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Background: There is rising concern on the impact of new strategies, such as high-dose chemotherapy (HDC) and immunotherapy, on the pattern of relapse in high-risk neuroblastoma (HR-NBL). Our aim is to evaluate the incidence and identify risk factors for first recurrence in the central nervous system (CNS) in HR-NBL., Patients and Methods: Data from patients with stage 4V HR-NBL included from February 2002 to June 2015 in the prospective HR-NBL trial of the European International Society of Pediatric Oncology Neuroblastoma Group were analysed. Characteristics at diagnosis, treatment and the pattern of first relapse were studied. CNS imaging at relapse was centrally reviewed., Results: The 1977 included patients had a median age of 3 years (1 day-20 years); 1163 were boys. Among the 1161 first relapses, 53 were in the CNS, with an overall incidence of 2.7%, representing 6.2% of all metastatic relapses. One- and three-year post-relapse overall survival was 25 ± 6% and 8 ± 4%, respectively. Higher risk of CNS recurrence was associated with female sex (hazard ratio [HR] = 2.0 [95% confidence interval {CI}: 1.1-3.5]; P = 0.016), MYCN-amplification (HR = 2.4 [95% CI: 1.2-4.4]; P = 0.008), liver (HR = 2.5 [95% CI: 1.2-5.1]; P = 0.01) or >1 metastatic compartment involvement (HR = 7.1 [95% CI: 1.0-48.4]; P = 0.047) at diagnosis. Neither HDC nor immunotherapy was associated with higher risk of CNS recurrence. Stable incidence of CNS relapse was reported over time., Conclusions: The risk of CNS recurrence is linked to both patient and disease characteristics, with neither impact of HDC nor immunotherapy. These findings support the current treatment strategy and do not justify a CNS prophylactic treatment., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pheochromocytoma and paraganglioma are rare neuroendocrine tumors. Knowledge about such neoplasms ameliorated in the last 10-15 years with the discovery of increasing number of germ line mutations even in apparently sporadic cases. Seemingly, genetic tests are going to be an integral part of diagnostic procedures. Standard therapies (advanced surgery, radiometabolic therapy, chemotherapy and radiotherapy) have revealed suboptimal results in tumor size reduction and survival. Currently, there is no standard therapeutic protocol and thus some patients end up with overtreatment while others are undertreated. An effective molecular target therapy aiming at permanent control of these highly complex neoplasms should be the aim of future efforts. In clinical setting investigatory trials with multiple drug therapies targeting a variety of different parallel pathways should be available. Successful management requires a multidisciplinary teamwork.

Gallium-68 DOTANOC is a high affinity somatostatin receptor ligand, first introduced in 2005 for imaging neuroendocrine tumors. Due to its technically simple production, broad availability, favourable biodistribution and advantageous dosimetry, although not approved yet in all European countries, gallium-68 DOTANOC has rapidly gained acceptance in the diagnostic and therapeutic work-flow of different types of neuroendocrine tumors. Principal indications in clinical practice in countries where it is officially approved include diagnosis and staging, restaging after treatment, identification of sites of unknown primary and selection of patients with neuroendocrine tumors eligible for therapy with somatostatin analogues.

Iodine-131 metaiodobenzylguanidine (I-131 MIBG) has been used for the diagnosis and treatment of malignant pheochromocytomas (PHEO) and paragangliomas (PGL) since 1980's. Despite increasing amount of experience with iodine-131 (I-131) MIBG therapy, many important questions still exist. In this article, we will discuss the current problems learned from clinical experience in diagnosis and therapy of PHEO/PGL with I-131 MIBG, and present a sample case to emphasize the critical aspects for an optimal treatment strategy.

Aim: Since the second half of the 1980s, (131)I-MIBG has been widely used for treatment of patients with malignant pheochromocytoma. In 1991, at the International Meeting in Rome, it was agreed that (131)I-MIBG therapy induces significant tumor responses in about 30-50% of cases, long-term stabilization of disease in several cases and significant reduction of cathecolamine-related symptoms in almost all patients. Nevertheless, more than 20 years later, its therapeutic use in malignant phaeochromocytoma has not yet been standardized. Aim of the present study was to compare the use of low versus intermediate activity of MIBG to achieve better results in a shorter time with higher activities., Methods: Two different modalities of (131)I-MIBG therapy were performed: before 2001, 12 patients (Group 1) received a fixed activity of 5.55 GBq/session. From 2001 to 2009, 16 patients (Group 2) were treated with 9.25-12.95 GBq/session., Results: As expected, the overall response rate in Group 2 are slightly better. The most important result of increasing the single session activity was the shorter median time to achieve a significant response (7 versus 19 months), which was obtained with a lower median cumulative activity (11 versus 22 GBq) in a lower median number of sessions (2 versus 7)., Conclusions: We demonstrated that intermediate single session activity shortened to one third the global treatment time, with similar efficacy and a moderate increment of toxicity. Consequently, the increase of (131)I-MIBG activity, without reaching myeloablative levels, can be recommended for standard treatment of pheochromocytoma and paraganglioma patients.

Aim: Neuroendocrine tumors over-express somatostatin receptors and literature data have demonstrated the efficacy of the peptide receptor radionuclide therapy with somatostatin analogues labelled with high activities of b-emitting radioisotopes, such as (90)Y and (177)Lu. Yttrium-90 is a pure high energy b-emitter while (177)Lu is a b/g emitter of medium energy. We decided to evaluate an original tandem treatment based on administration of radiolabeled [DOTA(0),Tyr(3)]octreotate (DOTA-TATE) alternating (177)Lu and 90Y. Aim of this study was to evaluate the feasibility, the efficacy and the toxicity of this treatment in neuroendocrine tumors expressing somatostatin receptors relapsed or refractory to conventional therapies., Methods: Patients were treated with four therapeutic cycles alternating [(177)Lu]DOTA-TATE (5.55 GBq) and [(90)Y]DOTA-TATE (2.6 GBq). Dosimetric evaluation after administration of [(177)Lu]DOTA-TATE allows to calculate the absorbed doses in healthy organs. Blood samples were collected at 5 min, 1, 6, 24, 48, 72, 96 h and scintigraphy was performed once a day for four days after administration. Toxicity was evaluated considering hematological parameters and renal toxicity was evaluated also by the glomerular filtration rate (GFR). Efficacy related with RECIST criteria., Results: Up to now 26 patients entered the study and 16 patients completed all cycles. Treatment was well tolerated with no adverse event registered. No damage to healthy organs was revealed in accordance with the calculated absorbed doses. We had a partial response in 10/15 patients evaluated three months after the fourth treatment., Conclusions: Up to now only a few patients participated in and concluded this study; preliminary results are encouraging and indicate the feasibility of the study.

Aim: This paper analyzes the available data on the dosimetric approach and describes the use of dosimetry in the Division of Nuclear Medicine of the National Cancer Institute in Milan. Dosimetry is rarely performed when planning radio-iodine activity, although most of the available guidelines do mention this possibility, without giving any well defined indication. Aim of the present research was to validate the usefulness of dosimetry in the management of metastatic thyroid cancer. Benua (1962) set the limit of blood absorbed dose at 2 Gy to avoid hematological toxicity. Maxon (1983) determined at 80 Gy the dose to achieve complete destruction of a metastatic lesion. Dorn (2003) combined red marrow and lesion dosimetry showing that high activity administrations with less that 3 Gy to the red marrow are a safe and more effective with respect to fixed activities administrations. Lee (2008) reported 50% responses with high activity administrations based on blood dosimetry, in 47 patients which were unsuccessfully previously treated with fixed activities. Sgouros (2005) and Song (2006) introduced key parameters as Biological Effective Dose and Uniform Equivalent Dose in order to describe the effects of continuous low dose rate irradiation and non uniform activity uptake, typical of nuclear medicine treatments., Methods: Red marrow and lesion dosimetry (planar view) were performed during the treatment, without changing the fixed activity schema., Results: This experience demonstrate first of all, that dosimetry is feasible in the clinical routine, and that it can provide the clinician with important information, no matter its often quoted limited numerical accuracy. A total of 17/20 lesion doses below 80 Gy have been detected. Three/17 (doses between 40 and 80 Gy) disappeared in the follow-up scintigram. Two/17 were undetectable at computed tomography or nuclear magnetic resonance. These data suggest that repetition of treatment on a lesion drastically reduces its uptake, with a loss of therapeutic efficacy along the sequence of fixed activity administrations., Conclusions: The usefulness of dosimetry should not be assessed only on the basis of patient survival or therapeutic efficacy; the possibility to avoid useless treatments should also be considered. According to the authors, individualized dosimetry could improve the management of metastatic differentiated thyroid cancer. Even post-therapeutic dosimetry, as performed at this institution, has a significant impact on clinical decision-making. The question for the future is how to include dosimetry into the patient management framework.

Thyroid cancer is the most common malignant cancer of the endocrine system. Treatment for well differentiated forms include surgery and radioactive iodine ablation. When cancer cells exhibit a less differentiated phenotype they may no longer be able to accumulate iodine, making 131-I administration ineffective. Recent studies have demonstrated the important role of therapeutic agents that have redifferentiating potential, leading to reactivation and expression of thyrocyte-specific genes, including those responsible for iodine uptake. This review will discuss the results of the most recent studies on drugs with redifferentiating properties and their application in patients with radioiodine refractory thyroid cancer.

Medullary thyroid carcinoma (MTC) is a relatively rare neuroendocrine tumour originating from the parafollicular C cells and releases calcitonin (hCt), carcinoembryonic antigen (CEA) and occasionally other substances. In 20-30% of cases MTC presents a germline mutation of the RET proto-oncogene and occurs in 3 different hereditary forms: familial MTC, multiple endocrine neoplasia (MEN) 2A and MEN 2B syndrome. Prognosis of MTC is largely related to tumour extension at disease onset. Surgery remains the most effective therapy for potential cure. Overall survival is strictly linked to the occurrence of relapse. After surgery, serum hCt remains the most sensitive test for occult disease. Diagnostic imaging work-up includes ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), bone scintigraphy, as the more frequent sites of recurrence or metastases are cervical and mediastinal lymph nodes, lungs, liver and bone. Nuclear medicine procedures include (111)In-labelled somatostatin analogs, radioiodinated metaiodobenzylguanidine (MIBG), and several PET radiopharmaceuticals. Experience with radionuclide therapy in MTC is restricted to few patients treated with (131)I-MIBG or (90)Y-DOTATOC. Since 1987, 1 027 diagnostic MIBG scans were performed in the Department Department of Diagnostic Imaging and Therapy of the Istituto Nazionale Tumori IRCCS Foundation (Milan, Italy), 85 of which for MTC, with a sensitivity of 38.7% in patients with evidence of disease and 30.7 % if all patients were considered. Since 1994, 13 MTC patients were treated with MIBG with 4 partial responses and 4 stable diseases. Patients with liver or bone involvement responded to therapy and showed long-term partial remission of disease, others showed stability of disease, which was apparently unrelated to therapy. Improvement of efficacy can be achieved through dosimetric calculation of administered activity.

Aim: The aims of this paper were to evaluate the clinical relevance of lymphoscintigraphy with intraoperative gamma-probe detection in identifying sentinel nodes (SNs) and to study the prognostic value of SN biopsy in head and neck melanoma patients., Methods: Sixty-one patients had lymphoscintigraphy with intradermal injections of 99mTc-Nanocoll (40 MBq), 24 h before surgery. Tumor-positive SNs patients underwent total lymph node dissection. Postoperative histological examination was performed. Patients were followed up for 1 to 5 years (median 3 years). The tumor relapses and the overall survival were evaluated by means of statistical methods., Results: Lymphoscintigraphy showed lymphatic distribution to more than one basin in 45 patients (74%), in 15 patients one basin was visualized and no basin in 1 patient. In 41 patients the SN was negative for metastases, while in 20 was positive. In a high percentage of patients (30%), metastatic involvement occurred in more than one lymph node basin. During follow-up in the negative SN group, 40 patients remained disease free and 1 relapsed. In the positive SN group, 10 patients remained disease free and 10 relapsed. Recurrence time ranged from 6 to 11 months. The overall survival of the SNs negative group was significantly higher than the positive SN group., Conclusions: This approach was able to distinguish: a) patients with tumor-negative SNs with a favorable clinical course (98% did not relapse, P<0.001); b) patients with tumor-positive SNs with a high rate of tumor relapse (50%, P<0.001). Therefore SN biopsy may give information about prognosis in head and neck melanoma patients.

Aim: The aim of the present paper is to describe the accuracy of gallium ((67)Ga) scintigraphy in adolescents and children with Hodgkin's disease (HD). We have studied the diagnostic value of this nuclear imaging technique at disease presentation (staging) and its prognostic value based on changes in (67)Ga uptake observed after treatment (response assessment)., Methods: From April 1985 to July 1999 74 consecutive untreated patients with a median age of 13 y underwent (67)Ga scans 48-72 h after injection of 37-111 MBq of (67)Ga-citrate. Planar whole-body scintigraphy was performed, supplemented with single photon emission tomography (SPET) of the mediastinum from 1996 onwards. Three patients did not undergo further scintigraphic examination because they were treated with radical surgery. After the 1st examination 71 of the 74 patients were monitored by 1-3 (67)Ga scans during the course of their disease. All of them had at least one (67)Ga scintigraphy at the end of the induction phase of chemotherapy, before any other therapeutic regimens were planned., Results: At disease presentation (67)Ga scintigraphy was positive in all patients, detecting 285 of 335 (85.0%) lymph nodal sites of disease. The best sensitivity was observed in the mediastinum (100%; 63/63) and the laterocervical supraclavicular region (85.6%; 125/146); it was lower for axillary (72.7%; 16/22) and retroperitoneal (68.7%; 11/16) lymph node masses. In detecting visceral involvement the sensitivity of (67)Ga scintigraphy was 66.6% (8/12) for lung and 80% (4/5) for bone involvement. Among 71 patients in follow-up, 2 showed rapid progression of disease during induction therapy while 69 patients were monitored for a long period. The response to therapy has been classified according to the changes observed on nuclear medicine or radiological images as complete response (CR) or partial response (PR). On the basis of (67)Ga scans 55 patients (72.4%) were considered as having a CR, while with radiological modalities (chest X-ray, CT, MRI) CR was observed in only 29 patients (40.8%). PR or progression was found with (67)Ga scintigraphy in 16 patients (22.5%) and with radiological modalities in 42 patients (59.1%). (67)Ga scan was concordant with clinical outcome in 97% (28/29). The diagnostic effectiveness of this imaging technique has been analysed by comparing the scintigraphic or radiological changes at the 1st scintigraphic/radiological follow-up examination after induction therapy with the clinical outcome. In this population the relapse rate was 50% (8/16) in the group that did not achieve a CR according to post-treatment (67)Ga scintigraphy, while it was only 10.9% (6/55) in the group that achieved a CR on the basis of scintigraphy findings. The overall survival (OS) and disease-free survival (DFS) were calculated by means of Kaplan-Meier cumulative survival plotting. When the 2 groups of patients with complete (CR) or incomplete normalisation (PR or progression) of (67)Ga scintigraphy were compared, both OS and DFS were found to be statistically different (p=0.0001 and p=0.0004, respectively). By contrast, no statistical difference was found when the radiological findings were considered as the criterion for assessment of tumour response. On the basis of X-ray results the relapse rate was 13.7% in patients with negative post-therapy findings and 23.8% in patients with positive radiological imaging., Conclusion: Our data demonstrate the high value of (67)Ga scintigraphy in HD staging in paediatric patients. In addition, evaluation of the (67)Ga uptake is very useful as a prognostic parameter; changes in (67)Ga uptake after therapy indicate a favourable prognosis, whereas children still positive on post-treatment (67)Ga scintigrams should be given more aggressive treatment.

Neuroendocrine tumours can be visualized by several nuclear medicine modalities based on different mechanisms of cellular uptake. The most widely used radiopharmaceutical are the metaiodobenzylguanidine (123I/131I MIBG) and pentetreotide (111In pentetreotide). The first tracer follows the metabolic pathway of norephinephrine while the second one binds to somatostatin receptors which are expressed with high intensity on the neuroendocrine tissue. Some radiopharmaceuticals (Anti-CEA, Anti-CgA, Anti-GD2 monoclonal antibodies) have today only an experimental value, others such as 99mTc(V)DMSA had in the past very limited indications (medullary thyroid cancer) but at present their production is going to be stopped. An interesting series of new peptides showing a great affinity for the receptors/structures expressed by the neuroendocrine tissue is under evaluation in order to obtain a better tumour specificity. Among the positron-emitting radiopharmaceuticals, the 18F-fluorodeoxyglucose (FDG), in spite it is considered the most widely used tracer for clinical PET in oncology, did not show a satisfactory uptake in the well differentiated neuroendocrine tissues. On the contrary 18F-FDG is the best radiopharmaceutical to visualize those rare poorly differentiated neurondocrine tumours with a high proliferative index. For this reason also in this area, new radiopharmaceuticals have been studies and developed. A serotonin precursor 5-hydroxytryptophan (5-HTP) labelled with 11C has shown an increased uptake in carcinoids. Another radiopharmaceutical in development for PET is 11C L-DOPA which seems to be useful in visualizing endocrine pancreatic tumours. 18F-DOPA whole body PET may be a more promising imaging approach. Aim of this review is to summarize the potential of nuclear medicine techniques in the diagnosis of neuroendocrine tumours and to stresses the renewed role of nuclear medicine in the management of this disease.

Biopsy of head and neck sentinel nodes (SNs) can be technically problematic due to the unpredictable and variable drainage patterns of this anatomic region. The aim of the present study was to evaluate the feasibility of SN biopsy for cutaneous melanoma of the head and neck. We performed SN biopsy in 17 patients affected by stage I cutaneous melanoma of the head and neck on the basis of lymphoscintigraphy, blue dye and gamma probe. A total of 24 procedures were performed. Drainage to more than one lymphatic basin was observed in five patients (two basins in three cases and three basins in two cases) and in all cases SN biopsy was performed in all basins. The biopsy distribution by site was: six cervical nodes, five parotid nodes, four supraclavicular and submandibular nodes, three auricular and axillary nodes. The SN identification rate was 87.5% (21/24); metastases were discovered in four cases, with a positivity rate of 23.6%. At the time of writing, 1 patient is alive with local disease, 3 patients are dead and 13 are alive and free of disease with a follow-up ranging from 1 to 40 months (median, 21 months) following SN biopsy. In our opinion preoperative lymphoscintigraphy and the intraoperative use of a gamma probe are useful for the identification of lymphatic drainage of cutaneous melanoma of the head and neck.

Background: 45 patients with neuroendocrine tumours (22 neuroblastomas, 10 phaeochromocytomas, 3 para-gangliomas, 6 medullary thyroid carcinomas and 4 carcinoids) underwent 131I-MIBG therapy., Methods: All patients, with the exception of 5 phaeochromocytoma cases with nonoperable disease, had previously been treated with conventional therapies. Patients had a previous diagnostic scintigraphy with 131I-MIBG (activity 20-44.4 MBq) or with 123I-MIBG (activity 74-222 MBq). The therapeutic activity for adults ranged from 3.7 to 7.4 GBq of 131I-MIBG; for children from 2.7 to 5.5 GBq. All treatments were repeated at not less than 4-weekly intervals. The neuroblastoma patients were divided into two groups: the first included 14 patients with advanced metastatic disease not responding to previous treatments; the second included 8 patients with documented residual neuroblastoma tissue that could not be surgically removed after first-line therapy., Results: In neuroblastoma patients with advanced disease resistant to previous therapies 2 out of 14 showed a partial response, 9 stable disease and 3 progression of cancer. In neuroblastoma patients with residual disease (7 evaluable out of 8) we obtained 3 partial responses; a stable response was observed in 3 patients. The results of MIBG therapy in the group of phaeochromocytoma patients (9 evaluable out of 10) consisted of 3 partial responses, 5 stable disease and 1 progression. Evaluation of the response carried out on the basis of biochemical parameters increased the responses and MIBG therapy showed good effectiveness in controlling the functional symptoms. In the group of paraganglioma patients we observed 1 complete, 1 partial and 1 stable response. In patients with medullary thyroid carcinoma a partial response was observed in 1 patient with mediastinal metastases and 2 disease stabilisations were seen in another 2 patients. Patients with carcinoids who underwent MIBG therapy showed 3 disease stabilisations. The overall toxicity was acceptable, especially considering that the majority of our patients had had previous myelotoxic treatments (chemotherapy and/or radiotherapy, alone or in combination)., Conclusions: On the basis of our experience we can conclude that 131I-MIBG therapy is effective and also well tolerated.

Background/aims: Abnormalities of biliary drainage have been documented at hepatobiliary scintigraphy in many but not all patients studied with cystic fibrosis-associated liver disease. Ursodeoxycholic acid was shown to be beneficial in this disease, mainly by improving biliary secretion. Therefore, patients with impaired biliary drainage are expected to obtain the greatest benefit from this treatment., Methods: We evaluated the effects of long-term treatment with ursodeoxycholic acid in 36 patients with cystic fibrosis-associated liver disease, and compared the response in patients presenting a normal (n=18) or delayed time of intestinal visualization (n=18) at baseline hepatobiliary scintigraphy., Results: The mean treatment duration was 58+/-26 (S.D.) months and 63+/-29 months in the groups with normal or delayed time of intestinal visualization, respectively. The time of intestinal visualization decreased (57+/-23%, p<0.001) from baseline in patients with initially abnormal values and became normal in four (22%). Treatment failure, i.e. lack of sustained normalization of serum liver enzymes or the occurrence of a clinically relevant adverse event, was more frequently observed in patients with a normal time of intestinal visualization at baseline (OR, 5.50; 95% CI, 1.32-22.7). When only clinically relevant adverse events were considered, they occurred in six of the latter patients (liver transplantation in one case, development of ultrasographic or endoscopic signs of portal hypertension in six cases), but in only one patient (development of portal hypertension) in the group with delayed time of intestinal visualization (OR, 10.82; 95% CI, 1.17-100.4)., Conclusions: Delayed intestinal visualization at hepatobiliary scintigraphy in patients with cystic fibrosis-associated liver disease seems to predict a better response to ursodeoxycholic acid.

Neuroendocrine tumours of the gastro-entero-pancreatic tract are an uncommon clinical entity and are believed to arise from the endocrine cells of the gastrointestinal tract. Somatostatin receptor imaging is a diagnostic tool which allows visualization of somatostatin receptor bearing tumours. This scintigraphic procedure is performed with indium-111 labelled octreotide, a somatostatin analogue, chelated with diethylene triamine penta-acetic acid. Radionuclide imaging consists in detecting the biodistribution of somatostatin receptors, normally expressed on the cell surface of neuroendocrine gastro-entero-pancreatic tumours. To date, five types of this receptor have been cloned: indium-111-labelled-pentetreotide can visualize tumours expressing type 2 and 5 receptors. The results of our study, which involved 81 neuroendocrine gastro-entero-pancreatic tumour patients, confirm the superior sensitivity of somatostatin receptor imaging (61%) for primary tumour evaluation with respect to conventional imaging modalities such as computed tomography (40%) or ultrasound (28%). Scintigraphic findings in metastatic liver disease proved to have a sensitivity of 89% for somatostatin receptor imaging, versus 81% and 88% for computed tomography and ultrasound, respectively. In 23% of patients, lesions were found with somatostatin receptor imaging which had been missed using the other diagnostic modalities; in 26% of the patients the therapeutic approach was modified after somatostatin receptor imaging.

A patient who had previously undergone ileal resection and liver transplantation for a gastroenteropancreatic (GEP) tumor was evaluated with somatostatin receptor scintigraphy (SRS) using 111In-DTPA-D-Phe1-pentetreotide. Eighteen months after surgery, during follow-up procedures, conventional imaging techniques (ultrasound, computed tomography, magnetic resonance imaging) only showed a relapse in the gastropancreatic lymph nodes, while SRS demonstrated skeletal spread. This case report emphasizes the clinical impact of SRS on the management of patients affected by neuroendocrine gastroenteropancreatic tumors.

Bone scintigraphy plays a major role in the diagnosis of bone metastases. The clinical utility of new biochemical markers of bone metabolism has recently been investigated in various bone diseases. This study evaluated the role of some bone metabolism markers in comparison with bone scan in the follow-up of breast cancer patients. We studied 149 patients with breast cancer, 33 (22%) of whom had bone metastases. IRMAs were used for the evaluation of blood levels of osteocalcin, bone alkaline phosphatase (BAP), the C-terminal propeptide of type I procollagen and the C-terminal cross-linked telopeptide of type I collagen (ICTP). Multivariate regression analysis showed that menopausal status (P=0.007) and metastatic bone lesions (P=0.001) affected bone marker levels. When considering post-menopausal women, the only subset in which bone metabolism marker behaviour could be reliably investigated, we found a high degree of overlap in marker distribution for scan-positive and scan-negative patients. Discrimination between scan-negative and scan-positive patients based on the above markers, taken singly or jointly, was assessed by means of logistic discriminant analysis. The best discrimination was achieved with BAP, closely followed by ICTP. BAP and ICTP together gave a slight improvement over the use of the two markers separately. However, even in this case the degree of discrimination was poor and its clinical utility was limited. In fact, to achieve a specificity of 95%, the sensitivity of the test was about 20%; conversely, with a sensitivity of 95%, the specificity was below 10%. In conclusion, based on our findings, we believe that blood levels of the investigated markers cannot replace bone scintigraphy in the follow-up of breast cancer patients for the early detection of bone metastases.