Sorafenib, a drug approved for the treatment of advanced renal cancer, inhibits RAF/MAPK pathway, vascular endothelial receptor-2 and -3, platelet-derived growth factor receptor-2 and -3, and c-Kit [1.Wilhelm S.M. Adnane L. Newell P. et al.Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther. 2008; 7: 3129-3140Crossref PubMed Scopus (1108) Google Scholar].Hypophosphatemia is a common side-effect, occurring in ∼45% of patients [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar]. This metabolic derangement is mostly asymptomatic, but the mechanisms involved are unclear [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar].The physiological balance of phosphate is maintained by the coordinated interactions of the small intestine, bone, parathyroid gland and kidneys [3.Berndt T. Kumar R. Phosphatonins and the regulation of phosphate homeostasis.Annu Rev Physiol. 2007; 69: 341-359Crossref PubMed Scopus (192) Google Scholar] (Figure 1).A major breakthrough in understanding the regulation of phosphate homeostasis was accomplished by the identification of serum fibroblast growth factor-23 (FGF23), a bone-derived hormone able to cause hypophosphatemia by increasing the urinary excretion and decreasing the intestinal absorption of phosphates [4.Razzasque M.S. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis.Nat Rev Endocrinol. 2009; 5: 611-619Crossref PubMed Scopus (312) Google Scholar].A 64-year-old male with metastatic kidney cancer received sorafenib (400 mg b.i.d. orally) till progression for a total of 11 months. No major toxic effects were recorded and particularly no diarrhea or mucositis was observed. Serum FGF23 together with serum calcium, phosphorus, parathyroid hormone (PTH), 1,25(OH)2 vitamin D, alkaline phosphatase, C-telopeptide of type I collagen (CTX), urinary calcium and phosphorus were measured at baseline condition and every month during the first 5 months. Renal and hepatic functions were within normality throughout the study. The patient who had normal baseline serum phosphorus levels developed hypophosphatemia after 1 month that persisted for two additional months and was associated with a decrease in serum calcium, urinary calcium and phosphate (Table 1). Serum PTH increased, while serum 1,25(OH)2 vitamin D and serum FGF23 decreased. Serum CTX also decreased, but serum alkaline phosphatase did not change (Table 1).Table 1Variation in time of phosphate regulation hormones during Sorafenib administrationFGF23aFGF23 normal values are not available, so only the trend of this hormone serum levels can be considered., pg/mlVitamin D, ng/mlbNormal vitamin D ≥30 ng/ml; insufficiency 10–29 ng/ml; deficiency <10 ng/ml.CTX, ng/l (0.0–1)ALP, U/l (30–120)PTH, pg/ml (10–65)Ca, mmol/lcAlbumin-corrected serum calcium. (2.1–2.55)Ca tot U 24 H, mmol/24 h (2.5–7.5)P, mg/dl (2.5–4.8)Phosph U 24 H, mg/24 h (400–1300)Baseline4.9220.4965302.671.254.1977First month4.5190.26901042.40.222.7787Second month3.815881102.30.22.5738Third month3.1130.17921622.30.22.6642Vitamin D administrationFourth month7.75210.2581812.430.53.0797Fifth month10.2230.4296572.530.93.4853Reference range enclosed in parenthesis.FGF23, serum fibroblast growth factor-23; CTX, C-telopeptide of type I collagen; ALP, serum alkaline phosphatase; PTH, serum parathyroid hormone; Ca, serum calcium; Ca tot U 24 H, 24-h urinary calcium; P, serum phosphate; Phosph U 24 H, 24-h urinary phosphate.a FGF23 normal values are not available, so only the trend of this hormone serum levels can be considered.b Normal vitamin D ≥30 ng/ml; insufficiency 10–29 ng/ml; deficiency <10 ng/ml.c Albumin-corrected serum calcium. Open table in a new tab Due to the severe hypovitaminosis D attained in the first 3 months, a single i.m. dose of cholecalciferol (300 000 U) was administered. In the subsequent 2 months, serum phosphate returned to normal, calcium and vitamin D slightly increased, PTH consistently decreased and FGF23 increased. Also, serum CTX levels increased, while serum alkaline phosphatase did not change (Table 1).The decrease in urinary phosphate and calcium levels over time and the decreasing trend of FGF23 levels suggest that drug-induced hypophosphatemia in this patient was sustained by a low intestinal phosphate absorption and/or low bone phosphate release, while FGF23 was not contributory. Sorafenib inhibited the osteoclast activity as documented by the decrease of serum CTX. The reduction in serum vitamin D levels and the normalization of phosphate levels after vitamin D supplementation suggest a predominant role of this hormone in this metabolic disorder. The mechanism by which sorafenib can cause hypovitaminosis D is unclear and deserves to be confirmed in a prospective study. Concomitant malabsorption can be conceivably excluded since no diarrhea was recorded.Prolonged hypovitaminosis D and hyperparathyroidism lead to osteomalacia, astenia, and increased risk for cardiovascular disease [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. These effects could negatively impact on long-term sorafenib tolerability. Moreover, since vitamin D has antiproliferative activities, hypovitaminosis D can also potentially influence the drug efficacy [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. Further studies are warranted to confirm the results of this paper, assess the prognostic significance of hypophosphatemia and define its appropriate treatment.fundingBayer to A.B.disclosureAB has received research funds from Bayer. All other authors declare no conflict of interest. Sorafenib, a drug approved for the treatment of advanced renal cancer, inhibits RAF/MAPK pathway, vascular endothelial receptor-2 and -3, platelet-derived growth factor receptor-2 and -3, and c-Kit [1.Wilhelm S.M. Adnane L. Newell P. et al.Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling.Mol Cancer Ther. 2008; 7: 3129-3140Crossref PubMed Scopus (1108) Google Scholar]. Hypophosphatemia is a common side-effect, occurring in ∼45% of patients [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar]. This metabolic derangement is mostly asymptomatic, but the mechanisms involved are unclear [2.Escudier B. Eisen T. Stadler W.M. et al.Sorafenib in advanced clear-cell carcinoma.N Engl J Med. 2007; 356: 125-134Crossref PubMed Scopus (4311) Google Scholar]. The physiological balance of phosphate is maintained by the coordinated interactions of the small intestine, bone, parathyroid gland and kidneys [3.Berndt T. Kumar R. Phosphatonins and the regulation of phosphate homeostasis.Annu Rev Physiol. 2007; 69: 341-359Crossref PubMed Scopus (192) Google Scholar] (Figure 1). A major breakthrough in understanding the regulation of phosphate homeostasis was accomplished by the identification of serum fibroblast growth factor-23 (FGF23), a bone-derived hormone able to cause hypophosphatemia by increasing the urinary excretion and decreasing the intestinal absorption of phosphates [4.Razzasque M.S. The FGF23-Klotho axis: endocrine regulation of phosphate homeostasis.Nat Rev Endocrinol. 2009; 5: 611-619Crossref PubMed Scopus (312) Google Scholar]. A 64-year-old male with metastatic kidney cancer received sorafenib (400 mg b.i.d. orally) till progression for a total of 11 months. No major toxic effects were recorded and particularly no diarrhea or mucositis was observed. Serum FGF23 together with serum calcium, phosphorus, parathyroid hormone (PTH), 1,25(OH)2 vitamin D, alkaline phosphatase, C-telopeptide of type I collagen (CTX), urinary calcium and phosphorus were measured at baseline condition and every month during the first 5 months. Renal and hepatic functions were within normality throughout the study. The patient who had normal baseline serum phosphorus levels developed hypophosphatemia after 1 month that persisted for two additional months and was associated with a decrease in serum calcium, urinary calcium and phosphate (Table 1). Serum PTH increased, while serum 1,25(OH)2 vitamin D and serum FGF23 decreased. Serum CTX also decreased, but serum alkaline phosphatase did not change (Table 1). Reference range enclosed in parenthesis. FGF23, serum fibroblast growth factor-23; CTX, C-telopeptide of type I collagen; ALP, serum alkaline phosphatase; PTH, serum parathyroid hormone; Ca, serum calcium; Ca tot U 24 H, 24-h urinary calcium; P, serum phosphate; Phosph U 24 H, 24-h urinary phosphate. Due to the severe hypovitaminosis D attained in the first 3 months, a single i.m. dose of cholecalciferol (300 000 U) was administered. In the subsequent 2 months, serum phosphate returned to normal, calcium and vitamin D slightly increased, PTH consistently decreased and FGF23 increased. Also, serum CTX levels increased, while serum alkaline phosphatase did not change (Table 1). The decrease in urinary phosphate and calcium levels over time and the decreasing trend of FGF23 levels suggest that drug-induced hypophosphatemia in this patient was sustained by a low intestinal phosphate absorption and/or low bone phosphate release, while FGF23 was not contributory. Sorafenib inhibited the osteoclast activity as documented by the decrease of serum CTX. The reduction in serum vitamin D levels and the normalization of phosphate levels after vitamin D supplementation suggest a predominant role of this hormone in this metabolic disorder. The mechanism by which sorafenib can cause hypovitaminosis D is unclear and deserves to be confirmed in a prospective study. Concomitant malabsorption can be conceivably excluded since no diarrhea was recorded. Prolonged hypovitaminosis D and hyperparathyroidism lead to osteomalacia, astenia, and increased risk for cardiovascular disease [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. These effects could negatively impact on long-term sorafenib tolerability. Moreover, since vitamin D has antiproliferative activities, hypovitaminosis D can also potentially influence the drug efficacy [5.Holick M.F. Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10457) Google Scholar]. Further studies are warranted to confirm the results of this paper, assess the prognostic significance of hypophosphatemia and define its appropriate treatment. fundingBayer to A.B. Bayer to A.B.

Persistent circadian rhythm of bone turnover in bone metastatic breast cancer suggests greater skeletal retention of bisphosphonates if administered in the night. We assessed differential effects of night vs morning administration of zoledronic acid (ZA) on bone turnover. Forty-four breast cancer patients with bone metastases were randomised to receive intravenous ZA (4 mg) at 1100 or 2300 hours every 28 days for four times. Urinary concentration N -telopeptide of type-I collagen (NTX) and deoxypyridinolines, and serum C-telopeptide of type-I collagen (CTX), bone alkaline phosphatase (ALP), osteocalcin and Parathyroid hormone (PTH) was measured in the morning at baseline and after 4, 7, 14, 28, 56 and 84 days. Urinary ZA concentration was also measured. Zoledronic acid caused significant decreases of NTX and CTX ( P <0.001), without any difference in percent changes between night and morning arms. Bone ALP and osteocalcin were also significantly affected by ZA ( P =0.001), without any difference between arms. Parathyroid hormone significantly increased in both the arms; PTH increase was lower in the night arm ( P =0.001). From the second administration onwards, urinary ZA level was significantly higher in the night arm ( P <0.01). Administration of ZA at two opposite phases of the circadian cycle causes similar changes of bone-turnover marker levels, but has differential effects on the level of serum PTH.

Bone metabolic disruption that occurs in bone metastatic prostate cancer could lead to disturbances of calcium metabolism. The prognostic role of either hypocalcemia or hypercalcemia was assessed in a consecutive series of hormone-refractory bone metastatic prostate cancer patients. Serum calcium was measured in 192 patients. The presence of hypocalcemia and hypercalcemia was related with baseline biochemical and clinical characteristics and the role of these two calcium disturbances in predicting prognosis and adverse skeletal-related events (SREs) was assessed. As compared to normocalcemic patients, hypocalcemic patients (n=51) had higher tumor load in bone (P=0.005), higher plasma chromogranin A (CgA, P=0.01), serum alkaline phosphatase (P=0.01), urinary N-telopeptide (NTX, P=0.002) and lower hemoglobin values (P=0.01), while hypercalcemic patients (n=16) had higher plasma CgA (P=0.001) and serum lactate dehydrogenase values (P=0.001), higher bone pain (P=0.003) and a lower frequency of pure osteoblastic lesions (P=0.001). Hypercalcemia was significantly associated with poor prognosis: hazard ratio (HR), 1.9 (95% confidence Interval (CI) 1.2-3.3) and higher risk to develop SREs HR, 2.5 (95% CI 1.2-5.2, P=0.01), while hypocalcemia was not associated with poor prognosis. The prognostic role of hypercalcemia was maintained in multivariate analysis after adjusting for validated prognostic parameters: HR, 2.72 (95% CI 1.1-6.8, P=0.03). These data suggest that serum calcium levels should be taken into account in the clinical decision-making process of bone metastatic prostate cancer patients. Patients with asymptomatic hypercalcemia could benefit of a strict follow-up and an immediate bisphosphonate treatment. Further prospective clinical trials are needed to confirm this finding.

The variability of serum osteoprotegerin (OPG) and soluble RANKL (sRANKL) along the 24-h cycle was assessed in 20 healthy women. No rhythmic variations of serum OPG, sRANKL or sRANKL/OPG ratio were detected as a group phenomenon. Timing of sampling is unlikely to influence the results of measurements of circulating OPG and sRANKL.

14091 The primary objective of this study was to validate the clinical significance of blood evaluation of CgA in NET patients at the diagnosis (PHASE I) and during 2 years of follow-up (PHASE II). From May 2003 to October 2004, 276 patients entered the study from 40 Italian centers: 270 were evaluable. All basal and every 3 months collected CgA blood samples were centrally measured in two reference laboratories (Orbassano-Turin and Venice) where ELISA (DAKO,Denmark) or IRMA (CIS-Schering, France) were performed to look at the correlation between the two methods and their sensitivity and specificity. Lab results at the baseline have been recently published (Leon et al., Intern. J. Biol. Markers, 2005). We are now collecting all the correlations between CgA and type and place of NETs; tumor bulk; metastatization; presence or not of specific syndrome;proliferation activity (Ki67); octreoscan; tumor specific markers. 223 patients (83%) had gastroenteropancreatic tumors, whereas 24 (9%) had medullary tyroid cancer, 16 (6%) Merkel cell carcinoma and 6 parathyroid NETs, pheochromocytoma, paraganglioma. Only 26% of GEP tumors presented with specific symptoms. At the entry in the study 58% of patients had a new diagnosis, 23% were in stable disease, whereas 18% had metastatic disease. According to the recent W.H.O. histologic classification (Solcia et al, 2000), 36% specific symptomatic patients had NE tumor, 57% well differentiated cancer and only 3% poor differentiated cancer, whereas 31% not symptomatic patients had NE tumor, 48% well differentiated and 16% poor differentiated cancer. This is the largest study worldwide performed on this topic and all the data about the correlation among all patient variables and CgA blood values will be ready in April 2006. Follow-up data will be evaluable next year. [Table: see text]

677 Background: Z is an effective bisphosphonate in preventing skeletal related events (SREs) in bone metastatic patients. Decrease in bone resorption markers during Z therapy is a potential surrogate of drug efficacy. Bone resorption markers maintain a circadian rhythmicity in metastatic BC patients (Generali et al ASCO 2005), suggesting that Z may be more active if administered in a chronomodulated way. Raised PTH after Z could impair the drug efficacy (Berruti et al ASCO 2006). Methods: Forty-four BC patients with bone metastases were randomised to receive Z, 4 mg i.v. at 11.00 p.m or 11 a.m every 28 days for 4 times. Serum cross laps (CTX), urinary n-telopeptide (NTX) and serum parathyroid hormone (PTH) levels were measured at baseline and after 4, 7, 14, 28, 56 and 84 days, respectively. Results: Z administration in the night resulted in a greater decrease of either serum CTX or urinary NTX and lower increase in serum PTH ( Table ) than morning administration. Conclusions: Z administration in the night might be more efficacious than morning administration. [Table: see text] No significant financial relationships to disclose.

The presence of neuroendocrine (NE) differentiation in the context of predominantly exocrine prostate cancer may play a key role in androgen-independent tumor growth. The prognostic significance of plasma chromogranin A (CgA) was assessed in a series of consecutive prostate cancer patients with hormone-refractory disease.One hundred and eight patients with newly diagnosed hormone-refractory prostate cancer entered the study. Plasma CgA levels and other biochemical parameters, such as serum prostate specific antigen, serum alkaline phosphatase, serum lactate dehydrogenase, serum albumin and hemoglobin concentration, were measured at baseline (i.e. when hormone refractoriness occurred) and their prognostic role was evaluated together with patient performance status, Gleason score (at diagnosis of prostate cancer) and the presence of visceral metastases. Furthermore, plasma CgA was prospectively evaluated in 50 patients undergoing chemotherapy.At baseline, 45 patients (43.3%) showed elevated CgA values. Plasma CgA negatively correlated with survival, either in univariate analysis (P = 0.008) or in multivariate analysis, after adjusting for previously mentioned prognostic parameters (P < 0.05). In the patient subset undergoing chemotherapy, median CgA (range) values were 13.3 (3.0-141.0) U/l at baseline, 19.1 (3.0-486.0) U/l after 3 months, 20.8 (3.0-702.0) U/l after 6 months and 39.4 (3.0-414.0) U/l after 9 months (P < 0.01). The corresponding supranormal rates were 17/50 (34%), 23/50 (46%), 26/50 (52%) and 34/50 (68%) respectively (P < 0.005).Elevated plasma CgA levels are frequently observed in prostate cancer patients with hormone-refractory disease and correlate with poor prognosis. NE differentiation in hormone- refractory patients is a time-dependent phenomenon and is not influenced by conventional antineoplastic treatments.

Most of the conventional adenocarcinomas of the prostate display focal neuroendocrine (NE) differentiation at diagnosis, usually revealed by immunohistochemistry as solitary or clusters of cells, in the context of predominantly exocrine tumors. Even though the biological and clinical significance of NE differentiation in prostate cancer is still to be elucidated, NE phenotype is emerging as an important factor in the prognosis, evolution and progression of prostate cancer. It seems to be particularly relevant in facilitating prostate cancer progression during the ordinary androgen-suppression therapy (LHRH-analogs +/- anti-androgens). Several mechanisms have been identified: NE cells are androgen receptor negative, therefore they survive to androgen deprivation; NE cells produce peptides, hormones and growth factors which could stimulate proliferation [chromogranin (A-CgA), PTHrp, bombesin, etc.], inhibit apoptosis (Survivin) and stimulate neoangiogenesis [vascular endothelial GF (VEGF)] of the neighbouring exocrine prostate cancer cells. NE differentiation appears to be a dynamic phenomenon. The NE phenotype expression increases during androgen-deprivation therapy and results more elevated in hormone refractory than in hormone sensitive disease. Pre-clinical and clinical studies demonstrated a direct stimulation of NE differentiation by androgen-suppression therapy, resulting in a dramatic increase in the number of cells expressing NE markers. CgA appears to be the most sensitive marker and is most frequently used for detecting NE phenotype either at the tissue level or in the general circulation. Elevated plasma CgA levels are frequently observed in hormone-refractory disease and correlate with poor prognosis. Even in hormone refractory disease, NE differentiation is a time-dependent phenomenon and is not influenced by conventional antineoplastic treatments.

9563 Background: neuroendocrine (NE) differentiation in prostate cancer (PC) is more frequently expressed in hormone refractory patients than in those with hormone naive disease. Chromogranin A (CgA) is the most employed marker to detect NE features. Methods: plasma CgA (ELISA kit, DAKO, Glostrup-Denmark, reference range in PC patients 2–20 U/L) was evaluated at baseline conditions in 108 consecutive patients with hormone refractory PC. Results: patients characteristics were as follows: median age 74 yrs (range 58–86), median ECOG performance status 1 (range 0–3). 105 patients (97.2%) had metastatic bone disease, 91 patients (84,2%) had elevated PSA values (median 97.0 ng/ml, range 0.1–3393.0). Median CgA values was 17.3 U/L (range 3.0–394.0), supranormal CgA values were recorded in 45 patients (43.3%). Baseline elevated plasma CgA correlated with a shorter survival perspect: 11.13 months (range: 3.5–18.7) vs 22.37 months (range: 13.7–31.0) (p=0.02). In a multivariate analysis, plasma CgA provided independent prognostic information [Hazard Risk 1.28 (95% Confidence interval 1.08–1.53), p<0.005] with respect to serum PSA [Hazard Risk 1.10 (95% Confidence Interval 1.02–1.19), p=0.01]. Plasma CgA was prospectively evaluated after 3, 6, and 9 months in 50 patients submitted to chemotherapy. Median CgA plasma levels (range) were: 13.3 U/l (3.0–141.0) at baseline and 19.1 (3.0–486.0), 20.8 (3.0–702.0) and 39.4 (3.0–414.0) after 3, 6 and 9 months, respectively (p<0.01); the corresponding supranormal rates were 17/50 (34%), 23/50 (46%), 26/50 (52%) and 34/50 (68%) (p<0.005). Conclusions: elevated plasma CgA is frequently observed in PC patients with hormone refractory disease and correlates with poor prognosis. The prognostic role of plasma CgA is independent to that of serum PSA. Plasma CgA values show a progressive increase during chemotherapy, suggesting that NE phenotype expression in hormone refractory PC patients is a time-dependent phenomenon and is not influenced by the cytotoxic treatment. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration DAKO Glostrup Denmark

Background Increased osteolysis usually accompanies sclerotic bone metastases from prostate cancer. This provides a rationale for the use of bisphosphonates to treat bone pain and prevent skeletal complications. Methods The fasting urinary levels of calcium, hydroxyproline (OHPRO), pyridinolines (PYD), deoxypyridinolines (DPYD), collagen cross-linked N-telopeptide (NTX) and the serum values of calcium, total alkaline phosphatase and relevant bone isoenzyme, bone gla protein (BGP), carboxy-telopeptide of type I collagen (ICTP) and parathyroid hormone (PTH) were determined at baseline and on the 15th, 30th, 60th and 90th days after single-dose (90 mg) pamidronate administration in 35 consecutive prostate cancer patients with bone metastases. These biochemical indices and serum interleukin 6 (IL-6) were also measured after four days in the last consecutive 17 cases. Results PYD, DPYD and NTX showed a significant decrease lasting four weeks (p<0.01, <0.01 and <0.001, respectively). OHPRO and ICTP did not change significantly. The NTX decline was greater than that of PYD and DPYD (maximum percent decrease: −71.3, −23.1 and −28.2, respectively). Bone formation markers and serum calcium did not change significantly. Serum PTH showed a rapid initial increase followed by a slow decrease (p<0.001). DPYD and NTX patterns did not correlate with changes in bone pain. As observed in the last 17 cases, the maximum osteolysis inhibition after pamidronate occurred on the fourth day after drug infusion. Serum IL-6 levels showed a short-lived decrease preceded by a transient rise on the fourth day. Conclusions Pamidronate is able to induce a decrease in bone resorption without significantly influencing bone formation. The maximum decrease in bone resorption occurs very early. NTX is the most sensitive bone resorption marker in bisphosphonate therapy monitoring. Changes in IL-6 but not bone resorption markers may be useful in the prediction of symptomatic response.

BACKGROUND:Neuroendocrine (NE) differentiation of prostate adenocarcinoma has received increasing attention in recent years as a result of possible implications for prognosis and therapy. The presence of NE tumor subpopulation can be gauged non invasively by measuring circulating levels of secretory products, primarily chromogranin A (CgA).METHODS:This article provides a review on published papers evaluating circulating CgA in prostate cancer patients.RESULTS:Circulating CgA levels were found to be higher in prostate cancer patients than in patients with benign or pre-malignant prostatic diseases. In patients with malignancy, they correlated either to the stage of disease or to the condition of hormone refractoriness. CgA levels did not correlate with serum prostate specific antigen (PSA) and were supranormal in the majority of advanced patients with PSA within normality. In hormone refractory cases, elevated CgA was a significant predictor of poor prognosis, independently from serum PSA. CgA values were not substantially affected by either endocrine therapy or chemotherapy. They were found to increase during androgen deprivation in some cases and this trend preceded that of PSA. The administration of a somatostatin analog in hormone refractory cases was able to reduce plasma CgA values consistently.CONCLUSIONS:Present data suggest a potential role of circulating CgA in the management of prostate cancer patients. CgA determination may be useful diagnostically and prognostically and could offer complementary information with respect to PSA. Serial evaluation of circulating CgA could provide information on changes in the NE phenotype expression as a consequence of tumor progression and/or treatment administration.

Background: Chromogranin A (CgA) is a secretory protein present in dense-core vesicles of neuroendocrine (NE) cells. Its ubiquitous presence in NE tissues makes it a suitable circulating marker of neoplasms of NE origin.Patients and Methods: Plasma CgA was determined in 178 patients with NE tumors and in 36 patients with non-endocrine malignancies. Circulating CgA was also serially evaluated in 39 NE cancer patients with advanced disease submitted to systemic therapy and in 14 patients with no evidence of disease (NED).Results: Supranormal CgA values were found in 81% of patients with advanced NE tumors and in only 91% of NED cases. Plasma CgA in patients with well differentiated NE tumors, such as carcinoids, carcinoma of gastrointestinal tract, pheocromocytoma, pancreatic NE carcinoma (either functioning or not functioning), medullary thyroid carcinoma and NE tumors from various primary sites, was higher and more frequently elevated than in patients with small-cell lung cancer (P < 0.001). Plasma CgA did not discriminate patients with NE from those with non NE neoplasms since it was found elevated in 44% of the latter cases. Plasma CgA pattern correlated with the disease response in patients submitted to cytotoxic treatment and with changes in clinical symptomathology in patients receiving somatostatin analogs.Conclusions: Our data confirm that CgA is the best circulating neuroendocrine marker available up to now available for the management of differentiated neuroendocrine malignancies irrespective of tumor location and functional status. CgA plasma levels could also identify the coexistence of neuroendocrine differentiation in the context of non-endocrine malignancies. Circulating CgA seems to be less useful in undifferentiated tumors such as small-cell lung cancer.

BACKGROUND. The concept that neuroendocrine cells detected within prostate adenocarcinoma produce paracrine factors, that may exert a proliferative effect on exocrine prostate tumor cells, provides a rationale for the use of somatostatin analogs with the aim to counteract or delay the tumor progression. This study was designed to provide preliminary information on the effect of the administration of a long-acting somatostatin analog, lanreotide, on plasma levels of chromogranin A (CgA). Secondary aims were the evaluation of changes in circulating prostate-specific antigen (PSA) and insulin-like growth factor-1 (IGF-1).METHODS. Lanreotide(Ipstyl 30 mg; Ipsen, Milan, Italy) was administered intramuscularly every 14 days for 2 months to nine heavily pretreated prostate cancer patients with hormone refractory disease. All patients had, at baseline conditions, CgA values above the normal range. Androgen deprivation was maintained during the study period, while other concomitant antineoplastic treatments were not allowed. Serum PSA levels and plasma CgA and IGF-1 values were measured every week.RESULTS. Lanreotide treatment was very well tolerated and no patient experienced major toxicity. Plasma CgA values at baseline: mean 109 U/liter, standard deviation +/- 85 decreased significantly after treatment as follows: 42 U/liter, +/- 17.8; 27.2 U/liter +/- 13.6; 31.4 U/liter, +/- 17.8 and 27.6 U/liter, +/- 17.0; after 7, 14, 21, and 28 days, respectively (P < 0.01, Friedman ANOVA). Serum PSA did not change. Baseline IGF-1 was found to be above the detection limit in four cases, all of them showing a decrease after lanreotide.CONCLUSIONS. Lanreotide administration to prostate cancer patients induces a decrease in plasma CgA and IGF-1 levels, without any influence on serum PSA values. Prostate 47:205-211,2001. (C) 2001 Wiley-Liss, Inc.

metastatic PC; 2) evaluate their prognostic significance; 3) compare values in patients with hormone-naive and hormone-refractory disease; and 4) assessBACKGROUND, Circulating neuroendocrine markers were measured in patients with prostate carcinoma (PC), prostatic intraepithelial neoplasia (PIN), and benign prostatic hypertrophy (BPH) with the goal to: 1) evaluate the differences in the expression of these markers in patients with benign, premalignant, and primary or changes after androgen deprivation or chemotherapy.METHODS. Serum neuron specific enolase (NSE) (immunoradiometric assay) and plasma chromogranin A (CgA) (enzyme-linked immunoadsorbent assay) were evaluated in 141 patients with BPH, 54 patients with PIN, and 159 patients with PC; 119 patients were bearing hormone-naive disease and 40 were bearing hormone-refractory disease. CgA was monitored in 31 patients submitted to androgen deprivation and in 24 patients receiving chemotherapy.RESULTS. Supranormal CgA was observed more frequently in patients with American Urologic Association (AUA) Stage D2 disease (45.5%) compared with those with Stage D1 disease (33.3%), Stage C disease (16.7%), Stage RIB disease (18.8%), PIN (25.9%), and BPH (17.0%) (P < 0.02). Supranormal NSE did not change in any of the patient subgroups. Elevated CgA was observed in 36.0% of patients with metastases who had hormone-naive disease and in 45.0% of patients with hormone-refractory disease (P value not significant). Supranormal NSE and CgA values were predictors for poor prognosis in patients with hormone-refractory disease. Elevated baseline CgA values decreased > 50% in 1 of 12 patients who received luteinizing hormone-releasing hormone analogs and in 2 of 12 patients who underwent chemotherapy.CONCLUSIONS. CgA appears to reflect the neuroendocrine activity of PC better than NSE. Elevated CgA. values correlate with poor prognosis and are scarcely influenced by either endocrine therapy or chemotherapy. (C) 2000 American Cancer Society.

Purpose: We evaluated the incidence of skeletal complications in patients with bone metastatic prostate cancer and hormone refractory disease. We also assessed the predictive role of bone turnover markers determined at baseline.Materials and Methods: A total of 112 patients were consecutively enrolled in our study from July 1990 to July 1998 and followed until death or the last followup. Bone pain, disease extent in bone, serum prostate specific antigen, hemoglobin, and a panel of bone formation and resorption markers were assessed at baseline before any second line treatment.Results: Skeletal complications in 34 patients (30.3%, estimated yearly incidence 12.3%) involved vertebral deformity or collapse requiring spinal orthosis in 20 (17.9%), spinal cord compression in 7 (6.2%), pathological bone fracture in 10 (8.9%), symptomatic hypercalcemia in 1 (0.9%) and symptomatic hypocalcemia in 1 (0.9%). Median time to the evidence of the initial skeletal complication was 9.5 months. These adverse events did not influence overall survival. At baseline patients with eventual skeletal complications had greater bone pain (p = 0.02), a heavier tumor load in bone (p = 0.005), lower performance status (p = 0.05), and higher serum alkaline phosphatase (p <0.02) and urinary deoxypyridoline (p <0.05) than their counterparts. Multivariate analysis revealed that only urinary deoxypyridinoline was independently associated with the onset of these events (p <0.02). The scatterplot of urinary deoxypyridinoline values in patients with and without skeletal complications enabled us to detect a cutoff of 38 pM./mM. for predicting 51% of skeletal events with only an 8% false-positive rate.Conclusions: Skeletal complications are common in patients with prostate cancer and hormone refractory disease. Bone loss is the major cause of onset. Baseline deoxypyridinoline at the cutoff point noted had moderate sensitivity but high specificity for predicting these adverse skeletal events.

Purpose: To provide preliminary data on whether the diagnostic role of serum prostate specific antigen (PSA) in assessing the response to treatment is improved by concomitant free PSA evaluation both markers were evaluated in 42 patients with advanced prostate cancer who received hormonal therapy and 57 with hormone refractory disease who received chemotherapy.Materials and Methods: PSA was assessed at baseline and every 3 months during treatment. Free PSA was assessed in stored serum samples obtained at baseline and at maximum PSA decrease. Free PSA was not measurable in 17 patients who received androgen deprivation (40.5%) and 2 who received chemotherapy (3.5%) because it was less than 1.5 ng./ml.Results: Of the 21 patients with greater than 50% PSA decrease after hormonal therapy free-to-total PSA increased in 12 (57.2%) and decreased in 9 (42.9%). Of the 20 patients with PSA response after chemotherapy free-to-total PSA increased in 18 (90.0%) and decreased in 2 (10.0%). Free-to-total PSA increased in 12 of the 20 patients (60.0%) with PSA stabilization after chemotherapy. Patients with an increase in free-to-total PSA after chemotherapy had greater survival compared to those with a decrease or no change (19.8 versus 15.5 months, respectively, p < 0.03).Conclusions: These data suggest that an effective cytotoxic regimen mainly affects the protein bound PSA fraction, The absence of a clear predominant pattern of free-to-total PSA in patients with PSA response to hormonal therapy and the high percentage of hormone sensitive patients in whom free PSA was not assessable at maximum PSA decrease suggest that free PSA evaluation is less useful in prostate cancer patients undergoing androgen deprivation.

BACKGROUND The alteration of the bone microenvironment as a consequence of skeletal metastases is poorly understood. The aim of this study was to search for patterns of bone markers in relation to primary tumor type, bone pain, and number of sites involved in patients with bone metastases. METHODS We studied 323 patients with bone metastases from various primary malignancies. We sequentially measured the serum concentrations of bone alkaline phosphatase [by an electrophoretic technique (BALP)], carboxy-terminal telopeptide of type I collagen (ICTP), calcium (CaS), intact parathyroid hormone (PTH), and the fasting urinary excretion of calcium (Ca:Cr). Immunoradiometric serum bone alkaline phosphatase (I-BALP) and urinary excretion of deoxypyridinoline (DPYD) were also assessed in the 175 cases. Data were analyzed as a function of bone pain (assessed by a validated pain questionnaire), the number of radiographically confirmed sites of bone involvement, and the most frequent primary tumor types: breast cancer (BC; 124 patients), prostate cancer (PC; 90 patients), and non-small cell lung cancer (LC; 49 patients). RESULTS Serum BALP and I-BALP correlated with the number of radiologically identified blastic bone lesions. BALP and I-BALP were more frequently increased in PC (72% for both measurements) than in BC (50% and 60%, respectively) or LC (3% and 5%, respectively; P <0.001 for BALP and P = 0.001 for I-BALP). ICTP and DPYD values did not differ among PC, BC, and LC, but they did show a direct relationship with the disease extent in bone (P <0. 001). CaS and Ca:Cr did not vary significantly according to the bone tumor burden. Bone pain directly correlated with ICTP (P <0.001), DPYD (P = 0.002), CaS (P <0.002), and Ca:Cr (P = 0.001), whereas the relationship was inverse for serum PTH (P = 0.002). When patients were stratified according to the primary tumor, ICTP correlated with the bone pain in all subsets (P <0.005, <0.005, and <0.001 for BC, PC, and LC, respectively), as did CaS and Ca:Cr in LC patients (P = 0.01 and 0.02, respectively) but not in PC and BC patients. CONCLUSIONS The patterns of bone turnover markers differ among the primary tumor types. Both resorption and formation markers reflect the number of radiographically identified sites of bone metastases, whereas resorption markers and serum calcium but not formation markers correlate with bone pain.

In order to study the relationship between circulating levels of CA 15-3 and the disease extent in predicting survival, we prospectively followed 312 breast cancer (BC) patients, from October 1988 to March 1995, from the time of first relapse. CA 15-3 values were assessed before treatment onset. Disease extent was defined as the percentage of liver or lung involvement and the number of bone segments positive at scintigraphy. The covariates were primary tumour characteristics (T, N and hormone receptor status) and patient characteristics at recurrence (menopause, performance status and age). Higher CA 15-3 serum levels were found in patients with visceral metastases or with pleural effusion. A logistic regression model selected disease extent in liver, lung and bone as independent variables for the determination of abnormal CA 15-3 values. Univariate survival analysis confirmed the positive prognostic influence of low CA 15-3 serum levels, absence of visceral metastases and the presence of only one metastatic site. Multivariate Cox's survival analysis selected disease extent in liver, lung, bone and soft tissue but not level of CA 15-3 as prognostic factors. In conclusion, CA 15-3 is not an independent variable in determining survival, its prognostic role being linked to the disease extent. This association suggests that CA 15-3 may be useful in assessing disease extent when this is not easily assessable.

Objective: To assess correlation between type of breast cyst and risk of breast cancer in women with gross cystic disease of the breast.Design: Cohort study of women with breast cysts aspirated between 1983 and 1993 who were followed up until December 1994 for occurrence of breast cancer.Setting: Major cancer prevention centre.Subjects: 802 women with aspirated breast cysts.Main outcome measures: Type of breast cyst based on cationic content of cyst fluid: type I (potassium:sodium ratio > 1.5), type II (potassium:sodium ratio < 1.5), or mixed (both types). Subsequent occurrence and type of breast cancer.Results: After median follow up of six years (range 2-12 years) 15 cases of invasive breast cancer and two ductal carcinomas in situ were diagnosed in the cohort: 12 invasive cancers (and two carcinomas in situ) among the 417 women with type I cysts, two cancers among the 325 women with type II cysts, and one among the 60 women with mixed cysts. The incidence of breast cancer in women with type I cysts was significantly higher than that in women with type II cysts (relative risk 4.62 (95% confidence interval 1.26 to 29.7)). These results were confirmed after adjustment for several risk factors for breast cancer (relative risk 4.24 (1.12 to 27.5)).Conclusions: The increased risk of breast cancer of women with breast cysts seems to be concentrated among women with type I breast cysts.

BACKGROUND. The so-called Bone Hunger Syndrome is a metabolic derangement that sometimes complicates the natural history of prostate cancer patients with osteoblastic bone metastases. An excessive bone formation leads to calcium entrapment in bone and the subsequent increase of parathyroid hormone (PTH) levels, in response to calcium demand. PTH elevation stimulates the osteoclasts in sites distant from those involving the tumor, leading to osteomalacia.METHODS. PTH and markers of bone turnover were monitored every 3 weeks, from the start of pamidronate treatment in a prostate cancer patient with progressive disease, to luteinizing hormone releasing hormone analog (LHRH-A) administration, developing hyper-parathyroidism, hypophosphatemia, and albumin corrected serum calcium close to the lower limit of normality. Serum bone alkaline phosphatase (BALP), assessed by two different methods: electrophoretic and immunoradiometric, and urinary levels of markers of bone collagen breakdown were also remarkably elevated.RESULTS. As a consequence of pamidronate infusion (60 mg e.v. every 3 weeks for a total of four times), BALP and PTH decreased consistently, serum calcium and phosphorus returned within the normal range, while markers of collagen resorption showed a significant decrease at the 9th week, preceded by a transient rise.CONCLUSIONS. This case report indicates that bisphosphonates could inhibit both osteoclast and osteoblast activity. The anti-osteoblastic effect is mainly responsible for the improvement of the pretreatment calcium imbalance of our patient towards hypocalcemia and the consequent hyperparathyroidism. (C) 1997 Wiley-Liss, Inc.