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Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600 wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients. Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1–25·7), 2-year overall survival was 63·8% (95% CI 53·3–72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1–66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43–1·26; p=0·26). Treatment-related grade 3–4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3–4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3–4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis. Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients. Bristol-Myers Squibb.

1. Trees commonly reproduce via masting cycles, which involves synchronized inter-annual variability in fruit crop size. A few individuals in a population will commonly produce much more fruit than others. If these trees produce fruit more frequently, as indicated by a lower inter-annual variability in fruit production, they may dominate fruit production over time. 2. By measuring fruit production of 1635 individuals of 10 temperate tree species across 4 years in northern lower Michigan, we estimated the inter-annual variability and synchrony in each species. We compared fruit production estimates with measurements of tree size, soil nutrient availability and neighbourhood crowding to investigate the source of inter-individual variation in number of fruit produced. 3. We found that trees' fruit production increased with tree size. The trees that accounted for the largest proportion of total fruit production had lower inter-annual variability and higher synchrony in fruit production. These 'super-producer' trees tended to have high nutrient availability and few neighbouring trees, but there were no effects of nutrient availability or neighbourhood crowding on fruit production in the population as a whole. 4. Synthesis. Masting is a population-level phenomenon, and is typically studied at this level. However, when we apply individual tree observations of fruit production to this phenomenon, it reveals super-producers which produce fruit more consistently than the rest of the population. By reducing inter-annual variability in fruit production, but increasing synchrony and making large numbers of fruit, super-producers may be able to reap the benefits of masting while governing population fruit production over time.

In tropical forest communities, seedling recruitment can be limited by the number of fruit produced by adults. Fruit production tends to be highly unequal among trees of the same species, which may be due to environmental factors. We observed fruit production for ~2,000 trees of 17 species across 3 years in a wet tropical forest in Costa Rica. Fruit production was modeled as a function of tree size, nutrient availability, and neighborhood crowding. Following model selection, tree size and neighborhood crowding predicted both the probability of reproduction and the number of fruit produced. Nutrient availability only predicted only the probability of reproduction. In all species, larger trees were more likely to be reproductive and produce more fruit. In addition, number of fruit was strongly negatively related to presence of larger neighboring trees in 13 species; presence of all neighboring trees had a weak‐to‐moderate negative influence on reproductive status in 16 species. Among various metrics of soil nutrient availability, only sum of base cations was positively associated with reproductive status, and for only four species. Synthesis Overall, these results suggest that direct influences on fruit production tend to be mediated through tree size and crowding from neighboring trees, rather than soil nutrients. However, we found variation in the effects of neighbors and nutrients among species; mechanistic studies of allocation to fruit production are needed to explain these differences. We observed fruit production for ~2,000 trees of 17 species across three years in a wet tropical forest in Costa Rica. Fruit production was negatively related to presence of larger neighboring trees in 13 species, but relationships between fruit production and soil nutrient availability were less common. These results suggest that influences on fruit production tend to be mediated through tree size and crowding rather than soil nutrients.

Background Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4–5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. Methods We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. Results The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. Conclusions These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis.

The Global Ecosystem Dynamics Investigation (GEDI) is a waveform lidar instrument on the International Space Station used to estimate aboveground biomass density (AGBD) in temperate and tropical forests. Algorithms to predict footprint AGBD from GEDI relative height (RH) metrics were developed from simulated waveforms with leaf-on (growing season) conditions. Leaf-off GEDI data with lower canopy cover are expected to have shorter RH metrics, and are therefore excluded from GEDI’s gridded AGBD products. However, the effects of leaf phenology on RH metric heights, and implications for GEDI footprint AGBD models that can include multiple nonlinear RH predictors, have not been quantified. Here, we test the sensitivity of GEDI data and AGBD predictions to leaf phenology. We simulated GEDI data using high-density drone lidar collected in a temperate mountain forest in the Czech Republic under leaf-off and leaf-on conditions, 51 d apart. We compared simulated GEDI RH metrics and footprint-level AGBD predictions from GEDI Level 4 A models from leaf-off and leaf-on datasets. Mean canopy cover increased by 31% from leaf-off to leaf-on conditions, from 57% to 88%. RH metrics < RH50 were more sensitive to changes in leaf phenology than RH metrics ⩾ RH50. Candidate AGBD models for the deciduous-broadleaf-trees prediction stratum in Europe that were trained using leaf-on measurements exhibited a systematic prediction difference of 0.6%–19% when applied to leaf-off data, as compared to leaf-on predictions. Models with the least systematic prediction difference contained only the highest RH metrics, or contained multiple predictor terms that contained both positive and negative coefficients, such that the difference from systematically shorter leaf-off RH metrics was partially offset among the multiple terms. These results suggest that, with consideration of model choice, leaf-off GEDI data can be suitable for AGBD prediction, which could increase data availability and reduce sampling error in some forests.

Purpose This international, multicenter, single-arm trial assessed efficacy and safety of intralesional rose bengal (PV-10) in 80 patients with refractory cutaneous or subcutaneous metastatic melanoma. Methods Sixty-two stage III and 18 stage IV melanoma patients with disease refractory to a median of six prior interventions received intralesional PV-10 into up to 20 cutaneous and subcutaneous lesions up to four times over a 16-week period and were followed for 52 weeks. Objectives were to determine best overall response rate in injected target lesions and uninjected bystander lesions, assess durability of response, and characterize adverse events. Results For target lesions, the best overall response rate was 51 %, and the complete response rate was 26 %. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8 % of patients having no evidence of disease after 52 weeks. Response was dependent on untreated disease burden, with complete response achieved in 50 % of patients receiving PV-10 to all of their disease. Response of target lesions correlated with bystander lesion regression and the occurrence of locoregional blistering. Adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events. Conclusions Intralesional PV-10 yielded durable local control with high rates of complete response. Toxicity was confined predominantly to the injection site. Cutaneous bystander tumor regression is consistent with an immunologic response secondary to ablation. This intralesional approach for local disease control could be complementary to current and investigational treatments for melanoma.

Regional-scale tree die-off events driven by drought and warming and associated pests and pathogens have occurred recently on all forested continents and are projected to increase in frequency and extent with future warming. Within areas where tree mortality has occurred, ecological, hydrological and meteorological consequences are increasingly being documented. However, the potential for tree die-off to impact vegetation processes and related carbon dynamics in areas remote to where die-off occurs has rarely been systematically evaluated, particularly for multiple distinct regions within a given continent. Such remote impacts can occur when climate effects of local vegetation change are propagated by atmospheric circulation-the phenomena of 'ecoclimate teleconnections'. We simulated tree die-off events in the 13 most densely forested US regions (selected from the 20 US National Ecological Observatory Network [NEON] domains) and found that tree die-off even for smaller regions has potential to affect climate and hence Gross Primary Productivity (GPP) in disparate regions (NEON domains), either positively or negatively. Some regions exhibited strong teleconnections to several others, and some regions were relatively sensitive to tree loss regardless of what other region the tree loss occurred in. For the US as a whole, loss of trees in the Pacific Southwest-an area undergoing rapid tree die-off-had the largest negative impact on remote US GPP whereas loss of trees in the Mid-Atlantic had the largest positive impact. This research lays a foundation for hypotheses that identify how the effects of tree die-off (or other types of tree loss such as deforestation) can ricochet across regions by revealing hot-spots of forcing and response. Such modes of connectivity have direct applicability for improving models of climate change impacts and for developing more informed and coordinated carbon accounting across regions.

Earth Observation data are uniquely positioned to estimate forest aboveground biomass density (AGBD) in accordance with the United Nations Framework Convention on Climate Change (UNFCCC) principles of ‘transparency, accuracy, completeness, consistency and comparability’. However, the use of space-based AGBD maps for national-level reporting to the UNFCCC is nearly non-existent as of 2023, the end of the first global stocktake (GST). We conduct an evidence-based comparison of AGBD estimates from the NASA Global Ecosystem Dynamics Investigation and ESA Climate Change Initiative, describing differences between the products and National Forest Inventories (NFIs), and suggesting how science teams must align efforts to inform the next GST. Between the products, in the tropics, the largest differences in estimated AGBD are primarily in the Congolese lowlands and east/southeast Asia. Where NFI data were acquired (Peru, Mexico, Lao PDR and 30 regions of Spain), both products show strong correlation to NFI-estimated AGBD, with no systematic deviations. The AGBD-richest stratum of these, the Peruvian Amazon, is accurately estimated in both. These results are remarkably promising, and to support the operational use of AGB map products for policy reporting, we describe targeted ways to align products with Intergovernmental Panel on Climate Change (IPCC) guidelines. We recommend moving towards consistent statistical terminology, and aligning on a rigorous framework for uncertainty estimation, supported by the provision of open-science codes for large-area assessments that comprehensively report uncertainty. Further, we suggest the provision of objective and open-source guidance to integrate NFIs with multiple AGBD products, aiming to enhance the precision of national estimates. Finally, we describe and encourage the release of user-friendly product documentation, with tools that produce AGBD estimates directly applicable to the IPCC guideline methodologies. With these steps, space agencies can convey a comparable, reliable and consistent message on global biomass estimates to have actionable policy impact.

Advanced melanoma has proven difficult to treat for many years, and no previous agent has shown improved survival in a phase 3 trial. The deepening understanding of tumor immunobiology and the complexity of the interactions between host T cells and cancer have led to novel treatment approaches. Among these, ipilimumab is a first-in-class T-cell potentiator that works by blocking cytotoxic T-lymphocyte antigen-4, a critical negative regulator of the antitumor T-cell response. From phase 1 studies, ipilimumab has shown encouraging activity in melanoma and other cancers, with unusual response patterns and mechanism-related, predictable toxicities that are medically manageable and mostly reversible but can sometimes be life threatening unless recognized and treated early. Early indications of a survival benefit in phase 2 studies have been confirmed recently in the first randomized phase 3 trial; the primary endpoint of the trial, overall survival (OS), was met with ipilimumab significantly prolonging median OS both as a single agent (10.1 months; p = 0.003) and combined with gp100 vaccine (10.0 months; p < 0.001) compared with vaccine control (6.4 months). Even more noteworthy was the improvement in long-term survival at 24 months from 13.7% (gp100 alone) to 21.6% and 23.5% for the combination and single ipilimumab, respectively. The addition of gp100 vaccine did not appear to impact OS since data for ipilimumab alone were similar to those for the combination with vaccine. Re-induction with ipilimumab in selected patients who progressed gave further clinical benefits. Ipilimumab has also shown promising activity in melanoma patients with brain metastases, and patients with non–small cell lung cancer, renal cell cancer, and castrate-resistant prostate cancer. Ipilimumab not only has a novel mechanism of action but demonstrates unique immune-related toxicities that require particular care in their recognition and treatment.

The anti-CTLA4 antibody, ipilimumab, has shown clinical activity against melanoma. Diarrhea due to immune-related colitis is the most frequent serious toxicity and, if untreated, may lead to intestinal perforation. Diarrhea treatment guidelines were developed based on clinical experience in over 2000 patients treated with ipilimumab, and these safety guidelines recommend systemic steroids as the first choice for the treatment of severe diarrhea. In this article, we present an alternative approach to the control of immune-related colitis by using the antitumor necrosis factor antibody, infliximab. Patients with metastatic melanoma received ipilimumab 10 mg/kg every 3 weeks for 4 doses, then every 3 months. Those who developed grade 2 diarrhea were treated with infliximab 5 mg/kg weeks 0 and 2 with mesalamine and loperamide. Steroids were given only for refractory cases requiring hospitalization. Of the first 3 cases of ipilimumab-induced diarrhea, 2 proved refractory and required hospitalization, but 1 recovered quickly without systemic steroids. We then added hydrocortisone enemas daily to the above regimen, and the next 3 patients recovered from grade 2 ipilimumab-induced colitis without difficulty. Treatment with infliximab, mesalamine, and hydrocortisone enemas may produce a rapid improvement in ipilimumab-induced colitis and avoid the administration of systemic steroids.