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Purpose: To evaluate local control and longitudinal endocrine data in monorchid patients treated with testicular-sparing surgery and adjuvant radiotherapy (RT) for seminomatous germ-cell tumors. Methods: We searched our database established in 2009 for patients with seminoma who received testis irradiation following partial orchiectomy up to 2018. Eleven patients were identified. All had associated germ cell neoplasia in situ (GCNIS) in surrounding parenchyma. Analysis focused on local control and testosterone levels preservation after RT. We considered age, baseline (pre-RT) testosterone and luteinizing hormone (LH) levels, residual testicular volume, tumor size, and testosterone and LH levels trend over time in order to identify any association with endocrine impairment leading to hormonal replacement need. Results: After a median follow-up of 21 months, no local or distant relapses were observed and hormonal function was maintained in 54.5% of patients (6/11). No significant interactions were observed for the investigated covariates. Notably, we observed an association between higher baseline testosterone levels and a decreased risk of exogenous androgen replacement (hazard ratio [HR] 0.409, 95% confidence interval [CI] 0.161–1.039, p = 0.060), whereas tumor size was associated with an increased risk of exogenous androgen replacement (HR 1.847, 95% CI 0.940–3.627, p = 0.075). Conclusions: Radiotherapy after testicular sparing surgery is effective in preventing local disease relapse in presence of GCNIS in the medium term. This strategy allows a preservation of adequate endocrine function in about half of patients. More patients and longer follow-up are needed to confirm these findings.

In recent years, machine learning algorithms have led to innovative tools for medical imaging analysis. The purpose of the present review was to summarize the literature on the developing field of deep learning (DL), particularly the application of convolutional neural networks (CNNs) in PET/CT and PET/MR. We performed the literature search, referring to “convolutional neural networks” and “positron emission tomography” on PubMed/MEDLINE, for potentially relevant articles published up until July 24th, 2020. After the screening process, 63 articles were finally included; these embraced both the technical (n = 23) and the clinical field (n = 40). Technical studies aimed at investigating the role of CNN-based methods for image quality improvement (n = 11) and on technical issues (n = 12), mainly attenuation correction. Clinical studies explored CNN applications in oncology lung cancer (n = 7), head and neck cancer (n = 4), esophageal cancer (n = 2), lymphoma (n = 3), prostate cancer (N = 4), cervical cancer (n = 1), sarcomas (n = 1), multiple cancer types (n = 4), in neurology (n = 10) and cardiology (n = 1); three additional studies belonged to “other” category. In oncology, the studies aimed at detection, diagnosis, and prognostication of cancer. In neurology, the majority of the studies aimed at diagnosing Alzheimer Disease and stratification of the risk. CNN-based algorithms demonstrated promising results with performances equal or even higher compared to conventional approaches. Overall, CNN applications for PET/CT and PET/MR are exponentially growing, demonstrating encouraging results for both technical and clinical purposes. Novel research strategies emerged to face the challenges of DL algorithms development. Education and confidence with DL-based tools are needed for proper technology implementation.

Primary hypothyroidism commonly occurs after radiotherapy (RT), and coincides with increased circulating thyroid-stimulating hormone (TSH) levels.We tested therefore the protective effect of suppressing TSH with L-thyroxine during RT for medulloblastoma/PNET and Hodgkin lymphoma (HL) in a prospective cohort study. From1998 to 2001, a total of 37 euthyroid children with medulloblastoma/PNET plus 14 with HL, scheduled for craniospinal irradiation and mediastinum/neck radiotherapy, respectively, underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginning and end of craniospinal iiradiation. From 14 days before and up to the end of radiotherapy, patients were administered L-thyroxine checking every 3 days TSH to ensure a value < 0.3 μIU/mL. During follow-up, blood tests and ultrasound were repeated; primary hypothyroidism was considered an increased TSH level greater than normal range. Twenty-two/37 patients with medulloblastoma/PNET and all the 14 patients with HL were alive after a median 231 months from radiotherapy with 7/22 and 8/14 having correctly reached TSH levels < 0.3 μIU/mL and well matched for other variables. Twenty years on, hypothyroidism-free survival rates differed significantly, being 60% ± 15% and 15.6% ± 8.2% in TSH-suppressed vs. not-TSH suppressed patients, respectively (P = 0.001). These findings suggest that hypothyroidism could be durably prevented in two populations at risk of late RT sequelae, but it should be confirmed in a larger cohort.

Introduction: Therapeutic decision-making in metastatic castration-resistant prostate cancer (mCRPC) represents an open challenge. Radium-223 is approved for patients with symptomatic bone metastases, no visceral involvement, progressing after at least 2 lines of systemic therapy, or ineligible for any other systemic treatment. Methods: We performed a retrospective, observational study on patients with mCRPC treated with radium-223 at our institution outside of clinical trials, to assess the safety and activity in a real-world population. Data regarding baseline patient/disease characteristics and treatment outcomes (number of cycles, treatment-related adverse events [AEs], cause of discontinuation, and best response) were collected. Results: Overall, 41 patients were treated from September 2015 to September 2018. Median age was 73 years; baseline Eastern Cooperative Oncology Group Performance Status (ECOG PS) was 0, 1, or 2 in 15%, 80%, and 5% of cases, respectively; and 3%, 41%, 44%, and 12% of patients had 20, and superscan bone lesions, respectively. A median number of 5 cycles (interquartile range 3–6) with median dose 19.52 MBq (interquartile range 12.87–24.83) was received. Treatment schedule was completed in 49% of cases; discontinuations due to AEs, disease-related death, or disease progression occurred in 24%, 33%, and 43% of patients, respectively. Any-grade AEs occurred in 73% and grade 3/4 treatment-related AEs occurred in 29% of patients, mainly anemia, decreased platelet count, and fatigue. No skeletal-related events or treatment-related deaths were recorded. After treatment, 66%, 2%, and 32% of patients had a stable, improved, or deteriorated ECOG PS versus baseline, respectively, and 24%, 61%, and 15% reported a stable, improved, or worsened pain symptom control. Post-treatment versus baseline alkaline phosphatase was reduced or stable in 46% and increased in 54% of patients, whereas prostate-specific antigen was decreased or stable in 83% and increased in 17% of patients. Conclusions: Our study provides clinically useful real-world data on radium-223, highlighting the importance of multidisciplinary patient management to guarantee the best continuum of care for patients with mCRPC.

Differentiated thyroid cancer (DTC) accounts for 95% of all thyroid cancers and is generally an indolent tumor, tending to present with limited loco-regional disease with an excellent long-term survival after treatment. However, 5–10% present with locally advanced disease and aero-digestive tract invasion or distant metastases that are the main cause of thyroid cancer-related deaths. The present review aims to underline the complex management of advanced DTC including treatment of gross extra-thyroidal extension, recurrent loco-regional, or distant metastatic disease. Radioiodine therapy is an effective treatment of advanced and/or metastatic DTC which contributes significantly to patients’ life expectancy. Multimodal approach based on surgical resection in combination with radioiodine therapy, interventional imaging treatment, and TSH suppression can significantly improve outcomes for this patients’ population.

Aim: Data from 69 well-differentiated gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionucleotide therapy + somatostatin analogs (SSAs) after SSA treatment failure were evaluated. Methods: We identified two groups: S1 – patients who kept the same SSA treatment beyond progression; S2 – patients who switched the SSA with another SSA after progression. Results: Median progression-free survival was 53 and 127 months in S1 and S2, respectively (p = 0.001; hazard ratio: 0.31; 95% CI: 0.15–0.63). Median overall survival was 69 versus 150 months in S1 and S2, respectively (p = 0.004; hazard ratio: 0.32; 95% CI: 0.14–0.71). Conclusion: In patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionucleotide therapy plus SSA after SSA failure, the ‘switch’ strategy of SSA after progression improve progression-free survival and overall survival.

Simple Summary Nongerminomatous germ cell tumors of the central nervous system are rare tumours. Differently from germinomas, they have a severe prognosis above all when presenting with high alfafetoprotein levels. We report the results of a combined chemo- and radiotherapy approach in 28 patients affected by this disease with craniospinal irradiation and a boost tailored on the response to pre-radiant chemotherapy. Metastatic patients and high-risk disease are discussed as well. The 5 years overall survival and event-free survival were both 81% while at 10 years they were 81% and 76% respectively. Our series, even if small, concerns nongerminomatous germ cell tumors only (whereas in some papers they are mixed with pure germinomas), furthermore our patients had a very long follow-up (over 11 years) with encouraging survival data for localized and metastatic disease. Improving survival while trying to contain/avoid the long-term sequelae of chemotherapy and radiotherapy are the main goals of future studies. Abstract Introduction: Due to the rarity of nongerminomatous germ cell tumors (NGGCT) with non-standard treatment as yet, we report retrospectively our 30 year experience with chemotherapy followed by craniospinal irradiation (CSI), plus a boost of whole ventricular irradiation (WVI)/tumor bed (TB), tailored to pre-radiation chemotherapy response. Methods: Between 1988 and 2016, 28 patients received four cycles of PEB (cisplatin/etoposide/bleomycin), then CSI, and two further PEB cycles. Between 1988 and1994, CSI was 25.5 Gy for patients in complete remission (CR), 30 Gy if in partial remission (PR) or metastatic, with a boost to TB up to 45–54 Gy. In the period of 1995–2010, the boost included WVI and any extra-ventricular tumor sites up to 45 Gy. After 2010, CSI was reduced to 25.5 Gy for all non-metastatic patients, and a boost was given only to TB up to 40.5/45.5 Gy, depending on patients’ CR/PR status. After 2003, patients with alfafetoprotein (αFP) > 1000 ng/mL received intensified treatment, also including autologous stem cell transplantation. Results: Among 28 patients (23 males; median age 12 years, 6 metastatic), 25 responded to PEB, and three progressed (PD) after one to four cycles; 26 received radiotherapy obtaining 13 CR, 7 PR and 5 stable disease (SD), 1 PD; 6 (21%) died (5 for disease, 1 for pneumonia while in CR). Five-year overall survival (OS) and progression-free survival (PFS) were both 81%; 10 year OS and PFS 81% and 76%, respectively (median follow-up 11 years). Conclusions: Survival for children with NGGCT, independently from disease extent, was encouraging. Further studies should elucidate which patients could benefit from reduced volume and dose irradiation.

Background According to published data, radiomics features differ between lesions of refractory/relapsing HL patients from those of long-term responders. However, several methodological aspects have not been elucidated yet. Purpose The study aimed at setting up a methodological framework in radiomics applications in Hodgkin’s lymphoma (HL), especially at (a) developing a novel feature selection approach, (b) evaluating radiomic intra-patient lesions’ similarity, and (c) classifying relapsing refractory (R/R) vs non-(R/R) patients. Methods We retrospectively included 85 patients (male:female = 52:33; median age 35 years, range 19–74). LIFEx (www.lifexsoft.org) was used for [18F]FDG-PET/CT segmentation and feature extraction. Features were a-priori selected if they were highly correlated or uncorrelated to the volume. Principal component analysis-transformed features were used to build the fingerprints that were tested to assess lesions’ similarity, using the silhouette. For intra-patient similarity analysis, we used patients having multiple lesions only. To classify patients as non-R/R and R/R, the fingerprint considering one single lesion (fingerprint_One) and all lesions (fingerprint_All) was tested using Random Undersampling Boosting of Tree Ensemble (RUBTE). Results HL fingerprints included up to 15 features. Intra-patient lesion similarity analysis resulted in mean/median silhouette values below 0.5 (low similarity especially in the non-R/R group). In the test set, the fingerprint_One classification accuracy was 62% (78% sensitivity and 53% specificity); the classification by RUBTE using fingerprint_All resulted in 82% accuracy (70% sensitivity and 88% specificity). Conclusions Lesion similarity analysis was developed, and it allowed to demonstrate that HL lesions were not homogeneous within patients in terms of radiomics signature. Therefore, a random target lesion selection should not be adopted for radiomics applications. Moreover, the classifier to predict R/R vs non-R/R performed the best when all the lesions were used.

Radium-223, a calcium mimetic bone-seeking radionuclide that selectively targets bone metastases with alpha particles, is approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC) and symptomatic bone metastases. In patients with mCRPC, treatment with radium-223 has been associated with survival benefit, regardless of prior docetaxel use, and also has a positive impact on symptomatic skeletal events and quality of life. Radium-223 is best suited for patients with symptomatic mCRPC and bone-predominant disease and no visceral metastases, and may lead to better outcomes when given early in the course of the disease. An expert multidisciplinary panel convened in Milan, Italy to review the current best-evidence literature on radium-223 and to convey their personal expertise with the use of radium-223 and identify possible strategies for best practice. This article summarizes the best available evidence for the use of radium-223, discusses the essential role of the multidisciplinary team in delivering effective treatment for mCRPC, clarifies pre- and post-treatment evaluation and monitoring, and outlines future scenarios for radium-223 in the treatment of men with MCRPC.

Peptide receptor radionuclide therapy is an effective, well-tolerated, treatment for well-differentiated neuroendocrine tumors, resulting in a significant survival benefit and improvement of quality of life. Very few data are available on peptide receptor radionuclide therapy effectiveness in grade 3 neuroendocrine carcinomas with high somatostatin receptor expression. We report the case of a 70-year-old woman with metastatic pancreatic grade 3 neuroendocrine carcinoma who underwent 6 cycles of tandem treatment with investigational radiopharmaceuticals Y-DOTATOC and Lu-DOTATOC achieving an impressive response.

Benign thyroid nodules are a common clinical occurrence and usually do not require treatment unless symptomatic. During the last years, ultrasound-guided minimally invasive treatments (MIT) gained an increasing role in the management of nodules causing local symptoms. In February 2018, the Italian MIT Thyroid Group was founded to create a permanent cooperation between Italian and international physicians dedicated to clinical research and assistance on MIT for thyroid nodules. The group drafted this list of statements based on literature review and consensus opinion of interdisciplinary experts to facilitate the diffusion and the appropriate use of MIT of thyroid nodules in clinical practice. (#1) Predominantly cystic/cystic symptomatic nodules should first undergo US-guided aspiration; ethanol injection should be performed if relapsing (level of evidence [LoE]: ethanol is superior to simple aspiration = 2); (#2) In symptomatic cystic nodules, thermal ablation is an option when symptoms persist after ethanol ablation (LoE = 4); (#3) Double cytological benignity confirmation is needed before thermal ablation (LoE = 2); (#4) Single cytological sample is adequate in ultrasound low risk (EU-TIRADS ≤3) and in autonomously functioning nodules (LoE = 2); (#5) Thermal ablation may be proposed as first-line treatment for solid, symptomatic, nonfunctioning, benign nodules (LoE = 2); (#6) Thermal ablation may be used for dominant lesions in nonfunctioning multinodular goiter in patients refusing/not eligible for surgery (LoE = 5); (#7) Clinical and ultrasound follow-up is appropriate after thermal ablation (LoE = 2); (#8) Nodule re-treatment can be considered when symptoms relapse or partially resolve (LoE = 2); (#9) In case of nodule regrowth, a new cytological assessment is suggested before second ablation (LoE = 5); (#10) Thermal ablation is an option for autonomously functioning nodules in patients refusing/not eligible for radioiodine or surgery (LoE = 2); (#11) Small autonomously functioning nodules can be treated with thermal ablation when thyroid tissue sparing is a priority and ≥80% nodule volume ablation is expected (LoE = 3).

In the last two decades, the demand for a personalized therapeutic approach has been constantly increasing, mainly due to the need to develop ever more effective therapeutic regimens, to improve outcome, and to avoid unnecessary treatments. Theranostics is an invaluable tool in personalized medicine; it is a treatment strategy in which the same (or very similar) agents are used for both diagnostic and therapeutic purposes. Particularly, theranostics is based on the integration of a diagnostic test and a specific treatment and it relies on the idea of selecting patients through a diagnostic study that could detect whether a patient will benefit from a certain therapy or not. After a brief historical review a critical update on theranostics will be provided in this chapter.

4112 Background: As demonstrated in the primary analysis of the phase 3 NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide, with a HR of 0.18 (95% CI: 0.11, 0.29; p < 0.0001), in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut neuroendocrine tumors (NETs). Here we report final overall survival (OS) for NETTER-1. Methods: In this international open-label trial, eligible patients were randomized to receive either four cycles of 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 ± 1 weeks plus long-acting octreotide 30 mg or high-dose long-acting octreotide 60 mg every 4 weeks (control arm), both on top of best supportive care. After disease progression on randomized treatment or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further anti-cancer treatment as recommended by their physicians. The primary endpoint was PFS per RECIST 1.1 and OS was a key secondary endpoint. Primary intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first. Results: Of 231 randomized patients, 101/117 (86.3%) in the 177Lu-DOTATATE arm and 99/114 (86.8%) in the control arm entered long-term follow-up. Final analysis occurred 5 years after the last patient was randomized, following 142 deaths, with a median follow-up of more than 76 months. During long-term follow-up, 41/114 (36%) of patients in the control arm received subsequent radioligand therapy (“cross-over”), the majority (22.8%) within 24 months. Median OS was 48.0 months (95% CI: 37.4, 55.2) in the 177Lu-DOTATATE arm and 36.3 months (95% CI: 25.9, 51.7) in the control arm. HR was 0.84 (95% CI: 0.60, 1.17) with p = 0.30 (unstratified 2-sided log-rank test). A total of 2/112 (1.8%) 177Lu-DOTATATE treated patients in the study developed myelodysplastic syndrome (MDS). No new cases of MDS or acute leukemia were reported in the long-term follow-up. Overall, no new safety signals emerged during long-term follow-up. Conclusions: Median OS was 48.0 months in the 177Lu-DOTATATE arm of the NETTER-1 trial and 36.3 months in the control arm. This difference was not statistically significant, potentially impacted by a high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. In overall conclusion, the NETTER-1 study demonstrated that 177Lu-DOTATATE yielded a clinically and statistically significant improvement in PFS as a primary endpoint (HR: 0.18, p < 0.0001) as well as a clinically meaningful trend towards improvement in median OS of 11.7 months. No new safety signals emerged during the 5-year long-term follow-up. Clinical trial information: NCT01578239.

// Emanuela Minna 1 , Paola Romeo 1 , Matteo Dugo 2 , Loris De Cecco 2 , Katia Todoerti 3 , Silvana Pilotti 4 , Federica Perrone 4 , Ettore Seregni 5 , Luca Agnelli 6 , Antonino Neri 6, 7 , Angela Greco 1 , Maria Grazia Borrello 1 1 Department of Experimental Oncology and Molecular Medicine, Molecular Mechanisms Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 Department of Experimental Oncology and Molecular Medicine, Functional Genomics Core Facility, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 3 Laboratory of Pre-Clinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy 4 Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 5 Department of Diagnostic Imaging and Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 6 Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy 7 Hematology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy Correspondence to: Maria Grazia Borrello, e-mail: mariagrazia.borrello@istitutotumori.mi.it Keywords: papillary thyroid carcinoma, miR-451a, miRNA, RET/PTC, AKT pathway Received: December 18, 2015 Accepted: January 26, 2016 Published: February 8, 2016 ABSTRACT Papillary Thyroid Carcinoma (PTC) is the most frequent thyroid cancer. Although several PTC-specific miRNA profiles have been reported, only few upregulated miRNAs are broadly recognized, while less consistent data are available about downregulated miRNAs. In this study we investigated miRNA deregulation in PTC by miRNA microarray, analysis of a public dataset from The Cancer Genome Atlas (TCGA), literature review and meta-analysis based on a univocal miRNA identifier derived from miRBase v21. A list of 18 miRNAs differentially expressed between PTC and normal thyroid was identified and validated in the TCGA dataset. Furthermore, we compared our signature with miRNA profiles derived from 15 studies selected from literature. Then, to select possibly functionally relevant miRNA, we integrated our miRNA signature with those from two in vitro cell models based on the PTC-driving oncogene RET/PTC1. Through this strategy, we identified commonly deregulated miRNAs, including miR-451a, which emerged also by our meta-analysis as the most frequently reported downregulated miRNA. We showed that lower expression of miR-451a correlates with aggressive clinical-pathological features of PTC as tall cell variant, advanced stage and extrathyroid extension. In addition, we demonstrated that ectopic expression of miR-451a impairs proliferation and migration of two PTC-derived cell lines, reduces the protein levels of its recognized targets MIF, c-MYC and AKT1 and attenuates AKT/mTOR pathway activation. Overall, our study provide both an updated overview of miRNA deregulation in PTC and the first functional evidence that miR-451a exerts tumor suppressor functions in this neoplasia.

445 Background: FDG-PET/CT has limited utility in clinical N0 (cN0) patients (pts) with MIBC who receive neoadjuvant chemotherapy and RC or RC alone (Dason, AUA19). Methods: In PURE-01 (NCT02736266), 3 courses of 200 mg pembrolizumab, q3 weeks, were administered prior to RC. Pts were assessed with thorax-abdomen CT scan and with PET/CT scan during screening and before RC. Imaging review and analysis was internally performed. For each pt with lymph node (LN) increased uptake in abdomino-pelvic area, the SUVmax and the short-axis size of the most intense LN were recorded. All pts underwent extended pelvic LN dissection (LND) with packeted node submission. Results: From 02/17 to 06/2019, 103 total evaluable pts (206 PET/TC scans) were enrolled ad treated. Six pts (5.8%) had LN uptake at baseline PET/CT: mean SUVmax=2.75; mean short axis: 6.2 mm. Eight pts (7.8%) had LN uptake at PET/CT post-pembrolizumab: mean SUVmax=4.21; mean short axis: 7.2mm. The rate of pathologic LN positive (pN+) disease was 15.5% (16 pts). The performance of post-pembrolizumab PET/CT in predicting pN+ disease is indicated in the Table. In total, 4/6 pts (66.7%) with baseline FDG uptake revealed as pN+ vs 12/97 (12.4%) with no baseline FDG uptakes (p=0.005). A total of 39 pts (37.9%) developed inflammatory FDG-uptakes post-pembrolizumab in several target organs/regions: top 5 sites were thyroid (N=21, 61.8%), stomach and mediastinum (13 pts each, 12.6%), lung (N=10, 9.7%), other lymph nodes (N=4, 3.9%). These changes were clinically evident (signs/symptoms or laboratory changes) in 15 pts (38.5%). Conclusions: Criteria for eligibility of cN0 pts to single-agent neoadjuvant pembrolizumab trials may be enhanced with PET/CT use. Three cycles of pembrolizumab determined profound inflammatory changes, whose long-term impact on safety is still to be determined. Clinical trial information: NCT02736266 . [Table: see text]

Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Six scientific Italian societies entitled to cure thyroid cancer patients (the Italian Thyroid Association, the Medical Endocrinology Association, the Italian Society of Endocrinology, the Italian Association of Nuclear Medicine and Molecular Imaging, the Italian Society of Unified Endocrine Surgery and the Italian Society of Anatomic Pathology and Diagnostic Cytology) felt the need to develop a consensus report based on significant scientific advances occurred in the field. The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.

Differentiated thyroid cancers are typically iodine-avid and can be effectively treated with radioiodine. In most patients, radioactive iodine therapy (RAI) is done for ablation of residual tissue or with adjuvant intent in case of suspected persistent disease after surgery. Patient with advanced or metastatic disease may also benefit from RAI. In this chapter, we will discuss the current role of 131I-iodide therapy, including patient’s selection and preparation, and the importance of individual response to therapy to guide subsequent patient management.

Peptide receptor radionuclide therapy (PRRT) is an effective and usually well-tolerated treatment for unresectable or metastatic neuroendocrine tumors expressing somatostatin receptors. The two radiopharmaceuticals most commonly used for PRRT are 90Y-DOTATOC and 177Lu-DOTATATE which have been demonstrated to provide effective tumor response and symptom relief and have positive impact on survival. Chronic side effects on the kidneys and bone marrow are generally mild. Future perspectives include combinations with innovative therapeutic agents or the use of alpha-emitting radionuclide to improve PRRT efficacy.

Neuroendocrine tumors (NETs) are a group of heterogeneous neoplasm derived from cells throughout the nervous and endocrine systems with different biological behavior, clinical presentation, and course. They are characterized by the hypersecretion of several bioamines and peptides which may serve as biomarker. In patients affected by NETs, circulating marker can offer relevant clinical information concerning diagnosis, support of other investigative modalities, demonstration of failure/efficacy of therapy, and indicator of prognosis.

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS

Purpose To check the impact on toxicity and on overall survival (OS) of a personalized two compartment (tumor vs non tumor) dosimetric treatment planning method in the treatment of hepatocarcinoma with 90Y glass microspheres. Methods 43 Child A strictly selected patients (series 1) had been previously treated with 90Y glass microspheres according to the standard mono-compartment planning of 120 Gy to the injected liver lobe. A retrospective analysis of 99mTc-MAA pre-treatment SPECT/CT images had allowed to determine NTCP and TCP [1] . A decompensation risk of 15% was adopted as planning limit, corresponding to NTCP15 = 75 Gy. Liver absorbed dose is averaged on the organ volume excluding tumors. Such planning method was then applied to 116 less selected Child A patients (series 3, comparable to series 1). Results With respect to series 1, administered activity in series 3 was doubled in half of patients, reduced of 50% in a quarter of patients. Toxicity rate was maintained below 15%. Patient were stratified as advanced (with Portal Vein Thrombosis (PVT)) vs intermediate (NO PVT). In the PVT subgroups, lesions had the same size distribution. Treatment planning improved median OS from 8 to 12 months (with Mantel Cox test (p = 0.067) i.e. close to significance). In the NO PVT subgroups the median OS was 17 vs 15 months (n.s.) i.e. maintained, despite the larger tumor sizes. Conclusions methodological limits were absence of scatter correction and mismatch between simulation and 90Y PET dosimetry. Results are really encouraging, since are the first indications of improved outcome thanks to dosimetric treatment planning.

The aim of the present study was to perform a systematic review of published studies to provide a robust estimation of the use of procalcitonin (ProCT) as a diagnostic marker of medullary thyroid carcinoma (MTC), with particular focus on its specificity and negative predictive value in excluding MTC. A comprehensive computer literature search was conducted to find relevant published articles on the topic. We used a search algorithm based on a combination of the terms ‘medullary,’ ‘thyroid,’ and ‘ProCT.’ The search was updated until February 2015. To expand our search, references of the retrieved articles were also screened. A total of 39 articles were retrieved, of which nine original papers published from 2003 to 2014 were selected for the review. Some of these studies used ProCT in the preoperative diagnosis of MTC, whereas others measured ProCT during the follow-up of patients who had been previously treated for MTC. Other laboratory measurements were performed in some of the included studies. The results of the majority of the studies indicate that ProCT measurement appears to be a very promising and reliable serum marker for the diagnosis of MTC, and it is not inferior to calcitonin (CT). The sample handling is less laborious, and in the few CT-negative cases reviewed, the assay had even greater sensitivity. It would be worthwhile to establish cutoff levels using larger patient series, because we speculate that this assay could potentially replace CT measurement in the future.

// Barbara Frigerio 1 , Gerben Franssen 5 , Elena Luison 1 , Alessandro Satta 1 , Ettore Seregni 2 , Marco Colombatti 3 , Giulio Fracasso 3 , Riccardo Valdagni 4 , Delia Mezzanzanica 1 , Otto Boerman 5 , Silvana Canevari 1,* and Mariangela Figini 1,* 1 Department of Experimental Oncology and Molecular Medicine, S.S. Molecular Therapies, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 2 S.C. Nuclear Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 3 Department of Medicine, University of Verona, Verona, Italy 4 Department of Oncology and Hemato-Oncology, Universita degli Studi di Milano, Radiation Oncology 1, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy 5 Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands * Co-last Authors Correspondence to: Mariangela Figini, email: // Keywords : scFv antibody fragment; 123 I-radiolabeled antibody; prostate cancer; prostate-specific membrane antigen; imaging Received : December 15, 2016 Accepted : December 18, 2016 Published : December 30, 2016 Abstract Purpose: In the context of prostate cancer (PCa) imaging, the aim of this study was to optimize ( in vitro ) the specificity and assess preclinically ( in vivo ) the tumor targeting properties of the 123 I-scFvD2B antibody specific for prostate-specific membrane antigen (PSMA). Experimental Design: The 123 I-labeling conditions of the antibody fragment scFvD2B, produced in an eukaryotic system under GMP-compliant conditions, were optimized and assessed for purity and immunoreactivity. The specificity and potency of tumor uptake were tested in three preclinical in vivo models of subcutaneously xenografted human tumors expressing different levels of PSMA (LNCaP, naturally expressing PSMA; PC3-PIP and LS174T-PSMA, transfected with PSMA) or PC3 and LS174T, as negative controls, to assess the clearance, biodistribution and imaging potential of 123 I-scFvD2B. Results: The set conditions of production and radiolabeling yielded a reagent suitable for human delivery thanks to the purity of the formulation and the high immunoreactivity. In all preclinical models 123 I-scFvD2B showed specific targeting only to PSMA-positive tumors with the final specific activity ranging up to 1500 MBq/mg. Despite different levels of PSMA expression, biodistribution analyses and SPECT/CT imaging demonstrated similar results and maximal signal-to-background ratios 24 hours after injection. Conclusions: Due to its in vitro and in vivo properties, 123 I-scFvD2B could be a promising tool for the early diagnosis of PCa, and may represent a molecular imaging option to monitor disease progression and assist in the clinical management of PCa patients.

Item does not contain fulltext Differentiated thyroid cancer is a rare malignancy, but leaves numerous survivors for life-long follow-up. The cornerstone in current guidelines for follow-up is by measuring the thyroid specific tumour marker, thyroglobulin in serum. Most patients can be followed by this method, but some thyroid cancer patients have antithyroglobulin antibodies in serum, both at diagnosis and after treatment, where follow-up is commenced. These antibodies interfere technically in the immunological methods for measuring thyroglobulin, and the antithyroglobulin antibody positive patients are thus eliminated from following current guidelines. In recent years studies have indicated that following the concentration of antithyroglobulin antibodies in serum may be a surrogate marker for recurrence of the thyroid carcinoma. This has recently resulted in publication of an expert position paper, providing a flow scheme for these particular patients. The current review summarises the literature which is the basis for the paper.

Intra-arterial radioembolization using microspheres labeled with the high-energy beta-emitter yttrium-90 (90Y) is an innovative therapeutic strategy for primary and secondary hepatic malignancies. An accurate imaging workup plays a pivotal role in correctly selecting patients for treatment, to avoid severe complications and in assessment of the post-administration microsphere distribution. Nuclear medicine imaging modalities are an integral part of a complex multidisciplinary approach. In particular, hepatic perfusion imaging with 99mTc-macroaggregated albumin particles (99mTc-MAA), which identifies extrahepatic accumulation of radiopharmaceutical and lung shunt, is necessary to correctly select patients who may benefit from the treatment. Furthermore, 99mTc MAA SPECT-based dose planning may optimize RE efficacy, overcoming the limitations of empirical methods to determine the activity to be administered. Quantitative assessment of the post-administration intrahepatic microsphere distribution with SPECT or PET is important for evaluation of toxicity and efficacy and can be used for the prediction of patient response and for patient-specific therapeutic dose optimization. Finally, [18F]FDG PET/CT imaging is important in the assessment of early response after RE and in predicting patient outcome. This review provides a comprehensive overview of multimodality imaging in the complex management of patients undergoing RE for liver tumors.

To assess the long-term safety of administering growth hormone (GH) in patients with GH deficiency due to treatment for childhood medulloblastoma and primitive neuroectodermal tumor (PNET). Data were retrospectively retrieved on children receiving GH supplementation, assessing their disease-free and overall survival outcomes and risk of secondary malignancies using Kaplan-Meier and Cox models. Overall 65 children were consecutively collected from May 1981 to April 2013. All patients had undergone craniospinal irradiation (total dose 18-39 Gy), and subsequently received GH for a median (interquartile range, IQR) of 81 (50.6-114.9) months. At a median (IQR) of 122.4 months (74.4-149.5) after the end of their adjuvant cancer treatment, two patients (3 %) experienced recurrent disease and 8 (12.3 %) developed secondary malignancies, all but one of them (an osteosarcoma) related to radiation exposure and occurring within the radiation fields. There was no apparent correlation between the administration of GH replacement therapy (or its duration) and primary tumor relapse or the onset of secondary malignancies [HR: 1.01 (95 % CI: 0.98, 1.03) for every additional 12 months of GH supplementation; p = 0.36). At univariate analysis, the large cell or anaplastic medulloblastoma subtype, metastases and myeloablative chemotherapy correlated with a higher risk of secondary malignancies (p

Thyroid carcinomas derived from follicular cells comprise papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC) and undifferentiated anaplastic thyroid carcinoma (ATC). PTC, the most frequent thyroid carcinoma histotype, is associated with gene rearrangements that generateRET/PTCandTRKoncogenes and withBRAF-V600Eand RAS gene mutations. These last two genetic lesions are also present in a fraction of PDTCs. The ERK1/2 pathway, downstream of the known oncogenes activated in PTC, has a central role in thyroid carcinogenesis. In this study, we demonstrate that theBRAF-V600E,RET/PTC, andTRKoncogenes upregulate the ERK1/2 pathway's attenuator cytoplasmic dual-phase phosphatase DUSP6/MKP3 in thyroid cells. We also show DUSP6 overexpression at the mRNA and protein levels in all the analysed PTC cell lines. Furthermore,DUSP6mRNA was significantly higher in PTC and PDTC in comparison with normal thyroid tissues both in expression profile datasets and in patients' surgical samples analysed by real-time RT-PCR. Immunohistochemical and western blot analyses showed that DUSP6 was also overexpressed at the protein level in most PTC and PDTC surgical samples tested, but not in ATC, and revealed a positive correlation trend with ERK1/2 pathway activation. Finally,DUSP6silencing reduced the neoplastic properties of four PTC cell lines, thus suggesting thatDUSP6may have a pro-tumorigenic role in thyroid carcinogenesis.

Papillary Thyroid Carcinoma (PTC) is the most frequent thyroid cancer. Although several PTC-specific miRNA profiles have been reported, only few upregulated miRNAs are broadly recognized, while less consistent data are available about downregulated miRNAs. In this study we investigated miRNA deregulation in PTC by miRNA microarray, analysis of a public dataset from The Cancer Genome Atlas (TCGA), literature review and meta-analysis based on a univocal miRNA identifier derived from miRBase v21. A list of 18 miRNAs differentially expressed between PTC and normal thyroid was identified and validated in the TCGA dataset. Furthermore, we compared our signature with miRNA profiles derived from 15 studies selected from literature. Then, to select possibly functionally relevant miRNA, we integrated our miRNA signature with those from two in vitro cell models based on the PTC-driving oncogene RET/PTC1. Through this strategy, we identified commonly deregulated miRNAs, including miR-451a, which emerged also by our meta-analysis as the most frequently reported downregulated miRNA. We showed that lower expression of miR-451a correlates with aggressive clinical-pathological features of PTC as tall cell variant, advanced stage and extrathyroid extension. In addition, we demonstrated that ectopic expression of miR-451a impairs proliferation and migration of two PTC-derived cell lines, reduces the protein levels of its recognized targets MIF, c-MYC and AKT1 and attenuates AKT/mTOR pathway activation.Overall, our study provide both an updated overview of miRNA deregulation in PTC and the first functional evidence that miR-451a exerts tumor suppressor functions in this neoplasia.

Incidental/therapeutic thyroid irradiation causes hypothyroidism and nodular disease. Increasing numbers of children are being cured of cancers by treatments that include radiation also involving the thyroid bed: these children warrant an early diagnosis and treatment of any radiation-related thyroid changes.In 1998 we retrospectively evaluated thyroid parenchyma/function in all patients irradiated between 1975 and 1997; thereafter, we prospectively evaluated all patients given thyroid irradiation by means of thyroid ultrasound and serum fT3, fT4, TSH and thyroglobulin.Of 596 eligible patients, 468 agreed to the retrospective evaluation: 128/468 had one or more thyroid nodules, and 73 of these 128 had concomitant or previously untreated hypothyroidism, while 22/128 had a differentiated carcinoma. Another 144/157 patients treated between 1998 and 2004 were evaluated and any iatrogenic hypothyroidism was promptly treated: 19/144 had nodules, all smaller than 1cm in diameter. The first patient group was studied retrospectively, so we have no precise record of the time of nodule occurrence or of their initial sizes. We found, however, that both the number of patients with nodules and the sizes of the nodules were significantly lower (p0.01) in the prospectively studied group (after a median follow-up of 81 months) than in the retrospectively studied group. Among all the patients with nodules, significantly more females developed cancer than males (p0.04).Early treatment for hypothyroidism and ultrasound evaluation of the parenchyma are needed to limit nodule onset and growth.

Hypothyroidism is one of the earliest endocrine effects of craniospinal irradiation (CSI). The effects of radiation also depend on circulating thyroid-stimulating hormone (TSH), which acts as an indicator of thyrocyte function and is the most sensitive marker of thyroid damage. Hence, our study was launched in 1998 to evaluate the protective effect of TSH suppression during CSI for medulloblastoma/primitive neuroectodermal tumor.From Jan 1998 to Feb 2001, a total of 37 euthyroid children scheduled for CSI for medulloblastoma/primitive neuroectodermal tumor underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginning and end of CSI. From 14 days before and up to the end of CSI, patients were administered l-thyroxine at suppressive doses; every 3 days, TSH suppression was checked to ensure a value0.3 mum/ml. During follow-up, blood tests and ultrasound were repeated after 1 year; primary hypothyroidism was considered an increased TSH level greater than normal range. CSI was done using a hyperfractionated accelerated technique with total doses ranging from 20.8-39 Gy; models were used to evaluate doses received by the thyroid bed.Of 37 patients, 25 were alive a median 7 years after CSI. They were well matched for all clinical features, except that eight children underwent adequate TSH suppression during CSI, whereas 17 did not. Hypothyroidism-free survival rates were 70% for the "adequately TSH-suppressed" group and 20% for the "inadequately TSH-suppressed" group (p = 0.02).Thyroid-stimulating hormone suppression with l-thyroxine had a protective effect on thyroid function at long-term follow-up. This is the first demonstration that transient endocrine suppression of thyroid activity may protect against radiation-induced functional damage.

The aim of this pilot study was to observe the variations of pain intensity on movement and at rest and the variation of analgesic drug consumption in patients with prostate cancer and painful bone metastases treated with a single dose of 1.0 mCi/kg of samarium-153 (153-Sm) lexidronam. Case series. The Nuclear Medicine Unit and Pain Therapy and Palliative Care Unit, National Cancer Institute of Milan, Italy. Thirteen outpatients with hormone refractory prostate cancer and painful multiple bone metastases. Infusion of a single dose of 1.0 mCi/kg of 153-Sm lexidronam, pain therapy, and the assessment of pain intensity at rest and on movement. Variation of pain intensity on movement and at rest by means of a verbal scale and the reduction of analgesic drug consumption 4 weeks after infusion of 153-Sm lexidronam. From baseline, 61.5% of patients reported a decrease of at least two levels of pain intensity on movement and 53.8% of patients had an improvement of pain at rest. Of the patients, 15.4% were not in pain at rest or on movement at baseline and continued to be free of pain 4 weeks after the administration of samarium. All ten patients, but one, who were on analgesic drugs before samarium infusion, reduced the regular drug administration or rescue medication. Bone marrow toxicity was mild and readily reversible in three patients. In patients with bone metastases, pain on movement is a frequent and often difficult clinical problem to treat and the most frequent cause of breakthrough pain. In patients with painful multiple bone metastases due to prostate cancer, the infusion of a single dose of 1.0 mCi/kg of 153-Sm lexidronam may be considered an effective and safe treatment for pain either at rest or during movement.

Background Prior to 1990s, papillary thyroid carcinomas (PTCs) in childhood/adolescence underwent a standard therapeutic approach (total thyroidectomy plus elective neck dissection, followed by radioactive iodine (RAI) ablation), with an overall survival of about 100%. The aim of this study is to outline the possibility of a conservative approach (hemithyroidectomy plus selective neck dissection of clinically involved nodes, followed by TSH-suppressive therapy) in a selected group of patients. Procedure From 1968 to 2001, 42 pediatric PTC patients were treated at our institution. Absence of distant metastases and a tumor clinically limited to one lobe were both present in 28 cases that underwent a radical (20 cases) or a conservative (8 cases) surgical approach at the thyroid level. At cervical node level, 10 patients underwent a radical and 32 a conservative surgical approach. Clinicopathologic features at onset, type of therapy (radical vs. conservative), post-operative complications, and outcome till May 31, 2004 were recorded. The impact of the type of surgery on outcome was evaluated. Results Overall and progression-free survival (PFS) curves were found to be independent of the type of therapy (radical vs. conservative) in subgroups of patients matched for extent of disease at onset. Post-operative complications occurred only with radical surgical approaches. Conclusions Childhood and adolescence PTCs show a high rate of spread but an excellent outcome independent of the type of therapy (radical vs. conservative). Taking into account the marked responsiveness to TSH-suppression and the complications after radical therapy, in selected cases, a conservative approach should be considered, reserving more aggressive therapies in case of metastases or relapse. © 2005 Wiley-Liss, Inc.

Background Thyroid carcinoma occurring as a second primary associated with head and neck squamous cell carcinoma (HNSCC) is unusual. The clinical management of thyroid cancer in such cases has been debated. Methods Between 1975 and 2004, we collected 33 cases. The associated thyroid carcinoma was diagnosed either during or as a consequence of surgery planned as head and neck cancer treatment. Results The associated thyroid carcinoma was never seen to recur. Five-year overall survival was 41%. Disease-free survival after 40 and 66 months was 11.1% and 5.6%, respectively. Conclusions We consider the treatment of thyroid cancer to be complete when the thyroid gland, either with or without lymph nodes, has been included in the specimen obtained during surgery for HNSCC. In the group of cases in which associated thyroid carcinoma was only found within the neck lymph nodes and the thyroid gland has not been treated, we discourage further surgical treatment or radioactive iodine therapy. © 2006 Wiley Periodicals, Inc. Head Neck, 2006

Background: We previously selected a panel of 3 breast cancer biomarkers (BC1, BC2, and BC3) from serum samples collected at a single hospital based on their collective contribution to the optimal separation of breast cancer patients and noncancer controls by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). The identities and general applicability of these markers, however, were unknown. In this study, we performed protein expression profiling on samples obtained from a second hospital, included a greater number of ductal carcinoma in situ (DCIS) cases, and performed purification and identification of the 2 confirmed markers.Methods: Using a case–control study design, we performed protein expression profiling on serum samples from the National Cancer Institute (Milan, Italy). The validation sample cohort consisted of 61 women with locally invasive breast cancer, 32 with DCIS, 37 with various benign breast diseases (including 13 atypical), and 46 age-matched apparently healthy women (age range, 44–68 years). Validated biomarkers were purified and identified with serial chromatography, 1-dimensional gel electrophoresis, in-gel ASP-N digestion, peptide mass fingerprinting, and tandem mass peptide sequencing.Results: The BC3 and BC2 expression patterns in this sample set were consistent with the first study sample set. BC3 and BC2 were identified to be complement component C3adesArg and a C-terminal–truncated form of C3adesArg, respectively.Conclusions: Evaluation of biomarkers in independent sample sets can help determine the broader utility of candidate markers, and protein identification permits understanding of their molecular basis. C3adesArg appears to lack specificity among patients with benign diseases, limiting its utility as a stand-alone tumor marker, but it may still be useful in a multimarker panel for early detection of breast cancer.

The monoclonal antibody (mAb) MOv18 binds the membrane alpha isoform of the folate receptor (FR) which is overexpressed in human ovarian carcinoma cells. Exploiting the targeting capacity of this mAb, we developed and preclinically validated a protocol for the stable labeling of the mAb with 90Y, an isotope which has shown promise in cancer radioimmunotherapy. MOv18 was derivatized with the stable macrocyclic ligand p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (Bz-DOTA). MOv18-Bz-DOTA conjugates were labeled with 90Y or 111In under metal-free and good laboratory practice conditions. At the optimal Bz-DOTA/mAb derivatization ratio of 4–5, conjugates maintained binding activity up to 6 months, were efficiently labeled with 90Y or 111In (mean labeling yield 85 and 64%, associated to a final mean specific activity of 74 and 37 MBq/mg) and displayed a mean immunoreactivity of 60 and 58%, respectively. The radiolabeled preparations were stable in human serum, with >97% radioactivity associated to mAb at 48 h after labeling. The ability of 90Y- and 111In-MOv18 to localize FR on tumors in vivo was analyzed in nude mice bearing tumors induced by isogenic cell lines differing only in the presence or absence of the relevant antigen [A431FR (FR-positive) and A431tMock (FR-negative)]. In vivo biodistribution in organs other than tumor was comparable in non-tumor-, A431tMock- and A431FR-bearing mice, whereas the median tumor uptake of the radiolabeled reagents, expressed as area under the curve (AUC) and maximum uptake (Umax), was significantly higher (sixfold to sevenfold) in A431FR than in A431tMock tumors (P=0.0465 and P=0.0332, respectively). Mean maximum uptake (% ID/g) for 90Y-MOv18 was 53.7 and 7.4 in A431FR and A431tMock respectively; corresponding values for 111In-Mov18 were 45.0 and 11.3. These data demonstrate the feasibility of 90Y-labeling of MOv18 without compromising antibody binding ability and the immunoreagent-specific localization in vivo on FR-expressing tumors, suggesting the suitability of 90Y-MOv18 for clinical studies.

NOTE. Median follow-up, 5.7 years (range, 1-8.7); Z-HDS, 5.9 (range, 1-8.3); HDS, 4.9 (range, 1.4-8.7).

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds NF-kappaB ligand, the final effector for osteoclastogenesis. OPG production is regulated by a number of cytokines and hormones. Osteopontin (OPN) is a secreted adhesive glycoprotein involved in tumour angiogenesis, and also a non-collagenous protein involved in bone turnover. OPN serum value is associated with tumour burden and survival in advanced breast cancer patients. The short-term effects of anastrozole on OPG and OPN serum values, and the usefulness of these analytes during follow-up were studied in 34 consecutive advanced breast cancer patients receiving anastrozole 1 mg/day. Blood samples were taken before treatment and at 2, 4, 8 and 12 weeks. OPG and OPN values were measured by ELISA. The results were analysed for all patients, and also separately for patients with (group A, 22 patients) and without (group B, 12 patients) bone metastasis. Whether the survival of all patients was related to their OPN serum values was also tested by placing patients into three groups (terciles) according to their baseline OPN values. No significant changes in OPG and OPN values were observed in the complete patient group. There was no difference in baseline OPG and OPN serum values between patients in groups A and B. In group A, a significant percentage increase in both OPG and OPN values from baseline was detected during treatment. No significant changes were reported for group B patients. Furthermore, in group A, a significant increase in both analytes was evident only for patients with progressive disease (PD). The Kaplan–Meier adjusted survival estimates for patients grouped according to tercile OPN values differed significantly (P = 0.001, log rank test). In conclusion, in the short term, anastrozole does not seem to affect OPG and OPN serum values in patients without bone disease. OPG and OPN appear to be useful predictors of the outcome of skeletal disease and elevated OPN values may be associated with short survival in advanced breast cancer patients.