Publications by authors named "Silvana Del Vecchio"

55 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

The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis.

Front Immunol 2020 16;11:1749. Epub 2020 Sep 16.

Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy.

Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key role in the neutrophil innate immune response, NETs are also involved in autoimmune diseases, like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and in other non-infectious pathological processes, as coagulation disorders, thrombosis, diabetes, atherosclerosis, vasculitis, and cancer. Recently, a large body of evidence indicates that NETs are involved in cancer progression and metastatic dissemination, both in animal models and cancer patients. Interestingly, a close correlation between cancer cell recruitment of neutrophils in the tumor microenvironment (Tumor Associated Neutrophils. TANs) and NET formation has been also observed either in primary tumors and metastatic sites. Moreover, NETs can also catch circulating cancer cells and promote metastasis. Furthermore, it has been reported that wake dormant cancer cells, causing tumor relapse and metastasis. This review will primarily focus on the pro-tumorigenic activity of NETs in tumors highlighting their ability to serve as a potential target for cancer therapy.
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http://dx.doi.org/10.3389/fimmu.2020.01749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524869PMC
April 2021

Breast Tumor Cell Invasion and Pro-Invasive Activity of Cancer-Associated Fibroblasts Co-Targeted by Novel Urokinase-Derived Decapeptides.

Cancers (Basel) 2020 Aug 24;12(9). Epub 2020 Aug 24.

Institute of Genetics and Biophysics "Adriano Buzzati Traverso", National Research Council, 80131 Naples, Italy.

Among peritumoral cells, cancer-associated fibroblasts (CAFs) are major facilitators of tumor progression. This study describes the effects of two urokinase-derived, novel decapeptides, denoted as Pep 1 and its cyclic derivative Pep 2. In a mouse model of tumor dissemination, using HT1080 fibrosarcoma cells, Pep 2 reduced the number and size of lung metastases. Specific binding of fluoresceinated Pep 2 to HT1080 and telomerase immortalised fibroblasts (TIF) cell surfaces was enhanced by αv overexpression or abolished by excess vitronectin, anti-αv antibodies or silencing of αv gene, identifying αv-integrin as the Pep 2 molecular target. In 3D-organotypic assays, peptide-exposed TIFs and primary CAFs from breast carcinoma patients both exhibited a markedly reduced pro-invasive ability of either HT1080 fibrosarcoma or MDA-MB-231 mammary carcinoma cells, respectively. Furthermore, TIFs, either exposed to Pep 2, or silenced for αv integrin, were impaired in their ability to chemoattract cancer cells and to contract collagen matrices, exhibiting reduced α-smooth muscle actin (α-SMA) levels. Finally, peptide exposure of αv-expressing primary CAFs led to the downregulation of α-SMA protein and to a dramatic reduction of their pro-invasive capability. In conclusion, the ability of the novel decapeptides to interfere with tumor cell invasion directly and through the down-modulation of CAF phenotype suggests their use as lead compounds for co-targeting anti-cancer strategies.
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http://dx.doi.org/10.3390/cancers12092404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564779PMC
August 2020

FDG-PET/CT imaging during the Covid-19 emergency: a southern Italian perspective.

Eur J Nucl Med Mol Imaging 2020 10 23;47(11):2691-2697. Epub 2020 Jun 23.

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

Purpose: To assess the impact of the Covid-19 pandemic on FDG-PET/CT work volume and to evaluate the occurrence of abnormal imaging findings suspicious or potentially diagnostic for interstitial pneumonia by Covid-19 infection in south Italy.

Methods: We retrospectively reviewed the number and the findings of FDG-PET/CT studies acquired between February and April 2020 during the Covid-19 pandemic at the University of Napoli Federico II. The number and the findings of FDG-PET/CT studies acquired in the corresponding period of 2019 were also assessed for direct comparison.

Results: The number of FDG-PET/CT studies performed during the pandemic (n = 299) and in the corresponding period of 2019 (n = 335) were comparable. The percentage of abnormal FDG-PET/CT findings, suspicious for interstitial pneumonia by Covid-19 infection, was significantly higher during the pandemic (9%) compared with that found in the corresponding period of 2019 (4%) (χ 5.45, P = 0.02). No significant differences were observed in the distribution of Covid-19 reporting and data system (CO-RADS) classification and in the maximum standardized uptake value between the pandemic (2.6 ± 2.2) and the corresponding period of 2019 (3.2 ± 1.4). Of note, patients with abnormal imaging findings during the pandemic time had clinical data and/or laboratory tests negative for Covid-19 infection.

Conclusion: Despite the restrictive medical measures for the emergency, the number of FDG-PET/CT studies was unchanged during the pandemic compared with the previous year. Our findings also indicate that Covid-19 infection was contained in our series of patients from southern Italy.
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http://dx.doi.org/10.1007/s00259-020-04931-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308109PMC
October 2020

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

Distribution of Mediastinal Lesions Across Multi-Institutional, International, Radiology Databases.

J Thorac Oncol 2020 04 20;15(4):568-579. Epub 2019 Dec 20.

The Chaim Sheba Medical Center, affiliated with the Tel Aviv University, Tel Aviv, Israel.

Introduction: Mediastinal lesions are uncommon; studies on their distribution are, in general, small and from a single institution. Furthermore, these studies are usually based on pathology or surgical databases and, therefore, miss many lesions that did not undergo biopsy or resection. Our aim was to identify the distribution of lesions in the mediastinum in a large international, multi-institutional cohort.

Methods: At each participating institution, a standardized retrospective radiology database search was performed for interpretations of computed tomography, positron emission tomography-computed tomography, and magnetic resonance imaging scans including any of the following terms: "mediastinal nodule," "mediastinal lesion," "mediastinal mass," or "mediastinal abnormality" (2011-2014). Standardized data were collected. Statistical analysis was performed.

Results: Among 3308 cases, thymomas (27.8%), benign mediastinal cysts (20.0%), and lymphomas (16.1%) were most common. The distribution of lesions varied among mediastinal compartments; thymomas (38.3%), benign cysts (16.8%), and neurogenic tumors (53.9%) were the most common lesions in the prevascular, visceral, and paravertebral mediastinum, respectively (p < 0.001). Mediastinal compartment was associated with age; patients with paravertebral lesions were the youngest (p < 0.0001). Mediastinal lesions differed by continent or country, with benign cysts being the most common mediastinal lesions in the People's Republic of China, thymomas in Europe, and lymphomas in North America and Israel (p < 0.001). Benign cysts, thymic carcinomas, and metastases were more often seen in larger hospitals, whereas lymphomas and thymic hyperplasia occurred more often in smaller hospitals (p < 0.01).

Conclusions: Our study confirmed that the spectrum and frequency of mediastinal lesions depend on mediastinal compartment and age. This information provides helpful demographic data and is important when considering the differential diagnosis of a mediastinal lesion.
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http://dx.doi.org/10.1016/j.jtho.2019.12.108DOI Listing
April 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

Translational molecular imaging in exocrine pancreatic cancer.

Eur J Nucl Med Mol Imaging 2018 12 17;45(13):2442-2455. Epub 2018 Sep 17.

Interventional Molecular Imaging Laboratory, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands.

Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the increased use of molecular imaging in PDAC preclinical research and in patient management.
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http://dx.doi.org/10.1007/s00259-018-4146-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208802PMC
December 2018

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

Performance of FDG-PET/CT in solitary pulmonary nodule based on pre-test likelihood of malignancy: results from the ITALIAN retrospective multicenter trial.

Eur J Nucl Med Mol Imaging 2018 10 7;45(11):1898-1907. Epub 2018 May 7.

Struttura Complessa di Medicina Nucleare, Ospedale San Giuseppe Moscati, Avellino, Italy.

Purpose: The aim of this study was to determine the performance of F-FDG-PET/CT in patients with solitary pulmonary nodule (SPN), stratifying the risk according to the likelihood of pulmonary malignancy.

Methods: FDG-PET/CT of 502 patients, stratified for pre-test cancer risk, were retrospectively analyzed. FDG uptake in SPN was assessed by a 4-point scoring system and semiquantitative analysis using the ratio between SUVmax in SPN and SUVmean in mediastinal blood pool (BP) and between SUVmax in SPN and SUVmean in liver (L). Histopathology and/or follow-up data were used as standard of reference.

Results: SPN was malignant in 180 (36%) patients, benign in 175 (35%), and indeterminate in 147 (29%). The 355 patients with a definitive SPN nature (malignant or benign) were considered for the analysis. Considering FDG uptake ≥ 2, sensitivity, specificity, positive (PPV) and negative (NPV) predictive values, and accuracy were 85.6%, 85.7%, 86%, 85.2%, and 85.6% respectively. Sensitivity and PPV were higher (P < 0.05) in intermediate and high-risk patients, while specificity and NPV were higher (P < 0.05) in low-risk patients. On receiver operating characteristic curve analysis, the cut-offs for better discrimination between benign and malignant SPN were 1.56 (sensitivity 81% and specificity 87%) and 1.12 (sensitivity 81% and specificity 86%) for SUVmax/SUVmeanBP and SUVmax/SUVmeanL respectively. In intermediate and high-risk patients, including the SUVmax/SUVmeanBP, the specificity shifted from 85% and 50% to 100%.

Conclusion: Visual FDG-PET/CT has an acceptable performance in patients with SPN, but accuracy improves when SUVratios are considered, particularly in patients with intermediate and high risk of malignancy.
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http://dx.doi.org/10.1007/s00259-018-4016-1DOI Listing
October 2018

Risk-related F-FDG PET/CT and new diagnostic strategies in patients with solitary pulmonary nodule: the ITALIAN multicenter trial.

Eur J Nucl Med Mol Imaging 2018 10 5;45(11):1908-1914. Epub 2018 May 5.

Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II, Napoli, Italy.

Purpose: Diagnosis of solitary pulmonary nodule (SPN) is an important public health issue and F-FDG PET/CT has proven to be more effective than CT alone. Pre-test risk stratification and clinical presentation of SPN could affect the diagnostic strategy. A relevant issue is whether thoracic segmental (s)-PET/CT could be implemented in patients with SPN. This retrospective multicenter study compared the results of FDG whole-body (wb)-PET/CT to those of s-PET/CT.

Methods: F-FDG PET/CT of 502 patients, stratified for pre-test cancer risk, were retrospectively analyzed. The thoracic part of wb-PET/CT, considered s-PET/CT, was compared to wb-PET/CT. Clinical and PET/CT variables were investigated for SPN characterization as well as for identification of patients in whom s-PET/CT could be performed. Histopathology or follow-up data were used as a reference.

Results: In the study population, 36% had malignant, 35% benign, and 29% indeterminate SPN. F-FDG uptake indicative of thoracic and extra-thoracic lesions was detectable in 13% and 3% of the patients. All patients with extra-thoracic metastases (n = 13) had thoracic lymph node involvement and highest F-FDG uptake at level of SPN (negative predictive value 100%). Compared to wb-PET/CT, s-PET/CT could save about 2/3 of F-FDG dose, radiation exposure or scan-time, without affecting the clinical impact of PET/CT.

Conclusion: Pre-test probability of malignancy can guide the diagnostic strategy of FDG-PET/CT in patients with SPN. In subjects with low-intermediate pretest probability s-PET/CT imaging might be planned in advance, while in those at high risk and with thoracic lymph node involvement a wb-PET/CT is necessary.
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http://dx.doi.org/10.1007/s00259-018-4043-yDOI Listing
October 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 new era of cancer immunotherapy: what can molecular imaging do to help?

Clin Transl Imaging 2017 Aug 21;5(4):299-301. Epub 2017 Jul 21.

Departments of Radiology, Medical Physics, Biomedical Engineering, and Materials Science and Engineering, University of Wisconsin, Madison, USA.

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http://dx.doi.org/10.1007/s40336-017-0241-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701751PMC
August 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

Integrin-dependent cell adhesion to neutrophil extracellular traps through engagement of fibronectin in neutrophil-like cells.

PLoS One 2017 6;12(2):e0171362. Epub 2017 Feb 6.

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

Neutrophil extracellular traps (NETs), originally recognized as a host defense mechanism, were reported to promote thrombosis and metastatic dissemination of cancer cells. Here we tested the role of integrins α5β1 and ανβ3 in the adhesion of cancer cells to NETs. Neutrophil-like cells stimulated with calcium ionophore (A23187) were used as a stable source of cell-free NETs-enriched suspensions. Using NETs as an adhesion substrate, two human K562 cell lines, differentially expressing α5β1 and ανβ3 integrins, were subjected to adhesion assays in the presence or absence of DNAse 1, blocking antibodies against α5β1 or ανβ3, alone or in combination with DNAse 1, and Proteinase K. As expected DNAse 1 treatment strongly inhibited adhesion of both cell lines to NETs. An equivalent significant reduction of cell adhesion to NETs was obtained after treatment of cells with blocking antibodies against α5β1 or ανβ3 indicating that both integrins were able to mediate cell adhesion to NETs. Furthermore, the combination of DNAse 1 and anti-integrin antibody treatment almost completely blocked cell adhesion. Western blot analysis and immunoprecipitation experiments showed a dose-dependent increase of fibronectin levels in samples from stimulated neutrophil-like cells and a direct or indirect interaction of fibronectin with histone H3. Finally, co-immunolocalization studies with confocal microscopy showed that fibronectin and citrullinated histone H3 co-localize inside the web-structure of NETs. In conclusion, our study showed that α5β1 and ανβ3 integrins mediate cell adhesion to NETs by binding to their common substrate fibronectin. Therefore, in addition to mechanical trapping and aspecific adsorption of different cell types driven by DNA/histone complexes, NETs may provide specific binding sites for integrin-mediated cell adhesion of neutrophils, platelets, endothelial and cancer cells thus promoting intimate interactions among these cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0171362PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293257PMC
August 2017

Generation of fluorescently labeled tracers - which features influence the translational potential?

EJNMMI Radiopharm Chem 2017 15;2(1):15. Epub 2017 Dec 15.

8Department of Radiology & Nuclear Medicine, Erasmus Medical Centre, Rotterdam, the Netherlands.

Given the increasing exploration of fluorescent tracers in the field of nuclear medicine, a need has risen for practical development guidelines that can help improve the translation aspects of fluorescent tracers. This editorial discusses the does and don'ts in developing fluorescence tracers. It has been put forward by the European Association of Nuclear Medicine (EANM) Translational Molecular Imaging & Therapy committee and has been approved by the EANM board.
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http://dx.doi.org/10.1186/s41181-017-0034-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824706PMC
December 2017

Preclinical imaging in oncology: advances and perspectives.

Q J Nucl Med Mol Imaging 2017 Mar 18;61(1):33-47. Epub 2016 Nov 18.

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

Preclinical imaging with radiolabeled probes became an integral part of the complex translational process that moves a newly developed compound from laboratory to clinical application. Imaging studies in animal tumor models may be undertaken to test a newly synthesized tracer, a newly developed drug or to interrogate, in the living organism, specific molecular and biological processes underlying tumor growth and progression. The aim of the present review is to outline the current knowledge and future perspectives of preclinical imaging in oncology by providing examples from recent literature. Among the biological processes and molecular targets that can be visualized with radiolabeled probes in animal tumor models, we focused on proliferation, expression of targets suitable for therapy, glycolytic phenotype, metastatic dissemination, tumor angiogenesis and survival. The major contribution of preclinical imaging emerging from these studies is the development and validation of imaging biomarkers that can be translated into the clinical context for patient selection and evaluation of tumor response to molecularly targeted agents.
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http://dx.doi.org/10.23736/S1824-4785.16.02949-6DOI Listing
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

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

Parametric MR dynamic imaging for breast lesions characterization and prediction of lymph nodes involvement.

Curr Radiopharm 2014 ;7(2):91-9

Nuclear Medicine Department, S. Andrea Hospital, Via Vittorio Veneto 197, 19100, La Spezia, Italy.

The main purpose of this study was to evaluate Gd-DTPA kinetics for the differential diagnosis between malignant and benign breast lesions. As a secondary aim, Gd-DTPA kinetics in malignant lesions was tested for predicting axillary lymph nodes involvement. Eighty-eight patients who underwent MRI for suspected breast tumor were selected from our database. All patients underwent the same acquisition protocol consisting of pre-contrast and dynamic contrastenhanced MRI. For all of them clinical and histopathological data were available. MR studies were performed on the same 1.5T scanner with a standard dedicated breast coil. Pre- and post-contrast dynamic images were used to calculate R1, R2 relaxation rates and proton density maps. The maximum influx rate (MIR) as well as the corresponding time (TMIR) were derived using R1 relaxation rate maps and relative changes as a function of time. Histopatological analysis led to the diagnosis of 46 breast carcinomas and 42 benign lesions. All breast carcinomas and 24 out of 42 benign lesions showed contrast-enhancement. The mean MIR was 0.75±0.14 (SD) sec-(2) in malignant tumors and 0.53±0.14 (SD) sec-(2) in contrast-enhancing benign breast lesions (p<0.0001). The TMIR was 1.40±0.43 min and 3.01±1.92 min (mean±SD) in enhancing malignant and benign lesions, respectively (p<0.0001). In malignant tumors, TMIR was not significantly different in node negative and node positive carcinomas whereas MIR was significantly lower in node negative carcinomas (0.67±0.11 versus 0.83±0.12 respectively, p<0.0001). Our findings suggest that quantitative assessment of Gd-DTPA kinetics may be an additional tool characterized for enhancing breast lesions and for predicting axillary lymph nodes involvement in malignant breast carcinoma.
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http://dx.doi.org/10.2174/1874471007666141110094425DOI Listing
October 2015

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