18F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard, 68Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors ...(NETs), given their logistic advantages. Recently, 18F-AlF-NOTA-octreotide (18F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with 68Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of 18F-AlF-OC compared with 68Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847). Methods: Seventy-five patients with histologically confirmed NET and routine clinical 68Ga-DOTATATE (n = 56) or 68Ga-DOTANOC (n = 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, −30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of 18F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between 18F-AlF-OC and 68Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUVmax and tumor-to-background ratios in concordant lesions. Results: In total, 4,709 different tumor lesions were detected: 3,454 with 68Ga-DOTATATE/NOC and 4,278 with 18F-AlF-OC. The mean DR with 18F-AlF-OC was significantly higher than with 68Ga-DOTATATE/NOC (91.1% vs. 75.3%; P < 10−5). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%–22.0%) higher than −15%, which is the prespecified boundary for noninferiority. The mean DDRs for the 68Ga-DOTATATE and 68Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3–19.3) and 27.5% (95% CI, 17.8–37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, −2.8%; 95% CI, −17.8 to 12.2). No significant differences in mean SUVmax were observed (P = 0.067), but mean tumor-to-background ratio was significantly higher with 18F-AlF-OC than with 68Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7; P = 0.001). Conclusion: 18F-AlF-OC is noninferior and even superior to 68Ga-DOTATATE/NOC PET in NET patients. This validates 18F-AlF-OC as an option for clinical practice somatostatin receptor PET.
Myasthenia gravis (MG) is an autoimmune disorder caused by autoantibodies that are either directed to the muscle nicotinic acetylcholine receptor (AChR) or to the muscle-specific tyrosine kinase ...(MuSK). These autoantibodies define two distinct subforms of the disease-AChR-MG and MuSK-MG. Both AChR and MuSK are expressed on the postsynaptic membrane of the neuromuscular junction (NMJ), which is a highly specialized region of the muscle dedicated to receive and process signals from the motor nerve. Autoantibody binding to proteins of the postsynaptic membrane leads to impaired neuromuscular transmission and muscle weakness. Pro-inflammatory antibodies of the human IgG1 and IgG3 subclass modulate the AChR, cause complement activation, and attract lymphocytes; together acting to decrease levels of the AChR and AChR-associated proteins and to reduce postsynaptic folding. In patients with anti-MuSK antibodies, there is no evidence of loss of junctional folds and no apparent loss of AChR density. Anti-MuSK antibodies are predominantly of the IgG4 isotype, which functionally differs from other IgG subclasses in its anti-inflammatory activity. Moreover, IgG4 undergoes a posttranslational modification termed Fab arm exchange that prevents cross-linking of antigens. These findings suggest that MuSK-MG may be different in etiological and pathological mechanisms from AChR-MG. The effector functions of IgG subclasses on synapse structure and function are discussed in this review.
F-labeled somatostatin analogs (SSAs) could represent a valid alternative to the current gold standard,
Ga-labeled SSAs, for somatostatin receptor imaging in patients with neuroendocrine tumors ...(NETs), given their logistic advantages. Recently,
F-AlF-NOTA-octreotide (
F-AlF-OC) has emerged as a promising candidate, but a thorough comparison with
Ga-DOTA-SSA in large patient groups is needed. This prospective, multicenter trial aims to demonstrate noninferiority of
F-AlF-OC compared with
Ga-DOTA-SSA PET in NET patients (ClinicalTrials.gov, NCT04552847).
Seventy-five patients with histologically confirmed NET and routine clinical
Ga-DOTATATE (
= 56) or
Ga-DOTANOC (
= 19) PET, performed within a 3-mo interval of the study scan (median, 7 d; range, -30 to +32 d), were included. Patients underwent a whole-body PET 2 h after intravenous injection of 4 MBq/kg of
F-AlF-OC. A randomized, masked consensus read was performed by 2 experienced readers to count tumor lesions. After unmasking, the detection ratio (DR) was determined for each scan, that is, the fraction of lesions detected on a scan compared with the union of lesions of both scans. The differential DR (DDR; difference in DR between
F-AlF-OC and
Ga-DOTATATE/NOC) per patient was calculated. Tracer uptake was evaluated by comparing SUV
and tumor-to-background ratios in concordant lesions.
In total, 4,709 different tumor lesions were detected: 3,454 with
Ga-DOTATATE/NOC and 4,278 with
F-AlF-OC. The mean DR with
F-AlF-OC was significantly higher than with
Ga-DOTATATE/NOC (91.1% vs. 75.3%;
< 10
). The resulting mean DDR was 15.8%, with a lower margin of the 95% CI (95% CI, 9.6%-22.0%) higher than -15%, which is the prespecified boundary for noninferiority. The mean DDRs for the
Ga-DOTATATE and
Ga-DOTANOC subgroups were 11.8% (95% CI, 4.3-19.3) and 27.5% (95% CI, 17.8-37.1), respectively. The mean DDR for most organs was higher than zero, except for bone lesions (mean DDR, -2.8%; 95% CI, -17.8 to 12.2). No significant differences in mean SUV
were observed (
= 0.067), but mean tumor-to-background ratio was significantly higher with
F-AlF-OC than with
Ga-DOTATATE/NOC (31.7 ± 36.5 vs. 25.1 ± 32.7;
= 0.001).
F-AlF-OC is noninferior and even superior to
Ga-DOTATATE/NOC PET in NET patients. This validates
F-AlF-OC as an option for clinical practice somatostatin receptor PET.
Protecting aboveground carbon stocks in tropical forests is essential for mitigating global climate change and is assumed to simultaneously conserve biodiversity. Although the relationship between ...tree diversity and carbon stocks is generally positive, the relationship remains unclear for consumers or decomposers. We assessed this relationship for multiple trophic levels across the tree of life (10 organismal groups, 3 kingdoms) in lowland rainforests of the Congo Basin. Comparisons across regrowth and old-growth forests evinced the expected positive relationship for trees, but not for other organismal groups. Moreover, differences in species composition between forests increased with difference in carbon stock. These variable associations across the tree of life contradict the implicit assumption that maximum co-benefits to biodiversity are associated with conservation of forests with the highest carbon storage. Initiatives targeting climate change mitigation and biodiversity conservation should include both old-growth and regenerating forests to optimally benefit biodiversity and carbon storage.
The sheep scab mite, Psoroptes ovis, is a major problem in the beef cattle industry, especially in Belgian Blue (BB) cattle. This breed is naturally more predisposed to psoroptic mange but reasons ...for this high susceptibility remain unknown. Different immune responses could be a potential cause; thus in this study, the cutaneous immune response and in vitro cellular immune response after antigen re-stimulation were examined in naturally infested BB. Cytokine production in the skin and in circulating re-stimulated peripheral blood mononuclear cells (PBMC) demonstrated a mixed pro-inflammatory Th2/Th17 profile, with transcription of IL-4, IL-13, IL-6 and IL-17. Strong IL-17 up-regulation in the skin of BB was associated with an influx of eosinophils and other immune cells, potentially leading towards more severe symptoms. Virtually no changes in cutaneous IFN-γ transcription were detected, while there was substantial IFN-γ up-regulation in re-stimulated PBMC from infested and uninfested animals, potentially indicating a role of this pro-inflammatory cytokine in the innate immune response. In Holstein-Friesian (HF) cattle, generally more resistant to P. ovis infection, a largely similar immunologic response was observed. Differences between HF and BB were the lack of cutaneous IL-17 response in infested HF and low transcription levels of IFN-γ and high IL-10 transcription in re-stimulated PBMC from both infested and uninfested animals. Further research is needed to identify potential cell sources and biological functions for these cytokines and to fully unravel the basis of this different breed susceptibility to P. ovis.
Infections in cattle with the gastric nematode Ostertagia ostertagi are associated with decreased acid secretion and profound physio-morphological changes of the gastric mucosa. The purpose of the ...current study was to investigate the mechanisms triggering these pathophysiological changes. O. ostertagi infection resulted in a marked cellular hyperplasia, which can be explained by increased transcriptional levels of signaling molecules related to the homeostasis of gastric epithelial cells such as HES1, WNT5A, FGF10, HB-EGF, AREG, ADAM10 and ADAM17. Intriguingly, histological analysis indicated that the rapid rise in the gastric pH, observed following the emergence of adult worms, cannot be explained by a loss of parietal cells, as a decrease in the number of parietal cells was only observed following a long term infection of several weeks, but is likely to be caused by an inhibition of parietal cell activity. To investigate whether this inhibition is caused by a direct effect of the parasites, parietal cells were co-cultured with parasite Excretory/Secretory products (ESP) and subsequently analyzed for acid production. The results indicate that adult ESP inhibited acid secretion, whereas ESP from the L4 larval stages did not alter parietal cell function. In addition, our data show that the inhibition of parietal cell activity could be mediated by a marked upregulation of inflammatory factors, which are partly induced by adult ESP in abomasal epithelial cells. In conclusion, this study shows that the emergence of adult O. ostertagi worms is associated with marked cellular changes that can be partly triggered by the worm's Excretory/secretory antigens.
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