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

Persistence of collective behavior at high spin in the N=88 nucleus Tb 153

Excited states in the N=88 nucleus Tb153 were observed up to spin ∼40 in an experiment utilizing the Gammasphere array. The Tb153 states were populated in a weak α4n evaporation channel of the Cl37 + Sn124 reaction. Two previously known sequences were extended to higher spins, and a new decoupled structure was identified. The πh11/2 band was observed in the spin region where other N=88 isotopes exhibit effects of prolate to oblate shape changes leading to band termination along the yrast line, whereas Tb153 displays a persistent collective behavior. However, minor perturbations of the very highest state in both signatures of this h11/2 band are observed, which perhaps signal the start of the transition towards band termination

High-spin terminating states in the N=88 Ho 155 and Er 156 isotones

The Sn124(Cl37,6nγ) fusion-evaporation reaction at a bombarding energy of 180 MeV has been used to significantly extend the excitation level scheme of 67155Ho88. The collective rotational behavior of this nucleus breaks down above spin I∼30 and a fully aligned noncollective (band terminating) state has been identified at Iπ=79/2-. Comparison with cranked Nilsson-Strutinsky calculations also provides evidence for core-excited noncollective states at Iπ=87/2- and (89/2+) involving particle-hole excitations across the Z=64 shell gap. A similar core-excited state in 68156Er88 at Iπ=(46+) is also presented

Collective structures up to spin ∼ 65h in the N 90 isotones 158Er and 157Ho

A new collective band with high dynamic moment of inertia in 158Er at spins beyond band termination has been found in addition to the two previously reported ones. The measured transition quadrupole moments (Qt) of these three bands are very similar. These three bands have been suggested to possess a triaxial strongly deformed shape, based on comparisons with calculations using the cranked Nilsson-Strutinsky model and with tilted axis cranking calculations using the Skyrme-Hartree-Fock model. In addition, three collective bands with similar high dynamic moments of inertia, tentatively assigned to 157Ho, have been observed. Thus, it is suggested that all these structures share a common underlying character and that they are most likely associated with triaxial strongly deformed minima which are predicted to be close to the yrast line at spin 50 - 70h

Splenic trauma: WSES classification and guidelines for adult and pediatric patients

Spleen injuries are among the most frequent trauma-related injuries. At present, they are classified according to the anatomy of the injury. The optimal treatment strategy, however, should keep into consideration the hemodynamic status, the anatomic derangement, and the associated injuries. The management of splenic trauma patients aims to restore the homeostasis and the normal physiopathology especially considering the modern tools for bleeding management. Thus, the management of splenic trauma should be ultimately multidisciplinary and based on the physiology of the patient, the anatomy of the injury, and the associated lesions. Lastly, as the management of adults and children must be different, children should always be treated in dedicated pediatric trauma centers. In fact, the vast majority of pediatric patients with blunt splenic trauma can be managed non-operatively. This paper presents the World Society of Emergency Surgery (WSES) classification of splenic trauma and the management guidelines

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Saliva study for a novel dental composite with polymeric matrix

Novel composite materials based on polymer matrix with inorganic filler were characterized to evaluate their potential application in dentistry. Previously reported filler and composites were investigated in correlation with their behavior in artificial saliva. The saliva study involved pH and microhardness determinations, ions release and saliva sorption during soaking in saliva for 30 days. The conclusion assessed was that the investigated composite materials showed a good behavior, comparable with commercially employed dental composites

Lentiviral expression of GAD67 and CCK promoter-driven opsins to target interneurons in vitro and in vivo

Background: The ability to manipulate the activity of interneurons with optogenetic tools offers the possibility of interfering with diseases caused by altered neuronal inhibition and synchrony, including epilepsy and schizophrenia. To develop vectors for therapeutic approaches, targeting optogenetic constructs to interneurons is therefore a key requirement. We investigated whether the interneuron-specific promoters glutamic acid decarboxylase (GAD)67 and cholecystokinin (CCK) allowed targeted lentiviral delivery of opsins to interneurons as a whole, or specifically CCK+ interneurons. Methods: We generated lentiviral (LV) plasmids encoding channelrhodopsin (ChR2) and halorhodopsin (NpHR) tagged with fluorophores and driven by GAD67 or CCK promoters. Adeno-associated virus (AAV) and LV vectors carrying opsins driven by pyramidal cell promoters were used as controls. We transduced neuronal cultures and rodent brain in vivo, immunostained specimens 6-8 weeks after in vivo injection and 7-14 days after in vitro transduction, and evaluated volume and specificity of expression by confocal microscopy. Results: In vitro, 90% (19/21) of LV-CCK-NpHR2.0-EYFP expressing neurons were CCK+. In vivo, LV-GAD67-ChR2-mCherry was expressed in 2.6% (5/193), LV-GAD67-NpHR2.0-EYFP in approximately 15% (43/279) and LV-CCK-NpHR2.0-EYFP in 47% (9/19) of hippocampal GABA+ interneurons. GAD67 vectors expressed in larger volumes than CCK-driven constructs. AAV vector controls achieved the largest expression volumes. Conclusions: LV-CCK-NpHR2.0-EYFP may be useful for targeting CCK+ interneurons in culture. GAD67/CCK-driven lentiviral constructs are expressed in vivo, although expression is not specific for interneurons. Overall, expression levels are low compared to opsins driven by pyramidal cell promoters. A better understanding of GAD67 and CCK promoter structure or alternative techniques is required to reliably target opsins to interneurons using viral vectors

Combining conventional and participatory approaches to identify and prioritise management and health-related constraints to smallholder pig production in San Simon, Pampanga, Philippines

Pork is the main meat produced and consumed in the Philippines. The majority of pigs are raised by smallholders who experience a range of constraints to their pig production. This study presents the findings of the first part of an overarching project that used an Ecohealth approach and aimed to improve the production and competitiveness of the smallholder pig system in an area of the Philippines. A participatory approach was embraced, combining conventional and participatory epidemiology methods followed by a stakeholder discussion. The first aim was to identify management and health-related constraints to pig production among smallholder famers in San Simon, Pampanga, Philippines. The second aim was for the project team and stakeholders to jointly prioritise activities for the immediate future to address these constraints. Key management and health-related constraints identified included inadequate water supply to pigs, particularly lactating and gestating sows, and a range of feeding-related issues. Diarrhoea was recognised as the disease syndrome of highest priority and limited record keeping meant that farmers were unable to assess the productivity and profitability of their pig farming enterprises. Actions jointly prioritised by stakeholders and the project team were: the appointment of a project coordinator within each barangay; conduct two sets of seminars, the first covering water and nutrition and the second piglet management and diarrhoea, to be delivered by technical experts but with farmer “trusted sources” also sharing their experiences; development of easily understandable leaflets and posters covering key technical information; promotion of nipple drinkers attached to five-gallon water containers and creep boxes for piglets, and conduct of a record keeping workshop with a small group of innovative farmers to develop a useful and usable tool for record keeping. The use of multiple approaches to data-gathering enabled triangulation of study findings. Without any one of these components the understanding of the pig production system would have been less complete and it is possible that the proposed actions would not have been as well-tailored to the needs of the farmers. The participatory approach, in particular the stakeholder discussion, provided the opportunity to embrace the “deciding together” and “acting together” stances of participation rather than the lower “information giving” stance, thereby giving stakeholders greater ownership of the future activities of the overarching project and beyond