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Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. One of the best established CLL prognostic markers is the somatic hypermutational status of the IGHVgene which is a part of the immunoglobulin heavy chain variable region. Technology for IGHV genotyping has been optimized and has been applied in routine diagnostics for the first time in Bulgaria. A total of 105 patients with CLL from different Bulgarian regions were tested. IGHV mutational status was determined by Sanger sequencing on total genomic DNA (gDNA) or RNA extracted from mononuclear cells. All sequencing profiles were analyzed with the IMGT/V-QUEST tool. Within the course of the analysis a high percentage of IGHV unmutated status was established in the Varna district on the Black Sea (Northeast Bulgaria). In addition, the IGHV genotyping performed on gDNA revealed a rare case with multiple rearrangements. The present data from IGHV genotyping will help in choosing the proper treatment for the benefit of Bulgarian CLL patients.

The ESA/JAXA BepiColombo mission is currently on its way to Mercury, aiming to unveil the secrets held by the innermost planet of the Solar System. The radio tracking measurements, in combination with the data acquired by the onboard accelerometer, will enable a precise navigation of the spacecraft addressing the scientific objectives of the mission. A series of planetary flybys are required during the interplanetary transfer orbit to save propellant for the orbital insertion around Mercury. We present here a joint analysis of the radio tracking and accelerometer measurements collected during the second Venus flyby and the first two Mercury flybys. A precise orbit determination process is carried out to yield a combined adjustment of the spacecraft trajectory and parameters associated with dynamical and observational modeling. The accelerometer data enabled the detection of unmodeled dynamical perturbations including outgassing and thermal recoil. Our analysis of Mercury flybys allowed us for the first time to combine BepiColombo and MErcury Surface, Space ENvironment, GEochemistry, and Ranging (MESSENGER) radiometric measurements, leading to significant improvements in the modeling of the gravitational forces.

Soil organic carbon (SOC) plays a vital role in global carbon cycling and sequestration, underpinning the need for a comprehensive understanding of its distribution and controls. This study explores the importance of various covariates on SOC spatial distribution at both local (up to 1.25 km) and continental (USA) scales using a deep learning approach. Our findings highlight the significant role of terrain attributes in predicting SOC concentration distribution with terrain, contributing approximately one-third of the overall prediction at the local scale. At the continental scale, climate is only 1.2 times more important than terrain in predicting SOC distribution, whereas at the local scale, the structural pattern of terrain is 14 and 2 times more important than climate and vegetation, respectively. We underscore that terrain attributes, while being integral to the SOC distribution at all scales, are stronger predictors at the local scale with explicit spatial arrangement information. While this observational study does not assess causal mechanisms, our analysis nonetheless presents a nuanced perspective about SOC spatial distribution, which suggests disparate predictors of SOC at local and continental scales. The insights gained from this study have implications for improved SOC mapping, decision support tools, and land management strategies, aiding in the development of effective carbon sequestration initiatives and enhancing climate mitigation efforts.

ABSTRACTIntroductionThe treatment landscape of non-small cell lung cancer (NSCLC) has seen significant advancements in recent years, marked by a shift toward target agents and immune checkpoint inhibitors (ICIs). However, chemotherapy remains a cornerstone of treatment, alone or in combination. Microtubule-targeting agents, such as taxanes and vinca alkaloids, play a crucial role in clinical practice in both early and advanced settings in NSCLC.Area coveredThis review outlines the mechanisms of action, present significance, and prospective advancements of microtubule-targeting agents (MTAs), with a special highlight on new combinations in phase 3 trials. The online databases PubMed, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched using the terms ‘Microtubule-targeting agents’ and ‘non-small cell lung cancer’ or synonyms, with a special focus over the last 5 years of publications.Expert opinionDespite the emergence of immunotherapy, MTA remains crucial, often used alongside or after immunotherapy, especially in squamous cell lung cancer. Next-generation sequencing expands treatment options, but reliable biomarkers for immunotherapy are lacking. While antibody-drug conjugates (ADCs) show promise, managing toxicities remain vital. In the early stages, MTAs, possibly with ICIs, are standard, while ADCs may replace traditional chemotherapy in the advanced stages. Nevertheless, MTAs remain essential in subsequent lines or for patients with contraindications.

The NFKBIEgene, which encodes the NF-κB inhibitor IκBε, is mutated in 3–7% of patients with chronic lymphocytic leukemia (CLL). The most recurrent alteration is a 4-bp frameshift deletion associated with NF-κB activation in leukemic B cells and poor clinical outcome. To study the functional consequences of NFKBIEgene inactivation, both in vitro and in vivo, we engineered CLL B cells and CLL-prone mice to stably down-regulate NFKBIEexpression and investigated its role in controlling NF-κB activity and disease expansion. We found that IκBε loss leads to NF-κB pathway activation and promotes both migration and proliferation of CLL cells in a dose-dependent manner. Importantly, NFKBIEinactivation was sufficient to induce a more rapid expansion of the CLL clone in lymphoid organs and contributed to the development of an aggressive disease with a shortened survival in both xenografts and genetically modified mice. IκBε deficiency was associated with an alteration of the MAPK pathway, also confirmed by RNA-sequencing in NFKBIE-mutated patient samples, and resistance to the BTK inhibitor ibrutinib. In summary, our work underscores the multimodal relevance of the NF-κB pathway in CLL and paves the way to translate these findings into novel therapeutic options.

Purpose: Immune checkpoint inhibitors (ICPIs) disrupting PD-1/PD-L1 axis have revolutionized the management of advanced non-small cell lung cancer (NSCLC). Some studies identified the development of endocrine toxicity as predictor of better survival in cancer patients treated with ICPIs. The aim of study was to evaluate survival and new onset of immune-related endocrine adverse events (irAEs) in patients treated with nivolumab for advanced NSCLC. Methods: In a prospective study, 73 patients with previously treated advanced NSCLC received nivolumab in monotherapy. Blood samples were collected at each cycle to monitor thyroid autoimmunity, thyroid, adrenal and somatotroph axes, while thyroid morphology was evaluated by ultrasonography. Results: An impaired thyroid function was recorded in 23.4% of patients (n= 15). Eight patients developed asymptomatic transient thyrotoxicosis (ATT) evolving to hypothyroidism in 50% of cases. In addition, seven patients developed overt hypothyroidism without ATT and with negative autoantibodies. Patients who developed hypothyroidism proved to have better overall survival (OS) as compared with non-developers at both univariate (p= 0.021) and multivariate analyses (p= 0.023). The survival curve of patients with reduced IGF-I at baseline, or displaying its reduction during the follow-up, showed significantly reduced median survival compared to patients with normal/high IGF-I levels (p= 0.031). Conclusions: Thyroid function abnormalities are the major irAEs in patients treated with nivolumab, and hypothyroidism onset is associated with prolonged survival. Our findings indicate that the development of hypothyroidism is a positive predictive biomarker of nivolumab antitumor efficacy in patients with NSCLC. Low IGF-I levels could represent a negative prognostic factor during nivolumab therapy.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that—in the case of the interdependent tumor cell morphology and adapted immune response—reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

IntroductionThe epidemiological surveillance of mesothelioma incidence is a crucial key for investigating the occupational and environmental sources of asbestos exposure. The median age at diagnosis is generally high, according to the long latency of the disease. The purposes of this study are to analyse the incidence of mesothelioma in young people and to evaluate the modalities of asbestos exposure.MethodsIncident malignant mesothelioma (MM) cases in the period 1993–2018 were retrieved from Italian national mesothelioma registry and analysed for gender, incidence period, morphology and exposure. Age-standardised rates have been calculated and the multiple correspondence analysis has been performed. The association between age and asbestos exposure has been tested by χ2test.ResultsFrom 1993 to 2018, 30 828 incident MM cases have been collected and 1278 (4.1%) presented diagnosis at early age (≤50 years). There is a substantial association between age at diagnosis and the type of asbestos exposure and a significantly lower frequency of cases with occupational exposure to asbestos (497 cases vs 701 expected) in young people has been documented. Paraoccupational and environmental exposure to asbestos have been found more frequent in young MM cases (85 and 93 observed cases vs 52 and 44 expected cases, respectively).ConclusionsMesothelioma incidence surveillance at population level and the anamnestic individual research of asbestos exposure is a fundamental tool for monitoring asbestos exposure health effects, supporting the exposure risks prevention policies. Clusters of mesothelioma incident cases in young people are a significant signal of a potential non-occupational exposure to asbestos.

AbstractPolymorphisms in the genes of drug-metabolizing enzymes have the potential to contribute to inter-individual differences in drug pharmacokinetics and toxicity. A custom next-generation sequencing (NGS) panel was used in 71 kidney transplanted patients to study the polymorphisms of 11 genes relevant to the metabolism of immunosuppressive drugs. Cyclosporine A and tacrolimus concentrations were determined by a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. More than 1000 polymorphisms were found in the studied 11 genes, and 45% of them were different non-synonymous variants. Eleven missense mutations were observed in the CYP3A7 gene, resulting in increased metabolism of tacrolimus at day 21 post-transplantation (6.7 µg/L vs. 10.3 µg/L; p = 0.048). Two alleles encoding a cytochrome P450 2D6 enzyme with impaired function—CYP2D6*4(non-functional) and CYP2D6*10(decreased function), were found in the studied group and both of them were associated with higher levels of tacrolimus at day 14 (10.1 µg/L; p = 0.021 and 9.7 µg/L; p = 0.036, vs. 7.7 µg/L respectively). Altered function of ABC transporters C3 and C2 was also associated with increased TAC concentration. ABCC3 significantly influenced TAC metabolism by itself, but polymorphisms affecting both ABCC3 and ABCC2 resulted in higher changes: 13.6 µg/L vs. 7.9 µg/L, day 14 (p = 0.003) and 20 µg/L versus 9.3 µg/L, day 21 (p = 0.019). All associations were also checked for variants affecting the activity of CYP3A4 and CYP3A5. Despite its small size, the study points out that the pharmacogenetics of calcineurin inhibitors may also be influenced by other genes besides CYP3A4 and CYP3A5.

ABSTRACTIntroductionIn recent years, immunotherapy has become a pillar in the treatment of advanced, non-oncogene-addicted non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-L1) expression is currently the only factor used to predict response to immunotherapy in clinical practice. Specifically, single-agent pembrolizumab as first-line therapy is approved for tumors with high expression of PD-L1 (≥50%) while immunotherapy and chemotherapy are approved for any PD-L1. However, combinations of immune-checkpoint inhibitors (ICIs) and other agents may confer higher benefit than immunotherapy alone in some circumstances.Areas coveredWe reviewed the available data regarding the combined use of ICIs and chemotherapy in patients with advanced, treatment-naïve NSCLC. In light of the benefit demonstrated in advanced disease, these combinations have been subsequently tested in other settings. We collected the most relevant findings regarding efficacy and safety of chemo-immunotherapy combinations in early and locally advanced NSCLC.Expert opinionImmune-chemotherapy combinations demonstrated benefit in the advanced setting, and this strategy in now being applied in the early and local advanced settings. A description of clinical and biological predictors of response is required in order to identify patients who may benefit the most from combination therapy.

Abstract:This article proposes a rethinking of the operations of surfaces, using the concept of ‘recursion’ to explore surfaces as not only spatial, but also temporal objects engaged in the production of continuity and rupture through time. The text engages with the transformation of a specific high relief at the Monument to the Soviet Army in Sofia, which in the past decade has been subjected to a series of material and semiotic modifications. The analysis of interventions on the relief created between 2011-2018 stimulates an engagement with a set of questions pertaining to the way in which surfaces are engaged in the production of temporal continuity and rupture. To achieve a theoretical intervention in monument, visual and urban studies, the article mobilises cultural topology and media theory, alongside scholarship dealing with Bulgarian post-communist urban space and politics.

Patients with cancer and acute ischemic stroke (AIS) face high rates of recurrent thromboembolism or death. To examine whether hematologic and embolic biomarkers soon after AIS are associated with subsequent adverse clinical outcomes. We prospectively enrolled 50 adults with active solid tumor cancer and AIS at two hospitals from 2016 to 2020. Blood was collected 72–120 h after stroke onset. A 30‐min transcranial Doppler (TCD) microemboli detection study was performed. The exposure variables were hematologic markers of coagulation (D‐dimer, thrombin‐antithrombin), platelet (P‐selectin), and endothelial activation (thrombomodulin, soluble intercellular adhesion molecule‐1 [sICAM‐1], soluble vascular cell adhesion molecule‐1 [sVCAM‐1]), and the presence of TCD microemboli. The primary outcome was a composite of recurrent arterial/venous thromboembolism or death. We used Cox regression to evaluate associations between biomarkers and subsequent outcomes. During an estimated median follow‐up time of 48 days (IQR, 18–312), 43 (86%) participants developed recurrent thromboembolism or death, including 28 (56%) with recurrent thromboembolism, of which 13 were recurrent AIS (26%). In unadjusted analysis, D‐dimer (HR 1.6; 95% CI 1.2–2.0), P‐selectin (HR 1.9; 95% CI 1.4–2.7), sICAM‐1 (HR 2.2; 95% CI 1.6–3.1), sVCAM‐1 (HR 1.6; 95% CI 1.2–2.1), and microemboli (HR 2.2; 95% CI 1.1–4.5) were associated with the primary outcome, whereas thrombin‐antithrombin and thrombomodulin were not. D‐dimer was the only marker associated with recurrent AIS (HR 1.2; 95% CI 1.0–1.5). Results were generally consistent in analyses adjusted for important prognostic variables. Markers of hypercoagulability and embolic disease may be associated with adverse clinical outcomes in cancer‐related stroke.

Patients with cancer and acute ischemic stroke (AIS) face high rates of recurrent thromboembolism or death.

Reliable composite forming experiments are required to characterize composite formability, to aid material development, and to validate process simulations models. Due to practical reasons, however, typically a limited amount of forming configurations is studied. The objective of this study is, therefore, to develop a methodology for obtaining controlled forming results in a wide range of configurations. Press forming experiments using a dome geometry were used to explore the formability of two commercial unidirectional thermoplastic composite materials. A variety of forming configurations was employed by changing the blank dimensions and layup. The observation of wrinkling defects was simplified by leaving an additional 3 mm tool gap. Blank width and layup had the most influence on the wrinkling severity, followed by blank thickness and length. Quasi-isotropic layups were found to produce wrinkles in nearly all cases, confirming a difficulty in general to form double curved parts. The size and number of wrinkles in these layups were found to change with the stacking sequence. Cross-ply layups showed better formability, but significant wrinkles were still observed depending on the orientation of the blank relative to the layup. The formability experiments using a dome geometry provided a reliable methodology for controlled forming results in many configurations using a generic toolset. Additionally, a comprehensive comparison of formability for two commercial thermoplastic UD materials in a variety of scenarios was provided.

Two-year mortality in patients with COPD is expected to be between 10% and 49% depending on the investigated subgroup and specific patients’ characteristics.

This paper presents an empirical analysis aimed at identifying chain migration patterns among university students from Sicily, Sardinia, and Apulia. Utilizing data from the national archive of university students enrolled in an Italian university from 2008 to 2017, we construct origin–destination matrixes and calculate residuals from a log-linear model to detect key student routes. Positive residuals between specific origin–destination pairs that persist over time can suggest significant attraction and potential chain migration. The results support a “large to large” and “small to small” city mobility model, particularly for Sicily and Sardinia. Students from Palermo, Catania, Messina, and Cagliari show strong connections with large cities such as Rome and Milan. Furthermore, results show historical links between Sardinia and Tuscany date back to the 1950s, and the enduring connections between Apulian students and universities in Emilia-Romagna, Veneto, and Lombardy have been evident since the 1970s. In Sicily, mobility patterns towards the Polytechnic of Turin began in the 1970s and persist today. These patterns underscore the influence of prior migrants on the mobility decisions of university students in Southern Italy, highlighting a potential chain migration effect.

Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1(feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1ain mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

We report the first calorimetric observation of the glass transition for a carbonate melt. A carbonate glass [55K2CO3–45MgCO3(molar)] was quenched from 780 °C at 0.1 GPa. The activation energy of structural relaxation close to the glass transition was derived through a series of thermal treatments comprising excursions across the glass transition at different heating rates. Viscosities just above the glass transition temperature were obtained by applying a shift factor to the calorimetric results. These viscosity measurements (in the range of 109Pa·s) at supercooled temperatures (ca. 230 °C) dramatically extend the temperature range of data for carbonates, which were previously restricted to superliquidus viscosities well below 1 Pa·s. Combining our calorimetrically derived results with published alkaline-earth carbonate melt viscosities at high temperatures yields a highly non-Arrhenian viscosity-temperature relationship and confirms that carbonate liquids are “fragile.” Based on simulations, fragile behavior is also exhibited by Na2CO3melt. In both cases, the fragility presumably relates to the formation of temperature-dependent low-dimensional structures and Vogel-Fulcher-Tammann (VFT) curves adequately describe the viscosity-temperature relationships of carbonate melts below 1000 °C.

Background: Although minimally invasive rectal surgery (MIRS) for cancer provides better recovery for similar oncologic outcomes over open approach, conversion is still required in 10% and its impact on short-term and long-term outcomes remains unclear. The aim of our study was to evaluate the impact of conversion on postoperative and oncologic outcomes in patients undergoing MIRS for cancer. Methods: From June 2011 to March 2020, we reviewed 257 minimally invasive rectal resections for cancer recorded in a prospectively maintained database, with 192 robotic and 65 laparoscopic approaches. Patients who required conversion to open (Conversion group) were compared to those who did not have conversion (No conversion group) in terms of short-term, histologic, and oncologic outcomes. Univariate and multivariate analyses of the risk factors for postoperative morbidity were performed. Results: Eighteen patients (7%) required conversion. The conversion rate was significantly higher in the laparoscopic approach than in the robotic approach (16.9% vs 3.6%, p< 0.01). Among the 4 reactive conversions, 3 (75%) were required during robotic resections. Patients in the Conversion group had a higher morbidity rate (83.3% vs 43.1%, p= 0.01) and more severe complications (38.9%, vs 18.8%, p= 0.041). Male sex [HR = 2.46, 95%CI (1.41–4.26)], total mesorectal excision [HR = 2.89, 95%CI (1.57–5.320)], and conversion (HR = 4.87, 95%CI [1.34–17.73]) were independently associated with a higher risk of overall 30-day morbidity. R1 resections were more frequent in the Conversion group (22.2% vs 5.4%, p= 0.023) without differences in the overall (82.7 ± 7.0 months vs 79.4 ± 3.3 months, p= 0.448) and disease-free survivals (49.0 ± 8.6 months vs 70.2 ± 4.1 months, p= 0.362). Conclusion: Conversion to laparotomy during MIRS for cancer was associated with poorer postoperative results without impairing oncologic outcomes. The high frequency of reactive conversion due to intraoperative complications in robotic resections confirmed that MIRS for cancer is a technically challenging procedure.

Purpose: This study aims to investigate the food choice motivations of rural households using a cross-sectional dataset of 510 households from northwest Vietnam interviewed in 2016. Design/methodology/approach: A modified Food Choice Questionnaire (FCQ) is used to assess factors related to food choice and explore relationships between food choice factors, diet quality and various sociodemographic characteristics. Findings: Results show four distinct food choice factors: “Natural and healthy,” “Familiarity,” “Balanced diet” and “Convenience.” Two distinct consumer clusters are identified: “Health-conscious” households and “Pragmatic” households. “Health-conscious” households rank “Balanced diet” and “Natural and healthy” highly, while “Pragmatic” households prioritize “Convenience” and “Familiarity.” “Health-conscious” households have significantly more diverse diets, are wealthier and have a greater geographic concentration in the high vegetable density per capita-high elevation areas (36%). Their main food preparers are more educated and about 13% have Kinh ethnicity. Research limitations/implications: Further research is warranted to explore the temporal dimension of parental food choice motivations given the changing agrifood system in Vietnam. Originality/value: This study is one of the few studies that assess the food choice motivations among ethnic minority groups in a rural setting.

The microtubule cytoskeleton forms complex macromolecular assemblies with a range of microtubule-associated proteins (MAPs) that have fundamental roles in cell architecture, division and motility. Determining how an individual MAP modulates microtubule behaviour is an important step in understanding the physiological roles of various microtubule assemblies. To characterize how MAPs control microtubule properties and functions, we developed an approach allowing for medium-throughput analyses of MAPs in cell-free conditions using lysates of mammalian cells. Our pipeline allows for quantitative as well as ultrastructural analyses of microtubule–MAP assemblies. Analysing 45 bona fide and potential mammalian MAPs, we uncovered previously unknown activities that lead to distinct and unique microtubule behaviours such as microtubule coiling or hook formation, or liquid–liquid phase separation along the microtubule lattice that initiates microtubule branching. We have thus established a powerful tool for a thorough characterization of a wide range of MAPs and MAP variants, thus opening avenues for the determination of mechanisms underlying their physiological roles and pathological implications.

Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission relative to placebo in patients with moderately to severely active ulcerative colitis. The HIBISCUS studies aimed to compare the efficacy and safety of etrolizumab to adalimumab and placebo for induction of remission in patients with moderately to severely active ulcerative colitis.

IMPORTANCE: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. OBJECTIVE: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer. DESIGN, SETTING, AND PARTICIPANTS: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. MAIN OUTCOMES AND MEASURES: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. RESULTS: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti–programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non–small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008). CONCLUSIONS AND RELEVANCE: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.