surgical cure cannot be achieved in most patients with invasive non-functioning pituitary macroadenoma (NFPA). Short-term residual tumor treatment with somatostatin analogs has produced disappointing results. This prospective case-control study assessed the efficacy of chronic treatment with long acting octreotide (octreotide LAR) on tumor volume in patients harboring post-surgical NFPA residue. The study population comprised 39 patients with NFPAs not cured by surgery. All patients underwent somatostatin receptor scintigraphy at least 6&nbsp;months after the last surgery. Patients with a positive pituitary level octreoscan at (n&nbsp;=&nbsp;26) received octreotide LAR (20&nbsp;mg every 28&nbsp;days) for 6512&nbsp;months (mean follow-up 37&nbsp;\ub1&nbsp;18&nbsp;months) (Treated group). Moreover, a fragment of tumor tissue from patients in the treated group was retrospectively collected to assess the immunohistochemical expression of somatostatin receptor subtypes (SSTRs). The patients with a negative octreoscan (n&nbsp;=&nbsp;13) formed the control group (mean follow-up 37&nbsp;\ub1&nbsp;16&nbsp;months). Hormonal, radiological and visual field parameters were periodically assessed. In the treated group, all tumors expressed at least one SSTR subtype. The SSTR5 subtype was the most abundant, followed by SSTR3. The tumor residue increased in five of 26 patients (19%) in the treated group and in seven of 13 controls (53%). Visual field and pituitary function did not change in any patient. This study indicates that SSTR5 and SSTR3 are the most frequently expressed SSTR subtypes in NFPAs and supports a potential role of SSTR subtypes in stabilization of tumor remnant from NFPAs