Bristol-Myers Squibb (South Korea)

Abstract Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non–small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1–NTRK1-rearranged lung cancer. Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400–9. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 339

PURPOSE: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has recently been shown to have activity as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). This phase II open-label study assessed brivanib as second-line therapy in patients with advanced HCC who had failed prior antiangiogenic treatment. EXPERIMENTAL DESIGN: Brivanib was administered orally at a dose of 800 mg once daily. The primary objectives were tumor response rate, time to response, duration of response, progression-free survival, overall survival (OS), disease control rate, time to progression (TTP), and safety and tolerability. RESULTS: Forty-six patients were treated. Best responses to treatment with brivanib (N = 46 patients) using modified World Health Organization criteria were partial responses for two patients (4.3%), stable disease for 19 patients (41.3%), and progressive disease for 19 patients (41.3%). The tumor response rate was 4.3%; the disease control rate was 45.7%. Median OS was 9.79 months. Median TTP as assessed by study investigators following second-line treatment with brivanib was 2.7 months. The most common adverse events were fatigue, decreased appetite, nausea, diarrhea, and hypertension. CONCLUSION: Brivanib had a manageable safety profile and is one of the first agents to show promising antitumor activity in advanced HCC patients treated with prior sorafenib.

Abstract RET fusions are oncogenic drivers of various tumors, including non–small cell lung cancers (NSCLC). The safety and antitumor activity of the multikinase RET inhibitor RXDX-105 were explored in a phase I/Ib trial. A recommended phase II dose of 275 mg fed daily was identified. The most common treatment-related adverse events were fatigue (25%), diarrhea (24%), hypophosphatemia (18%), maculopapular rash (18%), and nonmaculopapular rash (17%). In the phase Ib cohort of RET inhibitor–naïve patients with RET fusion–positive NSCLCs, the objective response rate (ORR) was 19% (95% CI, 8%–38%, n = 6/31). Interestingly, the ORR varied significantly by the gene fusion partner (P < 0.001, Fisher exact test): 0% (95% CI, 0%–17%, n = 0/20) with KIF5B (the most common upstream partner for RET fusion–positive NSCLC), and 67% (95% CI, 30%–93%, n = 6/9) with non-KIF5B partners. The median duration of response in all RET fusion–positive NSCLCs was not reached (range, 5 to 18+ months). Significance: Although KIF5B–RET is the most common RET fusion in NSCLCs, RET inhibition with RXDX-105 resulted in responses only in non–KIF5B–RET-containing cancers. Novel approaches to targeting KIF5B–RET-containing tumors are needed, along with a deeper understanding of the biology that underlies the differential responses observed. This article is highlighted in the In This Issue feature, p. 305

The aim of this study was to describe the mutational characteristics in Korean hereditary spherocytosis (HS) patients. Relevant literatures including genetically confirmed cases with well-documented clinical summaries and relevant information were also reviewed to investigate the mutational gene- or domain-specific laboratory and clinical association. Twenty-five HS patients carried one heterozygous mutation of ANK1 (n = 13) or SPTB (n = 12) but not in SPTA1, SLC4A1, or EPB42. Deleterious mutations including frameshift, nonsense, and splice site mutations were identified in 91% (21/23), and non-hotspot mutations were dispersed across multiple exons. Genotype-phenotype correlation was clarified after combined analysis of the cases and the literature review; anemia was most severe in HS patients with mutations on the ANK1 spectrin-binding domain (p < 0.05), and SPTB mutations in HS patients spared the tetramerization domain in which mutations of hereditary elliptocytosis and pyropoikilocytosis are located. Splenectomy (17/75) was more frequent in ANK1 mutant HS (32%) than in HS with SPTB mutation (10%) (p = 0.028). Aplastic crisis occurred in 32.0% of the patients (8/25; 3 ANK1 and 5 SPTB), and parvovirus B19 was detected in 88%. The study clarifies ANK1 or SPTB mutational characteristics in HS Korean patients. The genetic association of laboratory and clinical aspects suggests comprehensive considerations for genetic-based management of HS.

Size-based filtration techniques have been developed for high-throughput isolation of extracellular vesicles (EVs). Conventional direct filtration systems have limitations in that large particles generally not only block the pores of the membrane but also damage the particles because of the high fluid pressure. Here, we propose a cyclic tangential flow filtration (TFF) system that includes two membranes with pore sizes of 200 and 30 nm, connected to a peristaltic pump that feeds the stream flowing to the membrane for continuous circulation. The cyclic TFF system is better able to isolate the specific 30-200 nm size range in one step through dual cyclic filtration compared with direct filtration (DF) and single cyclic TFF (scTFF). We further introduced a buffer-exchange process to the dcTFF system after filtration to remove contaminants for more efficient purification. As a result of comparative evaluation of dcTFF and ExoQuick, EVs isolated by dcTFF had more abundant exosome markers and active EVs. The cyclic TFF system not only has great potential to separate EVs with high selectivity and separation efficiency in small volumes of samples but can also be used in clinical applications, including medical diagnostic procedures.

The development of new biomarkers for ovarian cancer is clearly necessary for the improved detection and monitoring of the disease. Surface enhanced laser desorption and ionization time-of-flight mass spectrometry (SELDI-TOF-MS) can be employed in the identification of differentially expressed proteins in cancer cells. The objective of this study was, then, to identify potential diagnostic serological biomarkers for ovarian cancer. We performed protein expression difference analyses of 45 serum samples using SELDI protein chip array. Forty-five sera obtained from ovarian cancer patients (n=35) and normal healthy females (n=10), were profiled on the surface of SELDI protein chip. The candidate biomarkers were purified by CM-Sepharose, and their N-terminal amino sequence was determined. The amounts of hemoglobin (Hb) in cancer patient's sera versus that of normal sera were measured by ELISA. Nine sera proteins that were found to be significantly differentially expressed (P<0.05) between the sera of ovarian cancer patients and that of normal healthy females were selected using the WCX2 array. The most distinctive polypeptide peaks detected in the ovarian cancer samples were at 15.1 and 15.8 kDa and these two peaks were identified as the hemoglobin-alpha (Hb-alpha) and -beta (Hb-beta) chain, respectively. ELISA indicated that the sensitivity for intact Hb level was 77% in sera obtained from ovarian cancer patients, as compared with normal healthy female sera. In conclusion, two ovarian cancer biomarker proteins were discovered and identified as Hb-alpha and Hb-beta. Hb levels were significantly different in ovarian cancer serum samples and those obtained from normal healthy females, as determined by ELISA. Additional studies are required to further validate Hb-alpha and Hb-beta biomarkers.

PURPOSE: The goals of this study were to investigate the clinical activity, safety, and biomarkers of dacomitinib, an irreversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, in recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). EXPERIMENTAL DESIGN: Patients were eligible if the diseases were not amenable to curative treatment and had progressed on platinum-based chemotherapy, and were treated with dacomitinib 45 mg/day. The primary endpoint was objective response rate by RECISTv1.1. Exploratory analysis included the characterization of somatic mutation, gene copy number, gene expression, p16(INK4A) expression by IHC, and investigation of their relationship with clinical outcomes. RESULTS: Forty-eight patients were evaluable for efficacy and toxicity. Ten patients (20.8%) had partial responses and 31 patients (65%) had stable diseases. The median progression-free survival (PFS) and overall survival (OS) were 3.9 months [95% confidence interval (CI), 2.9-5.0] and 6.6 months (95% CI, 5.4-10.3). Adverse events were mostly grade 1-2. Mutations in the PI3K pathway (PIK3CA, PTEN) and high expression of inflammatory cytokines (IL6, IL8, IL1A, IL1B, IL4, and TNF) were significantly associated with shorter PFS (2.9 vs. 4.9 months without mutations, P = 0.013; 2.8 vs. 9.9 months with low expression, P = 0.004). Those harboring PI3K pathway mutations or high inflammatory cytokine expression had shorter median OS (6.1 vs. 12.5 months lacking PI3K pathway mutations and with low inflammatory cytokine expression, P = 0.005). CONCLUSIONS: Dacomitinib demonstrated clinical efficacy with manageable toxicity in platinum-failed R/M-SCCHN patients. Screening of PI3K pathway mutation and inflammatory cytokine expression may help identify which R/M-SCCHN patients are likely to gain benefit from dacomitinib.

4577 Background: Brivanib is an orally available dual inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signaling. FGF pathway activation is of increasing importance in the setting of liver fibrosis and HCC. This phase II study aimed to assess the efficacy and safety of brivanib in patients (pts) with unresectable, locally advanced or metastatic HCC who had received either no prior systemic therapy (Cohort A) or one prior regimen of angiogenesis inhibitor (Cohort B). Methods: Eligible pts had biopsy-proven HCC or had radiological evidence of HCC and were serology positive for Hep B or C with alpha fetoprotein levels ≥ 400 μg/L. Pts received brivanib 800 mg qd. Efficacy endpoints included OS, PFS, TTP, ORR, and DCR. Safety was assessed throughout the study. Serum levels of a biomarker, Collagen IV (a component of the basement membrane of blood vessels), were measured on day 1, weeks 3 and 6, and at end of treatment. Results: Interim results are reported. From December 2006 to October 2008, 96 patients were enrolled (Cohort A: 55 pts; Cohort B: 41 pts). In Cohort B, 38 pts had failed sorafenib and 3 had failed thalidomide. In Cohort A, median OS (95% CI) was 10 (6.8,-) months. Most frequently reported grade 3/4 AEs were fatigue (16%), AST elevation (19%), and hyponatremia (41%) in Cohort A and hypertension (7.3%), diarrhea (4.9%), and headache (4.9%) in Cohort B. 24 pts died in Cohort A and 5 pts in Cohort B, none were considered treatment-related. Treatment-induced reductions in serum Collagen IV appear to correlate with long term outcome (PFS and OS). Conclusions: Brivanib has activity as both first-line and second-line post-sorafenib systemic treatment in HCC. Collagen IV, a novel serum angiogenic biomarker, appears to be associated with outcome. [Table: see text] [Table: see text]

The emergence of Chat Generative Pre-trained Transformer (ChatGPT), a chatbot developed by OpenAI, has garnered interest in the application of generative artificial intelligence (AI) models in the medical field. This review summarizes different generative AI models and their potential applications in the field of medicine and explores the evolving landscape of Generative Adversarial Networks and diffusion models since the introduction of generative AI models. These models have made valuable contributions to the field of radiology. Furthermore, this review also explores the significance of synthetic data in addressing privacy concerns and augmenting data diversity and quality within the medical domain, in addition to emphasizing the role of inversion in the investigation of generative models and outlining an approach to replicate this process. We provide an overview of Large Language Models, such as GPTs and bidirectional encoder representations (BERTs), that focus on prominent representatives and discuss recent initiatives involving language-vision models in radiology, including innovative large language and vision assistant for biomedicine (LLaVa-Med), to illustrate their practical application. This comprehensive review offers insights into the wide-ranging applications of generative AI models in clinical research and emphasizes their transformative potential.

This study investigated the effect of low-power, non-thermal atmospheric pressure plasma (NT-APP) treatments, in pulsed and conventional modes, on the adhesion of resin composite to dentin and on the durability of the bond between resin composite and dentin. A pencil-type NT-APP jet was applied in pulsed and conventional modes to acid-etched dentin. The microtensile bond strength (MTBS) of resin composite to dentin was evaluated at 24 h and after thermocycling in one control group (no plasma) and in two experimental groups (pulsed plasma and conventional plasma groups) using the Scotchbond Multi-Purpose Plus Adhesive System. Data were analyzed using two-factor repeated-measures anova and Weibull statistics. Fractured surfaces and the bonded interfaces were evaluated using a field-emission scanning electron microscope. Although there were no significant differences between the plasma treatment groups, the plasma treatment improved the MTBS compared with the control group. After thermocycling, the MTBS did not decrease in the control or conventional plasma group but increased in the pulsed plasma group. Thermocycling increased the Weibull moduli of plasma-treated groups. In conclusion, plasma treatment using NT-APP improved the adhesion of resin composite to dentin. Using a pulsed energy source, the energy delivered to the dentin was effectively reduced without any reduction in bond strength or durability.

PURPOSE: In EGFR-mutated metastatic non-small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if EGFR-activating mutation subtypes impact treatment outcomes in the phase III RELAY study. Associations between EGFR mutation type and preexisting co-occurring and treatment-emergent genetic alterations were also explored. PATIENTS AND METHODS: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg; RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1-defined progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses. RESULTS: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and comutational profiles. One-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL-treated patients with ex19del and ex21L858R. Baseline TP53 comutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. EGFR T790M mutation rate at progression was similar between treatment arms and by mutation type. CONCLUSIONS: RAM+ERL provided significant clinical benefit for both EGFR ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these EGFR mutation types.

The amino sugar galactosamine (galN) induces alterations in the hepatic uridine nucleotide pool and has been widely used as a model of human viral hepatitis. Histopathological and clinical chemistry analyses of a cohort of rats following administration of galN revealed extreme interindividual variability in the extent of the toxic response which enabled classification of 'responder' and 'non-responder' phenotypes. An integrative metabolic profiling approach was applied to characterize biomarkers of exposure to galN in urine, serum, feces and liver from responders and non-responders. The presence of N-acetylglucosamine and galN in the urine correlated with the occurrence and extent of toxic response. Conversely, the novel identification of galN-pyrazines in the feces of non-responders and their virtual absence in the feces of responders suggests an alternative means of distribution and metabolism of galN in non-responders. The absence of the UDP-hexosamines in the liver of non-responders further supports differential metabolism of galN and suggests an ability of non-responders to avoid UDP-glucose depletion. An observed disturbance of gut microbial derived metabolites in the urine and feces of non-responders may suggest a role of the microflora in reducing the effective dose of galN. This systems level metabonomic approach has provided new mechanistic insights into differential response to galN and is widely applicable to the study of interindividual variation in metabolism for any xenobiotic intervention.

Pazopanib is an orally bioavailable, ATP-competitive, multitargeted tyrosine kinase inhibitor mainly targeting VEGFR2 and PDGFR tyrosine kinases, but the biologic sequences of pazopanib activities beyond antiangiogenesis are poorly defined. We used a panel of 38 gastric cancer cell lines to test the efficacy of pazopanib. In a growth inhibition assay, genomic changes indicated that pazopanib had differential effects on cell growth. Treatment of the KATO-III, OCUM-2M, SNU-16, and HSC-39 gastric cancer cell lines harboring FGFR2 amplification with pazopanib resulted in marked decreases of cell survival with IC50 in ranges of 0.1 to 2.0 μmol/L, whereas the same treatment of those cell lines without FGFR2 amplification had no growth-inhibitory effects. In the ectopic FGFR2-expressing model, treatment with the indicated concentrations of pazopanib significantly inhibited cell growth and colony formation by FGFR2-expressing NIH 3T3 cells with wild-type (WT) FGFR2 and mutant FGFR2 (S252W). Pazopanib also selectively suppressed constitutive FGFR2 signaling and phosphorylation of downstream effectors. In cell-cycle analysis, FGFR2-amplified cells underwent cell-cycle arrest at the G1-S phase after pazopanib treatment, whereas there were no significant effects on cell-cycle progression in cells without FGFR2 amplification treated with pazopanib. In addition, pazopanib increased a substantial fraction of sub-G1 only in FGFR2-amplified cells. These findings show that the activation of FGFR2 signaling by amplification may be a critical mediator of cell proliferation in a small subset of gastric cancer patients and that pazopanib may provide genotype-correlated clinical benefits beyond the setting of highly vascular tumors.

Abstract Purpose: To evaluate drug–drug interactions between the human epidermal growth factor receptor 2 (HER2)–targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd; DS-8201a) and the OATP1B/CYP3A inhibitor ritonavir or the strong CYP3A inhibitor itraconazole. Patients and Methods: Patients with HER2-expressing advanced solid tumors were enrolled in this phase I, open-label, single-sequence crossover study (NCT03383692) and received i.v. T-DXd 5.4 mg/kg every 3 weeks. Patients received ritonavir (cohort 1) or itraconazole (cohort 2) from day 17 of cycle 2 through the end of cycle 3. Primary endpoints were maximum serum concentration (Cmax) and partial area under the concentration-time curve from beginning of cycle through day 17 (AUC17d) for T-DXd and deruxtecan (DXd) with (cycle 3) and without (cycle 2) ritonavir or itraconazole treatment. Results: Forty patients were enrolled (cohort 1, n = 17; cohort 2, n = 23). T-DXd Cmax was similar whether combined with ritonavir [cohort 1, cycle 3/cycle 2; 90% confidence interval (CI): 1.05 (0.98–1.13)] or itraconazole [cohort 2, 1.03 (0.96–1.09)]. T-DXd AUC17d increased from cycle 2 to 3; however, the cycle 3/cycle 2 ratio upper CI bound remained at ≤1.25 for both cohorts. For DXd (cycle 3/cycle 2), Cmax ratio was 0.99 (90% CI, 0.85–1.14) for cohort 1 and 1.04 (0.92–1.18) for cohort 2; AUC17d ratio was 1.22 (1.08–1.37) and 1.18 (1.11–1.25), respectively. The safety profile of T-DXd plus ritonavir or itraconazole was consistent with previous studies of T-DXd monotherapy. T-DXd demonstrated promising antitumor activity across HER2-expressing solid-tumor types. Conclusions: T-DXd was safely combined with ritonavir or itraconazole without clinically meaningful impact on T-DXd or DXd pharmacokinetics.

7004 Background: Previous data with dasatinib (SPRYCEL®), a short-acting oral multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, have shown the safety and efficacy of the 70 mg BID dose in CP-CML patients. Surprisingly, phase-I data (NEJM 2006;354:2531) demonstrated complete hematologic (CHR) and major cytogenetic responses (MCyR) among CP-CML patients at total daily doses (TDD) of 100 mg and 140 mg in both the BID and QD schedule, despite the achievement of only transient inhibition of BCR-ABL by dasatinib when administered once daily. Methods: Patients with CP-CML resistant or intolerant to imatinib were randomized to one of 4 dasatinib arms: 1) 100 mg QD; 2) 50 mg BID; 3) 140 mg QD; 4) 70 mg BID. In this randomized, prospective, open-label trial, the primary objective compared the CyR rate among the BID and QD arms. Secondary objectives included comparison of the CyR rate between TTDs of 100 and 140 mg and the safety among the 4 arms. Results: 662 patients were randomized from July 2005 to March 2006 and received treatment. Response rates, with a median duration of treatment of 8 months, are shown below. Duration of CyR and progression-free survival were similar across all 4 arms. There was significantly less grade (Gr) 3–4 neutropenia (P=0.035), thrombocytopenia (P=0.001), anemia (P=0.032), and pleural effusions (P=0.028) in the 100-mg QD arm compared to the other 3 arms combined. No differences were seen across the 4 arms in the rates of other adverse events. There were fewer interruptions and reductions and the least number of patients discontinuing treatment for drug-related toxicity in the 100-mg QD arm. Conclusions: Dasatinib 100 mg QD offers the most favorable benefit-risk ratio in CP-CML. This trial provides the first evidence that intermittent kinase inhibition can achieve deep clinical remissions and is associated with an improved safety profile. One-year follow-up on all subjects, molecular response rates, and BCR-ABL mutation data will be presented. [Table: see text] [Table: see text]

1006 Background: Patients with MBC who have progressed after anthracyclines and taxanes have limited treatment options. Ixabepilone, a novel epothilone B analog, is active in resistant breast cancer. Methods: In this large multinational phase III trial, patients with MBC who were anthracycline pretreated and met predefined resistance criteria to taxanes were randomized to ixabepilone (40mg/m 2 IV over 3h Q3w) + capecitabine (1,000mg/m 2 PO BID Q14d) or capecitabine (1,250mg/m 2 PO BID Q14d). The primary endpoint was progression-free survival (PFS); secondary endpoints included objective response rate (ORR), safety, and overall survival (available after 2007). Response and progression were assessed by an independent review committee (IRC) and the investigators (INV). Results: 752 patients were randomized. Median age was 53; 84% had visceral disease, 48% and 43% had 1 and =2 prior metastatic regimens. Median of 5 and 4 cycles of ixabepilone + capecitabine and capecitabine were administered. Ixabepilone + capecitabine was superior to capecitabine. Significant benefit was consistently maintained across predefined subgroups, including HER2-/ER- /PR- and HER2+. *Primary analysis of PFS; hazard ratio= 0.75. Grade (G) 3/4 adverse events included neuropathy (ixabepilone + capecitabine 23% vs capecitabine 0%), hand-foot syndrome (18% vs 17%), and fatigue (9% vs 3%). Neuropathy was cumulative and reversible (median time to resolution of G3/4 to baseline/G1 was 6 weeks). G3 and 4 neutropenia were reported in 32% and 36% vs 9% and 2%, respectively; febrile neutropenia was 5% with ixabepilone + capecitabine. Toxic death rate was 3% vs 1%. Patients with liver dysfunction were at greater risk. Conclusions: Ixabepilone + capecitabine has superior efficacy to capecitabine across endpoints and has a manageable safety profile in this heavily pretreated population. It offers a new potential option for patients with MBC. [Table: see text] No significant financial relationships to disclose.

Gwang Cheon Jang*, Yoon-Seok Chang*, Sun Hee Choi, Woo-Jung Song, Soo-Young Lee, Hae-Sim Park; KAAACI Work Group (Hye-Ryun Kang, Yeong-Min Ye, Hyun-Jung Jin, Mi Yong Shin, Soo-Jin Lee, Hye One Kim, Jihyun Kim, Jae-Woo Jung); Headquarters of Korean Anaphylaxis Campaign (Hee-Bom Moon), Youngmin Ahn Department of Pediatrics, National Health Insurance Corporation Ilsan Hospital, Goyang; Department of Internal Medicine, Seoul National University College of Medicine, Seoul; Department of Pediatrics, Kyung Hee University School of Medicine, Seoul; Department of Pediatrics, Ajou University School of Medicine, Suwon; Department of Allergy & Clinical Immunology, Ajou University School of Medicine, Suwon; Korean Academy of Asthma, Allergy and Clinical Immunology, Anaphylaxis Work Group, Seoul; Headquarters of Korean Anaphylaxis Campaign, Seoul; Department of Pediatrics, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea

Objectives: Thymic epithelial tumors (TETs) are rare malignant tumors that exhibit heterogeneous histology and clinical behavior. As immune check point inhibitors, drugs targeting anti-programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown remarkable results against many cancers; thus, the importance of PD-1/PD-L1 immunohistochemistry as a predictive or prognostic biomarker has grown. However, limited data on PD-L1 and PD-1 expression in TETs have been reported; moreover, these results have been variable. Here, we examined the expression of PD-1/PD-L1 proteins in TETs and analyzed the clinicopathologic significance of this expression. Patients and Methods: A tissue microarray was constructed using 368 samples of TETs, each in triplicate. Immunohistochemistry for PD-L1 (SP263 assay) and PD-1 in TETs and CD8 in thymic carcinoma (TC) was performed; next, correlations with clinicopathologic characteristics were analyzed. PD-L1high was designated as 50% of tumor proportion score; PD-1high and CD8high were defined as 5% and 1% of tumoral immune cells, respectively. Results: The cohort consisted of 308 patients with thymomas and 60 patients with TC. PD-L1 positivity was identified in 90.6% (328/362, 1%) of TETs, PD-1 expression of intra-/peritumoral T cells was identified in 53.6% (194/362) of TETs and CD8 positivity was identified in 11 % (7/60, 1%) of TC. Of the 362patients, 141 (39.0%) exhibited high PD-L1 expression (PD-L1high). The PD-L1high thymoma group was correlated with high Masaoka-Koga stage (p < 0.001), type B3 histology (p < 0.001), and myasthenia gravis (p < 0.001). This group exhibited poor overall survival (OS, p = 0.003, log-rank) and worse disease-free survival (DFS, p = 0.042, log-rank). No survival differences were detected between PD-L1high and PD-L1low groups in TC. Additionally, there was no correlation between PD-1 expression and survival in patients with TETs. Multivariate analysis revealed that PD-L1high expression was an independent poor prognostic factor (p = 0.047, HR 2.087, 95% CI, 1.009-4.318) in thymomas. Conclusions: To our knowledge, this is the largest study on TETs published in English literature. This study provides useful information regarding the prognosis of and potential therapeutic options for patients with TETs.

BACKGROUND: Although there is growing evidence of the use of artificial intelligence (AI) techniques in sports, ethical issues surrounding AI use are being discussed at a minimal level. Thus, this systematic scoping review aimed to summarize the current ethical implications associated with using AI in sports. METHODS: In this study, a total of 9 databases-MEDLINE/PubMed, Embase, Cochrane Library, ProQuest, EBSCOhost, IEEE Xplore, Web of Science, Scopus, and Google Scholar-were searched. The review protocol was registered (https://osf.io/42a8q) before extracting data. The search yielded 397 studies, and 25 studies met the inclusion and exclusion criteria. RESULTS: The 25 studies were categorized into 4 primary ethical concerns: fairness and bias, transparency and explainability, privacy and data ethics, and accountability in AI's application in sports. These categorizations were derived based on the systematic review of ethical issues highlighted across the selected studies. Fifteen studies delved into fairness and bias, focusing on how AI can perpetuate existing inequalities in sports. Thirteen studies addressed the lack of transparency, emphasizing the challenges in interpretability and trust in AI-driven decisions. Privacy and data ethics emerged as significant in 22 studies, highlighting risks related to the misuse of athletes' sensitive data. Finally, accountability was examined in 8 studies, stressing the ethical obligations of AI developers and users in sports contexts. The thematic analysis revealed overlapping concerns, as some studies addressed multiple issues simultaneously. CONCLUSION: Future research should focus on developing ethical frameworks tailored to underrepresented sports contexts and creating global standards for AI regulation in sports. This includes investigating the implications of AI applications in amateur sports, enhancing diversity in AI training datasets, and exploring the integration of ethical AI practices across various sports governance structures.

In South Korea, surveillance of antimicrobial drug resistance in Neisseria gonorrhoeae is extremely limited. We describe the emergence and subsequent national spread of N. gonorrhoeae strains with mosaic penA alleles associated with decreased susceptibility and resistance to extended-spectrum cephalosporins. From 2012 through 2017, the proportion of mosaic penA alleles in gonococcal-positive nucleic acid amplification test (NAAT) specimens across South Korea increased from 1.1% to 23.9%. Gonococcal strains with mosaic penA alleles emerged in the international hubs of Seoul in Gyeonggi Province and Busan in South Gyeongsang Province and subsequently spread across South Korea. Most common was mosaic penA-10.001 (n = 572 isolates; 94.7%), which is associated with cefixime resistance. We also identified mosaic penA-34.001 and penA-60.001, both of which are associated with multidrug-resistant gonococcal strains and spread of cefixime and ceftriaxone resistance. Implementation of molecular resistance prediction from N. gonorrhoeae-positive nucleic acid amplification test specimens is imperative in South Korea and internationally.