[18F]FDG-PET/CT in patients with Radioiodine-Refractory Thyroid Cancer in therapy with Lenvatinib

Background. Monitoring tumor response to oncologic treatment is an integral and increasingly important function of [18F]FDG-PET/CT. The possibility to differentiate as early as possible “responders” from “non-responders” patients during oncologic therapies can maximize the effectiveness of patient care. Moreover, oncologic imaging is expected to have a major role not only in the individual patient, but also in clinical trials designed to help select which new therapies should be advanced to progressively larger and more expensive clinical trials. The metabolic response assessed by [18F]FDG-PET/CT as a leading indicator of tumor response may be even more predictive of outcome than morphologic criteria, especially in the case of new cytostatic drugs. Recently, in agreement with the 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer, AIFA has approved the use of Lenvatinib, a new Multikinase Inhibitor (MKI), for the management of patients with progressive metastatic Radioiodine-Refractory Thyroid Cancer. Tumor response to MKIs in this setting is currently assessed by Response Evaluation Criteria in Solid Tumors (RECIST) and patient symptoms, while the role of [18F]FDG-PET/CT seems under-explored. Aim. To assess the role of [18F]FDG-PET/CT in monitoring tumor response to Lenvatinib in progressive metastatic Radioiodine-Refractory Thyroid Cancer patients and to predict prognosis with respect to different quantitative parameters. Patients and Methods. From December 2014 to September 2016, 33 patients with progressive Radioiodine-Refractory Thyroid Cancer (M/F=17/16; mean age: 65 years+/- 8,7; histologic type: 21 papillary thyroid carcinoma, 8 follicular thyroid carcinoma, 3 poorly differentiated thyroid carcinoma, 1 oxyphilic cells) were enrolled at the Department of Endocrinology of the University of Pisa to be submitted to treatment with Lenvatinib (24 mg/day). All patients underwent a baseline [18F]FDG-PET/CT scan, then repeated after about 1, 2, 6 and 12 months during therapy. All scans were performed with a PET/CT Discovery 710 scanner (GE Healthcare, Milwaukee, USA), including acquisition from the cranial vertex to half thigh, about 60 minutes after the injection of [18F]FDG (3.7 MBq/Kg). Patients fasted for at least 4 hours and finger stick blood glucose levels were <200 mg/dl prior to injection. Metabolic response to therapy was assessed in each site of disease (thyroid bed, lymph node, lung, bone, and other sites) during follow-up by qualitative evaluation, PET Response Criteria in Solid Tumors (PERCIST 1.0), maximal standardized uptake value (SUVmax), and metabolic tumor volume (MTV) and total lesion glycolysis (TLG), as measures of metabolic tumor burden. TLGwb and MTVwb were then determined by adding together the MTV and TLG of each site of disease to provide an index of the overall malignant process in the entire body. Results. All patients had high metastatic metabolic involvement disease in more than two sites, in particular at the lymph nodes (32/33 patients) and in the lung (27/33 patients). Fifteen out of 33 patients died during follow-up (median of survival 19.9 months), while 18/33 patients are still alive, though with a reduced dose of Lenvatinib because of adverse effects. During the follow-up 21/33 patients presented progression metabolic disease (PMD) by PERCIST, 14/21 after about 1 month since the onset of therapy. The lack of early metabolic response assessed by PERCIST criteria was significantly associated with mortality, although the response by PERCIST at the end of follow-up was obviously found to be more predictive of outcome. In multivariate analysis, SUVmax, MTVwb and TLGwb of the overall malignant process in the entire body at baseline were not significantly associated with overall survival (OS), although the majority of patients had decrease in total metabolic tumor burden during treatment. The reduction of both TLGwb and MTVwb was statistically significant only between the baseline PET/CT scan and the first control scan. Subsequently, tumor response, in terms of total tumor burden, showed a slight decrease, but remained essentially stable. This was also confirmed with respect to target lesions in thyroid bed, lymph nodes, and in the lungs, whose mean values of SUVmax, TLG and MTV showed an initial statistically significant decrease between the baseline PET/CT scan and the first control scan. Moreover, based on logistic regression there was a significant statistical evidence (likelihood-ratio test p <0.01) that OS depended on the persistence of TLG response (total and target ΔTLG %) at lymph node level after a median of 4.7 months of treatment. On the other hand, in bone metastases there was not a statistically significant response to therapy during follow up. Conclusion. Quantitative [18F]FDG-PET/CT can be a useful tool to evaluate tumor response during MKIs therapy in progressive metastatic Radioiodine-Refractory Thyroid Cancer patients

IL VALORE PROGNOSTICO DELLA STADIAZIONE MOLECOLARE DEL LINFONODO SENTINELLA NEI PAZIENTI AFFETTI DA MELANOMA CUTANEO

Scopi di questa tesi di laurea sono stati: 1) verificare l’accuratezza diagnostica dell’analisi molecolare (RT-PCR) del linfonodo sentinella (SLN) nell’identificazione delle micrometastasi di pazienti affetti da melanoma cutaneo; 2) determinare se i pazienti con SLN negativo alle tecniche istopatologiche convenzionali (PATH) e positivi all’analisi molecolare (PCR ) hanno un rischio superiore di ripresa di malattia (loco-regionale e/o a distanza) rispetto ai pazienti con SLN negativo ad entrambe le metodiche. Sono stati arruolati 124 pazienti consecutivi affetti da melanoma cutaneo in stadio clinico I e II e sottoposti a linfoscintigrafia e biopsia radioguidata del SLN. Tutti i loro linfonodi sentinella sono stati analizzati in parallelo sia con RT-PCR (per valutare l’espressione dell’mRNA che codifica per la tirosinasi ed il MART-1) sia con tecniche istopatologiche convenzionali (colorazioni con ematossilina-eosina ed immunoistochimica). I risultati dell’analisi molecolare e delle tecniche istopatologiche convenzionali sono stati correlati con la sopravvivenza libera da malattia e con la sopravvivenza globale. I linfonodi sentinella (SLNs) di 23/124 pazienti (18.5%) sono risultati essere positivi per la presenza di metastasi sia alla PATH che alla RT–PCR (gruppo PATH+/PCR+). I SLNs di 16 pazienti (13%) sono risultati negativi alla PATH e positivi alla RT–PCR (gruppo PATH-/PCR+). I SLNs di 85 pazienti (68.5%) sono risultati negativi sia alla PATH sia alla RT–PCR (gruppo PATH-/PCR-). Dopo una mediana di follow-up di 54.8 mesi, le percentuali di ripresa di malattia nei tre gruppi sono risultate statisticamente significative (gruppo PATH+/PCR+, 65%; gruppo PATH-/PCR+, 38%; gruppo PATH-/PCR-, 15%). Nel gruppo PATH+/PCR+ si sono verificati 11 decessi (48 %), 3 decessi (19%) nel gruppo PATH-/PCR+ e 9 decessi (11%) nel gruppo PATH-/PCR-. Nella nostra esperienza l’analisi molecolare è risultata più sensibile rispetto alle tecniche istopatologiche convenzionali nel rilevare la presenza di metastasi a livello del linfonodo sentinella di pazienti affetti da melanoma. Inoltre, la stadiazione molecolare del SLN consente di individuare un sottogruppo di pazienti (PATH-/PCR+) con una prognosi intermedia (rispetto ai pazienti PATH-/PCR- e quelli PATH+/PCR+), che potrebbero beneficiare di un più intenso follow-up e di trattamenti con interferone ad alti dosaggi (e/o più aggressivi schemi chemioterapici) nel tentativo di ottenere benefici in termini di sopravvivenza

Sentinel lymph node biopsy in breast cancer:a technical and clinical appraisal

Breast cancer is the most common type of cancer diagnosed in women worldwide. Regional lymph node status is one of the strongest predictors of long-term prognosis in primary breast cancer. Sentinel lymph node biopsy (SLNB) has replaced axillary lymph node dissection as the standard surgical procedure for staging clinically tumor-free regional nodes in patients with early-stage breast cancer. SLNB staging considerably reduces surgical morbidity in terms of shoulder dysfunction and lymphedema, without affecting diagnostic accuracy and prognostic information. Clinicians should not recommend axillary lymph node dissection for women with early-stage breast cancer who have tumor-free findings on SLNB because there is no advantage in terms of overall survival and disease-free survival. Starting from the early 1990s, SLNB has increasingly been used in breast cancer management, but its role is still debated under many clinical circumstances. Moreover, there is still a lack of standardization of the basic technical details of the procedure that is likely to be responsible for the variability found in the false-negative rate of the procedure (5.5-16.7%). In this article, we report the aspects of SLNB that are well established, those that are still debated, and the advancements that have taken place over the last 20 years. We have provided an update on the methodology from both a technical and a clinical point of view in the light of the most recent publications

Dosimetry of 177 Lu-PSMA-617 after mannitol infusion and glutamate tablet administration: Preliminary results of EUDRACT/RSO 2016-002732-32 IRST protocol

Radio-ligand therapy (RLT) with 177 Lu-PSMA-617 is a promising option for patients with metastatic castration-resistant prostate-cancer (mCRPC). A prospective phase-II study (EUDRACT/RSO,2016-002732-32) on mCRPC is ongoing at IRST (Meldola, Italy). A total of 9 patients (median age: 68 y, range: 53–85) were enrolled for dosimetry evaluation of parotid glands (PGs), kidneys, red marrow (RM) and whole body (WB). Folic polyglutamate tablets were orally administered as PGs protectors and 500 mL of a 10% mannitol solution was intravenously infused to reduce kidney uptake. The whole body planar image (WBI) and blood samples were acquired at different times post infusion (1 h, 16–24 h, 36–48 h and 120 h). Dose calculation was performed with MIRD formalism (OLINDA/EXM software). The median effective half-life was 33.0 h (range: 25.6–60.7) for PGs, 31.4 h (12.2–80.6) for kidneys, 8.2 h (2.5–14.7) for RM and 40.1 h (31.6–79.7) for WB. The median doses were 0.48 mGy/MBq (range: 0.33–2.63) for PGs, 0.70 mGy/MBq (0.26–1.07) for kidneys, 0.044 mGy/MBq (0.023–0.067) for RM and 0.04 mGy/MBq (0.02–0.11) for WB. A comparison with previously published dosimetric data was performed and a significant difference was found for PGs while no significant difference was observed for the kidneys. For PGs, the possibility of reducing uptake by administering glutamate tablets during RLT seems feasible while further research is warranted for a more focused evaluation of the reduction in kidney uptake

Radioguided occult lesion localization technical procedures and clinical applications

Purpose: Regarding radioguided surgery, the concept of “radioguided occult lesion localization” (ROLL) is based on both preoperative interventional imaging and intraoperative radioguided detection of a clinically occult neoplastic lesion. Methods: This methodology consists in the direct administration into the lesion of99mTc–macroaggregated human albumin formed by relatively large particles retained at the injection site, which direct radioguided excisional biopsy. Results: This modality has expanded from the classic application of ROLL for nonpalpable breast lesions to other tumors, such as solitary pulmonary nodules or recurrences from differentiated thyroid carcinoma. In 2011, in order to improve the classification of different radioguided surgical procedures, ROLL applications were included in the more complete concept of GOSTT (Guided intraOperative Scintigraphic Tumor Targeting). This concept was introduced to include the entire range of basic and advanced radioguided procedures necessary to supply a “road map” for the surgeon. Conclusions: The terms ROLL and GOSTT have further developed by incorporating novel modalities such as hybrid tracers for simultaneous fluorescence and radioactive signal detection and innovative navigation systems based on mixed-reality protocols

Clinical Impact of Radioguided Localization in the Treatment of Solitary Pulmonary Nodule: A 20-Year Retrospective Analysis

Purpose Incidental solitary pulmonary nodules (SPNs) have become an increasingly common CT finding worldwide. Although there are currently many imaging strategies for evaluating SPNs, the differential diagnosis and management of SPNs remains complex because of overlap between benign and malignant processes. Moreover, transbronchial or percutaneous CT-guided biopsies do not always allow definitive diagnoses. In such cases, video-assisted thoracic surgery (VATS) has become the preferred surgical procedure for diagnosis and, in selected cases, for treatment of indeterminate SPNs. The difficulties in localizing smaller, deeper, and ground-glass nodules have been approached with different techniques. The aim of this study was to report 20 years of experience with radioguided thoracoscopic resection of SPNs at the Regional Centre of Nuclear Medicine of Pisa. Methods Three hundred ninety-five patients with SPNs less than 2 cm and deeper than 5 mm below the visceral pleura underwent CT-guided injection of a suspension composed of 0.1 to 0.2 mL99mTc-labeled human albumin macroaggregates (99mTc-MAA) and of 0.2 to 0.3 mL of nonionic contrast medium into or adjacent to the SPN. During VATS, the pulmonary area with the highest target/background ratio identified by an 11-mm-diameter collimated thoracoscopic gamma probe was resected. Results From 1997 to 2016, approximately 395 patients with SPN underwent VATS wedge resection using the radioguided technique. Mean SPN size was 13 mm (range, 5-20 mm) with mean distance of 15 mm (range, 6-39 mm) from the visceral pleura. Mean VATS procedural time was 40 minutes (range, 20-90 minutes), with an average time of 3 minutes (range, 1-5 minutes) to localize the nodule. Neither mortality nor major perioperative complication was reported. The success rate of VATS with radioguidance in our series was 99%. Histological examination revealed 206 benign lesions (52%), 59 primary lung tumors (15%), and 130 metastatic nodules (33%). Conclusions This study demonstrates that radioguided SPN localization by VATS is a feasible, safe, and rapid procedure with highly successful rate of SPN resection

Sentinel Lymph Node Biopsy in Breast Cancer: Indications, Contraindications, and Controversies

Axillary lymph node status, a major prognostic factor in early-stage breast cancer, provides information important for individualized surgical treatment. Because imaging techniques have limited sensitivity to detect metastasis in axillary lymph nodes, the axilla must be explored surgically. The histology of all resected nodes at the time of axillary lymph node dissection (ALND) has traditionally been regarded as the most accurate method for assessing metastatic spread of disease to the locoregional lymph nodes. However, ALND may result in lymphedema, nerve injury, shoulder dysfunction, and other short-term and long-term complications limiting functionality and reducing quality of life. Sentinel lymph node biopsy (SLNB) is a less invasive method of assessing nodal involvement. The concept of SLNB is based on the notion that tumors drain in an orderly manner through the lymphatic system. Therefore, the SLN is the first to be affected by metastasis if the tumor has spread, and a tumor-free SLN makes it highly unlikely for other nodes to be affected. Sentinel lymph node biopsy has become the standard of care for primary treatment of early breast cancer and has replaced ALND to stage clinically node-negative patients, thus reducing ALND-associated morbidity. More than 20 years after its introduction, there are still aspects concerning SLNB and ALND that are currently debated. Moreover, SLNB remains an unstandardized procedure surrounded by many unresolved controversies concerning the technique itself. In this article, we review the main indications, contraindications, and controversies of SLNB in breast cancer in the light of the most recent publications

Rethinking Tako-tsubo Cardiomyopathy:The Contribution of Myocardial Pathology and Molecular Imaging

Background: Despite substantial research, the mechanisms behind stress Tako-tsubo cardiomyopathy (TTC) remain rather elusive.Objective: The purpose of this paper was to provide a detailed review of the mainstream factors underlying the pathophysiology of TTC, highlighting the novel contributions of molecular pathology and in-vivo molecular imaging. Methods: A careful literature review selected all papers discussing TTC, specifically those providing novel insights from myocardial pathology and cardiac molecular imaging. Results: Results concerning myocardial pathology, defect extension, sites and relationships between functional parameters underline the existence of a causal relationship between a determi-nant (e.g., the release of catecholamines induced by stress) and an outcome for TTC, which is not limited to a reversible contractile cardiomyopathy, but it includes reversible changes in myocardi-al perfusion and a long-lasting residual deficit in sympathetic function. Besides, they reinforce the hypothesis that sympathetic nerves may exert a complex control on cardiac contractile function, which is likely to be direct or indirect through metabolism and microvascular perfusion changes during anaerobic and aerobic conditions. Conclusion: TTC is characterized by acute transient left ventricular systolic dysfunction, which can be challenging to distinguish from myocardial infarction at presentation. Catecholamine-induced myocardial injury is the most established theory, but other factors, including myocardial metabolism and perfusion, should be considered of utmost importance. Each effort to clarify the numerous pathways and emerging abnormalities may provide novel approaches to treat the acute episode, avoid recurrences, and prevent major adverse cardiovascular events.</p

Rethinking Tako-tsubo Cardiomyopathy:The Contribution of Myocardial Pathology and Molecular Imaging

Background: Despite substantial research, the mechanisms behind stress Tako-tsubo cardiomyopathy (TTC) remain rather elusive.Objective: The purpose of this paper was to provide a detailed review of the mainstream factors underlying the pathophysiology of TTC, highlighting the novel contributions of molecular pathology and in-vivo molecular imaging. Methods: A careful literature review selected all papers discussing TTC, specifically those providing novel insights from myocardial pathology and cardiac molecular imaging. Results: Results concerning myocardial pathology, defect extension, sites and relationships between functional parameters underline the existence of a causal relationship between a determi-nant (e.g., the release of catecholamines induced by stress) and an outcome for TTC, which is not limited to a reversible contractile cardiomyopathy, but it includes reversible changes in myocardi-al perfusion and a long-lasting residual deficit in sympathetic function. Besides, they reinforce the hypothesis that sympathetic nerves may exert a complex control on cardiac contractile function, which is likely to be direct or indirect through metabolism and microvascular perfusion changes during anaerobic and aerobic conditions. Conclusion: TTC is characterized by acute transient left ventricular systolic dysfunction, which can be challenging to distinguish from myocardial infarction at presentation. Catecholamine-induced myocardial injury is the most established theory, but other factors, including myocardial metabolism and perfusion, should be considered of utmost importance. Each effort to clarify the numerous pathways and emerging abnormalities may provide novel approaches to treat the acute episode, avoid recurrences, and prevent major adverse cardiovascular events.</p

Rethinking Tako-tsubo Cardiomyopathy:The Contribution of Myocardial Pathology and Molecular Imaging

Background: Despite substantial research, the mechanisms behind stress Tako-tsubo cardiomyopathy (TTC) remain rather elusive.Objective: The purpose of this paper was to provide a detailed review of the mainstream factors underlying the pathophysiology of TTC, highlighting the novel contributions of molecular pathology and in-vivo molecular imaging. Methods: A careful literature review selected all papers discussing TTC, specifically those providing novel insights from myocardial pathology and cardiac molecular imaging. Results: Results concerning myocardial pathology, defect extension, sites and relationships between functional parameters underline the existence of a causal relationship between a determi-nant (e.g., the release of catecholamines induced by stress) and an outcome for TTC, which is not limited to a reversible contractile cardiomyopathy, but it includes reversible changes in myocardi-al perfusion and a long-lasting residual deficit in sympathetic function. Besides, they reinforce the hypothesis that sympathetic nerves may exert a complex control on cardiac contractile function, which is likely to be direct or indirect through metabolism and microvascular perfusion changes during anaerobic and aerobic conditions. Conclusion: TTC is characterized by acute transient left ventricular systolic dysfunction, which can be challenging to distinguish from myocardial infarction at presentation. Catecholamine-induced myocardial injury is the most established theory, but other factors, including myocardial metabolism and perfusion, should be considered of utmost importance. Each effort to clarify the numerous pathways and emerging abnormalities may provide novel approaches to treat the acute episode, avoid recurrences, and prevent major adverse cardiovascular events.</p