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Abstract Background Immunotherapy has revolutionized cancer treatment. Recent studies have suggested that the efficacy of immunotherapy can be further enhanced by the influence of gut microbiota. In this study, we aimed to investigate the impact of bacteria on the effectiveness of cancer immunotherapy by combining analysis of clinical samples with validation in animal models. Methods In order to characterize the diversity and composition of microbiota and its relationship with response to immune checkpoint inhibitors (ICIs), 16S ribosomal RNA (rRNA) and GC–MS sequencing was performed on 71 stool samples from patients with advanced non‐small cell lung cancer (NSCLC) prior to treatment with immune checkpoint blockade (ICB). Furthermore, fecal microbiota transplantation (FMT) was performed from different patients into mice and a subcutaneous tumor model established using the Lewis lung cancer cell line to evaluate the therapeutic effect of PD‐1 on mice with varying gut microbiota. Results The results demonstrated a significant association between elevated gut microbiota diversity and response to treatment with ICIs, p 0.05. The diversity of gut microbiota consistently correlated with an optimistic prognosis in NSCLC patients with immunotherapy, which could be functionally mediated by SCFAs. Conclusion The findings of the present study indicated that the diversity of gut microbiota and SCFAs is related to the efficacy of immunotherapy. FMT can effectively delay tumor progression, and enhance the effect of immunotherapy, thus providing evidence for improving the efficacy of immunotherapy in NSCLC patients.

Abstract Background The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib‐refractory, anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. Methods In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two‐sided 95% confidence intervals (CIs). Next‐generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. Results At the data cut‐off date (August 31, 2022), with a median follow‐up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3‐53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. Conclusion Ensartinib led to a favorable OS in patients with advanced, crizotinib‐resistant, and ALK‐positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Objective To analyze the clinical efficacy of full-visualization single-channel endoscopic lumbar interbody fusion (PE-PLIF) in the treatment of lumbar degenerative diseases, and to explore the application skills and significance of endoscopic spinal canal decompression and interbody fusion. Methods From January 2021 to December 2022, 50 patients who underwent PE-PLIF in The Affiliated Huai ‘an No.1 Hospital of Nanjing Medical University were selected retrospectively. A total of 56 lower lumbar segments were treated with spinal canal decompression and interbody fusion. The expandable cage implantation technique was used for spinal canal decompression, intervertebral fusion, and percutaneous pedicle screw internal fixation. The visual analogue scale (VAS) score of low back pain and lower limb pain, Oswestry disability index (ODI), and modified MacNab scoring system were used to evaluate the clinical efficacy before and after operation. Results The VAS scores of low back pain were 5.2±1.1, 2.2±0.7, 1.5±0.6, 1.3±0.7, 1.0±0.9 before operation, 1 day, 3 months, 6 months after operation and at the last follow-up, respectively. The VAS scores of lower limb pain were 7.2±1.0, 2.0±1.0, 0.5±0.3, 0.3±0.2, 0.3±0.2, respectively. The ODI was 66.3±7.4, 16.6±5.0, 12.4±3.6 and 10.7±3.3 before operation, 3 months, 6 months after operation and at the last follow-up, respectively. The VAS score and ODI score decreased after operation, and the differences were statistically significant compared with those before operation (P

Introduction Postoperative delirium (POD) is the most common acute fluctuating mental state change after hip fractures in older adults. Postoperative pain is a Grade A risk factor for POD and is closely related to the prognosis of patients undergoing hip fracture surgery. The fascia iliac block has a definite analgesic effect and few side effects, and several studies have reported that it reduces the occurrence of POD in patients undergoing general anaesthesia for hip fracture surgery. Liposomal bupivacaine is a local anaesthetic with a long half-life that significantly reduces the use of opioids and is conducive to patient prognosis and recovery. However, whether regional nerve block analgesia can decrease the occurrence of POD in elderly patients undergoing hip fracture surgery has not been reported.Methods and analysis This is a single-blinded, randomised, parallel-controlled prospective clinical study. Participants will be randomly assigned preoperatively to either the liposomal bupivacaine (ie, Exparel) or ropivacaine groups by block randomisation. Then, the occurrence of POD (primary outcome) and postoperative pain (secondary outcome) will be evaluated.Ethics and dissemination This research protocol complies with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 guidelines and is approved by the Ethics Committee of Shanghai General Hospital (ID 2023–437). The original data are expected to be released in July 2029 on the ResMan original data-sharing platform (IPD-sharing platform) of the China Clinical Trial Registry, which can be viewed on the following website: http://www.medresman.org.cn.PROSPERO registration number ChiCTR2300074022.

The accurate assessment of tree volume is crucial for developing forest management plans, and this can be achieved using tree volume models. In this study, data on individual trees were collected and calculated, including the diameter at breast height (D), ground diameter (DG), tree height (H), and tree volume (V). A total of 400 Populus × tomentosa Carrière, 400 Populus tomentosa Carr, and 400 Populus × canadensis Moench trees were sampled. Two compatible volume model systems were established using corresponding methods. The models consisted of the following five types: V-DH, V-D, V-DG, H-D, and DG-D. In our calculations, before the horizontal line was the dependent variable, and behind the horizontal line was the independent variable. Variations in preferences for the H-D models were observed among the tree species, with the logistic function proving the most suitable for Populus × tomentosa Carrière, Chapman–Richard function for Populus tomentosa Carr, and power function for Populus × canadensis Moench. Among the three volume models, the V-DH model exhibited a superior performance, with its R2 values ranging from 0.965 to 0.984 and mean estimated error (MPE) values ranging from 1.26% to 1.78%. Following this was the V-D model, with R2 values between 0.9359 and 0.9704 and MPE values between 1.71% and 2.46%. The V-DG model ranked third, with R2 values ranging from 0.8746 to 0.9501 and MPE values ranging from 2.33% to 3.16%. In the H-D model, the R2 and MPE values ranged from 0.4998 to 0.7851 and from 1.31% to 1.45%, respectively. For the DG-D model, the R2 values ranged from 0.9563 to 0.9868 and the MPE values ranged from 0.47% to 0.68%. Comparing both compatible methods, the nonlinear seemingly uncorrelated regression (NSUR) was more effective. The three volume models demonstrated high levels of accuracy and compatibility, providing a reliable scientific foundation for forest management and the formulation of harvesting plans in Beijing, with significant practical implications.

Abstract This phase I/II trial characterized the tolerability, safety, and antitumor activities of unecritinib, a novel derivative of crizotinib and a multi-tyrosine kinase inhibitor targeting ROS1, ALK, and c-MET, in advanced tumors and ROS1 inhibitor-naive advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements. Eligible patients received unecritinib 100, 200, and 300 mg QD, and 200, 250, 300, and 350 mg BID in a 3 + 3 design during dose escalation and 300 and 350 mg BID during expansion. Phase II trial patients received unecritinib 300 mg BID in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) per independent review committee (IRC). Key secondary endpoints included intracranial ORR and safety. The ORR of 36 efficacy evaluable patients in the phase I trial was 63.9% (95% CI 46.2%, 79.2%). In the phase II trial, 111 eligible patients in the main study cohort received unecritinib. The ORR per IRC was 80.2% (95% CI 71.5%, 87.1%) and the median progression-free survival (PFS) per IRC was 16.5 months (95% CI 10.2, 27.0). Additionally, 46.9% of the patients who received recommended phase II dose of 300 mg BID experienced grade 3 or higher treatment-related adverse events. Treatment-related ocular disorders and neurotoxicity occurred in 28.1% and 34.4% of patients, respectively, but none was grade 3 or higher. Unecritinib is efficacious and safe for ROS1 inhibitor-naive patients with ROS1-positive advanced NSCLC, particularly patients with brain metastases at baseline, strongly supporting that unecritinib should become one of the standards of care for ROS1-positive NSCLC. ClinicalTrials.gov identifier: NCT03019276 and NCT03972189.

Abstract Background QL1706 (PSB205) is a single bifunctional MabPair (a novel technical platform) product consisting of two engineered monoclonal antibodies (anti-PD-1 IgG4 and anti-CTLA-4 IgG1), with a shorter elimination half-life (t1/2) for CTLA-4. We report results from a phase I/Ib study of QL1706 in patients with advanced solid tumors who failed standard therapies. Methods In the phase I study, QL1706 was administered intravenously once every 3 weeks at one of five doses ranging from 0.3 to 10 mg/kg, and the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of QL1706 were investigated. In the phase Ib study, QL1706 was administered at the RP2D intravenously every 3 weeks, and the preliminary efficacies in non-small cell lung cancer (NSCLC), nasopharyngeal carcinoma (NPC), cervical cancer (CC), and other solid tumors were evaluated. Results Between March 2020 and July 2021, 518 patients with advanced solid tumors were enrolled (phase I, n = 99; phase Ib, n = 419). For all patients, the three most common treatment-related adverse events (TRAEs) were rash (19.7%), hypothyroidism (13.5%), and pruritus (13.3%). The TRAEs and immune-related adverse events (irAEs) of grade ≥ 3 occurred in 16.0% and 8.1% of patients, respectively. In phase I, 2 of 6 patients in the 10mg/kg group experienced dose-limiting toxicities (DLTs) (grade 3 thrombocytopenia and grade 4 immune-mediated nephritis), so the maximum tolerated dose (MTD) was reached at 10 mg/kg. The RP2D was determined to be 5 mg/kg based on comprehensive analysis of tolerability, PK/PD, and efficacy. For all patients who received QL1706 at the RP2D, the objective response rate (ORR) and median duration of response were 16.9% (79/468) and 11.7 months (8.3—not reached [NR]), respectively; and the ORRs were 14.0% (17/121) in NSCLC, 24.5% (27/110) in NPC, 27.3% (15/55) in CC, 7.4% (2/27) in colorectal cancer, 23.1% (6/26) in small cell lung cancer. For immunotherapy-naive patients, QL1706 exhibited promising antitumor activities, especially in NSCLC, NPC, and CC, with ORRs of 24.2%, 38.7%, and 28.3%, respectively. Conclusions QL1706 was well tolerated and demonstrated promising antitumor activity in solid tumors, especially in NSCLC, NPC, and CC patients. It is currently being evaluated in randomized phase II (NCT05576272, NCT05179317) and phase III (NCT05446883, NCT05487391) trials. Trial Registration ClinicalTrials.gov Identifier: NCT04296994 and NCT05171790.

Background Lung squamous cell carcinoma (LUSC) remains a leading cause of cancer-related deaths with few therapeutic strategies. Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy in patients with LUSC. However, ICIs could also lead to a unique spectrum of immune-related adverse events (irAEs), which dampen the clinical outcome. In-depth characterization of the immune hallmarks of antitumor responses and irAEs remains an unmet need to maximize ICI-treatment benefits of patients.Methods We performed single-cell RNA sequencing (scRNA-seq) on pre-ICI and on-ICI treatment tumor biopsies. We used bulk RNA-seq data of matched pretreatment/on-treatment tumors and irAE affected organs to validate observations from scRNA-seq analysis. Two independent patient cohorts were collected to determine circulating tumor necrosis factor (TNF) protein expression levels.Results We found that increased proportions of a macrophage subcluster with highly expressed secreted phosphoprotein 1 (SPP1) and two tumor cell subclusters in irAE patients, whereas proportions of two cytotoxic CD8+ T cell subclusters were higher in patients with partial response (PR). TNF signaling pathway was conversely associated with treatment efficacy and irAE development in most macrophage and tumor cell subclusters. Cell–cell communications for TNF ligand-receptor pairs between macrophage/T cells and tumor cells were also bidirectionally remodeled in responders versus non-responders and irAE versus non-irAE patients. Bulk RNA-seq analysis on matched pretreatment/on-treatment tumors and irAE affected organs revealed remarkably enhanced macrophage abundance and TNF signaling pathway in on-treatment tumors and organs developed irAEs. Furthermore, we observed significantly increased circulating TNF protein in plasma or serum of irAE patients but not ICI responders, based on analysis of two independent LUSC patient cohorts and one published ICI patient cohort.Conclusions Our data depicts specific reprogramming of macrophage, T cells and tumor cells associated with ICI response and irAEs, elucidates divergent roles of TNF signaling in antitumor immunity and irAEs, and highlights the significance of TNF expression in irAE development in the LUSC setting.

Background Treatment options are limited for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) after treatment failure with EGFR tyrosine kinase inhibitors (TKIs). This multicenter open-label, phase II study aims to evaluate the efficacy and safety of tislelizumab plus chemotherapy (cohort 1, TIS+chemo) or tislelizumab plus chemotherapy and bevacizumab (cohort 2, TIS+chemo+ beva) in EGFR-mutated non-squamous NSCLC patients who progressed on EGFR TKI therapies. Here, the primary analysis of the TIS+chemo cohort is reported.Methods In the TIS+chemo cohort, patients with EGFR-sensitizing mutations with prior EGFR TKI failure received tislelizumab plus carboplatin and nab-paclitaxel as induction treatment, followed by maintenance with tislelizumab plus pemetrexed. The primary endpoint was 1-year progression-free survival (PFS) rate. The planned sample size was 66 with a historical control of 7%, an expected value of 20%, a one-sided α of 0.05, and a power of 85%.Results Between July 11, 2020 and December 13, 2021, 69 patients were enrolled. As of June 30, 2022, the median follow-up was 8.2 months. Among the 62 patients in the efficacy analysis set, estimated 1-year PFS rate was 23.8% (90% CI 13.1% to 36.2%), and its lower bound of 90% CI was higher than the historical control of chemotherapy (7%), which met the primary endpoint. The median PFS was 7.6 (95% CI 6.4 to 9.8) months. Median overall survival (OS) was not reached (95% CI 14.0 to not estimable), with a 1-year OS rate of 74.5% (95% CI 56.5% to 86.0%). The objective response rate and disease control rate were 56.5% (95% CI 43.3% to 69.0%) and 87.1% (95% CI 76.1% to 94.3%), respectively. Patients who had progressed on first-generation/second-generation and third-generation EGFR-TKIs at baseline had shorter PFS than those who progressed on first-generation/second-generation EGFR-TKIs (median 7.5 vs 9.8 months, p=0.031). Patients with positive ctDNA had shorter PFS (median 7.4 vs 12.3 months, p=0.031) than those with negative ctDNA. No grade 5 treatment-emergent adverse events (TEAEs) were observed. Grades 3–4 TEAEs occurred in 40.6% (28/69) of patients. Grades 3–4 immune-related AEs occurred in 5 (7.2%) patients.Conclusion The study met the primary endpoint for the TIS+chemo cohort. Tislelizumab plus chemotherapy is effective with an acceptable safety profile for EGFR-mutated non-squamous NSCLC after EGFR TKI failure.