Purpose: Measurements of non-displaceable binding (V ND ) of positron emission tomography (PET) ligands are not often made in vivo in humans because they require ligands to displace binding to target receptors and there are few readily available, safe ones to use. A technique to measure V ND for ligands for the 18-kDa translocator protein (TSPO) has recently been developed which compares the total volume of distribution (V T ) before and after administration of the TSPO ligand XBD173. Here, we used XBD173 with an occupancy plot to quantify V ND for two TSPO radiotracers, [ 18 F]GE-180 and [ 11 C]PBR28, in cohorts of people with multiple sclerosis (MS). Additionally, we compared plots of subjects carrying high (HAB) or mixed binding (MAB) affinity polymorphisms of TSPO to estimate V ND without receptor blockade. Procedures: Twelve people with MS underwent baseline MRI and 90-min dynamic [ 18 F]GE-180 PET or [ 11 C]PBR28 PET (n = 6; three HAB, three MAB each). Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model. V ND was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173) and the polymorphism plot (by modelling the differences in signal across presence and absence of rs6971 genotypes). Results: Whole brain V T (mean ± standard deviation) was 0.29 ± 0.17 ml/cm 3 for [ 18 F]GE-180 and 5.01 ± 1.88 ml/cm 3 for [ 11 C]PBR28. Using the occupancy and polymorphism plots respectively, V ND for [ 18 F]GE-180 was 0.11 ml/cm 3 (95 % CI = 0.02, 0.16) and 0.20 ml/cm 3 (0.16, 0.34), accounting for, on average, 55 % of V T in the whole brain. For [ 11 C]PBR28, these values were 3.81 ml/cm 3 (3.02, 4.21) and 3.49 ml/cm 3 (1.38, 4.27), accounting for 67 % of average whole brain V T .Sujata Sridharan and Joel Raffel are joint first authors. Conclusions:Although V T for [ 18 F]GE-180 is low, indicating low brain penetration, half the signal shown by MS subjects reflected specific TSPO binding. V T for [ 11 C]PBR28 was higher and two thirds of the binding was non-specific. No brain ROIs were devoid of specific signal, further confirming that true reference tissue approaches are potentially problematic for estimating TSPO levels.

Schizophrenia does not affect treatment delivery or outcomes in women with breast cancer. The presence of schizophrenia should not be a limiting factor for entry into clinical trials. Breast cancer patients with this illness should be offered standard treatment without discrimination, including entry into clinical trials.

It is well recognised that the majority of the impact of multiple sclerosis (MS), both personal and societal, arises in the progressive phase where disability accumulates inexorably. As such, progressive MS (PMS) has been the target of pharmacological therapies for many years. However, there are no current licensed treatments for PMS. This stands in marked contrast to relapsing remitting MS (RRMS) where trials have resulted in numerous licensed therapies. PMS has proven to be a more difficult challenge compared to RRMS and this review focuses on secondary progressive MS (SPMS), where relapses occur before the onset of gradual, irreversible disability, and not primary progressive MS where disability accumulation occurs without prior relapses. Although there are similarities between the two forms, in both cases pinpointing when PMS starts is difficult in a condition in which disability can vary from day to day. There is also an overlap between the pathology of relapsing and progressive MS and this has contributed to the lack of well-defined outcomes, both surrogates and clinically relevant outcomes in PMS. In this review, we used the search term 'randomised controlled clinical drug trials in secondary progressive MS' in publications since 1988 together with recently completed trials where results were available. We found 34 trials involving 21 different molecules, of which 38% were successful in reaching their primary outcome. In general, the trials were well designed (e.g. double blind) with sample sizes ranging from 35 to 1949 subjects. The majority were parallel group, but there were also multi-arm and multidose trials as well as the more recent use of adaptive designs. The disability outcome most commonly used was the Expanded Disability Status Scale (EDSS) in all phases, but also magnetic resonance imaging (MRI)-measured brain atrophy has been utilised as a surrogate endpoint in phase II studies. The majority of the treatments tested in SPMS over the years were initially successful in RRMS. This has a number of implications in terms of targeting SPMS, but principally implies that the optimal strategy to target SPMS is to utilise the prodrome of relapses to initiate a therapy that will aim to both prevent progression and slow its accumulation. This approach is in agreement with the early targeting of MS but requires treatments that are both effective and safe if it is to be used before disability is a major problem. Recent successes will hopefully result in the first licensed therapy for PMS and enable us to test this approach.