Il ruolo della PET/TC con 18F-DOPA nella diagnosi e nel follow-up dei paragangliomi surrenalici ed extra-surrenalici

I paragangliomi (PGL) sono dei rari tumori che originano da agglomerati di cellule neuroendocrine, detti paragangli, connessi al sistema nervoso simpatico e parasimpatico, che si caratterizzano per la capacità di produrre, metabolizzare, immagazzinare e secernere catecolamine. I PGL del simpatico originano dalla midollare del surrene (feocromocitomi) o dai gangli simpatici dell’addome e del torace e si caratterizzano per l’ipersecrezione di catecolamine. I PGL del parasimpatico si localizzano invece a livello del distretto testa-collo (HNPGL) e secernono catecolamine solo in una minoranza dei casi. La presentazione clinica è eterogenea con sintomi correlati all’ipersecrezione di catecolamine per i PGL simpatici, mentre gli HNPGL possono essere asintomatici o determinare disturbi da effetto massa. Si tratta di neoplasie a lento accrescimento e tendenzialmente benigne che possono presentarsi in forma sporadica o associate a sindromi ereditarie, con età di insorgenza variabile e senza prevalenza di sesso. La diagnosi di questi tumori si basa su indagini biochimiche (dosaggio di catecolamine e/o loro metaboliti nel plasma e nelle urine), morfologiche (TC e RM) e funzionali (scintigrafia e PET). Scopo dello studio: l’obiettivo di questo studio è stato quello di valutare l’utilità clinica della PET/TC con 18F-DOPA nei pazienti con PGL surrenalici ed extra-surrenalici. Materiali e metodi: ventisei pazienti consecutivi con sospetto PGL o recidiva di PGL sono stati studiati con RM (e/o TC) e con 18F-DOPA PET/TC. La conferma istologica è stata ottenuta in venti casi. In tredici pazienti è stato eseguito lo studio delle mutazioni per i geni di suscettibilità del PGL (VHL, RET, SDHx, TMEM127). Risultati: quattordici pazienti sono risultati affetti da PGL (8 HNPGL, 1 PGL toracico e 5 PGL addominali), nei restanti 12 pazienti sono state riscontrate formazioni di altra natura. Dei tredici pazienti in cui è stata effettuata l’analisi genetica, tre presentavano mutazioni del gene SDHD, due del gene SDHC, uno del gene SDHB e uno del gene TMEM. La 18F-DOPA PET/TC ha evidenziato una patologica captazione del tracciante in tredici pazienti su ventisei, riuscendo ad identificare tutti i PGL, ad eccezione di un paziente con metastasi ossee da pregresso feocromocitoma maligno. Nei pazienti non affetti da PGL non è stata riscontrata alcuna captazione patologica di 18F-DOPA. Nella popolazione complessiva, la 18F-DOPA PET/TC ha mostrato una sensibilità del 92.8%, una specificità del 100%, un valore predittivo positivo e negativo rispettivamente del 100% e del 92.3% e un’accuratezza diagnostica del 96.2%. Nel sottogruppo di pazienti con sospetto PGL del collo/torace, la sensibilità, la specificità, il valore predittivo positivo e negativo e l’accuratezza diagnostica sono risultate del 100%. Nel sottogruppo di pazienti con sospetto PGL addominale la sensibilità è stata dell’80%, la specificità del 100%, il valore predittivo positivo e negativo rispettivamente del 100% e del 91.7% e l’accuratezza diagnostica del 93.7%. Conclusioni: questo studio conferma che la 18F-DOPA PET/TC è uno strumento diagnostico importante per l’identificazione dei PGL, in particolare per quelli localizzati nel distretto testa/collo, indipendentemente dall’assetto genetico

Toward the discovery and development of PSMA targeted inhibitors for nuclear medicine applications

Background: The rising incidence rate of prostate cancer (PCa) has promoted the development of new diagnostic and therapeutic radiopharmaceuticals during the last decades. Promising im-provements have been achieved in clinical practice using prostate specific membrane antigen (PSMA) labeled agents, including specific antibodies and small molecular weight inhibitors. Focusing on molecular docking studies, this review aims to highlight the progress in the design of PSMA targeted agents for a potential use in nuclear medicine. Results: Although the first development of radiopharmaceuticals able to specifically recognize PSMA was exclusively oriented to macromolecule protein structure such as radiolabeled monoclonal antibodies and derivatives, the isolation of the crystal structure of PSMA served as the trigger for the synthesis and the further evaluation of a variety of low molecular weight inhibitors. Among the nuclear imaging probes and radiotherapeutics that have been developed and tested till today, labeled Glutamate-ureido inhibitors are the most prevalent PSMA-targeting agents for nuclear medicine applications. Conclusion: PSMA represents for researchers the most attractive target for the detection and treatment of patients affected by PCa using nuclear medicine modalities. [99mTc]MIP-1404 is considered the tracer of choice for SPECT imaging and [68Ga]PSMA-11 is the leading diagnostic for PET imaging by general consensus. [18F]DCFPyL and [18F]PSMA-1007 are clearly the emerging PET PSMA candidates for their great potential for a widespread commercial distribution. After paving the way with new imaging tools, academic and industrial R&Ds are now focusing on the development of PSMA inhibitors labeled with alpha or beta minus emitters for a theragnostic application

Sentinel lymph node mapping in breast cancer: a critical reappraisal of the internal mammary chain issue

Although, like the axilla, the internal mammary nodes (IMNs) are a first-echelon nodal drainage site in breast cancer, the importance of their treatment has long been debated. Seminal randomized trials have failed to demonstrate a survival benefit from surgical IMN dissection, and several retrospective studies have shown that IMNs are rarely the first site of recurrence. However, the recent widespread adoption of sentinel lymph node (SLN) biopsy has stimulated a critical reappraisal of such early results. Furthermore, the higher proportion of screening-detected cancers, improved imaging and techniques (i.e., lymphoscintigraphy for radioguided SLN biopsy) make it possible to visualize lymphatic drainage to the IMNs. The virtually systematic application of adjuvant systemic and/or loco-regional radiotherapy encourages re-examination of the significance of IMN metastases. Moreover, randomized trials testing the value of postmastectomy irradiation and a meta-analysis of 78 randomized trials have provided high levels of evidence that local-regional tumor control is associated with long-term survival improvements. This benefit was limited to trials that used systemic chemotherapy, which was not routinely administered in the earlier studies. However, the contribution from IMN treatment is unclear. Lymphoscintigraphic studies have shown that a significant proportion of breast cancers have primary drainage to the IMNs, including approximately 30% of medial tumors and 15% of lateral tumors. In the few studies where IMN biopsy was performed, 20% of sentinel IMNs were metastatic. The risk of IMN involvement is higher in patients with medial tumors and positive axillary nodes. IMN metastasis has prognostic significance, as recognized by its inclusion in the American Joint Committee on Cancer staging criteria, and seems to have similar prognostic importance as axillary nodal involvement. Although routine IMN evaluation might be indicated, it has not been routinely performed, perhaps because IMN drainage with lymphoscintigraphy is more difficult to demonstrate than axillary drainage. This difference is due to technical reasons and not the absence of lymphatics to the IMN. Recent anatomical studies have confirmed a model of breast lymphatic drainage that comprises superficial, deep and perforating systems. The superficial system drains to the axilla, usually to a lymph node posterior to the pectoralis minor muscle. The deep system drains to the axilla and also anastomoses with the perforating system which drains to the IMNs. The perforating system does not connect with the superficial system. The prevalence of IMN drainage tends to reflect the method of lymphoscintigraphy, where peritumoral (deep lymphatic system) injections have a much higher likelihood of IMN drainage than subareolar or subdermal (superficial lymphatic system) injections. The fused SPECT/CT images represent a further technical solution to increase the identification of IMNs and consequently can significantly reduce the false negative rate of sentinel lymph node biopsy. Before mature results from current and future randomized trials assessing the benefit of IMN irradiation become available, lymphoscintigraphy and IMNs biopsy may be used to guide decisions regarding systemic and local-regional treatment. However, even in patients with visualized primary IMN drainage, the potential benefit of treatment should be balanced against the risk of added morbidity

Metabolic and Hormonal Determinants of Glomerular Filtration Rate and Renal Hemodynamics in Severely Obese Individuals

Objective: Renal function is often compromised in severe obesity. A true measurement of glomerular filtration rate (GFR) is unusual, and how estimation formulae (EstForm) perform in such individuals is unclear. We characterized renal function and hemodynamics in severely obese individuals, assessing the reliability of EstForm. Methods: We measured GFR (mGFR) by iohexol plasma clearance, renal plasma flow (RPF) by 123I-ortho-iodo-hippurate, basal and stimulated vascular renal indices, endothelium-dependent and -independent vasodilation using flow-mediated dilation (FMD) as well as metabolic and hormonal profile in morbid, otherwise healthy, obese subjects. Results: Compared with mGFR, the better performing EstForm was CKD-EPI (5.3 ml/min/1.73 m2 bias by Bland-Altman analysis). mGFR was directly related with RPF, total and incremental glucose AUC, and inversely with PTH and h8 cortisol. Patients with mGFR below the median shown significantly higher PTH and lower vitamin D3. Basal or dynamic renal resistive index, FMD, pulse wave velocity were not related with mGFR. In an adjusted regression model, renal diameter and plasma flow remained related with mGFR (R2 = 0.67), accounting for 15% and 21% of mGFR variance, respectively. Conclusions: CKD-EPI formula should be preferred in morbid obesity; glucose increments during oral glucose tolerance test correlate with hyperfiltration; RPF and diameter are independent determinants of mGFR; slightly high PTH values, frequent in obesity, might influence mGFR

Sentinel node mapping in melanoma of the back: SPECT/CT helps discriminate "True" and "False" in-transit lymph nodes

A 32-year-old man with melanoma on the right paramedian region of the lower back underwent lymphoscintigraphy for radioguided sentinel node (SN) biopsy. Planar imaging showed the presence of 2 sites of radioactivity accumulation corresponding to an axillary SN and to an "in-transit" SN, located on the right side of the upper trunk. A further "hot spot" placed on the left paramedian region of the lower back was identified by planar lymphoscintigraphy. This last finding could be mistaken for another "in-transit" SN, but SPECT/CT demonstrated it was actually a nonspecific radiopharmaceutical accumulation at the level of the right renal pelvis

Dynamic 3D analysis of myocardial sympathetic innervation: An experimental study using 123I-MIBG and a CZT camera

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Sentinel lymph node mapping in melanoma: The issue of false-negative findings

Management of cutaneous melanoma has changed after introduction in the clinical routine of sentinel lymph node biopsy (SLNB) for nodal staging. By defining the nodal basin status, SLNB provides a powerful prognostic information. Nevertheless, some debate still surrounds the accuracy of this procedure in terms of false-negative rate. Several large-scale studies have reported a relatively high false-negative rate (5.6%-21%), correctly defined as the proportion of false-negative results with respect to the total number of "actual" positive lymph nodes. In this review, we identified all the technical aspects that the nuclear medicine physician, the surgeon, and the pathologist should take into account to improve accuracy of the procedure and minimize the false-negative rate. In particular, SPECT/CT imaging detects more SLNs than those found by planar lymphoscintigraphy. Furthermore, the nuclear medicine community should reach a consensus on the radioactive counting rate threshold to better guide the surgeon in identifying the lymph nodes with the highest likelihood of housing metastases ("true biologic SLNs"). Analysis of the harvested SLNs by conventional techniques is also a further potential source for error. More accurate SLN analysis (eg, molecular analysis by reverse transcriptase-polymerase chain reaction) and more extensive SLN sampling identify more positive nodes, thus reducing the false-negative rate.The clinical factors identifying patients at higher-risk local recurrence after a negative SLNB include older age at diagnosis, deeper lesions, histological ulceration, and head-neck anatomic location of the primary lesion.The clinical impact of a false-negative SLNB on the prognosis of melanoma patients remains controversial, because the majority of studies have failed to demonstrate overall statistically significant disadvantage in melanoma-specific survival for false-negative SLNB patients compared with true-positive SLNB patients.When new more effective drugs will be available in the adjuvant setting for stage III melanoma patients, the implication of an accurate staging procedure for the sentinel lymph nodes will be crucial for both patients and clinicians. Standardization and accuracy of SLN identification, removal, and analysis are required

The value of oro-pharyngo-esophageal scintigraphy in the management of patients with aspiration into the tracheo-bronchial tree and consequent dysphagia

Tracheo-bronchial aspiration is the most invalidating condition which can happen to patients affected by dysphagia, especially when caused by central neurologic disorders; the associated pneumonia episodes represent the most frequent cause of death in these patients. Oro-pharyngo-esophageal scintigraphy (OPES) allows both functional imaging and semiquantitative evaluation of the subsequent phases of swallowing. CASE REPORT: We evaluated by means of OPES a woman who had previously undergone high-dose external beam radiation therapy for a nasopharyngeal carcinoma, which determined tissue fibrosis and progressive dysphagia. CONCLUSION: In this patient with dysphagia, OPES was a simple, inexpensive, noninvasive, and reliable technique that allowed to show the presence of bolus aspiration and quantified tracheobronchial aspirate