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Purpose: This prospective study evaluated whether peripheral blood biomarkers and metabolic parameters on F-18 fludeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) could be associated with clinical outcome in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI)., Methods: Data from 33 patients with NSCLC and treated with ICI were collected. Complete blood cell counts before and at the first restaging were measured. All patients underwent F-18 FDG PET/CT at baseline, while 25 patients at the first restaging. Progression-free survival (PFS) and overall survival (OS) were determined and compared using the Kaplan-Meier and the log-rank test. The median follow-up was 11.3 months (range 1-17 months)., Results: Multivariate analyses demonstrated that low neutrophil-to-lymphocyte ratio (NLR < 4.9) and low total lesion glycolysis (TLG < 541.5 ml) at the first restaging were significantly associated with PFS (both p = 0.019) and OS (p = 0.001 and p = 0.048, respectively). An immune-metabolic-prognostic index (IMPI), based on post-NLR and post-TLG was developed, categorizing 3 groups: high risk, 2 factors; intermediate risk, 1 factor; low risk, 0 factors. Median PFS for low, intermediate and high risk was 7.8 months (95% CI 4.6-11.0), 5.6 months (95% CI 3.8-7.4), and 1.8 months (95% CI 1.6-2.0) (p < 0.001) respectively. Likewise, median OS was 15.2 months (95% CI 10.9-19.6), 13.2 months (95% CI 5.9-20.3), and 2.8 months (95% CI 1.4-4.2) (p < 0.001), respectively., Conclusion: IMPI at the first restaging, combining both inflammatory and metabolic biomarkers, was correlated with PFS and OS. IMPI can be a potentially valuable tool for identifying NSCLC patients who are likely to benefit from ICI.

Our purpose was to evaluate the diagnostic role of 18 F-3,4-dihydroxyphenylalanine (DOPA) PET/CT at the time of staging in children with neuroblastoma and to investigate its ability to assess treatment response. We also investigated the prognostic value of 18 F-DOPA PET/CT at the same time points. Methods: We enrolled children with neuroblastoma at onset. Before and after induction chemotherapy, all patients underwent 18 F-DOPA PET/CT and 123 I-metaiodobenzylguanidine (MIBG) scanning plus SPECT/CT. 18 F-DOPA PET/CT results were compared with those of 123 I-MIBG whole-body scanning (WBS). For each modality, patient-based analysis and lesion-based analysis were performed and sensitivity was calculated. We applied scoring systems to 123 I-MIBG scanning and 18 F-DOPA PET/CT (i.e., 123 I-MIBG WBS score and whole-body metabolic burden [WBMB], respectively) and evaluated the association between these parameters, the principal neuroblastoma risk factors, and outcome. Results: We enrolled 16 high-risk and 2 intermediate-risk neuroblastoma patients. On patient-based analysis, sensitivity in detecting primary tumors, soft-tissue metastases, and bone or bone-marrow metastases was 83%, 50%, and 92%, respectively, for 123 I-MIBG WBS versus 94%, 92%, and 100%, respectively, for 18 F-DOPA PET/CT. On lesion-based analysis, the sensitivity of 18 F-DOPA PET/CT in detecting soft-tissue and bone or bone-marrow metastases was 86% and 99%, respectively-significantly higher than that of 123 I-MIBG WBS, at 41% and 93%, respectively. After therapy, on patient-based analysis, the sensitivity in detecting primary tumors, soft-tissue metastases, and bone or bone-marrow metastases was 72%, 33%, and 38%, respectively, for 123 I-MIBG WBS versus 83%, 75% and 54%, respectively, for 18 F-DOPA PET/CT. On lesion-based analysis, the sensitivity of 18 F-DOPA PET/CT in detecting soft-tissue and bone or bone-marrow metastases was 77% and 86%, respectively-significantly higher than that of 123 I-MIBG WBS, at 28% and 69%, respectively. During follow-up, 8 cases of disease progression and 5 deaths occurred. On multivariate analysis, only posttherapeutic 18 F-DOPA WBMB (>7.5) was associated with progression-free survival. Conclusion: 18 F-DOPA PET/CT is more sensitive than 123 I-MIBG WBS in staging neuroblastoma patients and evaluating disease persistence after chemotherapy. In a time-to-event analysis, posttherapeutic 18 F-DOPA WBMB remained the only risk factor associated with disease progression., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Circulating tumor cells (CTC) count and characterization have been associated with poor prognosis in recent studies. Our aim was to examine CTC count and its association with metabolic parameters and clinical outcomes in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI). For this prospective study, data from 35 patients (23 males, 12 females) were collected and analyzed. All patients underwent an 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scan and CTC detection through Isolation by Size of Tumor/Trophoblastic Cells (ISET) from peripheral blood samples obtained at baseline and 8 weeks after ICI initiation. Association of CTC count with clinical and metabolic characteristics was studied. Progression-free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and the log-rank test. Median follow-up was 13.2 months (range of 4.9-21.6). CTC were identified in 16 out of 35 patients (45.7%) at baseline and 10 out of 24 patients at 8 weeks (41.7%). Mean CTC numbers before and after 8 weeks were 15 ± 28 and 11 ± 19, respectively. Prior to ICI, the mean CTC number was significantly higher in treatment-naïve patients (34 ± 39 vs. 9 ± 21, p = 0.004). CTC count variation (ΔCTC) was significantly associated with tumor metabolic response set by European Organization for Research and Treatment of Cancer (EORTC) criteria ( p = 0.033). At the first restaging, patients with a high tumor burden, that is, metabolic tumor volume (MTV) and total lesion glycolysis (TLG), had a higher CTC count ( p = 0.009). The combination of mean CTC and median MTV at 8 weeks was associated with PFS ( p < 0.001) and OS ( p = 0.024). Multivariate analysis identified CTC count at 8 weeks as an independent predictor for PFS and OS, whereas ΔMTV and maximum standardized uptake value variation (ΔSUVmax) was predictive for PFS and OS, respectively. Our study confirmed that CTC number is modulated by previous treatments and correlates with metabolic response during ICI. Moreover, elevated CTC count, along with metabolic parameters, were found to be prognostic factors for PFS and OS.

Background: Immune checkpoint inhibitors (ICI) have achieved astonishing results and improved overall survival (OS) in several types of malignancies, including advanced melanoma. However, due to a peculiar type of anti-cancer activity provided by these drugs, the response patterns during ICI treatment are completely different from that with "old" chemotherapeutic agents., Objective: To provide an overview of the available literature and potentials of 18F-FDG PET/CT in advanced melanoma during the course of therapy with ICI in the context of treatment response evaluation., Method: Morphologic criteria, expressed by Response Evaluation Criteria in Solid Tumors (RECIST), immune-related response criteria (irRC), irRECIST, and, more recently, immune-RECIST (iRECIST), along with response criteria based on the metabolic parameters with 18F-Fluorodeoxyglucose (18FFDG), have been explored., Results: To overcome the limits of traditional response criteria, new metabolic response criteria have been introduced on time and are being continuously updated, such as the PET/CT Criteria for the early prediction of Response to Immune checkpoint inhibitor Therapy (PECRIT), the PET Response Evaluation Criteria for Immunotherapy (PERCIMT), and "immunotherapy-modified" PET Response Criteria in Solid Tumors (imPERCIST). The introduction of new PET radiotracers, based on monoclonal antibodies combined with radioactive elements ("immune-PET"), are of great interest., Conclusion: Although the role of 18F-FDG PET/CT in malignant melanoma has been widely validated for detecting distant metastases and recurrences, evidences in course of ICI are still scarce and larger multicenter clinical trials are needed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: The purpose of this study was to assess the predictive and prognostic role of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in candidates with stage III non-small-cell lung cancer (NSCLC) to neoadjuvant chemotherapy., Patients and Methods: Sixty-six patients with stage III NSCLC treated with induction chemotherapy from March 2013 to December 2017 were retrospectively identified. Response assessment were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and European Organisation for Research and Treatment of Cancer (EORTC) criteria. 18F-FDG PET/CT metabolic parameters were analyzed as absolute values as well as percentage changes (Δ) between 2 consecutive scans, for primary tumor (T) and for regional lymph nodes (N). All clinical variables and metabolic parameters were compared with treatment response and correlated with progression-free survival (PFS) and overall survival (OS), based on a median follow-up of 9.4 months., Results: Post-induction therapy standardized uptake value (SUV)max&#95;T, SUVmean&#95;T, metabolic tumor volume (MTV&#95;T), and total lesion glycolysis of the tumor (TLG&#95;T) varied significantly between responders and non-responders (6.6 vs. 13.8; P = .001; 4.2 vs. 8.1; P < .001; 6 vs. 17.9; P = .002; and 24.1 vs. 136.3; P < .001, respectively). Likewise, percentage changes (Δ&#95;T) were significantly different between the 2 groups (P < .001). Along with primary tumor, also post-SUVmax&#95;N, post-SUVmean&#95;N, and post-TLG&#95;N (P = .024, P = .015, and P = .024, respectively), as well as all percentage changes (Δ&#95;N) were different between responders and non-responders. RECIST 1.1 and EORTC response classifications were discordant in 27 patients (40.9%; κ = 0.265; P = .003). On multivariate analysis, post-TLG&#95;N was an independent predictor for both PFS and OS, whereas RECIST 1.1 was a predictor only for OS., Conclusions: Several metabolic parameters may differentiate responders from non-responders following neoadjuvant chemotherapy in stage III NSCLC. As compared with RECIST 1.1, EORTC seems to be more appropriate for evaluation therapeutic response. Finally, post-TLG&#95;N has significant prognostic information., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The major applications for molecular imaging with PET in clinical practice concern cancer imaging. Undoubtedly, 18F-FDG represents the backbone of nuclear oncology as it remains so far the most widely employed positron emitter compound. The acquired knowledge on cancer features, however, allowed the recognition in the last decades of multiple metabolic or pathogenic pathways within the cancer cells, which stimulated the development of novel radiopharmaceuticals. An endless list of PET tracers, substantially covering all hallmarks of cancer, has entered clinical routine or is being investigated in diagnostic trials. Some of them guard significant clinical applications, whereas others mostly bear a huge potential. This chapter summarizes a selected list of non-FDG PET tracers, described based on their introduction into and impact on clinical practice.

Herein, we report imaging findings related to an ectopic focus of thyroid tissue in a young female with Graves' disease. The occurrence of ectopic thyroid tissue affects approximately 7% of adult population and represents commonly an occasional finding. Only rarely ectopic tissue can present with metastasis or develop a primary thyroid carcinoma. Multimodality imaging may be of help in this case to detect thyroid ectopia, although recent studies question its capability to differentiate benign from malignant tissue.

Response assessment in malignant lymphoma has progressively evolved in the last 20 years, leading to continuous adaptations to clinical requirements and technology improvements. The latest challenge in treatment evaluation is represented by immunomodulatory drugs, capable of stimulating response to cancer by unleashing the immune system of the host. Despite the consolidated consensus on the use of Deauville score and Lugano criteria for the assessment of first-line therapeutic regimens, during other lines of treatment and, particularly, during the course of immunotherapy, response parameters and clinical evidence appear less clear., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Metabolic information provided by 18F-FDG PET/CT are useful for initial staging, therapy planning, response evaluation, and to a lesser extent for the follow-up of non-small cell lung cancer (NSCLC). To date, there are no established clinical guidelines in treatment response and early detection of recurrence., Objective: To provide an overview of 18F-FDG PET/CT in NSCLC and in particular, to discuss its utility in treatment response evaluation and restaging of lung cancer., Methods: A comprehensive search was used based on PubMed results. From all studies published in English those that explored the role of 18F-FDG PET/CT in the treatment response scenario were selected., Results: Several studies have demonstrated that modifications in metabolic activity, expressed by changes in SUV both in the primary tumor as well as in regional lymph nodes, are associated with tumor response and survival. Beside SUV, other metabolic parameters (i.e. MTV, TLG, and percentage changes) are emerging to be helpful for predicting clinical outcomes., Conclusion: 18F-FDG parameters appear to be promising factors for evaluating treatment response and for detecting recurrences, although larger prospective trials are needed to confirm these evidences and to determine optimal cut-off values., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

In the current paper, we aimed to investigate circulating tumor cells (CTCs) in non-small cell lung carcinoma (NSCLC) candidates to immunotherapy and correlate findings with clinical and metabolic parameters. Seventeen metastatic NSCLC patients (12 males, 5 females), were prospectively enrolled. All patients underwent 18 F-Fluorodeoxyglucose (FDG) PET/CT and CTCs detection before treatment. CTCs isolation by size was carried out with the ISET method. CTCs were characterized based on cytopathological features and were compared with smoking status, histological subtype, pre-immunotherapy treatment, PDL-1 expression, performance status, and semi-quantitative parameters on PET, including SUVmax, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG). We found CTCs in 10 out of 17 patients (59%). Mean number of CTCs was 3 (range 1-7). Only one cell with 3 malignant features was detected in the blood of a healthy control out of 7 (16%). A significantly lower number of CTCs was found in patients previously treated with chemotherapy (P=0.041). No correlation between CTCs and other clinical pathologic characteristics was observed. Patients with an extensive tumor burden, i.e. MTV and TLG, were associated with a higher number of CTCs (P=0.004 and P=0.028, respectively). Likewise, patients with a higher metabolism determined with SUVmean resulted having a higher CTCs count (P=0.048). The presence of CTCs was associated with tumor uptake and metabolic burden on PET/CT, while results were influenced by previous chemotherapy. Whether confirmed in larger series, the combination of the presence of CTCs and FDG PET metabolic parameters might improve prognostic stratification and allow more personalized treatment paradigm., Competing Interests: E.L. reports receiving an individual grant from AIRC and the Italian Ministry of Health. A.C. is supported by fellowships provided by AIRC. S.M. reports fellowship support from Fondazione Umberto Veronesi. G.V. reports receiving personal fees from Ab Medica SpA, and grants from AIRC, the Ministry of Health, the Italian National Insurance Institute for Workplace Injuries (INAIL), and the National Cancer Institute (NCI)., (AJNMMI Copyright © 2019.)

Objectives: In-vivo characterization of malignant pleural mesothelioma (MPM) with C-methionine PET/computed tomography (MET PET)., Methods: Between September 2014 and February 2016, 30 consecutive patients with clinical suspicion of MPM were prospectively recruited. The study was approved and registered at www.clinicaltrials.gov (NCT02519049). Patients were evaluated at baseline with MET PET (experimental) and fluorine-18 fluorodeoxyglucose PET/computed tomography (FDG PET) (standard). Principal parameters analyzed were SUVmax, SUVmean, metabolic tumor volume (MTV), and metabolic tumor burden (MTB  = MTV ×SUVmean). The reference standard for diagnostic performance was based on histology., Results: The presence of malignancy was confirmed in 29/30 patients: 23 (76.6%) with MPM (20 epithelioid, two biphasic, and one sarcomatoid), five (16.6%) with adenocarcinoma of the lung, and one (3.3%) with an undifferentiated carcinoma. In one case, diagnosis was benign pleural inflammation. All tumors showed increased uptake of C-methionine: median SUVmax, SUVmean, MTV, and MTB were, respectively, 5.70 [95% confidence interval (CI): 4.51-6.79], 3.15 (95% CI: 2.71-3.40), 33.85 (95% CI: 14.08-66.64), and 105.25 (95% CI: 41.77-215.25). Pathology data revealed MTV and MTB to be significantly higher in nonepithelioid histology (P < 0.05). The other parameters showed a homogeneous distribution across the tumor types. Overall, MET PET identified 49 lymph nodes, compared with 34 nodes on FDG PET, demonstrating a sensitivity of 91% (95% CI: 80-96%), a positive predictive value of 92% (95% CI: 82- 97%), and an accuracy of 85% (P = 0.0042)., Conclusions: MET PET is able to characterize MPM lesions regardless of histology. This technique shows higher sensitivity than FDG PET for the identification of secondary lymph nodes.

Purpose: To determine the heterogeneity of glucose uptake applying fractal analysis on positron emission tomography/computed tomography (PET/CT) with 2-deoxy-2-[ 18 F]fluoro-D-glucose ([ 18 F]FDG) images in patients with non-small cell lung carcinoma (NSCLC) before surgery, and to assess whether this heterogeneity was associated with disease-free survival (DFS)., Procedures: [ 18 F]FDG PET/CT scans of 113 patients' prior surgery were retrospectively revised. PET DICOM images were analyzed for fractal geometry using a ad hoc software to automatically determine the following indexes: (a) mean intensity value (MIV), (b) standard deviation (SD), (c) relative dispersion (RD), (d) three-dimensional (3D) histogram of the fractal dimension (3D HIST FR DIM), and (e) fractal dimension in 3D (3D-FD). All the fractal indexes were subsequently compared with metabolic parameters and disease-free survival (DFS)., Results: We found a significant correlation between 3D-FD and SUVmax, SUVmean, MTV, and TLG. Additionally, positive correlations between MIV, SD, and all metabolic parameters were also detected. Patients with high 3D-FD tumor (≥ 1.62) showed significantly higher values of SUVmax, SUVmean, MTV, and TLG than those with lower 3D-FD. In univariate analysis, median 3D-FD and median TLG were significantly associated with DFS (p = 0.04 and p = 0.03, respectively). These findings were confirmed on log-rank test. On multivariate analysis, among age, stage disease, histotype, 3D-FD, and metabolic parameters, only 3D-FD was identified as independent prognostic factor for DFS (p = 0.032; HR 0.418, 95 % CI 0.189-0.926). 3D-FD was different between adenocarcinoma and squamous cell carcinoma (1.60 versus 1.88, p = 0.014), and 3D-FD value was found higher in advanced stage disease., Conclusions: Metabolic heterogeneity determined applying fractal principles on PET images can be considered as a novel imaging biomarker for survival in patients with NSCLC.

Purpose: To evaluate the clinical-pathological and prognostic significance of the circulating PD-L1 level in patients with surgically treated NSCLC, by combining data for PD-L1 expression with other immune-related markers and tumor metabolism., Methods: Overall, 40 patients with resected NSCLC (stage Ia-IIIa) who had preoperative blood storage and underwent staging PET/CT were enrolled for the study. In all cases, we determined plasma levels of PD-L1 (pg/ml), immune-reactive areas (IRA %) covered by CD3, CD68, CD20, CD8, PD-1, and PD-L1 in the tumor specimen, and metabolic parameters on PET, i.e., SUV max , SUV peak , metabolic tumor volume (MTV), and total lesion glycolysis (TLG). Variables were statistically analyzed to establish their association with disease-free survival (DFS)., Results: The circulating levels of PD-L1 in the bloodstream could be determined in 38/40 (95%) samples. The mean and median expression levels were 34.86 pg/ml and 24.83 pg/ml, respectively. We did not find any statistically significant correlation between circulating PD-L1 and tissue expression of PD-L1/PD-1. Some mild degree of positive correlation was determined between tissue PD-L1 and SUV max (ρ = 0.390; p = 0.0148). Hierarchical clustering combining circulating, tissue, and metabolic parameters identified clusters with high metabolic tumor burden or high expression of plasma PD-L1 levels (Z score ≥ 2) as having a poor DFS (p = 0.033). The multivariate analysis detected stage and metabolism (i.e., SUV max and SUV peak ) as independent prognostic factors for DFS., Conclusion: Plasma levels of PD-L1 are independent of the expression of PD-1/PD-L1 in NSCLC tumor tissue and, when combined with other clinical-pathological parameters, allow for the identification of clusters with different outcomes.

Stem cells can stay quiescent for a long period of time or proliferate and differentiate into multiple lineages. The activity of stage-specific metabolic programs allows stem cells to best adapt their functions in different microenvironments. Specific cellular phenotypes can be, therefore, defined by precise metabolic signatures. Notably, not only cellular metabolism describes a defined cellular phenotype, but experimental evidence now clearly indicate that also rewiring cells towards a particular cellular metabolism can drive their cellular phenotype and function accordingly. Cellular metabolism can be studied by both targeted and untargeted approaches. Targeted analyses focus on a subset of identified metabolites and on their metabolic fluxes. In addition, the overall assessment of the oxygen consumption rate (OCR) gives a measure of the overall cellular oxidative metabolism and mitochondrial function. Untargeted approach provides a large-scale identification and quantification of the whole metabolome with the aim to describe a metabolic fingerprinting. In this review article, we overview the methodologies currently available for the study of in vitro stem cell metabolism, including metabolic fluxes, fingerprint analyses, and single-cell metabolomics. Moreover, we summarize available approaches for the study of in vivo stem cell metabolism. For all of the described methods, we highlight their specificities and limitations. In addition, we discuss practical concerns about the most threatening steps, including metabolic quenching, sample preparation and extraction. A better knowledge of the precise metabolic signature defining specific cell population is instrumental to the design of novel therapeutic strategies able to drive undifferentiated stem cells towards a selective and valuable cellular phenotype.

Background: Positron emission tomography (PET) is a valuable tool for the characterization of brain tumors in vivo. However, few studies have investigated the correlation between carbon-11-methionine (11C-METH) PET metrics and the clinical, radiological, histological, and molecular features of patients affected by lower grade gliomas (LGGs). The present observational study evaluated the relationships between 11C-METH PET metrics and structural magnetic resonance imaging (MRI) findings with the histomolecular biomarkers in patients with LGGs who were candidates for surgery., Methods: We enrolled 96 patients with pathologically proven LGG (51 men, 45 women; age 44.1 ± 13.7 years; 45 with grade II, 51 with grade III), who had been referred from March 2012 to January 2015 for tumor resection and had undergone preoperative 11C-METH PET. The semiquantitative metrics for 11C-METH PET included maximum standardized uptake value (SUVmax), SUV ratio to normal brain, and metabolic tumor burden (MTB). The PET semiquantitative metrics were analyzed and compared with the MRI features, histological diagnosis, isocitrate dehydrogenase-1/2 status, and 1p/19q codeletion., Results: Histological grade was associated with SUVmax (P = 0.002), SUV ratio (P = 0.011), and MTB (P = 0.001), with grade III lesions showing higher values. Among the nonenhancing lesions on MRI, SUVmax (P = 0.001), SUV ratio (P = 0.003) and MTB (P < 0.001) were significantly different statistically for grade II versus grade III. The MRI lesion volume correlated poorly with MTB (r 2  = 0.13). The SUVmax and SUV ratio were greater (P < 0.05) in isocitrate dehydrogenase-1/2 wild-type lesions, and the SUV ratio was associated with the presence of the 1p19q codeletion., Conclusions: The 11C-METH PET metrics correlated significantly with histological grade and the molecular profile. Semiquantitative PET metrics can improve the preoperative evaluation of LGGs and thus support clinical decision-making., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Irregularity in shape and behavior is the main feature of every anatomical system, including human organs, tissues, cells, and sub-cellular entities. It has been shown that this property cannot be quantified by means of the classical Euclidean geometry, which is only able to describe regular geometrical objects. In contrast, fractal geometry has been widely applied in several scientific fields. This rapid growth has also produced substantial insights in the biomedical imaging. Consequently, particular attention has been given to the identification of pathognomonic patterns of "shape" in anatomical entities and their changes from natural to pathological states. Despite the advantages of fractal mathematics and several studies demonstrating its applicability to oncological research, many researchers and clinicians remain unaware of its potential. Therefore, this review aims to summarize the complexity and fractal geometry of nuclear medicine images.

Tumor response is often used as a surrogate marker for survival practically in all clinical trials. Therefore, robust and valid response criteria during the course of trials are fundamental for the assessment of response to therapy. This aspect, however, becomes particularly challenging when it comes to bone metastases. In the era of targeted therapies and immune-checkpoint inhibitors (ICI), response assessment by morphologic-based criteria cannot detect the real tumor response and, consequently, fail to demonstrate the actual clinical benefit. This review will focus on some of the most common morphologic and metabolic response criteria and their application for bone lesions, highlighting relative strengths and weaknesses as well as potential future methods in the era of target therapies and immunotherapy with ICI.

Background: Stereotactic biopsy is consistently employed to characterize cerebral lesions in patients who are not suitable for microsurgical resection. In the past years, technical improvement and neuroimaging advancements contributed to increase the diagnostic yield, the safety, and the application of this procedure. Currently, in addition to histological diagnosis, the molecular analysis is considered essential in the diagnostic process to properly select therapeutic and prognostic algorithms in a personalized approach. The present study reports our experience with frameless stereotactic brain biopsy in this molecular era., Methods: One hundred forty consecutive patients treated from January 2013 to September 2018 were analyzed. Biopsies were performed using the Brainlab Varioguide® frameless stereotactic system. Patients' clinical and demographic data, the time of occupation of the operating room, the surgical time, the morbidity, and the diagnostic yield in providing a histological and molecular diagnosis were recorded and evaluated., Results: The overall diagnostic yield was 93.6% with nine procedures resulting non-diagnostic. Among 110 patients with glioma, the IDH-1 mutational status was characterized in 108 cases (98.2%), resulting wild-type in all subjects but 3; MGMT methylation was characterized in 96 cases (87.3%), resulting present in 60 patients, and 1p/19q codeletion was founded in 6 of the 20 cases of grade II-III gliomas analyzed. All the specimens were apt for molecular analysis when performed. Bleeding requiring surgical drainage occurred in 2.1% of the cases; 8 (5.7%) asymptomatic hemorrhages requiring no treatment were observed. No biopsy-related mortality was recorded. Median length of hospital stay was 5 days (IQR 4-8) with mean surgical time of 60.77 min (± 23.12) and 137.44 ± 24.1 min of total occupation time of the operative room., Conclusions: Stereotactic frameless biopsy is a safe, feasible, and fast procedure to obtain a histological and molecular diagnosis.

Aim: The aim of this study was to analyze the economic efficiency of second-line diagnostic investigations in patients with undetermined lung nodules., Participants and Methods: A retrospective review of all surgical cases included in the DANTE trial from 2001 to 2006 for lung cancer screening was performed. Overall, 217 patients and 261 lung nodules were analyzed. The cohort was divided into patients investigated with PET and/or computed tomography (CT)-guided biopsy (PET-CTB protocol; N=100), compared with those assessed with serial low-dose CT scans (standard protocol; N=161). Outpatient's and inpatient's costs were expressed in euros and derived from the Italian National Health Service. Ineffective costs were defined as the cost of procedures that lead to avoidable surgical intervention., Results: The diagnostic accuracy of the two protocols was 91% for the standard (sensitivity 100%, specificity 91%, positive predictive value 26%, and negative predictive value 100%) and 90% for the PET-CTB protocol (sensitivity 98%, specificity 81%, positive predictive value 85%, and negative predictive value 97%). Average costs for outpatient's diagnostics were 694 and 1.462 euros, respectively, for the standard and PET-CTB protocol. Average inpatient's costs for both protocols were 12.121 euros. The two protocols showed comparable effectiveness in terms of outpatient's costs (94 and 90%, respectively; P=0.252). Inpatient's costs were effective in 36% of cases monitored according to the standard protocol compared with 85% of patients investigated with PET-CTB protocol. Ineffective costs corresponded to 64 and 15%, respectively (P<0.0001)., Conclusion: Despite a higher average cost for outpatient's diagnostics, the implementation of PET imaging with or without CT-guided needle biopsy in the workup of suspicious lung nodules results in reduced unnecessary harm and costs related to inpatient's procedures.

Objectives: In Siewert type I/II oesophageal adenocarcinoma, the sensitivity and specificity of computed tomography (CT), positron emission tomography (PET)-CT and endoscopic ultrasound (EUS) for assessment of the N descriptor in defined groups of lymph nodes were investigated., Methods: CT, PET/CT, EUS images and the pathological data of 101 oesophageal adenocarcinomas submitted to primary resection were compared. The lymph nodes were identified as (a) right paratracheal/subcarinal/pulmonary ligament; (b) paraoesophageal; (c) paracardial; (d) left gastric artery, lesser curvature; (e) coeliac trunk, hepatic/splenic artery., Results: Of the 2451 lymph nodes identified, 273 (11.1%) were histologically positive. Overall sensitivity, specificity and negative and positive predictive value for detection of lymph nodes metastatic were respectively: CT sensitivity 39%, specificity 86%, negative 58% and positive 74% predictive value; PET/CT sensitivity 30%, specificity 98%, negative 58% and positive 93% predictive value; EUS sensitivity 50%, specificity 81%, negative 72% and positive 62% predictive value. The sensitivity of CT, PET/CT and EUS in the thoracic nodal groups (a) and (b) was, respectively, 58.3%, 7.1% and 87.5% and 33.3%, 20% and 80%. Sensitivity was below 47% for all tests in the abdominal nodal groups. In contrast, specificity (88.6-100%) was super imposable in all nodal groups. The strength of agreement among the 3 imaging techniques was poor (kappa < 0.30) for the thoracic anatomical groups of interest: (a) lower paratracheal/subcarinal/pulmonary ligament and (b) paraoesophageal; it was moderate/good (kappa >0.30) for the abdominal N groups of interest: c, d and e., Conclusions: The diagnostic performance of CT, PET and EUS for assessing the N descriptor in the paracardial and abdominal stations close to the primary tumour is not satisfactory. EUS can efficiently assess the presence/absence of nodal metastases in the thoracic stations., Clinical Trial Registration: ClinicalTrials.gov number: NCT03529968., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

These joint practice guidelines, or procedure standards, were developed collaboratively by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the working group for Response Assessment in Neurooncology with PET (PET-RANO). Brain PET imaging is being increasingly used to supplement MRI in the clinical management of glioma. The aim of these standards/guidelines is to assist nuclear medicine practitioners in recommending, performing, interpreting and reporting the results of brain PET imaging in patients with glioma to achieve a high-quality imaging standard for PET using FDG and the radiolabelled amino acids MET, FET and FDOPA. This will help promote the appropriate use of PET imaging and contribute to evidence-based medicine that may improve the diagnostic impact of this technique in neurooncological practice. The present document replaces a former version of the guidelines published in 2006 (Vander Borght et al. Eur J Nucl Med Mol Imaging. 33:1374-80, 2006), and supplements a recent evidence-based recommendation by the PET-RANO working group and EANO on the clinical use of PET imaging in patients with glioma (Albert et al. Neuro Oncol. 18:1199-208, 2016). The information provided should be taken in the context of local conditions and regulations.

Introduction: Diffusion-weighted MRI (DWI) contributes to N staging of rectal cancers and diagnosis of colorectal liver metastases (CLM). About 15% of CLM patients have loco-regional lymph node (LN) metastases that impact prognosis and treatment strategy. This retrospective study is the first one to evaluate quantitative ADC measurement as a tool to identify metastatic LNs in patients with liver metastases from colorectal cancer., Methods: All consecutive patients undergoing surgery for CLM between 2008 and 2015 were considered. Inclusion criteria were: intraoperative retrieval of at least one LN; LN ≥ 5 mm; DWI performed ≤2 months before surgery. The ADC and ADC ratio (ADC LN /ADC CLM ) were computed by two radiologists for all the LNs., Results: Among 555 patients operated for CLM, 32 met the inclusion criteria. Fifty-six LNs were analyzed and 28 were metastatic. ADC and ADC ratio in metastatic LNs were lower than in benign LNs (ADC = 1.37 vs. 1.83 × 10 -3  mm 2 /s, p < 0.001; ADC ratio  = 1.26 vs. 1.73, p < 0.001). The optimal cut-off value for ADC was 1.48 x 10 -3  mm 2 /s (AUC = 0.85, p < 0.001, sensitivity/specificity/accuracy 79%/93%/86% in per LN-analysis and 94%/86%/91% in per-patient analysis). The optimal cut-off for ADC ratio was 1.15 (AUC = 0.80, p < 0.001, sensitivity/specificity/accuracy 69%/93%/81% and 76%,93%/84%). Excellent inter- and intra-operators' agreements were observed., Conclusion: In patients with CLM, ADC values < 1.48 x 10 -3  mm 2 /s can be postulated as a cut-off to distinguish metastatic LNs., (Copyright © 2018. Published by Elsevier Ltd.)

Our aim was to evaluate Hodgkin Lymphoma (HL) response to checkpoint inhibitors with 18 F-FDG PET/CT. Forty three refractory or relapsed HL patients were investigated before immunotherapy, 8 weeks and 17 weeks after administration of either nivolumab or pembrolizumab. The median follow-up was 19 months. Best clinical response was complete response (CR) in 26 patients, partial response (PR) in 5 patients, stable disease (SD) in 8 patients, and progression disease (PD) in 4 patients. At the early assessment, Deauville Score (DS) resulted significantly different in responder group compared to nonresponders. SUVmax was significantly lower in responders, while there was no relevant modification in the tumor burden. At interim evaluation, DS well differentiated responder group. A significant decrease in glucose metabolism and tumor burden parameters was observed in responder patients, who presented with a longer progression-free survival then nonresponders. 18 F-FDG PET/CT provides a reliable indication of treatment response under checkpoints inhibitors, even at an early assessment.

Purpose: We present the results of an investigation of the role of FDG PET in response evaluation of bulky masses in paediatric patients with Hodgkin's lymphoma (HL) enrolled in the Italian AIEOP-LH2004 trial., Methods: We analysed data derived from 703 patients (388 male, 315 female; mean age 13 years) with HL and enrolled in 41 different Italian centres from March 2004 to September 2012, all treated with the AIEOP-LH2004 protocol. The cohort comprised 309 patients with a bulky mass, of whom 263 were evaluated with FDG PET at baseline and after four cycles of chemotherapy. Responses were determined according to combined functional and morphological criteria. Patients were followed up for a mean period of 43 months and for each child we calculated time-to-progression (TTP) and relapse rates considering clinical monitoring, and instrumental and histological data as the reference standard. Statistical analyses were performed for FDG PET and morphological responses with respect to TTP. Multivariate analysis was used to define independent predictive factors., Results: Overall, response evaluation revealed 238 PET-negative patients (90.5%) and 25 PET-positive patients (9.5%), with a significant difference in TTP between these groups (mean TTP: 32.67 months for negative scans, 23.8 months for positive scans; p < 0.0001, log-rank test). In the same cohort, computed tomography showed a complete response (CR) in 85 patients (32.3%), progressive disease (PD) in 6 patients (2.3%), and a partial response (PR) in 165 patients (62.7%), with a significant difference in TTP between patients with CR and patients with PD (31.1 months and 7.9 months, respectively; p < 0.001, log-rank test). Similarly, there was a significant difference in relapse rates between PET-positive and PET-negative patients (p = 0000). In patients with PR, there was also a significant difference in TTP between PET-positive and PET-negative patients (24.6 months and 34.9 months, respectively; p < 0.0001). In the multivariate analysis with correction for multiple testing, only the PET result was an independent predictive factor in both the entire cohort of patients and the subgroup showing PR on CT (p < 0.01)., Conclusion: After four cycles of chemotherapy, FDG PET response assessment in paediatric HL patients with a bulky mass is a good predictor of TTP and disease outcome. Moreover, in patients with a PR on CT, PET was able to differentiate those with a longer TTP. In paediatric HL patients with a bulky mass and in patients with a PR on CT, response on FDG PET was an independent predictive factor.

This paper follows the immunotherapy symposium held during the European Association of Nuclear Medicine (EANM) 2017 Annual Congress. The biological basis of the immune checkpoint inhibitors and the drugs most frequently used for the treatment of solid tumours are reviewed. The issues of pseudoprogression (frequency, timeline), hyperprogression and immune-related side effects are discussed, as well as their implications for patient management. A review of the recent literature on the use of FDG PET for assessment of immunotherapy is presented, and recommendations are provided for assessing tumour response and reporting immune-related side effects with FDG PET based on published data and experts' experience. Representative clinical cases are also discussed.

Nuclear medicine has a central role in the diagnosis, staging, response assessment and long-term follow-up of neuroblastoma, the most common solid extracranial tumour in children. These EANM guidelines include updated information on 123 I-mIBG, the most common study in nuclear medicine for the evaluation of neuroblastoma, and on PET/CT imaging with 18 F-FDG, 18 F-DOPA and 68 Ga-DOTA peptides. These PET/CT studies are increasingly employed in clinical practice. Indications, advantages and limitations are presented along with recommendations on study protocols, interpretation of findings and reporting results.

Oligometastatic disease represents a clinical and anatomical manifestation between localised and polymetastatic disease. In prostate cancer, as with other cancers, recognition of oligometastatic disease enables focal, metastasis-directed therapies. These therapies potentially shorten or postpone the use of systemic treatment and can delay further metastatic progression, thus increasing overall survival. Metastasis-directed therapies require imaging methods that definitively recognise oligometastatic disease to validate their efficacy and reliably monitor response, particularly so that morbidity associated with inappropriately treating disease subsequently recognised as polymetastatic can be avoided. In this Review, we assess imaging methods used to identify metastatic prostate cancer at first diagnosis, at biochemical recurrence, or at the castration-resistant stage. Standard imaging methods recommended by guidelines have insufficient diagnostic accuracy for reliably diagnosing oligometastatic disease. Modern imaging methods that use PET-CT with tumour-specific radiotracers (choline or prostate-specific membrane antigen ligand), and increasingly whole-body MRI with diffusion-weighted imaging, allow earlier and more precise identification of metastases. The European Organisation for Research and Treatment of Cancer (EORTC) Imaging Group suggests clinical algorithms to integrate modern imaging methods into the care pathway at the various stages of prostate cancer to identify oligometastatic disease. The EORTC proposes clinical trials that use modern imaging methods to evaluate the benefits of metastasis-directed therapies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

CD8 + T cells infiltrating tumors are largely dysfunctional, but whether a subset maintains superior functionality remains ill defined. By high-dimensional single cell analysis of millions of CD8 + T cells from 53 individuals with lung cancer, we defined those subsets that are enriched in tumors compared with cancer-free tissues and blood. Besides exhausted and activated cells, we identified CXCR5 + TIM-3 - CD8 + T cells with a partial exhausted phenotype, while retaining gene networks responsible for stem-like plasticity and cytotoxicity, as revealed by single cell sequencing of the whole transcriptome. Ex vivo, CXCR5 + TIM-3 - CD8 + T cells displayed enhanced self-renewal and multipotency compared with more differentiated subsets and were largely polyfunctional. Analysis of inhibitory and costimulatory receptors revealed PD-1, TIGIT, and CD27 as possible targets of immunotherapy. We thus demonstrate a hierarchy of differentiation in the context of T cell exhaustion in human cancer similar to that of chronically infected mice, which is further shown to disappear with disease progression., (© 2018 Brummelman et al.)

Background: In the era of image-guided radiotherapy, PET has become an important tool for tumor delineation in several types of cancer. The aim of this study was to evaluate the effect of this imaging modality in treatment planning of a cohort of patients with prostate cancer eligible for radiotherapy., Methods: From September 2011 to January 2016, 135 consecutive patients (median age 69 years, range: 53-89) were referred to our department for radiation therapy with radical intent (n=28), for postoperative adjuvant (n=13) or salvage treatment (n=50), for re-irradiation (n=19), or for radiotherapy on oligometastases (n=25). Before planning the radiotherapy course, patients were submitted to carbon-11-choline PET (Cho-PET) to confirm the indication to radiotherapy and the irradiation volumes., Results: Among the 135 patients subjected to Cho-PET, the indication to radiotherapy was modified in 66 (48.8%) cases based on the Cho-PET result. In particular, Cho-PET helped to better define the radiotherapy programme in 12 out of 28 (42.8%) patients who were candidates for primary radiation therapy, 33 (52.4%) of 63 patients undergoing adjuvant/salvage radiotherapy, and 21 out of 44 (47.7%) patients with relapsed/metastatic disease. Overall biochemical response is documented by mean and median prostate specific antigen values, which changed from 15.29 to 4.00 ng/ml, respectively, before to mean 4.74 ng/ml and median 0.81 ng/ml after therapy (P=0.05)., Conclusion: In our series, Cho-PET had a significant effect on radiotherapy planning of patients affected by prostate cancer, determining a change in management in 48.8% of cases, considering all therapeutic indications.

Purpose: 68 Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography may represent the most promising imaging modality to identify and risk stratify prostate cancer in patients with contraindications to or negative multiparametric magnetic resonance imaging., Materials and Methods: In this prospective observational study we analyzed 68 Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography in a select group of patients with persistently elevated prostate specific antigen and/or Prostate Health Index suspicious for prostate cancer, negative digital rectal examination and at least 1 negative biopsy. The cohort comprised men with equivocal multiparametric magnetic resonance imaging (Prostate Imaging-Reporting and Data System, version 2 score of 2 or less), or an absolute or relative contraindication to multiparametric magnetic resonance imaging. Sensitivity, specificity and CIs were calculated compared to histopathology findings. ROC analysis was applied to determine the optimal cutoff values of 68 Ga labeled prostate specific membrane antigen uptake to identify clinically significant prostate cancer (Gleason score 7 or greater)., Results: A total of 45 patients with a median age of 64 years were referred for 68 Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography between January and August 2017. The 25 patients (55.5%) considered to have positive positron emission tomography results underwent software assisted fusion biopsy. We determined the uptake values of regions of interest, including a median maximum standardized uptake value of 5.34 (range 2.25 to 30.41) and a maximum-to-background standardized uptake value ratio of 1.99 (range 1.06 to 14.42). Mean and median uptake values on 68 Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography (ie the maximum standardized uptake value or the maximum-to-background standardized uptake value ratio) were significantly higher for Gleason score 7 lesions than for Gleason score 6 or benign lesions (p <0.001). On ROC analysis a maximum standardized uptake value of 5.4 and a maximum-to-background standardized uptake value ratio of 2 discriminated clinically relevant prostate cancer with 100% overall sensitivity in each case, and 76% and 88% specificity, respectively., Conclusions: Our findings support the use of 68 Ga labeled prostate specific membrane antigen positron emission tomography/computerized tomography for primary detection of prostate cancer in a specific subset of men., (Copyright © 2018 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

The treatment algorithm of advanced non-small-cell lung cancer is rapidly evolving. This result is mostly related to the availability in clinical practice of checkpoint inhibitors targeting the programmed death-1 (PD-1) and its ligands (PD-Ls) immunosuppressive pathway. Although patient's selection in the first-line setting relies essentially on high levels of PD-L1 tumor expression, treatment choice in pretreated patients is more challenging and, although clinical and biological characteristics might be of help, there is an urgent need for novel tools to better identify sensitive and resistant patients. In this context, the integration of molecular markers and immune-PET imaging might represent a potentially effective strategy to refine patient selection.

Objectives: This study aimed to determine the prognostic role of textural features and their association with metabolic parameters, hypoxia, and cancer-related immune markers in non-small-cell lung cancer (NSCLC) patients., Patients and Methods: The trial was registered at http://www.clinicaltrials.gov (NCT02519062). From January 2010 to May 2014, 44 patients (male : female=33 : 11; median age: 69.5 years), referred to our Institution for NSCLC resection, were enrolled. Tumor specimens were assessed for HIF-1α, CD68-TAMs, CD8-TILs, PD-1-TILs, and PD-L1 expressions. All patients underwent fluorine-18-fluorodeoxyglucose (F-FDG) PET before surgery. Semiquantitative parameters included maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolic tumor volume, and total lesion glycolysis, whereas for heterogeneity, we considered tumor sphericity, skewness, kurtosis, entropy, and energy. Parameters were correlated with disease-free survival (DFS) considering a median follow-up of 22.7 months., Results: SUVmax (cutoff: 7.9; P=0.015), SUVpeak (cutoff: 6.7; P=0.013), SUVmean (cutoff: 5.5; P=0.028), metabolic tumor volume (cutoff: 3.6 cm; P=0.027), and entropy (cutoff: 1.89; P=0.045) showed a statistically significant association with DFS. Also, a high expression of cytoplasmic HIF-1α (score 3) was associated with DFS (hazard ratio: 0.09; P=0.003). All F-FDG PET variables differed significantly in tumors with high or low entropy (≤1.89). Also, a significantly higher level of mean CD8-TILs was observed in tumors with higher entropy (P=0.041).Using identified prognostic factors, we developed a scoring system, which was confirmed to be associated with DFS (P<0.004). On receiver operating characteristics analysis, a score above 3 was defined as the optimal cutoff point., Conclusion: Tumor heterogeneity, metabolic parameters, and high expression of hypoxia were found to be prognostic factors in NSCLC patients who were candidates for surgery. Higher levels of entropy appear to be associated with increased density of CD8-TILs. The combination of investigated prognostic factors enabled the development of a potential scoring system associated with DFS.

Introduction: The present study investigated the utility of fluorine-18 ( 18 F) fluoro-2-deoxy-d-glucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT) in assessing bone marrow involvement (BMI) compared with bone marrow biopsy (BMB) in newly diagnosed pediatric Hodgkin lymphoma (HL)., Patients and Methods: A total of 224 pediatric patients with HL underwent 18 F-FDG PET/CT at staging. BMB or follow-up imaging was used as the standard of reference for the evaluation of BMI., Results: 18 F-FDG PET/CT was negative for BMI in 193 cases. Of the 193 patients, the findings for 16 were originally reported as doubtful and later interpreted as negative for BMI, with negative findings on follow-up imaging and BMB. At BMB, 1 of the 16 patients (6.25%) had BMI. Of the 193 patients, 192 (99.48%) had negative BMB findings. Thus, the 18 F-FDG PET/CT findings were truly negative for 192 patients and falsely negative for 1 patient for BMI., Conclusion: 18 F-FDG PET/CT showed high diagnostic performance in the evaluation of BMI in pediatric HL. Thus, BMB should be ideally reserved for patients presenting with doubtful 18 F-FDG PET/CT findings for BMI., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Our objective was to evaluate the biodistribution, kinetics, and radiation dosimetry of 64 CuCl 2 in humans and to assess the ability of 64 CuCl 2 PET/CT to detect prostate cancer (PCa) recurrence in patients with biochemical relapse. Methods: We prospectively evaluated 50 PCa patients with biochemical relapse after surgery or external-beam radiation therapy. All patients underwent 64 CuCl 2 PET/CT, 18 F-choline PET/CT, and multiparametric MRI within 15 d of each other. Experienced readers interpreted the images, and the detection rate (DR) of each imaging modality was calculated. Histopathology, when available; clinical or laboratory response; and multidisciplinary follow-up were used to confirm the site of disease. In parallel, biodistribution, kinetics of the lesions, and radiation dosimetry of 64 CuCl 2 were evaluated. Results: From a dosimetric point of view, an administered dose of 200 MBq for 64 CuCl 2 translated into a 5.7-mSv effective dose. Unlike 18 F-choline, 64 CuCl 2 was not excreted or accumulated in the urinary tract, thus allowing thorough pelvic exploration. The maximum 64 CuCl 2 uptake at the sites of PCa relapse was observed 1 h after tracer injection. In our cohort, 64 CuCl 2 PET/CT proved positive in 41 of 50 patients, with an overall DR of 82%. The DRs of 18 F-choline PET/CT and multiparametric MRI were 56% and 74%, respectively. The difference between the DRs of 64 CuCl 2 PET/CT and 18 F-choline PET/CT was statistically significant ( P < 0.001). Interestingly, on considering prostate-specific antigen (PSA) value, 64 CuCl 2 PET/CT had a higher DR than 18 F-choline PET/CT in patients with a PSA of less than 1 ng/mL. Conclusion: The biodistribution of 64 CuCl 2 is more suitable than that of 18 F-choline for exploring the pelvis and prostatic bed. The 64 CuCl 2 effective dose is like those of other established PET tracers. In patients with biochemical relapse and a low PSA level, 64 CuCl 2 PET/CT shows a significantly higher DR than 18 F-choline PET/CT., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Surgery, radiation therapy and chemotherapy are the oldest modalities for cancer treatment. However, as part of a continuous research in medicine, in order to improve therapeutic precision and biological effectiveness, there is an increasing interest into the use of heavy particle (e.g. protons or heavy ions) in the treatment of solid tumors. However, the restricted availability of the technology has concentrated the expertise in highly specialized centers that take care and treat extreme cases and rare pathologies. One of the tumors that has mostly beneficiated from heavy ion therapy is represented by adenoid cystic carcinoma (ACC) of the head and neck. In the current review we will focus our attention on the role of heavy particle therapy in general, with particular interest on ACC. The article will also summarize recent clinical evidence comparing traditional radiotherapy with the new heavy particles. Moreover, molecular imaging features of this uncommon tumor with 18 F-FDG and 11 C-MET will be discussed and illustrated., Competing Interests: None.

The rapidly evolving knowledge on tumor immunology and the continuous implementation of immunotherapy in cancer have recently led to the FDA and EMA approval of several checkpoint inhibitors as immunotherapic agents in clinical practice. Anti-CTLA-4, anti-PD-1, and anti-PDL-1 antibodies are becoming standard of care in advanced melanoma, as well as in relapsed or metastatic lung and kidney cancer, demonstrating higher and longer response compared to standard chemotherapy. These encouraging results have fostered the evaluation of these antibodies either alone or in combination with other therapies in several dozen clinical trials for the treatment of multiple tumor types. However, not all patients respond to immune checkpoint inhibitors, hence, specific biomarkers are necessary to guide and monitor therapy. The utility of PD-L1 expression as a biomarker has varied in different clinical trials, but, to date, no consensus has been reached on whether PD-L1 expression is an ideal marker for response and patient selection; approximately 20-25% of patients will respond to immunotherapy with checkpoint inhibitors despite a negative PD-L1 staining. On the other hand, major issues concern the evaluation of objective response in patients treated with immunotherapy. Pure morphological criteria as commonly used in solid tumors (i.e. RECIST) are not sufficient because change in size is not an early and reliable marker of tumor response to biological therapies. Thus, the scientific community has required a continuous adaptation of immune-related response criteria (irRC) to overcome the problem. In this context, metabolic information and antibody-based imaging with positron emission tomography (PET) have been investigated, providing a powerful approach for an optimal stratification of patients at staging and during the evaluation of the response to therapy. In the present review we provide an overview on the clinical characteristics of patient selection when using imaging predictors of outcome in solid tumors treated with checkpoint-inhibitors.

Introduction: aim is outcome of 11C-Choline-PET guided SBRT on lymph node metastases., Materials and Methods: patients with 1 - 4 lymph node metastases detected by 11C-choline-PET were treated with SBRT. Toxicity, treated metastases control and Progression Free Survival were computed., Results: twenty-six patients, 38 lymph node metastases were irradiated. No grade ≥ 2 toxicity. Median PSA-nadir after RT was 1.02 ng/mL. Post-treatment 11C-Choline-PET showed metabolic complete response in 17 metastases (44,7%), partial response in 9 metastases (38%)., Conclusion: SBRT is effective and safe for lymph node metastases. PET is important in identification of gross tumor and evaluation of the response.

The aim of this study was to evaluate the role of metabolic parameters analyzed at baseline and at interim FDG-PET in predicting disease outcome in unresectable MPM patients receiving pemetrexed-based chemotherapy. A consecutive series of MPM patients treated between February 2004 and July 2013 with first-line pemetrexed-based chemotherapy, and evaluated by FDG-PET and CT scan at baseline and after two cycles of chemotherapy, was reviewed. Best CT scan response was assessed according to modified RECIST criteria. Progression-free survival (PFS) and overall survival (OS) were correlated with FDG-PET parameters, such as maximum standardized uptake value (SUV max ), total lesion glycolysis (TLG), and percentage changes in SUV max (∆SUV) and TLG (∆TLG). Overall, 142 patients were enrolled; 77 (54%) received talc pleurodesis before chemotherapy. Baseline SUV max and TLG showed a statistically significant correlation with PFS and OS (P < 0.05) in both group of patients (treated and untreated with pleurodesis). In 65 patients not receiving pleurodesis, SUV max reduction ≥25% (∆SUV ≥ 25%) and TLG reduction ≥30% (∆TLG ≥ 30%) were significantly associated with longer PFS (P < 0.05). Patients showing both ∆SUV ≥ 25% and ∆TLG ≥ 30% responses had a significant reduction in the risk of disease progression (HR:0.31, P < 0.001) and death (HR:0.52, P = 0.044). Neither ∆SUV nor ∆TLG showed similar association with survival outcomes in patients treated with pleurodesis. Our study confirmed the prognostic role of baseline FDG-PET in a large series of MPM patients treated with first-line pemetrexed-based chemotherapy. Moreover, use of ∆SUV ≥ 25% and ∆TLG ≥ 30% as cut-off values to define early metabolic response supported the role of FDG-PET in predicting disease outcome and treatment response in patients not receiving pleurodesis., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: The aim of this study was to report the impact of C-choline PET/CT on the management of patients with hepatocellular carcinoma (HCC) and incorporate into a refined algorithm combining diagnostic imaging and multidisciplinary team (MDT) discussion., Patients and Methods: From February 2010 to February 2016, the charts of all patients discussed in the liver MDT were revised. Suspected or confirmed HCC lesions or Barcelona Clinic Liver Cancer stages A, B or C with a C-choline PET/CT performed in our hospital were included in the analyses. Overall, 73 patients (male : female=59 : 14; median age: 75 years) were enrolled. Forty-two (57%) patients were newly diagnosed, whereas 31 (43%) came to our attention at disease recurrence. Seven (10%) patients were Barcelona Clinic Liver Cancer stage 0, 31 (42%) patients were stage A, 15 (20%) patients were stage B, and 18 (25%) patients were stage C. The reference standards for ultimate imaging validation were either histology or MDT consensus. A minimum follow-up of 6 months was established., Results: Overall eight (10%) patients were initially referred for chemotherapy (sorafenib), 43 (59%) for surgery, two (3%) for surgery or transarterial embolization, five (7%) for follow-up only, one (1%) for extrahepatic radiotherapy, seven (10%) for stereotactic body radiation therapy of the liver, six (8%) for transarterial embolization, and one (1%) for liver transplant. After C-choline PET/CT and MDT discussion, in seven patients the diagnosis changed, in six patients the treatment was changed, and in nine patients both the diagnosis and the treatment were changed. Overall, in 30% of our patients, the diagnosis or treatment was altered on the basis of our algorithm of management., Conclusion: The incorporation of C-choline PET/CT into the MDT discussion altered the diagnosis/treatment of one-third of HCC patients. We propose a novel diagnostic algorithm to be refined in referral centers for HCC management.

Two hundred and ten nuclear medicine physicians, radiologists, and hematologists from 26 countries attended the 6th International Workshop on Positron Emission Tomography (PET) in Lymphoma and Myeloma held in Menton, France, in September 2016. The meeting was under the auspices of the European Lymphoma Institute (ELI), the European Association of Nuclear Medicine (EANM) the Lymphoma Study Association (LYSA), the Italian Foundation on Lymphoma (FIL) and the Carnot Institute for Lymphoma (CALYM). Forty scientific posters were presented. For the first time, specialists in the field of multiple myeloma (MM) were involved in the expert session. The aim was to establish from the experience of Italian and French studies new guidelines of FDG-PET/CT reporting for myeloma staging and restaging. The meeting dedicated an entire session to MM imaging followed by a session on the role of PET in Peripheral T cell Lymphoma. An entire session addressed the issues of Deauville scale particularly for end treatment assessment and the challenging consequences of immunomodulatory treatments on PET reporting. A specific session presented the potential role of baseline metabolic tumor measurement to predict outcome and identify different risk categories and the main results obtained in different lymphoma entities were described. Whether it could replace clinical staging has been extensively discussed. The more recent results obtained in the H10 trial have been presented and compared to the published data in early stage Hodgkin lymphoma. Finally, the ongoing studies using PET for guiding therapeutic strategies have been reported by the various lymphoma cooperative groups that participated to the meeting.

Purpose: We evaluated the relationship between 11 C-methionine PET ( 11 C-METH PET) findings and molecular biomarkers in patients with supratentorial glioma who underwent surgery., Methods: A consecutive series of 109 patients with pathologically proven glioma (64 men, 45 women; median age 43 years) referred to our Institution from March 2012 to January 2015 for tumour resection and who underwent preoperative 11 C-METH PET were analysed. Semiquantitative evaluation of the 11 C-METH PET images included SUVmax, region of interest-to-normal brain SUV ratio (SUVratio) and metabolic tumour volume (MTV). Imaging findings were correlated with disease outcome in terms of progression-free survival (PFS), and compared with other clinical biological data, including IDH1 mutation status, 1p/19q codeletion and MGMT promoter methylation. The patients were monitored for a mean period of 16.7 months (median 13 months)., Results: In all patients, the tumour was identified on 11 C-METH PET. Significant differences in SUVmax, SUVratio and MTV were observed in relation to tumour grade (p < 0.001). IDH1 mutation was found in 49 patients, 1p/19q codeletion in 58 patients and MGMT promoter methylation in 74 patients. SUVmax and SUVratio were significantly inversely correlated with the presence of IDH1 mutation (p < 0.001). Using the 2016 WHO classification, SUVmax and SUVratio were significantly higher in patients with primary glioblastoma (IDH1-negative) than in those with other diffuse gliomas (p < 0.001). Relapse or progression was documented in 48 patients (median PFS 8.7 months). Cox regression analysis showed that SUVmax and SUVratio, tumour grade, tumour type on 2016 WHO classification, IDH1 mutation status, 1p/19q codeletion and MGMT promoter methylation were significantly associated with PFS. None of these factors was found to be an independent prognostic factor in multivariate analysis., Conclusion: 11 C-METH PET parameters are significantly correlated with histological grade and IDH1 mutation status in patients with glioma. Grade, pathological classification, molecular biomarkers, SUVmax and SUVratio were prognostic factors for PFS in this cohort of patients. The trial was registered with ClinicalTrials.gov (registration: NCT02518061).

Background: The current standard of care for newly diagnosed glioblastoma (GBM) is surgical resection, followed by radiation therapy (RT) with concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT). The patients outcome is still poor. In this study we evaluated hypofractionated radiation therapy (HFRT), instead of standard fractionated radiation therapy, with concomitant and adjuvant TMZ chemotherapy, in terms of safety and effectiveness., Methods: Patients with newly diagnosed GBM, Karnofsky performance scale (KPS) ≥70, and tumor up to 10 cm underwent maximal feasible surgical resection were treated. HFRT consisted of 60 Gy, in daily fractions of 4 Gy given 5 days per week for 3 weeks. The primary endpoints were overall survival (OS), progression free survival (PFS), and incidence of radiation induced brain toxicity. Secondary endpoint was the evaluation of neurocognitive function., Results: A total of 97 patients were included in this phase II study. The median age was 60.5 years (range 23-77 years). Debulking surgery was performed in 83.5% of patients, HFRT was completed in all 97 patients, concurrent and adjuvant TMZ in 93 (95.9%). The median number of TMZ cycles was six (range 1-12 cycles). No severe toxicity occurred and the neuropsychological evaluation remained stable. At a median follow up time of 15.2 months the median OS time, 1,2-year OS rate were 15.9 months (95% CI 14-18), 72.2% (95% CI 62.1-80) and 30.4% (95% CI 20.8-40.6). Age, KPS, MGMT methylation status, and extent of surgical resection were significant factors influencing the outcome., Conclusion: HFRT with concomitant and adjuvant TMZ chemotherapy is an effective and safe treatment., Competing Interests: CONFLICTS OF INTEREST L. Cozzi acts as Scientific Advisor to Varian Medical Systems and is Clinical Research Scientist at Humanitas Cancer Center. All other co-authors have no conflicts of interest

Objective: The aim of this study was to analyse early and delayed acquisition on copper-64 diacetyl-bisN4-methylthiosemicarbazone (Cu-ATSM) PET/CT in a small cohort of patients by comparing semiquantitative and computer-aided fractal geometry analyses., Patients and Methods: Five cancer patients, including non-small-cell lung cancer and head and neck cancer, were investigated with Cu-ATSM PET/CT. Participants received an intravenous injection of Cu-ATSM according to body size and were imaged 60 min (early) and 16 h (delayed) later on hybrid PET/CT. Reconstructed images were visualized on advanced workstations for the definition of semiquantitative parameters: standardized uptake value (SUV)max, SUVratio-to-muscle, SUVmean, hypoxic volume (HV) and hypoxic burden (HB=HV×SUVmean). DICOM data retrieved from both scans were analysed using an ad-hoc computer program to determine the mean intensity value, SD, relative dispersion, three-dimensional histogram fractal dimension and three-dimensional fractal dimension., Results: All tumour lesions showed increased uptake of Cu-ATSM at early evaluation, with a median SUVratio-to-muscle of 4.42 (range: 1.58-5.62), a median SUVmax of 5.3 (range: 1.9-7.3), a median SUVmean of 2.8 (range: 1.5-3.9), a median HV of 41.6 cm (range: 2.8-453.7) and a median HB of 161.5 cm (range: 4.4-1112.5). All semiquantitative data obtained at 1 h were consistent with the parameters obtained on delayed imaging (P>0.05). A borderline statistically significant difference was found only for SUVmax of the muscle (P=0.045). Fractal geometry analysis on DICOM images showed that all parameters at early imaging showed no statistically significant difference with late acquisition (P>0.05)., Conclusion: Our findings support the consistency of Cu-ATSM PET/CT images obtained at early and delayed acquisition for the assessment of tumour lesions.