Lutetium [177Lu]-DOTA-TATE in gastroenteropancreatic-neuroendocrine tumours: rationale, design and baseline characteristics of the Italian prospective observational (REAL-LU) study.

PURPOSE: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [177Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [177Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein. METHODS: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [177Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [177Lu]Lu-DOTA-TATE for GEP-NETs in Italy. RESULTS: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [177Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry. CONCLUSION: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature. STUDY REGISTRATION: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1.

Prevention of systemic toxicity in hyperthermic isolated lung perfusion using radioisotopic leakage monitoring.

RATIONALE: Hyperthermic isolated lung Perfusion (ILuP) is used to deliver high-dose chemotherapy to pulmonary metastases while sparing systemic toxicity. Accurate leakage monitoring is however necessary. This study aimed to verify the accuracy of radionuclide leakage monitoring in patients undergoing ILuP, by comparing this method with serial blood sampling. METHODS: A total of 15 consecutive ILuP procedures were performed on eleven patients affected by lung metastases from soft tissue sarcoma. After establishing isolated perfusion, erythrocytes of systemic blood (SB) were labelled with 0.2 MBq/kg of 99mTc. The baseline SB counting rate (CR) was assessed using a γ-probe. Subsequently, erythrocytes of the circuit blood (CB) were labelled with 2 Mbq/kg of 99mTc. Radioactivity leakage factor (RLF) was continuously measured using a formula, accounting for CR, systemic/circuit activity ratio and total/systemic volume ratio. The TNF-α concentration in SB and CB was measured by enzymelinked immunosorbent assay (ELISA) throughout the procedure. RESULTS: RLF averaged 2.3 ± 1.5%, while the systemic/circuit TNF-α ratio was 0.05 ± 0.12%. These two indices were strictly correlated in all of the procedures (average Rvalue 0.88 ± 0.07). RLF exceeded 5% during three of 15 procedures, prompting the application of compensatory manoeuvres. ELISA confirmed a marked increase in systemic TNF-α levels in these patients (2.6 ± 3.5 ng/ml). Conversely, patients whose RLF did not exceed the 5% threshold presented a mean TNF-α of 0.02 ± 0.005 ng/ml (p < 0.01). CONCLUSIONS: In patients submitted to ILuP, RLF monitoring is feasible and accurate. Moreover, it grants immediate results, permitting for the adoption of corrective manoeuvres for leakage, thus minimising toxicity.

Doxorubicin Effect on Myocardial Metabolism as a Prerequisite for Subsequent Development of Cardiac Toxicity: A Translational 18F-FDG PET/CT Observation.

The present translational study aimed to verify whether serial 18F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive 18F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min-1 × g-1 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min-1 × g-1, P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min-1 × g-1, P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline 18F-FDG uptake. These results imply that low myocardial 18F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.

A PET/CT approach to spinal cord metabolism in amyotrophic lateral sclerosis.

PURPOSE: In amyotrophic lateral sclerosis, functional alterations within the brain have been intensively assessed, while progression of lower motor neuron damage has scarcely been defined. The aim of the present study was to develop a computational method to systematically evaluate spinal cord metabolism as a tool to monitor disease mechanisms. METHODS: A new computational three-dimensional method to extract the spinal cord from (18)F-FDG PET/CT images was evaluated in 30 patients with spinal onset amyotrophic lateral sclerosis and 30 controls. The algorithm identified the skeleton on the CT images by using an extension of the Hough transform and then extracted the spinal canal and the spinal cord. In these regions, (18)F-FDG standardized uptake values were measured to estimate the metabolic activity of the spinal canal and cord. Measurements were performed in the cervical and dorsal spine and normalized to the corresponding value in the liver. RESULTS: Uptake of (18)F-FDG in the spinal cord was significantly higher in patients than in controls (p < 0.05). By contrast, no significant differences were observed in spinal cord and spinal canal volumes between the two groups. (18)F-FDG uptake was completely independent of age, gender, degree of functional impairment, disease duration and riluzole treatment. Kaplan-Meier analysis showed a higher mortality rate in patients with standardized uptake values above the fifth decile at the 3-year follow-up evaluation (log-rank test, p < 0.01). The independence of this value was confirmed by multivariate Cox analysis. CONCLUSION: Our computational three-dimensional method enabled the evaluation of spinal cord metabolism and volume and might represent a potential new window onto the pathophysiology of amyotrophic lateral sclerosis.

Baseline and ongoing PET-derived factors predict detrimental effect or potential utility of 18F-FDG PET/CT (FDG-PET/CT) performed for surveillance in asymptomatic lymphoma patients in first remission.

PURPOSE: To identify both clinical and FDG PET/CT-derived factors predicting the occurrence of relapse, or conversely, the likelihood of false positive findings in surveillance FDG-PET/CT studies (PETsv). METHODS: The study included 149 asymptomatic patients with Hodgkin's lymphoma (HL) (n = 55) or diffuse large B cell lymphoma (DLBCL) (n = 94) in first remission. PETSv studies were performed 12, 18, 24 and 36 months thereafter. Logistic regression analysis was performed to identify clinical and imaging-derived predictors of either PET-detected relapse or false-positive (FP) results. Tested clinical variables were: 1) age, 2) HL vs. DLBCL, 3) stage of disease, 4) bulky disease, 5) previous radiotherapy. PET/CT-derived variables were: 1) maximum standardized uptake value at baseline, 2) size-incorporated maximum standardized uptake value (SIMaxSUV) at baseline, 3) positive interim PET(PET-2), 4) presence of hot spots likely to be unrelated to the disease in final PET, 5) residual non-FDG avid mass. RESULTS: Accuracy was 88 % for PETsv1, 95 % for PETsv2, 95 % for PETsv3 and 91 % for PETsv4. However, PPV was relatively low in all PETsv. Best predictors of relapse were result of interim PET, HL versus NHL type, SIMaxSUV, age ≥ 60. Best predictors of FP were previous radiotherapy and hot spots unrelated to the disease in final PET. CONCLUSIONS: The present study confirms the need of restricting the use of surveillance PET/CT to patients at high risk of relapse. Information derived from PET/CT performed at baseline (metabolic disease burden), in the course (PET2) and at the end of therapy (unrelated hot spots) can help to select high-risk patients and also to identify patients more likely to present equivocal findings at PETsv.

Clinical efficacy of radioiodine therapy in multinodular toxic goiter, applying an implemented dose calculation algorithm.

Radioiodine is a common therapeutic option for Multinodular Toxic Goiter (MTG). We evaluated an algorithm for personalized radioiodine activity calculation. Ninety-three (28 male, 65 female; 43-84 years) patients with MTG eligible for radioiodine treatment (131I-iodide) were studied. The quantity of 131I-iodide to be administered was estimated by Thyroid Volume Reduction (TVR) algorithm, developed for Graves' disease. It takes into account 131I uptake, its effective half-life (T1/2eff), thyroid volume, and its expected reduction during treatment. A comparison with the activity calculated by other dosimetric protocols and the "fixed" activity method was performed. 131I uptake was measured by external counting, thyroid volume by ultrasonography (US), thyroid stimulating hormone (TSH), and thyroid hormones by standard immunometric methods. In a follow-up of 6-120 months, remission of hyperthyroidism after a single 131I-iodide treatment was observed in 76 patients (64 euthyroid, 12 hypothyroid). The thyroid volume reduction observed by US after the treatment fairly correlated with what predicted by our model; T1/2eff was highly variable and critically affected dose calculation. The administered activities (median 526 MBq, range 156-625 MBq) were slightly lower than the "fixed" activities (600 MBq) and with respect to the other protocols' prescriptions (-15/38%); the median 131I activity administered to relapsed patients (605 MBq) was significantly greater (P=0.01) with respect to the dose administered to cured patients (471 MBq). Our study shows that an effective cure of MTG can be obtained with relatively low 131I activities and probably with a relatively low incidence of hypothyroidism, using TVR method.

Reduced coronary flow reserve in patients with primary hyperparathyroidism: a study by G-SPECT myocardial perfusion imaging.

PURPOSE: The mechanisms underlying increased cardiovascular risk in primary hyperparathyroidism (pHPT) have not been fully defined. Recently, this issue has become the subject of renewed interest due to the increasing evidence that the endothelium and vascular wall are targets for parathyroid hormone (PTH). The aim of this study was to measure regional coronary flow reserve (CFR) to determine whether the vascular damage induced by pHPT extends to affect the coronary microvascular function. METHODS: A total of 22 pHPT patients without a history of coronary artery disease and 7 age-matched control subjects were recruited. Dipyridamole myocardial blood flow (MBF) was assessed using 99mTc-sestamibi by measuring first-transit counts in the pulmonary artery and myocardial count rate from G-SPECT images. Baseline MBF was estimated 2 h later according to the same procedure. Regional CFR was defined as the ratio between dipyridamole and baseline MBF using a 17-segment left ventricular model. RESULTS: Three pHPT patients showed reversible perfusion defects and were excluded from the analysis. In the remaining 19, CFR was significantly lower with respect to the control subjects (1.88±0.64 vs. 3.36±0.66, respectively; p<0.01). Moreover, patients studied for more than 28 months from pHPT diagnosis showed lower CFR values than the others (1.42±0.18 vs. 2.25±0.64, respectively; p<0.01). Consequently, the time from diagnosis to the nuclear study showed a reasonable correlation with the degree of CFR impairment (Spearman's rho -0.667, p<0.02). CONCLUSION: pHPT is associated with a significant dysfunction of the coronary microcirculation. This disorder might contribute to the high cardiovascular risk of conditions characterized by chronic elevations in serum PTH levels.

Whole body and cardiac metaiodobenzylguanidine kinetics in Parkinson disease and multiple system atrophy: implications for the diagnostic role of imaging.

PURPOSE OF THE REPORT: This study investigates whether combined analysis of I-123 metaiodobenzylguanidine (MIBG) kinetics in the heart and in the whole body can improve the accuracy of differential diagnosis between idiopathic Parkinson disease (PD) and a Parkinson variant of multiple system atrophy (MSA-P). MATERIALS AND METHODS: A total of 30 patients with clinical suspicion of PD (n = 16) or MSA-P (n = 14) underwent MIBG whole-body planar imaging. Final diagnosis was confirmed at follow-up. Images were collected 30 minutes and 4 hours after tracer injection. Myocardial uptake was evaluated by measuring heart/mediastinum (H/M) ratio and the percent fraction of the injected dose retained by the heart (calculated by whole-body counts). Tracer washout was measured from both the heart and the whole body. RESULTS: H/M ratio was lower in PD than in MSA-P at early imaging (1.32 +/- 0.21 vs. 1.81 +/- 0.46, respectively, P < 0.01), although a large overlap in individual data was observed. By contrast, % of injected dose taken up by the heart documented a large difference between PD and MSA-P (0.97% +/- 0.51% vs. 1.91% +/- 0.66% of the dose, P < 0.01), and a very small overlap in individual values. There was no difference in the heart washout between the 2 Groups (31% +/- 13% vs. 32% +/- 15%, P = 0.9), while tracer loss from the whole body was higher in PD than in MSA-P (29% +/- 12% vs. 19% +/- 10%, P < 0.01). CONCLUSIONS: PD and its correlated global postganglionic dysfunction alter MIBG kinetics in the heart and in the whole body. Image analysis accounting for tracer kinetics in the whole body may improve the diagnostic accuracy of this test in patients with suspected PD or MSA-P.

Witnessing ischemia or proofing coronary atherosclerosis: two different windows on the same or on different pathways precipitating cardiovascular events?

Risk stratification and prevention of future cardiac events is an extremely relevant part of the daily medical practice in the large population of asymptomatic or scarcely symptomatic patients. The strategies available to this purpose encompass programs intended either to reduce progression and complications of atherosclerosis, and revascularization procedures aimed to reduce total ischemic burden. The former represents a primary prevention approach and fights the substrate of ischemic heart disease. The latter, instead, is used to reduce the total ischemic burden and thus implies to identify those patients in whom ischemia can be life threatening because of its severity and extension. Today, at least two imaging methods are available for this task: coronary calcium scoring by x-ray CT and ischemia assessment by myocardial perfusion imaging. Although both approaches can accurately estimate cardiovascular risk, from a theoretical point of view, the assessment of ischemia evaluates the functional consequences of coronary obstructions and thus the target of revascularization procedure, while estimating the total atherosclerotic burden represents an indirect index of it. This difference might appear academic in its nature, given the current model of ischemic heart disease pathophysiology that assumes and predicts a very tight correlation between the severity of a coronary stenosis and its capability to cause ischemia. However, the majority of studies focused on the combined risk assessment with both approaches confirm the relevance of this issue. In fact, among 7785 patients reported in the literature, coronary calcium scoring most often resulted in positive findings (78%). However, this sign of atherosclerosis was associated with inducible ischemia in only one-fifth of patients. In the near future, coronary calcium scoring will be easily and immediately completed by the noninvasive definition of coronary stenoses. At that time we will face a still largely unknown risk: the presence of a stenosis in the absence of symptoms and of ischemia. Evaluating the effectiveness of different protocols will thus be needed to improve our capability to help these patients.

Whole-body evaluation of MIBG tissue extraction in a mouse model of long-lasting type II diabetes and its relationship with norepinephrine transport protein concentration.

UNLABELLED: Accelerated cardiac washout of (123)I-metaiodobenzylguanidine (MIBG), which is clinically used as an index of cardiac neuropathy in diabetes, is ascribed to decreased norepinephrine reuptake into synaptic vesicles. However, accelerated washout frequently contrasts with preserved early tracer uptake, whose significance remains undetermined. The aim of this study was to investigate in a mouse model of long-lasting type II diabetes whether the mismatch between MIBG early uptake and washout is the consequence of a more generalized disorder of the autonomic nervous system. METHODS: Nine mice were given low doses of streptozotocin by intraperitoneal injection for 5 consecutive days. At 7 mo after streptozotocin, MIBG kinetics were evaluated by heart and liver time-activity curves and by tracer accumulation in the bladder. Data were compared with those obtained in 10 sham mice and correlated with the cardiac and hepatic tissue expression of norepinephrine transporter (NET) as assessed with a (3)H-desipramine saturation binding assay. RESULTS: In diabetic mice, myocardial and liver MIBG retention was reduced at 2 h and was associated with both increased tracer washout and reduced NET density. The rate of myocardial washout correlated with the degree of urinary MIBG excretion. CONCLUSION: The paradoxic observation of preserved early uptake associated with accelerated washout of MIBG in diabetes seems to be explained by a generalized disorder in NET function leading to reduced whole-body tracer removal from the blood and increased tracer availability for early myocardial uptake.