A three-arm randomised phase II study of the MEK inhibitor selumetinib alone or in combination with paclitaxel in metastatic uveal melanoma.

AIMS: The MAPK pathway is constitutively activated in uveal melanoma (UM). Selumetinib (AZD6244, ARRY-142886), a MEK inhibitor, has shown limited activity as monotherapy in metastatic UM. Pre-clinical studies support synergistic cytotoxic activity for MEK inhibitors combined with taxanes, and here we sought to assess the clinical efficacy of combining selumetinib and paclitaxel. PATIENTS AND METHODS: Seventy-seven patients with metastatic UM who had not received prior chemotherapy were randomised to selumetinib alone, or combined with paclitaxel with or without interruption in selumetinib two days before paclitaxel. The primary endpoint was progression free survival (PFS). After amendment, the combination arms were combined for analysis and the sample size adjusted to detect a hazard ratio (HR): 0.55, 80% power at 1-sided 5% significance level. RESULTS: The median PFS in the combination arms was 4.8 months (95% CI: 3.8 - 5.6) compared with 3.4 months (2.0 - 3.9) in the selumetinib arm (HR 0.62 [90% CI 0.41 - 0.92], 1-sided p-value = 0.022). ORR was 14% and 4% in the combination and monotherapy arms respectively. Median OS was 9 months for the combination and was not significantly different from selumetinib alone (10 months) with HR of 0.98 [90% CI 0.58 - 1.66], 1-sided p-value = 0.469. Toxicity was in keeping with the known profiles of the agents involved. CONCLUSIONS: SelPac met its primary endpoint, demonstrating an improvement in PFS for combination selumetinib and paclitaxel. No improvement in OS was observed, and the modest improvement in PFS is not practice changing.

Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma.

Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.

Cost-effectiveness of Intervention Implementation Support for Reducing Eating Disorder Symptoms Among College Students.

Implementation support for prevention interventions is receiving increased attention, as many organizations receive training in evidence-based practices but do not deliver the interventions optimally. The Body Project, a four-session program, significantly reduces eating disorder symptoms and future disorder onset among group participants when delivered by peer educators at colleges/universities. Costs and cost-effectiveness of the program were examined using data from a randomized trial that compared three levels of implementation support at 63 colleges: (1) a train-the-trainer (TTT) workshop alone, (2) TTT plus a technical assistance (TA) workshop, or (3) TTT plus TA plus monthly quality assurance (QA) consultations. Effectiveness was measured by the production of reliable change in eating disorder symptoms from pretest to posttest. Costs and cost-effectiveness of two levels of implementation support are reported, comparing TTT-only with TTT + TA + QA (effectiveness of the TTT + TA condition did not differ from TTT-only) and using results from an earlier study as a proxy for a no-treatment control. Two perspectives are considered: a sponsoring organization providing the training at multiple sites and a college delivering the intervention to its eligible students. From the perspective of a sponsoring organization, adding both the TA training and QA support improves the cost-effectiveness per eligible student receiving the intervention. From the perspective of costs for a college to deliver the intervention, receiving TA training and QA support is also more cost-effective than the training workshop alone, whether the peer educators are paid or unpaid and whether costs of group supervision are included or excluded. Results converge with previous research showing that more intensive implementation support can be more cost-effective.

Is being anti-vegan a distinct dietarian identity? An investigation with omnivores, vegans, and self-identified "anti-vegans".

Adding to research on the form and content of anti-vegan sentiment, recent scholarship has identified a group of individuals who self-subscribe as "anti-vegan". Here, we sought to determine whether anti-veganism might reflect a distinct dietarian identity with its own unique ideological profile. Two-hundred and fourteen vegans, 732 omnivores, and 222 self-identified "anti-vegans" were assessed using a survey methodology that included the Dietarian Identity Questionnaire and ideological markers related to dark humour, social dominance orientation (SDO), speciesism, male-role norms, moral relativism, and attitudes toward science. Our analysis revealed a dietarian identity unique to anti-vegans. The dietary patterns of anti-vegans were more central to their identity than for omnivores, though marginally lower than vegans. Like vegans, anti-vegans scored highly on dietarian measures of private regard and personal dietary motivations, and lower than omnivores on public regard. The diets of anti-vegans were more morally motivated than omnivores. However, anti-vegans scored higher than both omnivores and vegans on a number of ideological measures including dark humour, SDO, speciesism, male-role norms, moral relativism, and distrust of science. Somewhat surprising, anti-vegans held greater trust than omnivores in the science of plant-based nutrition. We discuss the unique dietarian identities of anti-vegans, considering both intra-group differences of omnivores and anti-vegans (e.g., in right-wing ideology), and inter-group similarities of vegans and anti-vegans (e.g., in diet centrality).

Evaluation of a novel eating disorder prevention program for young women with type 1 diabetes: A preliminary randomized trial.

OBJECTIVE: Evaluate whether the Body Project prevention program adapted for young women with type 1 diabetes (Diabetes Body Project) reduces eating disorder (ED) risk factors and symptoms. METHODS: Young women (aged 15-30) at high-risk for EDs due to having type 1 diabetes and body image concerns (N = 55) were randomized to virtually delivered Diabetes Body Project groups or an educational control condition, completing measures at pretest, posttest, and 3-month follow-up. RESULTS: Diabetes Body Project versus the control participants showed significantly greater reductions in thin-ideal internalization, body dissatisfaction, diabetes distress, diabetes eating pathology, and ED symptoms by posttest, and greater reductions in diabetes eating pathology and ED symptoms, and greater improvements in quality of life by 3-month follow-up, which were medium to large effects (d's ranged from -0.43 to -0.90). Although control participants showed a worsening of glycemic control (time in range) verses Diabetes Body Project participants, this difference was non-significant (d = 0.26). CONCLUSIONS: Virtually delivered Diabetes Body Project decreased ED risk factors and symptoms in young women with type 1 diabetes. A well powered randomized controlled trial is warranted to evaluate this intervention over longer follow-up.

A randomized trial of two group-delivered transdiagnostic eating disorder treatments: Dissonance-based treatment versus interpersonal psychotherapy.

OBJECTIVE: Test whether a group-delivered dissonance-based transdiagnostic eating disorder treatment, Body Project Treatment (BPT), produces greater reductions in eating disorder symptoms and higher abstinence from eating disorder behaviors and remittance from eating disorder diagnoses than group-delivered transdiagnostic interpersonal psychotherapy (IPT). METHOD: Women with a range of eating disorders (N = 73) were randomized to 8-week group-implemented BPT or IPT and completed surveys and masked diagnostic interviews at pretest, posttest, and 6-month follow-up. RESULTS: Participants randomized to BPT versus IPT showed significantly greater reductions in eating disorder symptoms (d = -.75), pursuit of the thin ideal (d = -.87), anxiety symptoms (d = -.76), and social impairment (d = -.59) through 6-month follow-up. By end of treatment, participants randomized to the BPT versus IPT did not significantly differ on abstinence from binge eating and purging (49% vs. 40%, respectively) or remittance from eating disorder diagnoses (54% vs. 40%, respectively). Participants randomized to BPT versus IPT did not differ significantly in average session attendance (5.8 vs. 6.9, respectively) or average homework assignments completed (4.6 vs. 5.6, respectively). The within-condition reductions in eating disorder symptoms for BPT did not significantly differ when implemented in person versus via synchronous video telepsychiatry (d = -1.39 vs. -1.09, respectively), though these effects should be considered preliminary because of the small cell sizes. CONCLUSIONS: The evidence that BPT produces greater reductions in eating disorder symptoms, pursuit of the thin ideal, anxiety symptoms, and social impairment than IPT is encouraging because it provides some assurance that the effects are present equating for the effects of expectancies, demand characteristics, and nonspecific factors. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Out-of-hours admissions in patients treated with immune checkpoint inhibitors and their primary management with steroids.

INTRODUCTION: The incidence of immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICI) is well described. However, the impact on emergency care services is not. This study investigated the incidence of irAEs out-of-hours, and the management used to mitigate symptoms and side effects. METHODS: This retrospective cohort study reviewed all emergency presentations triaged by the acute oncology team between December 2021 and June 2022, between 5 pm and 9 am. Patients were identified from triage audit sheets and remaining data points were retrieved from electronic health records. Inclusion criteria included all adult patients admitted on an ICI at one tertiary centre. RESULTS: In 7 months, 970 patients called the acute oncology helpline 11% (n = 109) of patients were on an ICI treatment. After clinical review, 78% (n = 70) resulted in hospital admissions, with length of stay cumulating to 496 bed days. 56% (n = 39) of patients delayed reporting symptoms, ranging between 12 hours and 10 days from symptom onset to seeking support. 49% (n = 34) patients received steroids to manage suspected irAEs. Dexamethasone was the most common steroid used in 71% (n = 24) of patients, and variation was found in prescribed doses. CONCLUSIONS: These results underline the urgent need to address patient and staff education on adverse effects related to ICI. Patients require a comprehensive understanding of the symptoms and importance of prompt reporting. Staff education on recognition and treatment management is needed to reduce variation in practice. Further research is needed to identify barriers in symptom reporting and focus on realtime reporting to reduce the out-of-hours burden on services.

Setting and Provider Predictors of Implementation Success for an Eating Disorder Prevention Program Delivered by College Peer Educators.

INTRODUCTION: College students face increased risk for a variety of mental health problems but experience barriers to treatment access. Prevention programs, including those implemented by peer educators, may decrease treatment needs and increase service access. We examined the implementation of an evidence-based eating disorder prevention program, Body Project, delivered by college peer educators at 63 colleges/universities, comparing three levels of implementation support: (1) Train-the-Trainer (TTT) training; (2) TTT plus a technical assistance workshop (TTT + TA); and (3) TTT + TA with one year of quality assurance calls (TTT + TA + QA). The present study tested the degree to which indicators proposed by the Consolidated Framework for Implementation Research (CFIR) were associated with core implementation outcomes. METHOD: We tested whether indices of CFIR domains (i.e., perceived intervention characteristics, outer and inner setting factors, provider characteristics, and implementation process) were correlated with three implementation outcomes (program reach, fidelity, effectiveness) during a 1-year implementation period. RESULTS: Greater program reach was associated with implementation process, specifically the completion of more implementation activities (ß = 0.46). Greater program fidelity was associated with higher positive (ß = 0.44) and lower negative (ß = - 0.43) perceptions of the Body Project characteristics, and greater reported general support for evidence-based practices (ß = 0.41). Greater effectiveness was associated with lower negative perceptions of Body Project characteristics (d = 0.49). CONCLUSIONS: Several implementation determinants proposed by the CFIR model predicted outcomes, especially intervention fidelity. Across the outcomes of interest, implementation determinants related to peer educator and supervisor perceived characteristics of the specific intervention and general attitudes towards evidence-based practices emerged as robust predictors to inform future work investigating ongoing implementation and sustainability of programs in university settings.

Evaluating whether a peer-led dissonance-based eating disorder prevention program prevents onset of each eating disorder type.

BACKGROUND: This study tested whether the dissonance-based Body Project eating disorder prevention program reduced onset of subthreshold/threshold anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and purging disorder (PD) over long-term follow-up. METHODS: Data were combined from three prevention trials that targeted young women at high-risk for eating disorders (N = 1092; M age = 19.3). Participants were randomized to Body Project groups led by peer educators or expressive writing/educational controls and completed masked diagnostic interviews over 2- to 4-year follow-ups. Logistic regressions tested whether onset of each eating disorder over follow-up differed between Body Project and control participants. RESULTS: Peer-led Body Project groups produced a 46% reduction in onset of subthreshold/threshold BN and a 62% reduction in onset of PD relative to controls over follow-up. Rates of onset of subthreshold/threshold AN and BED did not significantly differ between peer-led Body Project participants and control participants. CONCLUSIONS: Results support the dissemination of the peer-led Body Project for reducing future onset of BN and PD. This study and recent research suggest that thin-ideal internalization, the risk factor for eating disorders targeted in the Body Project, may be more relevant for predicting onset of BN and PD compared to AN and BED. Findings support the development of a version of the Body Project aimed to reduce risk factors that have predicted future onset of all four types of eating disorders (e.g. overvaluation of weight/shape, fear of weight gain), which may more effectively prevent all eating disorder types.

Tebentafusp: a first-in-class treatment for metastatic uveal melanoma.

Tebentafusp is a first-in-class immunotherapy agent that comprises an engineered T-cell receptor targeting a gp100 epitope presented by human leukocyte antigen-A*02:01 cells, fused to an anti-CD3 single-chain variable fragment. Tebentafusp is both the first bispecific T-cell engager to show efficacy in the treatment of advanced solid cancer and the first anti-cancer treatment to demonstrate an overall survival benefit in patients with uveal melanoma (UM). This review article will focus on the clinical development of tebentafusp, the mechanism of action and resultant evolution of the management of advanced UM.

An experimental test of increasing implementation support for college peer educators delivering an evidence-based prevention program.

OBJECTIVE: College students are at particularly high risk for mental health problems, such as eating disorders, which are associated with functional impairment, distress, and morbidity, but barriers limit implementation of evidence-based interventions at colleges. We evaluated the effectiveness and implementation quality of a peer educator (PE) delivered eating disorder prevention program (the Body Project [BP]), which has a broad evidence-based using a train-the-trainer (TTT) approach and experimentally evaluated three levels of implementation support. METHOD: We recruited 63 colleges with peer educator programs and randomly assigned them to (a) receive a 2-day TTT training in which peer educators were trained to implement the Body Project and supervisors were taught how to train future peer educators (TTT), (b) TTT training plus a technical assistance (TA) workshop (TTT + TA), or (c) TTT plus the TA workshop and quality assurance (QA) consultations over 1-year (TTT + TA + QA). Colleges recruited undergraduates (N = 1,387, 98% female, 55% White) to complete Body Project groups. RESULTS: There were no significant differences across condition for attendance, adherence, competence, and reach, though nonsignificant trends suggested some benefit of TTT + TA + QA relative to TTT for adherence and competence (ds = .40 and .30). Adding TA and QA to TTT was associated with significantly larger reductions in risk factors and eating disorder symptoms. CONCLUSIONS: Results suggest that the Body Project can be effectively implemented at colleges using peer educators and a TTT approach and that adding TA and QA resulted in significantly larger improvements in outcomes for group participants, and marginally higher adherence and competence. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Efficacy of virtual delivery of a dissonance-based eating disorder prevention program and evaluation of a donation model to support sustained implementation.

OBJECTIVE: Evaluate whether the Body Project prevention program reduces eating disorder risk factors and symptoms when implemented via synchronous video telepsychiatry, which could markedly increase the reach of this intervention and test whether a pay-it-forward donation model could support sustained implementation of this intervention. METHOD: Young women at high risk for eating disorders because of body image concerns (N = 75; age range 16-27) were randomized to Body Project groups delivered virtually by peer educators or a waitlist control condition; participants who completed the Body Project for free because of past donations were encouraged to donate money so that this intervention could be provided for free to others. RESULTS: Participants randomized to virtually delivered Body Project groups showed significantly or marginally greater pretest-to-posttest reductions in pursuit of the thin ideal, body dissatisfaction, dieting, negative affect, and eating disorder symptoms than controls. The average effect was large (d = .79), which was 49% larger than the average effect observed previously for in-person peer-educator-delivered Body Project groups (d = .53; [.76-.53 = .23/.53 = 49%]). However, only 3.6% of participants donated money to support future implementation of this intervention. CONCLUSIONS: The evidence that the Body Project produced large reductions in eating disorder risk factors and symptoms when implemented virtually and that the effects were larger than for in-person Body Project groups suggests it would be useful to implement this prevention program virtually, which could expand the reach of this intervention. Future studies should evaluate alternative methods for supporting sustained implementation of this prevention program. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Total serum N-glycans associate with response to immune checkpoint inhibition therapy and survival in patients with advanced melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions. Tumours are characterized by aberrant glycosylation which may contribute to their progression and hinder an effective antitumour immune response. METHODS: We aim at identifying novel glyco-markers of response and survival by leveraging the N-glycome of total serum proteins collected in 88 ICI-naive patients with advanced melanoma from two European countries. Samples were collected before and during ICI treatment. RESULTS: We observe that responders to ICIs present with a pre-treatment N-glycome profile significantly shifted towards higher abundancy of low-branched structures containing lower abundances of antennary fucose, and that this profile is positively associated with survival and a better predictor of response than clinical variables alone. CONCLUSION: While changes in serum protein glycosylation have been previously implicated in a pro-metastatic melanoma behaviour, we show here that they are also associated with response to ICI, opening new avenues for the stratification of patients and the design of adjunct therapies aiming at improving immune response.

Implementation factors that predict larger effects from a peer educator delivered eating disorder prevention program at universities.

OBJECTIVE: Identify implementation factors, including intervention, facilitator, participant, and college factors, that were associated with larger reductions in eating disorder symptoms for undergraduates who completed a dissonance-based eating disorder prevention program delivered by peer educators in an implementation support trial. The goal was to determine how to maximize the effects of this prevention program in future implementation efforts. METHOD: We recruited 63 universities with peer educator programs and randomly assigned them to three levels of implementation support for delivery of an evidence-based eating disorder prevention program (the Body Project). The present report investigated whether several intervention, facilitator, participant, and college characteristics were associated with the magnitude of reductions in eating disorder symptoms among 1,387 undergraduates who completed the Body Project. RESULTS: Significantly greater reductions in eating disorder symptoms were found for the four-session versus two-session version of the Body Project (d = -.36), when Body Project groups were delivered virtually versus in-person (d = -.22), when observation-based supervision was provided to peer educators during intervention implementation versus when it was not (d = -.15), and for larger versus smaller universities (d = -.24). Although effects were small, the additive effect was medium (d = -.50). CONCLUSIONS: Results suggest that if the goal is to optimize the effects of the Body Project, peer educator programs at universities should implement the full four-session version of the prevention program that contains all of the dissonance-inducing activities and home exercises, implement this prevention program virtually, and provide supervision to facilitators implementing this prevention program. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Enhancing Efficacy of a Brief Obesity and Eating Disorder Prevention Program: Long-Term Results from an Experimental Therapeutics Trial.

Objective: Test whether the efficacy of Project Health, an obesity/eating disorder prevention program, is improved by delivering it in single-sex groups and adding food response inhibition and attention training. Method: High-risk young adults (N = 261; M age = 19.3, 74% female) were randomized to (1) single-sex or (2) mixed-sex groups that completed food response inhibition and attention training or (3) single-sex or (4) mixed-sex groups that completed sham training with nonfood images in a 2 × 2 factorial design. Results: There was a significant sex-composition by training-type by time interaction; participants who completed single- or mixed-sex Project Health groups plus food response and attention training showed significant reductions in body fat over a 2-year follow-up, though this effect was more rapid and persistent in single-sex groups, whereas those who completed single- or mixed-sex Project Health groups plus sham training did not show body fat change. However, there were no differences in overweight/obesity onset over the follow-up. The manipulated factors did not affect eating disorder symptoms or eating disorder onset, but there was a significant reduction in symptoms across the conditions (within-condition d = -0.58), converging with prior evidence that Project Health produced larger reductions in symptoms (within-condition d = -0.48) than educational control participants. Average eating disorder onset over the 2-year follow-up (6.4%) was similar to that observed in Project Health in a past trial (4.5%). Conclusions: Given that Project Health significantly reduced future onset of overweight/obesity in a prior trial and the present trial found that body fat loss effects were significantly greater when implemented in single-sex groups and paired with food response and attention training, there might be value in broadly implementing this combined intervention.

Evidence that a novel transdiagnostic eating disorder treatment reduces reward region response to the thin beauty ideal and high-calorie binge foods.

BACKGROUND: Findings from brain imaging studies with small samples can show limited reproducibility. Thus, we tested whether the evidence that a transdiagnostic eating disorder treatment reduces responsivity of brain valuation regions to thin models and high-calorie binge foods, the intervention targets, from a smaller earlier trial emerged when we recruited additional participants. METHODS: Women with DSM-5 eating disorders (N = 138) were randomized to the dissonance-based body project treatment (BPT) or a waitlist control condition and completed functional magnetic resonance imaging (fMRI) scans assessing neural response to thin models and high-calorie foods at pretest and posttest. RESULTS: BPT v. control participants showed significantly greater reductions in responsivity of regions implicated in reward valuation (caudate) and attentional motivation (precuneus) to thin v. average-weight models, echoing findings from the smaller sample. Data from this larger sample also provided novel evidence that BPT v. control participants showed greater reductions in responsivity of regions implicated in reward valuation (ventrolateral prefrontal cortex) and food craving (hippocampus) to high-calorie binge foods v. low-calorie foods, as well as significantly greater reductions in eating disorder symptoms, abstinence from binge eating and purging behaviors, palatability ratings for high calorie foods, monetary value for high-calorie binge foods, and significantly greater increases in attractiveness ratings of average weight models. CONCLUSIONS: Results from this larger sample provide evidence that BPT reduces valuation of the thin ideal and high-calorie binge foods, the intervention targets, per objective brain imaging data, and produces clinically meaningful reductions in eating pathology.

HIV-related Merkel cell carcinoma: A report of three cases from the UK.

Merkel cell carcinoma (MCC) of the skin is a rare, aggressive and often fatal neuroendocrine skin cancer. The incidence of MCC has significantly increased in the last decades. Factors that have been associated with the development of MCC include infection with Merkel Cell polyomavirus (MCPyV), ultraviolet exposure, hematologic malignancies and immunosuppression.We present three cases of patients living with HIV who were diagnosed with MCC. HIV cases associated with MCC have been rarely reported and to our knowledge, not yet before in the UK.

Circulating inflammatory proteins associate with response to immune checkpoint inhibition therapy in patients with advanced melanoma.

BACKGROUND: Inflammation can modulate tumour growth and progression, and influence clinical response to treatment. We investigated the potential of circulating inflammatory proteins for response stratification of immune checkpoint inhibitor (ICI) therapy for advanced melanoma. METHODS: Study subjects were 87 patients with unresectable stage III or IV cutaneous melanoma from the multiple centres across the United Kingdom (UK) and the Netherlands (NL) who received ipilimumab, nivolumab, or pembrolizumab, or a combination of ipilimumab and nivolumab. Serum samples were collected before and during ICI therapy at follow-up visits scheduled every third week over a 12-week period. We performed targeted quantification of 92 proteins involved in inflammation and tested for association of their pre-treatment and on-treatment levels, as well as longitudinal changes, with overall response rate, progression-free survival, and overall survival. FINDINGS: We observed consistently higher pre-treatment levels of interleukin-6 (IL-6), hepatocyte growth factor (HGF), and monocyte chemotactic protein 2 (MCP-2), in non-responders compared to responders (meta-analysis p=3.31 × 10-4, 2.29 × 10-4, and 1.02 × 10-3, respectively). Patients' stratification according to the median value of IL-6, HGF, and MCP-2 highlighted a cumulative negative effect of pre-treatment levels of the three proteins on response (p=1.13 × 10-2), with overall response rate among patients presenting with combined elevated IL-6, HGF, and MCP-2 levels being three-fold lower (26.7%) compared to patients with none of the three proteins elevated (80.0%, p=9.22 × 10-3). Longitudinal data analysis showed that on-treatment changes in circulating inflammatory proteins are not correlated with response. INTERPRETATION: Our findings are in line with an increasing body of evidence that the pro-inflammatory cytokine IL-6 can influence response to ICI in advanced melanoma, and further support a role of circulating HGF and MCP-2 levels as prognostic biomarkers as suggested by previous smaller studies. Inflammatory proteins may serve as predictive biomarkers of ICI response and valuable targets for combination therapy. FUNDING: This work was supported by the Seerave Foundation and Dutch Cancer Society.

Cross-cohort gut microbiome associations with immune checkpoint inhibitor response in advanced melanoma.

The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.

Behavioral Consistency in the Digital Age.

Efforts to infer personality from digital footprints have focused on behavioral stability at the trait level without considering situational dependency. We repeated a classic study of intraindividual consistency with secondary data (five data sets) containing 28,692 days of smartphone usage from 780 people. Using per-app measures of pickup frequency and usage duration, we found that profiles of daily smartphone usage were significantly more consistent when taken from the same user than from different users (d > 1.46). Random-forest models trained on 6 days of behavior identified each of the 780 users in test data with 35.8% accuracy for pickup frequency and 38.5% accuracy for duration frequency. This increased to 73.5% and 75.3%, respectively, when success was taken as the user appearing in the top 10 predictions (i.e., top 1%). Thus, situation-dependent stability in behavior is present in our digital lives, and its uniqueness provides both opportunities and risks to privacy.