Does FDG PET-Based Radiomics Have an Added Value for Prediction of Overall Survival in Non-Small Cell Lung Cancer?

Objectives: Radiomics and machine learning are innovative approaches to improve the clinical management of NSCLC. However, there is less information about the additive value of FDG PET-based radiomics compared with clinical and imaging variables. Methods: This retrospective study included 320 NSCLC patients who underwent PET/CT with FDG at initial staging. VOIs were placed on primary tumors only. We included a total of 94 variables, including 87 textural features extracted from PET studies, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. We used the least absolute shrinkage and selection operator (LASSO) regression to select variables with the highest predictive value. Although several radiomics variables are available, the added value of these predictors compared with clinical and imaging variables is still under evaluation. Three hundred and twenty NSCLC patients were included in this retrospective study and underwent 18F-FDG PET/CT at initial staging. In this study, we evaluated 94 variables, including 87 textural features, SUVmax, MTV, TLG, TNM stage, histology, age, and gender. Image-based predictors were extracted from a volume of interest (VOI) positioned on the primary tumor. The least absolute shrinkage and selection operator (LASSO) Cox regression was used to reduce the number of variables and select only those with the highest predictive value. The predictive model implemented with the variables selected using the LASSO analysis was compared with a reference model using only a tumor stage and SUVmax. Results: NGTDM coarseness, SUVmax, and TNM stage survived the LASSO analysis and were used for the radiomic model. The AUCs obtained from the reference and radiomic models were 80.82 (95%CI, 69.01-92.63) and 81.02 (95%CI, 69.07-92.97), respectively (p = 0.98). The median OS in the reference model was 17.0 months in high-risk patients (95%CI, 11-21) and 113 months in low-risk patients (HR 7.47, p < 0.001). In the radiomic model, the median OS was 16.5 months (95%CI, 11-20) and 113 months in high- and low-risk groups, respectively (HR 9.64, p < 0.001). Conclusions: Our results indicate that a radiomic model composed using the tumor stage, SUVmax, and a selected radiomic feature (NGTDM_Coarseness) predicts survival in NSCLC patients similarly to a reference model composed only by the tumor stage and SUVmax. Replication of these preliminary results is necessary.

Multivariable Risk Modelling and Survival Analysis with Machine Learning in SARS-CoV-2 Infection.

AIM: To evaluate the performance of a machine learning model based on demographic variables, blood tests, pre-existing comorbidities, and computed tomography(CT)-based radiomic features to predict critical outcome in patients with acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We retrospectively enrolled 694 SARS-CoV-2-positive patients. Clinical and demographic data were extracted from clinical records. Radiomic data were extracted from CT. Patients were randomized to the training (80%, n = 556) or test (20%, n = 138) dataset. The training set was used to define the association between severity of disease and comorbidities, laboratory tests, demographic, and CT-based radiomic variables, and to implement a risk-prediction model. The model was evaluated using the C statistic and Brier scores. The test set was used to assess model prediction performance. RESULTS: Patients who died (n = 157) were predominantly male (66%) over the age of 50 with median (range) C-reactive protein (CRP) = 5 [1, 37] mg/dL, lactate dehydrogenase (LDH) = 494 [141, 3631] U/I, and D-dimer = 6.006 [168, 152.015] ng/mL. Surviving patients (n = 537) had median (range) CRP = 3 [0, 27] mg/dL, LDH = 484 [78, 3.745] U/I, and D-dimer = 1.133 [96, 55.660] ng/mL. The strongest risk factors were D-dimer, age, and cardiovascular disease. The model implemented using the variables identified using the LASSO Cox regression analysis classified 90% of non-survivors as high-risk individuals in the testing dataset. In this sample, the estimated median survival in the high-risk group was 9 days (95% CI; 9-37), while the low-risk group did not reach the median survival of 50% (p < 0.001). CONCLUSIONS: A machine learning model based on combined data available on the first days of hospitalization (demographics, CT-radiomics, comorbidities, and blood biomarkers), can identify SARS-CoV-2 patients at risk of serious illness and death.

Medical Imaging of Inflammations and Infections of Breast Implants.

Breast implants are widely used for reconstructive and/or cosmetic purposes. Inflammations and infections of breast implants represent important complications in clinical practice. The proper management of complications is necessary: diagnostic imaging plays a key role in detecting sites of inflammation and/or infection. The present review aims to illustrate the radiological findings of these conditions with different imaging techniques, such as mammography (MX), ultrasound (US), magnetic resonance imaging (MRI), and nuclear medicine imaging. A knowledge of these findings is essential for radiologists and nuclear medicine physicians to provide helpful information for the clinical management of these complications.

Assessment of Response to Immunotherapy in Patients with Hodgkin Lymphoma: Towards Quantifying Changes in Tumor Burden Using FDG-PET/CT.

Immune checkpoint inhibitors are currently the standard of care for many advanced solid tumors, and they have been recently approved for the treatment of relapsed/refractory Hodgkin lymphoma and primary mediastinal B cell lymphoma. Assessments of the response to immunotherapy may be complicated by the occurrence of the flare/pseudoprogression phenomenon, consisting of initial tumor enlargement and even the appearance of new lesions, followed by a response, which may initially be indistinguishable from true progression. There have been efforts to characterize and capture the new patterns of response observed during immunotherapy, namely, pseudoprogression and delayed response, and several immune-related response criteria have been proposed. Confirming progression on a subsequent scan and measuring the total tumor burden are both common in immune-related criteria. Due to the peculiarity of hematologic malignancies, lymphoma-specific immune-related criteria have been developed (LYRIC), and they have been evaluated in research studies in comparison to the Lugano Classification. In this review work, we illustrate the evolution of the response criteria in lymphomas from the first CT-based criteria to the development of the PET-based Lugano Classification, further refined to take into account the flare phenomenon encountered during immunotherapy. We also describe the additional contribution of PET-derived volumetric parameters to the interpretation of responses during immunotherapy.

Machine Learning Model to Predict Diagnosis of Mild Cognitive Impairment by Using Radiomic and Amyloid Brain PET.

PURPOSE: The study aimed to develop a deep learning model for predicting amnestic mild cognitive impairment (aMCI) diagnosis using radiomic features and amyloid brain PET. PATIENTS AND METHODS: Subjects (n = 328) from the Alzheimer's Disease Neuroimaging Initiative database and the EudraCT 2015-001184-39 trial (159 males, 169 females), with a mean age of 72 ± 7.4 years, underwent PET/CT with 18 F-florbetaben. The study cohort consisted of normal controls (n = 149) and subjects with aMCI (n = 179). Thirteen gray-level run-length matrix radiomic features and amyloid loads were extracted from 27 cortical brain areas. The least absolute shrinkage and selection operator regression was used to select features with the highest predictive value. A feed-forward neural multilayer network was trained, validated, and tested on 70%, 15%, and 15% of the sample, respectively. Accuracy, precision, F1-score, and area under the curve were used to assess model performance. SUV performance in predicting the diagnosis of aMCI was also assessed and compared with that obtained from the machine learning model. RESULTS: The machine learning model achieved an area under the receiver operating characteristic curve of 90% (95% confidence interval, 89.4-90.4) on the test set, with 80% and 78% for accuracy and F1-score, respectively. The deep learning model outperformed SUV performance (area under the curve, 71%; 95% confidence interval, 69.7-71.4; 57% accuracy, 48% F1-score). CONCLUSIONS: Using radiomic and amyloid PET load, the machine learning model identified MCI subjects with 84% specificity at 81% sensitivity. These findings show that a deep learning algorithm based on radiomic data and amyloid load obtained from brain PET images improves the prediction of MCI diagnosis compared with SUV alone.

Methodological Aspects and the Prognostic Value of Metabolic Tumor Volume assessed with 18F-FDG PET/CT in Lymphomas.

Although metabolic tumor volume (MTV) assessed with pretreatment 18F-FDG PET/CT has shown significant prognostic value across many lymphoma types, it is still not used in clinical practice due to technical concerns and the lack of standardisation. Numerous studies on the prognostic value of MTV in lymphomas have been published in recent years, but there is still no full agreement on the best methodology for MTV calculation. In this paper, we reviewed the methodological aspects of MTV assessment and reported recent works about its impact on outcome in lymphomas, with a focus on Hodgkin lymphoma (HL) and diffuse large B cell lymphoma (DLBCL).

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

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 improvements 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.

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.

11C-choline PET/CT predicts survival in prostate cancer patients with PSA < 1 NG/ml.

PURPOSE: The main drawback of 11C-choline PET/CT for restaging prostate cancer (PCa) patients with biochemical failure is the relatively low positive detection rate for prostate specific antigen (PSA) < 1 ng/ml. This study assessed whether 11C-choline PET/CT predicts survival in PCa patients with PSA < 1 ng/ml. METHODS: This retrospective study included 210 PCa patients treated with radical prostatectomy who underwent 11C-choline PET/CT from December 1, 2004 to July 31, 2007 due to biochemical failure. PCa-specific survival was estimated using Kaplan-Meier curves. Cox regression analysis was used to evaluate the association between clinicopathologic variables and PCa-specific survival. PCa-specific survival was computed as the interval from radical prostatectomy to PCa-specific death. RESULTS: Median follow-up after radical prostatectomy was 6.9 years (95% confidence interval, CI, 2.0-14.5 years). 11C-choline PET/CT was positive in 20.5% of patients. Median PCa-specific survival was 13.4 years (95% CI, 9.9-16.8 years) in patients with positive 11C-choline PET/CT, and it was not achieved in patients with negative 11C-choline PET/CT (log-rank, chi-square = 15.0, P < 0.001). Ten-year survival probabilities for patients with negative 11C-choline PET/CT and for patients with positive 11C-choline PET/CT were 86.0% (95% CI: 80.7%-91.3%) and 63.6% (95% CI: 54.5-72.7%). At multivariate analysis, only 11C-choline PET/CT significantly predicted PCa-specific survival (hazard ratio = 2.54, 95% CI, 1.05-6.13, P = 0.038). Patients with pathological 11C-choline uptake in the prostatic bed or in pelvic lymph nodes had longer PCa-specific survival in comparison to patients with pathological tracer uptake in the skeleton (log-rank: chi-square = 27.4, P < 0.001). CONCLUSION: Despite the relatively low positive detection rate for PSA < 1 ng/ml, positive 11C-choline PET/CT predicts PCa-specific survival in this low PSA range. As long as more sensitive radiotracers, such as 68Ga-PSMA-11, do not become more widely available, these results might support a broader use of radiolabeled choline in restaging PCa for PSA < 1 ng/ml.

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.

Amyloid burden identifies neuropsychological phenotypes at increased risk of progression to Alzheimer's disease in mild cognitive impairment patients.

PURPOSE: The extent of amyloid burden associated with cognitive impairment in amnestic mild cognitive impairment is unknown. The primary aim of the study was to determine the extent to which amyloid burden is associated to the cognitive impairment. The secondary objective was to test the relationship between amyloid accumulation and memory or cognitive impairment. MATERIALS AND METHODS: In this prospective study 66 participants with amnestic mild cognitive impairment underwent clinical, neuropsychological and PET amyloid imaging tests. Composite scores assessing memory and non-memory domains were used to identify two clinical classes of neuropsychological phenotypes expressing different degree of cognitive impairment. Detection of amyloid status and definition of optimal amyloid ± cutoff for discrimination relied on unsupervised k-means clustering method. RESULTS: Threshold for identifying low and high amyloid retention groups was of SUVr = 1.3. Aß + participants showed poorer global cognitive and episodic memory performance than subjects with low amyloid deposition. Aß positivity significantly identified individuals with episodic memory impairment with a sensitivity and specificity of 80 and 79%, (χ2 = 21.48; P < 0.00001). Positive and negative predictive values were 82 and 76%, respectively. Amyloid deposition increased linearly as function of memory impairment with a rate of 0.13/ point of composite memory score (R = -44, P = 0.0003). CONCLUSION: The amyloid burden of SUVr = 1.3 allows early identification of subjects with episodic memory impairment which might predict progression from MCI to Alzheimer's disease. TRIAL REGISTRATION: EudraCT 2015-001184-39.

[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.

The relationship between local recurrences and distant metastases in prostate cancer: can 11C-choline PET/CT contribute to understand the link?

PURPOSE: Previous studies in prostate cancer (PCa) patients tried to correlate the onset of local recurrence (LR) with the development of distant metastases and formulated, based on theoretical and experimental data, hypotheses linking the two events. We aimed to address this issue with 11C-choline positron emission tomography/computed tomography (PET/CT). METHODS: This retrospective study included 491 PCa patients previously treated with radical prostatectomy who had undergone 11C-choline PET/CT owing to biochemical failure. Further inclusion criteria were availability of clinical and pathological variables for survival analysis. Statistical significance was taken at P < 0.05. RESULTS: Seventy-two patients (14.7%) had evidence of LR at 11C-choline PET/CT. The frequency of LR increased from 13.8% in the interval 0-4 years after prostatectomy, to 23.9% in the 12-16-year interval (P = 0.080). On the contrary, the frequency of lymph node metastases (overall rate in the 0-16 years interval after prostatectomy: 26.3%) and of bone metastases (overall rate: 13.8%) decreased significantly over time. Kaplan-Meier curves showed no significant group difference in the rates of lymph node or bone metastases between patients with LR and patients without LR. LR significantly predicted PCa-specific survival at univariate analysis, but the statistical significance was lost at multivariate analysis. CONCLUSION: We found no differences in the rates of lymph node and bone metastases between patients with and without LR. An inverse time-dependent trend was observed in the frequency of LR on one side and of lymph node and bone metastases on the other side. These findings were discussed in relation to previous theories linking LR to distant metastases and our study design.

PET/CT With 68Ga-PSMA in Prostate Cancer: Radiopharmaceutical Background and Clinical Implications.

BACKGROUND AND OBJECTIVE: In the last twenty years, positron emission tomography / computed tomography (PET/CT) with radiolabeled choline, represented the most powerful imaging modality for prostate cancer (PCa). However, the low positive detection rate of the technique for PSA < 1 ng/ml prompted the development of other tracers for imaging PCa. METHODS: We performed a critical review of 68Ga-PSMA, a receptor ligand tracer, which has been identified as the most promising radiopharmaceutical for imaging PCa. RESULTS: The most promising feature of this radiopharmaceutical is the high positive detection rate for prostate specific antigen (PSA) levels < 1 ng/ml or less (i.e., PSA < 0.5 ng/ml). 68Ga-PSMA detection rate is also sensitive to PSA kinetics, expressed either as PSA doubling time or PSA velocity. There are initial results indicating that 68Ga-PSMA may significantly affect the clinical management of PCa patients, even though the additional advantages in comparison to radiolabeled choline need to be further supported in future perspective studies. Other clinical implications, such as whether 68Ga-PSMA PET/CT predicts PCa-specific survival, have not yet been investigated. Numerous clinical studies have been published, some of them with histopathological verification so that despite the recent introduction in the clinical field reliable estimation of sensitivity and specificity of 68Ga-PSMA PET/CT have been obtained through meta-analyses. Most clinical studies with PET/CT with 68Ga-PSMA are retrospective, single-institutional studies and in many cases include heterogeneous patient cohorts. Thus, multidisciplinary, well-throughout prospective trials are needed to better define the clinical implications of 68Ga- PSMA PET/CT in PCa patients. The increasing availability of positron emission tomography / magnetic resonance (PET/MR) hybrid devices promotes the use of this radiopharmaceutical especially at initial staging when identification of tumor localization and of extra-prostatic disease represent clinically relevant questions. PSMA cold ligands can also be labeled with beta emitters with good chemical stability so that 68Ga-PSMA PET/CT can be used to guide radiometabolic therapy of advanced metastatic PCa patients through 177Lu-labeled PSMA ligands. CONCLUSION: PSMA labeled ligands appear very promising for diagnosis and treatment of PCa.

PET/MR Tomographs: A Review with Technical, Radiochemical and Clinical Perspectives.

BACKGROUND AND OBJECTIVE: In the last decade, an increasing number of positron emission tomography / magnetic resonance (PET/MR) tomographs were installed and many clinical studies were performed in the neurological field. METHODS: Although PET/MR has many favorable properties to support the application in brain imaging, attenuation correction, and therefore accurate quantification, is a problem that still requires optimal solution. RESULTS: In this review we have summarized the three main methods that are currently used to correct attenuation in PET/MR, namely atlas- or template-based methods, segmentation-based methods, and reconstruction-based methods. There is currently active ongoing research to refine available methods and improvements are reasonably expected in the next years. Clinical studies using PET/MR focused mainly on neurodegenerative and neurooncological disorders. PET/MR hybrids tomographs provided promising scientific results and were logistically more convenient for patients. Additionally, in order to explore all potential clinical benefits of this hybrid technology, the design and development of multimodal contrast agents has constantly increased the attention of radiochemists. Many PET/MR dual probes have been already devised, particularly in the nanotechnology field, sometimes preceding the identification of a clear diagnostic application in medicine. CONCLUSION: In the near future, we predict more clinical studies as the availability of PET/MR will further increase and new tracers for neurodegenerative disorders will accept broader clinical acceptance.

PET and PET/CT with radiolabeled choline in prostate cancer: a critical reappraisal of 20 years of clinical studies.

We here aim to provide a comprehensive and critical review of the literature concerning the clinical applications of positron emission tomography/computed tomography (PET/CT) with radiolabeled choline in patients with prostate cancer (PCa). We will initially briefly summarize the historical context that brought to the synthesis of [11C]choline, which occurred exactly 20 years ago. We have arbitrarily grouped the clinical studies in three different periods, according to the year in which they were published and according to their relation with their applications in urology, radiotherapy and oncology. Studies at initial staging and, more extensively, studies in patients with biochemical failure, as well as factors predicting positive PET/CT will be reviewed. The capability of PET/CT with radiolabeled choline to provide prognostic information on PCa-specific survival will also be examined. The last sections will be devoted to the use of radiolabeled choline for monitoring the response to androgen deprivation therapy, radiotherapy, and chemotherapy. The accuracy and the limits of the technique will be discussed according to the information available from standard validation processes, including biopsy or histology. The clinical impact of the technique will be discussed on the basis of changes induced in the management of patients and in the evaluation of the response to therapy. Current indications to PET/CT, as officially endorsed by guidelines, or as routinely performed in the clinical practice will be illustrated. Emphasis will be made on methodological factors that might have influenced the results of the studies or their interpretation. Finally, we will briefly highlight the potential role of positron emission tomography/magnetic resonance and of new radiotracers for PCa imaging.

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.

Radiopharmaceuticals for the Diagnosis and Therapy of Neuroendocrine Differentiated Prostate Cancer.

Neuroendocrine differentiation of prostate cancer (PCa) is a relatively frequent event, generally understudied, that carries important prognostic information. It is the most frequently observed during the advanced stages of disease, when PCa has lost its sensitivity to androgen deprivation therapy or to chemotherapy, moderate to diffuse bone metastatic spread dominates the imaging scenario and it is responsible for painful clinical symptomatology. However, evidences indicate that neuroendocrine differentiation is a progressive phenomenon that starts at the very early part of the pathogenesis of cancer transformation contributing to it. Neuroendocrine tumor phenotypes have reduced capability to secrete the prostate specific antigen (PSA) and therefore PSA does not represent a reliable marker to follow-up neuroendocrine differentiation. Tumor progression may be monitored by measuring plasma concentration of neuroendocrine tumor markers, primarily chromogranin A and neuron-specific enolase. Several nuclear medicine tracers are available for studying different biochemical properties of tumor cells with neuroendocrine differentiation. Single photon computed emission tomography (SPECT) with [111In-diethylenetriaminepentaacetic acid] ([111In-DTPA0])- octreotide (Octreoscan) has been extensively used in the past. However, the development of the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), which in comparison to DTPA allows higher affinity bindings for beta-emitting radionuclides and for somatostatin (SST) analogues, and the increased availability of the Germanium-68/Gallium-68 (68Ge/68Ga)-generator, which enables positron emission tomography/computed tomography (PET/CT) imaging, have allowed the synthesis of several PET tracers for different SST receptors. The receptor of the bombesin/ gastrin releasing peptide (GRP), which is overexpressed in PCa with neuroendocrine differentiation, also represents an innovative research field with diagnostic and therapeutic applications through, respectively, positron and beta emitters. At the moment, however, we observe some discrepancy between the high number of preclinical studies and the small number of clinical studies, most likely related to competing and, at the moment, more effective radiopharmaceuticals for imaging and for radiometabolic therapy, such PET/CT with radiolabeled choline and prostate-specific membrane antigene (PSMA)-ligands, the latter being labeled either with 68Ga for imaging or with Lutetium-177 for therapy. Radium-223 dichloride has also been recently successfully introduced for palliative therapy of bone metastases in PCa. For these reasons, while the development of radiopharmaceuticals for diagnosis and therapy (theranostics concept) of neuroendocrine differentiated PCa is scientifically stimulating, the ultimate clinical impact remains presently difficult to predict. Similar effectiveness in comparison to other forms of diagnostic and radiometabolic radiopharmaceuticals that have already gained convincing acceptance among referring clinicians needs to be demonstrated.

Clinical applications of choline PET/CT in brain tumors.

Malignant gliomas and metastatic tumors are the most common forms of brain tumors. From a clinical perspective, neuroimaging plays a significant role, in diagnosis, treatment planning, and follow-up. To date MRI is considered the current clinical gold standard for imaging, however, despite providing superior structural detail it features poor specificity in identifying viable tumors in brain treated with surgery, radiation, or chemotherapy. In the last years functional neuroimaging has become largely widespread thanks to the use of molecular tracers employed in cellular metabolism which has significantly improved the management of patients with brain tumors, especially in the post-treatment phase. Despite the considerable progress of molecular imaging in oncology its use in the diagnosis of brain tumors is still limited by a few wellknown technical problems. Because 18F-FDG, the most common radiotracer used in oncology, is avidly accumulated by normal cortex, the low tumor/background signal ratio makes it difficult to distinguish the tumor from normal surrounding tissues. By contrast, radiotracers with higher specificity for the tumor are labeled with a short half-life isotopes which restricts their use to those centers equipped with a cyclotron and radiopharmacy facility. 11C-choline has been reported as a suitable tracer for neuroimaging application. The recent availability of choline labeled with a long half-life radioisotope as 18F increases the possibility of studying this tracer's potential role in the staging of brain tumors. The present review focuses on the possible clinical applications of PET/CT with choline tracers in malignant brain tumors and brain metastases, with a special focus on malignant gliomas.