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Chronic wounds are globally a leading cause of morbidity, and the associated healthcare costs for wound care have become a billion-dollar burden. Both natural and synthetic biomaterials, either individually or in combination, have been extensively investigated for their healing properties. The formation of protein-polysaccharide complexes through non-covalent interactions relies on the distinct physicochemical properties of the biomacromolecules involved, as well as a range of environmental factors. The present study focuses on developing sustainable, high-value biomaterials starting from food industry by-products, specifically whey protein isolate (WPI) and chitosan (CS), to be used in the design of scaffolds intended for the treatment of skin lesions. The quaternary CS derivative N,N,N-trimethyl chitosan (TMC), characterized by a high solubility in a wide pH range, was also considered. Mixtures based on CS/TMC and WPI were prepared and thoroughly characterized, considering thermal treatment, polymer MW, and pH as variables. Two different grades of CS were considered: medium (MCS) and low MW (LCS); and three different experimental conditions were analyzed: (i) denaturation of WPI alone by thermal treatment; (ii) thermal treatment of the mixture; (iii) no thermal treatment. In vitro studies were performed to assess biocompatibility and antioxidant activity of the complexes formed. To the best of our knowledge, this is the first time that complexes based on CS or TMC with WPI are produced and characterized as biomaterials intended for wound healing.

In this work, alternative process chains for sewage sludge treatment by hydrothermal carbonization (HTC) and pyrolysis and the subsequent utilization of biochar and hydrochar were investigated by means of a comparative life cycle assessment (LCA). The mono-incineration of sewage sludge was defined as the benchmark process, being the main valorization route in several countries. The results revealed an advantage for HTC compared to pyrolysis and mono-incineration in most environmental impact categories, thanks to the higher char yield and the lower energy request. The global warming potential (GWP) of using hydrochar ranged from −71.4 to 7.7 g CO2-eq. kg−1 sewage sludge. However, the direct material application of the hydrochar in agriculture showed an increased toxicity potential, so that an energy utilization appears to be more environmentally friendly. For the pyrolysis route, a slightly higher energy demand and thus a higher environmental impact was determined, whereby GWP was between −11.7 to 9.1 g CO2-eq. kg−1 sewage sludge. The direct material application of the biochar in agriculture also showed low toxicity potentials while achieving nutrient recycling for phosphorus and a long-term carbon sequestration potential. Overall, ecological advantages were demonstrated for both thermochemical processes, making pyrolysis and HTC promising alternatives for sustainable sludge management.

PurposeCirculating tumor DNA (ctDNA) analyses allow for postoperative risk stratification in patients with curatively treated colon and breast cancers. Use of ctDNA in esophagogastric cancers (EGC) is less characterized and could identify high-risk patients who have been treated with curative intent.MethodsIn this retrospective analysis of real-world data, ctDNA levels were analyzed in the preoperative, postoperative, and surveillance settings in patients with EGC using a personalized multiplex polymerase chain reaction-based next-generation sequencing assay. Plasma samples (n = 943) from 295 patients at > 70 institutions were collected before surgery, postoperatively, and/or serially during routine clinical follow-up from September 19, 2019, to February 21, 2022. ctDNA detection was annotated to clinicopathologic features and recurrence-free survival.ResultsA total of 295 patients with EGC were analyzed, and 212 patients with stages I-III disease were further explored. Pretreatment ctDNA was detected in 96% (23/24) of patients with preoperative time points. Postoperative ctDNA was detected in 23.5% (16/68) of patients with stage I-III EGC within 16 weeks (molecular residual disease window) after surgery without receiving systemic therapy. ctDNA detection at any time point after surgery (hazard ratio [HR], 23.6; 95% CI, 10.2 to 66.0; P < .0001), within the molecular residual disease window (HR, 10.7; 95% CI, 4.3 to 29.3; P < .0001), and during the surveillance period (HR, 17.7; 95% CI, 7.3 to 50.7; P < .0001) was associated with shorter recurrence-free survival. In multivariable analysis, ctDNA status and clinical stage of disease were independently associated with outcomes.ConclusionUsing real-world data, we demonstrate that postoperative tumor-informed ctDNA detection in EGC is feasible and allows for enhanced patient risk stratification and prognostication during curative-intent therapy.

This document provides recommendations regarding the role of imaging in the staging and follow-up of esophageal cancer. For initial clinical staging, locoregional extent and nodal disease are typically assessed with esophagogastroduodenoscopy and esophageal ultrasound. FDG-PET/CT or CT of the chest and abdomen is usually appropriate for use in initial clinical staging as they provide additional information regarding distant nodal and metastatic disease. The detection of metastatic disease is critical in the initial evaluation of patients with esophageal cancer because it will direct patients to a treatment pathway centered on palliative radiation rather than surgery. For imaging during treatment, particularly neoadjuvant chemotherapy, FDG-PET/CT is usually appropriate, because some studies have found that it can provide information regarding primary lesion response, but more importantly it can be used to detect metastases that have developed since the induction of treatment. For patients who have completed treatment, FDG-PET/CT or CT of the chest and abdomen is usually appropriate for evaluating the presence and extent of metastases in patients with no suspected or known recurrence and in those with a suspected or known recurrence. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Neurodegenerative diseases were mostly perceived as diseases of ageing populations, but now-a-days, these diseases pose a threat to populations of all age groups despite significant improvements in quality of life. Almost all essential oils (EOs) have been reported to have some neuroprotective abilities and have been used as supplements for good mental health over the centuries. This review highlights the therapeutic potential of one such monoterpene phenolic EO, carvacrol (CV), that has the potential to be used as a main therapeutic intervention for neurodegenerative disorders. Three libraries, Google Scholar, PubMed, and ScienceDirect, were explored for research studies related to the neuroprotective roles of CV. All the research articles from these libraries were sorted out, with the first article tracing back to 2009, and the latest article was published in 2024. The positive effects of CV in the treatment of Alzheimer’s and Parkinson’s Diseases, multiple sclerosis, ischemia, and behavioural disorders have been supported with evidence. This review not only focused on study designs and the pharmacological pathways taken by CV for neuroprotection but also focused on demographics, illustrating the trend of CV research studies in certain countries and the preferences for the use of in vitro or in vivo models in studies. Our review provides useful evidence about the neuroprotective potential of CV; however, a lack of studies was observed regarding CV encapsulation in proper dosage forms, in particular nanoparticles, which could be further explored for CV delivery to the central nervous system.

Lipid nanoparticles (LNPs) have shown promise as a delivery system for nucleic acid-based therapeutics, including DNA, siRNA, and mRNA vaccines. The immune system plays a critical role in the response to these nanocarriers, with innate immune cells initiating an early response and adaptive immune cells mediating a more specific reaction, sometimes leading to potential adverse effects. Recent studies have shown that the innate immune response to LNPs is mediated by Toll-like receptors (TLRs) and other pattern recognition receptors (PRRs), which recognize the lipid components of the nanoparticles. This recognition can trigger the activation of inflammatory pathways and the production of cytokines and chemokines, leading to potential adverse effects such as fever, inflammation, and pain at the injection site. On the other hand, the adaptive immune response to LNPs appears to be primarily directed against the protein encoded by the mRNA cargo, with little evidence of an ongoing adaptive immune response to the components of the LNP itself. Understanding the relationship between LNPs and the immune system is critical for the development of safe and effective nucleic acid-based delivery systems. In fact, targeting the immune system is essential to develop effective vaccines, as well as therapies against cancer or infections. There is a lack of research in the literature that has systematically studied the factors that influence the interaction between LNPs and the immune system and further research is needed to better elucidate the mechanisms underlying the immune response to LNPs. In this review, we discuss LNPs’ composition, physico-chemical properties, such as size, shape, and surface charge, and the protein corona formation which can affect the reactivity of the immune system, thus providing a guide for the research on new formulations that could gain a favorable efficacy/safety profile.

PURPOSE: Subset analyses from phase III evaluation of epidermal growth factor receptor inhibition (EGFRi) suggest improved outcomes in patients with EGFR-amplified gastroesophageal adenocarcinoma (GEA), but large-scale analyses are lacking. This multi-institutional analysis sought to determine the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to date. PATIENTS AND METHODS: A total of 60 patients from 15 tertiary cancer centers in six countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing, plasma circulating tumor DNA next-generation sequencing, and/or fluorescence in situ hybridization performed by a Clinical Laboratory Improvement Amendments approved laboratory. Treatment patterns and outcomes analysis was also performed using a deidentified clinicogenomic database (CGDB). RESULTS: Sixty patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52%) with concurrent chemotherapy. Across treatment lines, patients achieved a 43% objective response rate with a median progression-free survival of 4.6 months (95% CI, 3.5 to 6.4). Patients receiving EGFRi in first-, second-, and third-line therapy achieved a median overall survival of 20.6 months (95% CI, 13.5 to not reached [NR]), 9 months (95% CI, 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95% CI, 8.7 to 14.2) median overall survival from first-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011-December 2020) suggests that only 5% of patients with EGFR-amplified GEA received EGFRi. CONCLUSION: Patients with EGFR-amplified GEA derive significant benefit from EGFRi. Further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

Preclinical studies of pro-remyelinating therapies for multiple sclerosis tend to neglect the effect of the disease-relevant inflammatory milieu. Interferon-gamma (IFN-γ) is known to suppress oligodendrocyte progenitor cell (OPC) differentiation and induce a recently described immune OPC (iOPC) phenotype characterized by expression of major histocompatibility complex (MHC) molecules. We tested the effects of cladribine (CDB), dimethylfumarate (DMF), and interferon-beta (IFN-β), existing anti-inflammatory therapies for MS, on the IFN-γ-induced iOPC formation and OPC differentiation block. In line with previous reports, we demonstrate that IFN-β and DMF inhibit OPC proliferation, while CDB had no effect. None of the drugs exhibited cytotoxic effects at the physiological concentrations tested in vitro. In a differentiation assay, none of the drugs were able to promote differentiation, under inflammatory or basal conditions. To study drug effects on iOPCs, we monitored MHC expression in vitro with live cell imaging using cells isolated from MHC reporter mice. IFN-β suppressed induction of MHC class II, and DMF led to suppression of both class I and II. CDB had no effect on MHC induction. We conclude that promoting proliferation and differentiation and suppressing iOPC induction under inflammatory conditions may require separate therapeutic strategies and must be balanced for maximal repair. Our in vitro MHC screening assay can be leveraged across cell types to test the effects of drug candidates and disease-related stimuli.

Loreto virus (LORV) is an insect-specific virus classified into the proposed taxon Negevirus. It was originally described in Iquitos, Peru, in 1977. Here, we describe three novel LORV genomes obtained from the isolates of three pooled samples of Trichoprosopon digitatum, Aedes (Ochlerotatus) fulvus, and Limatus durhamii collected in Ilhéus—Bahia, 2014. Samples were submitted to RNA sequencing on the Illumina platform to recover the LORV genome. The genomes presented, on average, 81.5% nucleotide identity and 92.6% global amino acid identity with the LORV reference genome (NC_034158). Subsequently, phylogenetic analysis was performed based on a multiple sequence alignment of the concatenated amino acid sequences predicted for the three ORFs of the Negevirus genomes, and the target sequences were clustered within the LORV clade. The taxon Negevirus is in constant expansion of its species content and host range. New data about insect specific negeviruses are important for virus evolution studies, along with those approaching interactions with the hosts and their influence in the transmission of arboviruses. Also, the assessment of these data may allow the development of biologic control strategies for arboviral vectors. This is the original report of the identification of LORV in Brazil, infecting three Culicidae species hosts native to the Atlantic Forest biome.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Abstract Background Throughout the COVID-19 pandemic, there was a detrimental impact to the symptoms and treatment of eating disorders, causing an increase in medical admissions and visits. Day treatment programs (DTPs), often used to bridge the gap between inpatient and outpatient treatment, were converted to online formats. This study aims to explore the impact of the transition to virtual DTPs on eating disorder treatment from the perspective of adolescents, their caregivers, and program staff. Methods Twelve participants (3 adolescents, 4 caregivers, 5 healthcare providers) in a virtual day treatment program were interviewed using a semi-structured interview guide. Interviews were transcribed and managed with qualitative software NVivo 11.0. Conventional analysis was used to inductively identify pertinent themes related to patient, caregiver, and healthcare staff perceptions and experiences of the virtual day treatment. Summative content analysis provided counts of the barriers and benefits of virtual day treatment as identified by participants. Results The majority of participants (10/12) had exposure to both virtual and in person settings, most participants (11/12) felt in-person day programs would be superior to virtual programs. Common limitations of the virtual format were feelings of isolation, less support from healthcare providers, parental burnout, and increased disordered eating. Common benefits were increased accessibility, parental involvement, improved communication with healthcare staff, and the ability for participants to be in their home environment and eat home food. Suggestions for improvement included designing a hybrid model of day treatment, increased family involvement, extending the day program to include dinners with family, and screening for patient appropriateness for the virtual setting. Conclusion This qualitative study suggests that there are many barriers to effective implementation of virtual day programs. However, the virtual DTP program offers increased accessibility to patients during a period of a health pandemic and to patients in rural/remote areas with limited treatment options. Suggestions provided by participants in this study, such as increased family involvement, frequency of in person check-ins and increased number of meals supported by the program, may help to improve outcomes in virtual day treatment programs.

Abstract Background The median eating duration in the U.S. is 14.75 h, spread throughout the period of wakefulness and ending before sleep. Food intake at an inappropriate circadian time may lead to adverse metabolic outcomes. Emerging literature suggests that time restricted eating (TRE) may improve glucose tolerance and insulin sensitivity. The aim was to compare 24‐h glucose profiles and insulin sensitivity in participants after completing 12 weeks of a behavioral weight loss intervention based on early TRE plus daily caloric restriction (E‐TRE+DCR) or DCR alone. Methods Eighty‐one adults with overweight or obesity (age 18–50 years, BMI 25–45 kg/m2) were randomized to either E‐TRE+DCR or DCR alone. Each participant wore a continuous glucose monitor (CGM) for 7 days and insulin sensitivity was estimated using the homeostatic model assessment of insulin resistance (HOMA‐IR) at Baseline and Week 12. Changes in CGM‐derived measures and HOMA‐IR from Baseline to Week 12 were assessed within and between groups using random intercept mixed models. Results Forty‐four participants had valid CGM data at both time points, while 38 had valid glucose, insulin, HOMA‐IR, and hemoglobin A1c (A1c) data at both timepoints. There were no significant differences in sex, age, BMI, or the percentage of participants with prediabetes between the groups (28% female, age 39.2 ± 6.9 years, BMI 33.8 ± 5.7 kg/m2, 16% with prediabetes). After adjusting for weight, there were no between‐group differences in changes in overall average sensor glucose, standard deviation of glucose levels, the coefficient of variation of glucose levels, daytime or nighttime average sensor glucose, fasting glucose, insulin, HOMA‐IR, or A1c. However, mean amplitude of glycemic excursions changed differently over time between the two groups, with a greater reduction found in the DCR as compared to E‐TRE+DCR (p = 0.03). Conclusion There were no major differences between E‐TRE+DCR and DCR groups in continuous glucose profiles or insulin sensitivity 12 weeks after the intervention. Because the study sample included participants with normal baseline mean glucose profiles and insulin sensitivity, the ability to detect changes in these outcomes may have been limited.

BackgroundPlatinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA.Materials and methodsWe conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively.ResultsIn 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination.ConclusionFor advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity.Implications for practiceThe rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.

Abstract Background Behavioral weight loss interventions can lead to an average weight loss of 5%–10% of initial body weight, however there is wide individual variability in treatment response. Although built, social, and community food environments can have potential direct and indirect influences on body weight (through their influence on physical activity and energy intake), these environmental factors are rarely considered as predictors of variation in weight loss. Objective Evaluate the association between built, social, and community food environments and changes in weight, moderate‐to‐vigorous physical activity (MVPA), and dietary intake among adults who completed an 18‐month behavioral weight loss intervention. Methods Participants included 93 adults (mean ± SD; 41.5 ± 8.3 years, 34.4 ± 4.2 kg/m2, 82% female, 75% white). Environmental variables included urbanicity, walkability, crime, Neighborhood Deprivation Index (includes 13 social economic status factors), and density of convenience stores, grocery stores, and limited‐service restaurants at the tract level. Linear regressions examined associations between environment and changes in body weight, waist circumference (WC), MVPA (SenseWear device), and dietary intake (3‐day diet records) from baseline to 18 months. Results Grocery store density was inversely associated with change in weight (β = −0.95; p = 0.02; R2 = 0.062) and WC (β = −1.23; p

The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and

Chile’s central-south region has experienced significant land use changes in the past fifty years, affecting native forests, agriculture, and urbanization. This article examines these changes and assesses their impact on native forest cover and agricultural land. Agricultural data for Chile (1980–2020) were obtained from public Chilean institutions (INE and ODEPA). Data on land use changes in central and south Chile (1975–2018), analysed from satellite images, were obtained from indexed papers. Urban area expansion in Chile between 1993 and 2020 was examined using publicly available data from MINVIU, Chile. Additionally, photovoltaic park data was sourced from SEA, Chile. Field crop coverage, primarily in central and southern Chile, decreased from 1,080,000 ha in 1980 to 667,000 ha in 2020, with notable decreases observed in cereal and legume crops. Conversely, the coverage of export-oriented orchards and vineyards increased from 194,947 ha to 492,587 ha. Forest plantations expanded significantly, ranging from 18% per decade in northern central Chile to 246% in the Maule and Biobío regions. This was accompanied by a 12.7–27.0% reduction per 10 years in native forest. Urban areas have experienced significant growth of 91% in the last 27 years, concentrated in the Mediterranean climate region. Solar photovoltaic parks have begun to increasingly replace thorn scrub (Espinal) and agricultural land, mirroring transformations seen in other Mediterranean nations like Spain and Portugal.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

PurposeTo evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA).Patients and methodsFPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer.ResultsSeventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of ≥ 10 mg/kg every 2 weeks for ≥ 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade ≥ 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response.ConclusionOverall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA.

BackgroundIsocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma.MethodsThis multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with ClinicalTrials.gov, NCT02989857.FindingsBetween Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6·9 months (IQR 2·8-10·9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2·7 months [95% CI 1·6-4·2] vs 1·4 months [1·4-1·6]; hazard ratio 0·37; 95% CI 0·25-0·54; one-sided p

PurposeTepotinib is an oral, potent, highly selective MET inhibitor. This first-in-man phase I trial investigated the MTD of tepotinib to determine the recommended phase II dose (RP2D).Patients and methodsPatients received tepotinib orally according to one of three dose escalation regimens (R) on a 21-day cycle: R1, 30-400 mg once daily for 14 days; R2, 30-315 mg once daily 3 times/week; or R3, 300-1,400 mg once daily. After two cycles, treatment could continue in patients with stable disease until disease progression or unacceptable toxicity. The primary endpoint was incidence of dose-limiting toxicity (DLT) and treatment-emergent adverse events (TEAE). Secondary endpoints included safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor effects.ResultsOne hundred and forty-nine patients received tepotinib (R1: n = 42; R2: n = 45; R3: n = 62). Although six patients reported DLTs [one patient in R1 (115 mg), three patients in R2 (60, 100, 130 mg), two patients in R3 (1,000, 1,400 mg)], the MTD was not reached at the highest tested dose of 1,400 mg daily. The RP2D of tepotinib was established as 500 mg once daily, supported by translational modeling data as sufficient to achieve ≥95% MET inhibition in ≥90% of patients. Treatment-related TEAEs were mostly grade 1 or 2 fatigue, peripheral edema, decreased appetite, nausea, vomiting, and lipase increase. The best overall response in R3 was partial response in two patients, both with MET overexpression.ConclusionsTepotinib was well tolerated with clinical activity in MET-dysregulated tumors. The RP2D of tepotinib was established as 500 mg once daily. MET abnormalities can drive tumorigenesis. This first-in-man trial demonstrated that the potent, highly selective MET inhibitor tepotinib can reduce or stabilize tumor burden and is well tolerated at doses up to 1,400 mg once daily. An RP2D of 500 mg once daily, as determined from translational modeling and simulation integrating human population pharmacokinetic and pharmacodynamic data in tumor biopsies, is being used in ongoing clinical trials.

PurposeThis randomized, multicenter, open-label, phase Ib/II study assessed durvalumab and tremelimumab in combination or as monotherapy for chemotherapy-refractory gastric cancer or gastroesophageal junction (GEJ) cancer.Patients and methodsSecond-line patients were randomized 2:2:1 to receive durvalumab plus tremelimumab (arm A), or durvalumab (arm B) or tremelimumab monotherapy (arm C), and third-line patients received durvalumab plus tremelimumab (arm D). A tumor-based IFNγ gene signature was prospectively evaluated as a potential predictive biomarker in second- and third-line patients receiving the combination (arm E). The coprimary endpoints were objective response rate and progression-free survival (PFS) rate at 6 months.ResultsA total of 113 patients were treated: 6 in phase Ib and 107 (arm A, 27; arm B, 24; arm C, 12; arm D, 25; arm E, 19) in phase II. Overall response rates were 7.4%, 0%, 8.3%, 4.0%, and 15.8% in the five arms, respectively. PFS rates at 6 months were 6.1%, 0%, 20%, 15%, and 0%, and 12-month overall survival rates were 37.0%, 4.6%, 22.9%, 38.8%, and NA, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 4%, 42%, 16%, and 11% of patients, respectively.ConclusionsResponse rates were low regardless of monotherapy or combination strategies. No new safety signals were identified. Including use of a tumor-based IFNγ signature and change in baseline and on-treatment circulating tumor DNA are clinically feasible and may be novel strategies to improve treatment response in this difficult-to-treat population.

The use, misuse, and overuse of antimicrobials is one of the main public health threats of the 21st century. We investigated the risk factor of the presence of extended-spectrum, cephalosporin-resistant Enterobacterales in feces of non-domestic and domestic birds and other domestic animals in Piauí State, northeast Brazil. We collected a total of 387 cloacal and rectal swab samples of free-living birds, domestic birds, and domestic mammals in five municipalities: Amarante, Água Branca, Lagoa Alegre, Parnaíba, and Teresina. A total of 59/387 (15.2%) of these samples harbored extended spectrum beta-lactamase (ESBL)-producing Enterobacterales. Using the MALDI-TOF technique, we identified fifty-seven samples as Escherichia coli and two samples as Klebsiella pneumoniae. Teresina and Parnaíba had the highest prevalence of animals with resistant bacteria (32.1% and 27.1%, respectively) and highest exposure risk factor (OR of 16.06 and 8.58, respectively, and p < 0.001 for all). Multidrug-resistant, ESBL-producing Enterobacterales were observed in 72.8% of the samples (43/59). For the free-living birds, the positive samples belonged to a great kiskadee (Pitangus sulphuratus) and a semipalmated sandpiper (Calidris pusilla) in migratory and resident species, respectively. For domestic animals, the swine samples showed the highest prevalence of antimicrobial resistance. The lack of access to veterinary care and information regarding antimicrobial therapy, along with the easy access to antimicrobials without medical prescription, favors the inadequate use of antimicrobials in Piauí.