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

Corrigendum to “Environmental and life-history factors influence inter-colony multidimensional niche metrics of a breeding Arctic marine bird” [Sci. Total Environ. 796 (2021) 148935] (Science of the Total Environment (2021) 796, (S0048969721040079), (10.1016/j.scitotenv.2021.148935))

The authors regret that the printed version of the above article contained an omission of an individual deserving of co-authorship. The correct and final version follows. The authors would like to apologise for any inconvenience caused. \u3c Reyd A. Smith1⁎, David J. Yurkowski2, Kyle J.L. Parkinson1, Jérôme Fort3, Holly L. Hennin4, H. Grant Gilchrist4, Keith A. Hobson5, Mark L. Mallory6, Paco Bustamante3, Jóhannis Danielsen7, Svend E. Garbus8, Sveinn A. Hanssen9, Jón Einar Jónsson10, Christopher J. Latty11, Ellen Magnúsdóttir10, Børge Moe9, Glen J. Parsons12, Christian Sonne8, Grigori Tertitski13, and Oliver P. Love1\u3e Windsor, Windsor, Ontario, Canada, N9B 3P4 2 Fisheries and Oceans Canada, Winnipeg, Manitoba, Canada, R3T 2N6 3 Littoral, Environnement et Sociétés (LIENSs), UMR 7266 CNRS – La Rochelle University, La Rochelle, France, FR-17000 4 Environment and Climate Change Canada, Ottawa, Ontario, Canada, K0A 1H0. 5 Western University, London, Ontario, Canada, N6A 3K7 6Acadia University, Wolfville, Nova Scotia, Canada, B4P 2R6 7 Faroe Marine Research Institute, Tórshavn, Faroe Islands, FO-110 8 Aarhus University, Roskilde, Denmark, DK-4000 9 Norwegian Institute for Nature Research, Tromsø, Norway, N-9296 10 University of Iceland\u27s Research Centre at Snæfellsnes, Hafnargata 3, 340, Stykkishólmur, Iceland 11 Arctic National Wildlife Refuge, U.S. Fish and Wildlife Service, Fairbanks, Alaska, United States, 99701 12 Nova Scotia Department of Lands and Forestry, Kentville, Nova Scotia, Canada, B4N 4E5 13 Institute of Geography of the Russian Academy of Sciences, Moscow, Russia, 119017\u3

The Modernization of the Autopsy: Application of Ultrastructural and Biochemical Methods to Human Disease

The autopsy has provided, and still provides, the stimulus for many attempts to reproduce disease in experimental animal models. This approach has become increasingly difficult, however, in the case of human disease, principally shock. The study of some pathological states in animal models requires testing in several species and final confirmation in man before this knowledge can be applied to living patients. In our studies the application of cell biology techniques at autopsy has permitted the generation of new hypotheses which are more amenable to further exploration in experimental models and can be more precisely related to human disease

Phosphorylated Dihydroceramides from Common Human Bacteria Are Recovered in Human Tissues

Novel phosphorylated dihydroceramide (PDHC) lipids produced by the periodontal pathogen Porphyromonas gingivalis include phosphoethanolamine (PE DHC) and phosphoglycerol dihydroceramides (PG DHC) lipids. These PDHC lipids mediate cellular effects through Toll-like receptor 2 (TLR2) including promotion of IL-6 secretion from dendritic cells and inhibition of osteoblast differentiation and function in vitro and in vivo. The PE DHC lipids also enhance (TLR2)-dependent murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. The unique non-mammalian structures of these lipids allows for their specific quantification in bacteria and human tissues using multiple reaction monitoring (MRM)-mass spectrometry (MS). Synthesis of these lipids by other common human bacteria and the presence of these lipids in human tissues have not yet been determined. We now report that synthesis of these lipids can be attributed to a small number of intestinal and oral organisms within the Bacteroides, Parabacteroides, Prevotella, Tannerella and Porphyromonas genera. Additionally, the PDHCs are not only present in gingival tissues, but are also present in human blood, vasculature tissues and brain. Finally, the distribution of these TLR2-activating lipids in human tissues varies with both the tissue site and disease status of the tissue suggesting a role for PDHCs in human disease

Barriers and incentives to orphan care in a time of AIDS and economic crisis: a cross-sectional survey of caregivers in rural Zimbabwe

BACKGROUND: Africa is in an orphan-care crisis. In Zimbabwe, where one-fourth of adults are HIV-positive and one-fifth of children are orphans, AIDS and economic decline are straining society's ability to care for orphans within their extended families. Lack of stable care is putting thousands of children at heightened risk of malnourishment, emotional underdevelopment, illiteracy, poverty, sexual exploitation, and HIV infection, endangering the future health of the society they are expected to sustain. METHODS: To explore barriers and possible incentives to orphan care, a quantitative cross-sectional survey in rural eastern Zimbabwe asked 371 adults caring for children, including 212 caring for double orphans, about their well-being, needs, resources, and perceptions and experiences of orphan care. RESULTS: Survey responses indicate that: 1) foster caregivers are disproportionately female, older, poor, and without a spouse; 2) 98% of non-foster caregivers are willing to foster orphans, many from outside their kinship network; 3) poverty is the primary barrier to fostering; 4) financial, physical, and emotional stress levels are high among current and potential fosterers; 5) financial need may be greatest in single-orphan AIDS-impoverished households; and 6) struggling families lack external support. CONCLUSION: Incentives for sustainable orphan care should focus on financial assistance, starting with free schooling, and development of community mechanisms to identify and support children in need, to evaluate and strengthen families' capacity to provide orphan care, and to initiate and support placement outside the family when necessary

Lipid Classes and Fatty Acid Patterns are Altered in the Brain of γ-Synuclein Null Mutant Mice

The well-documented link between α-synuclein and the pathology of common human neurodegenerative diseases has increased attention to the synuclein protein family. The involvement of α-synuclein in lipid metabolism in both normal and diseased nervous system has been shown by many research groups. However, the possible involvement of γ-synuclein, a closely-related member of the synuclein family, in these processes has hardly been addressed. In this study, the effect of γ-synuclein deficiency on the lipid composition and fatty acid patterns of individual lipids from two brain regions has been studied using a mouse model. The level of phosphatidylserine (PtdSer) was increased in the midbrain whereas no changes in the relative proportions of membrane polar lipids were observed in the cortex of γ-synuclein-deficient compared to wild-type (WT) mice. In addition, higher levels of docosahexaenoic acid were found in PtdSer and phosphatidylethanolamine (PtdEtn) from the cerebral cortex of γ-synuclein null mutant mice. These findings show that γ-synuclein deficiency leads to alterations in the lipid profile in brain tissues and suggest that this protein, like α-synuclein, might affect neuronal function via modulation of lipid metabolism

Wealthy and healthy? New evidence on the relationship between wealth and HIV vulnerability in Tanzania

Using AIS/DHS data for Tanzania in 2003-4, 2007-8 and 2011-12 and borrowing from the methodology used in Parkhurst (2010) we analyse the changing relationship between wealth and HIV prevalence in Tanzania. Findings are tabulated, graphed and discussed. We find the relationship is multifaceted and dynamic: women are disproportionately affected in all wealth quintiles and experience a stronger ‘wealth effect’; some groups experience an increase in prevalence even as population prevalence declines. Relative wealth and poverty are associated with increased prevalence, suggesting that structural drivers create a variety of risk situations – as well as protective factors – affecting different groups. We also consider data on testing refusals: wealthier men were consistently more likely to decline testing. Continuing to unpack this complex and shifting relationship is necessary in order to fully understand the structural drivers of HIV transmission and access of testing services, enabling the formulation of appropriate policy responses