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Huali Wu,1 Ramesh K Ramanathan,2 Beth A Zamboni,3 Sandra Strychor,4 Suresh Ramalingam,5 Robert P Edwards,4 David M Friedland,4 Ronald G Stoller,4 Chandra P Belani,4 Lauren J Maruca,4 Yung-Jue Bang,6 William C Zamboni11UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA; 2Translational Research Division, The Translational Genomics Research Institute, Scottsdale, AZ, USA; 3Department of Mathematics, Carlow University, Pittsburgh, PA, USA; 4School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; 5Winship Cancer Institute, Emory University, Atlanta, GA, USA; 6College of Medicine, Seoul National University, Seoul, KoreaAbstract: S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic–pharmacodynamic (PK–PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK–PD models were developed and fit simultaneously to the PK–PD data, using NONMEM®. The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis–Menten kinetics in the myelosuppression-based model. The mechanism-based PK–PD model characterized the nonlinear PK disposition, and the bidirectional PK–PD interaction between S-CKD602 and monocytes.Keywords: population pharmacokinetics, pharmacodynamics, PEGylated liposome, nonlinear kinetics

Purpose: The role of (18)F FDG-PET in hepatocellular carcinoma (HCC) has not been firmly established. We conducted this study to investigate the clinical implication of SUVmax on (18)F FDG-PET as a prognostic factor in patients with HCC, especially in the metastatic setting. Methods: HCC patients with extrahepatic metastatic lesions were enrolled that were evaluated by (18)F FDG-PET before palliative systemic therapy, between January 2002 and December 2009 at the Seoul National University Hospital. We retrospectively analyzed the clinical outcome and the value of the SUVmax. Results: A total of 25 patients (men, 88.0%) were enrolled. The response rate and disease control rate was 18.2% (95% CI: 2.1-34.3) and 32.0% (95% CI: 16.3-56.5), respectively. The progression-free survival (PFS) and overall survival (OS) were 2.3 months (95% CI: 1.1-3.4) and 14.2 months (95% CI: 9.1-19.2), respectively. The univariate analysis of OS showed that SUVmax and alphafetoprotein (AFP) were significant prognostic factors (P = 0.023 and P = 0.006, respectively). The multivariate analysis of OS showed that SUVmax and AFP were significant prognostic factors (P = 0.008 and P = 0.006, respectively). SUVmax and AFP were independent prognostic factors for PFS, too (P = 0.010 and P = 0.016, respectively). When the patients were divided according to the SUVmax and AFP, the patients with an SUVmax < 4.9 and an AFP ≤ 400 ng/ml showed longer OS and PFS than the patients with SUVmax ≥ 4.9 or AFP > 400 ng/ml (26.7 months vs. 9.3 months, P < 0.001 and 5.6 months vs. 1.7 months, P = 0.012, respectively). Conclusions: The SUVmax of the (18)F FDG-PET has a prognostic value for OS and PFS in patients with metastatic HCC undergoing systemic therapy. The combined analysis of the SUVmax with AFP might provide more detailed prognostic information. [ABSTRACT FROM AUTHOR]

Background: STEALTH®® liposomal CKD-602 (S-CKD602), a camptothecin analog, is eliminated by the reticuloendothelial system (RES), which consists of cells, including monocytes. We evaluated the relationship between monocyte and absolute neutrophil counts (ANCs) in the blood and pharmacokinetic disposition of S-CKD602 and nonliposomal CKD-602 (NL-CKD602) in patients. Methods: As part of a phase I study of S-CKD602 and phase I and II studies of NL-CKD602, the percent decreases in ANC and monocytes at their nadir were calculated. After S-CKD602, the amount of CKD-602 recovered in urine was measured. Results: For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43 ±± 31 and 58 ±± 26%, respectively ( P == 0.001). For S-CKD602 in patients ≥≥60, the percent decrease in ANC and monocytes were 41 ±± 31 and 45 ±± 36%, respectively ( P == 0.50). For NL-CKD602 ( n == 42), the percent decrease in ANC and monocytes were similar ( P > 0.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 ( R2 == 0.82), compared with patients ≥≥60 ( R2 == 0.30). Conclusions: Monocytes are more sensitive to S-CKD602, compared with neutrophils, and the increased sensitivity is related to the liposomal formulation, not CKD-602. These results suggest that monocytes engulf S-CKD602, which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in patients <60. [ABSTRACT FROM AUTHOR]

Background: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase.Methods: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy.Results: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.Conclusions: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.). [ABSTRACT FROM AUTHOR]

Background: There is no standard palliative chemotherapy regimen in biliary tract cancers (BTC). Fluoropyrimidine or gemcitabine, with or without platinum, are most frequently used. We conducted this study to clarify the efficacy of palliative chemotherapy in BTC.Methods: Patients with unresectable BTC treated with palliative chemotherapy between Oct 2001 and Aug 2006 at Seoul National University Hospital were reviewed retrospectively. Histologically confirmed cases of intrahepatic cholangiocarcinoma, gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater carcinoma were enrolled. We analyzed the efficacy of regimens: gemcitabine (G) versus fluoropyrimidine (F) and with or without platinum (P).Results: A total of 243 patients were enrolled. 159 patients (65%) were male and the median age of the patients was 60 years (range 26-81). Intrahepatic cholangiocarcinoma, gallbladder cancer, extrahepatic bile duct cancer, and ampulla of Vater carcinoma were 92, 72, 58, and 21 cases, respectively. The median progression free survival (PFS) was 4.3 months (95% CI, 3.7-4.9) and median overall survival (OS) was 8.7 months (95% CI, 7.4-10.0). Ninety-nine patients received G-based chemotherapy (94 GP, 5 G alone), and 144 patients received F-based chemotherapy (83 FP, 61 F alone). The response rate (RR), disease control rate (DCR), PFS and OS of G-based chemotherapy versus F-based chemotherapy were 16.7% vs. 19.5% (P=0.591), 52.8% vs. 58.9% (P=0.372), 4.0 months vs. 4.3 months (P=0.816), and 7.8 months vs. 9.1 months (P=0.848), respectively. Sixty-six patients received F or G without P, and 177 patients received F or G with P. The RR, DCR, PFS and OS of chemotherapy without P versus chemotherapy including P were 12.7% vs. 20.6% (P=0.169), 46.0% vs. 60.6% (P=0.049), 3.3 months vs. 4.4 months (P=0.887), and 10.6 months vs. 8.1 months (P=0.257), respectively.Conclusion: In unresectable BTC, F-based and G-based chemotherapy showed similar efficacy in terms of RR, DCR, PFS and OS. The benefit of adding P to F or G was not significant except for DCR. Further prospective studies which define the efficacy of various chemotherapeutic regimens in BTC are warranted. [ABSTRACT FROM AUTHOR]

Triple-negative (TN) breast cancer, which is defined as being negative for the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2), represents a subset of breast cancer with different biologic behaviour. We investigated the clinicopathologic characteristics and prognostic indicators of lymph node-negative TN breast cancer.~Background~Background~Medical records were reviewed from patients with node-negative breast cancer who underwent curative surgery at Seoul National University Hospital between Jan. 2000 and Jun. 2003. Clinicopathologic variables and clinical outcomes were evaluated.~Methods~Methods~Among 683 patients included, 136 had TN breast cancer and 529 had non-TN breast cancer. TN breast cancer correlated with younger age (< 35 y, p = 0.003), and higher histologic and nuclear grade (p < 0.001). It also correlated with a molecular profile associated with biological aggressiveness: negative for bcl-2 expression (p < 0.001), positive for the epidermal growth factor receptor (p = 0.003), and a high level of p53 (p < 0.001) and Ki67 expression (p < 0.00). The relapse rates during the follow-up period (median, 56.8 months) were 14.7% for TN breast cancer and 6.6% for non-TN breast cancer (p = 0.004). Relapse free survival (RFS) was significantly shorter among patients with TN breast cancer compared with those with non-TN breast cancer (4-year RFS rate 85.5% vs. 94.2%, respectively; p = 0.001). On multivariate analysis, young age, close resection margin, and triple-negativity were independent predictors of shorter RFS.~Results~Results~TN breast cancer had higher relapse rate and more aggressive clinicopathologic characteristics than non-TN in node-negative breast cancer. Thus, TN breast cancer should be integrated into the risk factor analysis for node-negative breast cancer.~Conclusion~Conclusions [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to evaluate the efficacy and toxicity of infusional 5-fluorouracil (5-FU), folinic acid and oxaliplatin (modified FOLFOX-6) in patients with advanced gastric cancer (AGC), as first-line palliative combination chemotherapy. We also analyzed the predictive or prognostic value of germline polymorphisms of candidate genes associated with 5-FU and oxaliplatin.Methods: Seventy-three patients were administered a 2 hour infusion of oxaliplatin (100 mg/m2) and folinic acid (100 mg/m2) followed by a 46 hour continuous infusion of 5-FU (2,400 mg/m2). Genomic DNA from the patients' peripheral blood mononuclear cells was extracted. Ten polymorphisms within five genes were investigated including TS, GSTP, ERCC, XPD and XRCC.Results: The overall response rate (RR) was 43.8%. Median time to progression (TTP) and overall survival (OS) were 6.0 months and 12.6 months, respectively. Toxicities were generally tolerable and manageable. The RR was significantly higher in patients with a 6-bp deletion homozygote (-6 bp/-6 bp) in TS-3'UTR (55.0% vs. 30.3% in +6 bp/+6 bp or +6 bp/-6 bp, p = 0.034), and C/A or A/A in XPD156 (52.0% vs. 26.1% in C/C, p = 0.038). The -6 bp/-6 bp in TS-3'UTR was significantly associated with a prolonged TTP and OS. In a multivariate analysis, the 6-bp deletion in TS-3'UTR was identified as an independent prognostic marker of TTP (hazard ratio = 0.561, p = 0.032).Conclusion: Modified FOLFOX-6 chemotherapy appears to be active and well tolerated as first line chemotherapy in AGC patients. The 6-bp deletion in TS-3'UTR might be a candidate to select patients who are likely to benefit from 5-FU based modified FOLFOX-6 in future large scale trial. [ABSTRACT FROM AUTHOR]

Zika virus (ZIKV) infection is primarily transmitted by mosquitoes and often asymptomatic in most individuals. Infection during pregnancy can lead to severe birth defects such as congenital microcephaly, and currently, there is no approved vaccine for ZIKV. Several studies are investigating the development of ZIKV vaccine using DNA and RNA as well as recombinant protein technologies; however, the outcomes thus far have not been consistently noteworthy. In this study, we designed an mRNA vaccine for ZIKV and evaluated its immunogenicity using a mouse model. Our vaccine, termed 3xEIII, encodes a triple repeat of domain III from the ZIKV E protein. We effectively encapsulated the mRNA within lipid nanoparticles (LNPs), administered 3xEIII to mice via two intramuscular injections, and assessed the induced humoral and cellular immune responses. Specifically, the vaccine elicited neutralizing antibodies that effectively eliminated ZIKV from the organs of challenged mice. Notably, 3xEIII conferred both protective effects and long-term immunity. In subsequent challenges conducted 40 weeks after boosting, immunized mice experienced temporary weight loss but showed significantly reduced viral titers in target organs by the 9th day post-infection. Conclusively from these findings, 3xEIII stands out as a promising noteworthy mRNA vaccine candidate for Zika virus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Importance: Little is known about the impact of different anesthetic agents used for routine magnetic resonance imaging (MRI) sedation on pulmonary function in children., Objective: To compare the incidence of pulmonary atelectasis after MRI sedation with propofol vs propofol-ketamine., Design, Setting, and Participants: This double-masked randomized clinical trial screened 117 consecutive pediatric patients aged 3 to 12 years with American Society of Anesthesiologists physical status I to II undergoing elective MRI under deep sedation from November 2, 2022, to April 28, 2023, at a tertiary referral center. Four patients met the exclusion criteria, and 5 patients refused to participate. The participants and outcome assessors were masked to the group allocation., Interventions: During the MRI, the propofol group received 0.2 mL/kg of 1% propofol and 2 mL of 0.9% saline followed by a continuous infusion of propofol (200 μg/kg/min) and 0.9% saline (0.04 mL/kg/min). The propofol-ketamine group received 0.2 mL/kg of 0.5% propofol and 1 mg/kg of ketamine followed by a continuous infusion of propofol (100 μg/kg/min) and ketamine (20 μg/kg/min)., Main Outcome and Measure: The incidence of atelectasis assessed by lung ultrasonography examination., Results: A total of 107 children (median [IQR] age, 5 [4-6] years; 62 male [57.9%]), with 54 in the propofol group and 53 in the propofol-ketamine group, were analyzed in this study. Notably, 48 (88.9%) and 31 (58.5%) patients had atelectasis in the propofol and propofol-ketamine groups, respectively (relative risk, 0.7; 95% CI, 0.5-0.8; P < .001). The incidence of desaturation and interruption of the MRI due to airway intervention or spontaneous movement did not significantly differ between the groups. The propofol-ketamine group showed a faster emergence time than the propofol group (15 [9-23] vs 25 [22-27] minutes in the propofol-ketamine vs propofol group; median difference in time, 9.0 minutes; 95% CI, 6.0-12.0 minutes; P < .001). No patient was withdrawn from the trial due to adverse effects., Conclusions and Relevance: In this randomized clinical trial, the propofol-ketamine combination reduced sedation-induced atelectasis while allowing for faster emergence compared with propofol alone., Trial Registration: cris.nih.go.kr Identifier: KCT0007699.

Purpose: Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS)., Methods: A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL)., Results: INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports., Conclusion: Regorafenib improves survival compared with placebo in refractory AGOC.

Vibrio vulnificus , an opportunistic human pathogen, employs biofilm formation as a key survival and virulence mechanism. BrpT, a transcriptional regulator, is essential for V. vulnificus biofilm development by regulating the expression of biofilm-related genes. In this study, we aimed to identify a small molecule inhibitor of BrpT to combat V. vulnificus biofilm formation. High-throughput screening of 7,251 compounds using an Escherichia coli reporter strain carrying the arabinose-inducible brp T gene and a BrpT-activated promoter fused to the luxCDABE operon identified a hit compound, BTI (BrpT Inhibitor). BTI potently inhibited BrpT activity in V. vulnificus (EC 50 of 6.48 μM) without affecting bacterial growth or host cell viability. Treatment with BTI significantly reduced the expression of the BrpT regulon and impaired biofilm formation and colony rugosity in V. vulnificus , thus increasing its susceptibility to antibiotics. In vitro biochemical analyses revealed that BTI directly binds to BrpT and inhibits its transcriptional regulatory activity. The identification of BTI as a specific inhibitor of BrpT that effectively diminishes V. vulnificus biofilm formation provides a promising foundation for the development of novel anti-biofilm strategies, with the potential to address the growing challenge of antibiotic resistance and improve the treatment of biofilm-associated infections.

Purpose: Lung-recruitment maneuvers (LRM) have been shown to reduce postoperative pain after laparoscopic surgery. This study aimed to investigate the association of LRM with the incidence of shoulder pain after laparoscopic cholecystectomy., Methods: A randomized controlled study was conducted with 110 patients undergoing elective laparoscopic cholecystectomy from July 2022 to March 2023. Participants were randomized to receive either routine exsufflation or LRM at pneumoperitoneum release. The postoperative shoulder pain and abdominal pain were assessed at 1, 4, 6, 12, and 24 h after surgery using a numeric rating scale. Analgesic consumption and postoperative nausea or vomiting (PONV) were evaluated during the first 24 h after surgery., Results: The incidence of shoulder pain during the first 24 h after surgery was significantly lower in the LRM group compared to the control group (26.9 vs. 59.3%; P = 0.001). The median [interquartile range] score of worst shoulder pain was significantly lower compared to the control group (3 [2-3] vs 4 [3-5.5]; P = 0.003). Participants in the LRM group showed reduced abdominal pain at rest at 4 and 24 h after surgery, and experienced significantly lower intensities of abdominal pain during mobilization at all time points over 24 h after surgery. There were no significant differences in opioid consumption or the incidence of PONV between the groups., Conclusions: LRM reduces both the incidence and intensity of shoulder pain during 24 h after laparoscopic cholecystectomy. Additionally, LRM was associated with reduced intensity of abdominal pain during mobilization over the study period., (© 2024. The Author(s) under exclusive licence to Japanese Society of Anesthesiologists.)

Background: The healthy worker effect may distort the association between exposure and health effects in workers. However, few studies have investigated both the healthy worker hire and survival effects simultaneously, and they are limited to mortality studies in male workers., Methods: We utilized a data set comprising South Korean diagnostic medical radiation workers registered in the National Dose Registry between 1996 and 2011, and merged it with mortality and cancer incidence data. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were computed for comparison with the general population. To account for time-varying confounders influenced by prior occupational radiation exposure, we applied g-estimation using structural nested accelerated failure time models and compared the outcomes with those from Weibull regression., Results: A total of 1831 deaths and 3759 first primary cancer cases were identified among 93 918 workers. Both male (SMR = 0.44; 95% CI: 0.42, 0.46) and female workers (SMR = 0.53; 95% CI: 0.46, 0.60) showed lower mortality rates compared with national rates. In the SIR analysis, male workers exhibited reduced risks of solid cancer whereas female workers had increased risks. The g-estimation-derived hazard ratios (HRs) from radiation exposure exceeded those from Weibull regression estimates for all-cause death (HR = 2.55; 95% CI: 1.97, 3.23) and all-cancer incidence (HR = 1.96; 95% CI: 1.52, 2.55) in male workers whereas female workers showed the opposite results., Conclusions: Comprehensive consideration of the healthy worker effect by sex is essential for estimating the unbiased impact of occupational exposure on health outcomes, notably in studies focusing on male mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: Atopic dermatitis (AD) is a chronic inflammatory cutaneous disorder, that emerges from intricate interplays among genetic predisposition, immune dysregulation, environmental factors, and compromised skin barrier. Understanding the inflammatory pathway in AD is important due to its fundamental role in the pathogenesis of AD. This study aimed to explore the diverse spectrum of proteins linked to the inflammation of AD and the relationship between systemic biomarkers and clinical severity in AD., Methods: We examined the blood samples from 48 patients with AD and 48 healthy controls (HCs) using the Proximity Extension Assay (Olink). Differentially expressed proteins (DEPs) were identified and Pearson correlation analysis was conducted to determine systemic proteomic biomarkers associated with severity of AD., Results: A total of 29 DEPs were significantly up-regulated and 2 DEPs were significantly down-regulated in AD compared with the HC. The MCP-4, IL-18, MCP-3, TNFRSF9, and IL-17C were the top 5 highest DEPs associated with the severity of AD., Conclusion: Our study sheds light on the intricate network of inflammatory proteins in AD and their potential implications for disease severity. Our results indicate that these systemic inflammatory proteins could be valuable for assessing AD severity and enhancing our understanding of the disease's complexity and its potential management strategies., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Cardiovascular diseases (CVDs) have been associated with atopic dermatitis (AD), including in Korean patients. Previous studies on AD have primarily focused on patients of European ancestry, while the Asian endotype exhibits distinct characteristics. This study aimed to characterize the blood proteomic signature of Korean patients with moderate-to-severe AD, with an emphasis on proteins related to CVDs., Methods: A total of 78 participants, including 39 patients with moderate-to-severe AD and 39 age- and sex-matched healthy controls, were enrolled. Blood proteomics analysis was performed using the Olink CVD II panel, which measures the expression levels of 92 proteins associated with CVDs., Results: Unsupervised hierarchical clustering revealed 44 upregulated and 5 downregulated proteins in AD patients compared to healthy controls. Principal component analysis (PCA) effectively distinguished AD patients from healthy subjects based on the complete set of proteins or the subset of upregulated proteins. A multiple linear regression model comprising CCL17 and FGF21 showed a strong correlation with disease severity (R = 0.619). Correlation analysis identified 25 highly correlated proteins, including STK4, ITGB1BP2, and DECR1, which were newly found to be upregulated in Korean AD patients. Pathway analysis highlighted the involvement of these proteins in vascular system, inflammation, and lipid metabolism pathways., Conclusion: The blood proteomic profile of moderate-to-severe AD patients in Korea differed from healthy controls using the CVD II panel. This study provides potential biomarkers for the AD-CVD association and insights into the pathways contributing to this relationship in the Korean population., Competing Interests: The authors declare that they have no competing interests., (© 2024 The Authors.)

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2 + ) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2 + gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies., (© 2024. The Author(s).)

Background: Efforts to profile atopic dermatitis (AD) tissues have intensified, yet comprehensive analysis of systemic immune landscapes in severe AD remains crucial., Methods: Employing single-cell RNA sequencing, we analyzed over 300,000 peripheral blood mononuclear cells from 12 severe AD patients (Eczema area and severity index (EASI) > 21) and six healthy controls., Results: Results revealed significant immune cell shifts in AD patients, including increased Th2 cell abundance, reduced NK cell clusters with compromised cytotoxicity, and correlated Type 2 innate lymphoid cell proportions with disease severity. Moreover, unique monocyte clusters reflecting activated innate immunity emerged in very severe AD (EASI > 30). While overall dendritic cells (DCs) counts decreased, a distinct Th2-priming subset termed "Th2&#95;DC" correlated strongly with disease severity, validated across skin tissue data, and flow cytometry with additional independent severe AD samples. Beyond the recognized role of Th2 adaptive immunity, our findings highlight significant innate immune cell alterations in severe AD, implicating their roles in disease pathogenesis and therapeutic potentials., Conclusion: Apart from the widely recognized role of Th2 adaptive immunity in AD pathogenesis, alterations in innate immune cells and impaired cytotoxic cells have also been observed in severe AD. The impact of these alterations on disease pathogenesis and the effectiveness of potential therapeutic targets requires further investigation., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: This study aimed to compare the analgesic effects of programmed intermittent epidural boluses (PIEB) and continuous epidural infusion (CEI) for postoperative analgesia after elective cesarean section (CS)., Methods: Seventy-four women who underwent elective CS were randomized to receive either PIEB or CEI. The PIEB group received 4 ml-intermittent boluses of 0.11% ropivacaine every hour at a rate of 120 ml/h. The CEI group received a constant rate of 4 ml/h of 0.11% ropivacaine. The primary outcome was the pain score at rest at 36 h after CS. Secondary outcomes included the pain scores during mobilization, time-weighted pain scores, the incidence of motor blockade, and complications-related epidural analgesia during 36 h after CS., Results: The pain score at rest at 36 h after CS was significantly lower in the PIEB group compared with that in the CEI group (3.0 vs. 0.0; median difference: 2, 95% CI [1, 2], P < 0.001). The mean time-weighted pain scores at rest and during mobilizations were also significantly lower in the PIEB group than in the CEI group (pain at rest; mean difference [MD]: 37.5, 95% CI [24.6, 50.4], P < 0.001/pain during mobilization; MD: 56.6, 95% CI [39.8, 73.5], P < 0.001). The incidence of motor blockade was significantly reduced in the PIEB group compared with that in the CEI group (P < 0.001)., Conclusions: PIEB provides superior analgesia with less motor blockade than CEI in postpartum women after CS, without any apparent adverse events.

Purpose: Clinical implications of neoadjuvant immunotherapy in patients with locally advanced but resectable head and neck squamous cell carcinoma (HNSCC) remain largely unexplored., Patients and Methods: Patients with resectable HNSCC were randomized to receive a single dose of preoperative durvalumab (D) with or without tremelimumab (T) before resection, followed by postoperative (chemo)radiotherapy based on multidisciplinary discretion and 1-year D treatment. Artificial intelligence (AI)-powered spatial distribution analysis of tumor-infiltrating lymphocytes and high-dimensional profiling of circulating immune cells tracked dynamic intratumoral and systemic immune responses., Results: Of the 48 patients enrolled (D, 24 patients; D+T, 24 patients), 45 underwent surgical resection per protocol (D, 21 patients; D+T, 24 patients). D±T had a favorable safety profile and did not delay surgery. Distant recurrence-free survival (DRFS) was significantly better in patients treated with D+T than in those treated with D monotherapy. AI-powered whole-slide image analysis demonstrated that D+T significantly reshaped the tumor microenvironment toward immune-inflamed phenotypes, in contrast with the D monotherapy or cytotoxic chemotherapy. High-dimensional profiling of circulating immune cells revealed a significant expansion of T-cell subsets characterized by proliferation and activation in response to D+T therapy, which was rare following D monotherapy. Importantly, expansion of specific clusters in CD8+ T cells and non-regulatory CD4+ T cells with activation and exhaustion programs was associated with prolonged DRFS in patients treated with D+T., Conclusions: Preoperative D±T is feasible and may benefit patients with resectable HNSCC. Distinct changes in the tumor microenvironment and circulating immune cells were induced by each treatment regimen, warranting further investigation., (©2024 American Association for Cancer Research.)

Developing new adjuvants that can effectively induce humoral and cellular immune responses while broadening the immune response is of great value. In this study, we aimed to develop single-stranded RNA adjuvants expressing (1) granulocyte monocyte colony-stimulating factor or (2) interleukin 18 based on the encephalomyocarditis virus internal ribosome entry site; we also tested their efficacy in combination with ovalbumin or inactivated influenza vaccines. Notably, cytokine-expressing RNA adjuvants increased the expression of antigen-presenting cell activation markers in mice. Specifically, when combined with ovalbumin, RNA adjuvants expressing granulocyte monocyte colony-stimulating factor increased CD4+ T-cell responses, while those expressing interleukin 18 increased CD8+ T-cell responses. Cytokine-expressing RNA adjuvants further increased the frequency of polyclonal T cells with the influenza vaccine and reduced the clinical illness scores and weight loss of mice after viral challenge. Collectively, our results suggest that cytokine-expressing RNA adjuvants can be applied to protein-based or inactivated vaccines to increase their efficacy., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The rapid development of messenger RNA (mRNA) vaccines formulated with lipid nanoparticles (LNPs) has contributed to control of the COVID-19 pandemic. However, mRNA vaccines have raised concerns about their potential toxicity and clinical safety, including side effects, such as myocarditis, anaphylaxis, and pericarditis. In this study, we investigated the potential of trehalose glycolipids-containing LNP (LNP S050L) to reduce the risks associated with ionizable lipids. Trehalose glycolipids can form hydrogen bonds with polar biomolecules, allowing the formation of a stable LNP structure by replacing half of the ionizable lipids. The efficacy and safety of LNP S050L were evaluated by encapsulating the mRNA encoding the luciferase reporter gene and measuring gene expression and organ toxicity, respectively. Furthermore, mice immunized with an LNP S050L-formulated mRNA vaccine expressing influenza hemagglutinin exhibited a significant reduction in organ toxicity, including in the heart, spleen, and liver, while sustaining gene expression and immune efficiency, compared to conventional LNPs (Con-LNPs). Our findings suggest that LNP S050L, a trehalose glycolipid-based LNP, could facilitate the development of safe mRNA vaccines with improved clinical safety., Competing Interests: The authors declare the following personal relationships which may be considered as potential competing interests: Sang-In Park is currently employed by SML Biopharm.The authors declare the following personal relationships which may be considered as potential competing interests: is currently employed by Jamia Millia Islamia. All authors have seen and approved the final version of the manuscript being submitted. They warrant that the article is the authors' original work, hasn't received prior publication and isn't under consideration for publication elsewhere., (© 2024 The Authors.)

Study Objective: To investigate the analgesic efficacy of erector spinae plane block (ESPB) in major gynecologic surgery, expressed as cumulative opioid consumption 24 h after surgery., Design: A single-center, patient-assessor blinded, randomized controlled study., Setting: Samsung medical center (tertiary university hospital), between February 2022 to January 2023., Patients: Eighty-eight females undergoing major surgery with long midline incision for gynecologic malignancy., Interventions: Patients were randomly assigned to receive standard systemic analgesia (Control group) or ESPB (ESPB group). ESPB was performed bilaterally at the level of the 9th thoracic vertebra with a mixture of 20 mL of 0.5% ropivacaine and 100 μg of epinephrine., Measurements: The primary outcome was cumulative opioid consumption at 24 h postoperatively. Secondary outcomes included opioid consumption and pain severity during the 72 h after surgery. The variables regarding postoperative recovery and patient-centered outcomes were compared., Main Results: The mean cumulative opioid consumption 24 h after surgery was 35.8 mg in the ESPB group, which was not significantly different from 41.4 mg in the control group (mean difference, 5.5 mg; 95% CI -1.7 to 12.8 mg; P = 0.128). However, patient satisfaction regarding analgesia was significantly higher in the ESPB group compared with the control group at 24 h postoperative (median difference, -1; 95% CI -3 to 0; P = 0.038). There were no significant differences in the variables associated with postoperative recovery., Conclusion: ESPB did not reduce opioid consumption during the 24 h postoperative but attenuated pain intensity during the early period after surgery., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Recently, endotracheal tubes with an embedded temperature sensor in the inner surface of the tube cuff (temperature tracheal tubes) have been developed. We sought to assess whether temperature tracheal tubes show a good agreement with esophageal temperature probes during surgery., Methods: We enrolled 40 patients who underwent laparoscopic surgery in an observational study. The tracheas of all patients were intubated with a temperature tracheal tube, and an esophageal temperature probe was inserted into the esophagus. Tracheal and esophageal temperatures were recorded at 15-min intervals until the end of surgery. Temperatures from both devices were analyzed using Bland-Altman analysis, four-quadrant plots, and polar plots., Results: We analyzed 261 data points from 36 patients. Temperatures ranges were 34.2 °C to 36.6 °C for the tracheal temperature tube and 34.7 °C to 37.2 °C for the esophageal temperature probe. Bland-Altman analysis showed an acceptable agreement between the two devices, with an overall mean bias (95% limit of agreement) of -0.3 °C (-0.8 °C to 0.1 °C) and a percentage error of 3%; the trending ability (temperature changes over time) between the two devices showed a concordance rate of 94% in four-quadrant plot (cut-off ≥ 92%), but this was higher than the acceptable mean angular bias of 177° (cut-off <  ± 5°) and radial limits of agreement of 52° (cut-off <  ± 30°) in the polar plot. Bronchoscopy during extubation and patient interviews at six hours postoperatively revealed no serious injuries related to the use of the temperature tracheal tube., Conclusion: The temperature tracheal tube showed an acceptable overall mean bias of -0.3 °C and a percentage error of 3%, but incompatible trending ability with the esophageal temperature probe., Study Registration: cris.nih.go.kr (KCT0007265); 22 April 2022., (© 2024. Canadian Anesthesiologists' Society.)

Paclitaxel, one of the most frequently used anticancer drugs, is dosed by body surface area, which leads to substantial inter-individual variability in systemic drug exposure. We evaluated clinical evidence regarding the scientific rationale and clinical benefit of individualized paclitaxel dosing based on measured systemic concentrations, known as therapeutic drug monitoring (TDM). In retrospective studies, higher systemic exposure is associated with greater toxicity and efficacy of paclitaxel treatment across several disease types and dosing regimens. In prospective trials, TDM reduces variability in systemic exposure, and has been demonstrated to reduce toxicity while retaining treatment efficacy for 3-weekly dosing in patients with advanced non-small cell lung cancer. Despite the demonstrated benefits of paclitaxel TDM, clinical adoption has been limited due to the challenges with sample collection and analysis. Based on our review, we strongly recommend TDM for patients receiving every 3-week paclitaxel in combination with a platinum agent for advanced NSCLC, due to the prospectively demonstrated clinical benefits, and find moderate evidence to recommend TDM for paclitaxel 3-hour infusions for other tumor types and preliminary evidence suggesting potential usefulness for paclitaxel administered by 1-hour infusions., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hertz, none declared;. Joerger, none declared;. Bang, Consulting/Advisory Board: Astellas, Amgen, Hanmi, Daewoong, SK Biopharm;. Mathijssen, none declared;. Zhou, none declared;. Zhang, none declared;. Gandara, none declared;. Stahl, none declared;. Monk, none declared;. Jaehde, none declared;. Beumer, none declared., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis., Methods: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety., Results: This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-‍34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-‍81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1)., Conclusion: The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC., Clinical Trial Information: FIH study, NCT02564900; DDI study, NCT03383692., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: GC1118 is a novel antibody targeting epidermal growth factor receptor (EGFR) with enhanced blocking activity against both low- and high-affinity EGFR ligands. A phase 1b/2a study was conducted to determine a recommended phase 2 dose (RP2D) of GC1118 in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) (phase 1b) and to assess the safety and efficacy of GC1118 plus FOLFIRI as a second-line therapy for recurrent/metastatic colorectal cancer (CRC) (phase 2a)., Materials and Methods: Phase 1b was designed as a standard 3+3 dose-escalation study with a starting dose of GC1118 (3 mg/kg/week) in combination with biweekly FOLFIRI (irinotecan 180 mg/m2; leucovorin 400 mg/m2; 5-fluorouracil 400 mg/m2 bolus and 2,400 mg/m2 infusion over 46 hours) in patients with solid tumors refractory to standard treatments. The subsequent phase 2a part was conducted with objective response rate (ORR) as a primary endpoint. Patients with KRAS/NRAS/BRAF wild-type, EGFR-positive, recurrent/metastatic CRC resistant to the first-line treatment were enrolled in the phase 2a study., Results: RP2D of GC1118 was determined to be 3 mg/kg/wk in the phase 1b study (n=7). Common adverse drug reactions (ADRs) observed in the phase 2a study (n=24) were acneiform rash (95.8%), dry skin (66.7%), paronychia (58.3%), and stomatitis (50.0%). The most common ADR of ≥ grade 3 was neutropenia (33.3%). ORR was 42.5% (95% confidence interval [CI], 23.5 to 62.0), and median progression-free survival was 6.7 months (95% CI, 4.0-8.0)., Conclusion: GC1118 administered weekly at 3 mg/kg in combination with FOLFIRI appears as an effective and safe treatment option in recurrent/metastatic CRC.

The human gut houses a diverse and dynamic microbiome critical for digestion, metabolism, and immune development, exerting profound effects on human health. However, these microorganisms pose a potential threat by breaching the gut barrier, entering host tissues, and triggering infections, uncontrolled inflammation, and even sepsis. The intestinal epithelial cells form the primary defense, acting as a frontline barrier against microbial invasion. Antimicrobial proteins (AMPs), produced by these cells, serve as innate immune effectors that regulate the gut microbiome by directly killing or inhibiting microbes. Abnormal AMP production, whether insufficient or excessive, can disturb the microbiome equilibrium, contributing to various intestinal diseases. This review delves into the complex interactions between AMPs and the gut microbiota and sheds light on the role of AMPs in governing host-microbiota interactions. We discuss the function and mechanisms of action of AMPs, their regulation by the gut microbiota, microbial evasion strategies, and the consequences of AMP dysregulation in disease. Understanding these complex interactions between AMPs and the gut microbiota is crucial for developing strategies to enhance immune responses and combat infections within the gut microbiota. Ongoing research continues to uncover novel aspects of this intricate relationship, deepening our understanding of the factors shaping gut health. This knowledge has the potential to revolutionize therapeutic interventions, offering enhanced treatments for a wide range of gut-related diseases., (© 2024. The Author(s).)

Background: The inflamed immune phenotype (IIP), defined by enrichment of tumor-infiltrating lymphocytes (TILs) within intratumoral areas, is a promising tumor-agnostic biomarker of response to immune checkpoint inhibitor (ICI) therapy. However, it is challenging to define the IIP in an objective and reproducible manner during manual histopathologic examination. Here, we investigate artificial intelligence (AI)-based immune phenotypes capable of predicting ICI clinical outcomes in multiple solid tumor types., Methods: Lunit SCOPE IO is a deep learning model which determines the immune phenotype of the tumor microenvironment based on TIL analysis. We evaluated the correlation between the IIP and ICI treatment outcomes in terms of objective response rates (ORR), progression-free survival (PFS), and overall survival (OS) in a cohort of 1,806 ICI-treated patients representing over 27 solid tumor types retrospectively collected from multiple institutions., Results: We observed an overall IIP prevalence of 35.2% and significantly more favorable ORRs (26.3% vs 15.8%), PFS (median 5.3 vs 3.1 months, HR 0.68, 95% CI 0.61 to 0.76), and OS (median 25.3 vs 13.6 months, HR 0.66, 95% CI 0.57 to 0.75) after ICI therapy in IIP compared with non-IIP patients, respectively (p<0.001 for all comparisons). On subgroup analysis, the IIP was generally prognostic of favorable PFS across major patient subgroups, with the exception of the microsatellite unstable/mismatch repair deficient subgroup., Conclusion: The AI-based IIP may represent a practical, affordable, clinically actionable, and tumor-agnostic biomarker prognostic of ICI therapy response across diverse tumor types., Competing Interests: Competing interests: JS and SB received institutional research funding from Lunit, Inc. HS, SP, SSh, YL, CHO, Seulki Kim, CO, Sukjun Kim, GP, SSo, WJ, SA and C-YO are employees of Lunit, Inc. Y-JB. is a Consultant/Advisory Board member for Merck Sharp and Dohme (MSD), Merck Serono, Daiichi-Sankyo, Astellas, Alexo Oncology, Samyang Biopharm, Hanmi, Daewoong, and Amgen, and received institutional research grants for clinical trials from Genentech/Roche, MSD, Merck Serono, Daiichi Sankyo, Astellas, and Amgen in the past 3 years. Other authors declare no potential conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Despite the increasing use of immediate breast reconstruction (IBR), its oncologic safety in the setting of neoadjuvant chemotherapy (NACT) needs to be comprehensively clarified in breast cancer management. The objective of the present study was to analyze the oncologic safety of IBR following NACT., Methods: In total, 587 patients with breast cancer who underwent a total mastectomy (TM) with IBR after NACT between 2008 and 2017 at a single institution were retrospectively reviewed. The reviewed patients with IBR following skin-sparing mastectomy (SSM) or nipple-sparing mastectomy (NSM) were matched 1:3 to patients who underwent TM alone after NACT. Matching variables included age, clinical T and N stages before NACT, response to NACT, pathologic T and N stages, and molecular subtypes., Results: After propensity score matching, 95 patients who underwent IBR following SSM/NSM after NACT (IBR group) and 228 patients who underwent TM alone after NACT (TM group) were selected. The median follow-up period was 73 (range, 5-181) months after matching. After matching, there were no significant differences between the two groups in 5-year locoregional recurrence-free survival (88.8% vs. 91.2%, p = 0.516), disease-free survival (67.3% vs. 76.6%, p = 0.099), distant metastasis-free survival (71.9% vs. 81.9%, p = 0.057), or overall survival (84.1% vs. 91.5, p = 0.061) rates. In multivariate analyses, conducting IBR was not associated with increased risks for locoregional recurrence, any recurrence, distant metastasis, or overall death., Conclusion: Our findings suggest that IBR following SSM/NSM elicits comparable long-term oncologic outcomes to those of TM alone in the setting of NACT., Competing Interests: The authors declare that they have no competing interests., (© 2024 Korean Breast Cancer Society.)