Background: Although modified FOLFIRINOX (mFOLFIRINOX) has improved survival in patients with resected pancreatic ductal adenocarcinoma (PDAC) in clinical studies, S-1 is also a treatment option with desirable efficacy and limited toxicity. We aimed to compare the efficacy and safety of adjuvant mFOLFIRINOX with those of S-1 monotherapy for PDAC. Objectives: This study aimed to compare the efficacy and safety of adjuvant mFOLFIRINOX versus S-1 monotherapy in resected PDAC. Design: A retrospective real-world study. Methods: Patients with resected PDAC who received adjuvant mFOLFIRINOX or S-1 chemotherapy at Peking Union Medical College Hospital were reviewed. Results: A total of 223 patients were included, with 141 receiving S-1 and 82 receiving mFOLFIRINOX. Patients who received mFOLFIRINOX were younger (median age: 55.5 vs 66 years, p < 0.001) and had a significantly lower proportion of early-stage disease (stage I: 20.7% vs 46.1%, p < 0.001). The median disease-free survival (18.1 vs 12.5 months, p = 0.021) and overall survival (51.4 vs 24.7 months, p = 0.006) of the mFOLFIRINOX group were significantly longer, even after adjustment for bias. However, the incidence of grade 3 or 4 adverse events (65.0% vs 39.4%, p = 0.007), especially fatigue and gastrointestinal toxicity, was greater in the mFOLFIRINOX group than in the S-1 group. Furthermore, the molecular features of the included patients were also explored, and KMT2D alterations may be prognostic indicators of poor survival outcomes. No correlation between alterations in the homologous recombination repair-related genes and prognosis was observed in postoperative patients with PDAC. Conclusion: The mFOLFIRINOX regimen as an adjuvant chemotherapy for patients with resected PDAC demonstrated better efficacy than did S-1 monotherapy.
Background and Objective:C-reactive protein (CRP), the neutrophil-to-lymphocyte ratio (NLR) and the monocyte-to-lymphocyte ratio (MLR) are routinely available inflammatory markers of uncertain relative prognostic value after stroke. This study aimed to investigate the associations of baseline CRP, NLR, and MLR with 12-month mortality and recurrence in patients with stroke. Methods:This single-center prospective cohort study enrolled hospitalized patients with stroke. Univariable analyses were performed to compare baseline characteristics according to 12-month mortality and recurrence status. Multivariable logistic regression models were constructed to evaluate the independent associations of CRP, NLR, and MLR with 12-month mortality and recurrence after adjustment for clinically relevant covariates. Results:A total of 2937 patients were included in the baseline analysis. Among them, 2166 were included in the 12-month mortality analysis, and 237 died during follow-up. In the multivariable logistic regression model, higher CRP was independently associated with an increased risk of 12-month mortality (OR = 1.01, 95% CI: 1.01-1.02, P < 0.001). NLR showed a borderline association with mortality (OR = 1.06, 95% CI: 1.00-1.13, P = 0.064), whereas MLR was not independently associated with mortality. A total of 2018 patients were included in the 12-month recurrence analysis, among whom 614 experienced recurrent events. In the multivariable model, higher CRP was independently associated with an increased risk of recurrence (OR = 1.01, 95% CI: 1.00-1.02, P = 0.025), whereas NLR and MLR was not independently associated with recurrence. Conclusion:Baseline CRP was independently associated with 12-month mortality and, more weakly, with recurrence. The mortality association was substantially stronger, and CRP should be regarded primarily as a marker of long-term mortality risk. NLR and MLR showed no independent association with either endpoint. CRP, combined with key clinical indicators, may assist long-term risk stratification after ischaemic stroke.
Background Aminopeptidase N (CD13) has been reported to be a prognostic factor in non-small cell lung cancer (NSCLC). DFP-14323 (INN: ubenimex) is a CD13 inhibitor and a low-toxicity, non-specific immunomodulator approved in Japan for the maintenance treatment of adult acute non-lymphocytic leukemia. Objectives This study explored the potential immunomodulatory synergy of DFP-14323 with EGFR-TKIs in patients with advanced NSCLC. Design A prospective, multicenter, open-label, single-arm phase II study. Methods Stage III/IV treatment-naïve patients with activating EGFR mutation-positive (Ex19del/L858R) NSCLC were treated with 10 mg/day of DFP-14323 and a starting dose of 20 mg/day of afatinib, continued until disease progression or intolerable toxicity. The primary endpoint was the disease control rate (DCR). A total of 26 patients were enrolled based on Simon’s two-stage design (threshold DCR of 70%, expected DCR of 90%; two-sided α=0.05, β error=0.20). Results The DCR as primary endpoint was 100% (95% confidence interval (CI), 86.8–100.0%). Independent radiological review at 72 weeks demonstrated a median progression-free survival (PFS) of 16.6 months (95% CI, 10.2–22.9). Updated investigator-exploratory follow-up revealed a median PFS was 23.1 months (95% CI, 12.9– not estimable; median follow-up period: 22.6 months). One grade 3 paronychia was considered DFP-14323-related, while other adverse events were attributable to afatinib. No grade 4-5 adverse events occurred. Grade 1 interstitial lung disease occurred in one patient and resolved quickly. Conclusions The combination of DFP-14323 and low-dose afatinib was considered to have the potential for future clinical utility for EGFR mutation-positive NSCLC. As the next step, a study evaluating this combination therapy in uncommon EGFR mutation-positive NSCLC is currently underway in Japan (jRCT2061230111).
Background Hepatocellular carcinoma (HCC) is driven by extensive metabolic reprogramming, vascular remodeling, and immune microenvironmental dysfunction. Although numerous stratification signatures have been proposed, few are grounded in clinically derived serum multi-omics and biologically linked to endothelial remodeling, endothelial regulation, and immune exclusion. Objectives This study aimed to identify a serum-derived lipid-endothelial program associated with immune exclusion and clinical stratification in HCC. Design A translational multi-omics study integrating clinically collected serum samples, public transcriptomic cohorts, single-cell RNA sequencing, and experimental validation. Methods Proteomic and metabolomic sequencing was performed on serum samples from patients with HCC and normal controls. Dysregulated pathways were integrated with transcriptomic data from TCGA-LIHC and ICGC-LIRI-JP cohorts to identify genes jointly associated with lipid metabolism and leukocyte transendothelial migration. A risk score was calculated using the expression of PON1, TXNRD1, CLDN4, CLDN6, CYP2C9, and CTSA. Higher expression of TXNRD1, CLDN4, CLDN6, and CTSA contributed to a higher risk score, whereas PON1 and CYP2C9 contributed protective coefficients. Immune contexture, tumor mutation burden, and exploratory therapeutic sensitivity patterns were further evaluated using transcriptome-based drug sensitivity prediction, followed by single-cell RNA sequencing and experimental expression validation. Results Serum multi-omics analysis revealed prominent dysregulation of lipid metabolic pathways and leukocyte transendothelial migration-related processes in HCC. Integrative analysis identified a six-gene lipid-endothelial signature (PON1, TXNRD1, CLDN4, CLDN6, CYP2C9, and CTSA) that stratified patients into high- and low-risk groups. In the TCGA-LIHC cohort, high-risk patients had significantly poorer overall survival than low-risk patients (log-rank P < 0.0001), and this survival-stratifying association was externally supported in the ICGC-LIRI-JP cohort (log-rank P = 0.016). The high-risk phenotype was associated with immune-excluded features, distinct somatic mutation patterns, and altered predicted sensitivity to several selected anticancer agents. Single-cell analysis and experimental assays further supported the association between the six-gene program, malignant epithelial states, endothelial-related remodeling, and immune microenvironmental heterogeneity. Conclusion This study defines a clinically derived lipid-endothelial program associated with immune exclusion, adverse prognosis, and potential differences in therapeutic vulnerability in HCC. The proposed signature provides a biologically informed framework for prognostic assessment and may support future evaluation of targeted interventions in HCC.
Background Neoadjuvant therapy (NAT) has shifted rectal cancer management toward organ preservation. However, achieving a complete response (CR) for “watch-and-wait” strategies is hindered by high response heterogeneity. Although immunotherapy-combined NAT has expanded the candidate pools, the predictive significance of molecular alterations remains unclear. Objectives This study aimed to evaluate clinical and genomic profiles of rectal cancer patients undergoing NAT to identify response predictors and to develop a nomogram for estimating CR probability. Design Retrospective, single-center cohort study. Methods This study included 437 patients with rectal adenocarcinoma at Fudan University Shanghai Cancer Center between December 2019 and March 2023. Patients underwent paired tumor and germline genomic sequencing (887-gene panel) before NAT. Logistic and Cox regression analyses were performed to identify clinical and genetic risk factors associated with tumor response and long-term survival. Results Of the 437 patients, 96.6% had microsatellite-stable (MSS) tumors. In the MSS locally advanced rectal cancer cohort (N = 307), the CR rate was 35.5%. Multivariate analysis identified immunotherapy-combined NAT (iTNT) (OR 4.41, 95% CI: 2.42–8.27), SYNE1 mutation (OR 2.12, 95% CI: 1.06–4.26), negative mesorectal fascia (MRF) status (OR 0.34, 95% CI: 0.17–0.66), and lower tumor location (OR 0.48, 95% CI: 0.27–0.84) as independent predictors of CR. KRAS mutation was the sole independent predictor of reduced disease-free survival (DFS; HR 1.93, 95% CI: (1.11–3.36), p = 0.020). KRAS G12D subtype was associated with the worst 2-year distant metastasis-free survival (71.3%) and exhibited a distinct predilection for lung metastasis. The clinical-genomic nomogram yielded strong discrimination (AUC = 0.705) and calibration, with favorable DCA net benefit. Conclusion Clinical and genomic features jointly determine outcomes in MSS rectal cancer. SYNE1 mutation serves as a novel biomarker for CR, while KRAS mutations, especially the G12D subtype, identify patients at high risk for systemic relapse. The clinical-genomic nomogram facilitates individualized selection for organ-preservation strategies.
T-cell engager (TCE)-based therapies represent an emerging and rapidly expanding class of immunotherapies in oncology. Initially developed for hematologic malignancies, TCEs are now entering the field of solid tumors. To date, two agents have received regulatory approval in this setting: Tebentafusp for metastatic uveal melanoma and Tarlatamab for small-cell lung cancer (SCLC). By physically linking a tumor-associated antigen (TAA) to a T-cell activating domain, most commonly cluster of differentiation (CD) 3, TCEs induce an immunological synapse that promotes targeted T-cell mediated cytotoxicity. This narrative review summarizes the most clinically relevant toxicities associated with TCEs in solid tumors, drawing on data from clinical trials and real-world experience. Tebentafusp exemplifies the safety profile of this therapeutic class, which is dominated by cytokine release syndrome (CRS) and cutaneous adverse events (AEs). These toxicities are typically early in onset, predictable, and reversible, occurring predominantly during the initial step-up dosing phase and decreasing substantially with subsequent administrations, consistent with immune adaptation. Tarlatamab, a Delta-like ligand 3 (DLL3) × CD3 bispecific TCE recently approved for SCLC, displays a toxicity profile similarly driven by immune activation, with CRS as the most frequent AE, generally of low grade and confined to early treatment cycles. In contrast, neurotoxicity including immune effector cell-associated neurotoxicity syndrome (ICANS) occurs more frequently, though events are usually low grade, delayed relative to CRS. Other TCEs currently in clinical development target a wide range of TAAs and display a broadly similar toxicity profile, with CRS emerging as a class effect related to CD3-mediated T-cell activation. The incidence and severity of CRS are influenced by dosing strategies, with step-up dosing mitigating early toxicity. Cutaneous, immune-related, and hematologic AEs are generally infrequent and rarely severe. Continued optimization of antigen selection, molecular engineering, and pharmacokinetic parameters will be critical to improving the safety profile of TCEs gathering data from clinical trials and real-world experience.
In the first-in-human (FIH) study, the intravenous (IV) administration represents a critical juncture where preclinical data meet human physiology, characterized by immediate systemic exposure and an extremely narrow margin for safety. The current management measures for these trials are fragmented and lack a systematic framework. This narrative review, informed by a structured synthesis of peer-reviewed literature, regulatory guidance documents, and systematic institutional experience from multiple IV FIH trials conducted between 2020 and 2025, summarizes the key risk factors for FIH-IV trials, including pharmacological uncertainties, formulation-related toxicity, infusion rate sensitivity, and participant heterogeneity. It further evaluates preventive strategies such as determination of starting dose, personnel management and ensuring operational readiness, standardization of medication preparation and administration, comprehensive safety monitoring, and emergency response coordination and infrastructure. The primary aim is to propose a conceptual, stratified risk management framework that categorizes trials into low-, moderate-, and high-risk levels based on drug-related, procedural, and participant-specific variables. Corresponding management strategies are then applied to each level: standardized for low risk, enhanced for moderate risk, and advanced for high risk. This structured approach optimizes safety assurance in high-risk trials while avoiding the overutilization of resources in low-risk settings. The proposed framework is intended as a conceptual supplement to existing regulatory guidelines (eg, ICH E6(R3), EMA FIH guideline) and requires prospective multicenter validation before broad implementation.
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used for type 2 diabetes, obesity, and broader cardiometabolic, cardiorenal, and metabolic liver disease indications, creating new challenges for perioperative medication safety. This review summarizes current evidence on GLP-1RA-associated delayed gastric emptying and proposes a structured pharmacist-led framework for individualized perioperative risk management. GLP-1RAs may increase the likelihood of residual gastric contents during anesthesia or procedural sedation despite adherence to standard fasting recommendations. Perioperative outcome studies have not consistently shown an increased risk of aspiration pneumonia; however, these findings should be interpreted in light of the low incidence of aspiration-related events, the predominance of retrospective study designs, residual confounding, and heterogeneous definitions of residual gastric contents. We review mechanisms of delayed gastric emptying, treatment- and patient-related risk modifiers, perioperative clinical evidence, areas of agreement and divergence among major guidance statements, gastric ultrasonography as a selective risk-mitigation tool, and medication-safety issues beyond aspiration, including oral drug absorption and postoperative resumption. Because perioperative GLP-1RA decisions require accurate medication history, last-dose verification, symptom assessment, evaluation of glycemic consequences of drug interruption, coordination with anesthesia and surgical teams, and safe postoperative restart planning, pharmacists are well positioned to support this process. The proposed pharmacist-led pathway provides a structured approach to GLP-1RA medication verification, gastrointestinal symptom screening, risk phenotyping, multidisciplinary escalation, day-of-surgery reassessment, postoperative restart planning, patient education, and documentation. Perioperative GLP-1RA management should not rely on routine discontinuation alone, but should integrate treatment phase, dose escalation, gastrointestinal symptoms, comorbid motility disorders, procedural urgency, anesthetic risk, oral medication considerations, and the metabolic consequences of withholding therapy. This pathway represents a structured implementation framework informed by current evidence and guidance; prospective evaluation in real-world perioperative settings is needed.
Background:Pediatric and adolescent nasopharyngeal carcinoma (pNPC) is a rare malignancy, and contemporary chemotherapy regimens are largely extrapolated from adult protocols. Adult-intensity chemotherapy is often associated with substantial toxicity in younger patients. Whether chemotherapy dose intensity can be safely reduced in children and adolescents with pNPC remains unclear. Objectives:This study aimed to evaluate the association between chemotherapy relative dose intensity (RDI) and survival outcomes in pNPC. Design:This was a single-center retrospective cohort study of pediatric and adolescent patients with locoregionally advanced nasopharyngeal carcinoma treated between 2006 and 2021. Methods:We retrospectively analyzed patients aged ≤21 years with newly diagnosed stage III-IVa (American Joint Committee on Cancer (AJCC) 8th edition) pNPC treated between 2006 and 2021. Relative dose intensity (RDI) of first-line chemotherapy was calculated and categorized as <85% versus ≥85%. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Multivariable Cox regression was used to evaluate the independent prognostic value of RDI and other covariates. Results:A substantial proportion of patients had an RDI <85%. In the overall cohort, RDI <85% was not significantly associated with worse survival outcomes in survival analyses. Pretreatment plasma Epstein-Barr virus (EBV) DNA level was independently associated with worse survival outcomes. In exploratory analyses, among patients with plasma EBV DNA <4000 copies/mL, RDI <85% suggested an association with worse OS (P for interaction=0.025). Conclusions:In pediatric and adolescent nasopharyngeal carcinoma, these findings suggest potential feasibility of dose reduction but require prospective validation. However, maintaining adequate chemotherapy intensity could be particularly important for patients with lower pretreatment plasma EBV DNA level. Pretreatment plasma EBV DNA may serve as a potential biomarker to guide individualized adjustment of chemotherapy dose intensity in pNPC, which warrants validation in larger studies.
Background Supraclavicular lymph node metastasis (SLNM) is a common subtype of oligometastatic stage IV esophageal squamous cell carcinoma (ESCC), with a better prognosis than multifocal metastatic disease. However, the optimal first-line treatment strategy for this specific subgroup remains unclear. Objectives This study evaluated the efficacy and safety of three first-line treatment modalities—chemoimmunotherapy (CI), concurrent chemoradiotherapy (CCRT), and chemoimmunotherapy followed by radiotherapy (CIRT)—in patients with ESCC with SLNM. Design This retrospective, multicenter cohort study analyzed data from 484 ESCC patients with SLNM treated at three major cancer centers in China. Methods Data from 484 patients between January 2019 and December 2024 were analyzed. Inverse probability of treatment weighting (IPTW) was applied to reduce selection bias. PFS and OS were estimated using the Kaplan–Meier method. Intergroup differences were compared using the log-rank test. The Fine–Gray competing risks model was applied to both unweighted and weighted cohorts to calculate the cumulative incidence. Cumulative incidence functions (CIF) were estimated using the Aalen–Johansen method. A two-sided P value < 0.05 was considered statistically significant. Results The CI, CCRT, and CIRT groups enrolled 145, 137, and 202 patients. In weighted Cox regression analysis, CIRT demonstrated superior PFS (adjusted HR (aHR)=0.73, 95% CI: 0.53–0.99, P=0.043) and OS (aHR=0.48, 95% CI: 0.31–0.75, P=0.001) compared to CI. CIRT demonstrated superior PFS compared with CCRT (HR = 0.67, 95% CI: 0.52–0.87, P = 0.003). The weighted median PFS in each group was as follows: CI group 11.0 months (95% CI: 8.0–15.0), CCRT group 11.0 months (95% CI: 10.0–14.0), CIRT group 16.0 months (95% CI: 13.0–20.0) (P = 0.002). Conclusion Compared with CI (systemic therapy alone), CIRT demonstrated potential advantages in PFS, OS, and locoregional control while maintaining acceptable toxicity. Compared with CCRT, CIRT demonstrated improved PFS with no significant differences in OS or locoregional recurrence. These findings suggest that CIRT may represent a promising first-line treatment option for patients with ESCC and SLNM.
Antibody-drug conjugates (ADCs) have emerged as a major therapeutic advance in ovarian cancer, particularly when platinum-based chemotherapy is not a treatment option. By selectively delivering potent cytotoxic payloads to tumor cells, ADCs such as mirvetuximab soravtansine (MIRV), targeting FRα, and trastuzumab deruxtecan (T-DXd), targeting HER2, have demonstrated clinically meaningful activity in selected populations. However, resistance to ADCs inevitably develops through diverse mechanisms, including payload resistance and target antigen downregulation. Continued translational research is therefore essential to identify predictive biomarkers and to optimize novel combination strategies. Beyond ADCs, other systemic approaches have demonstrated survival improvements in PROC even in biomarker-unselected populations, including the addition of the glucocorticoid receptor antagonist relacorilant to nab-paclitaxel and immune–chemotherapy combinations such as pembrolizumab plus paclitaxel with or without bevacizumab. Future directions aim to prioritize synergistic combinations to overcome resistance. This includes pairing ADCs with replication stress inhibitors like ATR inhibitors and WEE1 inhibitors or integrating them with next-generation immuno-oncology platforms such as bispecifics, T-cell engagers, and cancer vaccines, as well as the integration of dynamic biomarkers and quantitative tools to define optimal treatment sequencing and improve patient outcomes in this challenging disease setting.
Background Limited-stage small cell lung cancer (LS-SCLC) frequently progresses to extensive-stage disease (ES-SCLC) after standard therapy. However, evidence regarding the efficacy and safety of various treatment regimens for this specific patient population remains limited. Objectives This study aimed to evaluate the efficacy and safety of various treatment regimens among patients who progressed from LS-SCLC to ES-SCLC after standard chemoradiotherapy. Design Survival analyses using propensity score matching (PSM) were conducted in patients with LS-SCLC who progressed to ES-SCLC to assess the efficacy and safety of multiple treatment regimens, especially immunotherapy. Methods This retrospective study included 378 patients with LS-SCLC who progressed to ES-SCLC at Shandong Cancer Hospital from January 2018 to December 2024. After propensity score matching (PSM), patients were divided into immunotherapy and non-immunotherapy groups. Data on treatment regimens and clinical outcomes, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), were collected. Kaplan–Meier analysis estimated PFS and OS, and Cox regression identified factors influencing OS. Results Median overall survival (mOS) and median progression-free survival (mPFS) in the immunotherapy group were longer than those in the non-immunotherapy group (16.4 vs 12.3 months, P < 0.05; 5.3 vs 4.9 months, P < 0.05, respectively). In an exploratory subgroup analysis, platinum-based regimens were associated with longer OS only in patients with a treatment-free interval (TFI) of 3 months or longer (median 19.3 vs 12.5 months; HR = 0.65, 95% CI 0.44–0.95, P < 0.05). Conclusion Our exploratory real-world data suggest that immunotherapy is associated with improved patient outcomes in patients with LS-SCLC who progress to ES-SCLC. Platinum-based regimens may be associated with better prognosis in the subgroup with a TFI of 3 months or longer. Given the exploratory nature, further prospective randomized trials are needed to confirm these observations.
Biomarker testing is central to precision oncology, enabling effective use of targeted therapies in hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC). Recommendations for current and future biomarker testing and diagnostic workflows were developed using a three-step approach: pre-meeting survey, descriptive analysis, and steering committee discussion. A panel of 14 experts from Latin America, Asia Pacific, the Middle East, and Africa developed recommendations using an expert opinion-based approach without a formal consensus methodology. Recommendations with >90% agreement were considered panel recommendations. Some recommendations are expert-driven and not yet standard-of-care. High agreement was observed for biomarker testing at diagnosis for estrogen receptor (ER), progesterone receptor (PR), HER2, and BReast CAncer gene (BRCA)1/2. For endocrine-resistant patients, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) testing is recommended at diagnosis; otherwise, during or after first-line treatment. AKT serine/threonine kinase 1 (AKT1) and phosphatase and tensin homolog (PTEN) testing can occur either during first-line treatment or at progression, while estrogen receptor 1 (ESR1) testing is advised at progression. Tumor tissue (preferably from a re-biopsy) is the preferred sample for PIK3CA, AKT1, and PTEN testing; if unavailable, primary tissue or circulating tumor DNA (ctDNA) may be considered. Blood is recommended for germline BRCA1/2 or PALB2 testing, while ctDNA is preferred for ESR1 detection. Next-generation sequencing (NGS) is the preferred method for most biomarkers, with polymerase chain reaction as an alternative where NGS is unavailable; PTEN may also be assessed using immunohistochemistry. Above 90% of experts proposed future biomarker testing at diagnosis for ER, PR, HER2, germline BRCA1/2, PALB2, PIK3CA, AKT1, PTEN, mismatch repair, microsatellite instability, tumor mutational burden, and neurotrophic tyrosine receptor kinase in all patients with HR+, HER2-negative mBC. This article offers a practical guide for biomarker testing in HR+, HER2-negative mBC.
Background Esophageal squamous cell carcinoma (ESCC) is a highly lethal malignancy for which immune checkpoint inhibitors (ICIs) have improved outcomes, yet significant inter-patient variability in response persists. Emerging evidence suggests that circadian rhythms modulate anti-tumor immunity, but the impact of ICI infusion timing on ESCC prognosis remains unexplored. Objective To determine whether the timing of ICI infusion impacts survival outcomes in patients with advanced ESCC and to identify an optimal infusion time window. Design A single-center, retrospective cohort study. Methods We included 339 patients with advanced ESCC who received ICI therapy at Zhejiang Cancer Hospital between June 2018 and September 2022. Infusion timing was examined using two metrics: (i) first infusion time, and (ii) average infusion time across the first three cycles. Restricted cubic spline models were applied to explore dose-response relationships with infusion time as a continuous variable. Patients were categorized as early (before 14:00) or late (at or after 14:00) for each metric. Survival outcomes were analyzed using univariate and multivariate Cox proportional hazards models and Kaplan-Meier methods. Sensitivity analyses included an alternative 13:30 cutoff and a subgroup analysis of patients receiving ICI monotherapy. The study was conducted in compliance with the STROBE guidelines. Results In the primary analysis of first infusion time, each one-hour delay was associated with increased risks of disease progression (HR=1.049, 95% CI: 1.003–1.097, P=0.036) and mortality (HR=1.062, 95% CI: 1.014–1.112, P=0.010). Kaplan-Meier analysis showed significantly better median PFS (6.2 vs. 5.3 months, P=0.010) and OS (13.3 vs. 12.4 months, P=0.026) in the Early-first versus Late-first group. In the secondary analysis of average infusion time during the first three cycles, each one-hour delay increased progression risk (HR=1.073, 95% CI: 1.001–1.151, P=0.027) and mortality risk (HR=1.092, 95% CI: 1.017–1.172, P=0.015), with Kaplan-Meier analysis showing a trend toward improved median PFS (6.2 vs. 5.6 months, P=0.098) and OS (13.4 vs. 12.1 months, P=0.057) in the Early-3M versus Late-3M group. Restricted cubic spline analysis revealed a nearly linear dose-response relationship (nonlinearity P>0.05). Conclusion The timing of ICIs infusions may be an independent prognostic factor for survival in advanced ESCC. Administration before 14:00 was associated with improved PFS and OS.
Background: Despite advances in endocrine therapy, patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) early breast cancer (eBC) remain at risk of recurrence (ROR). Chemotherapy is often used in high-risk cases, but not all patients benefit. Objectives: To evaluate whether chemotherapy can be safely omitted in patients with stage II, grade 2/3 HR+/HER2− eBC who convert to low genomic risk (ROR-low) following neoadjuvant ribociclib plus letrozole. Methods: RIBOLARIS (NCT05296746) is an open-label, multicenter phase II trial in patients with stage II, grade 2 or 3, HR+/HER2− eBC defined as high risk based on a Ki-67 index ⩾20% and/or high genomic risk by a validated gene expression signature. All patients receive six 28-day cycles of neoadjuvant ribociclib (600 mg/day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day). Following surgery, patients with ROR-low or pathological complete response continue adjuvant ribociclib (400 mg/day for 30 months) and endocrine therapy (⩾5 years), whereas patients with ROR-medium/high receive standard chemotherapy followed by ribociclib and endocrine therapy. The primary endpoint is 5-year distant metastasis-free survival (DMFS) in the ROR-low cohort. Interim futility analyses are planned at 300 and 800 patient-years (PYs), with the primary analysis after 1300 PYs. The study targets enrollment of 1100 patients, anticipating 400 ROR-low cases, providing ⩾90% power to detect a 5-year DMFS of 96% versus a benchmark of 90.6% (MINDACT trial high-risk subgroup). Discussion: RIBOLARIS is the first prospective trial to evaluate a chemotherapy-free, ribociclib-based strategy in high-risk HR+/HER2− eBC based on neoadjuvant molecular response. By integrating genomic risk reclassification into treatment decision-making, this study aims to demonstrate that patients achieving ROR-low status can maintain excellent long-term outcomes without chemotherapy, while avoiding unnecessary exposure to adjuvant chemotherapy, and to highlight the role of tumor profiling after neoadjuvant endocrine therapy plus cyclin-dependent kinase 4 and 6 inhibitors in optimizing post-neoadjuvant therapy. Trial registration: NCT05296746; EudraCT# 2021-002322-24.
Background Inetetamab and pyrotinib have shown promising activity in HER2-positive metastatic breast cancer (MBC). However, real-world data on their combination with chemotherapy (IPyC) across different treatment lines remain limited. Objectives This multicenter retrospective study aimed to describe the outcomes associated with a dual HER2-targeting strategy IPyC in HER2-positive MBC across treatment lines in real-world clinical practice. Design Multicenter retrospective study. Methods Between July 2020 and August 2024, 301 patients with HER2-positive MBC from five tertiary centers in China received IPyC until disease progression or unacceptable toxicity. Key outcome measures included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR). Cox proportional hazards models were used to identify potential prognostic factors. Results The median IPyC associated PFS and OS for the entire cohort were 12.0 months (95% CI: 10-15) and 33.0 months (95% CI: 28-42), respectively, with an ORR of 50.2% and a CBR of 80.4%. The IPyC associated PFS varied significantly by treatment line (23.0, 17.0, and 6.0 months for first-line, second-line, and ≥third-line, respectively; p<0.001). In first-line setting, baseline lymphovascular invasion (LVI) and multiple metastases were independent prognostic factors, and trastuzumab-naïve patients had a numerically longer median PFS of 27.0 months than those with prior trastuzumab exposure. In second-line setting, patients with secondary resistance to trastuzumab achieved a median PFS of 24.0 months. A new central nervous system (CNS) metastasis incidence was observed in 6.6% (5/76) of patients without baseline CNS metastases in the first-line IPyC treatment setting. The IPyC regimen was associated with manageable toxicity, with grade 3-4 diarrhea (26.2%), neutropenia (16.6%), and leukopenia (12.6%) as the most common adverse events (AEs). Conclusion As a retrospective descriptive study, our analysis describes the use and outcomes of the IPyC regimen across multiple lines of therapy in HER2-positive MBC, highlighting the need for and supporting the design of prospective studies to evaluate this regimen.
Background: The optimal approach to treatment intensification for epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma with brain metastases remains a topic of debate, especially in the context of high-risk molecular features such as TP53 co-mutation. The extent to which baseline clinical risk influences treatment efficacy is yet to be determined. Objectives: We aim to systematically evaluate the prognostic significance of EGFR/TP53 co-mutations in treatment-naïve patients with lung adenocarcinoma and newly diagnosed brain metastases. Design: This study enrolled 218 treatment-naïve patients with EGFR-mutant lung adenocarcinoma and brain metastases who received first-line third-generation EGFR-tyrosine kinase inhibitors (TKIs). Treatment effects were evaluated using interaction models stratified by Lung-molGPA scores. Stratification: Group A (Lung-molGPA 1–2) versus Group B (Lung-molGPA 2.5–4). Methods: Within each group, the influence of TP53 co-mutations on survival was analyzed. Additionally, among patients with TP53 co-mutations, the effects of cranial radiotherapy (CRT) and treatment with either third-generation EGFR-TKIs monotherapy or third-generation EGFR-TKIs combined with chemotherapy on overall survival (OS) were further investigated, taking into account the Lung-molGPA scores. Results: The Lung-molGPA significantly influenced the prognostic impact of TP53 mutations and the survival benefits of treatment intensification strategies (log-rank test p = 0.044, hazard ratio (HR) = 2.1832, 95% confidence interval (CI): 1.023–4.661). In patients with low Lung-molGPA scores, intensification with CRT did not correlate with a survival advantage (32.2 vs 28.0 m, log-rank test p = 0.5088, HR = 1.417, 95% CI: 0.4768–4.211). Conversely, in patients with high Lung-molGPA scores, both CRT and systemic intensification were associated with improved outcomes (44.0 vs 26.3 m, log-rank test p = 0.0054, HR = 0.3199, 95% CI: 0.1585–0.6456; 20.1 vs 32.3 m, log-rank test p = 0.0074, HR = 2.547, 95% CI: 1.113–5.831). Conclusion: Baseline clinical risk, as delineated by the Lung-molGPA, serves as a crucial determinant of therapeutic benefit in cases of EGFR-mutant lung adenocarcinoma with cerebral metastases. Implementing risk-adapted treatment intensification strategies could potentially prevent overtreatment in patients classified as low-risk, while simultaneously optimizing clinical outcomes in high-risk cohorts.
Background:Immune checkpoint inhibitors (ICIs) combined with first-line platinum-etoposide have changed the standard treatment of extensive-stage small-cell lung cancer (ES-SCLC), yet the role of consolidative thoracic radiotherapy (cTRT) in the chemo-immunotherapy era remains unclear. Objectives:To evaluate the association of cTRT after first-line chemo-immunotherapy with survival outcomes and treatment-related toxicity in ES-SCLC. Design:Systematic review and meta-analysis. Data Sources and Methods:We systematically identified studies evaluating cTRT following first-line chemo-immunotherapy in ES-SCLC. Overall survival (OS) and progression-free survival (PFS) were pooled using hazard ratios (HRs), and safety outcomes were pooled using risk differences (RDs), each with 95% confidence intervals (CIs). Results:Seventeen studies (all non-randomized) involving 2,263 patients were included. cTRT was associated with improved OS (HR 0.63, 95% CI 0.56-0.71; p<0.001; I2=0%) and PFS (HR 0.56, 95% CI 0.46-0.68; p<0.00001). Sensitivity analyses restricted to propensity score-adjusted studies and anti-PD-L1-based regimens showed consistent results. cTRT increased any-grade pneumonitis (RD 0.12, 95% CI 0.03-0.21) and esophagitis (RD 0.22, 95% CI 0.04-0.40), without a significant increase in overall grade ≥3 adverse events (RD 0.02, 95% CI -0.05 to 0.09). Conclusion:In ES-SCLC treated with first-line chemo-immunotherapy, cTRT was associated with improved survival and increased localized thoracic toxicity, particularly any-grade pneumonitis and esophagitis, without a significant increase in overall grade ≥3 adverse events. Pending prospective randomized validation, these results could support the use of cTRT after the disease control with first-line chemo-immunotherapy.
Introduction:Postoperative cognitive dysfunction (POCD) is a common condition that greatly threatens patients' quality of life. While mechanical bowel preparation (MBP) enhances surgical visibility, its effect on postoperative complication rates remains debated. This study aims to evaluate the effect of MBP on POCD in patients undergoing colorectal surgery and to investigate its association with tau protein, brain-derived neurotrophic factor (BDNF) and lipopolysaccharide-binding protein (LBP) levels. Methods:This is a single-center randomized controlled trial. 80 eligible ASA-PS II-III colorectal surgery patients were randomized into his pilot study, which was designed as a randomized controlled trial. Cognitive function was assessed preoperatively (T1), postoperatively on day 15 (T2), and on day 90 (T3) using the Montreal Cognitive Assessment (MoCA). Blood samples were collected simultaneously from the patients for biomarker analysis. A decline of > 1 standard deviation from baseline on the MoCA was defined as POCD. Results:The incidence of POCD was significantly lower in patients without MBP compared to those with MBP (7.5% vs. 55%). At T3, BDNF levels were significantly higher in Group I than in Group II (p < 0.001). LBP levels were significantly higher in Group II than in Group I at T3 (p = 0.001). In patients with POCD, tau protein levels were significantly higher at T2 and T3 (p = 0.007; p = 0.012), while BDNF levels were significantly lower at T3 (p < 0.001). Conclusion:MBP was associated with a higher incidence of POCD in patients undergoing colorectal surgery; however, these preliminary findings require confirmation in larger trials.
