Breaking Down Combination Strategies: PD-1/PD-L1 Inhibitors with Chemotherapy, Anti- Angiogenesis, or Both in Driver Gene-Negative NSCLC Clinical Outcomes and Mechanistic Insights

Breaking Down Combination Strategies: PD-1/PD-L1 Inhibitors with Chemotherapy, Anti- Angiogenesis, or Both in Driver Gene-Negative NSCLC Clinical Outcomes and Mechanistic Insights | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Breaking Down Combination Strategies: PD-1/PD-L1 Inhibitors with Chemotherapy, Anti- Angiogenesis, or Both in Driver Gene-Negative NSCLC Clinical Outcomes and Mechanistic Insights Yali Yi, Zhiqin Lu, Wenjie Xu, Yuxi Luo, Fujuan Zeng, Daya Luo, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6594933/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Brain metastasis from lung adenocarcinoma poses clinical challenges. Patients with driver gene-negative lung adenocarcinoma brain metastases have a relatively poor prognosis, and conventional treatments are inadequate. Immune checkpoint inhibitors (ICIs) represent a cornerstone in first-line therapy for metastatic non-small cell lung cancer. This study aims to explore the efficacy and mechanisms of ICIs combined with chemotherapy and anti-angiogenesis therapy, providing a theoretical basis and potential intervention points for treating driver gene-negative lung adenocarcinoma brain metastases. Methods: Clinical data of patients with driver gene-negative lung adenocarcinoma brain metastases who received immunotherapy from May 2020 to July 2022 at Nanchang University the Second Hospital center were collected. The study validated efficacy and mechanisms at cellular and animal model levels, including the hypoxia status and blood-brain barrier permeability and immune micro-environment status. Results: This study enrolled 179 patients with driver gene-negative non-small cell lung cancer brain metastases who received immunotherapy. Comparison among PD-1/PD-L1 inhibitor plus chemotherapy and anti-angiogenesis therapy (n=37), PD-1/PD-L1 inhibitor plus chemotherapy (n=54), anti-angiogenesis therapy alone (n=53), and PD-1/PD-L1 inhibitor monotherapy (n=35) showed median overall survival (OS) of 21.20 vs 16.00 vs 16.53 vs 9.30 months, respectively (P=0.013), and median intracranial progression-free survival (iPFS) of 15.20 vs 11.30 vs 9.03 vs 8.10 months, respectively (P=0.118). In a brain metastasis animal model, mice treated with PD-1 inhibitor plus bevacizumab and pemetrexed exhibited the lowest tumor fluorescence intensity. The combined therapy significantly improved tumor hypoxia, enhanced blood-brain barrier permeability in mice, and increased coverage of perivascular cells. The combination therapy decreased M2-type macrophages and increased M1-type macrophages in mouse brain tissue, elevated PD-L1 expression, and increased CD8+ T cells. Conclusion: PD-1/PD-L1 inhibitor combined with chemotherapy and anti-angiogenesis therapy appears to be an optimal strategy for driver gene-negative lung adenocarcinoma brain metastases. This combination therapy activates the immune micro-environment, improve hypoxia, enhance blood-brain barrier permeability and promote vascular normalization. driver gene-negative lung adenocarcinoma brain metastases immune combination therapy anti-angiogenesis therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Brain metastasis (BM) from lung adenocarcinoma represents a clinical challenge and a focus of intense research. Approximately 10% to 20% of advanced lung cancer patients present with BM at initial diagnosis, and 20% to 40% develop BM during the course of their disease(1). BM significantly impacts cognitive function, survival and quality of life, with a median survival of only 1-2 months. With extended survival in lung cancer, the incidence of BM is steadily increasing(2). The advent of next-generation targeted therapies has notably prolonged survival in driver gene-positive non-small cell lung cancer (NSCLC) patients with BM(3). However, prognosis remains poorer for driver gene-negative lung adenocarcinoma BM, and traditional treatments often fall short of clinical needs. Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone in first-line therapy for metastatic NSCLC, offering new hope in treatment. Prospective clinical studies have shown benefits of ICIs in BM patients, though they constitute a limited proportion (9%-17.5%) of trial participants. PD-L1 positivity correlates with greater benefit from immune therapy. However, response rates to ICIs as monotherapy generally remain below 30% in low PD-L1 expressions(4-6). BM lesions often exhibit low PD-1/PD-L1 expression and limited infiltration of tumor infiltrating lymphocytes (TILs)(7, 8), contributing to suboptimal responses to immune monotherapy. Thus, there is an urgent need to enhance the efficacy of ICIs and broaden the population benefiting from them. The phase III clinical trial, Impower150, first reported the combination of immune therapy with anti-angiogenic targeting, suggesting that the quadruple regimen of atezolizumab plus bevacizumab plus platinum-based doublet has superior efficacy compared to the triplet regimen(9). Recent exploratory analyses within the BM subgroup of Impower150 indicated that the ABCP regimen (atezolizumab, bevacizumab, carboplatin, paclitaxel) delayed time to new BM development (HR=0.68) compared to BCP (HR=0.68) and ACP (HR=1.55)(9). Thus, multimodal therapy holds promise for achieving durable metastatic control and survival. By targeting key immune checkpoints PD-1/PD-L1 and combining chemotherapy with anti-angiogenic therapy, it is theoretically possible to enhance T cell cytotoxicity. Further preclinical and clinical trials are urgently needed to provide definitive evidence and explore optimal immune-based combination therapies that effectively inhibit intracranial lesion progression. This study aims to investigate the efficacy and mechanisms of PD-1 inhibitor combined with chemotherapy and anti-angiogenesis therapy, providing a theoretical basis and potential intervention strategies for clinical management of driver gene-negative lung adenocarcinoma brain metastases. Methods 1. Patients Retrospective collection was conducted at the Second Affiliated Hospital of Nanchang University from May 2020 to July 2022, focusing on patients with advanced lung cancer and brain metastases treated with PD-1/PD-L1 inhibitors. Clinical data encompassed age, gender, smoking history, PS score, pathological type, PD-L1 expression level, distant metastases, initial diagnosis with concurrent brain metastasis, active brain metastases, number and diameter of brain metastases, history of radiotherapy, lines of immunotherapy, and combined immunotherapy regimens. Tumor response was assessed using the modified RECIST 1.1 for immune-based therapeutics (iRECIST). Overall survival (OS) was the primary endpoint, with immune-related progression-free survival (iPFS) as the secondary endpoint. Inclusion criteria: (1) Pathologically confirmed advanced lung cancer at our center; (2) Age between 18 and 80 years; (3) Driver gene mutations tested negative; (4) MRI or enhanced CT used for quantifiable brain lesions identification. Exclusion criteria: (1) History of other cancers; (2) Presence of leptomeningeal metastases at BM diagnosis; (3) Brain metastasis resection; (4) Loss to follow-up. 2. Cell culture The mouse-derived lung adenocarcinoma cell line LLC cells (EGFR wild-type) and RAW246.1 mouse macrophages were purchased from Pro-cell (Wuhan, China) and cultured in high-glucose DMEM medium supplemented with 10% fetal bovine serum and 1% antibiotic solution. Cultures were maintained in a humidified incubator at 5% CO2. LLC cells were stably transfected with lentiviral vector GV260 (Genomeditech, Shanghai, China) carrying a luciferase reporter gene (-luc). 3. Driver gene-negative lung adenocarcinoma brain metastases animal model (LLC-BM) The animals used in this study were C57BL/6J male mice, aged 6-8 weeks and weighing 19-21g, purchased from Jie Cui Medicine Co., Ltd. (Nanjing, China), and housed at the Experimental Animal Center of Nanchang University under a 12-hour light/dark cycle at a temperature of 25°C with ample food and water. All experimental procedures were approved by the Institutional Animal Ethics Committee of Nanchang University (Approval No. NCULAE-20221031140). LLC-luc tumor cells were prepared for injection after trypsin digestion and washing with PBS. Cell concentration in PBS for each injection was adjusted to 1×10^6 cells using Trypan Blue staining for live cell counting. Mice were anesthetized with 4% isoflurane inhalation. Under sterile conditions, the skin of the mice was disinfected with ethanol, and a skin incision (1 cm) was made to expose the skull for positioning at the bregma. EGFR wild-type lung cancer cells (LLC) labeled with luciferase were injected using a stereotactic apparatus (coordinates: 1 mm anterior and 3 mm right lateral to the bregma, depth 3 mm)(10), with a total volume of 5 µl of Luciferase-LLC (1x10^6 cells/ml), to establish a driver gene-negative NSCLC brain metastasis model (LLC-BM), evaluated for tumor growth via live imaging and histological staining. 4. LLC-BM treatments After establishing the LLC-BM model, on day 7 post-modeling, tumor formation was confirmed using in vivo live imaging, and mice were randomized into the following treatment groups: (1) Control group; (2) Anti-PD-1 monotherapy group; (3) Anti-PD-1 combined with chemotherapy group; (4) Anti-PD-1 combined with anti-angiogenic therapy group; (5) Anti-PD-1 + chemotherapy + anti-angiogenic therapy group, with 8 mice per group and a total of 40 mice. The dosage of anti-PD-1 inhibitor was 10 mg/kg, administered once weekly(11). The dosage of chemotherapy drug (pemetrexed) was 100 mg/kg, administered once weekly(12). The dosages of anti-angiogenic drugs (bevacizumab) were 10 mg/kg and 2 mg/kg, administered twice weekly(13). All drugs were administered via intraperitoneal injection for a total of 3 weeks. Live imaging was performed weekly during the treatment period, and mouse body weight was monitored twice weekly. Experimental endpoints included a reduction in body weight exceeding 20% or significant clinical symptoms, at which point mice were euthanized, and tissues were collected for formalin fixation or frozen storage. 5. EB staining and FITC staining Evans blue (EB) staining combined with confocal laser scanning microscopy was used to observe the fluorescence intensity of Evans blue dye in brain slices, enabling detection of changes in vascular morphology at the blood-brain barrier. Quantitative analysis of the infiltrated Evans blue dye content in brain tissue was performed. FITC (Fluorescein Isothiocyanate) labeling was employed for microcirculation and cell permeability studies, detected via fluorescence microscopy. Evans blue dye (Sigma E2129-10G) at 647 nm (red light) was injected intravenously at 2% EB (diluted in 4 ml/kg saline), circulated for 50 minutes. FITC staining (Sigma FD2000S-100MG) at wavelengths 494-520 nm (green light) was administered after 50 minutes of EB circulation, with 6 mg/ml FITC (diluted in 4 ml/kg saline), circulated for an additional 10 minutes before euthanizing the mice by decapitation and promptly freezing the brain tissue in liquid nitrogen for 5 minutes, followed by storage at -80°C. Brain tissue was then placed in a -20°C cryostat for at least 1 hour for temperature equilibration, embedded in tissue-Tek OCT compound (frozen section embedding medium), and coronally sliced (from bregma -1 mm to +1 mm) into 10 μm sections. Sections were mounted on slides and placed in a light-shielded box to prevent fluorescence quenching. Remaining brain tissue was stored at -80°C. Slides were air-dried at room temperature before fluorescence imaging and scanning. 6. Immunofluorescence Staining Fresh-frozen or formalin-fixed tissue sections (5-7um) were fixed in 4%PFA (15min), permeabilized with 0.1% Tween-20/PBS (5 min), and blocked with 5% BSA/10% normal serum (1 h). Primary antibodies (e.g., anti-CD31, 1:200; anti-NG2, 1:100, Servicebio, Wuhan, China) were applied overnight at 4°C, followed by species-matched fluorophore-conjugated secondary antibodies (1:200, 1 h, dark, Servicebio, Wuhan, China). Nuclei were counterstained with DAPI (1 ug/mL, 5 min), and slides were mounted with antifade medium. Imaging was performed using a confocal microscope, with fluorescence intensity quantified via ImageJ. Controls included isotype-matched IgG and unstained samples. 7. Immunohistochemistry (IHC) Staining Formalin-fixed, paraffin-embedded tissue sections (4 um) were deparaffinized, rehydrated, and subjected to antigen retrieval in citrate buffer (pH 6.0) using a pressure cooker (20 min). Endogenous peroxidase activity was blocked with 3% H₂O₂ (10 min), followed by protein blocking with 5% BSA (30 min). Primary antibodies (e.g., anti-PD-L1, 1:200; anti-CD8, 1:100; anti-CD31, 1:200; IBA1, 1:200; Servicebio, Wuhan, China) were incubated overnight at 4°C, then detected using HRP-conjugated secondary antibodies (1:500, 1 h; Servicebio, Wuhan, China) and DAB chromogen (5 min). Slides were counterstained with hematoxylin, dehydrated, and mounted. Staining was evaluated by two pathologists using light microscopy, with scoring based on intensity and distribution. 8.Statistical Analysis Clinical data were analyzed using log-rank tests and Kaplan-Meier survival analysis to compare overall survival (OS) and intracranial progression-free survival (iPFS). Factors influencing OS and iPFS were assessed using Cox proportional hazards models. A significance level of P < 0.05 was considered statistically significant. Data analysis was conducted using R version 4.3.0 (April 21, 2023). Experimental data, represented by three or more numerical values, underwent paired sample t-tests for pairwise comparisons and one-way analysis of variance (ANOVA) for comparisons involving three or more groups. All analyses were performed using GraphPad Prism 9.0 (GraphPad Prism Software, Inc.) or IBM SPSS Statistics 23 software. Statistical significance levels were denoted as follows: * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001. Experiments were repeated three times to ensure reliability of the findings. Results 1.PD-1/PD-L1 Inhibitors Combined with Chemotherapy and Anti-angiogenic Therapy Prolong Survival in Driver Gene-Negative Lung Adenocarcinoma Brain Metastases Patients This study enrolled 179 patients with driver gene-negative non-small cell lung cancer (NSCLC) brain metastases who received immune therapy. Among them, 129 (72.07%) were male and 50 (27.93%) were female, with a mean age of 61.75 years. A history of smoking was present in 105 patients (58.66%), and 141 patients (78.77%) had a performance status (PS) score ≤1. Lung adenocarcinoma was diagnosed in 105 patients (58.66%), squamous cell carcinoma in 61 patients (34.08%), and other types in 13 patients (7.26%). Treatment strategies included PD-1/PD-L1 inhibitor monotherapy (ICIs) in 35 patients (19.55%), PD-1/PD-L1 inhibitor plus anti-angiogenesis therapy (ICIs+anti-VEGF) in 53 patients (29.61%), PD-1/PD-L1 inhibitor plus chemotherapy (ICIs+chemotherapy) in 542 patients (30.17%), and PD-1/PD-L1 inhibitor plus chemotherapy and anti-angiogenesis therapy (ICIs+chemotherapy+anti-VEGF) in 37 patients (20.67%). Age, gender, smoking history, performance status (PS), PD-L1 expression, number of brain metastases (BM), and treatment strategy are included as prognostic factors for predicting the prognosis of lung cancer patients with brain metastases (BM). Table 1 summarizes the patients' clinical and pathological characteristics. Univariate analysis identified several factors associated with overall survival (OS), including sex (HR=0.62, 95% CI=0.41-0.93; P=0.020), PS score (HR=2.28, 95% CI=1.47-3.53; P=0.001), PD-L1 expression (HR=0.31, 95% CI=0.17-0.57; P=0.001), number of distant metastases (HR=2.10, 95% CI=1.24-3.56; P=0.006), active brain metastases (HR=1.91, 95% CI=1.29-2.83; P=0.001), number of brain metastases (HR=1.71, 95% CI=1.15-2.56; P=0.009), and brain metastasis diameter (HR=0.36, 95% CI=0.40-0.90; P=0.014). Factors with a univariate P-value < 0.05 were included in the multivariate analysis. Multivariate analysis confirmed that sex, PS score, PD-L1 expression, number of distant metastases, number of brain metastases, brain metastasis diameter, and treatment strategy were independent prognostic factors influencing OS (see Table 2). As of July 2022, the median follow-up time was 19.03 months. PD-1/PD-L1 inhibitor combination therapy (n=144) significantly prolonged median OS compared to PD-1/PD-L1 inhibitor monotherapy (n=35) (16.80 vs 9.30 months, P=0.011). The median intracranial progression-free survival (iPFS) was 12.00 vs 8.10 months, P=0.258 (Figure 1A, B). Specifically, PD-1/PD-L1 inhibitor plus chemotherapy and anti-angiogenesis therapy (n=37) showed median OS of 21.20 months compared to 16.00 months for PD-1/PD-L1 inhibitor plus chemotherapy (n=54), 16.53 months for PD-1/PD-L1 inhibitor plus anti-angiogenesis therapy (n=53), and 9.30 months for PD-1/PD-L1 inhibitor monotherapy (n=35), with a significant difference (P=0.013). Median iPFS was 15.20 vs 11.30 vs 9.03 vs 8.10 months, respectively (P=0.118) (Figure 1C, D). PD-L1 expression level emerged as an independent prognostic factor, with patients having ≥50% PD-L1 expression showing longer OS (24.7 months) and iPFS (18.20 months), while those with PD-L1 < 1% had poorer OS (9.05 months, P=0.001) and iPFS (7.20 months, P=0.046) (Figure 1E, F). Of the patients, 105 (58.66%) had died by the last follow-up, while 74 (41.34%) were still alive. These results underscore that patients with PD-L1 < 1% in lung cancer brain metastases have worse survival outcomes. Compared to PD-1/PD-L1 inhibitor monotherapy or immune-based combinations with chemotherapy or immune-based combinations with anti-angiogenic therapy, PD-1/PD-L1 inhibitors combined with chemotherapy and anti-angiogenic therapy demonstrate longer overall survival (OS) and intracranial progression-free survival (iPFS). 2. PD-1/PD-L1 Inhibitors combined Chemotherapy and Anti-Angiogenic Therapy Enhance Anti-Tumor Efficacy in a Murine Model of Driver Gene-Negative Lung Adenocarcinoma with Brain Metastases Based on the current treatment protocols, clinical outcomes remain uncertain, particularly for patients with low PD-L1 expression levels (<1%), who exhibit poorer responses. Our previous retrospective clinical analyses suggest that combining immunotherapy with chemotherapy and anti-angiogenic treatments may yield better survival outcomes. To further explore the efficacy and underlying mechanisms, we conducted the animal studies. We will use the LLC mouse lung adenocarcinoma cell line, which is EGFR mutation-negative, injecting luciferase-LLC cells (1x10^5 cells/ml, 5 µl total volume) into the striatum of C57 mice (coordinates: 1 mm anterior to bregma, 3 mm right, 3 mm deep) to establish the LLC-BM model. Tumor formation and PD-L1 expression in the LLC-BM model will be confirmed through pathological staining. Two weeks post-injection, intracranial tumors were detected in the mice, with immunohistochemical analysis (CD274) indicating PD-L1 expression below 1%, suggesting an immune-low-responsive state in the LLC-BM tumors (Figure 2A, B). Once the model was stably established, we proceeded with grouped drug interventions. In preliminary experiments, we observed a significant increase in mouse mortality after a single administration of a combination of three drugs (PD-1 inhibitor, 10 mg/kg bevacizumab, and 100 mg/kg pemetrexed) at usually doses, which we attributed to increased toxicity. Consequently, we reduced the doses of bevacizumab and/or pemetrexed for subsequent experiments. The groups were as follows: (1) control, (2) PD-1 inhibitor, (3) PD-1 inhibitor + pemetrexed (100 mg/kg), (4) PD-1 inhibitor + bevacizumab (2 mg/kg), (5) PD-1 inhibitor + bevacizumab (10 mg/kg), (6) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (100 mg/kg), and (7) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (50 mg/kg). Each group consisted of 8 mice, totaling 56 mice. Drug administration commenced post-tumor formation, with bi-weekly body weight monitoring and weekly fluorescence imaging for three weeks. Mice were euthanized upon >20% body weight loss or significant clinical symptoms, and brain tissue and serum samples were collected. In vivo fluorescence imaging revealed that group (vi) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (100 mg/kg) exhibited the lowest tumor fluorescence intensity and continuous tumor size reduction (Figures 2C-E). Survival analysis showed that the control group (1) had a median survival of 18 days, whereas group (4) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (100 mg/kg) had the longest median survival (31 days), followed by group (3) PD-1 inhibitor + pemetrexed (100 mg/kg) with 27 days (P < 0.0001) (Figure 2D). These results suggest that the combination of PD-1 inhibitor with chemotherapy and anti-angiogenic therapy provides the most effective tumor suppression in mice. 3. PD-1 inhibitors combined with chemotherapy and anti-angiogenic therapy enhance blood-brain barrier permeability and promote vascular normalization Previous animal experiments in our study indicated that triple therapy (PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy) achieved the best antitumor effects in LLC-BM mice. To explore potential therapeutic mechanisms, mice were divided into five groups: (1) control, (2) PD-1 inhibitor monotherapy, (3) PD-1 inhibitor + chemotherapy (Pemetrexed), (4) PD-1 inhibitor + anti-angiogenic therapy (bevacizumab), and (5) PD-1 inhibitor + chemotherapy (Pemetrexed) + anti-angiogenic therapy (bevacizumab). To assess blood-brain barrier permeability, mice were euthanized half an hour after intravenous injection of EB dye and FITC fluorescent dye, and fresh brain tissues were collected and frozen in liquid nitrogen. Frozen sections were then prepared and scanned using fluorescence microscopy. The left side shows gross images of corresponding mouse brain tissues, while the right-side displays results of EB and FITC staining. Significantly increased vascular permeability was observed in the group (5) (Figure 3A). These results suggest that PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy significantly enhances blood-brain barrier permeability in mice. Vascular coverage by pericytes is an important marker of vascular normalization. To evaluate vascular normalization post-treatment, we performed dual immunofluorescence staining to assess the expression levels of endothelial cells (CD31) and pericytes (NG2) in each group. Results showed a significant decrease in CD31 expression post-treatment, although differences between groups were not distinct. Conversely, pericyte coverage (NG2) significantly increased post-treatment, particularly in the PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy group (Figure 3B). These results suggest that PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy enhances blood-brain barrier permeability and pericyte coverage, facilitating vascular normalization. 4. PD-1 inhibitors combined with chemotherapy and anti-angiogenic therapy activate the immune microenvironment To explore whether the tumor microenvironment is activated after treatment, we conducted immunofluorescence and immunohistochemistry assays for the macrophage (IBA-1), PD-L1, CD31 and CD8. Immunohistochemistry results indicated increased CD8 infiltration, decreased macrophage (IBA-1) infiltration, elevated PD-L1 expression, and no statistically significant change in blood vessel numbers. However, there was a trend towards reduced abnormal vessels and a shift towards linear, less tortuous vessel morphology, which was most pronounced in the PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy group (Figure 4A). Immunofluorescence staining results showed a gradual decrease in M2-type macrophages (Arg-1) and an increase in M1-type macrophages (iNOS) post-treatment, with this effect particularly significant in the triple therapy group (Figure 4B). These findings collectively suggest that PD-1 inhibitors combined with chemotherapy and anti-angiogenic therapy promote vascular normalization, enhance CD8-positive T cell numbers and PD-L1 expression, reduce macrophage infiltration, and shift the immunosuppressive microenvironment towards an activated state. These results suggest that PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy activated the immune microenvironment. Discussion This study represents the first clinical and in vivo experimental comparison of immunotherapy combinations for the treatment of driver gene-negative lung adenocarcinoma brain metastases. Our findings suggest that the combination of PD-1/PD-L1 inhibitors with chemotherapy and anti-angiogenic therapy may constitute the optimal treatment regimen for these metastases. PD-1/PD-L1 inhibition combined with chemotherapy and anti-angiogenic therapy enhances the expression of CD8-positive T cells and PD-L1, while suppressing infiltration of M2 macrophages, thereby reversing the immunosuppressive microenvironment to an activated state. Moreover, this combination enhances blood-brain barrier permeability, and increases pericyte coverage, promoting vascular normalization, thus exerting antitumor effects. Combination therapy mitigates the risk of drug resistance to monotherapy and enhances treatment efficacy. However, conventional cytotoxic agents exhibit limited utility in managing brain metastases due to poor blood-brain barrier (BBB) penetration and efflux pump activity. Although the BBB is often compromised in brain metastases, the distribution of chemotherapeutic drugs remains partially restricted. Anti-angiogenic co-treatment increases BBB permeability, boosting chemotherapeutic delivery and tumor cytotoxicity. The disorganized nature of tumor angiogenesis results in immature, malformed vessels. Since anticancer drugs rely on blood flow for delivery, this vascular dysfunction further hinders drug distribution. An emerging question arises: Rather than inhibiting angiogenesis outright, could promoting vascular maturation improve therapeutic delivery? Vascular Normalization: A Paradigm Shift in Antiangiogenic Therapy Proposed by Rakesh Jain(14), the vascular normalization theory offers a transformative perspective—modulating (rather than ablating) tumor vasculature to restore structural and functional integrity. This approach: Corrects immunosuppressive TME. Enhances intra-tumoral drug penetration (particularly in hypoxic cores), Synergizes with chemotherapy, TKIs, and ICIs by improving perfusion and immune infiltration. Immunomodulatory Effects of Antiangiogenic Agents Targeted therapies like regorafenib demonstrate TME-modulating effects; in hepatocellular carcinoma models, they elevate intratumoral CD8+ T-cell infiltration(15). Anti-angiogenic TKIs regulate antitumor immunity through both vascular-dependent and -independent mechanisms, facilitating immune cell recruitment and tumor recognition, thereby potentiating combination therapies(16). These effects underpin their synergy with immune checkpoint inhibitors (ICIs) in reshaping the TME(17). Our study demonstrates that the triple combination of immunotherapy, chemotherapy, and anti-angiogenic therapy synergistically enhances CD8+ T-cell infiltration, upregulates PD-L1 expression, promotes vascular normalization, and reactivates the immunosuppressive tumor micro-environment. This study integrates clinical datasets and animal models to evaluate the efficacy and mechanisms of immune-combination therapy in driver mutation-negative lung adenocarcinoma (LUAD) with brain metastases, providing actionable insights for clinical translation. Limitations: 1.Retrospective Design: The clinical analysis was limited to a single-center, retrospective cohort, which may introduce selection bias. 2. Model Constraints: The LLC-BM syngeneic model (a localized brain lesion model) is suitable for therapeutic response assessment but does not recapitulate the full metastatic cascade from primary lung tumors to brain metastases. Conclusion This study is the first clinical and in vivo experimental comparison of immunotherapy combinations for the treatment of driver gene-negative lung adenocarcinoma brain metastases. It has important guiding significance for the clinical treatment of brain metastases from lung cancer. We observed PD-1/PD-L1 blockade combined with chemotherapy and anti-angiogenesis therapy activates the immune microenvironment, improve hypoxia, enhance blood-brain barrier permeability, and promote vascular normalization. PD-1/PD-L1 blockade combined with chemotherapy and anti-angiogenesis therapy appears to be an optimal strategy for driver gene-negative lung adenocarcinoma brain metastases. Declarations • Acknowledgements We thank Xingpeng Qiu for conducting and analyzing proteomics. • Funding This study was supported by the National Natural Science Foundation of China [grant numbers 82260628, 82060577, to AW L], the National Science Foundation of Jiangxi Province [grant numbers 20232ACB206042, to AW L; Wu Jieping Medical Foundation [grant numbers 320.6750.2023-16-8, to AW L]. • Author information Authors and Affiliations Department of Oncology, The second affiliated hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China Yali Yi, Zhiqin Lu, Wenjie Xu, Yuxi Luo, Fujuan Zeng, Zhimin Zeng, Le Xiong, Jing Cai &Anwen Liu Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Ministry of Education, (The Second Affiliated Hospital of Nanchang University) Jiangxi Medical College, Nanchang University, Nanchang 330031, China Anwen Liu & Jing Cai School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi Province, 330006, China Daya Luo • Authorship Anwen Liu, Long Huang and Zhimin Zeng contributed to the conception and design of the study. Yali Yi drafting the article or revising it critically for important intellectual content. Daya Luo and Jing Cai and Le Xiong participated in the implementation and discussion of experiments. Yali Yi, Wenjie Xu and Yuxi Luo performed experiments. Fujuan Zeng and Zhiqin Lu performed bioinformatics analysis. All authors approved the final version of the manuscript. • Corresponding author Correspondence to Jing Cai and Anwen Liu. Ethics declarations • Ethical Approval The experiment was approved by the Ethics Committee of Second Affiliated Hospital of Nanchang University Medical Research and the Nanchang University Approval for Research Involving Animals (20221031140). • Consent for publication Not applicable. • Availability of supporting data The data used to support the finding of this study are available from the corresponding author upon request. • Competing interests The authors declare that they have no competing interests. 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Estrogen Promotes Resistance to Bevacizumab in Murine Models of NSCLC. J Thorac Oncol. 2021;16(12):2051-64. Huang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73(10):2943-8. Shigeta K, Matsui A, Kikuchi H, Klein S, Mamessier E, Chen IX, et al. Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. J Immunother Cancer. 2020;8(2). Yi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer. 2019;18(1):60. Tang L, Chen Z, Yang J, Li Q, Wang S, Mo T, et al. Single-cell and Bulk RNA-Seq reveal angiogenic heterogeneity and microenvironmental features to evaluate prognosis and therapeutic response in lung adenocarcinoma. Front Immunol. 2024;15:1352893. Tables Table 1. Characteristic of BM Patients Variables Total (n = 179) Mean ± SD or n (%) ICI alone (n = 35) Mean ± SD or n (%) ICI+anti-VEGF (n = 53) Mean ± SD or n (%) ICI+Chemo (n = 54) Mean ± SD or n (%) ICI+Chemo +anti-VEGF (n = 37) Mean ± SD or n (%) P Age 61.75 ± 8.48 61.66 ± 8.62 62.74 ± 9.58 61.61 ± 8.48 60.62 ± 6.65 0.711 Age 0.368 <65 99 (55.31) 19 (54.29) 26 (49.06) 29 (53.70) 25 (67.57) ≥65 80 (44.69) 16 (45.71) 27 (50.94) 25 (46.30) 12 (32.43) Sex 0.008 female 50 (27.93) 13 (37.14) 14 (26.42) 7 (12.96) 16 (43.24) male 129 (72.07) 22 (62.86) 39 (73.58) 47 (87.04) 21 (56.76) Smoke 0.193 Former or current 105 (58.66) 21 (60.00) 34 (64.15) 34 (62.96) 16 (43.24) Non-smoker 74 (41.34) 14 (40.00) 19 (35.85) 20 (37.04) 21 (56.76) PS score 0.485 1 38 (21.23) 7 (20.00) 13 (24.53) 8 (14.81) 10 (27.03) Pathological 0.001* adenocarcinoma 105 (58.66) 12 (34.29) 39 (73.58) 32 (59.26) 22 (59.46) others 13 (7.26) 2 (5.71) 5 (9.43) 6 (11.11) 0 (0.00) Squamous-carcinoma 61 (34.08) 21 (60.00) 9 (16.98) 16 (29.63) 15 (40.54) PD-L1 <.001 =50% 35 (19.55) 5 (14.29) 8 (15.09) 6 (11.11) 16 (43.24) 1-49% 47 (26.26) 9 (25.71) 11 (20.75) 13 (24.07) 14 (37.84) unknow 43 (24.02) 5 (14.29) 15 (28.30) 16 (29.63) 7 (18.92) Systematic metastasis sites 0.763 3 21 (11.73) 3 (8.57) 7 (13.21) 8 (14.81) 3 (8.11) Initial diagnosis BM <.001 no 66 (36.87) 14 (40.00) 30 (56.60) 9 (16.67) 13 (35.14) yes 113 (63.13) 21 (60.00) 23 (43.40) 45 (83.33) 24 (64.86) active BM 0.061 no 89 (49.72) 22 (62.86) 20 (37.74) 31 (57.41) 16 (43.24) yes 90 (50.28) 13 (37.14) 33 (62.26) 23 (42.59) 21 (56.76) BM num 0.382 =3 59 (33.33) 12 (34.29) 19 (35.85) 20 (38.46) 8 (21.62) BM size <.001 =1cm 134 (74.86) 20 (57.14) 34 (64.15) 49 (90.74) 31 (83.78) RT 0.070 no 87 (48.60) 23 (65.71) 24 (45.28) 27 (50.00) 13 (35.14) yes 92 (51.40) 12 (34.29) 29 (54.72) 27 (50.00) 24 (64.86) Combine Therapy <.001 no 35 (19.55) 35 (100.00) 0 (0.00) 0 (0.00) 0 (0.00) yes 144 (80.45) 0 (0.00) 53 (100.00) 54 (100.00) 37 (100.00) Bevacizumab <.001 no 89 (49.72) 35 (100.00) 0 (0.00) 54 (100.00) 0 (0.00) yes 90 (50.28) 0 (0.00) 53 (100.00) 0 (0.00) 37 (100.00) ICI line <.001* 1 81 (45.25) 7 (20.00) 14 (26.42) 45 (83.33) 15 (40.54) 2 57 (31.84) 14 (40.00) 23 (43.40) 8 (14.81) 12 (32.43) 3 37 (20.67) 14 (40.00) 12 (22.64) 1 (1.85) 10 (27.03) 4 4 (2.23) 0 (0.00) 4 (7.55) 0 (0.00) 0 (0.00) iPD 0.499 0 66 (36.87) 11 (31.43) 17 (32.08) 21 (38.89) 17 (45.95) 1 113 (63.13) 24 (68.57) 36 (67.92) 33 (61.11) 20 (54.05) Death 0.071 0 74 (41.34) 10 (28.57) 18 (33.96) 26 (48.15) 20 (54.05) 1 105 (58.66) 25 (71.43) 35 (66.04) 28 (51.85) 17 (45.95) ICIs, immune checkpoint inhibitors, ICIs+chemo, ICIs+chemotherapy, BM num, number of brain metastasis, BM size, Diameter of brain metastases. Table 2. Univariate and Multivariate Analysis Variables Univariate Multivariate β P HR (95%CI) β P HR (95%CI) Age 0.01 0.307 1.01 (0.99 ~ 1.04) Age =65 0.31 0.111 1.37 (0.93 ~ 2.01) Sex female 1.00 (Reference) 1.00 (Reference) male -0.48 0.020 0.62 (0.41 ~ 0.93) -0.54 0.020 0.58 (0.37 ~ 0.92) Smoke Former or current 1.00 (Reference) Non-smoker -0.20 0.313 0.82 (0.55 ~ 1.21) PS 1 0.82 <.001 2.28 (1.47 ~ 3.53) 0.83 <.001 2.30 (1.44 ~ 3.65) Pathological adenocarcinoma 1.00 (Reference) others 0.49 0.150 1.64 (0.84 ~ 3.20) Squamous carcinoma -0.15 0.493 0.86 (0.56 ~ 1.32) PD-L1 =50% -1.16 <.001 0.31 (0.17 ~ 0.57) -0.85 0.012 0.43 (0.22 ~ 0.83) 1-49% -0.64 0.010 0.53 (0.32 ~ 0.86) -0.40 0.173 0.67 (0.37 ~ 1.19) unknow -0.96 <.001 0.38 (0.22 ~ 0.65) -0.76 0.009 0.47 (0.26 ~ 0.83) Mx1 3 0.74 0.006 2.10 (1.24 ~ 3.56) 0.69 0.019 1.99 (1.12 ~ 3.54) Initial diagnosis BM no 1.00 (Reference) yes 0.02 0.913 1.02 (0.69 ~ 1.51) sBM no 1.00 (Reference) 1.00 (Reference) yes 0.65 0.001 1.91 (1.29 ~ 2.83) 0.57 0.014 1.77 (1.12 ~ 2.80) BM num =3 0.54 0.009 1.71 (1.15 ~ 2.56) 0.46 0.033 1.58 (1.04 ~ 2.42) BM size =1cm -0.51 0.014 0.60 (0.40 ~ 0.90) -0.08 0.750 0.92 (0.55 ~ 1.54) ICI RT 0 1.00 (Reference) 1 0.11 0.709 1.11 (0.64 ~ 1.93) 2 -0.30 0.213 0.74 (0.46 ~ 1.19) 3 -0.13 0.699 0.88 (0.44 ~ 1.72) ICI line 1 1.00 (Reference) 1.00 (Reference) 2 0.21 0.387 1.23 (0.77 ~ 1.96) 0.20 0.495 1.22 (0.69 ~ 2.16) 3 0.72 0.004 2.06 (1.26 ~ 3.37) 0.51 0.128 1.66 (0.86 ~ 3.18) 4 2.55 <.001 12.76 (4.38 ~ 37.24) 2.23 <.001 9.31 (2.60 ~ 33.28) Treatment strategy ICIs alone 1.00 (Reference) 1.00 (Reference) ICIs+chemotherapy -0.50 0.075 0.61 (0.35 ~ 1.05) -0.35 0.338 0.71 (0.35 ~ 1.44) ICIs+anti-VEGF -0.37 0.162 0.69 (0.41 ~ 1.16) -0.67 0.033 0.51 (0.28 ~ 0.95) ICIs+chemotherapy+anti-VEGF -1.01 0.001 0.36 (0.19 ~ 0.68) -1.14 0.002 0.32 (0.15 ~ 0.66) β：Standardization coefficient；HR: Hazard Ratio；CI: Confidence Interval；Mxs, systematic metastasis sites; sBM, active brain metastasis; BM num, number of brain metastasis; BM size, Diameter of brain metastasis Additional Declarations No competing interests reported. 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B. The iPFS of NSCLC patients with BM received PD-1 inhibitors. The blue line means ICI monotherapys. The red line means ICI combined anti-VEGF therapys. The green line means ICI combined chemotherapy. The peacock blue line means ICI combined chemotherapy and anti-VEGF therapys. OS，overall survival. iPFS，intracranial progression-free survival.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6594933/v1/c12a3ec62d31611c0ab8f8d8.png"},{"id":82604795,"identity":"ad0f0680-bae4-4933-b3db-905db2127235","added_by":"auto","created_at":"2025-05-13 09:58:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":5321596,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnti-tumor effect and survival analysis of PD-1 inhibitor combination therapy in LLC-BM\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. the H\u0026amp;E staining of LLC-BM model. B. the PD-L1 expression level of LLC-BM model. C. (1) control, (2) PD-1 inhibitor, (3) PD-1 inhibitor + pemetrexed (100 mg/kg), (4) PD-1 inhibitor + bevacizumab (2 mg/kg), (5) PD-1 inhibitor + bevacizumab (10 mg/kg), (6) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (100 mg/kg), and (7) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (50 mg/kg). D. Statistical results of survival time of mice in each group. E. Statistical results of fluorescence intensity in vivo imaging of mice in each group. (n=8/group, ****, p\u0026lt;0.0001). BM, brain metastasis.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6594933/v1/7fa8afeff4df248af5d97795.png"},{"id":82607338,"identity":"67ed2ddc-34a8-4537-aca1-7f4374b08357","added_by":"auto","created_at":"2025-05-13 10:14:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":4190984,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe staining results of blood-brain barrier permeability in LLC-BM model\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Gross brain tissue images, EB staining and FITC staining results in five groups in the LLC-BM model: control group, PD-1 inhibitor alone group, PD-1 inhibitor + chemotherapy (Pemetrexed) group, PD-1 inhibitor + anti-angiogenesis (10mg/kg bevacizumab) group, and PD-1 inhibitor + chemotherapy (Pemetrexed)+ anti-angiogenesis (2mg/kg bevacizumab) group. The scale bar is 100μm. And Statistical results of EB staining and FITC staining. B. Immunofluorescence staining results of CD31 and NG2 of vascular endothelial cells in brain tissues in five groups. The scale bar is 50μm. and Statistical results of CD31 staining, NG2 staining statistics. ** P\u0026lt;0.01. **** P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6594933/v1/a3cf18e527708e18914c9b0e.png"},{"id":82604794,"identity":"db175202-8bc9-40c8-b5de-1b3904d995f1","added_by":"auto","created_at":"2025-05-13 09:58:35","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":6071116,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in tumor microenvironment in mice in each group after intervention in LLC-BM model\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. In the LLC-BM model, immunohistochemical and statistical results of brain tissue in five groups: 1. control group, 2. PD-1 inhibitor alone group, 3. PD-1 inhibitor + chemotherapy (Pemetrexed) group, 4. PD-1 inhibitor + anti-angiogenesis (10mg/kg bevacizumab) group, and 5. PD-1 inhibitor + chemotherapy (Pemetrexed)+ anti-angiogenesis (2mg/kg bevacizumab) group. The scale bar is 50μm. * P\u0026lt;0.05, ns is not statistically significant. B. Statistical chart of each group of indicators including IBA-1,PD-L1,CD31, CD8, Hypoxia and M1/M2. C. Immunofluorescence staining of each group. Blue is DAPI, representing the cell nucleus, and green is HIF-α, representing hypoxia. The scale bar is 50μm. D. Immunofluorescence staining results of M1 and M2 type macrophages in brain tissue. Red is iNOS, representing M1 type macrophages, and green is Arg-1, representing M2 type macrophages. The scale bar is 100μm. ns means no significant, *P\u0026lt;0.05, ***P\u0026lt;0.001, **** P\u0026lt;0.0001.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6594933/v1/a236eabab6dc86463cb3fd83.png"},{"id":83985268,"identity":"f020f59f-b7b0-422d-9e48-c95d7780fea5","added_by":"auto","created_at":"2025-06-05 11:02:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":17537383,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6594933/v1/b2cb99f5-69ff-40a2-9502-5326c9f4ba7a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Breaking Down Combination Strategies: PD-1/PD-L1 Inhibitors with Chemotherapy, Anti- Angiogenesis, or Both in Driver Gene-Negative NSCLC Clinical Outcomes and Mechanistic Insights","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBrain metastasis (BM) from lung adenocarcinoma represents a clinical challenge and a focus of intense research. Approximately 10% to 20% of advanced lung cancer patients present with BM at initial diagnosis, and 20% to 40% develop BM during the course of their disease(1). BM significantly impacts cognitive function, survival and quality of life, with a median survival of only 1-2 months. With extended survival in lung cancer, the incidence of BM is steadily increasing(2). The advent of next-generation targeted therapies has notably prolonged survival in driver gene-positive non-small cell lung cancer (NSCLC) patients with BM(3). However, prognosis remains poorer for driver gene-negative lung adenocarcinoma BM, and traditional treatments often fall short of clinical needs. Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone in first-line therapy for metastatic NSCLC, offering new hope in treatment. Prospective clinical studies have shown benefits of ICIs in BM patients, though they constitute a limited proportion (9%-17.5%) of trial participants. PD-L1 positivity correlates with greater benefit from immune therapy. However, response rates to ICIs as monotherapy generally remain below 30% in low PD-L1 expressions(4-6). BM lesions often exhibit low PD-1/PD-L1 expression and limited infiltration of tumor infiltrating lymphocytes (TILs)(7, 8), contributing to suboptimal responses to immune monotherapy. Thus, there is an urgent need to enhance the efficacy of ICIs and broaden the population benefiting from them.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe phase III clinical trial, Impower150, first reported the combination of immune therapy with anti-angiogenic targeting, suggesting that the quadruple regimen of atezolizumab plus bevacizumab plus platinum-based doublet has superior efficacy compared to the triplet regimen(9). Recent exploratory analyses within the BM subgroup of Impower150 indicated that the ABCP regimen (atezolizumab, bevacizumab, carboplatin, paclitaxel) delayed time to new BM development (HR=0.68) compared to BCP (HR=0.68) and ACP (HR=1.55)(9). Thus, multimodal therapy holds promise for achieving durable metastatic control and survival. By targeting key immune checkpoints PD-1/PD-L1 and combining chemotherapy with anti-angiogenic therapy, it is theoretically possible to enhance T cell cytotoxicity. Further preclinical and clinical trials are urgently needed to provide definitive evidence and explore optimal immune-based combination therapies that effectively inhibit intracranial lesion progression. This study aims to investigate the efficacy and mechanisms of PD-1 inhibitor combined with chemotherapy and anti-angiogenesis therapy, providing a theoretical basis and potential intervention strategies for clinical management of driver gene-negative lung adenocarcinoma brain metastases.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e1.\u0026nbsp; \u0026nbsp;\u0026nbsp;Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRetrospective collection was conducted at the Second Affiliated Hospital of Nanchang University from May 2020 to July 2022, focusing on patients with advanced lung cancer and brain metastases treated with PD-1/PD-L1 inhibitors. Clinical data encompassed age, gender, smoking history, PS score, pathological type, PD-L1 expression level, distant metastases, initial diagnosis with concurrent brain metastasis, active brain metastases, number and diameter of brain metastases, history of radiotherapy, lines of immunotherapy, and combined immunotherapy regimens. Tumor response was assessed using the modified RECIST 1.1 for immune-based therapeutics (iRECIST). Overall survival (OS) was the primary endpoint, with immune-related progression-free survival (iPFS) as the secondary endpoint.\u003c/p\u003e\n\u003cp\u003eInclusion criteria: (1) Pathologically confirmed advanced lung cancer at our center; (2) Age between 18 and 80 years; (3) Driver gene mutations tested negative; (4) MRI or enhanced CT used for quantifiable brain lesions identification.\u003c/p\u003e\n\u003cp\u003eExclusion criteria: (1) History of other cancers; (2) Presence of leptomeningeal metastases at BM diagnosis; (3) Brain metastasis resection; (4) Loss to follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2.\u0026nbsp; \u0026nbsp;\u0026nbsp;Cell culture\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mouse-derived lung adenocarcinoma cell line LLC cells (EGFR wild-type) and RAW246.1 mouse macrophages were purchased from Pro-cell (Wuhan, China) and cultured in high-glucose DMEM medium supplemented with 10% fetal bovine serum and 1% antibiotic solution. Cultures were maintained in a humidified incubator at 5% CO2. LLC cells were stably transfected with lentiviral vector GV260 (Genomeditech, Shanghai, China) carrying a luciferase reporter gene (-luc).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.\u0026nbsp; \u0026nbsp;\u0026nbsp;Driver gene-negative lung adenocarcinoma brain metastases animal model (LLC-BM)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe animals used in this study were C57BL/6J male mice, aged 6-8 weeks and weighing 19-21g, purchased from Jie Cui Medicine Co., Ltd. (Nanjing, China), and housed at the Experimental Animal Center of Nanchang University under a 12-hour light/dark cycle at a temperature of 25°C with ample food and water. All experimental procedures were approved by the Institutional Animal Ethics Committee of Nanchang University (Approval No. NCULAE-20221031140).\u003c/p\u003e\n\u003cp\u003eLLC-luc tumor cells were prepared for injection after trypsin digestion and washing with PBS. Cell concentration in PBS for each injection was adjusted to 1×10^6 cells using Trypan Blue staining for live cell counting. Mice were anesthetized with 4% isoflurane inhalation. Under sterile conditions, the skin of the mice was disinfected with ethanol, and a skin incision (1 cm) was made to expose the skull for positioning at the bregma. EGFR wild-type lung cancer cells (LLC) labeled with luciferase were injected using a stereotactic apparatus (coordinates: 1 mm anterior and 3 mm right lateral to the bregma, depth 3 mm)(10), with a total volume of 5 µl of Luciferase-LLC (1x10^6 cells/ml), to establish a driver gene-negative NSCLC brain metastasis model (LLC-BM), evaluated for tumor growth via live imaging and histological staining.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4.\u0026nbsp; \u0026nbsp;\u0026nbsp;LLC-BM treatments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAfter establishing the LLC-BM model, on day 7 post-modeling, tumor formation was confirmed using in vivo live imaging, and mice were randomized into the following treatment groups: (1) Control group; (2) Anti-PD-1 monotherapy group; (3) Anti-PD-1 combined with chemotherapy group; (4) Anti-PD-1 combined with anti-angiogenic therapy group; (5) Anti-PD-1 + chemotherapy + anti-angiogenic therapy group, with 8 mice per group and a total of 40 mice. The dosage of anti-PD-1 inhibitor was 10 mg/kg, administered once weekly(11). The dosage of chemotherapy drug (pemetrexed) was 100 mg/kg, administered once weekly(12). The dosages of anti-angiogenic drugs (bevacizumab) were 10 mg/kg and 2 mg/kg, administered twice weekly(13). All drugs were administered via intraperitoneal injection for a total of 3 weeks. Live imaging was performed weekly during the treatment period, and mouse body weight was monitored twice weekly. Experimental endpoints included a reduction in body weight exceeding 20% or significant clinical symptoms, at which point mice were euthanized, and tissues were collected for formalin fixation or frozen storage.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e5.\u0026nbsp; \u0026nbsp;\u0026nbsp;EB staining and FITC staining\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEvans blue (EB) staining combined with confocal laser scanning microscopy was used to observe the fluorescence intensity of Evans blue dye in brain slices, enabling detection of changes in vascular morphology at the blood-brain barrier. Quantitative analysis of the infiltrated Evans blue dye content in brain tissue was performed. FITC (Fluorescein Isothiocyanate) labeling was employed for microcirculation and cell permeability studies, detected via fluorescence microscopy. Evans blue dye (Sigma E2129-10G) at 647 nm (red light) was injected intravenously at 2% EB (diluted in 4 ml/kg saline), circulated for 50 minutes. FITC staining (Sigma FD2000S-100MG) at wavelengths 494-520 nm (green light) was administered after 50 minutes of EB circulation, with 6 mg/ml FITC (diluted in 4 ml/kg saline), circulated for an additional 10 minutes before euthanizing the mice by decapitation and promptly freezing the brain tissue in liquid nitrogen for 5 minutes, followed by storage at -80°C. Brain tissue was then placed in a -20°C cryostat for at least 1 hour for temperature equilibration, embedded in tissue-Tek OCT compound (frozen section embedding medium), and coronally sliced (from bregma -1 mm to +1 mm) into 10 μm sections. Sections were mounted on slides and placed in a light-shielded box to prevent fluorescence quenching. Remaining brain tissue was stored at -80°C. Slides were air-dried at room temperature before fluorescence imaging and scanning.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e6. Immunofluorescence Staining\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFresh-frozen or formalin-fixed tissue sections (5-7um) were fixed in 4%PFA (15min), permeabilized with 0.1% Tween-20/PBS (5 min), and blocked with 5% BSA/10% normal serum (1 h). Primary antibodies (e.g., anti-CD31, 1:200; anti-NG2, 1:100, Servicebio, Wuhan, China) were applied overnight at 4°C, followed by species-matched fluorophore-conjugated secondary antibodies (1:200, 1 h, dark, Servicebio, Wuhan, China). Nuclei were counterstained with DAPI (1 ug/mL, 5 min), and slides were mounted with antifade medium. Imaging was performed using a confocal microscope, with fluorescence intensity quantified via ImageJ. Controls included isotype-matched IgG and unstained samples.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e7. Immunohistochemistry (IHC) Staining\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFormalin-fixed, paraffin-embedded tissue sections (4 um) were deparaffinized, rehydrated, and subjected to antigen retrieval in citrate buffer (pH 6.0) using a pressure cooker (20 min). Endogenous peroxidase activity was blocked with 3% H₂O₂ (10 min), followed by protein blocking with 5% BSA (30 min). Primary antibodies (e.g., anti-PD-L1, 1:200; anti-CD8, 1:100; anti-CD31, 1:200; IBA1, 1:200; Servicebio, Wuhan, China) were incubated overnight at 4°C, then detected using HRP-conjugated secondary antibodies (1:500, 1 h; Servicebio, Wuhan, China) and DAB chromogen (5 min). Slides were counterstained with hematoxylin, dehydrated, and mounted. Staining was evaluated by two pathologists using light microscopy, with scoring based on intensity and distribution.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e8.Statistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical data were analyzed using log-rank tests and Kaplan-Meier survival analysis to compare overall survival (OS) and intracranial progression-free survival (iPFS). Factors influencing OS and iPFS were assessed using Cox proportional hazards models. A significance level of P \u0026lt; 0.05 was considered statistically significant. Data analysis was conducted using R version 4.3.0 (April 21, 2023). Experimental data, represented by three or more numerical values, underwent paired sample t-tests for pairwise comparisons and one-way analysis of variance (ANOVA) for comparisons involving three or more groups. All analyses were performed using GraphPad Prism 9.0 (GraphPad Prism Software, Inc.) or IBM SPSS Statistics 23 software. Statistical significance levels were denoted as follows: * P \u0026lt; 0.05, ** P \u0026lt; 0.01, *** P \u0026lt; 0.001, **** P \u0026lt; 0.0001. Experiments were repeated three times to ensure reliability of the findings.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e1.PD-1/PD-L1 Inhibitors Combined with Chemotherapy and Anti-angiogenic Therapy Prolong Survival in Driver Gene-Negative Lung Adenocarcinoma Brain Metastases Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study enrolled 179 patients with driver gene-negative non-small cell lung cancer (NSCLC) brain metastases who received immune therapy. Among them, 129 (72.07%) were male and 50 (27.93%) were female, with a mean age of 61.75 years. A history of smoking was present in 105 patients (58.66%), and 141 patients (78.77%) had a performance status (PS) score ≤1. Lung adenocarcinoma was diagnosed in 105 patients (58.66%), squamous cell carcinoma in 61 patients (34.08%), and other types in 13 patients (7.26%). Treatment strategies included PD-1/PD-L1 inhibitor monotherapy (ICIs) in 35 patients (19.55%), PD-1/PD-L1 inhibitor plus anti-angiogenesis therapy (ICIs+anti-VEGF) in 53 patients (29.61%), PD-1/PD-L1 inhibitor plus chemotherapy (ICIs+chemotherapy) in 542 patients (30.17%), and PD-1/PD-L1 inhibitor plus chemotherapy and anti-angiogenesis therapy (ICIs+chemotherapy+anti-VEGF) in 37 patients (20.67%). Age, gender, smoking history, performance status (PS), PD-L1 expression, number of brain metastases (BM), and treatment strategy are included as prognostic factors for predicting the prognosis of lung cancer patients with brain metastases (BM). Table 1 summarizes the patients' clinical and pathological characteristics.\u003c/p\u003e\n\u003cp\u003eUnivariate analysis identified several factors associated with overall survival (OS), including sex (HR=0.62, 95% CI=0.41-0.93; P=0.020), PS score (HR=2.28, 95% CI=1.47-3.53; P=0.001), PD-L1 expression (HR=0.31, 95% CI=0.17-0.57; P=0.001), number of distant metastases (HR=2.10, 95% CI=1.24-3.56; P=0.006), active brain metastases (HR=1.91, 95% CI=1.29-2.83; P=0.001), number of brain metastases (HR=1.71, 95% CI=1.15-2.56; P=0.009), and brain metastasis diameter (HR=0.36, 95% CI=0.40-0.90; P=0.014). Factors with a univariate P-value \u0026lt; 0.05 were included in the multivariate analysis. Multivariate analysis confirmed that sex, PS score, PD-L1 expression, number of distant metastases, number of brain metastases, brain metastasis diameter, and treatment strategy were independent prognostic factors influencing OS (see Table 2).\u003c/p\u003e\n\u003cp\u003eAs of July 2022, the median follow-up time was 19.03 months. PD-1/PD-L1 inhibitor combination therapy (n=144) significantly prolonged median OS compared to PD-1/PD-L1 inhibitor monotherapy (n=35) (16.80 vs 9.30 months, P=0.011). The median intracranial progression-free survival (iPFS) was 12.00 vs 8.10 months, P=0.258 (Figure 1A, B). Specifically, PD-1/PD-L1 inhibitor plus chemotherapy and anti-angiogenesis therapy (n=37) showed median OS of 21.20 months compared to 16.00 months for PD-1/PD-L1 inhibitor plus chemotherapy (n=54), 16.53 months for PD-1/PD-L1 inhibitor plus anti-angiogenesis therapy (n=53), and 9.30 months for PD-1/PD-L1 inhibitor monotherapy (n=35), with a significant difference (P=0.013). Median iPFS was 15.20 vs 11.30 vs 9.03 vs 8.10 months, respectively (P=0.118) (Figure 1C, D). PD-L1 expression level emerged as an independent prognostic factor, with patients having ≥50% PD-L1 expression showing longer OS (24.7 months) and iPFS (18.20 months), while those with PD-L1 \u0026lt; 1% had poorer OS (9.05 months, P=0.001) and iPFS (7.20 months, P=0.046) (Figure 1E, F). Of the patients, 105 (58.66%) had died by the last follow-up, while 74 (41.34%) were still alive. These results underscore that patients with PD-L1 \u0026lt; 1% in lung cancer brain metastases have worse survival outcomes. Compared to PD-1/PD-L1 inhibitor monotherapy or immune-based combinations with chemotherapy or immune-based combinations with anti-angiogenic therapy, PD-1/PD-L1 inhibitors combined with chemotherapy and anti-angiogenic therapy demonstrate longer overall survival (OS) and intracranial progression-free survival (iPFS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e2. PD-1/PD-L1 Inhibitors combined Chemotherapy and Anti-Angiogenic Therapy Enhance Anti-Tumor Efficacy in a Murine Model of Driver Gene-Negative Lung Adenocarcinoma with Brain Metastases\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the current treatment protocols, clinical outcomes remain uncertain, particularly for patients with low PD-L1 expression levels (\u0026lt;1%), who exhibit poorer responses. Our previous retrospective clinical analyses suggest that combining immunotherapy with chemotherapy and anti-angiogenic treatments may yield better survival outcomes. To further explore the efficacy and underlying mechanisms, we conducted the animal studies. We will use the LLC mouse lung adenocarcinoma cell line, which is EGFR mutation-negative, injecting luciferase-LLC cells (1x10^5 cells/ml, 5 µl total volume) into the striatum of C57 mice (coordinates: 1 mm anterior to bregma, 3 mm right, 3 mm deep) to establish the LLC-BM model. Tumor formation and PD-L1 expression in the LLC-BM model will be confirmed through pathological staining. Two weeks post-injection, intracranial tumors were detected in the mice, with immunohistochemical analysis (CD274) indicating PD-L1 expression below 1%, suggesting an immune-low-responsive state in the LLC-BM tumors (Figure 2A, B). Once the model was stably established, we proceeded with grouped drug interventions. In preliminary experiments, we observed a significant increase in mouse mortality after a single administration of a combination of three drugs (PD-1 inhibitor, 10 mg/kg bevacizumab, and 100 mg/kg pemetrexed) at usually doses, which we attributed to increased toxicity. Consequently, we reduced the doses of bevacizumab and/or pemetrexed for subsequent experiments. The groups were as follows: (1) control, (2) PD-1 inhibitor, (3) PD-1 inhibitor + pemetrexed (100 mg/kg), (4) PD-1 inhibitor + bevacizumab (2 mg/kg), (5) PD-1 inhibitor + bevacizumab (10 mg/kg), (6) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (100 mg/kg), and (7) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (50 mg/kg). Each group consisted of 8 mice, totaling 56 mice. Drug administration commenced post-tumor formation, with bi-weekly body weight monitoring and weekly fluorescence imaging for three weeks. Mice were euthanized upon \u0026gt;20% body weight loss or significant clinical symptoms, and brain tissue and serum samples were collected.\u003c/p\u003e\n\u003cp\u003eIn \u003cem\u003evivo\u003c/em\u003e fluorescence imaging revealed that group (vi) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (100 mg/kg) exhibited the lowest tumor fluorescence intensity and continuous tumor size reduction (Figures 2C-E). Survival analysis showed that the control group (1) had a median survival of 18 days, whereas group (4) PD-1 inhibitor + bevacizumab (2 mg/kg) + pemetrexed (100 mg/kg) had the longest median survival (31 days), followed by group (3) PD-1 inhibitor + pemetrexed (100 mg/kg) with 27 days (P \u0026lt; 0.0001) (Figure 2D). These results suggest that the combination of PD-1 inhibitor with chemotherapy and anti-angiogenic therapy provides the most effective tumor suppression in mice.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3. PD-1 inhibitors combined with chemotherapy and anti-angiogenic therapy enhance blood-brain barrier permeability and promote vascular normalization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrevious animal experiments in our study indicated that triple therapy (PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy) achieved the best antitumor effects in LLC-BM mice. To explore potential therapeutic mechanisms, mice were divided into five groups: (1) control, (2) PD-1 inhibitor monotherapy, (3) PD-1 inhibitor + chemotherapy (Pemetrexed), (4) PD-1 inhibitor + anti-angiogenic therapy (bevacizumab), and (5) PD-1 inhibitor + chemotherapy (Pemetrexed) + anti-angiogenic therapy (bevacizumab). To assess blood-brain barrier permeability, mice were euthanized half an hour after intravenous injection of EB dye and FITC fluorescent dye, and fresh brain tissues were collected and frozen in liquid nitrogen. Frozen sections were then prepared and scanned using fluorescence microscopy. The left side shows gross images of corresponding mouse brain tissues, while the right-side displays results of EB and FITC staining. Significantly increased vascular permeability was observed in the group (5) (Figure 3A). These results suggest that PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy significantly enhances blood-brain barrier permeability in mice. Vascular coverage by pericytes is an important marker of vascular normalization. To evaluate vascular normalization post-treatment, we performed dual immunofluorescence staining to assess the expression levels of endothelial cells (CD31) and pericytes (NG2) in each group. Results showed a significant decrease in CD31 expression post-treatment, although differences between groups were not distinct. Conversely, pericyte coverage (NG2) significantly increased post-treatment, particularly in the PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy group (Figure 3B). These results suggest that PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy enhances blood-brain barrier permeability and pericyte coverage, facilitating vascular normalization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e4. PD-1 inhibitors combined with chemotherapy and anti-angiogenic therapy activate the immune microenvironment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo explore whether the tumor microenvironment is activated after treatment, we conducted immunofluorescence and immunohistochemistry assays for the macrophage (IBA-1), PD-L1, CD31 and CD8. Immunohistochemistry results indicated increased CD8 infiltration, decreased macrophage (IBA-1) infiltration, elevated PD-L1 expression, and no statistically significant change in blood vessel numbers. However, there was a trend towards reduced abnormal vessels and a shift towards linear, less tortuous vessel morphology, which was most pronounced in the PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy group (Figure 4A). Immunofluorescence staining results showed a gradual decrease in M2-type macrophages (Arg-1) and an increase in M1-type macrophages (iNOS) post-treatment, with this effect particularly significant in the triple therapy group (Figure 4B). These findings collectively suggest that PD-1 inhibitors combined with chemotherapy and anti-angiogenic therapy promote vascular normalization, enhance CD8-positive T cell numbers and PD-L1 expression, reduce macrophage infiltration, and shift the immunosuppressive microenvironment towards an activated state. These results suggest that PD-1 inhibitor combined with chemotherapy and anti-angiogenic therapy activated the immune microenvironment.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study represents the first clinical and in \u003cem\u003evivo\u003c/em\u003e experimental comparison of immunotherapy combinations for the treatment of driver gene-negative lung adenocarcinoma brain metastases. Our findings suggest that the combination of PD-1/PD-L1 inhibitors with chemotherapy and anti-angiogenic therapy may constitute the optimal treatment regimen for these metastases. PD-1/PD-L1 inhibition combined with chemotherapy and anti-angiogenic therapy enhances the expression of CD8-positive T cells and PD-L1, while suppressing infiltration of M2 macrophages, thereby reversing the immunosuppressive microenvironment to an activated state. Moreover, this combination enhances blood-brain barrier permeability, and increases pericyte coverage, promoting vascular normalization, thus exerting antitumor effects.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCombination therapy mitigates the risk of drug resistance to monotherapy and enhances treatment efficacy. However, conventional cytotoxic agents exhibit limited utility in managing brain metastases due to poor blood-brain barrier (BBB) penetration and efflux pump activity. Although the BBB is often compromised in brain metastases, the distribution of chemotherapeutic drugs remains partially restricted. Anti-angiogenic co-treatment increases BBB permeability, boosting chemotherapeutic delivery and tumor cytotoxicity.\u003c/p\u003e\n\u003cp\u003eThe disorganized nature of tumor angiogenesis results in immature, malformed vessels. Since anticancer drugs rely on blood flow for delivery, this vascular dysfunction further hinders drug distribution. An emerging question arises: Rather than inhibiting angiogenesis outright, could promoting vascular maturation improve therapeutic delivery? Vascular Normalization: A Paradigm Shift in Antiangiogenic Therapy Proposed by Rakesh Jain(14), the vascular normalization theory offers a transformative perspective\u0026mdash;modulating (rather than ablating) tumor vasculature to restore structural and functional integrity. This approach: Corrects immunosuppressive TME. Enhances intra-tumoral drug penetration (particularly in hypoxic cores), Synergizes with chemotherapy, TKIs, and ICIs by improving perfusion and immune infiltration. Immunomodulatory Effects of Antiangiogenic Agents Targeted therapies like regorafenib demonstrate TME-modulating effects; in hepatocellular carcinoma models, they elevate intratumoral CD8+ T-cell infiltration(15). Anti-angiogenic TKIs regulate antitumor immunity through both vascular-dependent and -independent mechanisms, facilitating immune cell recruitment and tumor recognition, thereby potentiating combination therapies(16). These effects underpin their synergy with immune checkpoint inhibitors (ICIs) in reshaping the TME(17). Our study demonstrates that the triple combination of immunotherapy, chemotherapy, and anti-angiogenic therapy synergistically enhances CD8+ T-cell infiltration, upregulates PD-L1 expression, promotes vascular normalization, and reactivates the immunosuppressive tumor micro-environment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study integrates clinical datasets and animal models to evaluate the efficacy and mechanisms of immune-combination therapy in driver mutation-negative lung adenocarcinoma (LUAD) with brain metastases, providing actionable insights for clinical translation. Limitations:\u003c/p\u003e\n\u003cp\u003e1.Retrospective Design: The clinical analysis was limited to a single-center, retrospective cohort, which may introduce selection bias. 2. Model Constraints: The LLC-BM syngeneic model (a localized brain lesion model) is suitable for therapeutic response assessment but does not recapitulate the full metastatic cascade from primary lung tumors to brain metastases.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study is the first clinical and in vivo experimental comparison of immunotherapy combinations for the treatment of driver gene-negative lung adenocarcinoma brain metastases. It has important guiding significance for the clinical treatment of brain metastases from lung cancer. We observed PD-1/PD-L1 blockade combined with chemotherapy and anti-angiogenesis therapy activates the immune microenvironment, improve hypoxia, enhance blood-brain barrier permeability, and promote vascular normalization. PD-1/PD-L1 blockade combined with chemotherapy and anti-angiogenesis therapy appears to be an optimal strategy for driver gene-negative lung adenocarcinoma brain metastases.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Acknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe\u0026nbsp;thank Xingpeng Qiu for conducting and analyzing proteomics.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Funding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the National Natural Science Foundation of China [grant numbers\u0026nbsp;82260628, 82060577,\u0026nbsp;to AW L], the National Science Foundation of Jiangxi Province [grant numbers\u0026nbsp;20232ACB206042, to AW L;\u0026nbsp;Wu Jieping Medical Foundation [grant numbers 320.6750.2023-16-8, to AW L].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003eAuthor information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Oncology, The second affiliated hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, China\u003c/p\u003e\n\u003cp\u003eYali Yi, Zhiqin Lu, Wenjie Xu, Yuxi Luo, Fujuan Zeng, Zhimin Zeng, Le Xiong, Jing Cai \u0026amp;Anwen Liu\u003c/p\u003e\n\u003cp\u003eBasic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Ministry of Education, (The Second Affiliated Hospital of Nanchang University) Jiangxi Medical College, Nanchang University, Nanchang 330031, China\u003c/p\u003e\n\u003cp\u003eAnwen Liu \u0026amp; Jing Cai\u003c/p\u003e\n\u003cp\u003eSchool of Basic Medical Sciences, Nanchang University,\u0026nbsp;Nanchang, Jiangxi Province, 330006, China\u003c/p\u003e\n\u003cp\u003eDaya Luo\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Authorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnwen Liu, Long Huang and Zhimin Zeng contributed to the conception and design of the study. Yali Yi drafting the article or revising it critically for important intellectual content. Daya Luo and Jing Cai and Le Xiong participated in the implementation and discussion of experiments. Yali Yi, Wenjie Xu and Yuxi Luo performed experiments. Fujuan Zeng and Zhiqin Lu performed bioinformatics analysis. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e•\u0026nbsp;\u003cstrong\u003eCorresponding author\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Jing Cai and Anwen Liu.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics declarations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003eEthical Approval\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe experiment was approved by the Ethics Committee of Second Affiliated Hospital of Nanchang University Medical Research and the Nanchang University Approval for Research Involving Animals (20221031140).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Consent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Availability of supporting data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data used to support the finding of this study are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e•\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Competing interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLamba N, Kearney RB, Catalano PJ, Hassett MJ, Wen PY, Haas-Kogan DA, et al. Population-based estimates of survival among elderly patients with brain metastases. Neuro Oncol. 2021;23(4):661-76.\u003c/li\u003e\n \u003cli\u003eWen J, Yu JZ, Liu C, Ould Ismail AAO, Ma W. Exploring the Molecular Tumor Microenvironment and Translational Biomarkers in Brain Metastases of Non-Small-Cell Lung Cancer. Int J Mol Sci. 2024;25(4).\u003c/li\u003e\n \u003cli\u003eKahraman S, Karakaya S, Kaplan MA, Goksu SS, Ozturk A, Isleyen ZS, et al. Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases. Sci Rep. 2024;14(1):5820.\u003c/li\u003e\n \u003cli\u003eGoldberg SB, Schalper KA, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, et al. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Lancet Oncol. 2020;21(5):655-63.\u003c/li\u003e\n \u003cli\u003eCrin\u0026ograve; L, Bronte G, Bidoli P, Cravero P, Minenza E, Cortesi E, et al. Nivolumab and brain metastases in patients with advanced non-squamous non-small cell lung cancer. Lung Cancer. 2019;129:35-40.\u003c/li\u003e\n \u003cli\u003eGadgeel SM, Lukas RV, Goldschmidt J, Conkling P, Park K, Cortinovis D, et al. Atezolizumab in patients with advanced non-small cell lung cancer and history of asymptomatic, treated brain metastases: Exploratory analyses of the phase III OAK study. Lung Cancer. 2019;128:105-12.\u003c/li\u003e\n \u003cli\u003eMansfield AS, Aubry MC, Moser JC, Harrington SM, Dronca RS, Park SS, et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol. 2016;27(10):1953-8.\u003c/li\u003e\n \u003cli\u003eZhou J, Gong Z, Jia Q, Wu Y, Yang ZZ, Zhu B. Programmed death ligand 1 expression and CD8(+) tumor-infiltrating lymphocyte density differences between paired primary and brain metastatic lesions in non-small cell lung cancer. Biochem Biophys Res Commun. 2018;498(4):751-7.\u003c/li\u003e\n \u003cli\u003eNogami N, Barlesi F, Socinski MA, Reck M, Thomas CA, Cappuzzo F, et al. IMpower150 Final Exploratory Analyses for Atezolizumab Plus Bevacizumab and Chemotherapy in Key NSCLC Patient Subgroups With EGFR Mutations or Metastases in the Liver or Brain. J Thorac Oncol. 2022;17(2):309-23.\u003c/li\u003e\n \u003cli\u003eLuo Z, Wu S, Zhou J, Xu W, Xu Q, Lu L, et al. All-stage targeted therapy for the brain metastasis from triple-negative breast cancer. Acta Pharm Sin B. 2023;13(1):359-71.\u003c/li\u003e\n \u003cli\u003eMoynihan KD, Opel CF, Szeto GL, Tzeng A, Zhu EF, Engreitz JM, et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat Med. 2016;22(12):1402-10.\u003c/li\u003e\n \u003cli\u003eShi H, Yu TK, Johnson B, Selvamani SP, Zhuang L, Lee K, et al. A combination of PD-1 and TIGIT immune checkpoint inhibitors elicits a strong anti-tumour response in mesothelioma. J Exp Clin Cancer Res. 2025;44(1):51.\u003c/li\u003e\n \u003cli\u003ePatel SA, Herynk MH, Cascone T, Saigal B, Nilsson MB, Tran H, et al. Estrogen Promotes Resistance to Bevacizumab in Murine Models of NSCLC. J Thorac Oncol. 2021;16(12):2051-64.\u003c/li\u003e\n \u003cli\u003eHuang Y, Goel S, Duda DG, Fukumura D, Jain RK. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res. 2013;73(10):2943-8.\u003c/li\u003e\n \u003cli\u003eShigeta K, Matsui A, Kikuchi H, Klein S, Mamessier E, Chen IX, et al. Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. J Immunother Cancer. 2020;8(2).\u003c/li\u003e\n \u003cli\u003eYi M, Jiao D, Qin S, Chu Q, Wu K, Li A. Synergistic effect of immune checkpoint blockade and anti-angiogenesis in cancer treatment. Mol Cancer. 2019;18(1):60.\u003c/li\u003e\n \u003cli\u003eTang L, Chen Z, Yang J, Li Q, Wang S, Mo T, et al. Single-cell and Bulk RNA-Seq reveal angiogenic heterogeneity and microenvironmental features to evaluate prognosis and therapeutic response in lung adenocarcinoma. Front Immunol. 2024;15:1352893.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Characteristic of BM Patients\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003eTotal (n = 179)\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD or n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003eICI alone (n = 35)\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD or n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eICI+anti-VEGF\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(n = 53)\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD or n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eICI+Chemo (n = 54)\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD or n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003eICI+Chemo\u003c/p\u003e\n \u003cp\u003e+anti-VEGF (n = 37)\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD or n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e61.75 \u0026plusmn; 8.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e61.66 \u0026plusmn; 8.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e62.74 \u0026plusmn; 9.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e61.61 \u0026plusmn; 8.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e60.62 \u0026plusmn; 6.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.711\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.368\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e99 (55.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e19 (54.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e26 (49.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e29 (53.70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e25 (67.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026ge;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e80 (44.69)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e16 (45.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e27 (50.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e25 (46.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e12 (32.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.008\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e50 (27.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e13 (37.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e14 (26.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e7 (12.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e16 (43.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e129 (72.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e22 (62.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e39 (73.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e47 (87.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e21 (56.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eSmoke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.193\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eFormer or current\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e105 (58.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e21 (60.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e34 (64.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e34 (62.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e16 (43.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eNon-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e74 (41.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e14 (40.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e19 (35.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e20 (37.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e21 (56.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003ePS score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.485\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;=1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e141 (78.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e28 (80.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e40 (75.47)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e46 (85.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e27 (72.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e38 (21.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e7 (20.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e13 (24.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (14.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e10 (27.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003ePathological\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; adenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e105 (58.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e12 (34.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e39 (73.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e32 (59.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e22 (59.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eothers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e13 (7.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e2 (5.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e5 (9.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (11.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eSquamous-carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e61 (34.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e21 (60.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e9 (16.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e16 (29.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e15 (40.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003ePD-L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e54 (30.17)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e16 (45.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e19 (35.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e19 (35.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026gt;=50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e35 (19.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e5 (14.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e8 (15.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e6 (11.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e16 (43.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1-49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e47 (26.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e9 (25.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e11 (20.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e13 (24.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e14 (37.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eunknow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e43 (24.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e5 (14.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e15 (28.30)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e16 (29.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e7 (18.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eSystematic metastasis sites\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.763\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;=3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e158 (88.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e32 (91.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e46 (86.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e46 (85.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e34 (91.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e21 (11.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e3 (8.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e7 (13.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (14.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e3 (8.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eInitial diagnosis BM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e66 (36.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e14 (40.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e30 (56.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e9 (16.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e13 (35.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e113 (63.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e21 (60.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e23 (43.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e45 (83.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e24 (64.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eactive BM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.061\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e89 (49.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e22 (62.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e20 (37.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e31 (57.41)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e16 (43.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e90 (50.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e13 (37.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e33 (62.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e23 (42.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e21 (56.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eBM num\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.382\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e118 (66.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e23 (65.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e34 (64.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e32 (61.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e29 (78.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026gt;=3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e59 (33.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e12 (34.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e19 (35.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e20 (38.46)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e8 (21.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eBM size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026lt;1cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e45 (25.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e15 (42.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e19 (35.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e5 (9.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e6 (16.22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026gt;=1cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e134 (74.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e20 (57.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e34 (64.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e49 (90.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e31 (83.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.070\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e87 (48.60)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e23 (65.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e24 (45.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e27 (50.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e13 (35.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e92 (51.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e12 (34.29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e29 (54.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e27 (50.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e24 (64.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eCombine Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e35 (19.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e35 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e144 (80.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e53 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e54 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e37 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eBevacizumab\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e89 (49.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e35 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e54 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e90 (50.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e53 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e37 (100.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eICI line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026lt;.001*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e81 (45.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e7 (20.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e14 (26.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e45 (83.33)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e15 (40.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e57 (31.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e14 (40.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e23 (43.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e8 (14.81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e12 (32.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e37 (20.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e14 (40.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e12 (22.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1 (1.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e10 (27.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e4 (2.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e4 (7.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e0 (0.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eiPD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.499\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e66 (36.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e11 (31.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e17 (32.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e21 (38.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e17 (45.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e113 (63.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e24 (68.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e36 (67.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e33 (61.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e20 (54.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.071\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e74 (41.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e10 (28.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e18 (33.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e26 (48.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e20 (54.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15px;\"\u003e\n \u003cp\u003e105 (58.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13px;\"\u003e\n \u003cp\u003e25 (71.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e35 (66.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 14px;\"\u003e\n \u003cp\u003e28 (51.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 17px;\"\u003e\n \u003cp\u003e17 (45.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eICIs, immune checkpoint inhibitors, ICIs+chemo, ICIs+chemotherapy, BM num, number of brain metastasis, BM size, Diameter of brain metastases.\u003c/p\u003e\n\n\u003cp\u003eTable 2. Univariate and Multivariate Analysis\u003c/p\u003e\n\u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 29px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 37px;\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" style=\"width: 32px;\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003eHR (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026beta;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003eHR (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.307\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.01 (0.99 ~ 1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026gt;=65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.37 (0.93 ~ 2.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003efemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003emale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.020\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.62 (0.41 ~ 0.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.020\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.58 (0.37 ~ 0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eSmoke\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eFormer or current\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eNon-smoker\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.313\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.82 (0.55 ~ 1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003ePS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026lt;=1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026gt;1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.82\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e2.28 (1.47 ~ 3.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e2.30 (1.44 ~ 3.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003ePathological\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eadenocarcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eothers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.150\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.64 (0.84 ~ 3.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eSquamous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.493\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.86 (0.56 ~ 1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003ePD-L1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026lt;1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026gt;=50%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-1.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.31 (0.17 ~ 0.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-0.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.012\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.43 (0.22 ~ 0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e1-49%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.010\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.53 (0.32 ~ 0.86)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.173\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.67 (0.37 ~ 1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eunknow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.96\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.38 (0.22 ~ 0.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.47 (0.26 ~ 0.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eMx1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026lt;=3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.74\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.006\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e2.10 (1.24 ~ 3.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.019\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.99 (1.12 ~ 3.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eInitial diagnosis BM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.913\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.02 (0.69 ~ 1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003esBM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eno\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.91 (1.29 ~ 2.83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.77 (1.12 ~ 2.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eBM num\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026lt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026gt;=3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.54\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.009\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.71 (1.15 ~ 2.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.58 (1.04 ~ 2.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eBM size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026lt;1cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026gt;=1cm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.014\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.60 (0.40 ~ 0.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.750\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.92 (0.55 ~ 1.54)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eICI RT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.709\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.11 (0.64 ~ 1.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.213\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.74 (0.46 ~ 1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.699\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.88 (0.44 ~ 1.72)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eICI line\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.387\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.23 (0.77 ~ 1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.495\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.22 (0.69 ~ 2.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e2.06 (1.26 ~ 3.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.128\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.66 (0.86 ~ 3.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e2.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e12.76 (4.38 ~ 37.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e2.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e9.31 (2.60 ~ 33.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eTreatment strategy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eICIs alone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e1.00 (Reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eICIs+chemotherapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.075\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.61 (0.35 ~ 1.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e0.338\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.71 (0.35 ~ 1.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eICIs+anti-VEGF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e0.162\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.69 (0.41 ~ 1.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.033\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.51 (0.28 ~ 0.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 29px;\"\u003e\n \u003cp\u003eICIs+chemotherapy+anti-VEGF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 7px;\"\u003e\n \u003cp\u003e-1.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 8px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 21px;\"\u003e\n \u003cp\u003e0.36 (0.19 ~ 0.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5px;\"\u003e\n \u003cp\u003e-1.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 6px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 20px;\"\u003e\n \u003cp\u003e0.32 (0.15 ~ 0.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026beta;：Standardization coefficient；HR: Hazard Ratio；CI: Confidence Interval；Mxs, systematic metastasis sites; sBM, active brain metastasis; BM num, number of brain metastasis; BM size, Diameter of brain metastasis\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"driver gene-negative, lung adenocarcinoma brain metastases, immune combination therapy, anti-angiogenesis therapy","lastPublishedDoi":"10.21203/rs.3.rs-6594933/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6594933/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eBrain metastasis from lung adenocarcinoma poses clinical challenges. Patients with driver gene-negative lung adenocarcinoma brain metastases have a relatively poor prognosis, and conventional treatments are inadequate. Immune checkpoint inhibitors (ICIs) represent a cornerstone in first-line therapy for metastatic non-small cell lung cancer. This study aims to explore the efficacy and mechanisms of ICIs combined with chemotherapy and anti-angiogenesis therapy, providing a theoretical basis and potential intervention points for treating driver gene-negative lung adenocarcinoma brain metastases.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eClinical data of patients with driver gene-negative lung adenocarcinoma brain metastases who received immunotherapy from May 2020 to July 2022 at Nanchang University the Second Hospital center were collected. The study validated efficacy and mechanisms at cellular and animal model levels, including the hypoxia status and blood-brain barrier permeability and immune micro-environment status.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThis study enrolled 179 patients with driver gene-negative non-small cell lung cancer brain metastases who received immunotherapy. Comparison among PD-1/PD-L1 inhibitor plus chemotherapy and anti-angiogenesis therapy (n=37), PD-1/PD-L1 inhibitor plus chemotherapy (n=54), anti-angiogenesis therapy alone (n=53), and PD-1/PD-L1 inhibitor monotherapy (n=35) showed median overall survival (OS) of 21.20 vs 16.00 vs 16.53 vs 9.30 months, respectively (P=0.013), and median intracranial progression-free survival (iPFS) of 15.20 vs 11.30 vs 9.03 vs 8.10 months, respectively (P=0.118). In a brain metastasis animal model, mice treated with PD-1 inhibitor plus bevacizumab and pemetrexed exhibited the lowest tumor fluorescence intensity. The combined therapy significantly improved tumor hypoxia, enhanced blood-brain barrier permeability in mice, and increased coverage of perivascular cells. The combination therapy decreased M2-type macrophages and increased M1-type macrophages in mouse brain tissue, elevated PD-L1 expression, and increased CD8+ T cells.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003ePD-1/PD-L1 inhibitor combined with chemotherapy and anti-angiogenesis therapy appears to be an optimal strategy for driver gene-negative lung adenocarcinoma brain metastases. This combination therapy activates the immune micro-environment, improve hypoxia, enhance blood-brain barrier permeability and promote vascular normalization.\u003c/p\u003e","manuscriptTitle":"Breaking Down Combination Strategies: PD-1/PD-L1 Inhibitors with Chemotherapy, Anti- Angiogenesis, or Both in Driver Gene-Negative NSCLC Clinical Outcomes and Mechanistic Insights","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-13 09:58:30","doi":"10.21203/rs.3.rs-6594933/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"16d418e1-a31e-452e-b04d-5a5d2f7319cc","owner":[],"postedDate":"May 13th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-05T10:53:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-13 09:58:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6594933","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6594933","identity":"rs-6594933","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}