TRAILBLAZER is a proof-of-concept phase 2 study (ClinicalTrials.gov, NCT04580498) of neoadjuvant retlirafusp alfa (an anti-PD-L1/TGF-β bifunctional agent) in unresectable stage III non-small cell lung cancer (NSCLC) not harboring EGFR or ALK alterations. During induction, retlirafusp alfa was administered either with chemotherapy or as monotherapy, followed by surgery or radiotherapy as assessed by a local multidisciplinary team and consolidation retlirafusp alfa. Patients without high PD-L1 expression were allocated to retlirafusp alfa plus chemotherapy (arm A; n = 88); patients with high PD-L1 expression were randomly allocated at a 1:1 ratio to retlirafusp alfa combination (arm B; n = 9) or monotherapy (arm C; n = 10). In this updated analysis (data cutoff, March 24, 2025), the median follow-up was 39.4 months. The event-free survival (EFS) rate at 3 years was 50.5% (95% CI 39.0-61.0) in arm A + B and 77.1% (34.5-93.9) in arm C; the corresponding overall survival (OS) rates at 3 years were 68.3% (95% CI 57.5-77.0) and 87.5% (38.7-98.1), respectively. Among 27 patients who underwent surgery, the 3-year EFS and OS rates were 69.5% (95% CI 48.1-83.5) and 84.9% (64.5-94.0), respectively, versus 50.8% (36.5-63.4) and 70.4% (56.7-80.5), respectively, in radiotherapy-treated patients. The safety data were consistent with those in a previous report. With extended follow-up, the study regimen showed sustained survival benefits with no new safety signals. Patients who underwent surgery after induction treatment achieved clinically meaningful survival gains. Our findings support the use of neoadjuvant immunotherapy with a response-adapted surgical strategy as a promising approach for unresectable stage III NSCLC.

8520 Background: Patients with EGFR-mutant NSCLC whose disease progresses on or after 3 rd generation EGFR TKI treatment often acquire resistance mutations, among which EGFR C797X is one of the most frequently reported. DZD6008 is a 4 th generation EGFR TKI, designed to target classical EGFR sensitizing mutations (L858R/19del), as well as resistant double (T790M and L858R/19del) and triple mutations (C797X, T790M and L858R/19del), with preclinical data showing high selectivity over wild-type EGFR and other kinases and full blood-brain-barrier (BBB) penetration. Here we report results in pretreated NSCLC patients with EGFR C797X mutations (C797X+) from phase 1/2 studies. Methods: TIAN-SHAN1 (NCT06905197) and TIAN-SHAN2 (NCT06813365; CTR20241790) are ongoing, multicenter phase 1/2 studies evaluating the safety, tolerability, and anti-tumor activity of DZD6008 in EGFR-mutant NSCLC patients, conducted in the US/Australia and China, respectively. The efficacy endpoints include objective response rate (ORR), duration of response (DoR) and progression-free survival (PFS) by investigator per RECIST v1.1, and safety endpoints include treatment-related adverse events (TRAEs) per CTCAE 5.0. Results: As of December 19, 2025, a total of 24 patients with confirmed C797X+ NSCLC were treated with once daily (QD) oral DZD6008 (20 mg, n=1; 40 mg, n=13; 60 mg, n=10), and had at least 1 post-baseline tumor assessment. The median age was 66.5 years, 58.3% were female, 91.7% were Asian, 58.3% had ECOG PS of 1. All patients had metastatic disease upon study entry and received median 2 (range 1 - 6) lines of prior therapies. Across all dose levels, tumor shrinkage was observed in 75% of patients, with an ORR of 41.7%. Intracranial anti-tumor activity was observed in patients with baseline brain metastasis. The doses of 40 mg and 60 mg QD were defined as the recommended phase 2 doses (RP2Ds). The ORRs were 23.1% and 60.0% at these two dose levels, respectively. The median DoR and median PFS were not reached for either dose. The 9-month PFS rates were 54.5% and 64.8%, respectively. DZD6008 was well tolerated at the doses evaluated, with no dose limiting toxicities observed. The majority of TRAEs were grade 1 or 2. The TRAEs with grade ≥3 included lymphocyte count decreased (8.3%), anemia, malaise, fatigue and amylase increased (all 4.2%). There were no Grade 5 TRAEs. Conclusions: DZD6008 demonstrated promising and durable anti-tumor activity in patients with EGFR C797X+ NSCLC with a manageable safety profile, supporting its potential use as a later line treatment option after 3 rd generation EGFR TKI failure. The updated data will be presented at the meeting. Clinical trial information: NCT06905197 , NCT06813365 .

Esophageal squamous cell carcinoma (ESCC) remains one of the leading causes of cancer-related mortality worldwide. Although immunotherapy has shown promising efficacy for locally advanced ESCC, the lack of reliable predictive tools and the marked heterogeneity of tumors make it difficult to accurately evaluate treatment responses. To address this challenge, we conducted a multicenter study aimed at developing and comparing predictive models based on habitat radiomics and traditional radiomic features to estimate pathological complete response (pCR) in patients receiving neoadjuvant immunotherapy and chemotherapy. Using multicenter data, we systematically assessed the performance of these models to determine the relative advantages of each feature type in predicting treatment outcomes and supporting personalized therapeutic strategies. This retrospective study analyzed ESCC patient data from three medical centers. Pre-treatment CT imaging was utilized for tumor region segmentation and the extraction of both Habitat Radiomics and traditional Radiomic Features. Feature selection was performed using LASSO regression, and machine learning models were developed based on these features. Several machine learning algorithms, including Support Vector Machines (SVM), Random Forest, and XGBoost, were employed for training and validation. Model performance was evaluated using metrics such as ROC curves, AUC, sensitivity, and specificity. The Habitat Radiomics model achieved AUCs of 0.938 in the training cohort, 0.896 in the internal validation cohort, 0.819 in external validation cohort 1, and 0.846 in external validation cohort 2, demonstrating strong and consistent predictive performance. In comparison, the traditional Radiomics model yielded AUCs of 0.941, 0.845, 0.796, and 0.729, respectively. Beyond higher AUC values, the Habitat Radiomics model also showed superior sensitivity and specificity in predicting pCR. Notably, the combined model that integrated both Habitat and traditional Radiomics features outperformed the individual models, achieving the highest AUC of 0.960 across cohorts and underscoring its superior predictive accuracy. This study demonstrates that Habitat Radiomics features provide significant advantages over traditional Radiomics in predicting immunotherapy response in ESCC patients. The combined model, integrating both feature sets, shows exceptional predictive performance, with promising clinical applications in personalized treatment strategies. Future research will explore the broader applicability of this model across different cancer types and its integration with additional biomarkers to further enhance prediction accuracy.

The benefit of endoscopy for non-cardia gastric cancer (GC) prevention lacks evidence from randomized controlled trials (RCTs). This study aimed to evaluate the effect of endoscopic screening for non-cardia GC through an RCT. We conducted a cluster RCT in rural Hua County, northern China (ClinicalTrials.gov, NCT01688908). A total of 668 villages were randomly selected and assigned to either undergo upper gastrointestinal endoscopic screening (screening group) or no screening (control group). Permanent residents aged 45-69 years were enrolled from January 2012 to September 2016. Non-cardia GC mortality between the two groups was compared in intention-to-treat, per-protocol, and subgroup analyses. Poisson regression fitted with generalized estimating equations was used, adjusting for baseline characteristics and accounting for village clustering. The study enrolled 17,104 participants in the screening group, of whom 15,165 (88.7

BackgroundThe classical prognostic indicators of lung cancer are no longer sufficient for prognostic stratification and individualized treatment of highly heterogeneous non-small cell lung cancer (NSCLC). This study aimed to establish a radiomics model to predict CD74 expression level in NSCLC patients and to explore its role in the tumor immune response and its prognostic value.MethodsThe prediction model was developed based on 122 NSCLC transcriptome samples, including 68 paired enhanced CT and transcriptome samples. Survival analysis, gene set variation analysis, and immune cell infiltration analysis were used to investigate the relationship between CD74 expression and tumor immune response. Logistic regression (LG) and support vector machine (SVM) analysis were used to construct the prediction model. The performance of the model was assessed with respect to its calibration, discrimination, and clinical usefulness.ResultsHigh CD74 expression is an independent prognostic factor for NSCLC and is positively correlated with antigen presentation and processing gene expression and antitumor immune cell infiltration. The radiomics prediction models for CD74 expression demonstrated good predictive performance. The areas under the receiver operating characteristic curves for the LG and SVM radiomics models were 0.778 and 0.729, respectively, in the training set and 0.772 and 0.701, respectively, in the validation set. The calibration and decision curve analysis curves demonstrated good fit and clinical benefit.ConclusionCD74 expression significantly impacts the prognosis of NSCLC patients. The radiomics model based on contrast-enhanced CT exhibits good performance and clinical practicability in predicting CD74 expression.

IntroductionPlasmablastic lymphoma (PBL) is a rare and highly aggressive form of non-Hodgkin lymphoma that is associated with a poor prognosis. Traditional chemotherapy has demonstrated limited efficacy for PBL. There is currently no standard treatment for patients with refractory or relapsing PBL. While CAR-T therapy has shown promising outcomes in leukemia, lymphoma and myeloma, evidence of its application in PBL remains scarce.Case presentationWe describe a 56-year-old patient diagnosed with PBL. The patient achieved short-term remission with bortezomib in combination with etoposide, dexamethasone, cyclophosphamide, and doxorubicin as first-line therapy. After disease progression, the patient received daratumumab combined with GemOx as second-line treatment but showed no response. Tumor biopsy after disease progression revealed strong positive CD22 and partial positive CD19 expression. The patient received CD19 and CD22 CAR-T therapies as the third-line treatment and achieved durable complete remission for more than one year with good tolerance.ConclusionA patient with refractory PBL achieved durable complete remission after CD19 and CD22 CAR-T therapies, suggesting this treatment may be effective for patients with refractory or relapsing PBL.

Central nervous system (CNS) involvement in peripheral T-cell lymphoma (PTCL) is rare and is associated with poor prognosis. This report presents two pathologically confirmed PTCL cases. Although cerebrospinal fluid (CSF) flow cytometry did not detect tumor cells, CSF analysis revealed significantly elevated interleukin (IL)-10 levels and an increased IL-10/IL-6 ratio, suggesting CNS involvement. Following effective chemotherapy, which crossed the blood-brain barrier, IL-10 levels and the IL-10/IL-6 ratio decreased significantly, with clinical improvement. These findings suggest that IL-10 is a valuable supplementary diagnostic marker for CNS involvement in PTCL. Whole-brain radiation therapy, as a consolidative treatment, may be effective for residual or refractory lesions and improve prognosis. We review these patients' clinical and diagnostic features and discuss the role of radiotherapy in the treatment of CNS involvement in PTCL.

Objective:Patients with hematological malignancies have an elevated risk of developing pneumonia after contracting COVID-19. Lymphoma is the most prevalent hematologic malignancy. It is critical to identify patients at high risk of contracting COVID-19-associated pneumonia. Methods:From January 11-31, 2023, we distributed questionnaires to patients diagnosed with lymphoma according to 2016 World Health Organization diagnostic and classification criteria. COVID-19 infection was confirmed based on symptoms and laboratory tests. Pneumonia was confirmed using computed tomography scans. Results:In total, 257 patients were included in this study; 221 patients (86.0%) had COVID-19 infection and 61 (27.6%) of these had pneumonia. Patients with B-cell non-Hodgkin lymphoma (B-NHL) had a significantly higher pneumonia incidence than patients with other lymphoma types (31.8% vs. 27.6%, P=0.005). Higher incidence of pneumonia was observed in patients receiving anti-CD20 therapy (30.0% vs. 16.3%, P=0.048) and Bruton's tyrosine kinase (BTK) inhibitor therapy (51.3% vs. 22.5%, P=0.001). B-NHL (hazard ratio [HR]=3.7, 95% confidence interval [CI] 1.4-10.0, P=0.009), anti-CD20 therapy (HR=2.3, 95% CI 1.0-5.2, P=0.050), BTK inhibitor (HR=3.6, 95% CI 1.8-7.4, P<0.001), active therapy (HR=3.0, 95% CI 1.5-5.7, P=0.001), and lack of disease remission (HR=3.7, 95% CI 1.8-7.4, P=0.001) were high-risk factors for developing pneumonia. Anti-PD-1 therapy was a protective factor against pneumonia development (HR=0.2, 95% CI 0.05-0.9, P=0.034). In multivariable analysis, BTK inhibitor (HR=3.5, 95% CI 1.6-8.0, P=0.003), active therapy (HR=3.3, 95% CI 1.6-6.8, P=0.001), and disease non-remission (HR=2.9, 1.3-6.4, P=0.007) were independent risk factors for pneumonia development after COVID-19 infection in patients with lymphoma. Conclusions:Patients with lymphoma receiving BTK inhibitors, undergoing active therapy, and lacking disease remission exhibited a higher risk for pneumonia associated with COVID-19.

The precise mechanisms underlying Parkinson's disease (PD) pathogenesis remain incompletely understood, particularly regarding the role of microglial inflammation and serotonin neuron survival. This protocol delineates a comprehensive framework for elucidating how methyltransferase-like 3 (Mettl3) modulates nuclear factor erythroid 2-related factor 2 (Nrf2) through N6-methyladenosine (m6A) modification, thereby attenuating microglial pyroptosis and preserving serotonin neurons in both in vitro and in vivo PD models. The primary goal is to furnish researchers with reproducible methodologies for dissecting epitranscriptomic regulation of neuroinflammatory pathways, commencing with lipopolysaccharide (LPS)-induced microglial activation in BV2 cells to simulate inflammatory cascades, followed by methylated RNA immunoprecipitation quantitative PCR (MeRIP-qPCR) for m6A analysis. In vivo, we detail the establishment of an MPTP-induced PD mouse model, complemented by stereotactic delivery of adeno-associated virus serotype 9 (AAV9) vectors for targeted Nrf2 modulation in the striatum. Behavioral evaluations encompass forelimb placement, accelerating rotarod, and open field tests to quantify motor deficits, while molecular assays include Western blotting for pyroptosis markers (e.g., NLRP3, cleaved-caspase-1), enzyme-linked immunosorbent assay (ELISA) for cytokines, and dihydroethidium (DHE) staining for reactive oxygen species (ROS) detection in serotonin neurons. Advanced microscopy techniques, such as immunohistochemistry for Iba1 and TPH2, enable visualization of microglial dynamics and serotonergic integrity. Results substantiate that Mettl3 deficiency exacerbates Nrf2 downregulation, NLRP3 inflammasome hyperactivation, pyroptotic cell death, and consequent serotonin neuron degeneration. This method not only provides a robust experimental scaffold for probing m6A-mediated neuroprotection but also highlights potential therapeutic avenues for mitigating PD progression through targeted modulation of the Mettl3/Nrf2 axis in neurodegenerative contexts.

The prognostic value of baseline bone mineral density (BMD) and posttreatment BMD decrease (BMDD) in non-small cell lung cancer (NSCLC) patients receiving immune checkpoint inhibitor (ICI) treatment remains unclear. We assembled data of 2096 patients with advanced NSCLC from five institutions to develop a combined model incorporating BMD/BMDD and clinical characteristics for noninvasive prognosis prediction. BMD was automatically assessed using a deep learning-based method. Compared with the physiological BMD group and the non-severe BMDD group, the pathological BMD group and the severe BMDD group had shorter progression-free survival (PFS) (hazard ratio [HR]: 1.19, p = 0.003; and HR: 1.19, p = 0.002, respectively) and overall survival (OS) (HR: 1.31, p < 0.001; and HR: 1.30, p < 0.001). Compared with the single BMD/BMDD model, the combined model had higher Harrell's concordance indexes (c-indexes) (PFS: 0.580 and OS: 0.654). Transcriptomic analysis of 130 patients from the NSCLC radiogenomic cohort revealed upregulation of epithelial-mesenchymal transition, inflammatory, and hypoxia pathways, and increased macrophage infiltration in tumors of patients with pathological BMD. This study showed that lower baseline BMD and more severe BMDD are associated with poorer prognosis. BMD in combination with clinical characteristics can help to improve risk stratification and prognosis prediction.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive B-cell malignancy with poor long-term survival. The MATRix regimen (high-dose methotrexate, cytarabine, thiotepa, and rituximab combination therapy) was considered as an effective therapy for the younger patients with PCNSL. However, due to severe hematologic toxicity, mainly caused by high-dose cytarabine, the regimen's application is limited in elderly patients with PCNSL. Therefore, a safe and effective regimen is essential for PCNSL patients across a broader age range. Orelabrutinib, a novel Bruton tyrosine kinase inhibitor with high positive cerebrospinal fluid concentration and fewer off-target effects, has demonstrated impressive efficacy and manageable safety in PCNSL. We aimed to evaluate the efficacy and safety of R-MTO regimen (rituximab, methotrexate, thiotepa, and orelabrutinib) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) in patients with PCNSL. This was a prospective, open-label, single-center, single-arm study. Patients with newly diagnosed PCNSL received 6-8 cycles of R-MTO regimen as induction therapy, consisting of rituximab 375 mg/m2 intravenously on day 0, methotrexate 3.5 g/m2 intravenously on day 1, thiotepa 30 mg/m2 intravenously on day 4, and oral orelabrutinib 150 mg once daily every 3 weeks. The treatment response was assessed by magnetic resonance imaging or positron emission tomography-computed tomography according to the International PCNSL Collaborative Group (IPCG) criteria. Patients without disease progression underwent consolidation treatment with high-dose chemotherapy (HCT) followed by auto-HSCT. The HCT regimen involved thiotepa 250 mg/m2 on days -7 and -6, busulfan 3.2 mg/kg on days -5 and -4, cytarabine 2 g/m2 every 12 hours on days -3 and -2. Hematopoietic stem cells were reinfused on day 0. The primary endpoint was 24-month progression-free survival (PFS) rate, evaluated by intention-to-treat. Secondary endpoints included complete Response (CR) rate, overall response rate (ORR), overall survival (OS), and safety. Between April 2022 and June 2025, 35 patients were enrolled, with a median age of 59 years (range, 28-75), and 19 (54.29%) were male. At the data cutoff, all patients had completed induction therapy, and the CR rate and ORR were 91.43% (32/35) and 97.14% (34/35) after 4 cycles of induction therapy, respectively. One patient with a P53 mutation did not respond to induction treatment and died 3.8 months after diagnosis. Fifteen (42.86%) patients underwent auto-HSCT, all achieving CR beforehand. One patient died from COVID-19 infection, and another relapsed and died after 6 cycles of R-MTO and auto-HSCT. The 18-month PFS and OS rates were 80.68% (95% CI 61.69-90.90) and 82.98% (95% CI 63.55-92.61), respectively. The most common adverse events associated with the R-MTO regimen were hematological toxicity, with grade 3-4 observed in 25.71% (9/35) of patients and grade 4 hematological toxicity in only 8.57% (3/35) of patients. The R-MTO induction treatment has demonstrated notable efficacy in achieving higher response rate among patients with newly diagnosed PCNSL, with a manageable safety profile. Further related data will be presented at a later date.

BACKGROUND:Neoadjuvant immunochemotherapy has revolutionized the treatment of non-small cell lung cancer. However, it presents significant surgical challenges, leading to controversy over the feasibility and safety of minimally invasive surgery. This study aims to assess the adequacy of minimally invasive surgery and preoperatively predict its difficulty for non-small cell lung cancer after neoadjuvant immunochemotherapy. METHODS:Initial stage IIA-IIIB (excluding stage T4N2) non-small cell lung cancer patients with neoadjuvant immunochemotherapy undergoing minimally invasive surgery or open thoracotomy at 12 institutions between 2019 and 2024 were retrospectively reviewed. Difficult minimally invasive surgery was defined by conversion to thoracotomy. Propensity score matching was applied to balance baseline characteristics. RESULTS:Of the 571 cases included, propensity score matching led to 240 patients per group. Minimally invasive surgery decreased intraoperative bleeding, shortened postoperative chest tube duration and hospitalization, ameliorated postoperative pain, and reduced postoperative complications compared to open thoracotomy. Moreover, minimally invasive surgery had an acceptable conversion rate of 15.8%, and notably, converted minimally invasive surgery achieved similar perioperative outcomes to open thoracotomy. Accumulated surgeons' experiences reduced minimally invasive surgery conversion rates and shortened surgical durations. Additionally, logistic regression identified squamous cell carcinoma, advanced preinduction N stage, preoperative tumor size >5 cm, advanced preoperative stage, and extended resection as independent risk factors for conversion. A nomogram was further established with good performance (area under curve value = 0.804) and clinical utility to predict conversion probability preoperatively. Finally, minimally invasive surgery and open thoracotomy achieved comparable event-free survival and overall survival profiles. CONCLUSIONS:Minimally invasive surgery achieved improved perioperative outcomes and similar oncologic efficacies to open thoracotomy. Moreover, minimally invasive surgery had an acceptable conversion rate, which would not compromise perioperative outcomes compared with open thoracotomy and could be effectively forecasted by a prediction model.

BackgroundDouble-expressor lymphoma (DEL) has a poorer prognosis than other subtypes of diffuse large B-cell lymphoma (DLBCL). This study is a multicenter, prospective, single-arm, phase 2 clinical study initiated by investigators to evaluate the efficacy and safety of combined zanubrutinib with R-CHOP, which includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for patients with DEL (stage II or more), as well as to explore factors related to efficacy preliminarily.MethodsFrom November 2020 to July 2022, 48 newly diagnosed patients were enrolled. All patients received twice-daily oral zanubrutinib (160 mg) for 6 months and standardized R-CHOP regimen for six to eight cycles.ResultsThe objective response rate (ORR) was 89.6%, with a complete response rate (CRR) of 83.3%. The median follow-up was 29.3 months. The median progression-free survival (PFS) and overall survival (OS) were not reached. The PFS and OS were 81.25% and 93.75% at 2 years, respectively. Grade >= 3 adverse events (AEs) were reported in 23 of 48 (47.9%) patients. Next-generation sequencing (NGS) results of 33 patients showed that TP53, MYD88, and PIM1 were the most common mutated gene. Multivariate analysis revealed that BCL-6 gene rearrangement was an adverse prognostic factor for both PFS (hazard ratio [HR], 0.247; 95% confidence article [CI], 0.068-0.9; p = .034) and OS (HR, 0.057; 95% CI, 0.006-0.591; p = .016), whereas the number of extranodal involvements also significantly influenced OS (HR, 15.12; 95% CI, 1.07-213.65; p = .044).ConclusionsZanubrutinib in combination with R-CHOP is an effective option for DEL patients, and the toxicity of zanubrutinib is entirely acceptable for patients.

KRASG12C inhibitors exhibit conspicuous clinical response in KRASG12C-mutant lung cancer, yet adaptive resistance, the rapid onset of intrinsic resistance, dampens their therapeutic success. Rational combination strategies could tackle this challenging problem. A high-throughput screening of a pharmacological library with 423 compounds revealed that napabucasin, a signal transducer and activator of transcription 3 (STAT3) inhibitor, synergistically potentiated the growth inhibition effect of the KRASG12C inhibitor sotorasib in sensitive and resistant KRASG12C NSCLC cell lines. Functional assays further revealed that the coordinated targeting of KRAS with STAT3 improved the inhibitory effect on tumor growth and augmented the infiltration and activation of natural killer (NK) cells within the tumor microenvironment. Mechanistically, KRASG12C inhibition induced compensatory activation of STAT3, contingent on concomitant suppression of downstream ERK signaling, abrogated by napabucasin. Moreover, we unveiled and verified the binding site of phosphorylated STAT3 at the HLA-B promoter, an inhibitor ligand for NK cells. Our study dissected an unknown mechanism of adaptive resistance to KRASG12C inhibitors, with the STAT3 activation sustaining the regrowth of tumor cells under KRAS inhibition and up-regulating HLA-B transcription to dampen the cytotoxicity of infiltrated NK cells.

BACKGROUND:Controversy persists regarding the efficacy of sublobar resection (SR) vs lobar resection (LR) for clinical stage IA non-small cell lung cancer with tumor spread through air spaces, thus suggesting that a 1-size-fits-all approach may be inappropriate for this heterogeneous population. This study aimed to identify the factors potentially modifying the survival benefits of LR over SR in clinical stage IA spread through air spaces-positive non-small cell lung cancer. METHODS:The study retrospectively reviewed consecutive peripheral clinical stage IA1 to IA2 spread of air spaces-positive non-small cell lung cancer in patients who underwent surgery between 2014 and 2020 at 6 high-volume institutions. Propensity score matching was used to mitigate selection bias. The primary end point was recurrence-free survival. RESULTS:Among 4555 cases, propensity score matching resulted in 1238 and 2476 patients in the SR and LR groups, respectively, who were included for further investigation. LR yielded better prognoses compared with SR in the overall cohort. Interaction and stratified analyses further revealed that LR significantly improved survival compared with SR in patients with clinical stage IA2, whereas survival outcomes were comparable between the 2 approaches in patients with clinical stage IA1 disease. In lymphovascular invasion-negative pathologic stage IA subcohorts, adjuvant therapy improved survival in pathologic stage IA2 to IA3 patients undergoing SR, but it showed no survival benefit in patients with pathologic stage IA1 disease or in patients with pathologic stage IA2 to 1A3 who underwent LR. CONCLUSIONS:Collectively, patients with clinical stage IA2 disease may derive greater benefit from LR, whereas patients with clinical stage IA1 disease could be considered appropriate candidates for SR. In cohorts with lymphovascular invasion-negative pathologic stage IA disease, adjuvant therapy could be recommended for patients with pathologic IA2 to IA3 after SR, whereas it may not be necessary for patients undergoing LR or for patients with pathologic stage IA1 disease.

Background:Effective time-limited therapies remain an unmet need in chronic lymphocytic leukaemia (CLL). We evaluated a novel regimen combining ibrutinib with intermittent fludarabine, cyclophosphamide, and rituximab (FCR) in patients with CLL. Methods:This single-arm, multicentre, phase 2 trial was conducted at three centres in China. Eligible participants were adults (aged 18-65 years) with previously untreated CLL requiring therapy according to the International Workshop on Chronic Lymphocytic Leukaemia criteria. The regimen consisted of ibrutinib (420 mg daily) combined with three cycles of FCR administered on days 1-3 of cycles 1, 5, and 9. After the completion of induction therapy, among patients who had achieved complete remission (CR) with undetectable minimal residual disease (uMRD): those without TP53 deletion or mutation could discontinue treatment; those with TP53 deletion or mutation continued maintenance therapy for 6 months before discontinuing treatment; all other patients continued ibrutinib until they achieved CR-uMRD, followed by an additional 6 months of treatment. The primary endpoint was CR rate at best response. This trial is registered with ClinicalTrials.gov, NCT03980002. Findings:Between June 1, 2019, and July 30, 2023, 50 patients were enrolled with a median follow-up of 55 months (IQR 40-65). The median age of participants was 57 years (IQR 48-62), and 36 (72%) were male. Among 47 patients with available IGHV data, 18 (38%) had unmutated IGHV. TP53 deletion/mutation were present in four (8%) patients. The CR rate, the primary outcome, was 70% (35/50) at best response. 18 patients (36%) achieved CR with undetectable MRD in both bone marrow and peripheral blood, discontinuing treatment post-induction. Four deaths occurred; one due to Richter's transformation, two from COVID-19, and one from cerebral infarction. Grade 3/4 neutropenia occurred in 13 (26%) patients, leucopenia in 11 (22%) patients, and lymphocytopenia in 12 (24%) patients. No therapy-related cases of myelodysplastic syndrome or acute myeloid leukaemia were observed. Interpretation:This regimen achieved deep remissions with manageable toxicity. Whilst acknowledging study limitations and that pathway inhibitors are the current standard of care, these findings provide proof-of-principle that this regimen could be a feasible, time-limited treatment option for CLL. Particularly in resource-limited healthcare systems where continuous novel agents are less accessible. Future studies should explore long-term durability beyond 5 years and validate MRD thresholds for treatment cessation. Funding:National Nature Science Foundation of China, the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and Beijing Xisike Clinical Oncology Research Foundation.

HMOX1 has gained increasing recognition across multiple malignancies; however, its precise oncogenic or tumor-suppressive roles remain incompletely defined. In this study, we comprehensively investigated HMOX1 across diverse tumor types utilizing the cancer genome atlas (TCGA). We further integrated data from multiple bioinformatics platforms, including TIMER2, UALCAN, GEPIA2, cBioPortal, R, GSCA, and LinkedOmics. Western blotting and quantitative real-time PCR (qRT-PCR) confirmed differential HMOX1 expression between normal renal epithelial cells and KIRC cells. Functional assays in vitro and in vivo demonstrated that HMOX1 regulates proliferation, migration, and cell-cycle progression in 786-O and Caki-1 cells. Pan-cancer analyses revealed that HMOX1 is aberrantly expressed across multiple malignancies with significant associations with the tumor stage. Survival analyses indicated that elevated HMOX1 expression predicted poor overall survival (OS) in LGG (P = 0.025) but favorable OS and disease-free survival (DFS) in KIRC (OS: P = 0.00062; DFS: P = 9 × 10-4). Moreover, mutations were the predominant genetic alteration affecting HMOX1, while promoter methylation was broadly reduced across cancers. HMOX1 expression positively correlated with immune infiltration by CD8+ T cells (KIRC: Spearman ρ = 0.26, FDR = 2.56 × 10-8) and macrophages (KIRC: Spearman ρ = 0.32, FDR = 2.77 × 10-13). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses in KIRC implicated HMOX1 in the chemokine and NF-κB signaling pathways. Both in vitro and in vivo experiments demonstrated that HMOX1 knockdown accelerates cell-cycle progression and enhances proliferation and migration in 786-O and Caki-1 cells. Collectively, our findings establish HMOX1 as a promising prognostic biomarker and potential immunotherapeutic target across multiple cancers.

Lung cancer remains a leading cause of cancer-related morbidity and mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for > 85