Explore the vast range of titles available.

There are currently no standard first-line treatment options for patients with higher grade 2–3, well-differentiated, advanced, gastroenteropancreatic neuroendocrine tumours. We aimed to investigate the efficacy and safety of first-line [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) treatment. NETTER-2 was an open-label, randomised, parallel-group, superiority, phase 3 trial. We enrolled patients (aged ≥15 years) with newly diagnosed higher grade 2 (Ki67 ≥10% and ≤20%) and grade 3 (Ki67 >20% and ≤55%), somatostatin receptor-positive (in all target lesions), advanced gastroenteropancreatic neuroendocrine tumours from 45 centres across nine countries in North America, Europe, and Asia. We used interactive response technologies to randomly assign (2:1) patients to receive four cycles (cycle interval was 8 weeks ± 1 week) of intravenous 177Lu-Dotatate plus intramuscular octreotide 30 mg long-acting repeatable (LAR) then octreotide 30 mg LAR every 4 weeks (177Lu-Dotatate group) or high-dose octreotide 60 mg LAR every 4 weeks (control group), stratified by neuroendocrine tumour grade (2 vs 3) and origin (pancreas vs other). Tumour assessments were done at baseline, week 16, and week 24, and then every 12 weeks until disease progression or death. The primary endpoint was progression-free survival by blinded, independent, central radiology assessment. We did the primary analysis at 101 progression-free survival events as the final progression-free survival analysis. NETTER-2 is registered with ClinicalTrials.gov, NCT03972488, and is active and not recruiting. Between Jan 22, 2020, and Oct 13, 2022, we screened 261 patients, 35 (13%) of whom were excluded. We randomly assigned 226 (87%) patients (121 [54%] male and 105 [46%] female) to the 177Lu-Dotatate group (n=151 [67%]) and control group (n=75 [33%]). Median progression-free survival was 8·5 months (95% CI 7·7–13·8) in the control group and 22·8 months (19·4–not estimated) in the 177Lu-Dotatate group (stratified hazard ratio 0·276 [0·182–0·418]; p<0·0001). During the treatment period, adverse events (of any grade) occurred in 136 (93%) of 147 treated patients in the 177Lu-Dotatate group and 69 (95%) of 73 treated patients in the control group. There were no study drug-related deaths during the treatment period. First-line 177Lu-Dotatate plus octreotide LAR significantly extended median progression-free survival (by 14 months) in patients with grade 2 or 3 advanced gastroenteropancreatic neuroendocrine tumours. 177Lu-Dotatate should be considered a new standard of care in first-line therapy in this population. Advanced Accelerator Applications, a Novartis Company.

Small Island Developing States (SIDS) face enormous sustainability challenges such as heavy reliance on imports to meet basic needs, tenuous resource availability, coastal squeeze, and reduced waste absorption capacity. At the same time, the adverse effects of global environmental change such as global warming, extreme events, and outbreaks of pandemics significantly hinder SIDS’ progress towards sustainable development. This paper makes a conceptual contribution by framing the vulnerability of small islands from the perspective of socio-metabolic risk (SMR). SMR is defined as systemic risk associated with the availability of critical resources, the integrity of material circulation, and the (in)equitable distribution of derived products and societal services in a socio-ecological system. We argue that specific configurations and combinations of material stocks and flows on islands and their ‘resistance to change’ contribute to the system’s proliferation of SMR. For better or for worse, these influence the system’s ability to consistently and effectively deliver societal services necessary for survival. By positioning SMR as a subset of systemic risk, the paper illustrates SMRs and tipping points on small islands using insights from three sectors: water, waste, and infrastructure. We also identify effective leverage points and adaptation strategies for building system resilience on small islands. In conclusion, our synthesis suggests that governing SMR on SIDS would mean governing socio-metabolic flows to avoid potential disruptions in the circulation of critical resources and the maintenance of vital infrastructures and services while inducing interventions towards positive social tipping dynamics. Such interventions will need strategies to reconfigure resource-use patterns and associated services that are sustainable and socially equitable.

Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population. In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783. Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2–13·3) in the everolimus group and 3·9 months (3·6–7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35–0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40–1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0). Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract. Novartis Pharmaceuticals Corporation.

Aims/hypothesisDiabetes is associated with an increased incidence of colorectal cancer (CRC). There exists conflicting evidence regarding the impact of diabetes on CRC-specific mortality (herein also referred to as cancer-specific mortality). The objectives of this study were to determine whether diabetes is associated with a more advanced CRC stage at diagnosis and with higher all-cause and cancer-specific mortality.MethodsThis retrospective cohort study used linked, population-based health databases from Ontario, Canada. Among individuals diagnosed with CRC from 2007 to 2015, we compared the likelihood of presenting with later- (III or IV) vs early- (I or II) stage CRC between patients with and without diabetes adjusting for relevant covariates. We then determined the association between diabetes and all-cause and CRC-specific mortality, after adjusting for CRC stage at diagnosis and other covariates.ResultsOf the 44,178 individuals with CRC, 11,822 (26.7%) had diabetes. After adjustment for CRC screening and other covariates, individuals with diabetes were not more likely to present with later-stage CRC (adjusted OR 0.97, 95% CI 0.93, 1.01). Over a median follow-up of 2.63 (interquartile range [IQR] 0.97–5.10) years, diabetes was associated with higher all-cause mortality (adjusted HR 1.08, 95% CI 1.04, 1.12) but similar cancer-specific survival (adjusted HR 1.0, 95% CI 0.95, 1.06).Conclusions/interpretationIndividuals with diabetes who develop CRC are not more likely to present with a later stage of CRC and have similar cancer-specific mortality compared with those without diabetes. Diabetes was associated with higher all-cause mortality in CRC patients, indicating that greater attention to non-cancer care is needed for CRC survivors with diabetes.

Background Immunotherapy in the presence of COVID-19 infections raises concerns because of potential overlapping clinical complications and immune system enhancement. Further investigation is warranted to establish its safety and to improve clinical decisions. Methods We conducted a retrospective cohort study using linked health administrative data from Ontario, Canada to assess 30-day mortality in patients with solid tumors who were treated with immunotherapy within 120 days before testing positive for COVID-19. A stepwise multivariable logistic regression model was used to identify clinical factors associated with 30-day mortality. Results Between January 2020 and April 2023, 281 patients tested positive for COVID-19 and were included in our study. The mean age was 68 (Standard Deviation: 10.3), 45% (127/281) were females and 58% (163/281) had lung cancer. 59% of patients (167/281) were treated with single agent immunotherapy, and almost 80% received at least one dose of COVID-19 vaccine. The 30-day mortality was 22% (63/281) and < 5% of patients were admitted to ICU or required ventilation. Factors associated with higher mortality were older age (Odds Ratio (OR) 1.60, 95% confidence interval (CI) 1.07–2.39), prior radiation therapy (OR 2.38, 95%CI 1.08–5.28), lower hemoglobin (< 10 g/dl) (OR 4.08, 95%CI 1.89–8.82) and higher leucocytes count (> 11,000/mm 3 ) (OR 3.63, 95%CI 1.55–8.52). Conclusions Immunotherapy does not seem to increase the risk of 30-day mortality in patients with COVID-19 infections compared to published outcomes of patients with cancer and COVID-19. Mortality was associated with certain clinical characteristics that need to be carefully examined when prescribing immunotherapy during future comparable pandemics.

In the phase III RADIANT‐4 study, everolimus improved median progression‐free survival (PFS) by 7.1 months in patients with advanced, progressive, well‐differentiated (grade 1 or grade 2), non‐functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35‐0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT‐4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8‐10.9) months in the everolimus arm vs 3.6 (1.9‐5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28‐0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3‐4 drug‐related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well‐differentiated, non‐functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT‐4 cohort. These results support the use of everolimus in patients with advanced, non‐functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783). This exploratory subgroup analysis of the RADIANT‐4 study is the first study to demonstrate that everolimus, a systemic targeted therapy, was associated with clinically meaningful improvement of 5.6 months in the median progression‐free survival with 50% reduction in risk of disease progression or death compared to placebo, in patients with advanced, progressive, well‐differentiated, nonfunctional lung neuroendocrine tumors (NET). This is the largest lung NET population ever included in a phase 3 trial.

Fecal occult blood tests (FOBT) are colorectal cancer screening tests used to identify individuals requiring further investigation with colonoscopy. Delayed colonoscopy after positive FOBT (FOBT+) is associated with poorer cancer outcomes. We assessed the effect of comorbidity on colonoscopy receipt within 12 months after FOBT+. Population-based healthcare databases from Ontario, Canada, were linked to assemble a cohort of 50-74-year-olds with FOBT+ results between 2008 and 2017. The associations between comorbidities and colonoscopy receipt within 12 months after FOBT+ were examined using multivariable cause-specific hazard regression models. Of 168,701 individuals with FOBT+, 80.5% received colonoscopy within 12 months. In multivariable models, renal failure (hazard ratio, HR 0.71, 95% confidence interval, CI 0.62 to 0.82), heart failure (HR 0.77, CI 0.75 to 0.80), and serious mental illness (HR 0.88, CI 0.85 to 0.92) were associated with the lowest colonoscopy rates, compared to not having each condition. The number of medical conditions was inversely associated with colonoscopy uptake (≥4 vs. 0: HR 0.64, CI 0.58 to 0.69; 3 vs. 0: HR 0.75, CI 0.72 to 0.78; 2 vs. 0: HR 0.87, CI 0.85 to 0.89). Having both medical and mental illness was associated with lower colonoscopy uptake relative to no comorbidity (HR 0.88, CI 0.87 to 0.90). Persons with medical and mental health conditions had lower colonoscopy rates after FOBT+ than those without these conditions. Better strategies are needed to optimize colorectal cancer screening and follow-up in individuals with comorbidities.

This editorial introduces the Special Issue “Metabolism of Islands”. It makes a case why we should care about islands and their sustainability. Islands are hotspots of biocultural diversity, and home to 600 million people that depend on one-sixth of the earth’s total area, including the surrounding oceans, for their subsistence. Today, they are on the frontlines of climate change and face an existential crisis. Islands are, however, potential “hubs of innovation” and are uniquely positioned to be leaders in sustainability and climate action. We argue that a full-fledged program on “island industrial ecology” is urgently needed with the aim to offer policy-relevant insights and strategies to sustain small islands in an era of global environmental change. We introduce key industrial ecology concepts, and the state-of-the-art in applying them to islands. Nine contributions in this Special Issue are briefly reviewed to highlight the metabolic risks inherent in the island cases. The contributors explore how reconfiguring patterns of resource use will allow island governments to build resilience and adapt to the challenges of climate change.

In the past decades, the Caribbean economy has transformed to rely primarily on tourism with a vast amount of infrastructure dedicated to this sector. At the same time, the region is subject to repeated crises in the form of extreme weather events that are becoming more frequent, deadly, and costly. Damages to buildings and infrastructure (or the material stocks) from storms disrupt the local economy by an immediate decline in tourists and loss of critical services. In Antigua and Barbuda (A&B), tourism contributes 80% to the GDP and is a major driver for adding new material stocks to support the industry. This research analyzes A&B’s material stocks (MSs) in buildings (aggregates, timber, concrete, and steel) using geographic information systems (GIS) with physical parameters such as building size and footprint, material intensity, and the number of floors. In 2004, the total MSs of buildings was estimated at 4.7 million tonnes (mt), equivalent to 58.5 tonnes per capita, with the share of non-metallic minerals to be highest (2.9 mt), followed by aggregates (1.2 mt), steel (0.44 mt), and timber (0.18 mt). Under the National Oceanic and Atmospheric Administration’s (NOAA’s) 2 meter (m) sea level rise scenario, an estimated 4% of the island’s total MSs would be exposed. The tourism sector would disproportionately experience the greatest exposure of 19% of its MSs. By linking stocks to services, our research contributes to the understanding of the complexities between the environmental and economic vulnerability of island systems, and the need for better infrastructure planning as part of resilience building.

Neuroendocrine tumours are increasing in incidence and cause a variety of symptoms. The mammalian target of rapamycin (mTOR) pathway plays a key role in neuroendocrine tumour (NET) pathogenesis, leading to increased lipid synthesis, protein synthesis and cellular growth. Upregulation of this pathway is noted in both hereditary and sporadic NETs. This understanding has led to investigations of mTOR inhibitors as therapy for metastatic NETs. After promising preclinical findings, everolimus, an mTOR inhibitor, was trialled in the RADIANT-1−4 studies on patients with advanced, well differentiated NETs. RADIANT-3 and RADIANT-4 established the efficacy of everolimus in improving progression-free survival (PFS) for metastatic NET of pancreatic, lung and gastrointestinal origin, leading to the US Food and Drug Administration (FDA) approval for its use in tumour control in those settings. Everolimus treatment is generally well tolerated; common adverse events include stomatitis, diarrhoea, rash and hyperglycaemia. Although discontinuation rates are low, many patients may require dose modification to successfully continue therapy. The combination of everolimus with somatostatin analogues (SSAs) (such as octreotide or pasireotide) or other targeted agents such as bevacizumab has not produced additional incremental benefit, and dual biologic therapy is not used widely. Ongoing trials are investigating everolimus compared with chemotherapy, optimal sequencing of therapy and combination of everolimus with radiotherapy. Future research should concentrate on identification of predictive biomarkers for benefit from mTOR therapy and include quality of life as a measure.