[Show abstract][Hide abstract] ABSTRACT: We report a simple method for the incorporation of Cu(I) or 64Cu(I) radionuclides in covellite nanocrystals (CuS NCs). After the in situ reduction of Cu(II) or 64Cu(II) ions by ascorbic acid, their incorporation in PEG-coated CuS NCs takes place at room temperature. In all the reaction steps the stability of the NCs under physiological conditions was ensured. The copper incorporation reaction could also take place on CuS NCs bearing biotin molecules at their surface, with no detrimental effects on the specific binding affinity of the NCs towards streptavidin after incorporation. At low loading of Cu ions, the strong near-infrared (NIR) absorption band of the starting CuS NCs was essentially preserved, which allowed for efficient plasmonic photo-thermal therapy (PPTT). The combined presence in the NCs of 64Cu ions, well suitable for positron emission tomography (PET), and of free carriers responsible for the NIR absorption, should enable their theranostic use as radiotracers and as photo-thermal probes in tumor ablation treatments. Moreover, the simplicity of the preparation scheme, which involves the use of radioactive species only as a last step, makes the protocol easily transferable to the clinical practice.
Full-text · Article · Nov 2015 · Journal of the American Chemical Society
[Show abstract][Hide abstract] ABSTRACT: Antibody-based reagents represent a promising strategy as clinical diagnostic tools. Prostate cancer (PCa) is the second-leading cause of death in males in the Western population. There is a presently unmet need for accurate diagnostic tool to localize and define the extent of both primary PCa and occult recurrent disease. One of the most suitable targets for PCa is the prostate-specific membrane antigen (PSMA) recognized by the monoclonal antibody D2B that we re-shaped into the single chain Fv (scFv format). Aim of this study was to evaluate in preclinical in vivo models the target specificity of scFvD2B after labelling with different radionuclides. (111)In radiolabelling was performed via the chelator Bz-NOTA, and (131)I radioiodination was performed using iodogen. The potential for molecular imaging and the biological behaviour of the radiolabelled scFvD2B were evaluated in mice bearing two subcutaneous PCa isogenic cell lines that differed only in PSMA expression. Biodistribution studies were performed at 3, 9, 15 and 24 h after injection to determine the optimal imaging time point. A significant kidney accumulation, as percentage of injected dose of tissue (%ID/g), was observed for (111)In-scFvD2B at 3 h after injection (45% ID/g) and it was maintained up to 24 h (26% ID/g). By contrast, kidney accumulation of (131)I-scFvD2B was only marginally (0.3% ID/g at 24 h). At the optimal time point defined between 15 h and 24 h, regardless of the radionuclide used, the scFvD2B was able to localize significantly better in the PSMA expressing tumours compared to the negative control; with (131)I-scFvD2B yielding a significantly better target/background ratio compared to (111)In-scFvD2B. These data suggest that, besides antigen specificity, chemical modification may affect antibody fragment biodistribution.
No preview · Article · Sep 2015 · Immunology letters
[Show abstract][Hide abstract] ABSTRACT: La cromogranina A (CgA) è una molecola costituita da 439 aminoacidi e peso molecolare di circa 48 kDa appartenente alla famiglia delle granine, gruppo di proteine acide, idrosolubili che si rinvengono all’interno dei granuli di secrezione delle cellule endocrine, neurondocrine e neuronali in associazione ai prodotti di secrezione specifici quali ormoni peptidici, neuro-trasmettitori e ammine. La CgA si caratterizza per la particolare composizione in amminoacidi, per la capacità di legare ioni calcio e, soprattutto, per costituire il precursore di numerosi frammenti. In questa rassegna verranno discusse le principali caratteristiche biologiche e l’utilizzo clinico della CgA e dei frammenti che da essa derivano.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to optimize the dosimetric approach and to review the absorbed doses delivered, taking into account radiobiology, in order to identify the optimal methodology for an individualized treatment planning strategy based on (99m)Tc-macroaggregated albumin (MAA) single photon emission computed tomography (SPECT) images.
We performed retrospective dosimetry of the standard TheraSphere® treatment on 52 intermediate (n = 17) and advanced (i.e. portal vein thrombosis, n = 35) hepatocarcinoma patients with tumour burden < 50 % and without obstruction of the main portal vein trunk. Response was monitored with the densitometric radiological criterion (European Association for the Study of the Liver) and treatment-related liver decompensation was defined ad hoc with a time cut-off of 6 months. Adverse events clearly attributable to disease progression or other causes were not attributed to treatment. Voxel dosimetry was performed with the local deposition method on (99m)Tc-MAA SPECT images. The reconstruction protocol was optimized. Concordance of (99m)Tc-MAA and (90)Y bremsstrahlung microsphere biodistributions was studied in 35 sequential patients. Two segmentation methods were used, based on SPECT alone (home-made code) or on coregistered SPECT/CT images (IMALYTICS™ by Philips). STRATOS™ absorbed dose calculation was validated for (90)Y with a single time point. Radiobiology was used introducing other dosimetric variables besides the mean absorbed dose D: equivalent uniform dose (EUD), biologically effective dose averaged over voxel values (BEDave) and equivalent uniform biologically effective dose (EUBED). Two sets of radiobiological parameters, the first derived from microsphere irradiation and the second from external beam radiotherapy (EBRT), were used. A total of 16 possible methodologies were compared. Tumour control probability (TCP) and normal tissue complication probability (NTCP) were derived. The area under the curve (AUC) of the receiver-operating characteristic (ROC) curve was used as a figure of merit to identify the methodology which gave the best separation in terms of dosimetry between responding and non-responding lesions and liver decompensated vs non-decompensated liver treatment.
MAA and (90)Y biodistributions were not different (71 % of cases), different in 23 % and uncertain in 6 %. Response correlated with absorbed dose (Spearman's r from 0.48 to 0.69). Responding vs non-responding lesion absorbed doses were well separated, regardless of the methodology adopted (p = 0.0001, AUC from 0.75 to 0.87). EUBED gave significantly better separation with respect to mean dose (AUC = 0.87 vs 0.80, z = 2.07). Segmentation on SPECT gave better separation than on SPECT/CT. TCP(50 %) was at 250 Gy for small lesion volumes (<10 cc) and higher than 1,000 Gy for large lesions (>10 cc). Apparent radiosensitivity values from TCP were around 0.003/Gy, a factor of 3-5 lower than in EBRT, as found by other authors. The dose-rate effect was negligible: a purely linear model can be applied. Toxicity incidence was significantly larger for Child B7 patients (89 vs 14 %, p < 0.0001), who were therefore excluded from dose-toxicity analysis. Child A toxic vs non-toxic treatments were significantly separated in terms of dose averaged on whole non-tumoural parenchyma (including non-irradiated regions) with AUC from 0.73 to 0.94. TD50 was ≈ 100 Gy. No methodology was superior to parenchyma mean dose, which therefore can be used for planning, with a limit of TD15 ≈ 75 Gy.
A dosimetric treatment planning criterion for Child A patients without complete obstruction of the portal vein was developed.
No preview · Article · Jun 2015 · European Journal of Nuclear Medicine
[Show abstract][Hide abstract] ABSTRACT: Aim of this study was to perform a systematic review of published studies to provide more 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 this topic. We used a search algorithm based on a combination of the terms "medullary", "thyroid" and "procalcitonin". 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 9 original papers, published from 2003 to 2014, were selected for the review. Some of these studies used ProCT in preoperative diagnosis of MTC, while the other ones measured ProCT during follow-up of patients previously treated for MTC. Other laboratory measurements were performed in some of the included studies. The majority of studies indicate that ProCT measurement appears a very promising and reliable serum marker for the diagnosis of MTC, not inferior to CT. The sample handling is less laborious and, in those few CT-negative cases, the assay even has greater sensitivity. It would be worthwhile to establish cut-off levels using larger patient-series, as one might speculate that this assay could even replace CT measurements in the future.
Full-text · Article · May 2015 · Endocrine Related Cancer
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Aug 2014 · Current Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous thyrotropin (TSH) is recommended by current clinical guidelines to detect occult disease with maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.
Full-text · Article · Apr 2014 · European Journal of Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Purpose
Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter (90Y) and a medium-energy beta/gamma emitter (177Lu) in patients with metastatic NET refractory to conventional therapy.
A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [177Lu]DOTA-TATE (5.55 GBq) and [90Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [177Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST.
Administration of tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment
The results of our study indicates that combined [90Y]DOTA-TATE and [177Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach.
No preview · Article · Feb 2014 · European journal of nuclear medicine and molecular imaging
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Abstract This study evaluated the effects of 10-day broccoli (250 g/day) intake on dietary markers and markers of inflammations in young male smokers. A dietary intervention study with a repeated measures crossover design was conducted. Circulating levels of carotenoids, folate, C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 6 receptor (IL-6sR) and adiponectin were measured. Broccoli intake significantly increased plasma levels of folate (+17%) and lutein (+39%), while no significant effect was observed for TNF-α, IL-6, IL-6sR or adiponectin. Plasma CRP decreased by 48% (post-hoc analysis, p < 0.05) following broccoli diet; this resulted to be independent from the plasma variations in lutein and folate. An inverse correlation between lycopene, TNF-α and IL-6sR was observed at baseline. In conclusion, broccoli consumption may reduce CRP levels in smokers, consistent with epidemiologic observations that fruit and vegetable intake is associated with lower circulating CRP concentrations.
No preview · Article · Sep 2013 · International Journal of Food Sciences and Nutrition
[Show abstract][Hide abstract] ABSTRACT: The incidence of thyroid carcinomas is steadily increasing. Primary tumors of the thyroid gland include carcinomas that originate from epithelial cells (carcinomas of thyrocytes and C-cells), and from non-epithelial cells (lymphomas and sarcomas). Thyrocytes are the main functional cells that produce thyroid hormones (T3 and T4), which are vital for human metabolism. The epithelial tumors can be divided into the well-differentiated (papillary and follicular carcinomas), poorly-differentiated, undifferentiated (anaplastic carcinomas) carcinomas, and tumor of the parafollicular or C-cells (medullary carcinoma). Three common histopathological diagnosis of papillary thyroid carcinomas (PTC) include classical PTC, follicular variant PTC and mixed PTC, and follicular thyroid carcinomas (FTC). Mixed medullary and follicular carcinomas are rare neoplasms which show morphologic features of both follicular and C-cell differentiation. These neoplasms must be distinguished from the follicular variant of medullary carcinoma and from medullary carcinoma with entrapped normal follicles. Table 8.1 summarizes the WHO classification of thyroid tumors published in 2004 . According to the American Cancer Society there are 37,000 new cases of thyroid cancer annually in the United States, with approximately 75 % occurring in women .
[Show abstract][Hide abstract] ABSTRACT: The incidence of neuroendocrine tumors is rising, and this rise is explained by more than just better diagnostic procedures. About 85% of these neoplasms arise in gastrointestinal or pulmonary sites, but cases where the location is more unusual also occur in clinical practice. The tailgut cyst is a rare entity well described in the medical literature, but a neuroendocrine tumor within such a cyst is a very rare event, with about 30 cases described in the literature to date. In this report we present the case of a young woman with this unusual diagnosis. The characteristics of the case differ from most previous case reports in a few respects: the patient was a young rather than middle-aged female; she had a presacral mass with a significant solid component; at diagnosis, there was evidence of a lytic lesion in the coccyx. Despite this particular medical presentation, radical surgery was accomplished. In this disease the greatest risk is local relapse, but adjuvant radiotherapy may compromise the patient's fertility. We therefore opted for strict control only, but this decision might be debatable.
[Show abstract][Hide abstract] ABSTRACT: 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.
No preview · Article · Jun 2013 · The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...
[Show abstract][Hide abstract] ABSTRACT: Background:
Even though the presence of antithyroglobulin antibodies (TgAbs) represents a significant problem in the follow-up of patients with differentiated thyroid cancer (DTC), the current guidelines on the management of DTC that have been published in recent years contain no text concerning the methods to be used for detecting such antibody-related interference in thyroglobulin (Tg) measurement or how to manage TgAb-positive patients in whom Tg cannot be used reliably as a tumor marker.
An international group of experts from the European Thyroid Association Cancer Research Network who are involved in the care of DTC patients met twice to form a consensus opinion on how to proceed with treatment and follow-up in TgAb-positive DTC patients based on the available evidence in the literature. Here we will report on the consensus opinions that were reached regarding technical and clinical issues.
This clinical opinion article provides an overview of the available evidence and the resulting consensus recommendations. The current literature does not provide sufficient data for giving evidence-based answers to many questions arising in the care of TgAb-positive DTC patients. Where insufficient evidence was available, a thorough discussion by a group of physician-scientists, all of whom have a distinguished track record in thyroid cancer care, was held to arrive at a consensus expert opinion. The questions and answers discussed were then summarized into an algorithm for the management of TgAb-positive patients.
We were able to define 26 consensus expert recommendations and a resulting algorithm for the care of TgAb-positive DTC patients.
Full-text · Article · May 2013 · Thyroid: official journal of the American Thyroid Association
[Show abstract][Hide abstract] ABSTRACT: Prostate carcinoma is the most common non-cutaneous cancer in developed countries and represents the second leading cause of death. Early stage androgen dependent prostate carcinoma responds well to conventional therapies, but relatively few treatment options exist for patients with hormone-refractory prostate cancer. One of the most suitable targets for antibody-mediated approaches is prostate specific membrane antigen (PSMA) which is a well known tumour associated antigen. PSMA is a type II integral cell-surface membrane protein that is not secreted, and its expression density and enzymatic activity are increased progressively in prostate cancer compared to normal prostate epithelium, thereby making PSMA an ideal target for monoclonal antibody imaging and therapy. To obtain a small protein that can better penetrate tissue, we have engineered a single-chain variable fragment (scFv) starting from the variable heavy and light domains of the murine anti-PSMA monoclonal antibody D2B. scFvD2B was analysed in vitro for activity, stability, internalisation ability and in vivo for targeting specificity. Maintenance of function and immunoreactivity as well as extremely high radiolabelling efficiency and radiochemical purity were demonstrated by in vitro assays and under different experimental conditions. Despite its monovalent binding, scFvD2B retained a good strength of binding and was able to internalise around 40% of bound antigen. In vivo we showed its ability to specifically target only PSMA expressing prostate cancer xenografts. Due to these advantageous properties, scFvD2B has the potential to become a good theranostic reagent for early detection and therapy of prostate cancers.
No preview · Article · Feb 2013 · European journal of cancer (Oxford, England: 1990)
[Show abstract][Hide abstract] ABSTRACT: Neuroendocrine tumors (NETs) are a group of tumors which frequently express somatostatin receptors (SSTRs) and represent 1 % of all neoplasms that may arise in the body. NETs of the gastro-entero-pancreatic tract (GEP NETs) and tumors of the sympatho-adrenal lineage are the most frequent tumors observed in clinical practice. Improved diagnostic techniques, both functional and anatomical, have resulted in an increased incidence of NETs. The term neuroendocrine defines cells that share common characteristics, such as the ability to take up and decarboxylate several amine precursors (APUD system), the absence of axons and synapses, the production of cell type-specific hormonal products and the demonstration of particular histopathological staining . The variation in biological characteristics of these tumors poses considerable problems when deciding the optimal treatment strategies.