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GC has received grants, research support or is coinvestigator in clinical trials by Bristol-Myers-Squibb, Celgene, Boehringer Ingelheim, Roche, Tigen Pharma, Iovance and Kite. GC has received honoraria for consultations or presentations by Roche, Genentech, BMS, AstraZeneca, Sanofi-Aventis, Nextcure and GeneosTx. GC has patents in the domain of antibodies and vaccines targeting the tumor vasculature as well as technologies related to T-cell expansion and engineering for T-cell therapy. GC receives royalties from the University of Pennsylvania. FH reports grants from Prostate Cancer Foundation, Bristol-Myers-Squibb, Accuray Inc, Bioprotect, and non-financial support from Roche ImFlame cooperative group, European Organization for Research and Treatment of Cancer (EORTC) chairman Gynecology Cancer Group. FH has received honoraria for consultations from

Increased body weight is independently associated with abnormal coronary circulatory function that progresses from an impairment in endothelium-related coronary vasomotion in overweight individuals to an impairment of the total vasodilator capacity in obese individuals. The findings that elevated leptin plasma levels in patients that are obese might exert beneficial effects on the coronary endothelium to counterbalance the adverse effects of increases in body weight on coronary circulatory function should be tested.

Background-Abnormal coronary endothelial reactivity has been demonstrated in diabetes and is associated with an increased rate of cardiovascular events. Our objectives were to investigate the presence of functional coronary circulatory abnormalities over the full spectrum of insulin resistance and to determine whether these would differ in severity with more advanced states of insulin resistance. Methods and Results-Myocardial blood flow (MBF) was measured with positron emission tomography and 13 N-ammonia to characterize coronary circulatory function in states of insulin resistance without carbohydrate intolerance (IR), impaired glucose tolerance (IGT), and normotensive and hypertensive type 2 diabetes mellitus (DM) compared with insulin-sensitive (IS) individuals. Indices of coronary function were total vasodilator capacity (mostly vascular smooth muscle-mediated) during pharmacological vasodilation and the nitric oxide-mediated, endothelium-dependent vasomotion in response to cold pressor testing. Total vasodilator capacity was similar in normoglycemic individuals (IS, IR, and IGT), whereas it was significantly decreased in normotensive (Ϫ17%) and hypertensive (Ϫ34%) DM patients. Compared with IS, endothelium-dependent coronary vasomotion was significantly diminished in IR (Ϫ56%), as well as in IGT and normotensive and hypertensive diabetic patients (Ϫ85%, Ϫ91%, and Ϫ120%, respectively). Conclusions-Progressively worsening functional coronary circulatory abnormalities of nitric oxide-mediated, endothelium-dependent vasomotion occur with increasing severity of insulin-resistance and carbohydrate intolerance. Attenuated total vasodilator capacity accompanies the more clinically evident metabolic abnormalities in diabetes.

For the past decade, PET with 18 F-fluoro-ethyl-tyrosine ( 18 F-FET) has been used in the evaluation of patients with primary brain tumors (PBTs), but so far series have reported only a limited number of patients. The purpose of this systematic review and metaanalysis was to assess the diagnostic performance of 18 F-FET PET in patients with suspicion of PBT. Methods: We examined studies published in the literature using MEDLINE and EMBASE databases. Inclusion criteria were use of 18 F-FET PET for initial assessment of patients with a newly diagnosed brain lesion; patients who had no radiotherapy, surgery, or chemotherapy before 18 F-FET PET; and use of histology as a gold standard. Metaanalysis was performed on a per-patient basis. We secondarily performed receiver-operating-characteristic analysis of pooled patients to determine tumor-to-background ratio (TBR) of 18 F-FET uptake and best diagnostic value. Results: Thirteen studies totaling 462 patients were included. For the diagnosis of PBT, 18 F-FET PET demonstrated a pooled sensitivity of 0.82 (95% confidence interval [CI], 0.74-0.88), specificity of 0.76 (95% CI, 0.44-0.92), area under the curve of 0.84 (95% CI, 0.80-0.87), positive likelihood ratio of 3.4 (95% CI, 1.2-9.5), and negative likelihood ratio of 0.24 (95% CI, 0.14-0.39). Receiver-operating-characteristic analysis indicated that a mean TBR threshold of at least 1.6 and a maximum TBR of at least 2.1 had the best diagnostic value for differentiating PBTs from nontumoral lesions. Conclusion: 18 F-FET PET demonstrated excellent performance for diagnosing PBTs. Strict standardization of PET acquisition protocols and prospective, multicenter studies investigating the added value over current MRI are now needed to establish 18 F-FET PET as a highly relevant tool for patient management.

Optimal vaccine strategies must be identified for improving T-cell vaccination against infectious and malignant diseases. MelQbG10 is a virus-like nano-particle loaded with A-type CpG-oligonucleotides (CpG-ODN) and coupled to peptide16–35 derived from Melan-A/MART-1. In this phase IIa clinical study, four groups of stage III-IV melanoma patients were vaccinated with MelQbG10, given (i) with IFA (Montanide) s.c.; (ii) with IFA s.c. and topical Imiquimod; (iii) i.d. with topical Imiquimod; or (iv) as intralymph node injection. In total, 16/21 (76%) patients generated ex vivo detectable Melan-A/MART-1-specific T-cell responses. T-cell frequencies were significantly higher when IFA was used as adjuvant, resulting in detectable T-cell responses in all (11/11) patients, with predominant generation of effector-memory-phenotype cells. In turn, Imiquimod induced higher proportions of central-memory-phenotype cells and increased percentages of CD127+ (IL-7R) T cells. Direct injection of MelQbG10 into lymph nodes resulted in lower T-cell frequencies, associated with lower proportions of memory and effector-phenotype T cells. Swelling of vaccine site draining lymph nodes, and increased glucose uptake at PET/CT was observed in 13/15 (87%) of evaluable patients, reflecting vaccine triggered immune reactions in lymph nodes. We conclude that the simultaneous use of both Imiquimod and CpG-ODN induced combined memory and effector CD8+ T-cell responses.

Since the seventies, positron emission tomography (PET) has become an invaluable medical molecular imaging modality with an unprecedented sensitivity at the picomolar level, especially for cancer diagnosis and the monitoring of its response to therapy. More recently, its combination with X-ray computed tomography (CT) or magnetic resonance (MR) has added high precision anatomic information in fused PET/CT and PET/MR images, thus compensating for the modest intrinsic spatial resolution of PET. Nevertheless, a number of medical challenges call for further improvements in PET sensitivity. These concern in particular new treatment opportunities in the context personalized (also called precision) medicine, such as the need to dynamically track a small number of cells in cancer immunotherapy or stem cells for tissue repair procedures. A better signal-to-noise ratio (SNR) in the image would allow detecting smaller size tumours together with a better staging of the patients, thus increasing the chances of putting cancer in complete remission. Moreover, there is an increasing demand for reducing the radioactive doses injected to the patients without impairing image quality. There are three ways to improve PET scanner sensitivity: improving detector efficiency, increasing geometrical acceptance of the imaging device and pushing the timing performance of the detectors. Currently, some pre-localization of the electron-positron annihilation along a line-of-response (LOR) given by the detection of a pair of annihilation photons is provided by the detection of the time difference between the two photons, also known as the time-of-flight (TOF) difference of the photons, whose accuracy is given by the coincidence time resolution (CTR). A CTR of about 10 picoseconds FWHM will ultimately allow to obtain a direct 3D volume representation of the activity distribution of a positron emitting radiopharmaceutical, at the millimetre level, thus introducing a quantum leap in PET imaging and quantification and fostering more frequent use of 11 C radiopharmaceuticals. The present roadmap article toward the advent of 10 ps TOF-PET addresses the status and current/future challenges along the development of TOF-PET with the objective to reach this mythic 10 ps frontier that will open the door to real-time volume imaging virtually without tomographic inversion. The medical impact and prospects to achieve this technological revolution from the detection and image reconstruction point-of-views, together with a few perspectives beyond the TOF-PET application are discussed. ContentsA. Introduction B. Medical impact B1. Clinical and research impact of 10 ps TOF-PET B2. Innovation for dynamic imaging C. Detection of annihilation photons C1. Design criteria for the detection chain for 10 ps TOF-PET C2. Perspectives on using inorganic scintillators for fast timing application C3. Perspectives on using Cherenkov light for fast timing applications C4. Perspectives on using nano-scintillators for fast timing applications C5. Perspectives on LAr and/or LXe ...

Objective To compare myocardial blood flow (MBF) and myocardial flow reserve (MFR) estimates from 82Rb PET data using ten software packages (SPs): Carimas, Corridor4DM, FlowQuant, HOQUTO, ImagenQ, MunichHeart, PMOD, QPET, syngo MBF, and UW-QPP. Background It is unknown how MBF and MFR values from existing SPs agree for 82Rb PET. Methods Rest and stress 82Rb PET scans of 48 patients with suspected or known coronary artery disease (CAD) were analyzed in 10 centers. Each center used one of the 10 SPs to analyze global and regional MBF using the different kinetic models implemented. Values were considered to agree if they simultaneously had an intraclass correlation coefficient (ICC) > 0.75 and a difference < 20% of the median across all programs. Results The most common model evaluated was the one-tissue compartment model (1TCM) by Lortie et al. (2007). MBF values from seven of the eight software packages implementing this model agreed best (Carimas, Corridor4DM, FlowQuant, PMOD, QPET, syngoMBF, and UW-QPP). Values from two other models (El Fakhri et al. in Corridor4DM and Alessio et al. in UW-QPP) also agreed well, with occasional differences. The MBF results from other models (Sitek et al. 1TCM in Corridor4DM, Katoh et al. 1TCM in HOQUTO, Herrero et al. 2TCM in PMOD, Yoshida et al. retention in ImagenQ, and Lautamäki et al. retention in MunichHeart) were less in agreement with Lortie 1TCM values. Conclusions SPs using the same kinetic model, as described in Lortie et al. (2007), provided consistent results in measuring global and regional MBF values, suggesting they may be used interchangeably to process data acquired with a common imaging protocol.