Comparaison de deux techniques de pré-purification des éluats de 68GA pour le marquage de peptides par automate de synthèse

National audienceObjectifs.–Le but de ce travail est d’évaluer, à travers différents essais cliniquesd’imagerie au68Ga en cours à Nantes, deux techniques de pré-purification deséluat de68Ga pour le marquage de peptides (DOTANOC et IMP288).Patients et méthodes.–Les deux techniques sont automatisées avec les appa-reils Eckert et Ziegler Modular-Lab PharmTracer®et Standard®. La technique1 consiste à fixer le68Ga issu du générateur sur une colonne échangeuse decations type STRATA-XC, pour récupérer une solution concentrée de68Ga dansle réacteur avec un mélange acétone/HCl 0,02 N. La technique 2 consiste à fixerle68Ga sur une colonne échangeuse de cations type Bond Elut-SCX, éluée avecun mélange concentré NaCl 5 M/HCl 0,1 N. Le radiomarquage de peptide avecla méthode 1 est réalisé en tampon acétate 0,2 M pH 4. Avec la méthode 2, ilest réalisé en tampon acétate 0,3 M pH 4,5 pour obtenir un pH final de 4. Lessolutions radiomarquées sont ensuite purifiées en ligne à l’aide de cartouchesde type Sep-Pack C18.Résultats.–Seule la technique 1 a été utilisée dans l’essai EUDRACT 2011-003542-40 (DOTANOC-68Ga) car disponible full GMP. Quelle que soit latechnique utilisée, les rendements de marquage se sont révélés acceptableset compris entre 60 et 80 %. Pour les essais EUDRACT 2011-005430-19 etEUDRACT 2011-002588-76 qui impliquent un peptide hydrophile (IMP 288),la technique 1 ne permet pas l’utilisation du système de purification etnécessite l’utilisation d’une quantité de peptide adaptée pour obtenir direc-tement une pureté radiochimique (PRC) > 90 % avec des activités spécifiques(AS) 80 MBq/nmoL et une PRC > 95 %.Conclusions.–La technique 1 bénéficie d’une méthode automatisée GMPmais ne permet pas la purification finale des peptides hydrophiles nid’atteindre des activités spécifiques élevées qui peuvent être obtenues avec latechnique 2

A Herbage Growth Model for Different Types of Natural Grassland

The aim of this work was to extend existing growth models established for pure stands to a wide range of grassland communities. For this purpose we built a simple growth model, including sub-models for radiation interception and use. Parameters for the effect of nutrient rates (N, P) and defoliation regimes were based on a plant trait database. Senescence and reproductive processes were particularly considered because of their importance in late spring growth. The model makes it possible to simulate the daily biomass production as a function of both environmental factors and the functional type of the dominant species in the community

Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors

Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 (177Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) (177Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with 177Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11

Head-to-head comparison between F-18-DOPA PET/CT and Ga-68-DOTA-peptide PET/CT in detecting intestinal neuroendocrine tumours:A systematic review and meta-analysis

Objective: The imaging of intestinal neuroendocrine tumours (NETs) relies on functional PET tracers; these tumours can be studied by means of both Ga-68-DOTA-peptides and F-18-DOPA PET/CT. As yet, it is unclear which of these two modalities offers the better sensitivity. We therefore conducted a meta-analysis to assess the available data. Design: PubMed, CENTRAL, Scopus and Web of Science were searched for studies comparing the sensitivity of Ga-68-DOTA-peptides and F-18-DOPA PET/CT; papers up to February 2021 were considered. Patients and Measurements: In each study, we considered sensitivity in terms of patient-based (PBA), region-based (RBA) and lesion-based analysis (LBA) and pooled the results yielded by each tracer. Multidisciplinary follow-up served as the standard of truth. Results: Of the 636 records identified, 6 articles published between 2008 and 2021 were finally selected, and 112 intestinal NET patients were included. The pooled sensitivity of F-18-DOPA PET/CT was 83%, 89% and 95% on PBA, RBA and LBA, respectively. Ga-68-DOTA peptide PET/CT showed sensitivity of 88%, 92% and 82% on PBA, RBA and LBA, respectively. No significant differences were found between the two tracers on PBA and RBA. By contrast, a clear trend towards significance in favour of F-18-DOPA PET/CT was identified on LBA. The presence of a significant difference in favour of F-18-DOPA PET/CT was confirmed in a subgroup analysis conducted only on the most recent and largest studies. In all three analyses, mild-to-high heterogeneity was found, while no publication bias was observed. Conclusion: Both F-18-DOPA PET/CT and Ga-68-DOTA-peptide PET/CT are reliable diagnostic procedures in patients with intestinal NETs. However, in terms of lesion detection, a non-negligible difference in favour of F-18-DOPA PET/CT was observed. Thus, the use of F-18-DOPA PET/CT could be considered as a first-line molecular procedure in intestinal NETs

Variation of LDMC and SLA Relationship Between Growth Forms in Natural Grasslands

In agro-ecological studies, there is a growing interest in measuring both leaf dry matter content (LDMC) and specific leaf area (SLA). This interest lies on the fact that leaf traits are linked to gradients of environmental factors and ecosystem functions. Working with three contrasting wild species, Garnier et al. (2001) proposed a model linking these two traits. The model shows a relatively simple non linear and negative correlation between LDMC and SLA. Nevertheless, none of the species used to build the model were grasses (GRA) or forb rosettes (ROS = i.e. dicotyledonous with large entire leaves and absence of stem at the vegetative stage); the species which make the largest contribution to the standing biomass of most natural grasslands. Furthermore, due to the divergent range of LDMC (and not SLA) values between these growth forms, Cruz et al. (2002) proposed that grass records alone could be used as an indicator of fertility gradients. The aim of this paper was to analyse discrepancies in the LDMC - SLA correlation with respect to model predictions in order to consider them in any development of LDMC-based tools for the management of natural vegetation

Real-world clinical outcomes associated with first-line palbociclib and aromatase inhibitor therapy among patients with HR+/HER2− advanced breast cancer in Europe

Purpose Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) combined with endocrine therapy is the recommended first-line (1L) treatment for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−)advanced breast cancer (ABC). Real-world evidence (RWE) describing 1L CDK4/6i regimens and associated clinical out-comes in Europe is limited. The study objective was to describe clinical characteristics, tumor response, and survival out-comes in patients with HR+/HER2− ABC.Methods This retrospective, observational cohort study used data from 52 treatment centers in the UK, Spain, and Germanyand included patients who initiated 1L palbociclib + aromatase inhibitor (AI) therapy for ABC between 2016 and 2020.Primary endpoints were real-world progression-free survival (rwPFS) and overall survival (OS).Results Data were abstracted from 856 patients. During treatment, complete response, partial response, or stable diseasewas achieved for 86.1% of patients in Spain, 80.7% in the UK, and 79.0% in Germany, while complete or partial responsewas achieved for 43.8% of patients in Spain, 34.9% in the UK, and 16.9% in Germany. Median rwPFS during treatment was28.1 months for patients in Spain, 33.9 months in the UK, and 48.1 months in Germany. Median OS was 51.3 months (95%CI 46.6–NE) in the UK, 65.2 months (95% CI 65.2–NE) in Germany, and not reached in Spain.Conclusion This RWE supports the clinical effectiveness of 1L palbociclib + AI in routine clinical practice in Europeancountries—consistent with the efficacy observed in clinical trials—and further supports the implementation of palbociclib-based regimens as frontline treatment of HR+/HER2− ABC

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov: NCT01578239, EudraCT: 2011-005049-11

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate: an analysis of the NETTER-1 study

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate. Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression. Results: Significantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden. Conclusions: 177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11