Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is mostly administered using a fixed injected activity (IA) per cycle. This empiric regime results in highly variable absorbed doses to the critical organs and undertreatment of the majority of patients. We conceived a personalized PRRT protocol in which the IA is adjusted to deliver a prescribed absorbed dose to the kidney, with the aim to safely increase tumour irradiation. We herein report on the initial results of our prospective study of personalized PRRT, the P-PRRT Trial (NCT02754297). METHODS: PRRT-naïve patients with progressive and/or symptomatic neuroendocrine tumour (NET) were scheduled to receive a four-cycle induction course of 177Lu-octreotate with quantitative SPECT/CT-based dosimetry. The IA was personalized according to the glomerular filtration rate and the body surface area for the first cycle, and according to the prior renal Gy/GBq for the subsequent cycles. The prescribed renal absorbed dose of 23 Gy was reduced by 25-50% in case of significant renal or haematological impairment. Responders were allowed to receive consolidation or maintenance cycles, for each of which 6 Gy to the kidney were prescribed. We simulated the empiric PRRT regime by fixing the IA at 7.4 GBq per cycle, with the same percentage reductions as above. Radiological, molecular imaging, biochemical, and quality of life responses, as well as safety, were assessed. RESULTS: Fifty-two patients underwent 171 cycles. In 34 patients who completed the induction course, a median cumulative IA of 36.1 (range, 6.3-78.6) GBq was administered, and the median cumulative kidney and maximum tumour absorbed doses were 22.1 (range, 8.3-24.3) Gy and 185.7 (range: 15.2-443.1) Gy respectively. Compared with the simulated fixed-IA induction regime, there was a median 1.26-fold increase (range, 0.47-2.12 fold) in the cumulative maximum tumour absorbed dose, which was higher in 85.3% of patients. In 39 assessable patients, the best objective response was partial response in nine (23.1%), minor response in 14 (35.9%), stable disease in 13 (33.3%) and progressive disease in three patients (7.7%). In particular, 11 of 13 patients (84.6%) with pancreatic NET had partial or minor response. The global health status/quality of life score significantly increased in 50% of patients. Acute and subacute side-effects were all of grade 1 or 2, and the most common were nausea (in 32.7% of patients) and fatigue (in 30.8% of patients) respectively. Subacute grade 3 or 4 toxicities occurred in less than 10% of patients, with the exception of lymphocytopenia in 51.9% of patients, without any clinical consequences however. No patient experienced severe renal toxicity. CONCLUSIONS: Personalized PRRT makes it possible to safely increase tumour irradiation in the majority of patients. Our first results indicate a favourable tolerance profile, which appears similar to that of the empiric regime. The response rates are promising, in particular in patients with NET of pancreatic origin.

White Matter Damage in the Semantic Variant of Primary Progressive Aphasia.

BACKGROUND: The semantic variant of primary progressive aphasia (svPPA) is a form of dementia, mainly featuring language impairment, for which the extent of white matter (WM) damage is less described than its associated grey matter (GM) atrophy. Our study aimed to characterise the extent of this damage using a sensitive and unbiased approach. METHODS: We conducted a between-group study comparing 10 patients with a clinical diagnosis of svPPA, recruited between 2011 and 2014 at a tertiary reference centre, with 9 cognitively healthy, age-matched controls. From diffusion tensor imaging (DTI) data, we extracted fractional anisotropy (FA) values using a tract-based spatial statistics approach. We further obtained GM volumetric data using the Freesurfer automated segmentation tool. We compared both groups using non-parametric Wilcoxon rank-sum tests, correcting for multiple comparisons. RESULTS: Demographic data showed that patients and controls were comparable. As expected, clinical data showed lower results in svPPA than controls on cognitive screening tests. Tractography showed impaired diffusion in svPPA patients, with FA mostly decreased in the longitudinal, uncinate, cingulum and external capsule fasciculi. Volumetric data show significant atrophy in svPPA patients, mostly in the left entorhinal, amygdala, inferior temporal, middle temporal, superior temporal and temporal pole cortices, and bilateral fusiform gyri. CONCLUSIONS: This syndrome appears to be associated not only with GM but also significant WM degeneration. Thus, DTI could play a role in the differential diagnosis of atypical dementia by specifying WM damage specific to svPPA.

Des atteintes à la substance blanche du cerveau dans le cas de la variante sémantique de l'aphasie primaire progressive. Contexte: La variante dite « sémantique ¼ de l'aphasie primaire progressive (vsAPP) constitue une forme de démence de laquelle découlent principalement des troubles du langage. À l'inverse de l'atrophie de la substance grise associée à cette démence, on a été moins portés à décrire les atteintes à la substance blanche. Notre étude entend donc cerner l'étendue de ces atteintes au moyen d'une approche à la fois sensible et neutre. Méthodes: Nous avons effectué une étude intergroupe en comparant 10 patients ayant reçu un diagnostic clinique de vsAPP à 9 témoins en santé sur le plan cognitif. À noter que ces 10 patients ont été recrutés entre 2011 et 2014 dans un centre de soins médicaux tertiaires. C'est à partir de données obtenues grâce à l'imagerie par tenseur de diffusion (diffusion tensor imaging) que nous avons extrait, au moyen d'une approche privilégiant les statistiques spatiales basées sur les voies neuronales, des valeurs d'anisotropie fractionnelle (FA). Nous avons en outre obtenu des données volumétriques concernant la substance grise en utilisant l'outil de segmentation automatisée Freesurfer. Nous avons ensuite comparé ces deux groupes à l'aide de tests des rangs signés de Wilcoxon non-paramétriques, et ce, en veillant à appliquer une correction en vue de nombreuses comparaisons. Résultats: D'entrée de jeu, précisons que nos données démographiques ont révélé que les patients et les témoins étaient comparables. Comme il fallait s'y attendre, nos données cliniques ont montré, dans le cadre de tests de dépistage cognitif, que les résultats des patients atteints de vsAPP se sont révélés inférieurs à ceux des témoins. Des examens de tractographie ont par ailleurs montré une diffusion déficiente chez ces 10 patients, les valeurs de FA ayant surtout diminué dans les faisceaux longitudinaux et uncinés, dans le cingulum et la capsule externe. Quant à nos données volumétriques, elles ont révélé une atrophie notable chez les patients atteints de vsAPP, surtout dans les régions suivantes : cortex entorhinal gauche, amygdale, temporale inférieure, mésiotemporale, temporale supérieure, cortex temporo-polaires et lobules fusiformes bilatéraux. Conclusions: Le syndrome évoqué ci-dessus semble être associé non seulement à une dégénérescence de la substance grise mais aussi à une dégénérescence importante de la substance blanche. En précisant de manière spécifique l'atteinte à la substance blanche que sous-tend la vsAPP, l'imagerie par tenseur de diffusion pourrait donc être appelée à jouer un rôle dans l'établissement de diagnostics différentiels pour des démences atypiques.

Validation of an Magnetic Resonance Imaging Acquisition and Review Protocol for Alzheimer's Disease and Related Disorders.

PURPOSE: Magnetic resonance imaging (MRI) of the brain allows for the identification of structural lesions typical of Alzheimer's disease (AD), the main cause of dementia. However, to have a clinical impact, it is imperative that acquisition and reporting of this MRI-based evidence be standardized, ensuring the highest possible reliability and reproducibility. Our objective was to validate a systematic radiological MRI acquisition and review process in the context of AD. METHODS: We included 100 individuals with a suspicion of dementia due to AD for whom MRI were acquired using our proposed protocol of clinically achievable acquisitions and used a unified reading grid to gather semi-quantitative evidence guiding diagnostic. MRIs were read by 3 raters with different experience levels. Interrater reliability was measured using Cohen's kappa statistic. RESULTS: Interrater reliability average for lesions occupying space, hemorrhage, or ischemia, was respectively 0.754, 0.715, and 0.501. Average reliability of white matter hyperintensity burden (Fazekas), global cortical atrophy, and temporal lobe atrophy (Scheltens) scales was 0.687, 0.473, and 0.621 (right)/0.599 (left), respectively. The kappas for regional cortical atrophy (frontal, parietal, occipital, temporal, and posterior cingulum) varied from 0.281-0.678. The average MRI reading time varied between 1.43-5.22 minutes. CONCLUSIONS: The presence of space occupying lesions, hemorrhagic or ischemic phenomena, and radiological scales have a good interrater reproducibility in MRI. Coupled with standardized acquisitions, such a protocol should be used when evaluating possible dementias, especially those due to probable AD.