Impact of Tracer Retention Levels on Visual Analysis of Cerebral [18F]- Florbetaben Pet Images.

BACKGROUND: To compare visual and semi-quantitative analysis of brain [18F]Florbetaben PET images in Mild Cognitive Impairment (MCI) patients and relate this finding to the degree of ß-amyloid burden. METHODS: A sample of 71 amnestic MCI patients (age 74 ± 7.3 years, Mini Mental State Examination 24.2 ± 5.3) underwent cerebral [18F]Florbetaben PET/CT. Images were visually scored as positive or negative independently by three certified readers blinded to clinical and neuropsychological assessment. Amyloid positivity was also assessed by semiquantitative approach by means of a previously published threshold (SUVr ≥ 1.3). Fleiss kappa coefficient was used to compare visual analysis (after consensus among readers) and semi-quantitative analysis. Statistical significance was taken at P<0.05. RESULTS: After the consensus reading, 43/71 (60.6%) patients were considered positive. Cases that were interpreted as visually positive had higher SUVr than visually negative patients (1.48 ± 0.19 vs 1.11 ± 0.09) (P<0.05). Agreement between visual analysis and semi-quantitative analysis was excellent (k=0.86, P<0.05). Disagreement occurred in 7/71 patients (9.9%) (6 false positives and 1 false negative). Agreement between the two analyses was 90.0% (18/20) for SUVr < 1.1, 83% (24/29) for SUVr between 1.1 and 1.5, and 100% (22/22) for SUVr > 1.5 indicating lowest agreement for the group with intermediate amyloid burden. CONCLUSION: Inter-rater agreement of visual analysis of amyloid PET images is high. Agreement between visual analysis and SUVr semi-quantitative analysis decreases in the range of 1.1

The brain cognitive reserve hypothesis: A review with emphasis on the contribution of nuclear medicine neuroimaging techniques.

Neuropathological and clinical evidence indicates that the clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain reserve capacity. The brain or cognitive reserve (BCR) hypothesis states that high premorbid intelligence, education, and an active and stimulating lifestyle provide reserve capacity, which acts as a buffer against the cognitive deficits due to accumulating neuropathology. Neuroimaging studies that assessed the BCR hypothesis are critically reviewed with emphasis on study design and statistical analysis. Many studies were performed in the last two decades owing to the increasing availability of positron emission tomography (PET) and PET/computed tomography scanners and to the synthesis of new radiopharmaceuticals, including tracers for amyloid and tau proteins. Studies with different tracers provided complementary consistent results supporting the BCR hypothesis. Many studies were appropriately designed with a measure of reserve, a measure of brain anatomy/function/neuropathology, and a measure of cognitive functions that are necessary. Most of the early studies were performed with PET and [ 18 F]fluorodeoxyglucose, and occasionally with [ 15 O]water, reporting a significant association between higher occupation/education and lower glucose metabolism (blood flow) in associative temporo-parietal cortex in patients with AD and also in patients with MCI, after correcting for the degree in the cognitive impairment. On the contrary, performances on several neuropsychological tests increased with increasing education for participants with elevated [ 11 C]PiB uptake. Studies with the tracers specific for tau protein showed that patients with AD with elevated tau deposits had higher cognitive performances compared with patients with similar levels of tau deposits. BCR in AD is also associated with a preserved cholinergic function. The BCR hypothesis has been validated with methodologically sound study designs and sophisticated neuroimaging techniques using different radiotracers and providing an explanation for neuropathological and clinical observations on patients with AD.

[68Ga]-Dota Peptide PET/CT in Neuroendocrine Tumors: Main Clinical Applications.

OBJECTIVE: Neuroendocrine Neoplasms (NENs) are generally defined as rare and heterogeneous tumors. The gastrointestinal system is the most frequent site of NENs localization, however they can be found in other anatomical regions, such as pancreas, lungs, ovaries, thyroid, pituitary, and adrenal glands. Neuroendocrine neoplasms have significant clinical manifestations depending on the production of active peptide. METHODS: Imaging modalities play a fundamental role in initial diagnosis as well as in staging and treatment monitoring of NENs, in particular they vastly enhance the understanding of the physiopathology and diagnosis of NENs through the use of somatostatin analogue tracers labeled with appropriate radioisotopes. Additionally, the use of somatostatin analogues provides the ability to in-vivo measure the expression of somatostatin receptors on NEN cells, a process that might have important therapeutic implications. RESULTS: A large body of evidences showed improved accuracy of molecular imaging based on PET/CT radiotracer with SST analogues (e.g. [68Ga]-DOTA peptide) for the detection of NEN lesions in comparison to morphological imaging modalities. So far, the role of imaging technologies in assessing treatment response is still under debate. CONCLUSION: This review offers the systems of classification and grading of NENs and summarizes the more useful recommendations based on data recently published for the management of patients with NENs, with special focus on the role of imaging modalities based on SST targeting with PET / CT radiotracers.

Sensitivity of fluorine-18-fluoromethylcholine PET/CT to prostate-specific antigen over different plasma levels: a retrospective study in a cohort of 192 patients with prostate cancer.

PURPOSE: Several factors have been identified that predict positive fluorine-18-fluoromethylcholine (F-FCH) PET/CT result in patients with prostate cancer undergoing PET/CT for biochemical failure. Among these factors, prostate-specific antigen (PSA) is the single factor most consistently associated with the prediction of positive F-FCH PET/CT. In this study, we wished to confirm this finding and expand it in a large series of patients. PATIENTS AND METHODS: We retrospectively analyzed 192 patients with prostate cancer who were recruited from the Nuclear Medicine Department of the Sant'Andrea Hospital of La Spezia, Italy, from March 2013 to March 2018 and who underwent F-FCH PET/CT owing to biochemical failure after radical prostatectomy. RESULTS: Median trigger PSA was 2.57 ng/ml. The overall positive detection rate of F-FCH PET/CT was 60.9%. The percent of positive scans was 30.5% for PSA less than 1 ng/ml, 59.4% (38/64) for PSA between 1 and 5 ng/ml, and 88.4% for PSA greater than 5 ng/ml (P<0.001). On univariate regression analysis, high PSA levels, biochemical failure during antiandrogenic therapy at the time of PET/CT, and older age significantly (P<0.05) predicted positive F-FCH PET/CT result. On multivariate regression analysis, only high PSA levels and biochemical failure during antiandrogenic therapy maintained the statistical significance (P<0.05). However, when the analysis was restricted to patients with PSA less than 1 ng/ml, PSA lost the statistical significance. Receiver operating characteristic analysis revealed an area under the curve of 0.795. The PSA cutoff value that best distinguished PET/CT-positive from PET/CT-negative patients was 2.57 ng/ml. Sensitivity and specificity at this PSA value were 66.7 and 76.0%, respectively. CONCLUSION: This study confirms that PSA robustly predicts positive PET/CT result with radiolabeled choline. Unfortunately, this study also confirms the limited sensitivity of F-FCH PET/CT for PSA less than 1 ng/ml, which currently represents the weakest point of the technique.

Molecular Imaging of Huntington's Disease.

The onset and the clinical progression of Huntington Disease (HD) is influenced by several events prompted by a genetic mutation that affects several organs tissues including different regions of the brain. In the last decades years, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) helped to deepen the knowledge of neurodegenerative mechanisms that guide to clinical symptoms. Brain imaging with PET represents a tool to investigate the physiopathology occurring in the brain and it has been used to predict the age of onset of the disease and to evaluate the therapeutic efficacy of new drugs. This article reviews the contribution of PET and MRI in the research field on Huntington's disease, focusing in particular on some most relevant achievements that have helped recognize the molecular changes, the clinical symptoms and evolution of the disease. J. Cell. Physiol. 232: 1988-1993, 2017. © 2016 Wiley Periodicals, Inc.

Radium 223 dichloride: a multidisciplinary approach to metastatic castration-resistant prostate cancer.

The role of nuclear medicine physicians in the multidisciplinary team for the management of patients with prostate cancer has been restricted because of a lack of available tools. The only drugs approved to relieve pain related to bone metastases were ß-emitting radiopharmaceuticals. These drugs did not prove to prolong survival when used as single agent and resulted associated with important adverse events. This situation has changed with the introduction of radium 223 because of evidence of improved survival in patients, the good safety profile and the opportunity to avoid clonal selection of tumor cells. Cooperation among physicians involved in cancer management will lead to improvements in the treatment of bone metastases due to prostate cancer and is thought to extend to other tumor types.

Disseminated bone metastases from occult thyroid cancer effectively treated with debulking surgery and a single dosimetry-guided administration of radioiodine.

In this paper we report on a successful management of multiple bone metastases from differentiated thyroid cancer. In 2007, a 75-year-old female patient, previously referred for thyroidectomy for multinodular goiter, underwent surgical removal of a lumbar mass with histological findings of metastasis from well differentiated thyroid cancer. After surgery, serum thyroglobulin (sTg) was 204.4 ng/mL. A diagnostic/dosimetric (123)I WBS was performed, following stimulation by rTSH. Serial WBSs were acquired, along with SPECT/CT and bone scan for localization of lesions. sTg raised to 3.810 ng/mL, and (123)I WBS showed thyroid remnants and numerous areas with high iodine-uptake corresponding to skeletal sites, the two largest loading on the skull, with osteolytic pattern. Calculated radiation absorbed dose for skull lesions, determined by mean of MIRD methodology, was 63.5 mGy/MBq. The patient underwent surgical removal of the two major skull lesions. Successively, 100 mCi (131)I was administered after stimulation by rTSH, with stimulated sTg 297 ng/mL. After 8 months, diagnostic WBS was negative both for remnants and metastases and rTSH-stimulated Tg was 0.6 ng/mL. To date, the patient has maintained sTg values <1 ng/mL during L-T4 suppressive therapy and after rTSH stimulations. In this unusual case of extensive bone cancerous involvement with high iodine avidity, a multidisciplinary approach based on surgery and dosimetry-guided radiometabolic therapy allowed to accurately assess the patient, execute a small number of treatments and achieve a complete remission of the disease in a very short time, with no additive morbidity.

Safety and antitumor efficacy of (153)Sm-EDTMP and docetaxel administered sequentially to patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Bone metastases are responsible for most of the morbidity associated with metastatic castration-resistant prostate cancer (mCRPC). Bone-seeking radiopharmaceuticals have been approved for palliation of painful skeletal metastases, but their clinical use is limited by concerns of toxicities both when administered alone and especially when combined with chemotherapy agents. OBJECTIVE: We investigated whether docetaxel administered to mCRPC patients after treatment with samarium-153-labeled ethylene-diamine-tetra-methylene-phosphonic acid (Sm-EDTMP) has increased toxicity and/or reduced antitumor efficacy. MATERIALS AND METHODS: Thirty mCRPC patients with skeletal metastases were enrolled. Patients received standard therapy with docetaxel (75 mg/m intravenously every 21 days for at least six cycles) on average 6 weeks after Sm-EDTMP (37 MBq/kg). Patients were monitored for the presence of toxicities, and antitumor efficacy was assessed by changes in serum prostate-specific antigen levels. Besides standard descriptive statistical analysis, progression-free survival and overall survival were defined using the Kaplan-Meier method. RESULTS: Over 80% of the patients showed favorable biochemical responses. Median time to progression was 9.1 months (mean 9.8, 95% confidence interval 7.8-9.9), and median overall survival was 19.9 months (mean 24.5, 95% confidence interval 16.9-22.8); five patients were still alive over 5 years after enrollment. No additional hematological toxicities were observed when docetaxel was administered after Sm-EDTMP other than those expected when administering the agent alone. CONCLUSION: Prior administration of Sm-EDTMP does not cause additional toxicities for subsequent treatment with docetaxel and does not reduce the antitumor efficacy of the latter. This work justifies further investigations on the possible synergistic effects of combined strategies with the two agents.

Optimal detection of sentinel lymph node metastases by intraoperative radioactive threshold and molecular analysis in patients with melanoma.

UNLABELLED: The aim of this study was to optimize a protocol for radioguided biopsy of the sentinel lymph node (SLN) in patients with melanoma. The protocol was based on a combination of ex vivo counting of the nodes detected intraoperatively and analysis of the harvested nodes by hematoxylin and eosin staining plus immunohistochemistry (conventional histopathology [PATH]) and by molecular biology (reverse-transcriptase polymerase chain reaction [RT-PCR]). METHODS: A total of 124 patients with primary clinical stage I-II (according to the American Joint Committee on Cancer) cutaneous melanoma underwent successful radioguided SLN biopsy. SLNs harvested for analysis included any additional nodes whose ex vivo counting rate exceeded 20% of the hottest node. All removed SLNs were examined by conventional PATH and with RT-PCR analysis for the expression of messenger RNA for tyrosinase and the melanoma antigens recognized by T cells. Complete lymph node dissection (CLND) was performed only in the case of SLN metastasis detected by PATH. Different combinations of the intraoperative parameters (only the hottest node and all nodes harvested) and of analysis (PATH and RT-PCR) were tested as predictors of clinical outcome on the basis of long-term follow-up (12-81 mo; median, 55 mo). RESULTS: A total of 197 SLNs were harvested, 41 of which harbored metastasis as detected by RT-PCR analysis; PATH detected metastasis in only 24 of 41 metastatic SLNs. In 5 of 41 instances, metastasis was not in the hottest SLN. The main factor determining correct classification of the SLN status was RT-PCR, which significantly improved detection of metastasis, even if applied only to the hottest node (P < 0.0001 vs. PATH analysis of either the hottest SLN or all nodes above the 20% threshold). Metastatic disease recurred locally in 5 patients who had not undergone CLND; RT-PCR analysis showed metastasis in 4 of these patients. The false-negative rate of SLN biopsy progressively decreased when applying PATH only to the hottest node (32.1%), additional RT-PCR to the hottest node (21.4%), PATH to all nodes (17.9%), and RT-PCR to all nodes (3.6%, P = 0.015 vs. PATH analysis of only the hottest SLN). CONCLUSION: On the basis of long-term follow-up (the gold standard for final clinical outcome of SLN biopsy), both 20% threshold and RT-PCR analysis should be applied for optimal detection of nodal metastases in patients with melanoma.

Comparison of different thyroid committed doses in radioiodine therapy for Graves' hyperthyroidism.

Despite vast worldwide experience in the use of 131I for treating Graves' disease (GD), no consensus of opinion exists concerning the optimal method of dose calculation. In one of the most popular equations, the administered (131)I dose is directly proportional to the estimated thyroid gland volume and inversely proportional to the measured 24-hour radioiodine uptake. In this study, we compared the efficiency of different tissue-absorbed doses to induce euthyroidism or hypothyroidism within 1 year after radioiodine therapy in GD patients. The study was carried out in 134 GD patients (age, 53 +/- 14 year; range, 16-82 year; thyroid volume, 28 +/- 18 mL; range, 6-95 mL; average 24-hour thyroid uptake, 72%) treated with (131)I therapy. The average radioiodine activity administered to patients was 518 +/- 226 MBq (range, 111-1110). The corresponding average thyroid absorbed dose, calculated by a modified Medical Internal Radiation Dose (MIRD) equation was 376 +/- 258 Gy (range, 99-1683). One year after treatment, 58 patients (43%) were hypothyroid, 57 patients (43%) were euthyroid, and 19 patients (14%) remained hyperthyroid. The patients were divided into 3 groups: 150 Gy (n = 32), 300 Gy (n = 58) and >300 Gy (n = 44). No significant difference in the rate of recurrent hyperthyroidism was found among the 3 groups (150 Gy: 15%; 300 Gy: 14%; and > or =300 Gy: 14%; chi-square test, p = 0.72). Whereas, the rate of hypothyroidism in the 3 groups was significantly correlated with the dose (150 Gy: 30%; 300 Gy: 46%; >300 Gy: 71%; chi-square test, p = 0.0003). The results obtained in this study show no correlation between dose and outcome of radioiodine therapy (in terms of persistent hyperthyroidism) for thyroid absorbed doses > or =150 Gy, while confirming the relation between the thyroid absorbed dose and the incidence of hypothyroidism in GD patients.