Is neoadjuvant immunotherapy necessary in patients with programmed death ligand 1 expression-negative resectable non-small cell lung cancer? A systematic review and meta-analysis.

OBJECTIVES: The aim of this study was to investigate the clinical benefit and necessity of neoadjuvant programmed cell death (or ligand) (PD-(L)1) blockades in resectable non-small cell lung cancer (NSCLC) patients with negative PD-L1 expression. MATERIALS AND METHODS: Randomized control trials (RCTs) that compared event-free survival (EFS), overall survival (OS), major pathological response (MPR), and/or pathological complete response (pCR) between neoadjuvant chemo-immunotherapy (nCIT) and neoadjuvant chemotherapy (nCT) for patients with resectable NSCLC stratified by PD-L1 expression were eligible for inclusion in the study. Data regarding the pathological response and EFS were evaluated by the odds ratio (OR) and hazard ratio (HR) with 95% confidence interval (CI) using random and fixed models. RESULTS: A total of six RCTs involving 3,194 patients with resectable NSCLC with or without neoadjuvant immunotherapy were included. Compared with nCT alone, nCIT significantly improved pCR (18.3 % vs. 3.0 %; OR, 5.64; 95 % CI, 3.22-9.89; P < 0.001), MPR (38.9 % vs. 15.5 %; OR, 3.57; 95 % CI, 2.10-6.05; P < 0.001), and EFS (HR, 0.75; 95 % CI, 0.62-0.90; P = 0.002) in PD-L1 <1 % NSCLC patients. In addition, PD-L1 ≥1 % was associated with higher rates of pCR (32.8 % vs. 18.3 %; OR, 2.28; 95 % CI, 1.40-3.73; P = 0.001) and MPR (53.9 % vs. 38.9 %; OR, 1.84; 95 % CI, 1.22-2.79; P = 004) and longer EFS (HR, 0.44 vs. 0.75) in the setting of nCIT compared with PD-L1 <1 %. nCIT improved only OS in NSCLC patients with PD-L1 ≥1 % but not in patients with PD-L1 <1 %. CONCLUSIONS: The use of nCIT should be recommended for resectable NSCLC patients with negative PD-L1 expression, as nCIT significantly improved the pathological response and EFS in these patients. The benefit to PD-L1-negative patients treated with nCIT on OS remains to be validated.

Rational application of EGFR-TKI adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant NSCLC: a systematic review and meta-analysis of 11 randomized controlled trials.

PURPOSE: To determine the role and rational application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant therapy in patients with completely resected stage IB-IIIA EGFR-mutant non-small-cell lung cancer (NSCLC). METHOD: Randomized controlled trials (RCTs) that compared the survival outcomes between adjuvant EGFR-TKIs and adjuvant chemotherapy or a placebo, or between different EGFR-TKI treatment durations for resected NSCLC, were eligible for inclusion. Disease-free survival (DFS) and overall survival (OS) with hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated as effective measures using random-effect or fixed-effect models. Subgroup analysis was also performed. RESULTS: Eleven RCTs involving 2102 EGFR-mutant NSCLC patients with or without EGFR-TKI adjuvant therapy were included. For all stage IB-IIIA NSCLC patients, EGFR-TKIs adjuvant therapy could not only significantly improve DFS (HR 0.43, 95% CI 0.30-0.63, P < 0.001) and 2- and 3-year DFS rates, but also improve OS (HR 0.72, 95% CI, 0.54-0.96, P = 0.024), compared with chemotherapy or the placebo. Further subgroup analyses indicated prolonged OS from first-generation EGFR-TKI adjuvant therapy in stage III patients, compared with chemotherapy or the placebo (HR for OS, 0.34; 95% CI, 0.18-0.63; P = 0.001). Of note, osimertinib adjuvant therapy led to the OS benefit expanding from stage III to stage II-III patients, with significantly improved DFS and a lower risk of brain recurrence, compared with the placebo. A 2-year treatment duration with EGFR-TKI adjuvant therapy showed a significantly lower recurrence risk than a ≤ 1-year duration. CONCLUSION: The DFS advantage from first-generation EGFR-TKI adjuvant therapy can translate into an OS benefit in stage III NSCLC patients. Osimertinib might be more suitable for adjuvant therapy than first-generation EGFR-TKIs, because of the lower recurrence rate and the potential OS benefit even in early-stage patients. The optimal treatment duration for EGFR-TKIs at different stages of disease needs to be validated.

Dual antitumor immunomodulatory effects of PARP inhibitor on the tumor microenvironment: A counterbalance between anti-tumor and pro-tumor.

Poly (ADP-ribose)-polymerases (PARPs) play an essential role in the maintenance of genome integrity, DNA repair, and apoptosis. PARP inhibitors (PARPi) exert antitumor effects via synthetic lethality and PARP trapping. PARPi impact the antitumor immune response by modulating the tumor microenvironment, and their effect has dual properties of promoting and inhibiting the antitumor immune response. PARPi promote M1 macrophage polarization, antigen presentation by dendritic cells, infiltration of B and T cells and their killing capacity and inhibit tumor angiogenesis. PARPi can also inhibit the activation and function of immune cells by upregulating PD-L1. In this review, we summarize the dual immunomodulatory effects and possible underlying mechanisms of PARPi, providing a basis for the design of combination regimens for clinical treatment and the identification of populations who may benefit from these therapies.

Efficacy and safety of combined immunotherapy and antiangiogenesis with or without chemotherapy for advanced non-small-cell lung cancer: A systematic review and pooled analysis from 23 prospective studies.

Purpose: Immune checkpoint and antiangiogenic inhibitors have a potentially synergistic antitumor effect. We aimed to assess the efficacy and safety of immunotherapy in combination with antiangiogenesis therapy with or without chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods: PubMed, Embase, the Cochrane library, Google Scholar, Ovid, Scopus, and Web of Science were searched for eligible trials. ClinicalTrials.gov and meeting abstracts were also searched for qualified clinical studies. The inclusion criteria were as follows: prospective studies (including single-arm studies) that evaluated efficacy and/or toxicity of immunotherapy combined with antiangiogenic agents (A + I) with or without chemotherapy (A + I + chemo) in patients with advanced or metastatic NSCLC; and primary outcome of each study reported at least one of these endpoints: progression-free survival (PFS), overall survival, objective response rate (ORR), disease control rate (DCR), or adverse events (AEs). Results: Twenty three prospective studies comprising 1,856 patients with advanced NSCLC were included. The pooled ORR, median PFS and estimated overall survival were 39%, 6.8 months [95% confidence interval (CI), 5.53-8.13], and 18.6 months in the overall group. Similar ORR and median PFS with A + I + chemo versus A + I were observed in patients treated in first-line setting [59% and 9.47 months (95% CI, 6.45-12.49) versus 52% and 10.9 months (95% CI, 1.81-19.98), respectively]. We also observed improved ORR and mPFS with A + I + chemo versus A + I in subsequent-line setting [56% and 8.1 months (95% CI, 5.00-11.26) versus 22% and 5.1 months (95% CI, 4.01-6.15), respectively]. Efficacy of A + I + chemo therapy was evident across different PD-L1 subgroups, especially in patients with EGFR mutations [ORR: 59%; mPFS: 8.13 months (95% CI: 5.00-11.26)] or baseline liver metastases. The incidence of AEs with a major grade of ≥3 in the overall, A + I, and A + I + chemo groups were 4.1% vs. 5.5% vs. 3.4% for proteinuria, 13.7% vs. 16.2% vs. 9.7% for hypertension, and 1.9% vs. 1.2% vs. 2.8% for rash, respectively. No new safety signals were identified in this pooled analysis. Conclusion: Immunotherapy combined with antiangiogenic agents with or without chemotherapy showed encouraging antitumor activity and an acceptable toxicity profile in treatment-naïve or pretreated patients with advanced NSCLC. Doublet treatment with immunotherapy and antiangiogenic agents might be a new option for patients with advanced NSCLC, especially those who are treatment-naive or cannot tolerate chemotherapy.

Efficacy of Osimertinib in EGFR-Mutated Advanced Non-small-Cell Lung Cancer With Different T790M Status Following Resistance to Prior EGFR-TKIs: A Systematic Review and Meta-analysis.

Purpose: Epidermal growth factor receptor (EGFR) T790M-negative/unknown advanced non-small cell lung cancer (NSCLC) patients lack subsequent approved targeted therapies. This meta-analysis aimed to assess the efficacy of osimertinib in advanced NSCLC patients with different T790M status after resistance to prior first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and to predict the subgroups that may benefit beside T790M-positive disease. Methods: PubMed, Embase, Web of Science, and Cochrane Library databases were searched for relevant trials. Meeting abstracts were also reviewed to identify appropriate studies. Studies evaluating the efficacy and/or survival outcomes of osimertinib in patients with different T790M status (positive, negative, or unknown) after resistance to prior first- or second-generation EGFR-TKIs were enrolled, and data were pooled to assess hazard ratios (HRs) or relative risk ratios (RRs) in terms of overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Results: A total of 1,313 EGFR-mutated NSCLC patients from 10 retrospective and one prospective studies treated with osimertinib after resistance to first- or second-generation EGFR-TKIs were included. In overall groups, T790M-positive patients showed an improved OS (HR=0.574, p=0.015), PFS (HR = 0.476, p = 0.017), and ORR (RR = 2.025, p = 0.000) compared with T790M-negative patients. In the brain metastases subgroup, no significant difference in OS was observed between T790M-positive and T790M-negative patients (HR = 0.75, p = 0.449) or between T790M-positive and T790M-unknown patients (HR = 0.90, p = 0.673). In the plasma genotyping subgroup, PFS was similar between T790M-positive and T790M-negative patients (HR = 1.033, p = 0.959). Conclusion: Patients with progressive brain metastases on first- or second-generation EGFR-TKIs can benefit from subsequent osimertinib therapy regardless of T790M status. Patients with plasma T790M-negative status and lack of tissue genotyping should be allowed to receive osimertinib treatment.

Impact of EGFR exon 19 deletion subtypes on clinical outcomes in EGFR-TKI-Treated advanced non-small-cell lung cancer.

OBJECTIVE: Exon 19 deletion (19del) is a sensitive mutation of epidermal growth factor receptor (EGFR) observed in non-small cell lung cancer (NSCLC), and consists of a large number of variants. It remains unclear whether 19del subtype impacts clinical outcomes following EGFR tyrosine kinase inhibitor (TKI) therapy. METHODS: We systematically searched web databases and identified eligible studies comparing the clinical outcomes of various EGFR 19del subtypes with EGFR-TKIs. The hazard ratio (HR) for progression-free survival (PFS) and overall survival (OS),as well as the risk ratio (RR) for objective response rate and the frequency of acquired T790M mutation were used as study endpoints. RESULTS: A total of eleven retrospective studies and one prospective study involving 1,630 NSCLC patients with EGFR 19del were included in this meta-analysis. Most of studies were from Asia, and the 19del subtypes in these studies were grouped differently. Patients harboring deletions starting from E746 had significantly longer OS than those with deletions starting from L747 (HR, 0.79; 95% CI: 0.65 to 0.96, P = 0.019), and relatively but not significantly longer PFS (HR, 0.86; 95% CI: 0.69 to 1.06, P = 0.160). Patients with E746_A750del, the most common 19del subtype, had a significantly higher frequency of acquired T790M mutation when treated with first- or second-generation EGFR-TKIs compared to those with other 19del subtypes (RR, 0.76; 95% CI: 0.64-0.89, P = 0.001). There were no differences in PFS between the E746_A750del group and the uncommon group, or between the 15-nucleotide deletion group and other patients. CONCLUSION: This is the first meta-analysis to present survival outcomes and acquired T790M mutation frequency in the context of EGFR 19del subtype with EGFR-TKI therapy. Patients with a deletion starting from E746 show better OS than those with other subtypes, and patients with E746_A750del subtype have a higher frequency of acquired T790M mutation.

Short-term outcomes and safety of radiotherapy for immediate breast reconstruction with autologous flap transfer following breast-conserving surgery.

BACKGROUND: The outcomes of immediate autologous breast reconstruction (IABR) after partial mastectomy followed by postoperative radiotherapy (RT) in terms of aesthetics, treatment-related complications, and local control are unclear. In this study, we evaluated the efficacy of IABR after partial mastectomy with or without breast RT, and thus the impact of radiation on autologous flap transfer. METHOD: A retrospective cohort study involving consecutive breast cancer patients who underwent IABR after partial mastectomy between July 2011 and December 2017 at Shengjing Hospital was performed. Patients were divided into two groups based on whether or not they received RT after IABR. We compared aesthetic outcomes and changes in the flap size over the three-dimensional coordinates at various timepoints (pre-RT, 1, 6, and 12 months post-RT), as well as postoperative complications, survival, and recurrence rates between the two groups. RESULTS: In total, 84 breast cancer patients were enrolled, with 32 patients in the RT group and 52 in the non-RT group. At a median follow-up time of 33.3 months, no significant difference was found in the rate of regional recurrence between the two groups (3.13% vs. 3.85%, P = 1.00), and no local recurrences occurred in either group. At the timepoints pre-RT, 1, and 6 months post-RT (approximately 4, 7, and 12 months after IABR, respectively), 77 (91.7%), 70 (83.3%), and 83 (98.8%) patients, respectively, had achieved very good or good cosmetic outcomes, and only changes in breast skin color at 1 month after RT significantly differed between the RT and non-RT groups, with very good or good cosmetic result rates of 62.5% vs. 96.2%, respectively (P < 0.001). No significant difference in the reduction of flap size was observed at any timepoint between the two groups. There were no significant differences between the two groups in the rates of postoperative complications including necrosis of the flap, infection, hematoma, or seroma (all P > 0.05). Additionally, no grade 3 or greater RT-associated adverse events occurred during or after RT. CONCLUSION: RT following IABR provides aesthetically satisfactory results without intolerable adverse complications and may safely be performed in patients who underwent IABR after partial mastectomy.

Rational Application of First-Line EGFR-TKIs Combined with Antiangiogenic Inhibitors in Advanced EGFR-Mutant Non-Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: A meta-analysis of randomized controlled trials (RCTs) was conducted to compare the difference in efficacy and safety between epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) with antiangiogenic inhibitors (A + T) and EGFR-TKI monotherapy in patients with treatment-naïve advanced EGFR-mutant non-small-cell lung cancer (NSCLC). METHODS: PubMed, Embase, Web of Science, and Cochrane electronic databases were searched for relevant RCTs. Meeting abstracts were also reviewed to identify appropriate studies. The endpoints included progression-free survival (PFS), overall survival (OS), 1- and 2-year OS rates, objective response rate (ORR), and grade ≥ 3 adverse events. All pooled outcomes were expressed using hazard ratios (HRs) or relative risk ratios (RRs). RESULTS: Data were collected from six eligible RCTs, which included 1,244 participants (619 in the A + T group and 625 in the TKI alone group). PFS was significantly improved with A + T compared to TKI alone (HR = 0.60; P < 0.01) regardless of EGFR mutation types (exon 19 deletion or L858R) and brain metastasis status (with or without brain metastases). There was no significant difference in median OS between the A + T and TKI alone groups (HR = 0.933; P = 0.551) regardless of EGFR mutation type. The ORR for A + T combination therapy was significantly increased compared to TKI monotherapy in exon 19 deletion subgroups (RR = 0.774; P = 0.008). There was no difference in the positive rates of acquired T790M mutation between the two groups (RR = 0.967; P = 0.846). More patients in the TKI alone group received a variety of subsequent systemic treatments than those in the A + T group (RR = 0.881; P = 0.002). CONCLUSION: Addition of antiangiogenic inhibitors to first-line EGFR-TKI therapy significantly reduced the risk of disease progression for patients with advanced EGFR-mutant NSCLC regardless of EGFR mutation type and brain metastasis status. The lack of OS benefit may be explained by differences in subsequent treatments rather than drug resistance mechanisms.

Efficacy and safety of recombinant human endostatin combined with radiotherapy or chemoradiotherapy in patients with locally advanced non-small cell lung cancer: a pooled analysis.

PURPOSE: To assess the efficacy and safety of recombinant human endostatin in combination with radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC). METHODS: We searched eligible literature in available databases using combinations of the following search terms: lung cancer, endostatin or endostar, radiotherapy or radiation therapy or chemoradiotherapy. The inclusion criteria were: prospective or retrospective (including single-arm) studies that evaluated the efficacy and safety of endostatin plus radiotherapy (ERT) or concurrent chemoradiotherapy (ECRT) in patients with LA-NSCLC. Primary outcomes included the following: objective response rate (ORR), local control rates (LCR), overall survival (OS), progression-free survival (PFS), and adverse events (AEs). Tests of heterogeneity, sensitivity, and publication bias were performed. RESULTS: A total of 271 patients with LA-NSCLC from 7 studies were enrolled, including six prospective trials and one retrospective study. The pooled median PFS was 11.3 months overall, 11.2 months in the ECRT group, and 11.8 months in the ERT group. Pooled median OS and ORR were 18.9 months and 77.2% overall, 18.4 months and 77.5% in the ECRT group, and 19.6 months and 76.1% in the ERT group, respectively. The incidences of major grade ≥ 3 AEs for all patients, subgroups of ECRT and ERT were 10.9% vs 11.9% vs 9.4% for radiation pneumonitis, 11.6% vs 12.2% vs 9.4% for radiation esophagitis, 35.5% vs 43.4% vs 0 for leukopenia, 27.8% vs 40.7% vs 2.1% for neutropenia, and 10.5% vs 12.3% vs 2.1% for anemia. CONCLUSIONS: Combined endostatin with RT or CCRT is effective and well tolerated in treating LA-NSCLC, and less toxicities occur. Further validation through prospective randomized control trials is required.

Metastatic Breast Cancer Coexisting With HER-2 Amplification and EGFR Exon 19 Deletion Benefits From EGFR-TKI Therapy: A Case Report.

Background: Patients with different molecular subtypes of breast cancers have different recurrence risks and prognoses. Clinical support and evidence to guide management are absent for patients with breast cancer coexisting with HER-2 amplification and EGFR mutations. Case presentation: We report a case of breast cancer coexisting with HER-2 amplification and EGFR exon 19 deletion (E19 del). The patient presented with solitary pulmonary nodule and enlargement of hilar and mediastinal lymph nodes 2 years after radical mastectomy. Biopsy of the subcarinal lymph node showed suspected adenocarcinoma. The specimen was too small for further immunohistochemistry, but an EGFR E19 del was discovered. Due to the primary diagnosis of EGFR-mutant lung adenocarcinoma, EGFR-TKI gefitinib was administered and resulted in 1 year of stable disease until the patient developed progression in the right pulmonary nodule with new metastatic cervical lymph nodes. According to histopathological findings of re-biopsy of the pulmonary nodule and left cervical and subcarinal lymph nodes, the patient was diagnosed with breast cancer with lung metastasis and multiple lymph node metastases. The patient received multiple anti-HER-2-targeted therapies (trastuzumab for 9.7 months, lapatinib for 9 months, and pyrotinib for 4+ months) and survived for more than 36 months after lung metastasis. Conclusions: This case suggested that breast cancer coexisting with HER-2 amplification and EGFR E19 del may be driven by both HER-2 and EGFR signaling pathways, and patients can benefit from EGFR-TKI and anti-HER-2 therapy.

Impact of pulmonary interstitial lesions on efficacy and prognosis of EGFR-TKI-treated advanced non-small cell lung cancers.

BACKGROUND: This study aimed to assess the impact of pre-existing pulmonary interstitial lesions (PIL) on the efficacy and prognosis of patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) treated with EGFR tyrosine kinase inhibitor (TKI). METHODS: Patients with advanced NSCLC harboring EGFR exon 19 deletion (E19 del) or exon 21 (E21) L858R were enrolled in this study. All patients underwent high resolution computed tomography (HRCT) chest scans prior to EGFR-TKI treatment. Pre-existing PIL was graded according to HRCT imaging (PIL 0, 1, 2, and 3). Cox proportional-hazards regression models were used to identify the prognostic factors for progression-free survival (PFS). RESULTS: A total of 134 eligible patients were enrolled. The overall objective response rate (ORR) and median PFS were 73.1% and 10.0 months (95% CI: 7.51-12.49), respectively. There were 62 (46.3%), 25 (18.7%), 28 (20.9%), and 19 (14.1%) cases of PIL grade 0, 1, 2, and 3, respectively, with median PFS and ORR of 12.9 months and 80.6%, 11.0 months and 72.0%, 10.0 months and 71.4%, and 7.0 months and 52.6%, respectively. Multivariate analysis showed that squamous cell carcinoma (vs. adenocarcinoma, HR =4.33), E21 L858R (vs. E19 del, HR =1.57), and PIL grade 3 (vs. grade 0-2, HR =1.60-2.48) were poor prognostic factors for PFS (P<0.05 for all). CONCLUSIONS: Pre-existing PIL grade is an independent prognostic factor for predicting resistance to EGFR-TKIs in patients with EGFR-mutant advanced NSCLC. Higher PIL grade suggests higher risk of early progression.

Neoadjuvant EGFR-TKI Therapy for EGFR-Mutant NSCLC: A Systematic Review and Pooled Analysis of Five Prospective Clinical Trials.

PURPOSE: The role of neoadjuvant epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) targeted therapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) has not been clarified. A pooled analysis of prospective clinical trials was conducted to evaluate the efficacy and safety of neoadjuvant EGFR-TKI therapy. METHODS: The PubMed, Embase, Web of Science, and Cochrane Library databases, as well as meeting abstracts were searched for prospective clinical trials evaluating the efficacy and safety of neoadjuvant EGFR-TKI for treatment of EGFR-mutant NSCLC. The main outcomes included the objective response rate (ORR), downstaging rate, surgical resection rate (SRR), pathologic complete response (pCR) rate, progression-free survival (PFS), and adverse events. RESULTS: A total of five, phase II, prospective, clinical trials involving 124 patients with resectable or potentially resectable EGFR-mutant NSCLC treated with neoadjuvant erlotinib or gefitinib treatment were included in this pooled analysis. The median neoadjuvant medication time was 42 (range, 21-56) days and the median time of response evaluation was 45 (range, 42-56) days. The pooled ORR was 58.5% [95% confidence interval (CI), 45.5%-71.8%] and the surgical resection and complete resection (R0) rates were 79.9% (95% CI, 65.3%-94.5%) and 64.3% (95% CI, 43.8%-84.8%), respectively. In the stage IIIA subgroup (n = 68), the pooled ORR, SRR, and R0 rate were 51.4%, 72.9%, and 57.0%, respectively, while the downstaging and pCR rates were 14.0% and 0.0%, respectively. The pooled median PFS and overall survival were 13.2 and 41.9 months, respectively. Of the most common grade 3/4 adverse events in the overall group, the incidences of hepatotoxicity and skin rash were 5.3% and 14.7%, respectively. The most commonly reported postoperative complications were lung infection, arrhythmia, and pneumothorax. CONCLUSION: Neoadjuvant EGFR-TKI therapy provides a feasible treatment modality for patients with resectable or potentially resectable EGFR-mutant NSCLC, with satisfactory surgical outcomes and low toxicity. Although further phase III clinical trials are needed to confirm these findings, it is necessary to explore the feasibility of a more effective EGFR-TKI combination neoadjuvant therapy given the modest downgrade and pCR rates for EGFR-TKI alone.

Effects of Dynamin-related Protein 1 Regulated Mitochondrial Dynamic Changes on Invasion and Metastasis of Lung Cancer Cells.

Objective: Mitochondrial imbalance of division and fusion will lead to uncontrolled cell growth. This study investigated the effects of mitochondrial dynamics regulated by dynamin-related protein 1 (Drp1) on the invasion and metastasis of lung cancer cells at the cellular level. Methods: Lentivirus-mediated RNAi and gene overexpression vectors containing shDrp1 and Lv-Drp1 were transfected into lung adenocarcinoma cell lines 95D and A549, respectively. An MTT assay was used to assess cell viability and a cell clone assay was used to evaluate the tumorigenic ability of lentivirus-infected cells. Cell invasion and wound healing assays were used to assess cell invasiveness and the migration rate after lentivirus infection. Annexin V-APC staining was used to determine the cell apoptosis rate. Results: In 95D cells, when the Drp1 gene is overexpressed (OE) the proliferation rate and apoptosis rate were significantly higher than those in the control group (NCOE) (P < 0. 05). There was no significant difference in clone number, invasion rate, and migration rate between the two groups (P > 0. 05). The proliferation rate and clone number in the shDrp1 infected 95D cell group (KD) were significantly lower than those in the control group (NCKD) (P < 0. 05). There was no difference in apoptosis rate, invasion rate, and migration rate between h (P > 0.05). In A549 cells, unlike in 95D cells, the invasion rate of the KD group was 25% lower than that of the NCKD group (P < 0.05). After 8 hours, the cell migration rates of the two groups were basically the same, but after 24 hours, the migration rate of the KD group was 10% lower than that of the NCKD group (P < 0.05). Compared with the NCOE group, the migration rate of the OE group increased significantly (P < 0.05). Conclusion: Mitochondrial Drp1 is associated with the proliferation, invasion, and metastasis of lung adenocarcinoma cells. Inhibition of Drp1 expression may contribute to anti-tumor therapy for lung cancer.

Rational application of the first-line chemotherapy and immune checkpoint inhibitors in advanced nonsmall cell lung cancer: A meta-analysis.

OBJECTIVE: To compare the relative efficacy of immune checkpoint inhibitors (ICIs) or chemotherapy (CT) alone, or their combination modality in the first-line treatment of advanced nonsmall cell lung cancer (NSCLC). METHODS: This meta-analysis was performed on the eligible randomized controlled trials (RCTs) after searching web databases and meeting abstracts. The main research endpoints were the comparisons of median overall survival (mOS), the OS rate of 6 months (OSR6m), 1 year (OSR1y) and 2 years (OSR2y), median progression-free survival (mPFS), the PFS rate of 6 months (PFSR6m) and 1-year (PFSR1y), objective response rates (ORR), and treatment-related adverse events (TRAEs). RESULTS: Eleven RCTs comprising 6278 cases were included. In the subgroup of programmed death-ligand 1 (PD-L1) ≥50%, compared with chemotherapy, the ICIs showed similar OSR6m (P > 0.05), but significantly improved efficacy in mOS, OSR1y, OSR2y, and ORR (all P < 0.05), also had less grade ≥ 3 TRAEs. Compared with pembrolizumab alone, pembrolizumab plus CT in the subgroup of PD-L1 ≥ 50% had similar mOS, OSR6m, OSR1y, and PFSR1y (all P > 0.05), but significantly improved mPFS, PFSR6m, and ORR (all P < 0.05 for interaction). Compared with the CT group, ICIs plus CT group with PD-L1 ≥ 50% or <1% showed significant benefit in OS, PFS, and ORR (all P < 0.05). However, in the ICIs plus CT group with 1% ≤ PD-L1 ≤ 49%, only PFS and ORR showed significant benefit compared with CT group (all P < 0.05), but not for results of OS. CONCLUSIONS: The findings support the rationale for using pembrolizumab alone in the first-line treatment of PD-L1 ≥ 50% advanced NSCLC due to the similar OS and lower grade ≥ 3 TRAEs. However, the combination of ICIs and chemotherapy is strongly recommended in patients with PD-L1 ≤ 49% for significant survival benefit.

Chest Wall Toxicity After Stereotactic Body Radiation Therapy: A Pooled Analysis of 57 Studies.

PURPOSE: The significance of clinical and dosimetric risk factors in relation to chest wall (CW) injury after stereotactic body radiation therapy (SBRT) for lung tumors were analyzed through a meta-analysis of 57 published studies. METHODS AND MATERIALS: Studies related to CW injury after lung SBRT were obtained through searching PubMed, Embase, and Cochrane electronic databases. An estimate of the incidence of CW pain (CWP) or rib fracture (RF) was derived using a Bayesian hierarchical model. Linear regression analysis was performed to assess the relationship between CWP or RF and clinical or dosimetric factors. RESULTS: A total of 57 studies incorporating 5985 cases reporting clinical data on CW injury after SBRT were analyzed. The overall CWP and RF rates by Bayesian hierarchical modeling were 11.0% (95% confidence interval [CI], 8.0-14.4) and 6.3% (95% CI, 3.7-9.7), respectively. The rates of grade ≥2 and grade ≥3 CWP were 6.2% (95% CI, 3.88-8.93) and 1.2% (95% CI, 0.48-2.12), respectively. Sex was significantly correlated with RF (P < .001), with female patients having a greater risk of RF than male patients (hazard ratio = 0.59; 95% CI, 0.46-0.76). No correlation was found between RF, grade ≥2 CWP, or grade ≥3 CWP, with the clinical and dosimetric factors of age, tumor size, origin of lung tumor, gross tumor volume, planning target volume, fractional dose, number of fractions, or biologically effective dose. However, tumor to CW distance (<16-25 mm), body mass index, maximum dose (Dmax) of 0.5 to 5 cm3, and the volume of CW or ribs receiving >30 Gy were significantly associated with CWP and RF. CONCLUSIONS: The overall rates of RF and grade ≥2 CWP after thoracic SBRT are relatively low. Sex, tumor to CW distance, maximum dose, and the radiation exposure of the CW or ribs are factors associated with the risk of CW toxicity after SBRT.

The influence of tumor heterogeneity on sensitivity of EGFR-mutant lung adenocarcinoma cells to EGFR-TKIs.

BACKGROUND: Studies have shown that extensive genetic or spatial heterogeneity is present within tumors. The present study explored the influence of heterogeneous cells in the tumor microenvironment (TME) on the sensitivity of EGFR-mutant lung adenocarcinoma cells to EGFR-TKIs and further investigated associated molecular mechanisms. METHODS: Tumor heterogeneity was simulated using transwell co-culture technique with H1975, A549 or MRC-5 cells grown in the upper chambers and PC-9 cells cultured in the bottom chamber. Each co-culture system was grouped based on different proportions of cells in the upper and lower chambers (from 1% to 300%), and each group was subdivided into erlotinib treatment group (erlotinib+) and erlotinib non-treatment group (erlotinib-). The viability of PC-9 cells was analyzed by CCK-8; HGF, IGF-1 and TGF-α were determined by ELISA; MET amplification was detected by qRT-PCR, and the relevant proteins were detected by Western blot. RESULTS: The viability of PC-9 cells increased with increased proportion of A549/PC-9 or MRC-5/PC-9 cells from 1% to 300%. HGF increased with increased proportion of H1975 cells from 1% to 300%. In all three co-culture systems, TGF-α production in the erlotinib+ subgroup was significantly lower than that in erlotinib- subgroup, and phosphorylated AKT protein showed an ascending tendency with the increased proportion of upper chamber cells relative to PC-9 cells from 1% to 300%. H1975 cells could induce MET amplification of PC-9 cells. MRC5 cells inhibited MET amplification. CONCLUSIONS: Tumor heterogeneity partially accounts for the resistance of EGFR-mutant lung adenocarcinoma cells to EGFR-TKIs. The possible mechanisms may be related to AKT signaling pathways activated by growth factors, which are secreted by heterogeneous cells in the TME under the pressure of EGFR-TKIs.

Impact of apatinib in combination with osimertinib on EGFR T790M-positive lung adenocarcinoma.

BACKGROUND: The purpose of this study was to investigate the anti-tumor activities and the mechanisms of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib, combined with the anti-angiogenic target drug apatinib, in the treatment of lung adenocarcinoma. We investigated the effects of these drugs in vitro in PC9 (E19 del) and H1975 (E21 L858R/E20 T790M) cell lines, as well as in vivo in both mouse and human experiments. METHODS: PC9 and H1975 cells were cultured in 96-well plates and incubated with osimertinib (1-100 nmol/L), or apatinib (100-1,000 nmol/L), or a combination of the two agents, for 48 h. Cell viability was determined using a Cell Counting Kit-8. The protein expression of EGFR and its downstream signaling pathway members (AKT and ERK) was detected by western blot. For in vivo experiments, BALB/c nude mice were subcutaneously inoculated with H1975 cells in a xenograft model of adenocarcinoma. Mice bearing tumors were treated with osimertinib alone or in combination with apatinib, and tumor growth curves were obtained. Furthermore, we evaluated the efficacy and safety of combined osimertinib and apatinib therapy in three patients with EGFR T790M positive lung adenocarcinoma, who had been previously sensitized to osimertinib but developed an acquired resistance. RESULTS: In vitro experiments revealed that osimertinib combined with apatinib increased the growth inhibition of PC9 and H1975 cells, simultaneously reducing the protein expression of phosphorylated EGFR and its downstream signaling pathway members in H1975 cells, compared to osimertinib treatment alone. In vivo experiments revealed that the combination of osimertinib and apatinib decreased tumor volume in an H1975 cell xenograft model, compared to osimertinib monotherapy at different dosages. All three patients with T790M positive lung adenocarcinoma that progressed following osimertinib treatment responded to continuous osimertinib in combination with apatinib, with a progression-free survival (PFS) range of 5-7 months. CONCLUSIONS: Apatinib can enhance the anti-tumor activity of osimertinib in the treatment of T790M positive lung adenocarcinoma. Further clinical studies are needed to confirm these results.

Durable Clinical Response to Pyrotinib After Resistance to Prior Anti-HER2 Therapy for HER2-Positive Advanced Gastric Cancer: A Case Report.

Background: Patients with advanced gastric cancer, especially the HER2-positive type, have a poor prognosis; there is a paucity of effective anti-HER2 drug therapies in patients who develop resistance to trastuzumab. Case presentation: We report the case of a 36-year-old male with HER2-positive gastric cancer with lung and liver metastases. The patient responded after treatment with trastuzumab combined with chemotherapy and attained a progression-free survival (PFS) of 17 months. Subsequently, the patient received apatinib that selectively inhibits the VEGFR2 and obtained an evident tumor response and a PFS of 8 months. When the disease progressed again, the regimen containing lapatinib failed. Then, the patient received treatment with nivolumab. However, he presented with hyper-progressive disease (HPD). Finally, he received a combination of capecitabine and pyrotinib, an irreversible dual TKI, acting on HER2 and EGFR. The tumor shrank markedly with this combination therapy. The mechanism of both HPD due to immunotherapy and the resistance to trastuzumab and lapatinib were investigated in this case. Loss of phosphatase and tensin homolog (PTEN) and new mutations of BRCA1 and KRAS were detected after resistance to trastuzumab and lapatinib. Conclusions: For patients with HER2-positive advanced gastric cancer who have developed resistance to trastuzumab, pyrotinib is a promising new agent, which can be used as salvage therapy.

Efficacy and safety of apatinib in patients with advanced nonsmall cell lung cancer that failed prior chemotherapy or EGFR-TKIs: A pooled analysis.

BACKGROUND: Apatinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits the vascular endothelial growth factor receptor-2. A weighted pooled analysis was performed to evaluate the clinical outcome, efficacy, and toxicity of apatinib in patients with advanced nonsmall cell lung cancer (NSCLC) that failed prior treatment with chemotherapy or epidermal growth factor receptor-TKIs (EGFR-TKIs). METHODS: The literature published in PubMed, Embase, and Cochrane Library databases was searched (from inception to November 30, 2017) for eligible trials using the following search terms: apatinib AND (lung cancer OR NSCLC). Meeting abstracts were also reviewed to identify appropriate studies. Inclusion criteria were as follows: prospective or retrospective studies that evaluated efficacy and/or safety of apatinib in patients with advanced NSCLC that failed prior chemotherapy or EGFR-TKIs; primary outcome included one of these endpoints, progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), or adverse events (AEs); English language; and number of cases in the study ≥10 cases. RESULTS: A total of 457 patients with advanced NSCLC were treated with apatinib in 14 studies (10 retrospective and 4 prospective studies) and were included in this pooled analysis. The pooled median PFS was 4.77 months [95% confidence interval (CI), 4.11-5.00] in all groups, 4.80 months (95% CI, 4.65-4.95) in the 750 mg apatinib (high-dose) group, and 3.88 months (95% CI, 3.11-4.65) in the 250 to 500 mg apatinib (low-dose) group. Median PFS stratified by single apatinib therapy or apatinib combined with continuous EGFR-TKIs was 4.76 months (95% CI, 3.66-5.06) and 5.20 months (95% CI, 3.66-6.74), respectively. The pooled median OS, ORR, and DCR values were 6.85 months, 18%, and 72%, respectively; pooled median ORR and DCR were 15% and 72% in the 750 mg apatinib group versus 20% and 72% in the 250 to 500 mg apatinib group. ORR and DCR stratified by therapeutic regimens were 14% and 70% for single-agent apatinib, 29% and 88% for apatinib combined with continuous EGFR-TKIs, and 26% and 63% for apatinib combined with chemotherapy, respectively. The pooled AE rates of grade 3/4 were hypertension (7%), proteinuria (3%), hand-foot-skin reaction (6%), fatigue (4%), decreased appetite (1.1%), oral mucositis (3%), and thrombocytopenia (3%). CONCLUSION: Apatinib has promising antitumor activity and manageable toxicity profile in patients with advanced NSCLC that failed prior chemotherapy or EGFR-TKIs. This result needs to be confirmed through the ongoing Phase III clinical trial.

Hybrid PET/MRI-based delineation of gross tumor volume in head and neck cancer and tumor parameter analysis.

OBJECTIVES: Accurate target delineation allows an increase in radiation dose to the target tumor while reducing damage to the surrounding normal tissue. However, there is currently no standard for evaluating volumes measured by different imaging modalities. The aim of this study is to evaluate the feasibility of contouring gross tumor volume (GTV) by PET/MRI in head and neck cancer, and to define an adaptive threshold level (aTL) for delineating the biological target volume (BTV). PATIENTS AND METHODS: Eighteen head and neck cancer patients underwent time of flight PET/MRI before chemoradiotherapy. Different GTVs of primary tumors and metastatic lymph nodes were manually contoured on MRI (GTVMRI), PET (GTVVIS), and fused PET/MRI (GTVFUS). An MRI-based GTV contour was substituted for the pathologic GTV. The percentile threshold boundary of the maximum standardized uptake value (SUVmax) for the BTV was determined when the volume of BTV approached that of GTVMRI. RESULTS: All GTVs were highly correlated (all Pearson's r>0.85, all P<0.001). Tumor diameter strongly correlated with GTVs (r=0.7-0.8 for all lesions and primary tumor; r=0.8-0.9 for lymph node metastases). aTL and SUVmax were moderately correlated for all lesions (r=-0.692, P<0.001) and were strongly correlated for primary tumors (r=-0.866, P<0.001). CONCLUSION: Delineating GTV on hybrid PET/MRIs is feasible, and aTL, the threshold boundary of BTV, was correlated inversely with the SUVmax.