Skeletal-Related Events in Patients With Multiple Myeloma: A Comprehensive Retrospective Cohort Study.

BACKGROUND: Multiple myeloma (MM) patients are at risk of skeletal-related events (SREs) like spinal cord compression, pathologic fractures, bone surgery, and radiation to bone. Real-world data regarding SREs in MM are limited. METHODS: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service (HIRA) database from 2007 to 2018. RESULTS: Over a 12-year study period, we identified 6,717 patients who developed symptomatic MM. After a median follow-up of 35.1 months (interquartile range [IQR], 20.8-58.2 months), 43.6% of these patients experienced SREs, and 39.6% had four or more SREs. One in five patients (20.0%) experienced pathologic fractures within the first year of follow-up. The median time to first SRE was 9.6 months (IQR, 1.2-25.8 months), with 3.0 months in the group with prior SREs and 19.8 months in the group without prior SREs. During follow-up, 78.5% of patients received bisphosphonates. Multiple logistic regression analysis revealed several factors associated with an increased risk of SREs, including being female (odds ratio [OR], 1.44), aged 50 or older (OR, 1.87), having cerebrovascular disease (OR, 1.34), undergoing first-line chemotherapy regimens not containing bortezomib or lenalidomide (OR, 1.49), and being in the group with prior SREs and bisphosphonate use (OR, 5.63), compared to the group without prior SREs and without bisphosphonate use. CONCLUSION: This population-based study is the first to report the incidence and risk factors of SREs in Korean MM patients, which can be used to assess their bone health.

Incidence of Venous Thromboembolism: The 3rd Korean Nationwide Study.

BACKGROUND: The incidence of venous thromboembolism (VTE) has gradually increased in the Korean population. This study aimed to evaluate the annual age- and sex-adjusted incidence rates (ASR) of VTE and anticoagulation trends between 2014 and 2018. METHODS: Using the Korean Health Insurance Review and Assessment Service database, we retrospectively identified VTE patients between 2014 and 2018 using both diagnostic and medication anticoagulant codes assigned within 6 months of the initial index event. Anticoagulant patterns were classified as follows: direct oral anticoagulants (DOAC), parenteral anticoagulants, warfarin, and mixed anticoagulation regimens. RESULTS: We identified 95,205 patients with VTE (female, 56.8%). The ASR for VTE per 100,000 person-years increased from 32.8 in 2014 to 53.7 cases in 2018 (relative risk of 1.63; 95% confidence interval, 1.6-1.67). The VTE incidence rates were 25 times higher in the ≥ 80 group than in the 30s group. VTE occurred 1.29 times more often in women than in men. The proportion of DOAC prescriptions increased from 40.5% to 72.8%, whereas warfarin prescriptions decreased from 27% to 5.6% in 2014 and 2018. CONCLUSION: In Korea, the ASRs of VTE continued to increase since 2014, but the rate of increase slowed in 2018. The VTE occurred more often in the elderly and in women. Five years after the introduction of DOACs in 2013, they accounted for 73% of all anticoagulants used to treat VTE.

Evaluation of the need for cytoreduction and its potential carcinogenicity in children and young adults with myeloproliferative neoplasms.

Myeloproliferative neoplasms are rare at a young age, and few reports have described the disease characteristics and outcomes in this group. This study aimed to elucidate the clinical course of essential thrombocythemia (ET) and polycythemia vera (PV) in children and young adults aged <39 years focusing on thromboembolic events (TE) and second primary malignancies (SPMs). A total of 990 patients who were diagnosed from 2008 to 2017 were included by analyzing the Health Insurance Review and Assessment Service database in Korea. The incidence was 2.53 per 1,000,000 for ET (643 patients; 276 male patients; median 31 years) and 1.37 per 1,000,000 for PV (347 patients; 309 male patients; median 32 years). Three ET patients developed secondary acute myelogenous leukemia and three developed secondary myelofibrosis. The 5-year cumulative incidence of TE was 14.2% in ET and 21.3% in PV. Thus, the incidence was higher in PV; in particular, arterial TE (ATE) was evidently higher in PV than in ET. The 5-year cumulative incidence of SPMs was 2.5% in ET and 2.6% in PV. While the use of both aspirin and hydroxyurea reduced the incidence of ATE, hydroxyurea significantly increased the incidence of SPMs. The incidence of ET and PV was very low, and ET was more common than PV in children and young adults. The high incidence of TE in young patients suggests the importance of thrombosis prevention. However, hydroxyurea appears to increase the incidence of SPMs; therefore, the risks and benefits should be considered.

Early-Life Stress Modulates Gut Microbiota and Peripheral and Central Inflammation in a Sex-Dependent Manner.

Recent studies have reported that changes in gut microbiota composition could induce neuropsychiatric problems. In this study, we investigated alterations in gut microbiota induced by early-life stress (ELS) in rats subjected to maternal separation (MS; 6 h a day, postnatal days (PNDs) 1-21), along with changes in inflammatory cytokines and tryptophan-kynurenine (TRP-KYN) metabolism, and assessed the differences between sexes. High-throughput sequencing of the bacterial 16S rRNA gene showed that the relative abundance of the Bacteroides genus was increased and that of the Lachnospiraceae family was decreased in the feces of MS rats of both sexes (PND 56). By comparison, MS increased the relative abundance of the Streptococcus genus and decreased that of the Staphylococcus genus only in males, whereas the abundance of the Sporobacter genus was enhanced and that of the Mucispirillum genus was reduced by MS only in females. In addition, the levels of proinflammatory cytokines were increased in the colons (IFN-γ and IL-6) and sera (IL-1ß) of the male MS rats, together with the elevation of the KYN/TRP ratio in the sera, but not in females. In the hippocampus, MS elevated the level of IL-1ß and the KYN/TRP ratio in both male and female rats. These results indicate that MS induces peripheral and central inflammation and TRP-KYN metabolism in a sex-dependent manner, together with sex-specific changes in gut microbes.

Retinal VEGFA maintains the ultrastructure and function of choriocapillaris by preserving the endothelial PLVAP.

Fenestrations in choriocapillaris act as a window for molecular transports between the retina and choroid, and is crucial for maintaining visual function. Plasmalemma vesicle-associated protein (PLVAP) is essential for the development of endothelial fenestrations. There is little knowledge about how the choriocapillaris maintains the fenestrated endothelium. This study aimed to evaluate the role of vascular endothelial growth factor-A (VEGFA)-PLVAP axis in the maintenance of choroidal fenestrations using oxygen-induced retinopathy (OIR) model. In C57BL/6 J mice, the mice with OIR on postnatal day 12 (P12) presented thicker endothelium and less fenestration compared to the non-OIR mice. However, the OIR on 17 mice showed thinner endothelium with more fenestration compared to OIR on P12. In vivo angiography demonstrated the presence of hyperpermeable choroidal vessels on P17 in OIR mice. These dramatic changes in choriocapillaris were not observed in the BALB/cJ OIR model. The ultrastructural changes in the choriocapillaris were correlated with temporal variations in the expression of VEGFA and PLVAP. VEGFA stimulated expression of PLVAP in the choroidal endothelial cells. Loss of PLVAP disrupts the polarized structure of the choriocapillaris leading to retinal degeneration. These results indicate that the expression of retinal VEGFA is essential for maintaining the structure and function of choriocapillaris by preserving the endothelial PLVAP.

Alpha-Smooth Muscle Actin-Positive Perivascular Cells in Diabetic Retina and Choroid.

Structural alterations of pericytes in microvessels are important features of diabetic retinopathy. Although capillary pericytes had been known not to have α-smooth muscle actin (αSMA), a recent study revealed that a specific fixation method enabled the visualization of αSMA along retinal capillaries. In this study, we applied snap-fixation in wild type and streptozotocin-induced diabetic mice to evaluate the differences in vascular smooth muscle cells of the retina and the choroid. Mice eyeballs were fixed in ice-cold methanol to prevent the depolymerization of filamentous actin. Snap-fixated retina showed αSMA expression in higher-order branches along the capillaries as well as the arterioles and venules, which were not detected by paraformaldehyde fixation. In contrast, most choriocapillaris, except those close to the arterioles, were not covered with αSMA-positive perivascular mural cells. Large choroidal vessels were covered with more αSMA-positive cells in the snap-fixated eyes. Diabetes induced less coverage of αSMA-positive perivascular mural cells overall, but they reached higher-order branches of the retinal capillaries, which was prominent in the aged mice. More αSMA-positive pericytes were observed in the choroid of diabetic mice, but the αSMA-positive expression reduced with aging. This study suggests the potential role of smooth muscle cells in the pathogenesis of age-related diabetic retinopathy and choroidopathy.

Utility of allogeneic hematopoietic stem cell transplantation using international donors in a homogenous ethnic population: question in the era of various alternative donors.

The advent of various alternative donors in allogeneic hematopoietic stem cell transplantation (HSCT) raises the question of using international donors, especially in ethnically homogenous populations. We analyzed the clinical outcome and medical expense of human leukocyte antigen (HLA)-matched HSCT using domestic and international donors. We analyzed the patients who received allogeneic HSCT at five medical centers in Korea in the last 10 years. Using propensity-score matching, we compared overall survival (OS), relapse-free survival (RFS), and transplantation-related complications. Medical expense was analyzed based on National Health Insurance Service (NHIS) data. A total of 269 patients were analyzed after 3:1 (domestic/international) matching. There was no difference in OS (p = 0.395) and RFS (p = 0.604) between the domestic and international donor groups (5-year OS rate 42.9 and 37.8%, 5-year RFS rate 37.6 and 33.5% for domestic and international groups, respectively). No difference in chronic graft-versus-host disease (GVHD) incidence was observed (34.2% in domestic and 35.9% in international group, p = 0.804). Early infection was more frequent in the domestic group (55.0 vs. 35.8%, p = 0.007), whereas infection after 30 days was more frequent in the international group (28.7 vs. 49.3%, p = 0.001). Mean medical expense was far higher in the international group, by US $51,944 in the entire follow-up period (p < 0.001). We would expect similar outcomes for international and domestic donors in terms of survival and treatment-related complications with HLA-matched HSCT in other ethnically homogenous populations. These findings should be considered together with the high cost of using international donors in the era of various alternative donors.

Current Management of Cancer-associated Venous Thromboembolism: Focus on Direct Oral Anticoagulants.

Cancer-associated venous thromboembolism (CAT) is a common complication associated with high morbidity and mortality. In accordance with major clinical trials comparing low-molecular-weight heparin (LMWH) with a vitamin K antagonist (VKA), LMWH is currently the standard treatment for CAT, owing to its efficacy for thrombosis recurrence and improved safety profile compared to VKA. Over the past few years, direct oral anticoagulants (DOACs) have emerged as potential alternative therapies to LMWH due to their convenient route of administration and predictable pharmacokinetics, but evidence for their use in CAT is inconclusive, as only a small fraction of the study populations in these trials had CAT. Recently, two large head-to-head trials comparing DOACs to LMWH in CAT patients reported comparable efficacies of DOACs with increased bleeding risk. Occasionally, CAT treatment can be challenging due to the heterogeneity of underlying malignancies and comorbidities. Renal insufficiency and gastrointestinal defects are the main obstacles in anticoagulant selection. Careful choice of treatment candidates and proper anticoagulant strategies are critical for the treatment of CAT; hence, more studies are required to address these challenges.

Punicalagin suppresses methicillin resistance of Staphylococcus aureus to oxacillin.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen that is cross-resistant to most ß-lactam antibiotics. We investigated whether oxacillin, which is a ß-lactam antibiotic, alone or in combination with punicalagin can affect the penicillin binding protein 2a (PBP2a)-mediated resistance of MRSA. Susceptibility testing of punicalagin with oxacillin was performed using the microdilution and checkerboard assay and the growth curve assay. Binding affinity of punicalagin for cell wall peptidoglycan (PGN) was confirmed by an increased concentration of PGN in bacterial cultures containing punicalagin. The level of PBP2a was analyzed by western blotting. Punicalagin exhibited antimicrobial activity in the viability assay and increased the susceptibility of MRSA to oxacillin. PGN interfered with the antimicrobial activity of punicalagin and prevented the synergistic activity of punicalagin and oxacillin. Increasing the concentration of punicalagin and maintaining a constant concentration of oxacillin resulted in synergistic suppression of the expression of the mec operon (mecA, mecI, and mecR1). The production of PBP2a was suppressed by the addition of punicalagin to oxacillin. Our findings demonstrate that punicalagin potentiates the effect of oxacillin on MRSA by reducing the transcription of mecA (a gene marker for methicillin resistance), which resulted in a reduced level of PBP2a.

Cryptotanshinone Induces Cell Cycle Arrest and Apoptosis of NSCLC Cells through the PI3K/Akt/GSK-3ß Pathway.

Cryptotanshinone (CTT) is a natural product and a quinoid diterpene isolated from the root of the Asian medicinal plant, Salvia miltiorrhizabunge. Notably, CTT has a variety of anti-cancer actions, including the activation of apoptosis, anti-proliferation, and reduction in angiogenesis. We further investigated the anti-cancer effects of CTT using MTS, LDH, and Annexin V assay, DAPI staining, cell cycle arrest, and Western blot analysis in NSCLC cell lines. NSCLC cells treated with CTT reduced cell growth through PI3K/Akt/GSK3ß pathway inhibition, G0/G1 cell cycle arrest, and the activation of apoptosis. CTT induced an increase of caspase-3, caspase-9, poly-ADP-ribose polymerase (PARP), and Bax, as well as inhibition of Bcl-2, survivin, and cellular-inhibitor of apoptosis protein 1 and 2 (cIAP-1 and -2). It also induced G0/G1 phase cell cycle arrest by decreasing the expression of the cyclin A, cyclin D, cyclin E, Cdk 2, and Cdk 4. These results highlight anti-proliferation the latent of CTT as natural therapeutic agent for NSCLC. Therefore, we investigated the possibility of CTT as an anti-cancer agent by comparing with GF, which is a representative anti-cancer drug.

Microplastic ingestion in aquatic and soil biota: A comprehensive review of laboratory studies on edible size and intake pattern.

Microplastic contamination is ubiquitous and can be transferred through the food chain to humans. However, studies on microplastic size have mainly focused on large animals with a body length >20 mm. To address this gap, we conducted a comprehensive review of 169 laboratory studies to determine the edible size of microplastics for macrofauna and flora in aquatic and soil biota. Our findings indicate that microplastics with a size of <300 µm and 1 µm, respectively, are edible for these organisms, which are positioned at the base of the food chain. We also analyzed intake and depuration patterns and identified factors affecting microplastic ingestion. Our study fills an important knowledge gap by identifying the range of microplastic sizes that can enter the food chain and be transferred to humans. The study findings have strong implications for the ecological risk assessment of microplastics and suggest a starting point for mitigating this threat.

Diagnostic Approaches to Investigate JAK2-Unmutated Erythrocytosis Based on a Single Tertiary Center Experience.

INTRODUCTION: Erythrocytosis is attributed to various clinical and molecular factors. Many cases of JAK2-unmutated erythrocytosis remain undiagnosed. We investigated the characteristics and causes of JAK2-unmutated erythrocytosis. METHODS: We assessed the clinical and laboratory results of patients with erythrocytosis without JAK2 mutations and performed targeted next-generation sequencing (NGS) panels for somatic and germline mutations. RESULTS: In total, 117 patients with JAK2-unmutated erythrocytosis were included. The median hemoglobin and hematocrit levels were 17.9 g/dL and 53.4%, respectively. Erythropoietin levels were not below the reference range. Thrombotic events were reported in 17 patients (14.5%). Among JAK2-unmutated patients, 44 had undergone targeted panel sequencing consisting of myeloid neoplasm-related genes, and 16 had one or more reportable variants in ASXL1 (5/44), TET2, CALR, FLT3, and SH2B3 (2/44). Additional testing for germline causes revealed eight variants in seven genes in eight patients, including NF1, BPGM, EPAS1, PIEZO1, RHAG, SH2B3, and VHL genes. One NF1 pathogenic, one BPGM likely pathogenic, and six variants of undetermined significance were detected. CONCLUSION: Somatic and germline mutations were identified in 36.4% and 33.3 % of the JAK2-unmutated group; most variants had unknown clinical significance. Not all genetic causes have been identified; comprehensive diagnostic approaches are crucial for identifying the cause of erythrocytosis.

A Phase II Study to Evaluate the Efficacy of Bortezomib in Combination with Thalidomide in Treatment-Naïve Waldenstrom Macroglobulinemia Patients.

PURPOSE: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM. MATERIALS AND METHODS: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM. RESULTS: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%). CONCLUSION: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.

False-positive results of galactomannan assays in patients administered glucose-containing solutions.

Galactomannan (GM) is a polysaccharide cell wall component released by Aspergillus spp., and an immunoenzymatic GM assay is used for the diagnosis of invasive pulmonary aspergillosis. We evaluated the cause of strong positivity for GM in patients with no typical signs of aspergillosis. Repeat assays were performed using different instruments and reagent lots, but there were no differences in results among the assays. Patients with strongly positive GM results were investigated. Medication histories revealed that 14 of 23 patients had been administered total parenteral nutrition solution from one manufacturer and 4 patients had been administered dextrose solution from a different manufacturer before being tested. The results of GM assays conducted on samples of dextrose solution and the glucose fraction of the total parenteral nutrition solution were strongly positive, confirming the causes of the false-positive reactions. We hypothesize that a trace amount of GM was introduced into the glucose-containing solutions because glucoamylase, which is necessary for the saccharification step of glucose synthesis, was derived from Aspergillus niger. To enhance patient care and prevent unnecessary antifungal prescriptions, healthcare providers and manufacturers of healthcare products need to be aware of the possibility of false-positive reactions for GM.

Microfibers from cigarette butts can induce exoskeletal alteration in whiteleg shrimp (Penaeus vannamei).

Cigarette butts (CB) are a source of microfibers (MFs) in aquatic environments, posing a risk to the health of aquatic organisms. Research has been focused on examining the toxicity of CBs on ecological receptors, including invertebrates. More focus has been on death, growth, or movement inhibition of but less on exoskeletal effects in malacostracans. We evaluated the alteration in the carapace structure of whiteleg shrimp (Penaeus vannamei Boone, 1931) caused by MFs derived from CBs (CB-MF). Exposure to CB-MF damaged the gills, the main organs adsorbing calcium in shrimps to generate a hard carapace, disturbing calcium uptake via respiration. Rapid ecdysis caused on CB-MF exposure reduced the environmental adaptation capacity of crustaceans in the absence of normal pigments in the chromatophore of the carapace. These findings indicate that MFs released from CBs released into the aquatic environment can adversely affect exoskeletal alteration within the overall ecosystem.

Understanding hazardous concentrations of microplastics in fresh water using non-traditional toxicity data.

Microplastic pollution has become a major environmental problem, indicating the need to implement quantitative governance standards in combination with reducing or banning single-use plastic. Previous studies have predicted no-effect concentrations for limited microplastic-based toxicity data but have not considered environmentally relevant sizes, shapes, or polymers. To provide high quantity and quality data for microplastics of different sizes, shapes, or polymer compositions, non-traditional and traditional toxicity data may need to be considered in combination. In this study, we reviewed toxicity data for microplastics in freshwaters from 2018 to 2022 and analyzed the toxicity data using traditional and non-traditional methods. Based on 166 chronic traditional toxicity data points, the hazard concentration (HC) values calculated from non-traditional toxicity endpoints or all toxicity endpoints were lower than those calculated from traditional toxicity endpoints. Based on 398 chronic traditional plus non-traditional toxicity data points, the HC values calculated from traditional plus non-traditional values were higher than those calculated from traditional toxicity values. With these results, we developed a new framework for deriving microplastic-specific hazardous concentrations, one that especially considers non-traditional toxicity endpoints and values for microplastics. Overall, this study offers a basis for future management strategies and associated frameworks for mitigating microplastic toxicity.

Potential effects of natural aging process on the characteristics and toxicity of facial masks: A zebrafish-based study.

The use of facial masks has increased and is therefore being recognized as a large source of environmental microplastics. Herein, we naturally aged disposable masks in a lake for eight weeks and compared the toxicity of mask-derived microplastics depending on the aging process using zebrafish (Danio rerio). Zebrafish were exposed to virgin and aged mask fragments (VF and AF, respectively) for eight weeks. The aging process induced cracks on the surface of mask fragments and chemical adsorption. Both VF and AFs damaged the zebrafish's liver, gills, and intestine and adversely affected their digestive ability, and their movement-aggression was decreased. These observations highlight the consequences of indiscriminately discarding masks or AFs following consumption. In conclusion, personal protective equipment waste in the environment should be appropriately managed to prevent negative impacts on aquatic organisms and, consequently, on humans via the food chain.

Non-traditional species sensitivity distribution approaches to analyze hazardous concentrations of microplastics in marine water.

Owing to their ubiquitous nature, microplastics are a major environmental concern. This study reviewed the toxicity data of microplastics in marine water, and analyzed their species sensitivity distribution (SSD) curves and hazardous concentrations (HCs). Toxicity database of no-observed effect concentration (NOEC), 50% effect concentration (EC50), and highest observed no-effect concentration (HONEC), and lethal, developing, reproductive, biochemical, and behavioral toxicity endpoints was used. Using 169 chronic NOEC databases, all non-traditional toxicity endpoint databases showed stronger HC values, better fit, and more variable toxicity sensitivity than those derived from traditional values. Moreover, using 426 chronic NOEC, EC50, and HONEC data points, HC values calculated from traditional plus HONEC toxicity values showed weaker HC values, slightly better fit, and more variable toxicity sensitivity than those derived from traditional toxicity values. The SSD approach using non-traditional toxicity and marine water toxicity data can expand the marine water toxicity database, including information on SSD curves and HCs of diverse microplastics.

Increased risk of venous and arterial thromboembolism in patients with colorectal cancer receiving cetuximab-based combination chemotherapy: A population-based study in Korea.

INTRODUCTION: Limited data exist on the risk of venous and arterial thromboembolisms (VTE and ATE) in patients receiving cetuximab plus chemotherapy. We aimed to determine the thromboembolic risk of patients with recurrent/metastatic colorectal cancer (CRC) treated with cetuximab plus chemotherapy compared to chemotherapy alone. METHODS: This population-based study used nationwide claims data from the Health Insurance Review and Assessment Service of South Korea from 2013 to 2020. Patients with recurrent/metastatic CRC treated with first-line oxaliplatin- or irinotecan-based doublets with or without cetuximab and no secondary prevention for VTE and ATE were included. Primary outcomes were the occurrence of any thromboembolic events, VTE, and ATE, which were determined using the cumulative incidence method incorporating death as a competing event. RESULTS: We identified 19,723 patients (cetuximab plus chemotherapy, N = 7630; chemotherapy alone, N = 12,093). The cumulative incidence of any thromboembolic events in patients with cetuximab plus chemotherapy was significantly higher than in those receiving chemotherapy alone (6-month, 5.62 % vs. 3.58 %, P < 0.0001). The rates of VTE (6-month, 5.11 % vs. 3.28 %, P < 0.0001) and ATE (6-month, 0.53 % vs. 0.32 %, P = 0.0218) were also higher in patients receiving cetuximab plus chemotherapy. In multivariable analysis, cetuximab plus chemotherapy was independently associated with developing any thromboembolic events (hazard ratio [HR], 1.63; 95 % confidence interval [CI], 1.42-1.87), VTE (HR, 1.62; 95 % CI, 1.40-1.87), and ATE (HR, 1.77; 95 % CI, 1.16-2.71). CONCLUSIONS: Cetuximab with irinotecan- or oxaliplatin-based doublet chemotherapy was associated with an increased risk of any thromboembolic events, VTE, and ATE; further studies are warranted to examine the underlying mechanisms.