BackgroundGlioma is a major cause of mortality among central nervous system tumors, with a generally poor prognosis. The lysyl oxidase (LOX) family, a group of copper-dependent amine oxidases, has been implicated in the progression of various cancers, but its specific role in glioma and its relationship with immune infiltration remains insufficiently explored. This study aims to investigate the LOX family’s expression, prognostic significance, and immune infiltration dynamics in glioma to identify potential therapeutic targets.MethodsA comprehensive analysis was conducted using public databases to assess gene expression, mutation frequency, and immune infiltration patterns related to the LOX family in glioma. The results were validated through survival analysis and immunohistochemistry. Functional assays, including EdU, Transwell, and flow cytometry, were used to evaluate glioma cell proliferation, migration, invasion, and apoptosis. Co-culture experiments with immune cells, ELISA, and a glioma transplantation model were employed to study the immune-modulatory effects of the LOX family. Gene and protein expression levels were further analyzed using qRT-PCR and Western blotting.ResultsThe LOX family was significantly upregulated in low-grade gliomas and strongly associated with poor clinical outcomes. Although mutation frequencies were low, the LOX family contributed to glioma progression through pathways involving metastasis, hypoxia response, angiogenesis, and immune cell infiltration. LOX expression correlated with increased infiltration of macrophages and eosinophils and decreased presence of Treg and CD8+ T cells. Knockdown of LOX genes impaired glioma cell functions, induced apoptosis, and altered immune cell behavior by reducing M2 macrophage polarization and enhancing CD8+ T cell activity.ConclusionsThe LOX family is overexpressed in glioma and is associated with poor prognosis and altered immune infiltration patterns. These findings highlight the LOX family as a promising prognostic marker and therapeutic target, particularly for enhancing the effectiveness of immunotherapy in glioma treatment.

Background Limited response to programmed death ligand-1 (PD-L1)/programmed death 1 (PD-1) immunotherapy is a major hindrance of checkpoint immunotherapy in non-small cell lung cancer (NSCLC). The abundance of PD-L1 on the tumor cell surface is crucial for the responsiveness of PD-1/PD-L1 immunotherapy. However, the negative control of PD-L1 expression and the physiological significance of the PD-L1 inhibition in NSCLC immunotherapy remain obscure.Methods Bioinformatics analysis was performed to profile and investigate the long non-coding RNAs that negatively correlated with PD-L1 expression and positively correlated with CD8+T cell infiltration in NSCLC. Immunofluorescence, in vitro PD-1 binding assay, T cell-induced apoptosis assays and in vivo syngeneic mouse models were used to investigate the functional roles of LINC02418 and mmu-4930573I07Rik in regulating anti-PD-L1 therapeutic efficacy in NSCLC. The molecular mechanism of LINC02418-enhanced PD-L1 downregulation was explored by immunoprecipitation, RNA immunoprecipitation (RIP), and ubiquitination assays. RIP, luciferase reporter, and messenger RNA degradation assays were used to investigate the m6A modification of LINC02418 or mmu-4930573I07Rik expression. Bioinformatics analysis and immunohistochemistry (IHC) verification were performed to determine the significance of LINC02418, PD-L1 expression and CD8+T cell infiltration.Results LINC02418 is a negative regulator of PD-L1 expression that positively correlated with CD8+T cell infiltration, predicting favorable clinical outcomes for patients with NSCLC. LINC02418 downregulates PD-L1 expression by enhancing PD-L1 ubiquitination mediated by E3 ligase Trim21. Both hsa-LINC02418 and mmu-4930573I07Rik (its homologous RNA in mice) regulate PD-L1 therapeutic efficacy in NSCLC via Trim21, inducing T cell-induced apoptosis in vitro and in vivo. Furthermore, METTL3 inhibition via N6-methyladenosine (m6A) modification mediated by YTHDF2 reader upregulates hsa-LINC02418 and mmu-4930573I07Rik. In patients with NSCLC, LINC02418 expression is inversely correlated with PD-L1 expression and positively correlated with CD8+T infiltration.Conclusion LINC02418 functions as a negative regulator of PD-L1 expression in NSCLC cells by promoting the degradation of PD-L1 through the ubiquitin-proteasome pathway. The expression of LINC02418 is regulated by METTL3/YTHDF2-mediated m6A modification. This study illuminates the underlying mechanisms of PD-L1 negative regulation and presents a promising target for improving the effectiveness of anti-PD-L1 therapy in NSCLC.

Importance The inability to obtain a pathological diagnosis in a certain proportion of patients with clinically diagnosed advanced lung cancer impedes precision treatment in clinical practice. Objective To evaluate the clinical outcome of first-line icotinib in patients with clinically diagnosed advanced lung cancer with unknown pathological status and positive epidermal growth factor receptor (EGFR)-sensitizing variants assessed by circulating tumor DNA (ctDNA). Design, Setting, and Participants The Efficiency of Icotinib in Plasma ctDNA EGFR Mutation-Positive Patients Diagnosed With Lung Cancer (CHALLENGE) trial is a prospective, multicentered, open-label, single-arm phase 2 nonrandomized clinical trial conducted between July 1, 2017, and July 31, 2019. Patients with systemic treatment-naive, clinically diagnosed advanced peripheral lung cancer, unknown pathological status, and positive pretreatment plasma EGFR-sensitizing variants were eligible. A total of 391 potentially eligible Chinese patients from 19 centers in China were screened for ctDNA EGFR variants by 3 independent detection platforms (Super amplification refractory mutation system [SuperARMS] polymerase chain reaction, droplet digital polymerase chain reaction, and next-generation sequencing), and those with EGFR variants tested by any platform were included. Analyses were conducted from September 9 to December 31, 2021. Interventions Enrolled patients were treated with oral icotinib tablets (125 mg 3 times daily) until disease progression, death, or treatment discontinuation due to various reasons, such as toxic effects and withdrawing consent. Main Outcomes and Measures The primary end point was objective response rate (ORR). The secondary end points included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and the concordance among the 3 detection platforms. Results Of 116 included patients, 76 (65.5%) were female, and the median (range) age was 64 (37-85) years. The median (IQR) follow-up duration was 36.3 (30.2-40.7) months. The ORR was 52.6% (95% CI, 43.1%-61.9%). The median PFS and OS were 10.3 months (95% CI, 8.3-12.2) and 23.2 months (95% CI, 17.7-28.0), respectively, and the DCR was 84.5% (95% CI, 76.6%-90.5%). The concordance rate among the 3 detection platforms was 80.1% (313 of 391), and the clinical outcomes in patients identified as positive by any platform were comparable. Conclusions and Relevance This prospective phase 2 nonrandomized clinical trial suggests that for patients with clinically diagnosed advanced lung cancer with unknown pathological status, ctDNA-based EGFR genotyping could help decision-making in particular clinical situations, while still warranting future larger-scaled real-world exploration. Trial Registration ClinicalTrials.gov Identifier: NCT03346811.

Objective The relationship between serum lipids and prognosis of gastric cancer has not been confirmed. Our purpose in the study was to investigate the associations between preoperative and postoperative serum lipids level and prognosis in patients with gastric cancer. Methods A retrospective study was performed on 431 patients who received radical (R0) gastrectomy from 2011 to 2013. Preoperative and postoperative serum lipids level were recorded. Clinical-pathological characteristics, oncologic outcomes, disease-free survival (DFS) and overall survival (OS) were collected. The prognostic significance was determined by Kaplan-Meier analysis and Cox proportional hazards regression model. Results There was no significant difference in DFS and OS according to preoperative serum lipids level. Regarding postoperative serum lipids level, compared to normal high-density lipoprotein cholesterol (HDL-C), low postoperative HDL-C level indicated a shorter OS (hazard ratio: 1.76, 99% confidence interval: 1.31–2.38; P=0.000) and a shorter DFS (hazard ratio: 2.06, 99% confidence interval: 1.55–2.73; P=0.000). However, other postoperative serum lipid molecules were not associated with DFS and OS. Conclusion Postoperative HDL-C might be an independent prognostic factor of gastric cancer.

Background:The efficacy of immune checkpoint inhibitors (ICIs) in pretreated EGFR-mutated non-small cell lung cancer (NSCLC) patients is controversial. We conducted this multicenter retrospective study to examine the efficacy of ICIs in a real world setting.Patients and methods:We collected 116 consecutive NSCLC patients with sensitive EGFR mutations who received ICIs alone or in combination after failure to respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs), and 99 patients were included for final analysis. The impacts of ICIs on the patients' objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. The relationships between outcomes and clinical characteristics were analyzed.Results:The ORR in patients with target lesions was 31.25% (95% CI: 22.18-41.52), and the DCR in all patients was 65.66% (95% CI: 55.44-74.91). The overall median PFS was 5.0 months (95% CI: 3.0-6.6), and the median OS was 15.9 months (95% CI: 10.8-23.8). The outcomes were better in patients receiving combination therapy with ECOG scores of 0-1 and no more than 2 lines of prior therapy, with a median PFS of 7.4 months (95% CI: 3.0-13.3) and a median OS of 29.0 months (95% CI: 11.7-NE). Primary EGFR mutation type and treatment mode were found to have a notable impact on clinical outcomes. Both median PFS and OS in patients with EGFR L858R mutation were significantly shorter than those in patients with EGFR exon 19 deletion (19del) (PFS: 2.5 versus 6.7 months, HR: 1.80, log-rank P=0.011; OS: 9.8 versus 26.9 months, HR: 2.48, log-rank P=0.002). Patients receiving combination therapy had notably longer median PFS and OS than those receiving monotherapy (PFS: 5.2 versus 3.0 months, HR: 0.54, log-rank P=0.020; OS: 19.0 versus 7.4 months, HR: 0.46, log-rank P=0.009).Conclusions:Our study suggests that ICI-based combination therapy is a potential strategy for EGFR-mutated NSCLC patients after EGFR-TKI failure. The efficacy may differ according to EGFR subtypes.

BackgroundLung cancer has considerably high mortality and morbidity rate. Lung adenocarcinoma (LUAD) tissues highly express lamin B1 (LMNB1), compared with normal tissues. In this study, we knocked down LMNB1 in LUAD cells A549 and NCI-1299 to explore the effect of its inhibition on the proliferation of cells and the potential mechanism.MethodsUsing bioinformatics methods, we analyzed the specificity of LMNB1 mRNA expression level in LUAD and its effect on prognosis from TCGA data. SiRNAs were used to knock down LMNB1 in the A549 cell line, and the knockdown effect was identified by western blotting and qRT-PCR. Through CCK8 cell proliferation assay, wound healing assay, TRAP, cloning formation Assay, DNase I-TUNEL assay, ATAC-seq, immunofluorescence, FISH, in vivo mouse xenograft studies, etc, we evaluated the influence and mechanism of LMNB1 on LUAD cell line proliferation in vitro and in vivo.ResultsAccording to bioinformatics analysis, LMNB1 is substantially abundant in LUAD tissues and is associated with tumor stage and patient survival (P < 0.05). After silencing LMNB1, the rate of cell growth, wound healing, the number of transwells, and the number of cell colonies all decreased significantly (P < 0.01). With the decreased LMNB1 expression, H3K9me3 protein expression decreases, chromosome accessibility increases, P53, P21, P16 and γ-H2AX protein expression increases, and the number of senescence staining positive cells increases. At the same time, in vivo mouse xenograft experiments showed that the tumor volume of the LMNB1-silenced group was significantly reduced, compared to that of the control group (P < 0.01), and the proliferation biomarker Ki-67 level (P < 0.01) was considerably reduced.ConclusionsOverexpression of LMNB1 in LUAD cells is significant, which has excellent potential to be an indicator for evaluating the clinical prognosis of LUAD patients and a target for precise treatment.

The role of programmed cell death ligand 1 (PD-L1) in suppressing antitumor immune responses has been widely reported, and recent studies showed that PD-L1 also plays an important role in epithelial-mesenchymal transition (EMT), determination of tumor cell phenotypes, metastasis, and drug resistance. Long non-coding RNAs (lncRNAs) are involved in a variety of epigenetic regulatory processes. The tumorigenesis and development of most cancers cannot be studied separately from their regulation by lncRNAs. To explore the epigenetic regulation of PD-L1, we identified an lncRNA, LINC00244, which reduced PD-L1 expression and predicted good clinical outcomes in hepatocellular carcinoma (HCC). LINC00244 inhibited the proliferation, invasion, and metastasis of HCC by downregulating PD-L1 expression. In addition, low LINC00244 expression activated epithelial-mesenchymal transition (EMT) pathways and facilitated the rapid growth and metastasis of HCC cells. Thus, LINC00244 is a potential therapeutic target for HCC.

Apatinib, a VEGFR2 receptor tyrosine kinase inhibitor, showed survival benefits in Asian patients with heavily pretreated advanced gastric cancer. However, the adverse event (AEs) profile of apatinib has limited its use. Dosing schedules are used to alleviate toxicities despite no supportive evidence. This study aimed to analyze the toxicity and effectiveness of apatinib alone, especially with different dosing strategies in advanced gastric cancer patients under a real-world setting. Data from the subpopulation of patients who failed ≥2 chemotherapy regimens enrolled in the AHEAD-G202 trial were analyzed. The primary endpoint was safety. The secondary endpoints were overall survival (OS) and progression-free survival (PFS). Totally 120 patients were included into three groups by the initial daily doses: 43 (35.8%) patients in the low-dose (250 mg) group, 67 (55.8%) patients in the mid-dose (425 mg to 500 mg) group, and 10 (8.3%) patients in the high-dose (675 to 850 mg) group. Grade 3/4 treatment-emergent AEs were infrequent (<5%), with the most commonly reported grade 3/4 AEs being hand-foot syndrome (4.2%), hypertension (4.2%,), fatigue (4.2%), and difficulty in swallowing (4.2%) which gradually decreased among the high-, mid-, and low-dose groups. The median OS and PFS were 6.33 months (95% CI, 4.57-7.73) and 3.83 months (95% CI: 1.40-4.20), respectively and were comparable among the three doses groups. We found heavily pretreated advanced gastric cancer patients can tolerate and benefit from lower-doses of apatinib therapy. The lower initial daily dosing strategy represents an alternative approach for optimizing apatinib dosing in clinical practice.

Supplemental Digital Content is available in the text Abstract Bevacizumab (BV) plus chemotherapy is broadly used in advanced ovarian cancer (OC). However, the efficacy of BV-based regimens for advanced OC patients is not satisfactory. Therefore, it is urgent to explore the predictive genetic biomarkers for BV. Tumor tissues from advanced OC patients receiving BV-based regimens were analyzed with a 150-gene targeted panel for next generation sequencing. The associations between gene alterations or clinicopathology features and progression-free survival (PFS) were analyzed by Kaplan–Meier curves or Cox regression. The association of the genetic alteration in potential predictive genes and expressions of 11 vascular endothelial growth factor-related genes were analyzed in The Cancer Genome Atlas cohort using 292 OC cases. Sixty two Chinese advanced OC patients treated with BV-based therapy were included. The median PFS of was 6.9 months, and objective response rate was 14.5%. In multivariate Cox regression analysis, the status of endothelial growth factor receptor (EGFR) (hazard ratio = 6.39, 95% confidence interval [CI] 2.25–18.13, P < .001) and human epidermal growth factor receptor 2 (HER2) (hazard ratio = 3.58, 95% CI 1.27–10.08, P = .016) were significantly correlated with PFS. MYC Proto-Oncogene amplification seemed to have a positive trend (hazard ratio = 0.21, 95% CI 0.05–1.02, P = .052). Moreover, EGFR and HER2 alterations were not prognostic factors of overall survival for OC in The Cancer Genome Atlas OC cohort. The vascular endothelial growth factor-related signature analysis indicated vascular endothelial factor A expression was upregulated with EGFR alterations (P = .034) which may be involved in BV resistance, and HER2 alterations were associated with hypoxia inducible factor 1 subunit alpha overexpression significantly (P = .029). EGFR or HER2 alterations are negative predictors of PFS for OC patient treated with BV plus chemotherapy. Therefore, the clinicians may consider to use alternative regimens such as anti-EGFR or anti-HER2 targeted therapy instead of BV-based regimens on these patients when standard care fail.

目的:观察腹腔灌注贝伐珠单抗联合化疗治疗卵巢癌所致粘连性肠梗阻的临床疗效,分析腹腔内血管内皮生长因子(VEGF)水平对贝伐珠单抗治疗卵巢癌腹腔粘连的临床意义.方法:将62例卵巢癌伴恶性不完全性肠梗阻患者随机分为实验组(n=32)和对照组(n=30),均用奥曲肽(60 mg/d连续3天)全身治疗,3周重复1次;同时腹腔内给予灌注化疗,每3周重复1次,连续治疗2周期.对照组给予吉西他滨和卡铂腹腔灌注治疗,实验组在上述治疗基础上联合贝伐珠单抗(5 mg/kg)治疗.评价患者疗效、不良反应.酶联免疫吸附法(ELISA)检测62例患者治疗前、后腹腔中VEGF水平.结果:实验组的有效率为87.50％,对照组为43.33％,差异有统计学意义(P<0.05).实验组和对照组患者耐受良好,不良反应无明显差异.治疗后对照组腹水VEGF水平为(139.89±10.89)pg/mL,明显低于治疗前的(310.59±13.63)pg/mL(P<0.05);实验组治疗后腹水VEGF水平为(81.57±4.71)pg/mL,明显低于治疗前的(309.67±11.02)pg/mL(P<0.05).治疗后VEGF水平实验组较对照组下降更为显著(P<0.05).结论:贝伐珠单抗联合化疗治疗晚期卵巢癌粘连性肠梗阻优于单纯腹腔灌注化疗,不良反应较少,安全性耐受性好.

Lactate dehydrogenase A (LDHA), a critical component of the glycolytic pathway, relates to the development of various cancers, including thyroid cancer. However, the regulatory mechanism of LDHA inhibition and the physiological significance of the LDHA inhibitors in papillary thyroid cancer (PTC) are unknown. Long non-coding RNA (lncRNA) plays a vital role in tumor growth and progression. Here, we identified a novel lncRNA LINC00671 negatively correlated with LDHA, downregulating LDHA expression and predicting good clinical outcome in thyroid cancer. Moreover, hypoxia inhibits LINC00671 expression and activates LDHA expression largely through transcriptional factor STAT3. STAT3/LINC00671/LDHA axis regulates thyroid cancer glycolysis, growth, and lung metastasis both in vitro and in vivo. In thyroid cancer patients, LINC00671 expression is negatively correlated with LDHA and STAT3 expression. Our work established STAT3/LINC00671/LDHA as a critical axis to regulate PTC growth and progression. Inhibition of LDHA or STAT3 or supplement of LINC00671 could be potential therapeutic strategies in thyroid cancer.

Background Kirsten rat sarcoma vial oncogene (KRAS) is one of the most prevalent oncogenes in multiple cancer types, but the incidence is different between the Asian and non-Asian populations. The recent development of KRAS G12C targeting drug has shown great promise. It is thus important to understand the genomic landscape of KRAS G12C in a specific population. Methods Sequencing data of 11,951 tumor samples collected from 11/2016 to 7/2019 from multiple centres in China were analyzed for KRAS mutation status. Concomitant genomic aberrations were further analyzed in tumors with KRAS G12C mutations, which were sequenced with comprehensive cancer panel including over 450 cancer-related genes. Smoking status and its correlation with KRAS were analyzed in 2,235 lung cancer cases within this cohort. Results KRAS mutations were identified in 1978 (16.6%) patient samples. Specifically, KRAS G12C accounted for 14.5% (n=286) of all KRAS mutations. G12C was most commonly seen in lung cancer (4.3%), followed by colorectal cancer (2.5%) and biliary cancer (2.3%). Almost all patients (99.6%) with G12C mutations had concomitant genomic aberrations. These were most commonly associated with the RAS/RTK pathway including BRAF and PI3KCA mutations. Moreover, KRAS mutation was positively correlated with smoking status in lung adenocarcinomas. Conclusions The overall incidence of KRAS G12C mutations remains low in the Chinese population. The most common tumor types harboring KRAS G12C mutations are in patients suffering from lung, colorectal and biliary cancers.

Background: Apatinib has been proved to be effective and well tolerated among patients in phase II and III studies. Here, we evaluated the safety and effectiveness of apatinib in advanced gastric cancer patients in a real-world setting. Methods: This study enrolled advanced gastric cancer patients who had progressed or relapsed despite systemic chemotherapy. The primary outcome was safety and the secondary outcomes included overall survival (OS) and progression-free survival (PFS). Results: A total of 337 patients were included. In total, 62 (18.4%), 102 (30.3%), and 173 (51.3%) patients received first, second, and third or higher line apatinib therapy, respectively. Grade 3/4 treatment-emergent adverse events (AEs) were infrequent (<5%), with hypertension (6.8%) being the only grade 3/4 AE occurring in more than 5% of the patients and across the low-dose (250 mg, 7.3%), mid-dose (425–500 mg, 6.1%), and high-dose group (675–850 mg, 2/15, 13.3%). The median OS and PFS were 7.13 months (95% CI, 6.17–7.93) and 4.20 months (95% CI, 4.60–4.77), respectively, and were comparable among the low-, mid-, and high-dose groups. Conclusion: Lower daily doses of apatinib achieved comparable OS and PFS versus higher daily doses of apatinib while maintaining a more benign safety profile in advanced gastric cancer patients. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT02668380.

EML4-ALKrearranged malignant pleural mesothelioma (MPM) is rare and its responses to anaplastic lymphoma kinase (ALK) inhibitors, including alectinib and lorlatinib, remain unexplored. In this case report, we describe a patient withEML4-ALK-rearranged stage IIIB MPM who was administered with alectinib and lorlatinib as first-line and fourth-line therapy, respectively. He had remarkable response evaluated as partial response on both regimens lasting approximately 3.5 months on each regimen. His plasma samples were collected during the treatment course and submitted for targeted sequencing to understand the molecular mechanisms of his therapeutic resistance. Sequencing analysis revealed the emergence ofALKI1171N and L1196M at alectinib progression. Meanwhile,ALKI1171N, L1196M, and G1202R mutations were identified at lorlatinib progression, wherein L1196M is confirmed to be incisto G1202R. We speculate that these multiple mutations synergistically mediated his resistance to both alectinib and lorlatinib. Our report describes the detection ofEML4-ALKrearrangement in a patient with MPM who had remarkable therapeutic response with ALK inhibitors. Moreover, our case also revealed acquired mechanisms of lorlatinib resistance mediated by multiple mutationsALKI1171N, L1196M, and G1202R, contributing an incremental step to our understanding of the complexity of acquired resistance mechanisms in sequential ALK inhibitor therapy. The reviews of this paper are available via the supplemental material section.

Millions of people are suffering from cancers, but accurate early diagnosis and effective treatment are still tough for all doctors. In recent years, long non-coding RNAs (lncRNAs) have been proven to play an important role in diseases, especially cancers. These lncRNAs execute their functions by regulating gene expression. Therefore, identifying lncRNAs which are related to cancers could help researchers gain a deeper understanding of cancer mechanisms and help them find treatment options. A large number of relationships between lncRNAs and cancers have been verified by biological experiments, which give us a chance to use computational methods to identify cancer-related lncRNAs. In this paper, we applied the convolutional neural network (CNN) to identify cancer-related lncRNAs by lncRNA's target genes and their tissue expression specificity. Since lncRNA regulates target gene expression and it has been reported to have tissue expression specificity, their target genes and expression in different tissues were used as features of lncRNAs. Then, the deep belief network (DBN) was used to unsupervised encode features of lncRNAs. Finally, CNN was used to predict cancer-related lncRNAs based on known relationships between lncRNAs and cancers. For each type of cancer, we built a CNN model to predict its related lncRNAs. We identified more related lncRNAs for 41 kinds of cancers. Ten-cross validation has been used to prove the performance of our method. The results showed that our method is better than several previous methods with area under the curve (AUC) 0.81 and area under the precision-recall curve (AUPR) 0.79. To verify the accuracy of our results, case studies have been done.

e21548 Background: Previous retrospective studies identified the mutation of serine/threonine-protein kinase (STK11, also known as Liver Kinase B1 [LKB1]) as predictor to the benefit from immune checkpoint inhibitor (ICI) in KRAS-mutant lung adenocarcinoma. This conclusion was drawn from merely the patients receiving ICI, lacking the indispensable control group undergoing chemotherapy. Therefore, we hereby revisit the impact of STK11 mutation in both immunotherapeutic and chemotherapeutic cohorts, in addition to TCGA database as a control cohort representing prognosis. Methods: 6 immunotherapeutic cohorts involving 807 patient-level data (Van Allen, Rizvi-34, Rizvi-240, MSKCC-75, MSKCC-350, and POPLAR/OAK-atezolizumab), 1 chemotherapeutic cohort (POPLAR/OAK-docetaxel, n = 244), and TCGA database (n = 485) were included to comprehensively re-examine the questionably predictive effect of STK11 mutation on the benefit from immunotherapy in patients with EGFR/ALK WT non-squamous NSCLC. Results: In the 6 immunotherapeutic cohorts, STK11 mutation was associated with shorter progression-free survival (PFS, HR = 1.54, 95%CI 1.17-2.03, P = 0.002) and overall survival (OS, HR = 1.57, 95%CI 1.16-2.11, P = 0.003), but no statistically lower overall response rate (ORR, RR = 0.71, 95%CI 0.39-1.28, P = 0.251). Similarly, in the patients receiving docetaxel, worse ORR and PFS at borderline level and significantly reduced OS (HR = 1.82, 95%CI 1.18-2.80, P = 0.006) were observed. Specifically, in the POPLAR/OAK cohort retrieved from two randomized controlled trials comparing atezolizumab and docetaxel, STK11 mutation and treatment choice separately impacted on OS, but the interaction between these two variables was barely profound (HR 1.10, 95%CI 0.60-2.01, P = 0.766), indicating the prognostic, but not predictive utility of STK11 mutation. Furthermore, in TCGA database, STK11 mutation was linked with poorer prognosis, with the similar hazard ratio in immunotherapeutic cohorts. Conclusions: Genomic abberation of STK11 remarkably worsens prognosis among 6 immunotherapeutic cohorts, 1 chemotherapeutic cohort, and TCGA database, demonstrating the prognostic, but not predictive utility of STK11 mutation in patients with EGFR/ALK WT non-squamous NSCLC.

e17037 Background: Bevacizumab(BV) plus chemotherapy is widely used in patients with advanced ovarian cancer(OC). However, there was not predict biomakers to determined the use of BV-based treatment in OC currently.Therefore, exploring the predict biomarkers for BV is imperative. Methods: Tumor issues of advanced OC treated with BV plus chemotherapy were used for next generation sequencing (NGS) with a 150-gene targeted panel. The correlation between Progression-Free Survival (PFS) and genes or clinicopathology features was analyzed by Kaplan-Meier or Cox regression. For multivariate Cox regression, all factors with a p-value < 0.05 in univariate Cox regression were included. The potential predictive genes would be analyzed with VEGF-related signatures by using 374 OC mRNA data from The Cancer Genome Atlas (TCGA).Statistical analysis was performed using GraphPad Prism and SPSS. Results: 62 Chinese advanced OC patients treated with BV-base therapy were enrolled in this study from May 2015 to March 2018.The median PFS of these patients was 5.7 months , while ORR and DCR rate was 14.5% and 96.8%, repecitively.Patients with EGFR or HER2 alterations had poorer PFS compared with wild-type (EGFR,4.2 months vs. 7.4 months,p = 0.019;HER2,3.8 months vs. 7.3 months, p = 0.045), while MYC amplification patients got better PFS than MYC wild-type patients(17.4 months vs. 6.0 months,p = 0.049). However, in multivariate Cox regression anlysis, EGFR and HER2 were significantly correlated with PFS(P < 0.001 and p = 0.016,respectively),and MYC amplification seemed to have a positive trend(p = 0.052).Moreover,patients with HER2 alterations has a poorer OS(p = 0.008).The VEGF-related signatures analysis results indicated EGFR variants may upregulated VEGFA expression to induced resistant of BV,while downregulation of HIF was significantly correlated with MYC amplification,which was beneficial to efficacy of BV.HER2 alterations has not correlated with VEGF pathways,suggesting HER2 was a poor prognosis of OC instead of an negative predictor of BV. Conclusions: NGS is an effective method to reveal the potential predictor for BV plus chemotherapy in advanced ovarian cancer, and the patients with EGFR or HER2 alterations should consider alternative regimens such as anti-EGFR or anti-HER2 target therapy instead of BV-based regimens.

Photothermal therapy is a local treatment method for cancer and the heat energy generated from it could destroy the tumor cells. This study is aimed to investigate the temperature distribution in tumor tissue and surrounding health tissue of tumor bearing mice applying mathematical simulation model. Tumor bearing mice treated by laser combined with or without indocyanine green. Monte Carlo method and the Pennes bio-heat equation were used to calculate the light distribution and heat energy. COMSOL Multiphysic was adopted to construct three dimensional temperature distribution model. This study revealed that the data calculated by simulation model is in good agreement with the surface temperature monitored by infrared thermometer. Effected by the optical parameters and boundary conditions of tissue, the highest temperature of tissue treated by laser combined with indocyanine green was about 65 °C which located in tumor tissue and the highest temperature of tissue treated by laser was about 43 °C which located under the tumor tissue. The temperature difference was about 20 °C. Temperature distribution in tissue was not uniform. The temperature difference in different parts of tumor tissue raised up to 15 °C. The temperature of tumor tissue treated by laser combined with indocyanine green was about 20 °C higher than that of the surrounding healthy tissue. Reasonably good matching between the calculated temperature and the measured temperature was achieved, thus demonstrated great utility of our modeling method and approaches for deepening understand in the temperature distribution in tumor tissue and surrounding healthy tissue during the laser combined with photosensitizer. The simulation model could provide guidance and reference function for the effect of photothermal therapy.

Aerobic glycolysis is a hallmark of cancer. Sine oculis homeobox 1 (SIX1), a key transcription factor in terms of regulating aerobic glycolysis (the Warburg Effect), plays a critical role in tumorigenesis of various cancer types, including breast cancer, liver cancer, and lung cancer. However, the upstream regulating mechanisms of SIX1 in melanoma remain to be determined. MicroRNAs (miRNAs) have emerged as key regulators in tumorigenesis and progression. Here, we initially showed that microRNA-150-5p (miR-150-5p) inhibits SIX1 expression by directly targeting its 3'-UTR in melanoma cells. miR-150-5p suppressed melanoma cell proliferation, migration, and invasion through inhibition of SIX1. Mechanistically, miR-150-5p dampens glycolysis by decreasing the glucose uptake, lactate production, ATP generation, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) by targeting SIX1. Importantly, glycolysis regulated by miR-150-5p/SIX1 axis is critical for its regulation of melanoma growth and metastasis both in vitro and in vivo. Collectively, our study demonstrates the importance of miR-150-5p/SIX1 axis in melanoma, which could be a promising therapeutic target in melanoma. (C) 2019 Elsevier Inc. All rights reserved.

Photothermal therapy, a type of laser application, has the ability to eradicate tumor cells by a local thermal effect and elicit a tumor specific immune response. Indocyanine green (ICG), a photosensitizer, can effectively elevate the local temperature by absorbing energy from the laser. The present study aimed to investigate the characteristics of temperature changes during photothermal therapy with an infrared thermometer in an ICG solution and in tumor-bearing mice treated with a combination of laser and ICG. Additionally, the present study observed the morphological changes of tumor tissue by hematoxylin-eosin staining following photothermal therapy. In the solution experiment, when the laser power density was 1 W/cm2 and the concentration of ICG was 0 or 0.0187 mg/ml, the temperature of the water was elevated by 3 and 28°C, respectively. In the tumor-bearing mice experiment, when the laser power density was 1 W/cm2 and the concentration of ICG was 0 and 0.1 mg/ml, the temperature of the tumor-bearing mice was elevated by 6.9 and 28.5°C, respectively. With an increase in laser power density, including 0.6, 0.8 and 1.0 W/cm2, the temperature was 23.3, 26.7 and 28.5°C, respectively. Pathological tissue sections demonstrated that a large number of tumor cells experienced necrosis, and the envelope of the tumor was destroyed. Numerous inflammatory cells, in particular lymphocytes, infiltrated into the tumor tissue following tumor tissue treatment with a combination of laser and ICG. These results indicated that a combination treatment with laser and ICG may significantly increase the temperature of the water solutions and in the tumor-bearing mice. The concentration of ICG and laser power density contributed to the temperature elevation, in particular to the concentration of ICG.