Publications by authors named "Rosa Fonti"

36 Publications

PET-Based Volumetric Biomarkers for Risk Stratification of Non-Small Cell Lung Cancer Patients.

Diagnostics (Basel) 2021 Jan 30;11(2). Epub 2021 Jan 30.

Department of Advanced Biomedical Sciences, University "Federico II", 80131 Naples, Italy.

Despite the recent advances in lung cancer biology, molecular pathology, and treatment, this malignancy remains the leading cause of cancer-related death worldwide and non-small cell lung cancer (NSCLC) is the most common form found at diagnosis. Accurate staging of the disease is a fundamental prognostic factor that correctly predicts progression-free (PFS) and overall survival (OS) of NSCLC patients. However, outcome of patients within each TNM staging group can change widely highlighting the need to identify additional prognostic biomarkers to better stratify patients on the basis of risk. 18F-FDG PET/CT plays an essential role in staging, evaluation of treatment response, and tumoral target delineation in NSCLC patients. Moreover, a number of studies showed the prognostic role of imaging parameters derived from PET images, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG). These parameters represent three-dimensional PET-based measurements providing information on both tumor volume and metabolic activity and previous studies reported their ability to predict OS and PFS of NSCLC patients. This review will primarily focus on the studies that showed the prognostic and predictive role of MTV and TLG in NSCLC patients, addressing also their potential utility in the new era of immunotherapy of NSCLC.
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http://dx.doi.org/10.3390/diagnostics11020210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911597PMC
January 2021

Brain Metastases Unresponsive to Immunotherapy Detected by 18F-FDG-PET/CT in a Patient with Melanoma.

Diagnostics (Basel) 2020 Jun 17;10(6). Epub 2020 Jun 17.

Department of Advanced Biomedical Sciences, University of Naples Federico II, 80131 Naples, Italy.

Recently, newer therapies such as immunotherapy have been increasingly used in the treatment of several tumors, including advanced melanoma. In particular, several studies showed that the combination of ipilimumab, an anti-Cytotoxic T-lymphocyte Associated Protein 4 (CTLA-4) monoclonal antibody and nivolumab, an anti-Programmed Death 1 (PD-1) monoclonal antibody, leads to improved survival in patients with metastatic melanoma. Despite that, immunotherapeutic agents may not reach therapeutic concentration in the brain due to the blood-brain barrier. We report the case of a 50-year-old man with advanced melanoma who underwent whole-body 18F-FDG-PET/CT before and after treatment with immunotherapy showing resistant brain metastases confirmed by subsequent MRI of the brain. Moreover, 18F-FDG-PET/CT was able to detect an immune-related adverse event such as enterocolitis that contributed to the worsening of patient conditions. This case shows how a whole-body methodology such as 18F-FDG-PET/CT can be useful in identifying melanoma cancer patients unresponsive to immunotherapy that may benefit from traditional palliative therapy in the effort to improve their quality of life.
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http://dx.doi.org/10.3390/diagnostics10060410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345060PMC
June 2020

Preclinical imaging for targeting cancer immune evasion.

Q J Nucl Med Mol Imaging 2020 Jun 14;64(2):186-193. Epub 2020 Apr 14.

Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy -

Novel anticancer immunotherapy strategies such as immune checkpoint blockade have been successfully employed in patients with a variety of cancers and became a therapeutic option in the treatment of several malignancies. However, long-term durable responses to immune checkpoint inhibitors are currently limited to a fraction of patients raising the need of an accurate selection of potentially responding patients. Although several biomarkers have been proposed for patient selection and prediction of response to immune checkpoint blockade, none can be considered as an absolute selection criterion. Whole-body imaging with tracers recognizing targets for immunotherapy by allowing visualization of target expression in all tumor and extratumoral sites at baseline and during disease evolution may provide reliable predictive imaging biomarkers. Here we will provide an overview of preclinical imaging studies aiming at the development and validation of tracers recognizing targets for immunotherapy that can be used for selection and monitoring of patients undergoing immunotherapy and for testing novel immunotherapeutic agents or strategies. Furthermore, we will focus on the selection of animal models based on the main purpose of the study and implications for clinical transfer of the results.
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http://dx.doi.org/10.23736/S1824-4785.20.03254-9DOI Listing
June 2020

Visual and volumetric parameters by 18F-FDG-PET/CT: a head to head comparison for the prediction of outcome in patients with multiple myeloma.

Ann Hematol 2020 Jan 27;99(1):127-135. Epub 2019 Nov 27.

Department of Medicine, Surgery and Dentistry, University of Salerno, Salerno, Italy.

In multiple myeloma (MM) patients, 18F-FDG-PET/CT allows either the detection of disease spread by using visual parameters based on the Italian Myeloma criteria for PET Use (IMPeTUs) or the direct measurement of metabolic tumor burden by volume-based parameters such as metabolic tumor volume (MTV). The purpose is to evaluate the contribution of visual and volumetric parameters in the prediction of progression-free survival (PFS) and overall survival (OS) in MM patients. Forty-seven patients in stage IIIA who had undergone whole-body 18F-FDG-PET/CT were retrospectively evaluated. In each patient, visual parameters were determined and compared with volumetric parameters for PFS and OS prediction after a mean follow-up period of 53 months. Among the visual and volumetric parameters tested, a statistically significant difference was found between maximum standardized uptake value, MTV, total lesion glycolysis, and number of lytic lesions of patients with (n = 26) or without (n = 21) progression (p = 0.0400, p = 0.0065, p = 0.015, and p = 0.0220, respectively) and of dead (n = 24) vs survivors (n = 23) (p = 0.0171, p = 0.0037, p = 0.0060, and p = 0.0270, respectively). At univariate and multivariate analysis, MTV and hemoglobin were predictive of both PFS (p = 0.008) and OS (p = 0.0026). The best MTV discriminative value assessed by receiver operating characteristic curve analysis for predicting both PFS and OS was 39.4 ml. By Kaplan-Meier analysis and log-rank test, PFS and OS were significantly better in patients with MTV ≤ 39.4 ml (p = 0.0004 and p = 0.0001, respectively) as compared with those having an MTV higher than the cutoff. The volume-based parameter MTV determined by 18F-FDG-PET/CT may be used in the prediction of PFS and OS in myeloma patients.
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http://dx.doi.org/10.1007/s00277-019-03852-2DOI Listing
January 2020

Total metabolic tumor volume by 18F-FDG PET/CT for the prediction of outcome in patients with non-small cell lung cancer.

Ann Nucl Med 2019 Dec 14;33(12):937-944. Epub 2019 Oct 14.

Department of Advanced Biomedical Sciences, University "Federico II", Via Pansini 5, Edificio 10, 80131, Naples, Italy.

Objective: Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are imaging parameters derived from 18F-FDG PET/CT that have been proposed for risk stratification of cancer patients. The aim of our study was to test whether these whole-body volumetric imaging parameters may predict outcome in patients with non-small cell lung cancer (NSCLC).

Methods: Sixty-five patients (45 men, 20 women; mean age ± SD, 65 ± 12 years), with histologically proven NSCLC who had undergone 18F-FDG PET/CT scan before any therapy, were included in the study. Imaging parameters including SUV, SUV, total MTV (MTV) and whole-body TLG (TLG) were determined. Univariate and multivariate analyses of clinical and imaging variables were performed using Cox proportional hazards regression. Survival analysis was performed using Kaplan-Meier method and log-rank tests.

Results: A total of 298 lesions were analyzed including 65 primary tumors, 114 metastatic lymph nodes and 119 distant metastases. MTV and TLG could be determined in 276 lesions. Mean value of MTV was 81.83 ml ± 14.63 ml (SE) whereas mean value of TLG was 459.88 g ± 77.02 g (SE). Univariate analysis showed that, among the variables tested, primary tumor diameter (p = 0.0470), MTV of primary tumor (p = 0.0299), stage (p < 0.0001), treatment (p < 0.0001), MTV (p = 0.0003) and TLG (p = 0.0002) predicted progression-free survival in NSCLC patients, while age (p = 0.0550), MTV of primary tumor (p = 0.0375), stage (p < 0.0001), treatment (p < 0.0001), MTV (p = 0.0001) and TLG (p = 0.0008) predicted overall survival. At multivariate analysis age, TLG and stage were retained in the model for prediction of progression-free survival (p < 0.0001), while age, MTV and stage were retained in the model for prediction of overall survival (p < 0.0001). Survival analysis showed that patients with TLG ≤ 54.7 g had a significantly prolonged progression-free survival as compared to patients with TLG > 54.7 g (p < 0.0001). Moreover, overall survival was significantly better in patients showing a MTV ≤ 9.5 ml as compared to those having MTV > 9.5 ml (p < 0.0001). Similar results were obtained in a subgroup of 43 patients with advanced disease (stages III and IV).

Conclusions: Whole-body PET-based volumetric imaging parameters are able to predict outcome in NSCLC patients.
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http://dx.doi.org/10.1007/s12149-019-01407-zDOI Listing
December 2019

Preclinical Imaging in Targeted Cancer Therapies.

Semin Nucl Med 2019 09 19;49(5):369-381. Epub 2019 Jun 19.

Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples, Italy. Electronic address:

Preclinical imaging with radiolabeled probes can provide noninvasive tools to test the efficacy of targeted agents in tumors harboring specific genetic alterations and to identify imaging parameters that can be used as pharmacodynamics markers in cancer patients. The present review will primarily focus on preclinical imaging studies that can accelerate the clinical approval of targeted agents and promote the development of imaging biomarkers for clinical applications. Since only subgroups of patients may benefit from treatment with targeted anticancer agents, the identification of a patient population expressing the target is of primary importance for the success of clinical trials. Preclinical imaging studies tested the ability of new radiolabeled compounds to recognize mutant, amplified, or overexpressed targets and some of these tracers were transferred to the clinical setting. More common tracers such as F-Fluorothymidine and F-Fluorodeoxyglucose were employed in animal models to test the inhibition of the target and downstream pathways through the evaluation of early changes of proliferation and glucose metabolism allowing the identification of sensitive and resistant tumors. Furthermore, since the majority of patients treated with targeted anticancer agents will invariably develop resistance, preclinical imaging studies were performed to test the efficacy of reversal agents to overcome resistance. These studies provided consistent evidence that imaging with radiolabeled probes can monitor the reversal of drug resistance by newly designed alternative compounds. Finally, despite many difficulties and challenges, preclinical imaging studies targeting the expression of immune checkpoints proved the principle that it is feasible to select patients for immunotherapy based on imaging findings. In conclusion, preclinical imaging can be considered as an integral part of the complex translational process that moves a newly developed targeted agent from laboratory to clinical application intervening in all clinically relevant steps including patient selection, early monitoring of drug effects and reversal of drug resistance.
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http://dx.doi.org/10.1053/j.semnuclmed.2019.06.003DOI Listing
September 2019

PET/CT in radiation oncology.

Semin Oncol 2019 06 26;46(3):202-209. Epub 2019 Jul 26.

Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples, Italy. Electronic address:

The progressive integration of positron emission tomography/computed tomography (PET/CT) imaging in radiation therapy has its rationale in the biological intertumoral and intratumoral heterogeneity of malignant lesions that require the individual adjustment of radiation dose to obtain an effective local tumor control in cancer patients. PET/CT provides information on the biological features of tumor lesions such as metabolism, hypoxia, and proliferation that can identify radioresistant regions and be exploited to optimize treatment plans. Here, we provide an overview of the basic principles of PET-based target volume selection and definition using F-fluorodeoxyglucose (F-FDG) and then we focus on the emerging strategies of dose painting and adaptive radiotherapy using different tracers. Previous studies provided consistent evidence that integration of F-FDG PET/CT in radiotherapy planning improves delineation of target volumes and reduces the uncertainties and variabilities of anatomical delineation of tumor sites. PET-based dose painting and adaptive radiotherapy are feasible strategies although their clinical implementation is highly demanding and requires strong technical, computational, and logistic efforts. Further prospective clinical trials evaluating local tumor control, survival, and toxicity of these emerging strategies will promote the full integration of PET/CT in radiation oncology.
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http://dx.doi.org/10.1053/j.seminoncol.2019.07.001DOI Listing
June 2019

Coordinate Modulation of Glycolytic Enzymes and OXPHOS by Imatinib in BCR-ABL Driven Chronic Myelogenous Leukemia Cells.

Int J Mol Sci 2019 Jun 27;20(13). Epub 2019 Jun 27.

Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy.

Since many oncogenes, including , may promote the acquisition and maintenance of the glycolytic phenotype, we tested whether treatment of BCR-ABL-driven human leukemia cells with imatinib, a selective BCR-ABL inhibitor, can modulate the expression of key glycolytic enzymes and mitochondrial complex subunits thus causing alterations of glucose metabolism. BCR-ABL-driven K562 and KCL-22 cells were incubated with increasing concentrations of imatinib to preliminarily test drug sensitivity. Then untreated and treated cells were analyzed for levels of BCR-ABL signaling mediators and key proteins of glycolytic cascade and oxidative phosphorylation. Effective inhibition of BCR-ABL caused a concomitant reduction of p-ERK1/2, p-AKT, phosphorylated form of STAT3 (at Tyr705 and Ser727), c-Myc and cyclin D1 along with an increase of cleaved PARP and caspase 3 at 48 h after treatment. Furthermore, a strong reduction of the hexokinase II (HKII), phosphorylated form of PKM2 (at Tyr105 and Ser37) and lactate dehydrogenase A (LDH-A) was observed in response to imatinib along with a strong upregulation of mitochondrial complexes (OXPHOS). According to these findings, a significant reduction of glucose consumption and lactate secretion along with an increase of intracellular ATP levels was observed in response to imatinib. Our findings indicate that imatinib treatment of BCR-ABL-driven human leukemia cells reactivates mitochondrial oxidative phosphorylation thus allowing potential co-targeting of BCR-ABL and OXPHOS.
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http://dx.doi.org/10.3390/ijms20133134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651622PMC
June 2019

Neutrophil Extracellular Traps as an Adhesion Substrate for Different Tumor Cells Expressing RGD-Binding Integrins.

Int J Mol Sci 2018 Aug 9;19(8). Epub 2018 Aug 9.

Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche, 80145 Naples, Italy.

Neutrophil extracellular traps (NETs), in addition to their function as a host defense mechanism, play a relevant role in thrombus formation and metastatic dissemination of cancer cells. Here we screened different cancer cell lines endogenously expressing a variety of integrins for their ability to bind to NETs. To this end, we used NETs isolated from neutrophil-like cells as a substrate for adhesion assays of HT1080, U-87 MG, H1975, DU 145, PC-3 and A-431 cells. Levels of α5, αIIb, αv, β1, β3 and β5 chains were determined by western blot analysis in all cell lines and levels of whole integrins on the plasma membrane were assessed by fluorescence-activated cell sorting (FACS) analysis. We found that high levels of α5β1, αvβ3 and αvβ5 enhance cell adhesion to NETs, whereas low expression of α5β1 prevents cell attachment to NETs. Excess of cyclic RGD peptide inhibited cell adhesion to NETs by competing with fibronectin within NETs. The maximal reduction of such adhesion was similar to that obtained by DNase 1 treatment causing DNA degradation. Our findings indicate that NETs from neutrophil-like cells may be used as a substrate for large screening of the adhesion properties of cancer cells expressing a variety of RGD-binding integrins.
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http://dx.doi.org/10.3390/ijms19082350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121671PMC
August 2018

2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography in primary extranodal lymphomas: treatment response evaluation and prognosis.

Q J Nucl Med Mol Imaging 2020 Jun 24;64(2):219-225. Epub 2018 Apr 24.

Scuola Medica Salernitana Department of Medicine, Surgery, and Dentistry, University of Salerno, Salerno, Italy.

Background: We evaluated the role of [18F]FDG PET/CT in tumor response assessment and prognosis of primary extranodal lymphoma (PEL) patients.

Methods: We examined retrospectively, 56 PEL patients: 31 with aggressive diffuse large B cell lymphoma (DLBCL) and 25 with indolent lymphoma (20 mucosa-associated lymphoid tissue lymphoma and five follicular lymphoma). All patients had undergone [18F]FDG PET/CT at diagnosis (PET-I) and 50 of them also after therapy (PET-II). Moreover, 52 patients were subjected to a mean follow-up period of 76 months.

Results: PET-I was positive in 50 (89%) patients (mean SUVmax 10.3±6.7). In the assessment of tumor response, according to Lugano classification, 45 patients showed complete metabolic response (CMR), four patients had partial metabolic response (PMR) and one had progressive metabolic disease (PMD). Based on 66% ΔSUVmax cut-off, among CMR patients, 41 showed a ΔSUVmax>66% whereas among non-responders, four patients showed a ΔSUVmax<66%. At follow-up, univariate analysis showed that age, performance status, prognostic index, ΔSUVmax and Lugano classification predicted progression-free survival (PFS) (P<0.05), while, performance status, prognostic index, ΔSUVmax and Lugano classification predicted overall survival (OS) (P<0.05). At multivariate analysis only Lugano classification was retained in the model for prediction of both PFS (P<0.05) and OS (P<0.05). By Kaplan-Meier analysis and log-rank testing both PFS and OS were significantly better in patients in CMR as compared to patients in PMR or PMD according to Lugano classification (P<0.01).

Conclusions: [18F]FDG PET/CT represents a useful tool in the detection of disease response and in the evaluation of outcome in PEL patients.
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http://dx.doi.org/10.23736/S1824-4785.18.03043-1DOI Listing
June 2020

Inositol Trisphosphate Receptor Type 3-mediated Enhancement of EGFR and MET Cotargeting Efficacy in Non-Small Cell Lung Cancer Detected by F-fluorothymidine.

Clin Cancer Res 2018 07 4;24(13):3126-3136. Epub 2018 Apr 4.

Institute of Biostructures and Bioimaging, National Research Council, Naples, Italy.

Our aim was to test whether imaging with F-fluorothymidine (F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small cell lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination. NSCLC cells bearing amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and posttreatment changes of F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA. Imaging studies showed a significant reduction of F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, -ratio = 6.215, = 0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib, whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras. Our findings indicate that F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3657DOI Listing
July 2018

The antiproliferative effect of pasireotide LAR alone and in combination with everolimus in patients with medullary thyroid cancer: a single-center, open-label, phase II, proof-of-concept study.

Endocrine 2018 10 23;62(1):46-56. Epub 2018 Mar 23.

Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.

Purpose: Medullary thyroid cancer (MTC) is a neuroendocrine tumour of the thyroid C cells. Pasireotide, a multi-receptor targeted somatostatin analogue, and everolimus, an inhibitor of mTOR, showed antitumour properties in neuroendocrine tumours. Aim of this study was to evaluate pasireotide alone and in combination with everolimus in patients with MTC.

Methods: Patients with progressive metastatic or persistent postoperative MTC received pasireotide LAR 60 mg/m for at least 6 months. Patients exhibiting progressive disease received everolimus 10 mg/d as combination therapy. Primary endpoint was progression free survival (PFS). Secondary endpoints included, overall survival, objective response rates, change in circulating markers, safety. Study registration no. NCT01625520.

Results: Nineteen consecutive patients were enrolled. Median follow-up was 31 months. Median PFS with pasireotide was 36 months (95% CI: 19.5-52.5). Nine patients (47%) had tumour progression: seven of them started everolimus in combination with pasireotide, achieving a median PFS of 9.0 months (95% CI: 0-21.83). Five of them (71%) had further tumour progression, one objective response (14.3%), one stopped treatment because of pulmonary embolism. Pasireotide alone and with everolimus was safe and required withdrawal only in one case. Diarrhoea and hyperglycaemia were the most frequent adverse events with pasireotide (grade 3 in 5.3% each). Hyperglycaemia was the most frequent grade 3 toxicity with the combination therapy (28.6%).

Conclusions: Pasireotide therapy shows antiproliferative effects in persistent postoperative MTC suggesting further investigation on larger series of patients. In progressive MTC lesions, the combination pasireotide plus everolimus may be of benefit. Both schemes were safe and well tolerated.
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http://dx.doi.org/10.1007/s12020-018-1583-7DOI Listing
October 2018

Metastasis to the Sellar/Suprasellar Region in a Patient With Endometrial Carcinoma Detected by 18F-FDG PET/CT.

Clin Nucl Med 2018 May;43(5):363-364

Metastases to pituitary gland, suprasellar region or skull base from endometrial carcinoma are an extremely rare occurrence. We report the case of a 77-year-old woman with metastasis to the sellar/suprasellar region from endometrial carcinoma revealed by F-FDG PET/CT and confirmed by subsequent CT and MRI of the brain. This case highlights the usefulness of a whole-body imaging methodology such as F-FDG PET/CT in the detection of distant and/or atypical sites of metastasis therefore being of help in guiding towards the correct diagnosis.
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http://dx.doi.org/10.1097/RLU.0000000000002037DOI Listing
May 2018

Prognostic role of FDG PET/CT in patients with differentiated thyroid cancer treated with 131-iodine empiric therapy.

Medicine (Baltimore) 2017 Oct;96(42):e8344

Istituto di Biostrutture e Bioimmagini, CNR Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli FedericoII IRCCS - SDN, Napoli Medicina Nucleare, IRCCS - CROB, Rionero in Vulture Dipartimento di Medicina, Chirurgia e Odontoiatria "Scuola Medica Salernitana," Università degli Studi di Salerno, Salerno, Italy.

Background: To assess the long-term prognostic value of F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with differentiated thyroid carcinoma (DTC) undergoing empiric radioiodine (RAI) therapy due to raising values of thyroglobulin (Tg).

Methods: Forty-nine patients with histological diagnosis of DTC (31 with papillary and 18 with follicular carcinoma) follow-up for a mean period of 7.9 ± 5 years after empiric RAI therapy were retrospectively analyzed.

Results: FDG-PET/CT was negative in 15 (30.6%) patients and positive in 34 (69.4%), whereas postradioiodine therapy whole body scan (t-WBS) was negative in 16 (32.7%) and positive in 33 (67.3%) patients. FDG-PET/CT and t-WBS were in agreement in 32 patients (7 both negative and 25 both positive); on the contrary, in 17 patients there was disagreement between FDG-PET/CT and t-WBS (P =ns). At short-term follow-up, Tg normalized in 19 (38.8%) patients and was unchanged or increased in 30 (61.2%). Of the 15 patients with negative FDG-PET/CT, 11 (73.3%) showed Tg normalization, whereas of the 34 patients with positive FDG-PET/CT, only 8 (23.5%) had Tg normalization (χ =8.9, P < .005). At multivariate analysis, FDG-PET/CT and Tg normalization at short-term follow-up were independent predictors of disease-free survival (χ =26.3, P < .0001), while Tg normalization was the only variable associated with overall survival χ =7.2, P < .01).

Conclusion: FDG-PET/CT in association with Tg normalization at short-term follow-up may be useful for long-term prognostic stratification in DTC patients.
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http://dx.doi.org/10.1097/MD.0000000000008344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5662418PMC
October 2017

Evaluation of metabolic response with F-FDG PET-CT in patients with advanced or recurrent thymic epithelial tumors.

Cancer Imaging 2017 Mar 7;17(1):10. Epub 2017 Mar 7.

Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, Edificio 10, 80131, Naples, Italy.

Background: Patients with advanced or recurrent thymic epithelial tumors (TETs) often need several consecutive lines of chemotherapy. The aim of this retrospective monocentric study was to test whether F-Fluorodeoxyglucose positron emission tomography-computed tomography (F-FDG PET-CT) is able to monitor standard chemotherapy efficacy in those patients and whether metabolic response correlates with morphovolumetric response as assessed by Response Evaluation Criteria in Solid Tumor (RECIST).

Methods: We evaluated 27 consecutive patients with advanced (16 patients) or recurrent (11 patients) TETs. All patients underwent F-FDG PET-CT before and after at least 3 cycles of chemotherapy. Maximum standardized uptake value (SUV) of all detected lesions was recorded and the most F-FDG avid lesion in each patient was selected for determination of percentage change of SUV (ΔSUV) in pre- and post-treatment scans. Tumor response was assessed by contrast-enhanced computed tomography (CE-CT) using RECIST criteria. Receiver operating characteristic (ROC) curve analysis was performed to define the optimal threshold of ΔSUV discriminating responders from non-responders.

Results: Metabolic response expressed as ΔSUV was significantly correlated with morphovolumetric response (Spearman's rank correlation, r = 0.64, p = 0.001). ROC curve analysis showed that a ΔSUV value of -25% could discriminate responders from non-responders with a sensitivity of 88% and a specificity of 80%. Conversely, basal SUV values were not predictive of morphovolumetric tumor response.

Conclusions: Our findings indicate that metabolic response assessed by F-FDG PET-CT, through evaluation of ΔSUV, may allow identification of responders and non-responders thus guiding adaptation of therapy in patients with advanced or recurrent TETs.
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http://dx.doi.org/10.1186/s40644-017-0112-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5339950PMC
March 2017

Early F-FDG uptake as a reliable imaging biomarker of T790M-mediated resistance but not MET amplification in non-small cell lung cancer treated with EGFR tyrosine kinase inhibitors.

EJNMMI Res 2016 Dec 10;6(1):74. Epub 2016 Oct 10.

Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, 80131, Naples, Italy.

Background: The two main mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) are the occurrence of T790M secondary mutation in the kinase domain of EGFR and MET amplification. The aim of the present study was to test whether early changes of F-fluorodeoxyglucose (F-FDG) uptake in animal models bearing erlotinib-resistant NSCLC may have different imaging patterns of response to erlotinib depending on the molecular mechanisms underlying resistance. Animal tumor models were developed using NSCLC H1975 cells bearing the T790M mutation and H1993 cells with MET amplification. Nude mice bearing erlotinib-resistant H1975 and H1993 xenografts (four animals for each cell line and for each treatment) were subjected to F-FDG PET/CT scan before and immediately after treatment (50 mg/kg p.o. for 3 days) with erlotinib, WZ4002, crizotinib, or vehicle. A three-dimensional region of interest analysis was performed to determine the percent change of F-FDG uptake in response to treatment. At the end of the imaging studies, tumors were removed and analyzed for glycolytic and mitochondrial proteins as well as levels of cyclin D1.

Results: Imaging studies with F-FDG PET/CT in H1975 tumor-bearing mice showed a reduction of F-FDG uptake of 25.87 % ± 8.93 % after treatment with WZ4002 whereas an increase of F-FDG uptake up to 23.51 % ± 9.72 % was observed after treatment with erlotinib or vehicle. Conversely, H1993 tumors showed a reduction of F-FDG uptake after treatment with both crizotinib (14.70 % ± 1.30 %) and erlotinib (18.40 % ± 9.19 %) and an increase of tracer uptake in vehicle-treated (56.65 % ± 5.65 %) animals. The in vivo reduction of F-FDG uptake was always associated with downregulation of HKII and p-PKM2 Tyr105 glycolytic proteins and upregulation of mitochondrial complexes (subunits I-IV) in excised tumors.

Conclusions: F-FDG uptake is a reliable imaging biomarker of T790M-mediated resistance and its reversal in NSCLC whereas it may not be accurate in the detection of MET-mediated resistance.
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http://dx.doi.org/10.1186/s13550-016-0229-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056924PMC
December 2016

Multimodal imaging with (18)F-FDG-PET/CT and (111)In-Octreotide SPECT in patients with metastatic medullary thyroid carcinoma.

Ann Nucl Med 2016 Apr 11;30(3):234-41. Epub 2016 Jan 11.

Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Pansini 5, Edificio 10, 80131, Naples, Italy.

Objective: The aim of our study was to determine the role of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) and indium-111 Octreotide single photon emission tomography ((111)In-Octreotide SPECT) in the evaluation of metastatic medullary thyroid carcinoma (MMTC).

Methods: Twenty-five MMTC patients were retrospectively evaluated. All patients had undergone whole-body (18)F-FDG-PET/CT including 20 who had also undergone (111)In-Octreotide SPECT within a maximum interval of 6 weeks. Diagnostic contrast-enhanced computed tomography (CT) alone or as part of (18)F-FDG-PET/CT examination was performed in all patients.

Results: Contrast-enhanced CT detected a total of 131 lesions including 79 enlarged lymph nodes and 14 bone lesions. (18)F-FDG-PET/CT visualized a total of 92 true positive lesions (SUVmax range 1.1-10.0, mean 4.0 ± 1.7) including 66 lymph nodes, 7 of which were not enlarged on CT, and 8 bone metastases. In the 20 patients studied with both techniques, a total of 64 and 46 true positive lesions were detected by (18)F-FDG-PET/CT and (111)In-Octreotide SPECT, respectively. In particular, (18)F-FDG uptake was found in 43 lymph nodes and in 7 bone metastases whereas (111)In-Octreotide uptake was detected in 27 lymph nodes and in 10 bone metastases.

Conclusions: In MMTC patients, (18)F-FDG-PET/CT provides a useful contribution mainly in evaluating lymph node involvement whereas (111)In-Octreotide SPECT can contribute to the detection and somatostatin receptor characterization especially of bone lesions.
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http://dx.doi.org/10.1007/s12149-015-1056-5DOI Listing
April 2016

Detection of Leptomeningeal Involvement by 18F-FDG-PET/CT in a Patient With Non-Hodgkin Lymphoma.

Clin Nucl Med 2016 Feb;41(2):169-72

From the *Institute of Biostructures and Bioimages, National Research Council; †Department of Hematology, University "Federico II"; ‡IRCCS-SDN; and §Department of Advanced Biomedical Sciences, University "Federico II," Naples, Italy.

Leptomeningeal infiltration of the brain or spinal cord by neoplastic cells may occur as complication of solid or hematopoietic tumors such as non-Hodgkin lymphoma. Previously rare, this event is becoming increasingly common as newer therapies can prolong survival but may not achieve therapeutic concentration in the central nervous system. Although prognosis is poor, early diagnosis and aggressive treatment may lead to prolonged survival and/or improvement of quality of life. We report a case of a 69-year-old man with leptomeningeal infiltration by non-Hodgkin lymphoma revealed by F-FDG-PET/CT and confirmed by subsequent spinal MRI and cerebrospinal fluid cytology.
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http://dx.doi.org/10.1097/RLU.0000000000001060DOI Listing
February 2016

Role of (68)Ga-DOTATATE PET/CT in patients with multiple endocrine neoplasia type 1 (MEN1).

Endocrine 2016 Jun 5;52(3):488-94. Epub 2015 Aug 5.

Division of Endocrinology, Department of Clinical Medicine and Surgery, "Federico II" University of Napoli, Via Sergio Pansini 5, 80131, Naples, Italy.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome predisposing to many endocrine and neuroendocrine tumors (NET). Conventional imaging (CI) cannot provide satisfactory results for all the different types of MEN1-related tumors. Objective of this prospective observational study was to evaluate the role of (68)Ga-DOTATATE PET/CT in MEN1 compared to CI. Diagnostic performance of (68)Ga-DOTATATE PET/CT for the detection of NET was evaluated as well as the prognostic role of SUVmax. Eighteen patients with genetically confirmed MEN1 were evaluated by (68)Ga-DOTATATE PET/CT, endoscopic ultrasounds, multidetector-row computed tomography, magnetic resonance imaging, and hormone/markers serum measurements. Four MEN1-related tumor sites (pancreas, pituitary, parathyroids, adrenals) were considered. Sensitivity and specificity of (68)Ga-DOTATATE PET/CT for the detection of NET were calculated. There was (68)Ga-DOTATATE PET/CT uptake in 11/11 patients with pancreatic lesions, in 9/12 with pituitary adenoma, in 5/15 with parathyroid enlargements, and in 5/7 with adrenal lesions. (68)Ga-DOTATATE PET/CT showed sensitivity and specificity of 100 and 100 % in pancreas, 75 and 83 % in pituitary, 28 and 100 % in parathyroids, and 62.5 and 100 % in adrenals, respectively. Compared with CI, no significant difference in sensitivity for pancreas, pituitary, and adrenals was found, while CI had a better sensitivity for parathyroids (p = 0.002). On the ROC analysis, progression of pancreatic lesions was significantly associated to SUVmax <12.3 (p < 0.05). (68)Ga-DOTATATE PET/CT is greatly helpful in the work-up of MEN1 providing a panoramic view of MEN1-related lesions. There is also a prognostic role of (68)Ga-PET in patients with MEN1-pancreatic lesions.
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http://dx.doi.org/10.1007/s12020-015-0702-yDOI Listing
June 2016

Reversal of Warburg Effect and Reactivation of Oxidative Phosphorylation by Differential Inhibition of EGFR Signaling Pathways in Non-Small Cell Lung Cancer.

Clin Cancer Res 2015 Nov 27;21(22):5110-20. Epub 2015 Jul 27.

Institute of Biostructures and Bioimages, National Research Council, Naples, Italy. Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.

Purpose: One of the hallmarks of cancer cells is the excessive conversion of glucose to lactate under normoxic conditions, also known as the Warburg effect. Here, we tested whether the targeted inhibition of EGFR may revert this effect and reactivate mitochondrial oxidative phosphorylation in non-small cell lung cancer (NSCLC).

Experimental Design: Sensitive (HCC827) and resistant (H1975 and H1993) NSCLC cells were treated with a panel of EGFR or MET inhibitors, and then tested for changes of EGFR signaling, glycolytic cascade, and mitochondrial function. Silencing of key glycolytic enzymes was then performed with targeted siRNAs. Furthermore, tumor-bearing nude mice treated with EGFR inhibitors were evaluated with (18)F-FDG PET/CT and tumors were analyzed for glycolytic and mitochondrial proteins.

Results: Effective inhibition of EGFR signaling in NSCLC cells induced a dramatic reduction of hexokinase II (HKII) and phospho-pyruvate kinase M2 (p-PKM2, Tyr105) levels as well as an upregulation of mitochondrial complexes subunits (OXPHOS). Accordingly, a decreased lactate secretion and increased intracellular ATP levels were also observed in response to EGFR inhibitors. Downregulation of HKII and PKM2 by targeted siRNA transfection did not cause upregulation of OXPHOS but enhanced the effects of EGFR TKIs. Conversely, selective inhibition of AKT and ERK1/2 caused OXPHOS upregulation and glycolysis inhibition, respectively. Similar findings were obtained in tumors from animals treated with appropriate EGFR inhibitors.

Conclusions: Our findings indicate that EGFR inhibitors may reactivate oxidative phosphorylation of cancer cells and provide a mechanistic clue for the rational combination of agents targeting EGFR-dependent proliferation and glucose metabolism in cancer therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0375DOI Listing
November 2015

18F-FDG PET/CT, 99mTc-MIBI, and MRI in the prediction of outcome of patients with multiple myeloma: a comparative study.

Clin Nucl Med 2015 Apr;40(4):303-8

From the *Institute of Biostructures and Bioimages, National Research Council, Naples; †Department of Medicine and Surgery, University of Salerno, Salerno; Departments of ‡Hematology, and §Advanced Biomedical Sciences, University of Federico II, Naples, Italy.

Purpose: The aim of this study was to compare the relative contribution of 18F-FDG PET/CT, 99mTc-MIBI, and MRI in predicting progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM) patients.

Patients And Methods: Thirty-three newly diagnosed MM patients had been evaluated in a previous study by 18F-FDG PET/CT, 99mTc-MIBI, and spine and pelvis MRI reporting focal lesions and diffuse bone marrow involvement. Twenty-seven patients were then subjected to a mean follow-up period of 58 months, whereas 6 patients were lost.

Results: 18F-FDG PET/CT, 99mTc-MIBI, and MRI were positive in 26, 24, and 22 patients, respectively, showing diffuse bone marrow involvement in 12, 21, and 17 patients and a total of 185, 56, and 39 focal lesions, respectively. At follow-up, 18 patients showed complete or partial remission, whereas 9 patients developed progressive disease, 7 of which died of myeloma. Univariate and subsequent multivariate analysis showed that F-FDG PET/CT focal uptake and Tc-MIBI focal and diffuse uptake predicted PFS (P = 0.0006), whereas 18F-FDG PET/CT focal uptake and 99mTc-MIBI focal uptake predicted OS (P = 0.0010). Although MRI diffuse pattern predicted PFS at univariate analysis (P = 0.0376), it was not retained in the model at multivariate analysis. Receiver operating characteristic curve analysis showed that the number of focal lesions best discriminating for PFS and OS prediction was 4 and 11 for 18F-FDG PET/CT and 2 in both cases for 99mTc-MIBI, respectively. By Kaplan-Meier analysis and log-rank testing, PFS and OS at follow-up were significantly better in patients showing a number of focal lesions at F-FDG PET/CT or Tc-MIBI lower than the respective cutoff (P = 0.03, P = 0.004, and P < 0.0001, respectively). Finally, PFS was significantly better in patients showing absent/faint diffuse Tc-MIBI uptake than in those having moderate/intense diffuse uptake (P = 0.0012).

Conclusions: 18F-FDG PET/CT and 99mTc-MIBI may be useful in predicting PFS and OS in myeloma patients.
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http://dx.doi.org/10.1097/RLU.0000000000000696DOI Listing
April 2015

Prognostic role of 18F-FDG PET/CT in the postoperative evaluation of differentiated thyroid cancer patients.

Clin Nucl Med 2015 Feb;40(2):111-5

From the *Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Salerno; †Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II; ‡Istituto di Biostrutture e Bioimmagini, CNR; §IRCSS SDN, Napoli; and ║IRCSS CROB, Rionero in Vulture, Italia.

Purpose: The aim of this study was to evaluate the role of F-FDG PET/CT performed after surgery but before radioiodine therapy in patients with differentiated thyroid cancer.

Procedures: FDG PET/CT was performed off l-thyroxine in 60 newly diagnosed differentiated thyroid cancer patients. Clinical and hematological evaluation as well as high-resolution neck ultrasound were performed. All patients underwent a complete follow-up (range, 6-67 months; mean [SD], 31.7 [20.6] months). The date of recurrence or the most recent office visit was recorded. Progression-free survival (PFS) is the primary end point of this study. Analysis was performed by Cox proportional hazards model. Survival curves were generated using Kaplan-Meier estimates, and the log-rank test was used to assess significance.

Results: FDG PET/CT was negative in 63% of patients, 20% had FDG thyroid bed uptake, 5% distant metastases, and 12% lymph node FDG uptake. In patients with positive FDG PET/CT scan (ie, those with distant metastases or lymph node uptake), a higher rate of recurrence was observed (50% vs 6%, P < 0.05). Thyroglobulin, neck ultrasound, stage, and FDG PET/CT correlated with PFS at univariate analysis. At multivariate analysis, only thyroglobulin and FDG PET/CT continued to be predictors of PFS. Patients with a negative FDG PET/CT scan have a better PFS either in the whole group or in those with elevated thyroglobulin level (both >2 ng/mL and >10 ng/mL).

Conclusions: FDG PET/CT was abnormal in 17% of patients. Moreover, FDG PET/CT has an independent prognostic role, with a better PFS in patients with a negative scan.
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http://dx.doi.org/10.1097/RLU.0000000000000621DOI Listing
February 2015

Contrast enhanced multi-detector CT and MR findings of a well-differentiated pancreatic vipoma.

World J Radiol 2014 Oct;6(10):840-5

Luigi Camera, Rosa Severino, Simone Maurea, Marco Salvatore, Department of Advanced Biomedical Sciences, Diagnostic Imaging Section, University "Federico II", 80131 Naples, Italy.

Pancreatic vipoma is an extremely rare tumor accounting for less than 2% of endocrine pancreatic neoplasms with a reported incidence of 0.1-0.6 per million. While cross-sectional imaging findings are usually not specific, exact localization of the tumor by means of either computed tomography (CT) or magnetic resonance (MR) is pivotal for surgical planning. However, cross-sectional imaging findings are usually not specific and further characterization of the tumor may only be achieved by somatostatin-receptor scintigraphy (SRS). We report the case of a 70 years old female with a two years history of watery diarrhoea who was found to have a solid, inhomogeneously enhancing lesion at the level of the pancreatic tail at Gadolinium-enhanced MR (Somatom Trio 3T, Siemens, Germany). The tumor had been prospectively overlooked at a contrast-enhanced multi-detector CT (Aquilion 64, Toshiba, Japan) performed after i.v. bolus injection of only 100 cc of iodinated non ionic contrast media because of a chronic renal failure (3.4 mg/mL) but it was subsequently confirmed by SRS. The patient first underwent a successful symptomatic treatment with somatostatin analogues and was then submitted to a distal pancreasectomy with splenectomy to remove a capsulated whitish tumor which turned out to be a well-differentiated vipoma at histological and immuno-histochemical analysis.
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http://dx.doi.org/10.4329/wjr.v6.i10.840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209429PMC
October 2014

Monitoring reversal of MET-mediated resistance to EGFR tyrosine kinase inhibitors in non-small cell lung cancer using 3'-deoxy-3'-[18F]-fluorothymidine positron emission tomography.

Clin Cancer Res 2014 Sep 22;20(18):4806-15. Epub 2014 Jul 22.

Institute of Biostructures and Bioimages, National Research Council, Naples, Italy. CEINGE-Advanced Biotechnologies, Naples Italy. Department of Advanced Biomedical Sciences, University "Federico II," Naples, Italy.

Purpose: MET amplification is one of the mechanisms underlying acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Here, we tested whether 3'-deoxy-3'-[(18)F]-fluorothymidine ([(18)F]FLT) positron emission tomography/computerized tomography (PET/CT) can detect MET-mediated resistance to EGFR TKIs and monitor the effects of MET inhibitors in NSCLC.

Experimental Design: H1993 and H820 NSCLC cells with high and low levels of MET amplification, respectively, and HCC827-expressing MET, but without gene amplification, were tested for the effects of MET inhibitors on the EGFR pathway and proliferation both in vitro and in vivo. Nude mice bearing NSCLCs with and without MET amplification were subjected to [(18)F]FLT PET/CT before and after treatment with crizotinib or erlotinib (50 mg/kg and 100 mg/kg p.o. for 3 days).

Results: H1993 cells showed high responsiveness to MET inhibitors and were resistant to erlotinib. Conversely, HCC827 cells showed high sensitivity to erlotinib and were resistant to MET inhibitors. Accordingly, H1993 tumors bearing MET amplification showed a mean reduction in [(18)F]FLT uptake of 28% and 41% after low- and high-dose treatment with crizotinib for 3 days, whereas no posttherapy changes of [(18)F]FLT uptake were observed in HCC827 tumors lacking MET amplification. Furthermore, a persistently high [(18)F]FLT uptake was observed in H1993 tumors after treatment with erlotinib, whereas HCC827 tumors showed up to 39% reduction of [(18)F]FLT uptake following erlotinib treatment. Imaging findings were confirmed by Ki67 immunostaining of tumor sections.

Conclusions: [(18)F]FLT PET/CT can detect MET-mediated resistance to EGFR TKIs and its reversal by MET inhibitors in NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-0264DOI Listing
September 2014

Combined imaging with 18F-FDG-PET/CT and 111In-labeled octreotide SPECT for evaluation of thymic epithelial tumors.

Clin Nucl Med 2013 May;38(5):354-8

Department of Biomorphological and Functional Sciences, University of Naples Federico II, Naples, Italy.

Purpose: This study aimed to test the role of combined imaging with 18F-FDG-PET/CT and 111In-octreotide SPECT in characterizing thymic epithelial tumors (TETs).

Methods: We evaluated 20 patients with newly diagnosed TETs who had undergone concomitant 18F-FDG-PET/CT and 111In-octreotide SPECT. Thymic epithelial tumors were classified by World Health Organization (WHO) as low-risk thymomas (5), high-risk thymomas (4), and thymic carcinomas (11, among which 6 neuroendocrine tumors). Patients were staged according to Masaoka system. 18F-FDG-PET/CT was performed and SUV(max) of primary tumors was recorded. 111In-octreotide SPECT of the thorax was performed, and tumor-to-background ratio was determined on the 24-hour coronal sections.

Results: All patients showed increased 18F-FDG uptake in mediastinal lesions. SUV(max) were significantly correlated with WHO classification (r = 0.66, P < 0.01) and with Masaoka stage (r = 0.60, P < 0.01). SUV(max) of low-risk thymomas (mean [SD], 2.87 [0.83]) were significantly lower than those of high-risk thymomas (mean [SD], 7.21 [1.73], P < 0.01) and of thymic carcinomas (mean [SD], 9.39 [5.80], P < 0.05), whereas no significant difference was found between high-risk thymomas and thymic carcinomas. SUV(max) of all high-risk thymomas and thymic carcinomas was 4.5 or greater. All primary tumors were detected by In-octreotide SPECT, and tumor-to-background ratios ranged between 1.67 and 10.10. No statistically significant correlation was found between tumor-to-background ratios and WHO classification (r = 0.24, P = 0.36) and Masaoka stages (r = 0.31, P = 0.23). However tumor-to-background ratios of thymic neuroendocrine tumors (mean [SD], 5.71 [3.09]) were significantly higher than those of all other TETs with SUV(max) of 4.5 or greater (mean [SD], 2.41 [0.56]; P < 0.05).

Conclusions: 18F-FDG-PET/CT scan allows to differentiate high-risk epithelial tumors and thymic carcinomas from low-risk thymomas, whereas 111In-octreotide SPECT may identify neuroendocrine tumors among those showing high 18F-FDG uptake.
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http://dx.doi.org/10.1097/RLU.0b013e318286bd84DOI Listing
May 2013

Evidence of brown fat activity in constitutional leanness.

J Clin Endocrinol Metab 2013 Mar 7;98(3):1214-8. Epub 2013 Feb 7.

Federico II University of Naples, Department of Clinical Medicine and Surgery, Via Pansini 5, Naples, Italy.

Background: Brown adipose tissue (BAT) was considered essentially nonexistent in adults until recent evidence obtained using 18-fluorodeoxyglucose (18-FDG) positron emission tomography/computed tomography. It seems to play a role in whole body metabolism, but it has not been evaluated in underweight conditions, such as in young females with constitutional leanness (CL) or anorexia nervosa (AN).

Subjects And Methods: Thirty-eight subjects were evaluated from October 2011 to March 2012 : 7 CL (21.7 ± 3.6 y, body mass index [BMI] 16.2 ± 1.0 kg/m(2)), 7 AN (23.4 ± 4.5 y, BMI 15.5 ± 0.8), 3 of the 7 AN after stable refeeding (R-AN, 21.3 ± 1.5 y, BMI 18.8 ± 1.1), and 24 normal weight (NW) women (25.6 ± 3.9 y, BMI 22.2 ± 1.5). Fasting resting metabolic rate and respiratory quotient were measured by indirect calorimetry, body composition by bioimpedentiometry (only in CL, AN, and refed AN), and BAT activity by 18-FDG positron emission tomography/computed tomography scan, all in standardized conditions.

Results: All CL (100%), none of the AN and refed AN (0%), and 3 of the 24 NW (12%) subjects showed FDG uptake. Average FDG maximum standardized uptake value was 11.4 + 6.7 g/mL in CL and 5.5 ± 1.2 g/mL (min 3.7, max 8.3) in the 3 NW subjects. In CL, the maximum standardized uptake value was directly correlated to resting metabolic rate, corrected for fat-free mass, and inversely correlated with respiratory quotient.

Conclusion: BAT activity has been shown in CL in resting thermoneutral conditions and may exert a role against adipose tissue deposition.
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http://dx.doi.org/10.1210/jc.2012-2981DOI Listing
March 2013

Metabolic tumor volume assessed by 18F-FDG PET/CT for the prediction of outcome in patients with multiple myeloma.

J Nucl Med 2012 Dec 15;53(12):1829-35. Epub 2012 Oct 15.

Institute of Biostructures and Bioimages-National Research Council, University Federico II, Naples, Italy.

Unlabelled: (18)F-FDG PET/CT allows the direct measurement of metabolic tumor burden in a variety of different malignancies. The aim of this study was to assess whether metabolic tumor volume (MTV) determined by (18)F-FDG PET/CT could be used in the prediction of progression-free and overall survival in multiple myeloma patients.

Methods: Forty-seven patients (18 women, 29 men; mean age ± SD, 63 ± 11 y) with stage IIIA disease who had undergone whole-body (18)F-FDG PET/CT were retrospectively evaluated. Images underwent a 3-dimensional region-of-interest analysis including all focal lesions with a maximum standardized uptake value > 2.5. The MTV of each lesion was calculated using an automated contouring program based on the standardized uptake value and developed with a threshold of 40% of the maximum standardized uptake value. The total MTV of each patient was defined as the sum of metabolic volume of all focal lesions. Patients were treated and then subjected to a mean follow-up period of 24 mo.

Results: In the 47 patients studied, MTV range was 1.3-316.3 mL, with a median of 23.7 mL. A direct, significant correlation was found between MTV and the percentage of diffuse infiltration of bone marrow by plasma cells (r = 0.46, P = 0.006), whereas hemoglobin levels were inversely correlated with MTV (r = -0.56, P = 0.0001). At follow-up, patients who developed progressive disease (n = 18) showed a significantly higher MTV (74.7 ± 19.3 vs. 29.8 ± 5.1 mL, P = 0.009) than patients without progressive disease (n = 29). Furthermore, patients who died of myeloma (n = 9) had a significantly higher MTV (123.2 ± 30.6 vs. 28.9 ± 4.2 mL, P = 0.0001) than survivors (n = 38). No differences in age, plasma cell infiltration, M protein, albumin, β2-microglobulin, performance status, International Staging System score, and presence or absence of a bone marrow transplant were found between groups. The MTV cutoff level was determined by receiver-operating-characteristic curve analysis, and the best discriminative value found for predicting progression-free and overall survival was 42.2 and 77.6 mL, respectively. By Kaplan-Meier analysis and log-rank testing, progression-free and overall survival at follow-up were significantly better in patients showing an MTV lower than the cutoff than in those having an MTV higher than the cutoff (χ(2) = 3.9, P = 0.04, and χ(2) = 56.3, P < 0.0001, respectively).

Conclusion: The direct measurement of tumor burden obtained by calculating MTV on (18)F-FDG PET/CT images may be used in the prediction of progression-free and overall survival in myeloma patients.
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http://dx.doi.org/10.2967/jnumed.112.106500DOI Listing
December 2012

Sorafenib in advanced iodine-refractory differentiated thyroid cancer: efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET.

Clin Endocrinol (Oxf) 2013 May;78(5):760-7

Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Via S. Pansini 5, Naples, Italy.

Context: Radioactive iodine is a crucial tool for treatment of differentiated thyroid cancer (DTC). In 5% of cases, DTCs lose I-131 avidity and assume an aggressive behaviour. Treatment options for iodine-refractory DTC are limited. We report the experience of off-label use of the tyrosine kinase inhibitor sorafenib for treatment of advanced iodine-refractory DTC.

Design: Patients with progressive DTC refractory to radioactive iodine were treated with sorafenib used off-label independently from their performance status. Primary study end-points were radiological response, progression-free survival (PFS) and safety. Secondary end-points were site-specific radiological response and overall survival (OS). An exploratory analysis of the role of serum thyroglobulin (Tg) and fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed.

Results: A total of 17 patients were included in the study. Median follow-up was 15·5 months. Clinical benefit was obtained in 71% of subjects (30% partial response and 41% stable disease). Sorafenib was mostly well tolerated, but a high incidence of fatal events was reported (three patients died from severe bleeding events and two from cardiac arrest). Median PFS was 9 months. Median OS was 10 months. The best responses were observed in lymph nodes and lung. Baseline Tg levels and the Tg response to treatment were correlated to both radiological response and PFS. Baseline FDG-PET assessment and early FDG-PET response were correlated to radiological response.

Conclusions: Sorafenib allows morphological disease control in the majority of patients with iodine-refractory DTC. Progression-free survival and overall survival were lower than in previous studies as a consequence of the worse clinical condition of our patients. Sorafenib is mostly well tolerated but could have been responsible for the reported fatal events. Baseline Tg and the Tg response to treatment could be useful for predicting morphological response and clinical outcome. Early FDG-PET response could be helpful for the timely identification of nonresponding patients.
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http://dx.doi.org/10.1111/cen.12057DOI Listing
May 2013

Gefitinib induction of in vivo detectable signals by Bcl-2/Bcl-xL modulation of inositol trisphosphate receptor type 3.

Clin Cancer Res 2008 Aug;14(16):5209-19

Institute of Biostructures and Bioimages, National Research Council.

Purpose: To test whether epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) induce detectable signals in tumor cells and whether such signals may reveal alterations of the apoptotic program.

Experimental Design: Tumor cells were treated with gefitinib or erlotinib and tested for their ability to accumulate 99mTc-Sestamibi, a radiolabeled lipophilic cation that localizes in mitochondria. Then we tested whether Bcl-2 and Bcl-xL alter the pattern of drug-dependent tracer accumulation while reducing tumor cell sensitivity to EGFR TKIs. The mechanism underlying the pattern of tracer accumulation was elucidated. Finally, imaging studies were done in animal models and lung cancer patients before and after treatment with EGFR TKIs using single-photon emission computed tomography and 99mTc-Sestamibi.

Results: Gefitinib increases accumulation of 99mTc-Sestamibi in Bcl-2-overexpressing cells and enhances the physical interaction of phosphorylated Bcl-2 with inositol trisphosphate receptor type 3 (IP3R3). Consequently, a relative increase of cytosolic and mitochondrial calcium levels occurs. Similarly, lung cancer cells showed an increase of tracer uptake and an enhanced interaction of Bcl-xL with IP3R3 on exposure to erlotinib concentrations achievable in plasma. The occurrence of these interactions was associated with an enhanced EGFR TKI-induced apoptosis resistance. Posttreatment imaging studies in nude mice bearing control and Bcl-2-overexpressing breast carcinomas showed a high tumor uptake of the tracer whereas baseline studies failed to visualize tumors. Similarly, an enhancement of tracer uptake could be detected in patients with lung cancer treated with erlotinib.

Conclusion: EGFR TKIs generate detectable signals by Bcl-2/Bcl-xL modulation of IP3R3 in tumor cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-0374DOI Listing
August 2008