Roberto Boni

Brief Report on the Use of Radiolabeled Somatostatin Analogs for the Diagnosis and Treatment of Metastatic Small-Cell Lung Cancer Patients

Introduction: The demonstration of type 2 somatostatin receptors (SSTRs) in small-cell lung cancer (SCLC) represents the rationale for the use of positron emission tomography/computed tomography (PET/CT) to determine SSTR expression, and select patients suitable for peptide radioreceptor radionuclide therapy (PRRT) in extensive-disease stage (ED) SCLC. Methods: We evaluated 24 ED-SCLC patients with radiolabeled SST-analog PET/CT. Lesions at PET/CT scan were semiquantitatively scored (from 0 to 3+) and compared with contrast-enhanced CT findings. Patients scored as 3+ were admitted to PRRT after dosimetric evaluation. Average injected activity/cycle was 2.6 GBq (90yttrium-PRRT) or 6.0 GBq (177lutetium-PRRT). PRRT efficacy was clinically and radiologically assessed. Results: PET/CT was negative in four of 24 patients, whereas in the remaining 20 cases uptake was scored as 1+ in seven of 20, 2+ in one of 20, and 3+ in 12 of 20. Primary tumor lesions showed uptake in 16 of 24 patients. Uptake in metastatic lesions was observed in four of four adrenals, two of five brain, 12 of 16 bone, three of eight liver, and 17 of 20 lymph node lesions. Of the 12 patients eligible for PRRT, 11 were eventually treated and four of 11 patients received multiple PRRT administrations. Dosimetry resulted in a BED for kidney of 7.5 Gy (range, 4–21); bone marrow provisional dosage was 0.43 Gy (range, 0.1–1.7). Hematological PRRT toxicity occurred in three of 11 patients. No clinical or objective responses were observed with disease progression occurring approximately 48 days (range, 9–32) after PRRT. Conclusion: Radiolabeled SST-analog PET/CT demonstrated enhanced SSTR expression in 50% of cases. Nevertheless, PRRT in ED-SCLC was ineffective, suggesting the need to anticipate or combine PRRT in a multimodality approach.

ED-B fibronectin expression is a marker of epithelial-mesenchymal transition in translational oncology

Fibronectin is a component of the extracellular matrix that links collagen fibers to integrins on the cells surface. The splicing isoforms, containing the ED-B domain, are not expressed in adult tissues but only in tumor stroma or during embryonic development. Fibroblasts and endothelial cells express ED-B fibronectin during angiogenesis. Also cancer cells can synthetize ED-B fibronectin, but its function in tumor growth needs to be further elucidated. We evaluated the expression of ED-B fibronectin in prostate cancer cell lines: PC3 and DU145. Using TGF-β, we induced epithelial to mesenchymal transition in culture and observed an increase of ED-B fibronectin expression. Thereafter, we evaluated the expression of ED-B fibronectin in multipotent mesangiogenic progenitor cells, and in mesenchymal stromal cells. The expression of ED-B fibronectin was much higher in mesenchymal than prostate cancer cells even after the epithelial to mesenchymal transition. Epithelial to mesenchymal transition is a key step for tumor progression contributing to the metastatic spread. Therefore, circulating cancer cells could seed into the metastatic niche taking advantage from the ED-B fibronectin that secrete their own.

Current Status of Molecular Imaging in Infections

There is an increased need to find non-invasive tools for early diagnosis and follow-up of infections. Nuclear medicine techniques may be used to diagnose, localize and evaluate the severity and the extent of infections before the occurrence of anatomical abnormalities. This review focuses on different approaches based on radiolabelled cells, peptides and antibodies or [18F]FDG to image infective diseases in agreement with what is being jointly evaluated by the European Association of Nuclear Medicine (EANM). This is particularly relevant, since the EANM has strated a wide program of collaboration with other European clinical societies to define common diagnostic flow-charts in many of these infective diseases. It emerges the role of radiolabelled WBC by SPECT/CT for prosthetic joint infections and of FDG by PET/CT for spondylodiscitis. Comparable values of accuracy have been described for WBC and FDG in the diagnosis of vascular fgraft infections, diabetic gfoot, endocarditis and peripheral bone osteomyelitis, with some exceptions.

Other Imaging Modalities in Infective Endocarditis Diagnosis

The recent development of hybrid molecular imaging equipment for both conventional nuclear medicine (e.g., SPECT/CT) and PET (e.g., PET/CT) has raised evidence of the impact of SPECT and PET performed with suitable infection imaging agents and co-registered with CT in the diagnosis of IE. Their unique whole-body exploring ability, i.e., to detect multiple sites of disease with a single examination, has been proven effective in guiding clinical management of patients in view of the selection of optimal treatment strategy. Radiolabeled leukocytes scintigraphy and [18F]FDG-PET/CT have been recently included in the 2015 Guideline for the management of infective endocarditis and proposed as diagnostic tools in the diagnostic flow chart of IE. In particular, molecular imaging techniques have been proposed to confirm/exclude IE in case of “possible” or “rejected” IE (as for FUO), and to assess the embolic burden in case of “definite” IE. The main added value of using these techniques are the reduction of the rate of misdiagnosed IE, classified in the ‘Possible IE’ category by using the Duke criteria alone and the detection of peripheral embolic and metastatic infectious events. Evidence is higher in case of and prosthetic valve IE (PVE), however, data show increased accuracy also in presence of native IE (NVE) and unconclusive clinical findings. This new approach to IE patient where imaging techniques including nuclear imaging are getting more and more important is based on the concept that IE is not a single disease but, rather, may present with very different aspects, depending on the first organ involved, the underlying cardiac disease (if any), the microorganism involved, the presence or absence of complications, and the patient’s characteristics. Therefore, a very high level of expertise is needed, coming from practitioners from several specialties, including microbiologists, imagers, clinicians and surgeon. Including all these specialists into the patients’ management is fundamental.

The “3M” Approach to Cardiovascular Infections: Multimodality, Multitracers, and Multidisciplinary

Cardiovascular infections are associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient management, as early treatment improves the prognosis. The diagnosis cannot be made on the basis of a single symptom, sign, or diagnostic test. Rather, the diagnosis requires a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data, and imaging data. The application of multimodality imaging, including molecular imaging techniques, has improved the sensitivity to detect infections involving heart valves and vessels and implanted cardiovascular devices while also allowing for early detection of septic emboli and metastatic infections before these become clinically apparent. In this review, we describe data supporting the use of a Multimodality, Multitracer, and Multidisciplinary approach (the 3M approach) to cardiovascular infections. In particular, the role of white blood cell SPECT/CT and [18F]FDG PET/CT in most prevalent and clinically relevant cardiovascular infections will be discussed. In addition, the needs of advanced hybrid equipment, dedicated imaging acquisition protocols, specific expertise for image reading, and interpretation in this field are discussed, emphasizing the need for a specific reference framework within a Cardiovascular Multidisciplinary Team Approach to select the best test or combination of tests for each specific clinical situation.

The Role of Nuclear Cardiac Imaging in Infective Endocarditis

Purpose of ReviewInfective endocarditis (IE) remains a deadly disease despite improvements in its management. Echocardiography is crucial for the diagnosis of IE; however, its value is operator-dependent and its sensitivity can decrease in the presence of valvular prosthesis. This review aims to provide an overview on the role of nuclear cardiac imaging in the diagnosis of IE.Recent FindingsAmong all nuclear cardiac imaging modalities, both radiolabeled leukocyte scintigraphy and 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG-PET/CT) have been recently introduced in the guidelines of European Society of Cardiology (ESC) for the management of IE. The ESC guidelines included some minor criteria (mainly clinical), and two different sets of major criteria based on blood culture and imaging, respectively. The positivity of either radiolabeled leukocyte scintigraphy or [18F]FDG-PET/CT images is considered itself a major criterion to diagnose IE. However, nuclear cardiac imaging analysis may be tricky and methodological and technical aspects should be carefully considered.SummaryAvailable evidence supports the role of nuclear cardiac imaging in the diagnosis and management of IE. However, all practitioners who act within the “Endocarditis Team” should present a very high level of expertise.

Miniaturized Radiochemical Purity Testing for 99mTc-HMPAO, 99mTc-HMDP, and 99mTc-Tetrofosmin

Quick methods are functional in clinical practice to ensure the fastest availability of radiopharmaceuticals. For this purpose, we investigated the radiochemical purity of the widely used 99mTc-hydroxymethylene diphosphonate, 99mTc-hexamethylpropyleneamine oxime, and 99mTc-tetrofosmin by reducing time as compared with the manufacturers method. Methods: We applied a miniaturized chromatographic method with a reduced strip development from 18 cm to 9 cm for all 3 radiopharmaceuticals. The specific support medium and solvent system of the manufacturers methods was kept unchanged for 99mTc-hydroxymethylene diphosphonate and 99mTc-tetrofosmin, whereas for 99mTc-hexamethylpropyleneamine oxime the instant thin-layer chromatography (ITLC) polysilicic gel (silicic acid [SA]) was replaced with a monosilicic gel (silicic gel [SG]) in the chromatographic system that uses methyl ethyl ketone as solvent. The method was applied and compared with the routine ITLC insert method in a total of 30 batches for each radiopharmaceutical. The precision of repeated tests was determined by comparison with the results of 10 replications on the same batch. Small volumes of concentrated 99mTcO4−, and 99mTc-albumin nanocolloid were used to produce potential radiochemical impurities. Correlation between the quick methods and the insert methods was analyzed using a nonparametric 2-tailed test and a 2 × 2 contingency table with the associated Fisher exact test to evaluate sensitivity and specificity. A receiver-operating-characteristic analysis was performed to evaluate the best cutoff. Results: The percentage radiochemical purity of the quick methods agreed with the standard chromatography procedures. We found that 99mTcO4 and colloidal impurities are not the only common radiochemical impurities with 99mTc-tetrofosmin, and shortening of the ITLC strip with respect to the manufacturers method will worsen system resolution and may produce inaccuracy. Conclusion: The miniaturized methods we described represent a fast and reliable alternative for 99mTc-exametazime and 99mTc-oxidronate quality control, with the upper cutoff for acceptable radiochemical purity values being 84% and 95%, respectively. For 99mTc-tetrofosmin radiochemical purity testing, a longer strip as described in the standard method is warranted.

PET/CT and PET/MRI in Neurology: Infection/Inflammation

For more than a century, X-ray was the only available modality allowing observation of inner workings of the human body. Today, a new generation of imaging devices is probing even deeper and transforming medicine in the process. Indeed, recent advances in imaging technology such as CT scans, MRIs, SPECT, and PET scans and other techniques have had a major impact on the diagnosis and treatment of disease. Nuclear medicine techniques for imaging inflammation and infection have enormously expanded gaining importance in the diagnostic setting as well as for prognostic implication and management of treatment. This important clinical role relies on the ability of functional imaging to pinpoint different components and phases of inflammatory and infectious diseases beside the pure morphological anomaly generally depicted by the majority of radiological imaging procedures. Indeed, the use of nuclear medicine techniques allows in vivo histological characterization of inflamed and infected tissues and highlights cells and phenomena principally involved, thus allowing definition of tailored personalized treatment.

Lymphoscintigraphy for the Differential Diagnosis of Peripheral Edema and Intracavitary Lymph Effusion

Patients with lower-extremity lymphedema initially present with unilateral painless swelling that starts on the dorsal aspect of the foot, but eventually progresses to involve the proximal portion of the limb. The edema is initially a pitting edema, but over time the subcutaneous tissue becomes fibrotic, resulting in nonpitting brawny edema. The edema can then spread circumferentially if treatment is not initiated, involving the skin, which becomes hyperkeratotic, hyperpigmented, and papillomatous or verrucous, with increased skin turgor. The Kaposi-Stemmer sign, in which the examiner is unable to pinch a fold of skin at the base of the second toe on the dorsal aspect of the foot, indicates clinical lymphedema [1–3]. Ultimately, the skin is at risk for ulcerating and subsequent infection. Swelling associated with lymphedema results in a sensation of heaviness, discomfort, and impaired mobility of the limb. Angiosarcoma may develop in chronic lymphedematous limbs (Stewart-Treves syndrome), but is most commonly seen in the upper extremity following mastectomy with axillary lymph node dissection [4]. This condition is often referred to as lymphangiosarcoma, which is actually a misnomer, since the tumor is not derived from lymphatic vessels, but is rather derived from vascular endothelial cells within a condition of chronic lymphedema.

Tecniche diagnostiche PET in oncologia

Le applicazioni della PET in oncologia riguardano pressoche tutti i tipi di neoplasie, utilizzando naturalmente i radiofarmaci piu idonei per ogni istotipo: tumori cerebrali, del distretto testa-collo, del polmone, della mammella, del tratto gastro-enterico, del sistema genito-urinario, di ossa, muscoli e tessuti molli, linfomi e mielomi, melanoma, neoplasie endocrine e neuroendocrine.