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Purpose: Primary tumor resection and metastasectomy are curative for metastatic colorectal cancer. However, there is still a paucity of data regarding the clinical outcomes and risk factors after disease recurrence and second metastasectomy., Materials and Methods: We retrospectively evaluated the clinical outcomes of patients who underwent the second metastasectomy. In addition, risk factors for the outcomes were analyzed., Results: A total of 94 patients (39 females and 55 males) received a second metastasectomy after the recurrence. Recurrent sites included the lung (47 patients), liver (36 patients), both lung and liver (four patients), and non-lung/non-liver (seven patients). Among them, 89 (94.7 %) patients achieved R0 resection, while three (3.2 %) and two (2.1 %) patients achieved R1 and R2 resections, respectively. The 5-year disease-free survival (DFS) and overall survival (OS) were 42.8±5.3 % and 67.2±4.9 %, respectively. Multivariable analysis for DFS identified that primary rectal cancer (hazard ratio [HR] 0.45, P=0.033) and disease-free interval after the first metastasectomy of ≥12 months (HR 0.39, P=0.002) were good predictive factors; in contrast, non-lung/non-liver metastasis (HR 3.32, P=0.020) was a poor predictive factor. Multivariable analysis for OS showed that age ≥70 years (HR 3.27, P=0.011), non-lung/non-liver metastasis (HR 4.04, P=0.024), and lesion number ≥2 (HR 2.25, P=0.023) were poor prognostic factors., Conclusion: Patients who underwent a second metastasectomy had a long-term disease-free state and good OS. Our data suggest that a second metastasectomy should be considered if a patient has a limited number of metastases confined to the liver and/or lung and long DFS after the first metastasectomy., 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 Elsevier Inc. All rights reserved.)

Background: In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial., Methods: The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or >6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS)., Results: A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG > 6 vs. CGD > 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]., Conclusion: Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Biliary tract cancers (BTCs) harbor an immunosuppressed tumor microenvironment and respond poorly to PD-1/PD-L1 inhibitors. Bevacizumab (anti-vascular endothelial growth factor) plus chemotherapy can promote anticancer immunity, augmenting response to PD-L1 inhibition., Patients and Methods: This randomized, double-blind, proof-of-concept phase II study enrolled patients (n = 162) with previously untreated advanced BTC (IMbrave151; ClinicalTrials.gov identifier: NCT04677504). Patients were randomly assigned 1:1 to receive cycles of atezolizumab (1,200 mg) plus bevacizumab (15 mg/kg) or atezolizumab plus placebo once every 3 weeks until disease progression or unacceptable toxicity. All patients received cisplatin (25 mg/m 2 ) plus gemcitabine (1,000 mg/m 2 ; cisplatin plus gemcitabine [CisGem]) on days 1 and 8 once every 3 weeks for up to eight cycles. Stratification of patients was by disease status, geographic region, and primary tumor location. The primary end point was progression-free survival (PFS). No formal hypothesis testing was performed. Exploratory correlative biomarker analysis was undertaken using transcriptome analysis (n = 95) and mutation profiling (n = 102) on baseline tumor samples., Results: Between February and September 2021, 162 patients were enrolled. Median PFS was 8.3 months in the bevacizumab arm and 7.9 months in the placebo arm (stratified hazard ratio [HR], 0.67 [95% CI, 0.46 to 0.95]). Median overall survival (OS) was 14.9 and 14.6 months in the bevacizumab and placebo arms, respectively (stratified HR, 0.97 [95% CI, 0.64 to 1.47]). The incidence of grade 3 or 4 adverse events was 74% in both arms. High VEGFA gene expression was associated with improved PFS (HR, 0.44 [95% CI, 0.23 to 0.83]) in the bevacizumab arm versus placebo., Conclusion: In unselected patients with advanced BTC, adding bevacizumab to atezolizumab plus CisGem modestly improves PFS but not OS. High VEGFA gene expression may represent a predictive biomarker of benefit from atezolizumab/bevacizumab, warranting further investigation.

Purpose: While fluoropyrimidine-based chemotherapy regimens are recommended second-line treatment for patients with advanced biliary tract cancer (BTC), there have been no studies comparing different regimens head-to-head., Materials and Methods: We performed individual patient-level meta-analysis based on data from the intention-to-treat population of the phase 2b NIFTY trial (liposomal irinotecan [nal-IRI] plus fluorouracil and leucovorin [5-FU/LV] vs. 5-FU/LV; NCT03542508) and the phase 2 FIReFOX trial (modified oxaliplatin plus 5-FU/LV [mFOLFOX] vs. modified irinotecan plus 5-FU/LV [mFOLFIRI]; NCT03464968). Pairwise log-rank tests and multivariable analysis using Cox proportional hazards modeling with shared frailty to account for the trial's effect were used to compare overall survival (OS) between regimens., Results: A total of 277 patients were included. The nal-IRI plus 5-FU/LV group (n=88) showed significantly better OS compared to the mFOLFOX group (n=49, pairwise log-rank, p=0.02), and mFOLFIRI group (n=50, p =0.03). Multivariable analysis showed consistent trends in OS with adjusted hazard ratios of 1.39 (mFOLFOX vs nal-IRI plus 5-FU/LV, 95% CI 0.93-2.07, p=0.11) and 1.36 (mFOLFIRI vs nal-IRI plus 5-FU/LV, 95% CI 0.92-2.03, p=0.13), respectively. Compared to the 5-FU/LV group, the mFOLFOX group and the mFOLFIRI group did not show differences in terms of OS (pairwise log-rank p=0.83 and p=0.58, respectively). The nal-IRI plus 5-FU/LV group experienced more frequent diarrhea, while the mFOLFOX group experienced peripheral neuropathy., Conclusion: Nal-IRI plus 5-FU/LV showed favorable survival outcomes compared to mFOLFOX, mFOLFIRI, or 5-FU/LV. The safety profiles of these regimens should be considered along with efficacy.

Background: Current guidelines recommend intervention for asymptomatic rheumatic mitral stenosis (MS) with mitral valve area ≤1.5 cm 2 based on indicators including pulmonary arterial systolic pressure (PASP) >50 mm Hg and new-onset atrial fibrillation; however, evidence supporting this is lacking., Methods: This single-center retrospective study included patients with rheumatic MS between 2006 and 2022. Pulmonary hypertension was evaluated by using echocardiography to estimate PASP. Primary outcomes were major adverse cardiovascular events (MACE), including all-cause mortality, hospitalization for heart failure, and arterial thromboembolic events for up to 5 years., Results: Overall, 287 patients with severe rheumatic MS were enrolled (mean age, 62.5±11.3 years; 74.6% women). During a median follow-up of 2.52 years, MACE occurred in 99 patients. There were no differences in echocardiographic parameters, such as the mean mitral valve pressure gradient, mitral valve area, and proportion of mitral valve area <1.0 cm 2 , between patients who developed primary outcomes and those who did not. Survival analysis showed a worse prognosis in patients with estimated PASP (ePASP) >50 mm Hg than in those with ePASP ≤50 mm Hg (log-rank P <0.001); however, atrial fibrillation was not a significant prognostic indicator. As a continuous variable, ePASP (mm Hg) was a significant predictor of MACE (adjusted hazard ratio, 1.027 [95% CI, 1.011-1.042]; P <0.001). Receiver operating characteristic analysis revealed an optimal ePASP threshold of >45 mm Hg, which was an independent predictor of MACE in patients with severe rheumatic MS (adjusted hazard ratio, 2.127 [95% CI, 1.424-3.177]; P <0.001). Competing risk analysis considering mitral valve intervention as a competing risk showed similar results., Conclusions: Our study demonstrated the prognostic significance of ePASP, rather than atrial fibrillation, in relation to MACE among patients with severe rheumatic MS. Additionally, we proposed a lower ePASP threshold (>45 mm Hg) as a predictor of an unfavorable prognosis., Competing Interests: None.

Purpose: This study aimed to compare tumor tissue DNA (ttDNA) and circulating tumor DNA (ctDNA) to explore the clinical applicability of ctDNA and to better understand clonal evolution in patients with metastatic colorectal cancer undergoing palliative first-line systemic therapy., Materials and Methods: We performed targeted sequencing analysis of 88 cancer-associated genes using germline DNA, ctDNA at baseline (baseline-ctDNA), and ctDNA at progressive disease (PD-ctDNA). The results were compared with ttDNA data., Results: Among 208 consecutively enrolled patients, we selected 84 (41 males; median age, 59 years; range, 35 to 90 years) with all four sample types available. A total of 202 driver mutations were found in 34 genes. ttDNA exhibited the highest mutation frequency (n=232), followed by baseline-ctDNA (n=155) and PD-ctDNA (n=117). Sequencing ctDNA alongside ttDNA revealed additional mutations in 40 patients (47.6%). PD-ctDNA detected 13 novel mutations in 10 patients (11.9%) compared to ttDNA and baseline-ctDNA. Notably, seven mutations in five patients (6.0%) were missense or nonsense mutations in APC, TP53, SMAD4, and CDH1 genes. In baseline-ctDNA, higher maximal variant allele frequency (VAF) values (p=0.010) and higher VAF values of APC (p=0.012), TP53 (p=0.012), and KRAS (p=0.005) mutations were significantly associated with worse overall survival., Conclusion: While ttDNA remains more sensitive than ctDNA, our ctDNA platform demonstrated validity and potential value when ttDNA was unavailable. Post-treatment analysis of PD-ctDNA unveiled new pathogenic mutations, signifying cancer's clonal evolution. Additionally, baseline-ctDNA's VAF values were prognostic after treatment.

Purpose: Thrombosis and bleeding significantly affect morbidity and mortality in myeloproliferative neoplasms (MPNs). The efficacy and safety of direct oral anticoagulants (DOACs) in MPN patients remain uncertain., Materials and Methods: We conducted a large, retrospective, nationwide cohort study using the Korean Health Insurance Review and Assessment Service database from 2010 to 2021., Results: Out of the 368 MPN patients included in the final analysis, 62.8% were treated with DOACs for atrial fibrillation (AF), and 37.2% for venous thromboembolism (VTE). The AF group was statistically older with higher CHA2DS2-VASc scores compared to the VTE group. Antiplatelet agents were used in 51.1% of cases, and cytoreductive drugs in 79.3%, with hydroxyurea being the most common (64.9%). The median follow-up was 22.3 months, with one-year cumulative incidence rates of thrombosis and bleeding at 11.1% and 3.7%, respectively. Multivariate analysis identified CHA2DS2-VASc scores ≥ 3 (HR=3.48), concomitant antiplatelet use (HR = 2.57), and cytoreduction (HR=2.20) as significant thrombosis risk factors but found no significant predictors for major bleeding., Conclusion: Despite the limitations of retrospective data, DOAC treatment in MPN patients seems effective and has an acceptable bleeding risk.

Background: Despite the detailed imaging information provided by optical coherence tomography (OCT) during percutaneous coronary intervention (PCI), clinical benefits of this imaging technique in this setting remain uncertain. The aim of the OCCUPI trial was to compare the clinical benefits of OCT-guided versus angiography-guided PCI for complex lesions, assessed as the rate of major adverse cardiac events at 1 year., Methods: This investigator-initiated, multicentre, randomised, open-label, superiority trial conducted at 20 hospitals in South Korea enrolled patients aged 19-85 years for whom PCI with drug-eluting stents was clinically indicated. After diagnostic angiography, clinical and angiographic findings were assessed to identify patients who met the criterion of having one or more complex lesions. Patients were randomly assigned 1:1 to receive PCI with OCT guidance (OCT-guidance group) or angiography guidance without OCT (angiography-guidance group). Web-response permuted-block randomisation (mixed blocks of four or six) was used at each participating site to allocate patients. The allocation sequence was computer-generated by an external programmer who was not involved in the rest of the trial. Outcome assessors were masked to group assignment. Patients, follow-up health-care providers, and data analysers were not masked. PCI was done according to conventional standard methods with everolimus-eluting stents. The primary endpoint was major adverse cardiac events (a composite of cardiac death, myocardial infarction, stent thrombosis, or ischaemia-driven target-vessel revascularisation), 1 year after PCI. The primary analysis was done in the intention-to-treat population. The margin used to establish superiority was 1·0 as a hazard ratio. This trial is registered with ClinicalTrials.gov (NCT03625908) and is completed., Findings: Between Jan 9, 2019, and Sept 22, 2022, 1604 patients requiring PCI with drug-eluting stents for complex lesions were randomly assigned to receive either OCT-guided PCI (n=803) or angiography-guided PCI (n=801). 1290 (80%) of 1604 patients were male and 314 (20%) were female. The median age of patients at randomisation was 64 years (IQR 57-70). 1588 (99%) patients completed 1-year follow-up. The primary endpoint occurred in 37 (5%) of 803 patients in the OCT-guided PCI group and 59 (7%) of 801 patients in the angiography-guided PCI group (absolute difference -2·8% [95% CI -5·1 to -0·4]; hazard ratio 0·62 [95% CI 0·41 to 0·93]; p=0·023). Rates of stroke, bleeding events, and contrast-induced nephropathy were not significantly different across the two groups., Interpretation: Among patients who required drug-eluting stent implantation for complex lesions, OCT guidance resulted in a lower incidence of major adverse cardiac events at 1 year compared with angiography guidance. These findings indicate the existence of a therapeutic benefit of OCT as an intravascular imaging technique for PCI guidance in patients with complex coronary lesions., Funding: Abbott Vascular and Cardiovascular Research Center., Translation: For the Korean translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests S-JH reports speaker fees from AstraZeneca, Amgen, ChongKunDang, Hanmi, and Viatris; and participation on the data safety monitoring board of the IVUS-DCB trial. S-JL reports research grants and speaker fees from Boston Scientific, Medtronic, ChongKunDang, and Sam Jin Pharmaceutical. JHH reports consulting and speaker fees from Abbott Vascular. J-WL reports consulting fees from Genoss; speaker fees from Yuhan, Boryoung, Sam Jin Pharmaceutical, ChongKunDang, Korea United Pharm, HK inno.N, Novartis, Boehringer Ingelheim, AstraZeneca, Medtronic, Abbott Vascular, Amgen, Sanofi, Boston Scientific, Daiichi-Sankyo, Daewoong Pharmaceutical, Biosensors, Dong-A ST, and JW Pharmaceutical; and participation on the data safety monitoring board of the Rescue-SHOCK trial. J-SK reports grants from Sam Jin Pharmaceutical, Yuhan, Daiichi-Sankyo, Biosensors, and Qualitech Korea and proctoring fees from Abbott Vascular. Y-GK reports research grants from Medtronic, Korea United Pharm, Cook Medical, Boston Scientific, Otsuka Korea, Dong-A ST, Sam Jin Pharmaceutical, Cordis, HK inno.N, and GC Biopharma. M-KH reports research grants, paid to their institution, from Sam Jin Pharmaceutical and ChongKunDang and honoraria for lectures from Medtronic and Edwards Lifesciences. YJ reports research grants, paid to their institution, from Abbott Vascular. B-KK reports research grants and speaker or consulting fees from Abbott Vascular, Yuhan, Sam Jin Pharmaceutical, ChongKunDang, Medtronic, Boston Scientific, Biotronik, Genoss, CGBIO, MicroPort, Daewoong Pharmaceutical, Amgen, Bayer Korea, DIO Medical, Hanmi, AstraZeneca, and Novartis. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Colonoscopy is a key procedure for the early detection of colorectal cancer. Despite its importance, the discomfort associated with colonoscopy often requires sedation, and the ideal sedation regimen remains to be determined. In this prospective randomized controlled trial, patients scheduled for colonoscopy were randomly assigned to two different sedation protocols. Group A received a combination of midazolam and propofol, while group B was given midazolam and pethidine. The study analyzed data from 51 patients, with 23 in group A and 28 in group B. The incidence of adverse events was similar across both groups. Additionally, no significant differences were observed in cecal intubation times or total procedure durations. Notably, group A had a lower frequency of required postural changes (1.0±.7 vs. 1.5±0.7, p=0.02) and a reduced rate of manual compression (52.2% vs. 82.1%, p=0.02). There were no significant differences between the groups regarding subjective pain or overall satisfaction. Both sedation regimens were found to be safe and effective. The midazolam and propofol combination was associated with a smoother procedure, evidenced by fewer postural adjustments and less manual compression needed during colonoscopy., Competing Interests: CONFLICT OF INTEREST STATEMENT: None declared., (© Chonnam Medical Journal, 2024.)

Background: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes., Methods: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS)., Results: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine., Conclusion: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC., Competing Interests: Declaration of Competing Interest LR reports consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Zymeworks. ACG reports consulting fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, IQVIA, MSD, Roche, Servier; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from AstraZeneca, Eisai. SLC serves an advisory member for AstraZeneca, MSD, Eisai, BMS, Ipsen, and Hengrui, received research funds from MSD, Eisai, Ipsen, SIRTEX, and Zailab, and honoraria from AstraZeneca, Eisai, Roche, Ipsen, and MSD. TP received consulting fees from Bayer, Ipsen, and AstraZeneca; institutional research funding from Roche, Bayer, and AstraZeneca; travel expenses from Roche. CB received honoraria as speaker (Astrazeneca, Incyte, Servier) and consultant (Incyte, Servier, Boehringer Ingelheim, Astrazeneca), received research funds (Avacta, Medannex, Servier) and her spouse is an employee of Astrazeneca. M. Ikeda reports honoraria from AstraZeneca, Chugai Pharma, Eisai, Incyte, Lilly Japan, MSD, Novartis, Ono Pharmaceutical, Takeda, Teijin Pharma, Nihon Servier, Taiho and research funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Chiome Bioscience, Chugai, Eisai, Eli Lilly Japan, Delta-Fly Pharma, Invitae, J-Pharma, Merck biopharma, Merus N.V., MSD, Novartis, Nihon Servier, Ono, Syneos Health, and Rakuten Medical. GWP: Advisories and/or Speaker fees: Servier, Bayer, Roche Amgen, Merck, MSD, BMS, Sanofi, Lilly, Astra Zeneca, Astellas, Pierre-Fabre, Incyte, Arcus, CECOG. F. F. has received travel support from Ipsen, Abbvie, Astrazeneca and speaker’s fees from AbbVie, MSD, Ipsen, Astrazeneca. LP: Advisory role: AstraZeneca, Servier, Travel expenses: AstraZeneca, Ipsen. GG: Consulting Fees: Astra Zeneca, MSD, Servier, Seagen, Bayer, Amgen, Novartis, Ipsen, BMS. Travel Expenses: Astra Zeneca, Servier, Bayer, Novartis. S.L. reports research funding (to Institution) from Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; personal honoraria as invited speaker from Amgen, Astra Zeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier; participation in advisory board for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm. JD received consulting fees and/or speaker honoraria from Amgen, AstraZeneca, Bayer, BMS, Eisai, Need Inc., Ipsen, Lilly, MediMix, Merck, MSD, Novartis, Roche and Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Timely palliative transition in patients with advanced cancer is essential for their improved quality of life and overall survival (OS). Most prognostic models have been developed focusing on weeks' survival. The current study aimed to compare the accuracies of several indicators, such as the Karnofsky Performance Scale (KPS), Clinicians' Prediction of Survival (CPS), and Edmonton Symptom Assessment System (ESAS), for predicting the survival of patients., Methods: Two hundred patients were enrolled at a single tertiary cancer center in South Korea between 2016 and 2019. We compared the discrimination of CPS versus KPS and ESAS total scores using the area under the receiver operating characteristic curve (AUROC) in 3-month and 6-month survival predictions., Results: The median age of patients was 66.0 years, and 128 (64%) were male. Two-thirds (66%) of the patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and 55.5% had a KPS of 80% or higher. The values of AUROC of CPS, KPS, and ESAS total score in 3-month survival prediction were 0.80 (95% confidence interval [CI]: 0.73-0.88), 0.71 (95% CI: 0.62-0.79), and 0.71 (95% CI: 0.62-0.81), respectively, whereas those in 6-month survival were 0.82 (95% CI: 0.76-0.88), 0.70 (95% CI: 0.63-0.78), and 0.63 (95% CI: 0.55-0.71), respectively., Conclusion: CPS showed the highest accuracy in predicting 3- and 6-month survival, whereas KPS had an acceptable accuracy. Experienced clinicians can rely on CPS to predict survival in months. We recommend the use of KPS with CPS to assist inexperienced clinicians., (© Sang-Yeon Suh et al., 2024. Published by Mary Ann Liebert, Inc.)

Background: Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution., Methods: We fabricated a Dectin-1-targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence-emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks., Results: The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway., Conclusions: Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1-targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β-dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy., Competing Interests: None.

Background: Outpatient monitoring of pulmonary congestion in heart failure (HF) patients may reduce hospitalization rates. This study tested the feasibility of non-invasive high-frequency bioelectrical impedance analysis (HF-BIA) for estimating lung fluid status., Methods: This prospective study included 70 participants: 50 with acute HF (HF group) and 20 without HF (control group). All participants underwent a supine chest CT scan to measure lung fluid content with lung density analysis software. Concurrently, direct segmental multi-frequency BIA was performed to assess the edema index (EI) of the trunk, entire body, and extremities., Results: The correlation coefficients between lung fluid content and EI measured using HF-BIA were r = 0.566 (p < 0.001) and r = 0.550 (p < 0.001) for the trunk and whole body, respectively. In the HF group, the trunk EI (0.402 ± 0.015) and whole body EI (0.402 ± 0.016) were significantly higher than those of the control group (trunk EI, 0.383 ± 0.007; whole body EI, 0.383 ± 0.007; all p < 0.001). The lung fluid content was significantly higher in the HF than that in the control group (23.7 ± 5.3 vs. 15.5 ± 2.8%, p < 0.001). The log value of NT pro-BNP was significantly correlated with trunk EI (r = 0.688, p < 0.001) and whole-body EI (r = 0.675, p < 0.001) measured by HF-BIA, and the lung fluid content analyzed by CT (r = 0.686, p < 0.001)., Conclusions: BIA-based EI measurements of the trunk and whole body significantly correlated with lung fluid content and NT pro-BNP levels. Non-invasive BIA could be a promising screening tool for lung fluid status monitoring in acute HF patients., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: Some studies suggest that TP53 mutations are associated with the response to immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and also contribute to sex disparities in several cancers. Thus, we hypothesized that TP53 mutations might serve as sex-dependent genomic biomarkers of ICI treatment response in patients with NSCLC., Materials and Methods: Clinical data of 100 patients with metastatic NSCLC treated with ICI monotherapy at Seoul National University Bundang Hospital (SNUBH) were retrospectively reviewed. Genomic and clinical datasets of TCGA and an ICI-treated lung cancer cohort (cBioPortal) were also analyzed., Results: In SNUBH cohort, no statistically significant difference was observed in disease control rate per the TP53 mutation status (p=0.503); however, female patients with TP53 mutated (MT) had a significantly prolonged median progression-free survival (PFS) compared to wild-type (WT) (6.1 months in TP53 MT vs. 2.6 months in TP53 WT; p=0.021). PD-L1 high (≥50%) expression was significantly enriched in female patients with TP53 MT (p=0.001). The analysis from publicly available dataset also revealed that females with NSCLC with TP53 MT showed significantly longer PFS than those with TP53 WT (p<0.001). In TCGA analysis, expression of immune-related genes, and TMB score in TP53 MT females were higher than in males without TP53 MT., Conclusion: Female patients with NSCLC with TP53 mutations had high PD-L1 expression and showed favorable clinical outcomes following ICI therapy, suggesting a need for further research to explore the role of TP53 mutations for sex disparities in response to ICI therapy.

Background: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis., Methods: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m 2 ) and cisplatin (25 mg/m 2 ) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235., Findings: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%])., Interpretation: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer., Funding: AstraZeneca., Competing Interests: Declaration of interests D-YO reports advisory fees from Arcus Biosciences, Aslan Pharmaceuticals, AstraZeneca, Basilea, Bayer, BeiGene, Bristol Myers Squibb/Celgene, Genentech/Roche, Halozyme, IQVIA, Merck Serono, Novartis, Taiho Pharmaceutical, Turning Point Therapeutics, Yuhan, and Zymeworks; and institutional research funding from Array BioPharma, AstraZeneca, BeiGene, Eli Lilly, Handok, MSD, Novartis, and Servier. ARH reports consulting fees from AstraZeneca, Bristol Myers Squibb, and Genentech/Roche; research funding from Genentech and Merck; and speakers bureau fees from Eisai and Bristol Myers Squibb. MB reports consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Ipsen, MSD, Roche, and Sirtex Medical; speakers bureau fees from Bayer, Eisai, and Roche; and support for travel and attending meetings from AstraZeneca, Bayer, and Sirtex Medical. TO reports advisory fees from AstraZeneca, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Incyte, Meiji Seika Pharma, Mundipharma, Nihon Servier, Nippon Shinyaku, Pfizer, Taiho Pharmaceutical, and Takara Bio; and speaker fees from AstraZeneca, Baxter, Bayer, Bristol Myers Squibb, Chugai Pharma, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, MSD, Nihon Servier, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. L-TC reports personal speaker fees from Bristol Myers Squibb, CStone, Eli Lilly, Ipsen, Ono Pharmaceutical, Novartis, PharmaEngine, and TTY; fees for medical monitoring for clinical trials for Taivex; fees received as a data and safety monitoring committee member for clinical trials for OBI Pharma; advisory fees from AstraZeneca, MSD, and SynCoreBio; speaker fees from AstraZeneca, HuniLife Biotechnology, Ono Pharmaceutical, ScinoPharm Taiwan, SynCoreBio, and TTY; and research funding from Celgene. MK reports research funding from AbbVie and Takeda; and honoraria from EA Pharma and AstraZeneca. JWK reports research funding from inno.N and Jeil Pharmaceutical; and consulting fees from AstraZeneca, BeiGene, BeyondBio, Bristol Myers Squibb/Celgene, Eisai, GC Cell, MSD Ono, Sanofi-Aventis, Servier, and TCUBEit. TS reports speaker fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Baxter, Eli Lilly, Mundipharma (Thailand), Janssen, MSD, Novartis, Roche, and Takeda; and advisory fees from Novartis and Roche. MI reports grant or research support from Aslan Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharma, Delta-Fly Pharma, EA Pharma, Eisai, Eli Lilly Japan, J-Pharma, Merck, Merus NV, Nihon Servier, Novartis, Ono Pharmaceutical, Pfizer, Takeda, and Yakult; fees or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas Pharma, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, MSD, Nihon Servier, Novartis, Otsuka, Dainippon Sumitomo Pharma, Taiho Pharmaceutical, Takeda, Teijin Pharma, and Yakult; and fees for participation on a data safety monitoring board or advisory board from Aslan Pharmaceuticals, Bayer, Bristol Myers Squibb, Chugai Pharma, Eisai, Eli Lilly Japan, GlaxoSmithKline, Nihon Servier, Novartis, and Takeda. J-SC reports grant or research support from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Janssen, Eli Lilly, Merck KGaA, MSD, MSD Oncology, Oncologie, Ono Pharmaceutical, Roche, Senhwa Biosciences, SynCore, and TTY; and consulting fees from Ono Pharmaceutical. PP reports personal fees for an advisory board from AstraZeneca, Sanofi-Aventis, Bristol Myers Squibb, Janssen Oncology, MSD, Pierre Fabre, Roche, and Servier; personal fees as an invited speaker from AstraZeneca, Ipsen, Pierre Fabre, and Merck; and being a principal investigator for AstraZeneca and Roche. HAB reports research funding from AbbVie, Agios, Arch Pharmalabs, ARMO BioSciences, Array BioPharma, Arvinas, AstraZeneca, Bayer, BIND Therapeutics, BioAtla, BioMed Valley Discoveries, Biotheryx, Boehringer Ingelheim, Bristol Myers Squibb, CALGB, CicloMed, Coordination Pharmaceuticals, CytomX, eFFECTOR Therapeutics, Eli Lilly, EMD Serono, Foundation Medicine, Gossamer Bio, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Infinity Pharmaceuticals, Janssen, Jiangsu Hengrui Pharmaceuticals, Jounce Therapeutics, Kymab, MacroGenics, MedImmune, Merck, Millennium/Takeda, miRNA Therapeutics, Moderna, NGM Bio, Novartis, Pfizer, Revolution Medicine, Roche/Genentech, Ryvu Therapeutics, Seattle Genetics, Tesaro, TG Therapeutics, Verastem Oncology, Vertex Pharmaceuticals, XBiotech, and Zymeworks; and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Forma Therapeutics, Grail, Incyte, Novartis, Pfizer, and Vincerx Pharma. VO reports grant or research support from Dr Reddy's Laboratories and Zydus Cadila; institutional fees for advisory board participation from AstraZeneca, Panacea Biotec, Dr Reddy's Laboratories, and Zydus Cadila; travel reimbursement as an invited speaker from AstraZeneca; other institutional financial interests with Alkem Laboratories, Eisai, Intas Pharmaceuticals, and Micro Labs; and non-financial interests with the Indian Association of Supportive Care in Cancer. ST reports honoraria from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, MSD, Novartis, and Roche; speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and non-financial interests with AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, and Roche. CM reports institutional grant or research support from AstraZeneca, Daiichi Sankyo, Eisai, J-Pharma, Hitachi, Merck BioReliance, MSD, Kyowa Kirin, Ono Pharmaceutical, Taiho Pharmaceutical, and Yakult Honsha; personal fees for advisory board participation from AstraZeneca, Boehringer Ingelheim, Merck BioReliance, MSD, Servier, Taiho Pharmaceutical, and Yakult; and personal fees received as an invited speaker from AstraZeneca, Eisai, Kyowa Kirin, MSD, Novartis, Servier, Taiho Pharmaceutical, Teijin Pharma, and Yakult Honsha. REZ reports speaker fees from Bristol Myers Squibb, Ipsen, and Novartis; and travel grants from Pierre Fabre. MGM reports grant or research support from Ipsen, NuCana, and Servier; consulting fees from AstraZeneca and Incyte; and honoraria from Advanced Accelerator Applications and AstraZeneca. AA reports research funding from Amgen, Bayer, and Bristol Myers Squibb; and advisory fees from AstraZeneca, Amgen, Eisai, and MSD. JEC reports advisory fees from MSD; and fees as an invited speaker for AstraZeneca, Boehringer Ingelheim, Takeda, and Roche. VB reports consulting fees from Bayer, Bristol Myers Squibb Russia, Eisai, MSD, Novartis, Pfizer, Roche Russia, and Takeda; and travel expenses from Bayer, Bristol Myers Squibb Russia, MSD, and Roche Russia. BT reports research funding from Adaptimmune, AstraZeneca, Bristol Myers Squibb, and Exelixis. SS reports grant or research support from Delta-Fly Pharma and Incyte. DT reports personal fees for advisory board participation from Amgen, AstraZeneca, MSD, Pierre Fabre, Roche, Sanofi, and Servier. LE reports personal fees for advisory board participation from Amgen, Merk, MSD, and Servier. MP reports personal fees for advisory board participation from Roche and Servier; personal fees as an invited speaker from AstraZeneca, Ewopharma, and Takeda; and non-financial interests with AstraZeneca and Sanofi. DBZ reports advisory fees from Cornerstone Pharmaceuticals, Ipsen, Jazz Pharmaceuticals/Zymeworks, and QED Therapeutics; and research funding from AstraZeneca, Bayer, Bristol Meyers Squibb, Cornerstone Pharmaceuticals, Daiichi Sankyo, Eli Lily, Ipsen, Roche/Genentech, Legend Biotech, Merck, and Seagen. VGG holds stock in RPG Life Sciences and Zydus Lifesciences. FD reports grant or research support from Amgen, AstraZeneca, Bristol Myers Squibb, Exelixis, Genentech, Ipsen, Signatera, and Taiho Pharmaceutical; consulting fees from AstraZeneca, Eisai, Exelixis, Genentech, and Ipsen; and payment or honoraria from Astellas, Eisai, Exelixis, Ipsen, Servier, and Sirtex Medical. JOP reports advisory board fees from Adicet Bio, AstraZeneca, Bristol Myers Squibb (Celgene), MediRama, MedPacto, Merck Serono, and Servier; support for travel to meetings from Minneamrita Therapeutics; and grant or research support from ABL Bio, Bristol Myers Squibb (Celgene), Eutilex, MedPacto, and Servier. HK, CM, and MŻ are employees of AstraZeneca. JW and NR are employees of and hold stock in AstraZeneca. AV reports speaker fees from BeiGene, Bristol Myers Squibb, Eisai, Imaging Equipment, Incyte, Ipsen, Jiangsu Hengrui Pharmaceuticals, Eli Lilly, MSD, Novartis, Pierre Fabre, and Roche; and advisory fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Daiichi Sankyo, Eisai, Ipsen, Incyte, Lilly, MSD, Pierre Fabre, Roche, and Sirtex Medical. JWV reports advisory fees from Agios, AstraZeneca, Autem Therapeutics, Baxter, Hutchison MediPharma, Image Equipment, NuCana, QED Therapeutics, Sirtex Medical, Servier, and Zymeworks; speaker fees from Incyte, Ipsen, and Mylan; and research funding from AstraZeneca and Redx. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Autophagy is a cellular process that degrades damaged cytoplasmic components and regulates cell death. The homeostasis of endothelial cells (ECs) is crucial for the preservation of glomerular structure and function in aging. Here, we investigated the precise mechanisms of endothelial autophagy in renal aging. The genetic deletion of Atg7 in the ECs of Atg7 flox/flox ;Tie2-Cre mice accelerated aging-related glomerulopathy and tubulointerstitial fibrosis. The EC-specific Atg7 deletion in aging mice induced the detachment of EC with the disruption of glomerular basement membrane (GBM) assembly and increased podocyte loss resulting in microalbuminuria. A Transwell co-culture system of ECs and kidney organoids showed that the iron and oxidative stress induce the disruption of the endothelial barrier and increase vascular permeability, which was accelerated by the inhibition of autophagy. This resulted in the leakage of iron through the endothelial barrier into kidney organoids and increased oxidative stress, which led to ferroptotic cell death. The ferritin accumulation was increased in the kidneys of the EC-specific Atg7-deficient aging mice and upregulated the NLRP3 inflammasome signaling pathway. The pharmacologic inhibition of ferroptosis with liproxstatin-1 recovered the disrupted endothelial barrier and reversed the decreased expression of GPX4, as well as NLRP3 and IL-1β, in endothelial autophagy-deficient aged mice, which attenuated aging-related renal injury including the apoptosis of renal cells, abnormal structures of GBM, and tubulointerstitial fibrosis. Our data showed that endothelial autophagy is essential for the maintenance of the endothelial barrier during renal aging and the impairment of endothelial autophagy accelerates renal senescence by ferroptosis and NLRP3 inflammasome signaling pathways. These processes may be attractive therapeutic targets to reduce cellular injury from renal aging.

Background/aims: : Recently, patients with pancreatic cancer (PC) who underwent resection have exhibited improved survival outcomes, but comprehensive analysis is limited. We analyzed the trends of contributing factors., Methods: : Data of patients with resected PC were retrospectively collected from the Korean Health Insurance Review and Assessment Service (HIRA) database and separately at our institution. Cox regression analysis was conducted with the data from our institution a survival prediction score was calculated using the β coefficients., Results: : Comparison between the periods 2013-2015 (n=3,255) and 2016-2018 (n=3,698) revealed a difference in the median overall survival (25.9 months vs not reached, p<0.001) when analyzed with the HIRA database which was similar to our single-center data (2013-2015 [n=119] vs 2016-2018 [n=148], 20.9 months vs 32.2 months, p=0.003). Multivariable analyses revealed six factors significantly associated with better OS, and the scores were as follows: age >70 years, 1; elevated carbohydrate antigen 19-9 at diagnosis, 1; R1 resection, 1; stage N1 and N2, 1 and 3, respectively; no adjuvant treatment, 2; FOLFIRINOX or gemcitabine plus nab-paclitaxel after recurrence, 4; and other chemotherapy or supportive care only after recurrence, 5. The rate of R0 resection (69.7% vs 80.4%), use of adjuvant treatment (63.0% vs 74.3%), and utilization of FOLFIRINOX or gemcitabine plus nab-paclitaxel (25.2% vs 47.3%) as palliative chemotherapeutic regimen, all increased between the two time periods, resulting in decreased total survival prediction score (mean: 7.32 vs 6.18, p=0.004)., Conclusions: : Strict selection of surgical candidates, more use of adjuvant treatment, and adoption of the latest combination regimens for palliative chemotherapy after recurrence were identified as factors of recent improvement.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Background: The efficacy and safety of each third-generation drug-eluting stent with ultrathin struts and advanced polymer technology remain unclear. We investigated the clinical outcomes of percutaneous coronary intervention using the Coroflex ISAR polymer-free sirolimus-eluting stent (SES) or Orsiro biodegradable polymer SES., Methods: The HOST-IDEA trial (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Coronary Intervention With Next-Generation Drug-Eluting Stent Platforms and Abbreviated Dual Antiplatelet Therapy), initially designed with a 2×2 factorial approach, sought to randomize patients undergoing percutaneous coronary intervention based on dual antiplatelet therapy duration (3 versus 12 months) and stent type (Coroflex ISAR versus Orsiro). Despite randomizing 2013 patients for dual antiplatelet therapy duration, the stent arm transitioned to a registry format during the trial. Among these, 328 individuals (16.3%) were randomized for Coroflex ISAR or Orsiro SES, while 1685 (83.7%) underwent percutaneous coronary intervention without stent-type randomization. In this study, the Coroflex ISAR (n=559) and Orsiro groups (n=1449) were matched using a propensity score. The prespecified primary end point was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularization at 12 months., Results: The baseline patient and procedural characteristics were well balanced between the Coroflex ISAR and Orsiro groups after propensity score matching (n=559, each group). The Coroflex ISAR group was significantly associated with a higher rate of target lesion failure, mainly driven by clinically driven target lesion revascularization, compared with the Orsiro group (3.4% versus 1.1%; hazard ratio, 3.21 [95% CI, 1.28-8.05]; P =0.01). A higher risk of target lesion failure in the Coroflex ISAR group was consistently observed across various subgroups. The rates of any bleeding (hazard ratio, 0.85 [95% CI, 0.51-1.40]; P =0.52) and major bleeding (hazard ratio, 1.58 [95% CI, 0.61-4.08]; P =0.34) were comparable between the 2 groups., Conclusions: In this propensity score-matched analysis of the stent arm registry from the HOST-IDEA trial, the Orsiro SES was associated with significantly better outcomes in terms of 1-year target lesion failure, mainly driven by clinically driven target lesion revascularization, than the Coroflex ISAR SES., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601157., Competing Interests: Dr Han reports grants from ChongKunDang and HanMi outside the submitted work. Dr K.W. Park reports speaker fees from Daiichi Sankyo, AstraZeneca, Sanofi, Bristol-Myers Squibb, Bayer, and Pfizer outside the submitted work. Dr H.-S. Kim reports grants or speaker fees from Daiichi Sankyo, Boston Scientific, Terumo, Biotronik, Dio, Medtronic, Abbott Vascular, Edwards Life Science, Amgen, and Behringer Ingelheim outside of the submitted work. The other authors report no conflicts.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Background and Aims: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer., Approach and Results: This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included adults who are treatment-naive with locally advanced/metastatic biliary tract cancer. Patients (N = 297) were randomized to receive an IV infusion of BA (2400 mg once/3 wk) plus GemCis (gemcitabine 1000 mg/m 2 +cisplatin 25 mg/m 2 on days 1 and 8/3 wk; 8 cycles) (BA group, n = 148) or placebo+GemCis (placebo group, n = 149). The primary end point was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cutoff: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naive when 80 progression-free survival events had occurred and ≥ 19 weeks of follow-up had been completed (BA, n = 73; placebo, n = 77). Median OS (95% CI) for the BA (11.5 mo [9.3-not estimable]) and placebo (11.5 mo [10.0-not estimable]) groups was comparable (hazard ration 1.23 [95% CI 0.66-2.28]; p = 0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively., Conclusions: BA+GemCis did not provide a clinically meaningful benefit compared with GemCis alone as first-line treatment for biliary tract cancer, and the study was discontinued early (terminated: August 20, 2021)., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

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., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

We aimed to characterize the genomes of monkeypox virus isolates from the Far East, providing insights into viral transmission and evolution. Genomic analysis was conducted on 8 isolates obtained from patients with monkeypox virus disease in the Republic of Korea between May 2022 and early 2023. These isolates were classified into Clade IIb. Distinct lineages, including B.1.1, A.2.1, and B.1.3, were observed in 2022 and 2023 isolates, with only the B.1.3 lineage detected in six isolates of 2023. These genetic features were specific to Far East isolates (the Republic of Korea, Japan, and Taiwan), distinguishing them from the diverse lineages found in the Americas, Europe, Africa, and Oceania. In early 2023, the prevalence of the B.1.3 lineage of monkeypox virus identified in six patients with no overseas travel history is considered as an indicator of the potential initiation of local transmission in the Republic of Korea., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: In patients undergoing percutaneous coronary intervention (PCI), the use of anti-inflammatory therapy with colchicine is associated with a reduction of recurrent ischemic events. The mechanisms of such findings are not fully elucidated., Objectives: To investigate the effects of colchicine versus aspirin on inflammation and platelet reactivity in patients with acute coronary syndrome (ACS) undergoing PCI., Methods: This observational study compared laboratory measurements in ACS patients receiving single antiplatelet therapy with ticagrelor or prasugrel plus colchicine (MACT) ( n  = 185) versus conventional dual-antiplatelet therapy (DAPT) with aspirin plus ticagrelor or prasugrel ( n  = 497). The primary outcome was the frequency of high residual inflammation, defined as high-sensitivity C-reactive protein (hs-CRP) ≥2 mg/L at 1 month post-PCI. Multiple sensitivity analyses were performed for the primary outcome, including multivariable adjustment, propensity-score matching, and inverse-probability weighted methods., Results: One month after PCI, patients treated with MACT had significantly lower levels of hs-CRP compared to those treated with DAPT (0.6 [0.4-1.2] vs. 0.9 [0.6-2.3] mg/L, p  < 0.001). The frequency of high residual inflammation was also lower in the MACT group (10.8% vs. 27.2%, p  < 0.001) (odds ratio [95% confidence interval] = 0.33 [0.20-0.54], p  < 0.001). This effect was consistent across sensitivity analyses. There was no difference in platelet reactivity between MACT and DAPT (49.6 ± 49.0 vs. 51.5 ± 66.4 P2Y 12 reaction unit [PRU] measured by VerifyNow, p  = 0.776)., Conclusion: In ACS patients undergoing PCI, MACT was associated with a lower rate of high residual inflammation without increasing platelet reactivity compared to conventional DAPT., Clinical Trial Registration: NCT04949516 for MACT pilot trial and NCT04650529 for Gyeongsang National University Hospital registry., Competing Interests: DG reports institutional research grants from AstraZeenca, Werfen, Medtronic, Bayer and Alpha MD, and speaker frees from AstraZeneca. DA declares that he has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, BristolMyers Squibb, Chiesi, CSL Behring, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; he also declares that his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, and the Scott R. MacKenzie Foundation. Y-HJ has received honoraria for lectures from Daiichi Sankyo, Sanofi-Aventis, Amgen, Han-mi Pharmaceuticals, and Dae-Woong Pharmaceuticals; and research grants or support from Yuhan Pharmaceuticals, Han-mi Pharmaceuticals, Sam-jin Pharmaceuticals, Biotronik, and U&I Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lee, Cho, Gorog, Angiolillo, Yun, Ahn, Koh, Park, Hwang, Hwang, Kim, Jang and Jeong.)

Lithium-sulfur batteries (LSBs) are superior next-generation batteries compared to commercial lithium-ion batteries (LiBs) because of their gravimetric energy densities, which provide longer battery life in a lighter package. However, the biggest hurdle for commercializing LSBs is their poor long-term cycling performance, which stems from polysulfide shuttling. To address this issue, we propose a novel approach: the use of glutamine, an amino acid, as an electrolyte additive to increase the cycling stability. Due to its molecular structure containing amines, the formation of Li dendrites was obstructed by homogenizing the Li-ion flux to shield the exceedingly active Li surfaces with glutamine, thereby reducing the overvoltage during Li plating and stripping. Additionally, the redox reactions of lithium polysulfides were enhanced, which helped to alleviate the shuttling of lithium polysulfides. Therefore, the addition of glutamine improved the stability and reduced the cell degradation rate by approximately 0.066% during high C-rate long-term cycling tests.

Previous studies have demonstrated the effects of theranostic agents on atherosclerotic plaques. However, there is limited information on targeted theranostics for photodynamic treatment of atherosclerosis. This study aimed to develop a macrophage-mannose-receptor-targeted photoactivatable nanoagent that regulates atherosclerosis and to evaluate its efficacy as well as safety in atherosclerotic mice. We synthesised and characterised D-mannosamine (MAN)-polyethylene glycol (PEG)-chlorin e6 (Ce6) for phototheranostic treatment of atherosclerosis. The diagnostic and therapeutic effects of MAN-PEG-Ce6 were investigated using the atherosclerotic mouse model. The hydrophobic Ce6 photosensitiser was surrounded by the hydrophilic MAN-PEG outer shell of the self-assembled nanostructure under aqueous conditions. The MAN-PEG-Ce6 was specifically internalised in macrophage-derived foam cells through receptor-mediated endocytosis. After laser irradiation, the MAN-PEG-Ce6 markedly increased singlet oxygen generation. Intravital imaging and immunohistochemistry analyses verified MAN-PEG-Ce6's specificity to plaque macrophages and its notable anti-inflammatory impact by effectively reducing mannose-receptor-positive macrophages. The toxicity assay showed that MAN-PEG-Ce6 had negligible effects on the biochemical profile and structural damage in the skin and organs. Targeted photoactivation with MAN-PEG-Ce6 thus has the potential to rapidly reduce macrophage-derived inflammatory responses in atheroma and present favourable toxicity profiles, making it a promising approach for both imaging and treatment of atherosclerosis., 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 B.V.)

Purpose: The female sex is reported to have a higher risk of adverse events (AEs) from cytotoxic chemotherapy. Few studies examined the sex differences in AEs and their impact on the use of medical services during adjuvant chemotherapy. This sub-study aimed to compare the incidence of any grade and grade ≥ 3 AEs, healthcare utilization, chemotherapy completion rate, and dose intensity according to sex., Materials and Methods: This is a sub-study of a multicenter cohort conducted in Korea that evaluated the impact of healthcare reimbursement on AE evaluation in patients who received adjuvant chemotherapy between September 2013 and December 2016 at four hospitals in Korea., Results: A total of 1,170 patients with colorectal, gastric, or non-small cell lung cancer were included in the study. Female patients were younger, had fewer comorbidities, and experienced less postoperative weight loss of > 10%. Females had significantly higher rates of any grade AEs including nausea, abdominal pain, stomatitis, vomiting, and neutropenia, and experienced more grade ≥ 3 neutropenia, nausea, and vomiting. The dose intensity of chemotherapy was significantly lower in females, and they also experienced more frequent dose reduction after the first cycle. Moreover, female patients receiving platinum-containing regimens had significantly higher rates of unscheduled outpatient visits., Conclusion: Our study found that females experienced a higher incidence of multiple any-grade AEs and severe neutropenia, nausea, and vomiting, across various cancer types, leading to more frequent dose reductions. Physicians should be aware of sex differences in AEs for chemotherapy decisions.

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.

Background/aims: Synchronous multiple gastric cancer (SMGC) accounts for approximately 6% to 14% of gastric cancer (GC) cases. This study aimed to identify risk factors for SMGC., Methods: A total of 14,603 patients diagnosed with GC were prospectively enrolled. Data including age, sex, body mass index, smoking, alcohol consumption, family history, p53 expression, microsatellite instability, cancer classification, lymph node metastasis, and treatment were collected. Risk factors were analyzed using logistic regression analysis between a single GC and SMGC., Results: The incidence of SMGC was 4.04%, and that of early GC (EGC) and advanced GC (AGC) was 5.43% and 3.11%, respectively. Patients with SMGC were older (65.33 years vs 61.75 years, p<0.001) and more likely to be male. Lymph node metastasis was found in 27% of patients with SMGC and 32% of patients with single GC. Multivariate analysis showed that SMGC was associated with sex (male odds ratio [OR], 1.669; 95% confidence interval [CI], 1.223 to 2.278; p=0.001), age (≥65 years OR, 1.532; 95% CI, 1.169 to 2.008; p=0.002), and EGC (OR, 1.929; 95% CI, 1.432 to 2.600; p<0.001). Survival rates were affected by Lauren classification, sex, tumor size, cancer type, distant metastasis, and venous invasion but were not related to the number of GCs. However, the survival rate of AGC with SMGC was very high., Conclusions: SMGC had unique characteristics such as male sex, older age, and EGC, and the survival rate of AGC, in which the intestinal type was much more frequent, was very good (Trial registration number: NCT04973631).

Importance: Cardiovascular benefits of mild to moderate alcohol consumption need to be validated in the context of behavioral changes. The benefits of reduced alcohol consumption among people who drink heavily across different subtypes of cardiovascular disease (CVD) are unclear., Objective: To investigate the association between reduced alcohol consumption and risk of major adverse cardiovascular events (MACEs) in individuals who drink heavily across different CVD subtypes., Design, Setting, and Participants: This cohort study analyzed data from the Korean National Health Insurance Service-Health Screening database and self-reported questionnaires. The nationally representative cohort comprised Korean citizens aged 40 to 79 years who had national health insurance coverage on December 31, 2002, and were included in the 2002 to 2003 National Health Screening Program. People who drank heavily who underwent serial health examinations over 2 consecutive periods (first period: 2005-2008; second period: 2009-2012) were included and analyzed between February and May 2023. Heavy drinking was defined as more than 4 drinks (56 g) per day or more than 14 drinks (196 g) per week for males and more than 3 drinks (42 g) per day or more than 7 drinks (98 g) per week for females., Exposures: Habitual change in heavy alcohol consumption during the second health examination period. People who drank heavily at baseline were categorized into 2 groups according to changes in alcohol consumption during the second health examination period as sustained heavy drinking or reduced drinking., Main Outcomes and Measures: The primary outcome was the occurrence of MACEs, a composite of nonfatal myocardial infarction or angina undergoing revascularization, any stroke accompanied by hospitalization, and all-cause death., Results: Of the 21 011 participants with heavy alcohol consumption at baseline (18 963 males [90.3%]; mean [SD] age, 56.08 [6.16] years) included in the study, 14 220 (67.7%) sustained heavy drinking, whereas 6791 (32.2%) shifted to mild to moderate drinking. During the follow-up of 162 378 person-years, the sustained heavy drinking group experienced a significantly higher incidence of MACEs than the reduced drinking group (817 vs 675 per 100 000 person-years; log-rank P = .003). Reduced alcohol consumption was associated with a 23% lower risk of MACEs compared with sustained heavy drinking (propensity score matching hazard ratio [PSM HR], 0.77; 95% CI, 0.67-0.88). These benefits were mostly accounted for by a significant reduction in the incidence of angina (PSM HR, 0.70; 95% CI, 0.51-0.97) and ischemic stroke (PSM HR, 0.66; 95% CI, 0.51-0.86). The preventive attributes of reduced alcohol intake were consistently observed across various subgroups of participants., Conclusions and Relevance: Results of this cohort study suggest that reducing alcohol consumption is associated with a decreased risk of future CVD, with the most pronounced benefits expected for angina and ischemic stroke.

Gastric cancer, a leading cause of cancer-related deaths globally, necessitates effective and early detection and treatment strategies. Endoscopic resection techniques, particularly endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD), have evolved significantly, enhancing the treatment of gastric neoplasms. Underwater endoscopic mucosal resection (UEMR) is a widely used technique for the resection of duodenal and colorectal neoplasms. However, the feasibility and efficacy of UEMR in the stomach are not well established. This retrospective observational study, conducted at a tertiary medical center, evaluated the efficacy and safety of UEMR in 81 patients with gastric neoplasms. Thus, it indicates that UEMR is a highly effective and safe technique for managing small to medium-sized gastric neoplasms, achieving 100% en bloc and 93.8% R0 resection rates with a low incidence of complications. Moreover, the procedure time was found to be significantly shorter for UEMR compared to ESD, thus highlighting its efficiency. While UEMR demonstrates high safety and efficacy, it is not suitable for all patients, with some requiring conversion to ESD as a treatment option. Despite the promising results, broader validation through extensive and randomized trials is recommended to establish UEMR as a standard approach in gastric cancer management.

Following the worldwide surge in mpox (monkeypox) in 2022, cases have persisted in Asia, including South Korea, and sexual contact is presumed as the predominant mode of transmission, with a discernible surge in prevalence among immunocompromised patients. Drugs such as tecovirimat can result in drug-resistant mutations, presenting obstacles to treatment. This study aimed to ascertain the presence of tecovirimat-related resistant mutations through genomic analysis of the monkeypox virus isolated from a reported case involving prolonged viral shedding in South Korea. Here, tecovirimat-resistant mutations, previously identified in the B.1 clade, were observed in the B.1.3 clade, predominant in South Korea. These mutations exhibited diverse patterns across different samples from the same patient and reflected the varied distribution of viral subpopulations in different anatomical regions. The A290V and A288P mutant strains we isolated hold promise for elucidating these mechanisms, enabling a comprehensive analysis of viral pathogenesis, replication strategies, and host interactions. Our findings imply that acquired drug-resistant mutations, may present a challenge to individual patient treatment. Moreover, they have the potential to give rise to transmitted drug-resistant mutations, thereby imposing a burden on the public health system. Consequently, the meticulous genomic surveillance among immunocompromised patients, conducted in this research, assumes paramount importance., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

This study aimed to compare and evaluate the efficacy of the blood pressure (BP) control and cholesterol-lowering effects and safety of combination therapy with telmisartan, rosuvastatin, and ezetimibe versus rosuvastatin and ezetimibe double therapy or telmisartan single therapy in dyslipidemia patients with hypertension. After a wash-out/therapeutic lifestyle change period of ≥4 weeks, a total of 100 eligible patients were randomized and received one of three treatments for 8 weeks: (1) telmisartan 80 mg/rosuvastatin 20 mg/ezetimibe 10 mg (TRE), (2) rosuvastatin 20 mg/ezetimibe 10 mg (RE), or (3) telmisartan 80 mg (T). The primary endpoint was the efficacy evaluation of TRE by comparing changes in mean sitting systolic blood pressure (msSBP) and mean percentage change in low-density lipoprotein-C (LDL-C) from baseline after 8 weeks of treatment. The least square (LS) mean (SE) changes in msSBP at 8 weeks compared with baseline were -23.02 (3.04) versus -7.18 (3.09) mmHg in the TRE and RE groups, respectively (p < .0001), and -25.80 (2.74) versus -14.92 (2.65) mmHg in the TRE and T groups, respectively (p = .0005). The percentage changes in the mean (SD) LDL-C at 8 weeks compared with baseline were -54.97% (3.49%) versus -0.17% (3.23%) in the TRE and T groups, respectively (p < .0001). No serious adverse events occurred, and no statistically significant differences in the incidence of overall AEs and adverse drug reactions occurred among the three groups. TRE therapy significantly decreased msSBP and LDL-C compared to RE or T therapy with comparable safety and tolerability profiles., (© 2024 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) has been reported to account for approximately 5-16% of all GCs with good prognosis compared to EBV-negative GC. We evaluated the clinicopathological characteristics of EBVaGC including survival rate in South Korea., Methods: A total of 4,587 patients with GC who underwent EBV in situ hybridization (EBV-ISH) were prospectively enrolled at the Seoul National University Bundang Hospital from 2003 to 2021. Age, sex, smoking status, cancer type and stage, tumor size and location, histological type, molecular features and survival information were analyzed., Results: A total of 456 patients with GC (9.9%) were positive for EBV. The EBVaGC group displayed a higher proportion of males (P < 0.001), a predominant presence in the proximal stomach (P < 0.001), a higher proportion of undifferentiated cancer (P < 0.001), and a lower cancer stage (P = 0.004) than the EBV-negative group. Cox multivariate analyses revealed age (hazard ratio [HR] = 1.025, P < 0.001), tumor size (HR = 1.109, P < 0.001), and cancer stage (stage2 HR = 4.761, P < 0.001; stage3 HR = 13.286, P < 0.001; stage4 HR = 42.528, P < 0.001) as significant risk factors for GC-specific mortality, whereas EBV positivity was inversely correlated (HR = 0.620, P = 0.022). Furthermore, the EBVaGC group displayed statistically significant survival advantages over the EBV-negative cancer group in terms of both overall (P = 0.021) and GC-specific survival (P = 0.007) on the Kaplan-Meier survival curve. However, this effect was evident only in males., Conclusions: EBVaGC patients showed better prognoses despite their association with proximal location and poorly differentiated histology in male, probably due to the difference in immunity between males and females., (© 2024. The Author(s).)

This study developed and validated a risk-scoring model, with a particular emphasis on medication-related factors, to predict emergency department (ED) visits among older Korean adults (aged 65 and older) undergoing anti-neoplastic therapy. Utilizing national claims data, we constructed two cohorts: the development cohort (2016-2018) with 34,642 patients and validation cohort (2019) with 10,902 patients. The model included a comprehensive set of predictors: demographics, cancer type, comorbid conditions, ED visit history, and medication use variables. We employed the least absolute shrinkage and selection operator (LASSO) regression to refine and select the most relevant predictors. Out of 120 predictor variables, 12 were integral to the final model, including seven related to medication use. The model demonstrated acceptable predictive performance in the validation cohort with a C-statistic of 0.76 (95% CI 0.74-0.77), indicating reasonable calibration. This risk-scoring model, after further clinical validation, has the potential to assist healthcare providers in the effective management and care of older patients receiving anti-neoplastic therapy., (© 2024. The Author(s).)

What Is This Summary About?: Researchers wanted to study whether the research drug zanidatamab could help people with a type of cancer called biliary tract cancer. In some people, biliary tract cancer cells make extra copies of a gene called HER2 (also called ERBB2). This is known as being HER2-amplified. Zanidatamab is an antibody designed to destroy cancer cells that have higher-than-normal HER2 protein or gene levels. Zanidatamab is currently under research and is not yet approved for any diseases. Participants in this phase 2b clinical study had tumors that were HER2-amplified and at the advanced or metastatic stage. Participants also had cancer which had become worse after previous chemotherapy or had side effects that were too bad to continue chemotherapy. They also had to meet other requirements to be enrolled. Researchers measured the amount of HER2 protein in the tumor samples of the participants who were enrolled. There were 80 participants with tumors that were both HER2 amplified and had higher-than-normal HER2 protein amounts (considered to be 'HER2-positive'). There were 7 participants with tumors that were HER2-amplified, but had little-to-no levels of the HER2 protein (considered to be 'HER2-low'). All participants in the study were treated with zanidatamab and no other cancer treatments once every 2 weeks., What Are the Key Takeaways?: In the HER2-positive group, 33 of 80 (41%) participants had their tumors shrink by 30% or more of their original size. In half of these participants, their tumors did not grow for 13 months or longer. No participant in the HER2-low group had their tumors shrink by 30% or more. In total, 63 of 87 participants (72%) had at least one side effect believed to be related to zanidatamab treatment. Most side effects were mild or moderate in severity. No participant died from complications related to zanidatamab. Diarrhea was one of the more common side effects and was experienced by 32 of 87 participants (37%). Side effects related to receiving zanidatamab through the vein, such as chills, fever, or high blood pressure, were experienced by 29 of 87 participants (33%)., What Are the Conclusions Reported by the Researchers?: The results of this study support the potential for zanidatamab as a new therapy for people with HER2-positive biliary tract cancer after they had already received chemotherapy. More research is occurring to support these results. Clinical Trial Registration: NCT04466891 (HERIZON-BTC-01 study).

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare type of liver tumour that exhibits both hepatocytic and biliary differentiation within the same tumour. The histology and genomic alterations of recurrent/metastatic cHCC-CC are poorly understood. We selected six patients with cHCC-CC whose recurrent or metastatic tumours were histologically confirmed. Four patients with classic cHCC-CCs and two with intermediate cell carcinomas (ICs) were included. The clinicopathological features were evaluated, and next-generation sequencing was performed in 17 multiregional and longitudinal tumour samples. The histology of recurrent/metastatic lesions of classic cHCC-CCs was variable: hepatocellular carcinoma (HCC) was observed in one (25.0%) patient, cHCC-CC in one (25.0%) patient, and cholangiocarcinoma (CC) in two (50.0%) patients. Among 13 samples from four classic cHCC-CC patients, the most frequent pathological variants were TP53 (46.2%), TERT promoter (38.5%), ARID1A mutations (23.1%), and MET amplification (30.8%). In the sequencing analysis of each HCC and CC component, three (75.0%) of the four classic cHCC-CCs shared pathogenic variants. A large proportion of mutations, both pathogenic and those of undetermined significance, were shared by each HCC and CC component. Regarding ICs, the ATM mutation was detected in one patient. In conclusion, the histology of recurrent/metastatic cHCC-CCs was heterogeneous. Genomic profiling of classic cHCC-CCs revealed similar genomic alterations to those of HCC. Considerable overlapping genomic alterations in each HCC and CC component were observed, suggesting a monoclonal origin. Genetic alterations in ICs were different from those in either HCC or CC, suggesting the distinct nature of this tumour., (© 2023 John Wiley & Sons Ltd.)

Purpose: Bone metastasis (BM) adversely affects the prognosis of gastric cancer (GC). We investigated molecular features and immune microenvironment that characterize GC with BM compared to GC without BM., Materials and Methods: Targeted DNA and whole transcriptome sequencing were performed using formalin-fixed paraffin-embedded primary tumor tissues (gastrectomy specimens) of 50 GC cases with distant metastases (14 with BM and 36 without BM). In addition, immunohistochemistry (IHC) for mucin-12 and multiplex IHC for immune cell markers were performed., Results: Most GC cases with BM had a histologic type of poorly cohesive carcinoma and showed worse overall survival (OS) than GC without BM (p < 0.05). GC with BM tended to have higher mutation rates in TP53, KDR, APC, KDM5A, and RHOA than GC without BM. Chief cell-enriched genes (PGA3, PGC, and LIPF), MUC12, MFSD4A, TSPAN7, and TRIM50 were upregulated in GC with BM compared to GC without BM, which was correlated with poor OS (p < 0.05). However, the expression of SERPINA6, SLC30A2, PMAIP1, and ITIH2 were downregulated in GC with BM. GC with BM was associated with PIK3/AKT/mTOR pathway activation, whereas GC without BM showed the opposite effect. The densities of helper, cytotoxic, and regulatory T cells did not differ between the two groups, whereas the densities of macrophages were lower in GC with BM (p < 0.05)., Conclusion: GC with BM had different gene mutation and expression profiles than GC without BM, and had more genetic alterations associated with a poor prognosis.

Background: The hospitalist system has been introduced to improve the quality and safety of inpatient care. As its effectiveness has been confirmed in previous studies, the hospitalist system is spreading in various fields. However, few studies have investigated the feasibility and value of hospitalist-led care of patients with cancer in terms of quality and safety measures. This study aimed to evaluate the efficacy of the Hospitalist-Oncologist co-ManagemEnt (HOME) system., Methods: Between January 1, 2019, and January 31, 2021, we analyzed 591 admissions before and 1068 admissions after the introduction of HOME system on January 1, 2020. We compared the length of stay and the types and frequencies of safety events between the conventional system and the HOME system, retrospectively. We also investigate rapid response system activation, cardiopulmonary resuscitation, unplanned intensive care unit transfer, all-cause in-hospital mortality, and 30-day re-admission or emergency department visits., Results: The average length of stay (15.9 days vs. 12.9 days, P < 0.001), frequency of safety events (5.6% vs. 2.8%, P = 0.006), rapid response system activation (7.3% vs. 2.2%, P < 0.001) were significantly reduced after the HOME system introduction. However, there was no statistical difference in frequencies of cardiopulomonary resuscitation and intensive care unit transfer, all-cause in-hospital morality, 30-day unplanned re-admission or emergency department visits., Conclusions: The study suggests that the HOME system provides higher quality of care and safer environment compared to conventional oncologist-led team-based care, and the efficiency of the medical delivery system could be increased by reducing the hospitalization period without increase in 30-day unplanned re-admission., (© 2023. The Author(s).)

Tumor-infiltrating lymphocytes (TIL) have been suggested as an important prognostic marker in colorectal cancer, but assessment usually requires additional tissue processing and interpretational efforts. The aim of this study is to assess the clinical significance of artificial intelligence (AI)-powered spatial TIL analysis using only a hematoxylin and eosin (H&E)-stained whole-slide image (WSI) for the prediction of prognosis in stage II-III colon cancer treated with surgery and adjuvant therapy. In this retrospective study, we used Lunit SCOPE IO, an AI-powered H&E WSI analyzer, to assess intratumoral TIL (iTIL) and tumor-related stromal TIL (sTIL) densities from WSIs of 289 patients. The patients with confirmed recurrences had significantly lower sTIL densities (mean sTIL density 630.2/mm 2 in cases with confirmed recurrence vs. 1021.3/mm 2 in no recurrence, p < 0.001). Additionally, significantly higher recurrence rates were observed in patients having sTIL or iTIL in the lower quartile groups. Risk groups defined as high-risk (both iTIL and sTIL in the lowest quartile groups), low-risk (sTIL higher than the median), or intermediate-risk (not high- or low-risk) were predictive of recurrence and were independently associated with clinical outcomes after adjusting for other clinical factors. AI-powered TIL analysis can provide prognostic information in stage II/III colon cancer in a practical manner., (© 2023. The Author(s).)

What Is This Summary About?: This is a summary describing the results of a Phase III study called TOPAZ-1. The study looked at treatment with durvalumab (a type of immunotherapy) and chemotherapy to treat participants with advanced biliary tract cancer (BTC). Advanced BTC is usually diagnosed at late stages of disease, when it cannot be cured by surgery. This study included participants with advanced BTC who had not received previous treatment, or had their cancer come back at least 6 months after receiving treatment or surgery that aimed to cure their disease. Participants received treatment with durvalumab and chemotherapy or placebo and chemotherapy. The aim of this study was to find out if treatment with durvalumab and chemotherapy could increase the length of time that participants with advanced BTC lived, compared with placebo and chemotherapy., What Were the Results of the Study?: Participants who took durvalumab and chemotherapy had a 20% lower chance of experiencing death at any point in the study compared with participants who received placebo and chemotherapy. The side effects experienced by participants were similar across treatment groups, and less than 12% of participants in either treatment group had to stop treatment due to treatment-related side effects., What Do the Results of the Study Mean?: Overall, these results support durvalumab and chemotherapy as a new treatment option for people with advanced BTCs. Based on the results of this study, durvalumab is now approved for the treatment of adults with advanced BTCs in combination with chemotherapy by government organizations in Europe, the United States and several other countries.

Purpose: This study evaluated whether combination therapy is more effective than monotherapy in elderly patients with metastatic or recurrent gastric cancer (MRGC) as first-line chemotherapy., Materials and Methods: Elderly (≥ 70 years) chemo-naïve patients with MRGC were allocated to receive either combination therapy (group A: 5-fluorouracil [5-FU]/oxaliplatin, capecitabine/oxaliplatin, capecitabine/cisplatin, or S-1/cisplatin) or monotherapy (group B: 5-FU, capecitabine, or S-1). In group A, starting doses were 80% of standard doses, and they could be escalated to 100% at the discretion of the investigator. Primary endpoint was to confirm superior overall survival (OS) of combination therapy vs. monotherapy., Results: After 111 of the planned 238 patients were randomized, enrollment was terminated due to poor accrual. In the full-analysis population (group A [n=53] and group B [n=51]), median OS of combination therapy vs. monotherapy was 11.5 vs. 7.5 months (hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.56 to 1.30; p=0.231). Median progression-free survival (PFS) was 5.6 vs. 3.7 months (HR, 0.53; 95% CI, 0.34 to 0.83; p=0.005). In subgroup analyses, patients aged 70-74 years tended to have superior OS with combination therapy (15.9 vs. 7.2 months, p=0.056). Treatment-related adverse events (TRAEs) occurred more frequently in group A vs. group B. However, among severe TRAEs (≥ grade 3), there were no TRAEs with a frequency difference of > 5%., Conclusion: Combination therapy was associated with numerically improved OS, although statistically insignificant, and a significant PFS benefit compared with monotherapy. Although combination therapy showed more frequent TRAEs, there was no difference in the frequency of severe TRAEs.

Background/aims: There are few reports regarding mixed carcinoma, defined as a mixture of glandular and poorly cohesive components, in patients with gastric cancer (GC). The aim of this study was to evaluate the proportion and characteristics of mixed carcinoma in GC patients., Methods: A total of 7,215 patients diagnosed with GC at Seoul National University Bundang Hospital were enrolled from March 2011 to February 2020. GC was divided into four groups (well-moderately differentiated GC, poorly differentiated GC, poorly cohesive carcinoma, and mixed carcinoma). The proportion of each GC type and the clinicopathological features were analyzed and divided into early GC and advanced GC., Results: The proportion of mixed carcinoma was 10.9% (n=787). In early GC, submucosal invasion was the most common in poorly differentiated (53.7%), and mixed carcinoma ranked second (41.1%). Mixed carcinoma showed the highest proportion of lymph node metastasis in early GC (23.0%) and advanced GC (78.3%). In advanced GC, the rate of distant metastasis was 3.6% and 3.9% in well-moderately differentiated GC and mixed carcinoma, respectively, lower than that in poorly differentiated GC (6.4%) and poorly cohesive carcinoma (5.7%), without statistical significance., Conclusions: Mixed carcinoma was associated with lymph node metastasis compared to other histological GC subtypes. And it showed relatively common submucosal invasion in early GC, but the rates of venous invasion and distant metastasis were lower in advanced GC. Further research is needed to uncover the mechanism underlying these characteristics of mixed carcinoma (Trial registration number: NCT04973631).

Background and Aims: Biliary tract cancers are rare, heterogeneous cancers with poor prognoses. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed death ligand 1, was evaluated in patients with locally advanced/metastatic chemorefractory biliary tract cancers., Approach and Results: This multicenter, single-arm, open-label, phase 2 study (NCT03833661) enrolled adults with locally advanced or metastatic biliary tract cancer that was intolerant to or had failed first-line systemic platinum-based chemotherapy. Patients received 1200 mg bintrafusp alfa intravenously Q2W. The primary endpoint was confirmed objective response according to Response Evaluation Criteria in Solid Tumors 1.1 assessed by IRC. Secondary endpoints included duration of response, durable response rate, safety, progression-free survival, and overall survival.Between March 2019 and January 2020, 159 patients were enrolled. Median follow-up was 16.1 (range, 0.0-19.3) months; 17 patients (10.7%; 95% CI: 6.4%-16.6%) achieved an objective response. Median duration of response was 10.0 (range, 1.9-15.7) months; 10 patients (6.3%; 95% CI: 3.1%-11.3%) had a durable response (≥6 mo). Median progression-free survival was 1.8 months (95% CI: 1.7-1.8 mo); median overall survival was 7.6 months (95% CI: 5.8-9.7 mo). Overall survival rates were 57.9% (6 mo) and 38.8% (12 mo). Grade ≥3 adverse events occurred in 26.4% of patients, including one treatment-related death (hepatic failure). Frequent grade ≥3 adverse events included anemia (3.8%), pruritus (1.9%), and increased alanine aminotransferase (1.9%)., Conclusions: Although this study did not meet its prespecified primary endpoint, bintrafusp alfa demonstrated clinical activity as second-line treatment in this hard-to-treat cancer, with durable responses and a manageable safety profile., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Two-photon microscopy (TPM) is an attractive biomedical imaging method due to its large penetration depth and optical sectioning capability. In particular, label-free autofluorescence imaging offers various advantages for imaging biological samples. However, relatively low intensity of autofluorescence leads to low signal-to-noise ratio (SNR), causing practical challenges for imaging biological samples. In this study, we present TPM using a pulse picker to utilize low pulse repetition rate of femtosecond pulsed laser to increase the pulse peak power of the excitation source leading to higher emission of two-photon fluorescence with the same average illumination power. Stronger autofluorescence emission allowed us to obtain higher SNR images of arterial and liver tissues. In addition, by applying the time gating detection method to the pulse signals obtained by TPM, we were able to significantly reduce the background noise of two-photon images. As a result, our TPM system using the pulsed light source with a 19 times lower repetition rate allowed us to obtain the same SNR image more than 19 times faster with the same average power. Although high pulse energy can increase the photobleaching, we also observed that high-speed imaging with low total illumination energy can mitigate the photobleaching effect to a level similar to that of conventional illumination with a high repetition rate. We anticipate that this simple approach will provide guidance for SNR enhancement with high-speed imaging in TPM as well as other nonlinear microscopy., (© 2023. Springer Nature Limited.)

Intracoronary optical coherence tomography (OCT) requires injection of flushing media for image acquisition. Alternative flushing media needs to be investigated to reduce the risk of contrast-induced renal dysfunction. We investigated the feasibility and safety of pentastarch (hydroxyethyl starch) for clinical OCT imaging. We prospectively enrolled 43 patients with 70 coronary lesions (46-stented; 24-native). Total 81 OCT pullback pairs were obtained by manual injection of iodine contrast, followed by pentastarch. Each pullback was assessed frame-by-frame using an automated customized lumen contour/stent strut segmentation algorithm. Paired images were compared for the clear image segments (CIS), blood-flushing capability, and quantitative morphometric measurements. Overall image quality, as assessed by the proportion of CIS, was comparable between the contrast- and pentastarch-flushed images (97.1% vs. 96.5%; p = 0.160). The pixel-based blood-flushing capability was similar between the groups (0.951 [0.947-0.953] vs. 0.950 [0.948-0.952], p = 0.125). Quantitative two- and three-dimensional morphometric measurements of the paired images correlated well (p < 0.001) with excellent inter-measurement variability. All patients safely underwent OCT imaging using pentastarch without resulting in clinically relevant complications or renal deterioration. Non-contrast OCT imaging using pentastarch is clinically safe and technically feasible with excellent image quality and could be a promising alternative strategy for patients at high risk of renal impairment., (© 2023. Springer Nature Limited.)

Background: After a brief period of dual antiplatelet therapy, P2Y 12 inhibitor monotherapy in the absence of aspirin effectively reduces bleeding without increasing recurrent ischemia in patients undergoing percutaneous coronary intervention (PCI). In addition, early anti-inflammatory therapies may have clinical benefits in acute coronary syndrome (ACS) patients., Objectives: The aim of this study was to investigate the feasibility of ticagrelor or prasugrel P2Y 12 inhibitor monotherapy combined with colchicine immediately after PCI in patients with ACS., Methods: This was a proof-of-concept pilot trial. ACS patients treated with drug-eluting stents were included. On the day after PCI, low-dose colchicine (0.6 mg daily) was administered in addition to ticagrelor or prasugrel maintenance therapy, whereas aspirin therapy was discontinued. The primary outcome was any stent thrombosis at 3 months. The key secondary outcomes were platelet reactivity measured by the VerifyNow assay (Accriva) before discharge and a reduction in high-sensitivity C-reactive protein (hs-CRP) over 1 month., Results: We enrolled 200 patients, 190 (95.0%) of whom completed the 3-month follow-up. The primary outcome occurred in 2 patients (1.0%): 1 definite and 1 probable stent thrombosis. The level of platelet reactivity overall was 27 ± 42 P2Y 12 reaction units, and only 1 patient had high platelet reactivity (>208 P2Y 12 reaction units). The hs-CRP levels decreased from 6.1 mg/L (IQR: 2.6-15.9 mg/L) at 24 hours after PCI to 0.6 mg/L (IQR: 0.4-1.2 mg/L) at 1 month (P < 0.001), and the prevalence of high-inflammation criteria (hs-CRP ≥2 mg/L) decreased from 81.8% to 11.8% (P < 0.001)., Conclusions: In ACS patients undergoing PCI, it is feasible to discontinue aspirin therapy and administer low-dose colchicine on the day after PCI in addition to ticagrelor or prasugrel P2Y 12 inhibitors. This approach is associated with favorable platelet function and inflammatory profiles. (Mono Antiplatelet and Colchicine Therapy [MACT]; NCT04949516)., Competing Interests: Funding Support and Author Disclosures This study was supported by the Cardiovascular Research Center, Seoul, Korea. Dr Jeong has received honoraria for lectures from AstraZeneca, Daiichi Sankyo, Sanofi, and Han-mi Pharmaceuticals; and has received research grants or support from Yuhan Pharmaceuticals, Han-mi Pharmaceuticals, Sam-jin Pharmaceuticals, Biotronik, and U and I Corporation. Dr Gorog has received institutional research grants from AstraZeneca, Werfen, Medtronic, Bayer, and Alpha MD; and has received speaker fees from AstraZeneca. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer., Methods: HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment., Findings: Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58-70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58-77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4-17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4-52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths., Interpretation: Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer., Funding: Zymeworks, Jazz, and BeiGene., Competing Interests: Declaration of interests JJH reports support from Zymeworks to self (uncompensated), and research support to institution for this work; grants or contracts from Bristol Myers Squibb, Boehringer Ingelheim, CytomX, Debiopharm, Eli Lilly, Genoscience, Incyte, Loxo@Lilly, Novartis, Polaris, Pfizer, Zymeworks, and Yiviva outside of this work; consulting fees or advisory board from Adaptimmune, AstraZeneca, Bristol Myers Squibb, Exelexis, Elevar, Eisai, Genoscience (uncompensated), Hepion, Imvax, Merck, Medivir, QED, Tyra, and Zymeworks (uncompensated) outside of this work. D-YO reports grants or contracts from AstraZeneca, Novartis, Array, Eli Lilly, Servier, BeiGene, MSD, and Handok to institution outside of this work; and participation on advisory boards for AstraZeneca, Novartis, Genentech/Roche, Merck Serono, Bayer, Taiho, ASLAN, Halozyme, Zymeworks, BMS/Celgene, BeiGene, Basilea, Turning Point, Yuhan, Arcus Biosciences, and IQVIA outside of this work. HJC reports consulting fees to self from Roche and AstraZeneca outside of this work. JWK reports grants or contracts from Inno.N and Jeil Pharm outside of this work; and consulting fees from AstraZeneca, Beyond Bio, Eisai, MSD, BeiGene, Bristol Myers Squibb/Celgene, GC Cell, ONO, Sanofi-Aventis, Servier, and TCUBEit outside of this work. H-MC reports funding for clinical trial from Zymeworks to institution for this work. HC-S reports consulting fees from TopAlliance outside of this work; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing or educational events from TopAlliance and AstraZeneca outside of this work. J-PM reports payment or honoraria for lectures from MSD, BMS, Bayer, Astellas, and Merck outside of this work. JB reports consultancy fees from Taiho, Incyte, Servier, BMS outside of this work; grants or contracts for research from Incyte outside of this work; and payment or honoraria as a speaker from Incyte and Servier outside of this work. MAT reports payment or honoraria as a speaker from Natera and Caris outside of this work. HW reports support from Zymeworks for this work; consulting fees from Oncosil outside of this work; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Servier, Pierre Fabre, Incyte, Bayer, Merck KGaA, Amgen, Roche/Genentech/FM, SIRTEX Medical, BMS (Celgene), BTG, and Seagen outside of this work; payment for expert testimony from Oncosil outside of this work; support for attending meetings and/or travel from Pierre Fabre, Servier, and Merck KGaA outside of this work; participation on a DSMB or advisory board from Incyte, Bayer, Merck KGaA, Amgen, Roche/Genentech/FM, SIRTEX Medical, Erytech Pharma, BMS (Celgene), BTG, and Seagen outside of this work; and leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from Pfizer and Zymeworks (trial steering committee for both) outside of this work. MD reports participation on advisory boards from Roche, Merck Serono, Amgen, Bayer, Servier, Pierre Fabre, BeiGene, AstraZeneca, Daiichi Sankyo, Merck-Sharp-Dohme, and Boehringer Ingelheim outside of this work; speaker in symposia from Roche, Merck Serono, Bayer, Merck-Sharp-Dohme, Servier, Pierre Fabre, and Daiichi Sankyo outside of this work; institutional research funding from Roche, Merck Serono, and Keocyt outside of this work; and participation in independent data monitoring committees for Roche and Pancan outside of this work. MD's spouse is head of the oncology business unit at Sandoz France. YB reports employment by BeiGene at the time of the study and ownership of BeiGene stock or stock options outside of this work. LB reports employment by Zymeworks at the time of the study and ownership of Zymeworks stock or stock options outside of this work. JM reports ownership of stock or stock options of BeiGene as an employee. PG reports employment by Zymeworks at the time of the study; support for attending meetings and/or travel from Zymeworks Inc outside of this work; and ownership of Zymeworks and Seagen stock or stock options outside of this work. SP reports advisory/consultancy fees to self from Zymeworks, Ipsen, Novartis, Janssen, Boehringer Ingelheim, and AskGene Pharma outside of this work; and a research grant or funding to their institution from Mirati Therapeutics, Lilly, Xencor, Novartis, Rgenix, Bristol-Myers Squibb, Astellas Pharma, Framewave, 4D Pharma, Boehringer Ingelheim, NGM Biopharmaceuticals, Janssen, Arcus Biosciences, Elicio Therapeutics, BioNtech, Ipsen, Zymeworks, Pfizer, ImmunoMET, Immuneering, Amal Therapeutics outside of this work. JF, LeB, TM, FX, JY, M-AL, EYC, and DUK declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)