Background: While recipient cytochrome P450 (CYP) genetic polymorphisms are established modulators of tacrolimus (TAC) pharmacokinetics, the combined effects of donor-derived hepatic and recipient intestinal CYP3A4/5 and CYP2C19 genotypes during voriconazole (VRC)-mediated CYP3A inhibition remain inadequately elucidated in liver transplantation. Objectives: This study evaluated the impact of donor and recipient CYP3A4/5 and CYP2C19 polymorphisms on TAC pharmacokinetics during VRC co-therapy in liver transplant recipients. Design: A retrospective study was conducted on 139 liver transplant patients receiving TAC-based immunosuppressive therapy at the First Affiliated Hospital of Sun Yat-sen University from December 2016 to June 2025. Methods: The liver transplant recipients were stratified into a VRC co-therapy group (n = 33) and a non-VRC control group (n = 106). TAC dose-corrected trough concentrations (C-0/D) were analyzed in relation to donor and recipient genotypes of CYP3A4*1G (rs2242480), CYP3A5*3 (rs776746), CYP2C19*2 (rs4244285), and CYP2C19*3 (rs4986893). Results: During VRC co-therapy, dual donor-recipient CYP3A4*1G CC carriers exhibited a 73% increase in TAC C-0/D compared with TT/TC genotypes (6.83 vs 3.95, p = 0.0031). Recipients grafted from CYP3A5 non-expresser donors exhibited 34% higher TAC C-0/D than those from CYP3A5 expressers (6.35 vs 4.75, p = 0.0196). Recipient CYP2C19 poor metabolizers demonstrated 36% elevated TAC C-0/D compared to extensive or intermediate metabolizers (6.47 vs 4.76, p = 0.0401). The magnitude of TAC-VRC interaction was modulated by both donor and recipient genotypes. Comparing with the control group, VRC co-therapy increased TAC C-0/D by 3.80- and 2.75-fold increases in CYP3A5 expresser and non-expresser recipients, respectively, and by 3.44- and 3.53-fold in recipients grafted from CYP3A5 expresser and non-expresser donors, respectively. Post-VRC discontinuation, TAC C-0/D remained significantly elevated for 5 days before returning to baseline level by day 6 (p < 0.0001). Conclusion: In summary, Donor and recipient CYP3A4/5 and CYP2C19 genotypes jointly influence TAC pharmacokinetics during VRC co-therapy. Genotype-guided dosing strategies integrating both donor and recipient genotypes may improve TAC dosing precision. TAC dose reinstatement may be deferred until day six following VRC discontinuation to avoid overexposure.

BACKGROUND:Amivantamab is a bispecific, epidermal growth factor receptor (EGFR) and MET-proto-oncogene (MET)-targeting antibody with immune cell-directing activity. In the global Phase 3 PAPILLON trial, amivantamab plus carboplatin-pemetrexed (amivantamab-chemotherapy) significantly improved progression-free survival (PFS) vs chemotherapy alone in previously untreated participants with locally advanced/metastatic NSCLC with EGFR exon 20 insertions (Ex20ins). We evaluated clinical outcomes in Asian participants in PAPILLON (NCT04538664). METHODS:Participants were randomized 1:1 to amivantamab-chemotherapy or chemotherapy alone. Study endpoints for this analysis were PFS by blinded independent central review (primary), objective response rate (ORR), duration of response (DoR), PFS after first subsequent therapy (PFS2), overall survival (OS), and safety (secondary). Crossover to amivantamab monotherapy was allowed when disease progressed on chemotherapy alone. RESULTS:Among 186 participants in the Asian sub-cohort, 97 received amivantamab-chemotherapy and 89 received chemotherapy. At median follow-up of 16.6 months, median PFS (95% confidence interval [CI]) in the amivantamab-chemotherapy/chemotherapy groups was 11.5/5.6 months (hazard ratio [HR] 0.34; 95%CI, 0.23-0.49; nominal p < 0.0001) arms. The ORR was 70% vs 51% (odds ratio 2.2, 95%CI, 1.2-3.9; nominal p = 0.012), DoR 10.1 vs 5.5 months. Median PFS2 was not estimable vs 18.8 months (HR 0.46, 95%CI 0.26-0.83; nominal p = 0.008), and median interim OS not estimable vs 24.4 months HR 0.65, 95%CI 0.34-1.24; nominal p = 0.189), respectively, despite substantial (73%) crossover. Safety profiles for both arms were similar to the overall PAPILLON population. CONCLUSIONS:Amivantamab-chemotherapy demonstrated superior PFS vs chemotherapy and represents a new standard of care for first-line treatment of Asian participants with Ex20ins-mutated NSCLC.

e20500 Background: T-DXd (5.4 mg/kg) is approved in multiple countries for pretreated unresectable/metastatic HER2m NSCLC; conditional approval in China was supported by DESTINY-Lung02 (DL-02) and DL-05 results. In DL-02, T-DXd showed encouraging CNS activity in this population. Here, we report a post-hoc analysis of DL-05 assessing T-DXd in pts from China with HER2m NSCLC with/without baseline (BL) CNS mets. Methods: DL-05 (NCT05246514), an open-label, single-arm, Phase 2 study, evaluated T-DXd (5.4 mg/kg Q3W IV) in pts from China with metastatic HER2m NSCLC with disease progression on/after ≥1 prior anticancer therapy. Pts with pretreated asymptomatic / neurologically stable CNS mets were eligible. Brain CT or MRI scans were performed in all pts at BL and study end. Pts with CNS mets had brain scans every 6 weeks from enrollment date to 48 weeks, then every 9 weeks until RECIST 1.1-defined progressive disease. Additional brain scans were carried out as clinically indicated. In pts with/without BL CNS mets, systemic efficacy (confirmed objective response rate [cORR], disease control rate [DCR], duration of response [DOR], and progression-free survival [PFS] by independent central review [ICR] per RECIST 1.1; and overall survival [OS]), CNS-PFS by ICR per CNS-modified RECIST 1.1, and safety were assessed. CNS-cORR, CNS-DCR, and CNS-DOR were evaluated in pts with measurable BL CNS mets. Results: At data cutoff (November 4, 2024), 72 pts had received T-DXd; 30 pts had BL CNS mets, including 10 with CNS-measurable disease. Median (range) duration of follow up for all pts was 20.2 (2–27) months. In pts with and without CNS mets, median (range) treatment duration was 7.6 (0.7–26.9) months and 10.5 (0.7–26.6) months, respectively. Systemic efficacy data and CNS-PFS are in the Table. In pts with measurable CNS mets (n=10), CNS-cORR was 40.0% (95% CI 12.2, 73.8; n=4, one complete response was reported), CNS-DCR was 100% (95% CI 69.2, 100), and median CNS-DOR was not evaluable (NE). Drug-related Grade ≥3 adverse events were reported in 60.0% (n=18) and 52.4% (n=22) of pts with and without CNS mets, respectively. Conclusions: T-DXd showed antitumor activity in pts from China with metastatic HER2m NSCLC with and without BL CNS mets; consistent with previous analyses, promising CNS activity was observed. No new safety signals were reported. Results support T-DXd use in pretreated pts with HER2m NSCLC, including those with CNS mets. Clinical trial information: NCT05246514 . BL CNS mets(n=30) No BL CNS mets(n=42) cORR, % (n)*95% CI 46.7 (14)28.3, 65.7 64.3 (27)48.0, 78.4 DCR, % (n)*95% CI 90.0 (27)73.5, 97.9 92.9 (39)80.5, 98.5 Median DOR, months (95% CI)* 7.1 (5.3, 15.3) 14.0 (5.8, NE) Median PFS, months (95% CI)* 8.0 (5.8, 16.5) 13.0 (7.2, NE) Median CNS-PFS, months (95% CI) 7.8 (5.6, 9.9) NE (NE, NE) Median OS, months (95% CI)* 16.6 (13.3, 21.7) 24.0 (19.9, NE) *Systemic assessment.

Trastuzumab deruxtecan (T-DXd) is a human epidermal growth factor receptor 2 (HER2)-targeting antibody–drug conjugate that has demonstrated encouraging efficacy and a manageable safety profile in the second-line or later setting for non-small cell lung cancer (NSCLC) harboring HER2 mutations. While T-DXd was approved for treating patients with locally advanced or metastatic HER2-mutant NSCLC in China, real-world data on its use in Chinese clinical practice are lacking. This study will collect real-world data on T-DXd to evaluate its effectiveness and safety in Chinese patients with HER2-mutant metastatic NSCLC, thereby providing additional evidence to the oncology community in China. RERUN is a prospective, multicenter, observational cohort study conducted at approximately 30 sites in China. Approximately 150 adult patients (≥ 18 years) with pathologically documented unresectable and/or metastatic non-squamous NSCLC harboring any known activating HER2 mutation are currently being enrolled. The follow-up period will last approximately 6 months after the last patient is enrolled, when sufficient progression-free survival (PFS) maturity (approximately 60

Background Lineage transformation from lung adenocarcinoma (LUAD) to small cell lung cancer (SCLC) represents a rare yet well-documented off-target mechanism associated with acquired resistance to tyrosine kinase inhibitors (TKIs). However, the relationship between this transformation and morphological changes remains inadequately understood. This study seeks to elucidate the molecular mechanisms by which RB1 depletion facilitates lineage transformation, with a particular emphasis on its role in morphological alterations. Methods Integrated molecular, morphological, and structural analyses were conducted in RB1-deficient LUAD models in vitro and in vivo. Functional perturbation and pharmacological inhibition of RB1-associated regulators were further performed to delineate the mechanism of the RB1/E2F1/HDAC1 axis. Results Patients with LUAD exhibiting low expression levels of TP53 and RB1 exhibited enhanced tumor invasion characteristics and a poor clinical prognosis. Our findings demonstrated that RB1 depletion induced epithelial-mesenchymal transition (EMT) characteristics in LUAD cells, as evidenced by spindle-shaped morphology, increased vimentin expression, and decreased E-cadherin expression. Furthermore, RB1 loss is responsible for nuclear abnormalities, including irregular distribution of nuclear hallmarks such as lamin A/C and emerin, which contribute to tumor aggressiveness. Through the downregulation of individual components of the RB1/E2F1/HDAC1 complex, we identified HDAC1 as a key regulatory factor influencing lamin A/C modification and nuclear deformation. Pharmacological inhibition of HDAC1 derivatives ameliorates the nuclear abnormalities observed in RB1-depleted lung cancer cells, suggesting a potential therapeutic strategy. Mechanistically, the loss of acetylated lamin A/C leads to its degradation and granular distribution, resulting in compromised nuclear mechanostability and defective cytoskeletal dynamics, which may elucidate the observed EMT. Conclusions Collectively, our findings suggested that the downregulation of RB1 significantly influences the morphology of LUAD by facilitating EMT and nuclear abnormalities through HDAC1-mediated deacetylation of lamin A/C. Future research should prioritize the development of targeted therapies aimed at restoring RB1 function or inhibiting HDAC1 to mitigate cancer progression, thereby enhancing patient stratification and treatment strategies in TKI-resistant LUAD.

Abstract Background: ROS1 tyrosine kinase inhibitors (TKIs) are highly effective in ROS1-positive non-small cell lung cancer (NSCLC), but acquired resistance remains a challenge, particularly solvent front (SF) mutations like G2032R and D2033N, and the central beta sheet (Cβ6) mutation L2086F. ANS03 is a next generation type II TKI targeting both ROS1 and TRK, possessing a broad spectrum of acquired drug-resistant mutation coverage. In preclinical studies, ANS03 was more potent than repotrectinib against SF mutations and more potent than repotrectinib or zidesamtinib against L2086F. Method: A phase 1 study (NCT06716138) was designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ANS03 in participants with locally advanced or metastatic solid tumors harboring a ROS1 or NTRK alteration. Dose escalation was determined by Bayesian optimal interval design. Response was assessed by investigators using RECIST V1.1. Results: As of January 6, 2026, the dose escalation study is ongoing. Five dose levels (15mg qd, 30mg qd, 45mg qd, 67.5mg qd and 90mg qd) have been completed. A total of 20 NSCLC patients harboring ROS1/NTRK fusions were enrolled. No dose-limiting toxicities were observed. The most frequently reported treatment related adverse events (TRAE) were low grade, including the elevation of AST/ALT (80%), bilirubin (35%) and LDH (35%). Grade ≥3 TRAE occurred in 25% of patients. Only low grade neurotoxicities (15%) including dizziness, dysgeusia and pain in the limbs occurred. Among 18 efficacy evaluable ROS1 fusion-positive cancers, objective response rates (ORRs) were 38.8% (7/18) for all enrolled patients and 54.5% (6/11) for patients previously received ≥2L systemic therapy and at least 1 prior ROS1 TKI. Of the latter, six patients were pre-treated with 2-4 ROS1 TKIs including lorlatinib, repotrectinib, taletrectinib, and zidesamtinib. Among heavily pretreated patients, one patient posted 5 prior lines of systemic therapy (3 prior TKIs) with an L2086F mutant cancer had a confirmed partial response (PR) with ANS03 at 12 weeks. Two additional patients who received ≥6 prior lines of systemic therapy and ≥4 prior TKIs had a PR at the first tumor assessment and remain on ANS03 therapy. Conclusions: ANS03 had a manageable safety profile with a low incidence of neurotoxicity. In ROS1 fusion-positive NSCLCs, promising preliminary anti-tumor activity was achieved, including against ROS1 L2086F. Citation Format: Alexander Drilon, Jia Yu, Zhiyong He, Yongsheng Wang, Kejing Tang, Tianqing Chu, Shutan Liao, Junjun Zhang, Xinlong Zheng, Jaime Rubio-Perez, Matteo Repetto, Brendan Putz, Shengxiang Ren. A phase I study of the type II ROS1 TRK inhibitor ANS03 in ROS1 fusion-positive lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT061.

The full text of this preprint has been withdrawn by the authors due to author disagreement with the posting of the preprint. Therefore, the authors do not wish this work to be cited as a reference. Questions should be directed to the corresponding author.

BACKGROUND:Bispecific antibodies targeting programmed death 1 (PD-1) and vascular endothelial growth factor (PD1-VEGF) have shown promising efficacy in non-small-cell lung cancer (NSCLC). In our previous report of the HARMONi-6 study, we aimed to evaluate the efficacy and safety of ivonescimab plus chemotherapy versus tislelizumab plus chemotherapy as a first-line therapy for patients with advanced squamous NSCLC. Ivonescimab combined with chemotherapy significantly prolonged progression-free survival compared with tislelizumab plus chemotherapy. Here we report the prespecified interim overall survival analysis. METHODS:HARMONi-6 is a double-blind, randomised, phase 3 trial, which was conducted at 50 hospitals across China. Patients aged 18-75 years with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC and an Eastern Cooperative Oncology Group performance status score of 0 or 1 were eligible for inclusion. Eligible patients were randomly assigned in a 1:1 ratio to receive ivonescimab or tislelizumab, in combination with paclitaxel and carboplatin for four cycles, followed by maintenance ivonescimab or tislelizumab monotherapy. The primary endpoint was progression-free survival assessed by the independent radiographic review committee as per Response Evaluation Criteria in Solid Tumours guidelines (version 1.1) in all randomly assigned patients. Overall survival was a key secondary endpoint; an interim analysis was planned when approximately 225 overall survival events were observed, but it was triggered after 204 overall survival events to meet regulatory deadlines. Safety, defined as adverse events and serious adverse events related to treatment, as well as adverse events related to immunity or VEGF blockade, were analysed in all randomly assigned patients who received at least one dose of the assigned study treatment. This study is registered at ClinicalTrials.gov (NCT05840016), has completed enrolment, and is ongoing for treatment and follow-up. FINDINGS:From Aug 17, 2023, to Jan 21, 2025, 761 patients were assessed for eligibility, and after 229 exclusions a total of 532 patients were randomly allocated (266 per group). 494 (93%) of patients were male and 38 (7%) of patients were female. The median age was 64 years (IQR 59-69). At data cutoff (Feb 27, 2026), 204 deaths had occurred: 84 (32%) patients in the ivonescimab plus chemotherapy group and 120 (45%) in the tislelizumab plus chemotherapy group. With a median follow-up of 21·4 months (95% CI 20·27-21·91), the median overall survival was 27·9 months (95% CI 27·89-not evaluable [NE]) with ivonescimab versus 23·7 months (20·11-NE) with tislelizumab (hazard ratio for death 0·66 [95% CI 0·50-0·87]; pone-sided=0·0017), meeting the prespecified boundary (p<0·0049). The overall survival benefit with ivonescimab plus chemotherapy was consistent across key subgroups. Treatment-related adverse events of grade 3 or higher occurred in 184 (69%) of 266 patients in the ivonescimab group and 156 (59%) of 265 patients in the tislelizumab group. The incidence of grade 3 or higher haemorrhage was seven (3%) of 266 and two (1%) of 265, respectively. INTERPRETATION:Ivonescimab plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival compared with tislelizumab plus chemotherapy in previously untreated patients with advanced squamous NSCLC. This regimen could provide a novel treatment option as first-line treatment in this patient group. FUNDING:Akeso Biopharma.

Introduction Trastuzumab deruxtecan (T-DXd) was approved in China in October 2024 for previously treated human epidermal growth factor receptor 2 (HER2)-mutant (HER2m) unresectable/metastatic non–small cell lung cancer (NSCLC), based on DESTINY-Lung02 and DESTINY-Lung05 primary results. Here, we report the DESTINY-Lung05 final analysis. Methods DESTINY-Lung05 (NCT05246514), an open-label, single-arm, multicenter, phase 2 study, investigated T-DXd (5.4 mg/kg once every 3 weeks) in patients from China with HER2m (locally or centrally confirmed activating HER2 exon 19/20 mutation) metastatic NSCLC with disease progression on/after ≥ 1 prior anticancer therapy. The primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 by independent central review (ICR). Secondary endpoints included progression-free survival (PFS) by ICR, overall survival (OS), and safety. Results As of November 4, 2024, 72 patients with HER2m NSCLC had received T-DXd 5.4 mg/kg; the median duration of follow-up was 20.2 months (range, 2-27). Confirmed ORR (ICR) was 56.9% (95% confidence interval [CI] 44.7-68.6). Median PFS (ICR) and OS were 9.9 months (95% CI 7.1-16.5) and 21.0 months (95% CI 17.5-not calculable), respectively. Grade ≥ 3 drug-related adverse events occurred in 40 (55.6%) patients. Adjudicated drug-related interstitial lung disease/pneumonitis events were observed in 9 (12.5%) patients (n = 8 grade 1/2; n = 1 grade 3). Conclusions With extended follow-up, T-DXd continued to demonstrate clinically meaningful and durable antitumor activity in patients from China with pretreated HER2m metastatic NSCLC, with no new safety signals. Results affirm the use of T-DXd as a treatment option in China for this patient population.

Purpose:Approximately 38% of Chinese patients with non-small cell lung cancer (NSCLC) exhibit a mutation in the epidermal growth factor receptor (EGFR) gene. Afatinib, which targets the EGFR, is approved for first-line treatment in advanced EGFR mutation-positive NSCLC worldwide. The aim of this prospective, observational and non-interventional real-world study was to examine the effectiveness and safety of first line afatinib in Chinese patients, newly diagnosed with EGFR mutation-positive NSCLC. Patients and Methods:Patients were enrolled at 10 sites in China from May 2020 to December 2021 and followed-up from May 2020 to December 2023. Adult patients (aged ≥18 years) were treated with oral afatinib 30 mg or 40 mg once daily. The primary outcome was time on treatment (TOT). Secondary outcomes were overall survival (OS), overall response rate (ORR) and safety. Results:A total of 72 patients were enrolled and treated with afatinib. Most were male (54.2%), Chinese (98.6%), never smokers (63.9%), and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (98.6%) and patients had a mean (SD) age of 62.2 (9.6) years. Median TOT overall was 14.4 months and was prolonged in younger (aged <65 years) vs older (aged ≥65 years) age groups, common vs uncommon baseline EGFR mutations, and higher afatinib starting dose (40 mg vs 30 mg). Median OS was not reached; the median follow-up time of the study was 25.1 months. ORR was 62.7% overall and was higher in common vs uncommon baseline EGFR mutations, higher afatinib starting dose, and with vs without brain metastases. The two most common treatment-emergent adverse events were diarrhea and rash. No new safety concerns were found. Conclusion:This study provides real-world evidence of the effectiveness and safety of afatinib as first-line therapy for Chinese patients with EGFR mutation-positive advanced NSCLC.

To investigate the efficacy and safety of osimertinib plus savolitinib for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and de novo MET aberrations, we conducted a randomized, multicenter, open-label, phase 2 study (ClinicalTrials.gov identifier: NCT05163249). Treatment-naïve patients with locally advanced or metastatic NSCLC harboring de novo MET amplification or overexpression and EGFR mutations were randomized to receive osimertinib monotherapy (cohort 1, 80 mg orally once daily) or combination therapy (cohort 2, osimertinib 80 mg orally once daily and savolitinib 300 mg orally twice daily). The primary endpoint was the confirmed objective response rate (ORR). A total of 44 patients were randomized to either cohort 1 (n = 23) or cohort 2 (n = 21). The pre-specified study endpoint was achieved. The confirmed ORR was 60.9% (95% confidence interval [CI]: 38.5-80.3) in cohort 1 and 90.5% (95% CI: 69.6-98.8) in cohort 2, with disease control rates of 87% (95% CI: 66.4-97.2) and 95.2% (95% CI: 76.2-99.9). Treatment-related adverse events of grade 3 or higher occurred in 2 patients (8.7%) in cohort 1 and 12 patients (57.1%) in cohort 2. Osimertinib plus savolitinib showed promising antitumor activity and manageable safety.

OBJECTIVE:This study aimed to evaluate the associations of free mycophenolic acid (f-MPA) concentration and total MPA (t-MPA) concentration with treatment response and haematologic toxicity and to determine whether f-MPA provides additional safety-related value for therapeutic drug monitoring (TDM) in patients with paediatric lupus nephritis (LN) treated with mycophenolate mofetil (MMF). METHODS:Sixty-five patients with paediatric LN receiving MMF were prospectively enrolled. The t-MPA and f-MPA were measured simultaneously using validated ultrafiltration and LC-MS/MS. Full pharmacokinetic profiles were obtained over 12 hours, and area under the concentration-time curve (AUC) was calculated for t-MPA (t-MPA-AUC) and f-MPA (f-MPA-AUC). Univariate analysis identified factors influencing efficacy (relapse-free survival) and adverse drug reaction (ADR) over 12 months. Receiver operating characteristic (ROC) curves established predictive thresholds and Kaplan-Meier methods analysed time-to-event. RESULTS:The 12-month relapse-free rate was 78.7% (95% CI 66.6% to 90.9%). Both t-MPA-AUC and f-MPA-AUC significantly correlated with relapse-free survival (ROC AUC 0.70 each; optimal thresholds: t-MPA-AUC=31.63 µg·h/mL, f-MPA-AUC=354.45 ng·h/mL). The average remission duration above these thresholds was 10.88 and 11.00 months. The overall MMF-related ADR incidence was 25.2%, including 17 haematological events (26.2%). The t-MPA-AUC, f-MPA-AUC, glucose, β2-microglobulin and C3 were haematological ADR risk factors. The f-MPA-AUC independently predicted haematological ADRs (optimal threshold: 492.96 ng·h/mL; specificity 86.2%). CONCLUSION:Both t-MPA-AUC and f-MPA-AUC effectively predict MMF efficacy in paediatric LN. However, f-MPA-AUC demonstrates superior predictive value for safety outcomes, specifically haematological ADRs. This supports f-MPA as a potentially better TDM metric for optimising MMF therapy safety in this population.

Objectives To investigate the relationship between intravenous polymyxin B (PMB) plasma exposure and clinical outcome in septic patients, and to determine the pharmacokinetics (PK) target. Patients and Methods: This single-center, observational study enrolled septic patients who received PMB therapy between July 2021 and July 2025. The primary clinical outcome was the clinical success rate. The secondary outcomes included 28-day all-cause mortality, 90-day survival time, bacterial clearance, ventilator-free days, ICU-free days and hospital-free days. The AUC ss,0−12h and C ss, avg were analyzed to identify their associations with clinical outcomes, and cut-off value were determined by receiver-operating characteristic (ROC) curves. Monte Carlo simulations were used to recommend initial dosing regimens based on weights and use of continuous renal replacement therapy (CRRT). Results A total of 82 septic patients were included. The clinical success rate was 37.8% with AUC ss, 0−12h cut-off value of 27.10 mg·h/L (C ss, avg 2.26 mg/L). In CRRT subgroup, the loading dose was a protective factor of 90-day survival time. The pneumonia subgroup had a success rate of 46.15%, with an AUC ss, 0–12h cut-off value of 25.47 mg·h/L. For non-CRRT patients weighing 40–80 kg, a 2.5 mg/kg loading dose followed by 1.5 mg/kg every 12 hours achieves a probability of target attainment (PTA) ≥ 90%; For CRRT patients, only patients weighing 40 kg achieved the PK target with a high-dose regimen. Conclusions For septic patients, PMB exposure is associated with clinical efficacy. Maintaining an AUC ss, 0−12h > 27.10 mg·h/L (C ss, avg of 2.26 mg/L) enhances clinical success. This study provides evidence for PMB therapeutic drug monitoring and initial dosing strategies.

INTRODUCTION: Ganciclovir (GCV) and its prodrug valganciclovir (VGCV) are commonly used to prevent and treat cytomegalovirus (CMV) infections in solid organ transplant recipients. Because of high interindividual pharmacokinetic variability, therapeutic drug monitoring (TDM) is important for optimizing therapy. Ganciclovir-triphosphate (GCV-TP), the active intracellular metabolite, is linked to both efficacy and toxicity; however, clinical monitoring is limited by analytical challenges. OBJECTIVES: To develop and validate a simple and sensitive liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for quantifying GCV-TP in human red blood cells (RBCs). METHODS: GCV-TP was extracted using protein precipitation, separated on a BioBasic AX column, and detected with tandem mass spectrometry using guanosine-13C10-5′-triphosphate as the internal standard. RESULTS: The assay was linear over 0.01–2.00 μg/mL (r2 ≥ 0.99), with intra- and inter-assay variability ≤7.99%. GCV-TP in RBC lysate was stable when stored at room temperature for 4 h or at 4 °C for 24 h. This method was applied to RBC samples from 27 renal transplant recipients receiving VGCV, with a median GCV-TP concentration of 180.8 pmol/8 ×109 RBC (IQR: 113.6–297.6 pmol/8 ×109 RBC). GCV-TP levels showed a significant correlation with VGCV dose (p = 0.020, r = 0.31) but not with plasma GCV concentrations (p > 0.05). CONCLUSION: This validated method enables reliable measurement of intracellular GCV-TP and may serve as a useful tool to support individualized VGCV therapy and pharmacodynamic monitoring in clinical practice.

OBJECTIVES:This study aimed to develop and validate integrated prediction models for pediatric lupus nephritis (LN) treated with a mycophenolate mofetil (MMF)-based induction regimen (combined with glucocorticoids and hydroxychloroquine), incorporating both disease heterogeneity and pharmacokinetic variability. The primary model predicts the achievement of low disease activity (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2 K] ≤ 4) at 12 months, while a secondary model predicts renal complete response during the same period. METHODS:A total of 120 children with LN treated with MMF between 2001 and 2025 were included. The follow-up time from MMF initiation was 12 months. Comprehensive data encompassing clinical phenotypes, organ function, immunological profiles, and pharmacokinetic parameters were collected. We employed a data-driven approach to select key features from a comprehensive set of variables reflecting disease heterogeneity and drug exposure. Seven machine learning (ML) algorithms were evaluated, with their performance assessed using area under the curve (AUC), precision, recall, F1-score, and accuracy. For the secondary outcome of complete renal response, a separate model was constructed using seven similar ML algorithms. For the primary outcome, the incremental value of adding pharmacokinetic data was quantified using the Net Reclassification Improvement (NRI). The optimal models were further validated using calibration curves and decision curve analysis, and interpreted via SHAP analysis. RESULTS:The final integrated model for predicting low disease activity, based on a logistic regression framework, demonstrated robust performance, achieving an AUC of 0.77 in the test set, with a supporting F1-score of 0.86. The incorporation of the area under the concentration-time curve for mycophenolic acid (MPA-AUC) provided significant incremental predictive value over a clinical-only model (ΔAUC = +0.05), which was further confirmed by an NRI of 0.1309. For predicting complete renal response, a random forest model achieved an AUC of 0.88. Key variables influencing treatment response across models included MPA exposure, corticosteroid dose, immunological, renal, and hepatic parameters. Both models were well-calibrated and provided significant net benefit in decision curve analysis. CONCLUSION:We present predictive models that incorporate a comprehensive profile of disease and drug-related heterogeneity to stratify pediatric patients with LN by their likelihood of responding to MMF. This integrated approach offers a strategy to optimize initial treatment selection by directly addressing the challenge of clinical variability.

Background: Following the 2021 first International Consensus on Severe Lung Cancer, global attention to patients with PS 2-4 has grown significantly. Recent advances in novel therapies, interventional techniques, and supportive care, along with emerging real world data, have expanded treatment opportunities for this population. To incorporate these advances, we have updated the consensus. Methods: A multidisciplinary panel comprising experts from oncology, radiation oncology, thoracic surgery, radiology, interventional medicine, respiratory medicine, critical care medicine, and nursing. After being presented with a comprehensive review of the current evidence pertaining to severe lung cancer and thorough discussions, the panel reached a consensus on 11 recommendations, each with over 70% expert agreement. Results: The 11 consensus points focused on definition and causes (n=2), assessment and general strategies (n=4), and specific treatment modalities (n=5) were updated or newly developed. This updated consensus emphasizes dynamic and precise detection, robust life support, flexible application of novel therapies, and MDT guided treatment adjustment based on PS dynamics. Early rehabilitation and comprehensive supportive care are integral to disease management. Conclusions: This consensus updates the definition, diagnostic evaluation, and treatment strategies, providing a practical framework for clinicians based on current evidence and multidisciplinary expert consensus. Prospective trials focusing specifically on patients with severe lung cancer are urgently needed.

Background: Venous thromboembolism (VTE) is a common and serious complication in patients with advanced non-small-cell lung cancer (NSCLC). While guidelines recommend prophylactic anticoagulation for cancer outpatients at high risk, its clinical implementation remains conservative in China. Objectives: This study aimed to investigate the current use of prophylactic anticoagulation for advanced NSCLC outpatients at high risk of VTE in China and explore factors influencing physicians’ decision-making. Methods: A descriptive cross-sectional survey using a convenience sampling approach was conducted from May to June 2025 among physicians from multiple top-tier tertiary hospitals across China. The survey assessed physicians’ knowledge, practices, and concerns regarding VTE risk assessment and prophylactic anticoagulation. Descriptive statistics and multiple response analyses were performed using SPSS 25.0. Results: A total of 235 valid responses were collected. Although 84.7% of physicians reported receiving anticoagulation training, only 57.8% routinely used the Khorana score for risk assessment. After excluding six physicians (2.7%) who reported never assessing VTE risk, 59.4% reported initiating prophylactic anticoagulation for patients with a Khorana score ≥ 2. Direct oral anticoagulants were preferred by 75.6% of physicians. Key concerns included management of bleeding events (78.6%) and adverse reactions monitoring (61.1%). Notably, only 49.4% of physicians reported being familiar with the Khorana score. Conclusions: Prophylactic anticoagulation for advanced NSCLC outpatients appears to remain underutilized in China. Limited familiarity with VTE risk assessment tools and concerns regarding bleeding risk may influence physicians’ clinical decisions. Educational initiatives and prospective studies may help improve guideline adherence.

BackgroundMushroom poisoning caused by Amanita phalloides, primarily mediated by the toxin α-amanitin (AMA), frequently leads to fatal liver failure, yet no specific antidote is currently available. Although AMA is known to inhibit RNA polymerase II, its complete cytotoxic mechanism remains unclear. This study aimed to repurpose the antifungal drug posaconazole as a first-in-class antidote targeting the host glycosylation machinery to mitigate AMA-induced liver injury.MethodsPosaconazole was identified through STT3B-focused virtual screening followed by in vitro cell-based screening. Its protective effects were evaluated in 2D and 3D cell cultures via microscopy, cell viability assays and Calcein-AM/PI staining. Therapeutic efficacy in vivo was assessed in a lethal mouse model by serum biochemical analysis, H&E, immunohistochemistry, and survival analysis. The interactions between posaconazole and STT3B was examined by molecular docking and an endoplasmic reticulum-localized luciferase reporter assay. N-glycosylation level was analyzed by lectin staining. ST6GAL1 was knockdown by shRNA. The concentrations of AMA were quantified by high-performance liquid chromatography.ResultsPosaconazole robustly protected human hepatocytes from AMA-induced toxicity in both 2D and 3D cultures. In a lethal mouse model, post-exposure treatment with posaconazole significantly attenuated AMA-induced liver injury and improves survival, achieving efficacy comparable to prior candidate. Mechanistically, posaconazole potentially inhibited the STT3B-mediated N-glycosylation, thereby suppressing down-stream sialylation. The genetic ablation of sialyltransferase ST6GAL1 confirmed that reduced sialylation limits cellular AMA uptake and confers resistance to toxicity.ConclusionOur work unveils a critical glycosylation-dependent pathway for AMA toxicity and nominates posaconazole as a clinically translatable, host-directed therapeutic candidate for the treatment of lethal Amanita phalloides poisoning.