ABSTRACT
Background: Elderly patients with locally advanced esophageal adenocarcinoma (EAC) have a poor prognosis. The purpose of this study was to identify prognostic factors and construct a risk stratification for assessing the prognosis of elderly (≥ 70 years old) EAC patients who receiving neoadjuvant chemoradiotherapy (NCRT) and esophagectomy. Methods: A total of 688 patients with non-metastatic locally advanced EAC who underwent NCRT and esophagectomy were selected from the Surveillance Epidemiology and End Results (SEER) database. Multivariable Cox analysis was used to identify prognostic factors of overall survival (OS). Restricted Cubic Splines (RCS) was used to examine the linear relationship between the number of lymph node dissection (LND) and OS. Result: RCS showed a linear relationship between LND and OS (P = 0.690). As the number of LND increased, the risk of death decreased. Multivariable analysis demonstrated that LND > 23, grade III/IV, and regional node positive were independent prognostic factors. Subgroup analysis indicated that enlarged lymph node dissection (LND > 23) did not improve OS in patients with grade I/II or T1-2 stage, whereas enlarged lymph node dissection significantly improved OS in patients with grade III/IV or T3-4 stage. Furthermore, we constructed a novel risk score based on LND, grade, and regional node status, which stratified patients into low-, medium-, and high-risk groups. Patients in the high-risk group (risk score = 3) had a worse prognosis. Conclusions: Enlarged lymph node dissection (LND > 23) improved OS in patients with grade III/IV or T3-4 stage. Moreover, a novel risk score was constructed, which facilitated risk stratification and postoperative surveillance in elderly EAC patients.
ABSTRACT
Immunochemotherapy is the first-line standard for extensive-stage small-cell lung cancer (ES-SCLC). Combining the regimen with anti-angiogenesis may improve efficacy. ETER701 was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that investigated the efficacy and safety of benmelstobart (a novel programmed death-ligand 1 (PD-L1) inhibitor) with anlotinib (a multi-target anti-angiogenic small molecule) and standard chemotherapy in treatment-naive ES-SCLC. The ETER701 trial assessed two primary endpoints: Independent Review Committee-assessed progression-free survival per RECIST 1.1 and overall survival (OS). Here the prespecified final progression-free survival and interim OS analysis is reported. Patients randomly received benmelstobart and anlotinib plus etoposide/carboplatin (EC; n = 246), placebo and anlotinib plus EC (n = 245) or double placebo plus EC ('EC alone'; n = 247), followed by matching maintenance therapy. Compared with EC alone, median OS was prolonged with benmelstobart and anlotinib plus EC (19.3 versus 11.9 months; hazard ratio 0.61; P = 0.0002), while improvement of OS was not statistically significant with anlotinib plus EC (13.3 versus 11.9 months; hazard ratio 0.86; P = 0.1723). The incidence of grade 3 or higher treatment-related adverse events was 93.1%, 94.3% and 87.0% in the benmelstobart and anlotinib plus EC, anlotinib plus EC, and EC alone groups, respectively. This study of immunochemotherapy plus multi-target anti-angiogenesis as first-line treatment achieved a median OS greater than recorded in prior randomized studies in patients with ES-SCLC. The safety profile was assessed as tolerable and manageable. Our findings suggest that the addition of anti-angiogenesis therapy to immunochemotherapy may represent an efficacious and safe approach to the management of ES-SCLC. ClinicalTrials.gov identifier: NCT04234607 .
ABSTRACT
Backgroud: The study aimed to analyze the efficacy and safety of PD-1 inhibitors plus chemotherapy with or without endostatin for stage IV lung squamous cell carcinoma (LUSC). Methods: A total of 219 patients with stage IV LUSC were included. 120 received PD-1 inhibitors plus chemotherapy with or without endostatin (IC ± A), of which 39 received endostatin (IC+A) and 81 did not receive endostatin (IC-A). 99 received chemotherapy with or without endostatin (C ± A). Endpoints included overall survival (OS), progression-free survival (PFS), adverse events (AEs), and immune-related adverse events (irAEs). Results: The median PFS in the IC ± A group versus the C ± A group was 8 and 4 months (P < 0.001), and the median OS was 17 and 9 months (P < 0.001). There was no significant difference in any grade AEs between the IC ± A and C ± A groups (P > 0.05). The median PFS in the IC+A group versus the IC-A group was 11 and 7 months (P = 0.024), and the median OS was 34 and 15 months (P = 0.01). There was no significant difference between the IC+A group and the IC-A group for all grade AEs and irAEs (P > 0.05). The subgroup analysis showed that patients with LIPI = 0 had significant OS and PFS benefits in IC+A group, while for patients with LIPI = 1-2, there was no significant difference in OS and PFS benefits between the IC+A group and IC-A group. Conclusions: PD-1 inhibitors plus chemotherapy with endostatin might be first-line treatment for patients with stage IV LUSC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Endostatins , Immune Checkpoint Inhibitors , Lung Neoplasms , Neoplasm Staging , Humans , Endostatins/therapeutic use , Endostatins/adverse effects , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/mortality , Lung Neoplasms/pathology , Middle Aged , Retrospective Studies , Aged , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/mortality , Carcinoma, Squamous Cell/pathology , Adult , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Treatment OutcomeABSTRACT
No studies have reported the effect of ribosomal protein L22 like 1 (RPL22L1) in lung adenocarcinoma (LUAD). Therefore, we aimed to systematically investigate the role of RPL22L1 in LUAD. The expression of RPL22L1 was analyzed using TCGA, GEO, TIMER, UALCAN databases, and validated by immunohistochemistry (IHC). Gene methylation analysis was performed using the UALCAN, GSCA and MethSurv databases. The immune infiltrates were investigated using the Single Sample Gene Set Enrichment Analysis (ssGSEA), TIMER database, and TISCH database. The results demonstrated that RPL22L1 was up-regulated in LUAD, and verified by IHC. Kaplan-Meier analysis suggested that patients with high RPL22L1 expression had poor prognosis. Multivariate analysis confirmed that RPL22L1 was an independent prognostic factor. Furthermore, RPL22L1 overexpression was associated with hypomethylation, and two CpGs of RPL22L1 were significantly associated with prognosis. Up-regulated RPL22L1 was enriched in MYC targets, E2F targets, G2M checkpoint, mTORC1 signaling, cell cycle, and so on. Moreover, RPL22L1 expression was negatively correlated with immune cell infiltration, and patients with high RPL22L1 expression had lower immune, stromal, and estimate scores. Single-cell analysis suggested that RPL22L1 might have a potential function in the tumor microenvironment (TME) of LUAD. In conclusion, RPL22L1 may be a promising biomarker for LUAD.
ABSTRACT
BACKGROUND: ATM and ATR are two critical factors to regulate DNA damage response (DDR), and their mutations were frequently observed in different types of cancer, including non-small cell lung cancer (NSCLC). Given that the majority of identified ATM/ATR mutations were variants of uncertain significance, the clinical/molecular features of pathogenic ATM/ATR aberrations have not been comprehensively investigated in NSCLC. METHODS: Next-generation sequencing (NGS) analyses were conducted to investigate the molecular features in 191 NSCLC patients who harbored pathogenic/likely pathogenic ATM/ATR mutations and 308 NSCLC patients who did not have any types of ATM/ATR variants. The results were validated using an external cohort of 2727 NSCLC patients (including 48 with ATM/ATR pathogenic mutations). RESULTS: Most pathogenic ATM/ATR genetic alterations were frameshift and nonsense mutations that disrupt critical domains of the two proteins. ATM/ATR-mutated patients had significantly higher tumor mutational burdens (TMB; P < 0.001) and microsatellite instabilities (MSI; P = 0.023), but not chromosomal instabilities, than those without any ATM/ATR variations. In particular, KRAS mutations were significantly enriched in ATM-mutated patients (P = 0.014), whereas BRCA2 mutations (P = 0.014), TP53 mutations (P = 0.014), and ZNF703 amplification (P = 0.008) were enriched in ATR-mutated patients. Notably, patients with ATM/ATR pathogenic genetic alterations were likely to be accompanied by mutations in Fanconi anemia (FA) and homologous recombination (HR) pathways, which were confirmed using both the study (P < 0.001) and validation (P < 0.001) cohorts. Furthermore, the co-occurrence of FA/HR aberrations could contribute to increased TMB and MSI, and patients with both ATM/ATR and FA/HR mutations tended to have worse overall survival. CONCLUSIONS: Our results demonstrated the unique clinical and molecular features of pathogenic ATM/ATR mutations in NSCLC, which helps better understand the cancerous involvement of these DDR regulators, as well as directing targeted therapies and/or immunotherapies to treat ATM/ATR-mutated NSCLC, especially those with co-existing FA/HR aberrations.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Fanconi Anemia , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Fanconi Anemia/genetics , Fanconi Anemia/metabolism , Lung Neoplasms/genetics , Mutation/genetics , Prognosis , Homologous Recombination/genetics , Carrier Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/genetics , Ataxia Telangiectasia Mutated Proteins/metabolismABSTRACT
Background: This study aimed to develop and validate a novel nomogram to predict survival in advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD-1) inhibitor plus chemotherapy with or without antiangiogenic therapy. Methods: A total of 271 patients with advanced NSCLC who received anti-PD-1 plus chemotherapy with or without antiangiogenic therapy were enrolled in our center and randomized into the training cohort (n = 133) and the internal validation cohort (n = 138). Forty-five patients from another center were included as an independent external validation cohort. The nomogram was created based on the multivariate Cox regression analysis to predict overall survival (OS) and progression-free survival (PFS). The performance of the nomogram was assessed using the concordance index (C-index), the time-dependent area under the receiver operating (ROC) curves (AUCs), calibration curves, and decision curve analysis (DCA). Results: Four factors significantly associated with OS were utilized to create a nomogram to predict OS: Eastern Cooperative Oncology Group performance status (ECOG PS), programmed cell death-ligand 1 (PD-L1) expression, chemotherapy cycle, and pretreatment lactate dehydrogenase-albumin ratio (LAR). Six variables significantly associated with PFS were incorporated into the development of a nomogram for predicting PFS: ECOG PS, histology, PD-L1 expression, chemotherapy cycle, pretreatment platelet to lymphocyte (PLR), and pretreatment LAR. The C-indexes of the nomogram for predicting OS and PFS were 0.750 and 0.747, respectively. The AUCs for predicting the 6-month, 12-month, and 18-month OS and PFS were 0.847, 0.791, and 0.776 and 0.810, 0.787, and 0.861, respectively. The calibration curves demonstrated a good agreement between predictions and actual observations. The DCA curves indicated that the nomograms had good net benefits. Furthermore, the nomogram model was well-validated in the internal and external cohorts. Conclusion: The novel nomogram for predicting the prognosis of advanced NSCLC receiving anti-PD-1 plus chemotherapy with or without antiangiogenic therapy may help guide clinical treatment decisions.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Nomograms , B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , AlbuminsABSTRACT
BACKGROUND: To establish a risk stratification score to facilitate individualized treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). METHODS: We enrolled 160 advanced EGFR-mutated NSCLC who received first-generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) with or without bevacizumab. Kaplan-Meier curves were used for survival analysis. Univariate and multivariate analyses were used to identify independent prognostic factors associated with progression-free survival (PFS) and overall survival (OS). RESULTS: There were 107 patients in EGFR-TKI monotherapy (T group) and 53 patients in EGFR-TKI with bevacizumab (A + T group). The median PFS in the A + T group was significantly longer than that in the T group (p = 0.002). No difference in the median OS between the A + T and T groups (p = 0.721). The multivariate analyses showed that Eastern Cooperative Oncology Group performance status (ECOG PS) and the pre-treatment lactate dehydrogenase-albumin ratio (LAR) were independent prognostic factors for PFS and OS. The LAR-ECOG PS (LAPS) score was constructed by combining the pre-treatment LAR and ECOG PS. We defined ECOG PS 2 and high pre-treatment LAR as a score of 1. Then, patients with a total LAPS score of 0 were categorized as low-risk and those with 1-2 scores were classified as high-risk. For patients in low-risk group, there was no significant difference in PFS, OS, objective response rate (ORR), and disease control rate (DCR) among those who received EGFR-TKI with or without bevacizumab. However, patients in high-risk group had a significant benefit in PFS and DCR when treated with EGFR-TKI plus bevacizumab compared to those who received EGFR-TKI alone. CONCLUSIONS: Novel LAPS score may help to facilitate individualized treatment of advanced EGFR-mutated NSCLC receiving EGFR-TKI with or without bevacizumab.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Albumins , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/antagonists & inhibitors , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , /therapeutic useABSTRACT
T-cell exhaustion (Tex) is considered to be a reason for immunotherapy resistance and poor prognosis in lung adenocarcinoma. Therefore, we used weighted correlation network analysis to identify Tex-related genes in the cancer genome atlas (TCGA). Unsupervised clustering approach based on Tex-related genes divided patients into cluster 1 and cluster 2. Then, we utilized random forest and the least absolute shrinkage and selection operator to identify nine key genes to construct a riskscore. Patients were classified as low or high-risk groups. The multivariate cox analysis showed the riskscore was an independent prognostic factor in TCGA and GSE72094 cohorts. Moreover, patients in cluster 2 with high riskscore had the worst prognosis. The immune response prediction analysis showed the low-risk group had higher immune, stromal, estimate scores, higher immunophenscore (IPS), and lower tumor immune dysfunction and exclusion score which suggested a better response to immune checkpoint inhibitors (ICIs) therapy in the low-risk group. In the meantime, we included two independent immunotherapy cohorts that also confirmed a better response to ICIs treatment in the low-risk group. Besides, we discovered differences in chemotherapy and targeted drug sensitivity between two groups. Finally, a nomogram was built to facilitate clinical decision making.
Subject(s)
Adenocarcinoma of Lung , Lung Neoplasms , Humans , Prognosis , T-Cell Exhaustion , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Immunotherapy , Lung Neoplasms/drug therapy , Lung Neoplasms/geneticsABSTRACT
BACKGROUND: This study aimed to compare the efficacy and safety of different treatment modalities for previously untreated advanced EGFR-mutated non-squamous non-small-cell lung cancer (NSCLC). METHODS: This retrospective study included 196 advanced EGFR-mutated non-squamous NSCLC. 107 received EGFR-tyrosine kinase inhibitor (EGFR-TKI) monotherapy (T), 53 received EGFR-TKI + bevacizumab (T + A), and 36 received EGFR-TKI + bevacizumab + chemotherapy (T + A + C). The endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: The median PFS was 27 months in the T + A + C group, 17 months in the T + A group, and 10 months in the T group. The multivariate analysis showed lower disease progression in the T + A + C group (HR, 0.377; 95% CI, 0.224-0.634; p < .001). Subgroup analysis showed that the T + A + C group did significantly improve PFS in patients with metastatic organs ≥2, brain metastases, liver metastases, and EGFR 19del compared to T + A group. No significant improvement in OS in the T + A + C group versus the T + A group, but a significant benefit in the subgroup of patients with metastatic organs ≥2. We also performed a subgroup analysis of the T + A + C group versus the T group, which similarly showed that the T + A + C group had better PFS than the T group in most subgroups, and the T + A + C group significantly improved OS in patients with metastatic organ ≥2 and liver metastases compared with the T group. The ORR was significantly higher in the T + A + C group than A + T and T groups (83.3% vs 71.7% vs 60.7%, p = .033). In safety, the T + A + C group had a higher incidence of AEs, but the majority was grade 1-2. The most frequent AEs of grade ≥ 3 were leukopenia (8.3%) and increased aminotransferase (8.3%) in the T + A + C group. CONCLUSIONS: First-generation EGFR-TKI plus bevacizumab plus chemotherapy was a promising strategy for advanced EGFR-mutated non-squamous NSCLC.
Subject(s)
Bevacizumab , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Bevacizumab/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , ErbB Receptors/genetics , Liver Neoplasms/secondary , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Mutation , Retrospective Studies , Brain Neoplasms/secondaryABSTRACT
OBJECTIVE: The purpose of this study was to compare the clinical outcomes and toxicities between induction chemotherapy (IC) + chemo-radiotherapy (CRT) and CRT alone in patients with locally advanced esophageal squamous cell carcinoma (ESCC), to explore the appropriate thoracic radiotherapy (TRT) timing after IC and to identify prognostic factors. METHODS: 450 ESCC patients were included from September 2011 to December 2020, 238 of whom received IC/CRT. Propensity score matching was performed to balance potential confounders between the two groups. Multivariate Cox regression analysis was used to identify the independent prognostic factors. RESULTS: Patients who received IC/CRT experienced improved overall survival (OS) (38.5 vs. 28.8 months) and progression-free survival (PFS) (41.0 vs. 22.0 months) before matching, with similar results after matching. In the IC/CRT group, early TRT had more favorable survival than late TRT both matching before and after. In subgroup analysis, early TRT combination concurrent chemotherapy had better OS and PFS than late TRT combination concurrent chemotherapy. In addition, early TRT had better survival benefits regardless of the N stage. Notably, the IC/CRT group and early TRT group had manageable toxicities reaction compared with CRT alone group and the late TRT group. The nomogram was developed to predict the OS and PFS based on multivariate analysis results. The C-index was 0.743 and 0.722, respectively. CONCLUSION: IC/CRT and early TRT could yield satisfactory clinical outcomes and controllable toxicities in locally advanced ESCC. The IC plus early concurrent CRT might be a promising treatment strategy for improving further survival in ESCC.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Esophageal Squamous Cell Carcinoma/drug therapy , Esophageal Squamous Cell Carcinoma/radiotherapy , Esophageal Neoplasms/drug therapy , Esophageal Neoplasms/radiotherapy , Induction Chemotherapy/adverse effects , Chemoradiotherapy/adverse effects , Retrospective StudiesABSTRACT
BACKGROUND: N7-Methylguanosine (m7G) and long non-coding RNAs (lncRNAs) have been widely studied in cancer and have been found to be useful for assessing tumor progression. However, the role of m7G-related lncRNAs in lung squamous cell carcinoma (LUSC) remains unclear. Thus, it is crucial to identify m7G-associated lncRNAs with definitive prognostic value. This study aimed to investigate the prognostic value, correlation with tumor mutation burden, and impact on the tumor immune microenvironment of m7G-related lncRNAs in LUSC. METHODS: LUSC transcriptome data and clinical data were downloaded from The Cancer Genome Atlas, and an m7G-related lncRNA-mRNA co-expression network was constructed using Pearson's correlation analysis. Cox regression analyses were used to determine a risk model for m7G-associated lncRNAs with prognostic value. The risk signature was verified using the Kaplan-Meier method, receiver operating characteristic curve analysis, and principal component analysis. A nomogram based on risk scores and clinical characteristics was then developed. Gene set enrichment analysis was used for functional annotation to analyze the risk signature. The association among the risk signature, tumor mutational burden, and tumor-infiltrating immune cells was then analyzed. RT-qPCR was used to investigate the expression of 6 m7G-related lncRNAs in LUSC cells. The cytological function of SRP14-AS1 was verified by wound-healing assay and transwell assay. RESULTS: A total of 293 m7G-related lncRNAs were identifed, 27 candidate m7G-related lncRNAs were signifcantly associated with overall survival (OS). Six of these lncRNAs (CYP4F26P, LINC02178, MIR22HG, SRP14-AS1, TMEM99, PTCSC2) were selected for establishment of the risk model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p < 0.001). Multivariate cox regression analysis indicated that the model could be an independent prognostic factor for LUSC (HR = 1.859; 95% CI 1.452-2.380, p < 0.001). The ROC curve analysis revealed that the AUCs for OS in the 3-, and 5-year were 0.682, 0.657, respectively. GSEA analysis revealed that the risk model was closely related to immune-related pathways. Compared with normal lung epithelial cells, four m7G-related lncRNAs were higher expressed in cancer cells and two were lower expressed, among which knockdown of SRP14-AS1 promoted the proliferation and migration of LUSC cells. CONCLUSION: A risk model based on six m7G-related lncRNAs with prognostic value may be a promising prognostic tool in LUSC and guide individualized patient treatment.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , RNA, Long Noncoding , Humans , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Gene Expression Regulation, Neoplastic , Lung Neoplasms/pathology , Prognosis , Carcinoma, Squamous Cell/pathology , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/genetics , Lung/pathology , Tumor Microenvironment/geneticsABSTRACT
Purpose: Carcinoma of unknown primary (CUP) is a clinically aggressive disorder with early tumor dissemination. Identifying molecular traits of CUP can be not only beneficial for a better therapeutic approach but also potentially valuable for patients with general metastatic dissemination. Patients and Methods: We retrospectively investigated a total of 35 unique CUP cases. Tumor tissue samples were available in 26 patients, and plasma samples were available in 22 patients. Targeted sequencing was performed with a panel of 416 pan cancer-related genes. Results: A genomic landscape of the CUP cohort showed that TP53 mutation was the most frequently observed mutation while MYC amplification was the most common CNV. Aberrant TP53, RTK-RAS, and PI3K signaling pathways were also prevalent, identified in more than half of the cases with tumor tissue. Around 58% of the CUP cases harbored homologous recombinant repair (HRR) pathway gene alterations. The tumor mutational load of CUP patients with altered HRR pathway displayed a significant increase than that of patients with intact HRR. Clinically actionable mutations were identified in eight patients, which may benefit from targeted therapies. Eight patients were treated with platinum-based chemotherapy, showing different responses, HRR, and LOH status. Conclusion: Collectively, our data have provided much-need insights into the treatment options for patients diagnosed with CUP in the era of precision medicine.
ABSTRACT
LESSONS LEARNED: The efficacy of second-line treatment for advanced non-small cell lung carcinoma (NSCLC) without a sensitizing driver gene mutation is still unsatisfactory. The combination of apatinib and chemotherapy improved progression-free survival in the second-line therapy of advanced NSCLC without a sensitizing mutation. This study offers a new treatment strategy for second-line treatment of such patients but requires confirmation in a larger multi-institutional trial. BACKGROUND: This study explored the efficacy and safety of apatinib combined with single-agent chemotherapy versus single-agent chemotherapy in the second-line treatment of advanced non-small-cell lung carcinoma (NSCLC) without driver mutations. METHODS: In this double-arm, open label, exploratory clinical study, we enrolled patients with unresectable locally advanced or advanced NSCLC without driver mutations that had progressed following first-line chemotherapy. The subjects were allocated into an experimental group and a control group by 2:1. The experimental group received apatinib combined with four cycles of docetaxel or pemetrexed until disease progression, intolerable toxicity, or discontinuation at the patient' request. The control group only received four cycles of docetaxel or pemetrexed. The primary endpoints were progression-free survival (PFS), and the secondary endpoints were overall survival (OS), disease control rate (DCR), and safety. RESULTS: Thirty-seven patients were enrolled. The efficacy of 33 patients was evaluated. The median PFS was 5.47 versus 2.97 months, the DCR was 95% versus 73%, and the objective response rate (ORR) was 27% versus 9% in the experimental versus control group. The OS was still under follow-up. The most common adverse effects included hypertension, hand-foot skin reaction (HFSR), and fatigue. CONCLUSION: Apatinib combined with single-agent chemotherapy may be a novel option for second-line treatment of advanced NSCLC.
Subject(s)
Antineoplastic Agents , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Pyridines , Adult , Aged , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Female , Humans , Lung Neoplasms/drug therapy , Male , Middle Aged , Pemetrexed/therapeutic use , Pyridines/therapeutic useABSTRACT
Lung cancer is leading cause of cancer death in the world. Chemotherapy is currently one of the standard treatments for lung cancer. Gemcitabine is a pyrimidine nucleoside drug which has been approved by FDA to treat lung cancer. However, acquired resistance inevitable develops after Gemcitabine treatment, limiting clinical efficacy. Lewis lung carcinoma (LLC) cells were treated with Gemcitabine and cell apoptosis and programmed cell death-ligand 1 (PD-L1) expression were analyzed by flow cytometry. LLC mouse model was established to analysis the proportion and programmed cell death-1 (PD-1) expression of CD8 + T cells. Anti-tumor effect by treating with Gemcitabine and anti-PD-1 antibody was measured through in vivo LLC mouse model. Gemcitabine treatment induces tumor cell apoptosis and PD-L1 expression. Further study showed that Gemcitabine treatment also increases CD8+ and CD4+ T cells proportion, PD-1 and PD-L1 expression in LLC mouse model. Combination therapy with Gemcitabine and αPD-1 not only has strong anti-tumor effect, but also could inhibit postsurgical recurrence of LLC. Our findings demonstrated that the combination therapy of Gemcitabine and αPD-1 is an effective therapeutic strategy for lung cancer.
Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Carcinoma, Lewis Lung/drug therapy , Deoxycytidine/analogs & derivatives , Immune Checkpoint Inhibitors/pharmacology , Animals , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Apoptosis/drug effects , B7-H1 Antigen/biosynthesis , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Carcinoma, Lewis Lung/immunology , Cell Line, Tumor , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Disease Models, Animal , Drug Synergism , Immune Checkpoint Inhibitors/therapeutic use , Lymphocytes, Tumor-Infiltrating/metabolism , Mice, Inbred C57BL , Neoplasm Recurrence, Local/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/biosynthesis , Programmed Cell Death 1 Receptor/genetics , Tumor Microenvironment/drug effects , Tumor Microenvironment/immunology , Up-Regulation , GemcitabineABSTRACT
INTRODUCTION: Cetuximab plus FOLFIRI (leucovorin, fluorouracil, and irinotecan) is the preferred first-line therapy for RAS and BRAF wild-type (RBWT) metastatic colorectal cancer (mCRC). To counter chemotherapy-induced side effects, use of maintenance therapy is suggested. Therefore, we evaluated the efficacy and safety of cetuximab maintenance therapy in patients after effective completion of first-line induction therapy. METHODS: This prospective study enrolled untreated patients with mCRC RBWT who received first-line cetuximab plus FOLFIRI therapy. Following this, patients with treatment response either entered observation (stop treatment) or maintenance treatment 1 (cetuximab plus irinotecan) groups. After 6-12 cycles of maintenance treatment 1, patients entered maintenance treatment 2 (cetuximab only). If a patient progressed on maintenance 2, cetuximab plus FOLFIRI was reintroduced. The primary end point was failure-free survival (FFS), whereas the secondary end points included disease control rate (DCR), objective remission rate (ORR), and progression-free survival (PFS). Safety events were also evaluated. RESULTS: Among 79 enrolled patients, 72 completed first-line treatment effectively (DCR 91.1%, ORR 63.9%) and 44 entered maintenance 1 [median PFS 1 (mPFS, maintenance 1) 6.1 months, 95% confidence interval (CI) 6.0-6.2; DCR 56.8%; ORR 22.7%]. Of them, 21 entered maintenance treatment 2 (mPFS2 8.7 months, 95% CI 3.3-14.1; DCR 28.6%; ORR 4.8%). Median FFS (mFFS) was significantly longer in the maintenance 1 group compared with the observation group [12.7 vs. 3.0 months; hazard ratio (HR) 0.202, 95% CI 0.111-0.369; P < 0.001]. Overall, mFFS was 19.0 and 9.3 months in maintenance and observation groups, respectively (HR 0.211, 95% CI 0.117-0.380; P < 0.001). Rash acneiform, mucositis, and asthenia were commonly observed adverse events during maintenance treatment. CONCLUSION: Maintenance treatment with cetuximab after first-line therapy significantly improved FFS, with an acceptable safety profile in untreated patients with mCRC RBWT. TRIAL REGISTRATION: Retrospectively registered, 2019/10/02, Chinese Clinical Trial Registry, ChiCTR number 1900026360.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cetuximab/therapeutic use , Colorectal Neoplasms/drug therapy , Fluorouracil/therapeutic use , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Neoplasm Metastasis/drug therapy , Proto-Oncogene Proteins B-raf/drug effects , Adolescent , Adult , Aged , Colorectal Neoplasms/genetics , Female , Humans , Maintenance Chemotherapy/methods , Male , Middle Aged , Neoplasm Metastasis/genetics , Progression-Free Survival , Prospective Studies , Young AdultABSTRACT
Lung cancer is the largest cause of morbidity and mortality among tumor diseases. Traditional first-line chemotherapeutic drugs are frequently accompanied by serious side effects when used to treat tumors, thus, novel drugs with reduced toxic effects may improve a patients' quality of life. Icariin, an extract of herba epimedii, has been demonstrated to exhibit multiple antitumor effects with low toxicity. In the present study, cell cycle analysis, apoptosis assays, DAPI staining, CCK8 assays, xenograft tumor models, mitochondrial membrane potential analysis, western blotting and reverse transcription-quantitative PCR were performed to determine the molecular mechanism underlying icariin activity in the human lung adenocarcinoma cell lines, A549 and H1975. The results showed that icariin reduced proliferation of A549 and H1975â¯cells in a time- and dose-dependent manner in vitro to a greater degree than the control BEAS-2B cells, and this was associated with increased apoptosis, but not with cell cycle progression. In vivo experiments showed that icariin treatment significantly decreased proliferation of H1975â¯cells in a xenograft mouse model. Mechanistically, icariin activated the mitochondrial pathway by inhibiting the activation of the PI3K-Akt pathway-associated kinase, Akt, resulting in the activation of members of the caspase family of proteins, and thus inducing apoptosis of A549â¯cells. Taken together, the results revealed that icariin has anti-cancer properties in lung cancer in vitro and in vivo without any noticeable toxic effects on normal lung epithelial cells. Icariin in combination with conventional anti-cancer agents may be an effective therapeutic strategy for treatment of lung carcinoma.
Subject(s)
Adenocarcinoma of Lung/metabolism , Flavonoids/pharmacology , Mitochondria/drug effects , A549 Cells , Animals , Apoptosis/drug effects , Caspases/metabolism , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , China , Drugs, Chinese Herbal/pharmacology , Flavonoids/metabolism , Humans , Lung Neoplasms/pathology , Membrane Potential, Mitochondrial/drug effects , Mice , Mice, Nude , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
SUMMARY: Here we developed a tool called Breakpoint Identification (BreakID) to identity fusion events from targeted sequencing data. Taking discordant read pairs and split reads as supporting evidences, BreakID can identify gene fusion breakpoints at single nucleotide resolution. After validation with confirmed fusion events in cancer cell lines, we have proved that BreakID can achieve high sensitivity of 90.63% along with PPV of 100% at sequencing depth of 500× and perform better than other available fusion detection tools. We anticipate that BreakID will have an extensive popularity in the detection and analysis of fusions involved in clinical and research sequencing scenarios. AVAILABILITY AND IMPLEMENTATION: Source code is freely available at https://github.com/SinOncology/BreakID. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Gene Fusion , Genomics , High-Throughput Nucleotide Sequencing , Humans , Neoplasms/genetics , Sequence Analysis, DNA , SoftwareABSTRACT
BACKGROUND: Lung cancer remains a major global health problem, which causes millions of deaths annually. Because the prognosis is mainly determined by the stage of lung cancer, precise early diagnosis is of great significance to improve the survival and prognosis. Circulating tumor DNA (ctDNA) has been recognized as a sensitive and specific biomarker for the detection of early- and late-stage lung cancer, and next-generation sequencing (NGS) of ctDNA has been accepted as a noninvasive tool for early identification and monitoring of cancer mutations. This study aimed to assess the value of NGS-based ctDNA analysis in detecting gene mutations in lung cancer patients. METHODS: A total of 101 subjects with pathological diagnosis of lung cancer were enrolled, and blood samples were collected. ctDNA samples were prepared and subjected to NGS assays. RESULTS: There were 31 cases harboring 40 gene mutations, and EGFR was the most frequently mutated gene (27.72%). In addition, there were seven cases with double mutations and one case with triple mutations, with EGFR p.T790M mutation exhibiting the highest frequency. CONCLUSION: Our findings demonstrate that NGS of ctDNA is effective in detecting gene mutations in lung cancer patients, and may be used as a liquid biopsy for lung cancer, which facilitates the development of precision treatment regimens for lung cancer.
ABSTRACT
This research was conducted to compare differences in colon cancer lymphatic vessel invasion (LVI) with D2-40 antibody labeling and regular HE staining, blood vessel invasion (BVI) with CD34 antibody labeling and HE staining and to assess the possibility of using D2-40-LVI/CD34-BVI in combination for predicting stage II colon cancer prognosis and guiding adjuvant chemotherapy.Anti-D2-40 and anti-CD34 antibodies were applied to tissue samples of 220 cases of stage II colon cancer to label lymphatic vessels and small blood vessels, respectively. LVI and BVI were assessed and multivariate COX regression analysis was performed for associations with colon cancer prognosis. Regular HE staining proved unable to differentiate lymphatic vessels from blood vessels, while D2-40 selectively labeled lymphatic endothelial cell cytosol and CD34 was widely expressed in large and small blood vessels of tumors as well as normal tissues. Compared to regular HE staining, D2-40-labeling for LVI and CD34-labeling for BVI significantly increased positive rate (22.3% vs 10.0% for LVI, and 19.1% vs 9.1% for BVI). Multivariate analysis indicated that TNM stage, pathology tissue type, post-surgery adjuvant chemotherapy, D2-40-LVI, and CD34-BVI were independent factors affecting whole group colon cancer prognosis, while HE staining-BVI, HE staining-LVI were not significantly related. When CD34-BVI/D2-40-LVI were used in combination for detection, the risk of death for patients with two or one positive results was 5.003 times that in the LVI(-)andBVI(-) group (95% CI 2.365 - 9.679). D2-40 antibody LVI labeling and CD34 antibody BVI labeling have higher specificity and accuracy than regular HE staining and can be used as molecular biological indicators for prognosis prediction and guidance of adjuvant chemotherapy for stage II colon cancer.
Subject(s)
Antibodies, Monoclonal, Murine-Derived , Antigens, CD34/immunology , Colonic Neoplasms/pathology , Lymphatic Metastasis/pathology , Vascular Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor , Colonic Neoplasms/mortality , Colonic Neoplasms/surgery , Cytosol/immunology , Endothelial Cells/immunology , Female , Humans , Lymphatic Vessels/pathology , Male , Middle Aged , Neoplasm Invasiveness/pathology , Prognosis , Retrospective StudiesABSTRACT
Id1 and NF-κB are highly expressed in oral squamous cell carcinoma (OSCC). Whether they have a synergistic role in the carcinogenesis of OSCC is unclear. The current study was designed to demonstrate the synergy of both Id1 and NF-κB in the underlying disease mechanisms of OSCC using in vitro and in vivo animal models. Id1 and NF-κB strengthened the expression of both CD133 and BMI-1 in OSCC cell cultures. CD133(+) and BMI-1(+) keratinocytes from OSCC tissues and cell cultures initiated the growth of xenograft tumors in SCID/Beige mice. Id1 and NF-κB regulate the expression of CD133 and BMI-1 in an additive or synergistic manner in OSCC, which is associated with the generation of naïve and self-renewable keratinocytes and initiate the growth of xenograft tumors in vivo.